INTRODUCTION TO PHARMACOLOGY

PHARMACOLOGY is the study of the interaction of chemicals with living organisms to produce biological effects. Drugs are any substances that bring about changes in the rate of a biological function. In most cases, drugs produce these effects through their interactions with a specific molecule that plays a regulatory role i.e. a receptor.

DRUG LEGISLATION has evolved in order to protect the consumer from 1) false claims of beneficial effects, 2) harmful effects and 3) inappropriate administration.

Standardization: relationship between drug dose and biological effect. Codes have been adopted for standardizing drug content. In the USA, drugs must comply with standards in the United States Pharmacopeia (USP) and/or the National Formulary. Standardization of doses is one of the biggest concerns with alternative therapies/health remedies.

USP: contains chemical, physical and biological information on all the active ingredients used in medications (e.g. USP aspirin (325 mg) must contain between 95% (309 mg) and 105% (341 mg) of the amount of aspirin indicated on the label.

Comprehensive Drug Abuse Prevention Act (Controlled Substance Act): Defined drug dependency and addiction, classified drugs into Schedules based on medical usefulness and abuse potential.

SCHEDULE CHARACTERISTICS RESTRICTIONS EXAMPLES

I high abuse potential; no accepted medical use; severe physical and/or psychological dependence

approved protocol necessary

heroin, marijuana, LSD

II high abuse potential; accepted medical uses; severe physical and/or psychological dependence

written Rx required; no refills; warning label on container

morphine, meperidine, codeine, secobarbital

III less abuse potential than II; accepted medical uses; moderate/low physical dependence or high psychological dependence

written or oral Rx required; Rx expires in 6 months; 5 refills in 6 months; warning label on container

preps with limited quantities of codeine, non-opioids (barbiturates) except those listed in another schedule

IVlower abuse potential than III; accepted medical uses; limited physical/psychological dependence

written/oral Rx; expires in 6 months; 5 refills in 6 months; warning label on container

some barbiturates (e.g., phenobarbital) and benzodiazepines (e.g., diazepam, alprazolam)

V low abuse potential compared to IV; accepted medical uses; limited physical/psychological dependence

may require Rx; depends on state law

Contain limited quantities of certain opioid substances (e.g., IMODIUM, AD)

DRUG DEVELOPMENT and ASSESSMENT OF SAFETY and EFFICACY Why test and control (placebo) groups in phase II studies? If only the sickest patient receive the drug (ones where other drugs have failed) the new drug being screened would appear less effective than placebo, even if it is not, simply because the patients receiving the drug are sicker to begin with. Conversely administering the drug to healthier patients might make it look more effective than it really is. In addition, the simple act of taking something contributes to the therapeutic response (placebo effect). What is informed consent? It is an explanation of the potential risks to healthy volunteers or patients before their enrollment in a clinical trial. An Institutional Review Board (IRB) must consent to a clinical trial and can stop a trial if it becomes concerned with results. It can also request changes in procedure. Compassionate use: Drugs that are made available to extremely ill patients OUTSIDE of clinical trials. BUT, such use comes with NO assurances that the drug/procedure will help nor that it is safe.

TRIALS TYPE PURPOSE LENGTH COST

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PRECLINICALin at least 2

animal species

Acute1. short-term effects of high doses2. identify target of toxicity

~5 years millionsChronic

1. effects of prolonged drug exposure at several doses2. males, females, and pregnant females (?)

File an Investigational New Drug (IND) application with the FDA

CLINICAL

Phase Iscreening for safety

(20-100 people)

1. usually performed in healthy volunteers or in patients on an older medication2. determine dosing guidelines3. compare human data with animal data

~1.5 years $10,000,000

Phase IIestablishing protocols

(50-300 patients)

1. preliminary estimates of drug doses and duration of treatment

2. homogeneous population of patients3. establishing end-points to determine exactly

what the drug can do4. first use of a control group (double-blind

studies)5. selecting patients for phase III studies

~2 years $20,000,000

Phase IIIdefining efficacy and

side effects(300-30,000 patients)

1. FDA releases drug into limited circulation2. validates phase II efficacy3. monitor nature and incidence of side effects

~3.5 years $45,000,000

File a New Drug Application (NDA) with the FDA

Review by the FDA ~1.5 years

Phase IVpost-marketing

surveillance

monitor long-term effectiveness and cost-effectiveness compared to other drugs on the market. Phase IV studies ultimately forced VIOXX off the market

ongoing

OVER-THE-COUNTER DRUGS AND SELF-MEDICATION

Properties of OTC Medications

1. for a drug to be available OTC, it must be safe for self-medication, must clearly indicate the contents, dosage, precautions and possible drug interactions.

2. low doses (sometimes less than therapeutic amounts)3. combinations of ingredients - fixed combination products. Thus if an increase in one

ingredient is needed, more of the other ingredients must be consumed as well, even if they are not needed.

Names of Drugs

1. chemical - precise description of a drug's chemical composition, i.e. S-6-Methoxy--methyl-2-naphthaleneacetic acid sodium salt

2. generic - general class of pharmacologically similar drugs (e.g. naproxen sodium)3. trade (brand; proprietary) - name of a drug designated by the drug company which makes and

markets it (e.g., ALLEVE). ALLEVE is the registered trade name of Bayer’s form of naproxen sodium while Naprosyn is made by Roche Pharmaceuticals.

Importance of knowing the generic name: there are many trade names for the same drug (e.g. propranolol, a beta () antagonist (blocker), is known by trade names such as DETENSOL, INDERAL, IPRAN, NOROPRANOL etc...). Therefore it becomes difficult to remember all the trade names and mistakes can and do occur. Such errors occurred when prescribing the drug omeprazole (LOSEC) for people with ulcers. Instead of prescribing omeprazole (LOSEC), furosemide (LASIX) was ordered. These two drugs have vastly different uses, omeprazole is a H+ pump inhibitor used to treat ulcers and furosemide is a diuretic used to control edema and hypertension. As a result of this confusion, LOSEC was renamed PRILOSEC.

Substitution of a generic drug for a brand name drug depends a great deal on the formulation of the generic drug. By law, generic drugs must contain all the active ingredients present in the brand name preparation and must be present at concentrations of 80-120% of that amount indicated on the label.

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However, absorption of a drug depends greatly on its formulation including its inactive ingredients. Therefore not all generic drugs have the same bioavailability even though they may contain the same amount of drug. Generic drugs can be substituted for trade name drugs unless the prescription reads DISPENSE AS WRITTEN (DAW). For example, Parke-Davis’ phenytoin (DILANTIN) is considered an extended action drug while some generic formulations of phenytoin are not. Thus, DILANTIN and generic phenytoin may not be therapeutically equivalent.

Study Questions

1. What is the purpose of drug legislation? DRUG LEGISLATION has evolved in order to protect the consumer from 1) false claims of beneficial effects, 2) harmful effects and 3) inappropriate administration.

2. What does it mean when a drug carries the USP label?Drug complies with the US Pharmacopeia in that it contains 95-105 percent of the drug in question.

3. Compare the characteristics of drugs in Schedules I-V.All schedules require a prescription except schedule I; Schedules 2-5 placement on schedule depend on the amount of drug; #1 has no accepted medical use;1>2>3>4>5

4. What is the purpose of drug testing in animals? To determine the short term affects of high doses, identify target of toxicity, effects of prolonged drug exposure at several doses, and the comparative effects on males, females, and pregnant females.

5. What kinds of studies are performed in phases 1-IV clinical trials?1Healthy volunteers; compares human verses animal data; dosing guidelines detrmn.2homogenous pop. of patients; control grp.double blind;select for phase 33FDA limited circ. Release;validation of phase 2 rslts;monitor side effectsNew drug app filed4 monitor long term and cost efxtvns.

6. Drugs can be described by 3 different names; what are they and what does each indicate?Chemical name- drug’s precise chemical compositionGeneric name- general class of pharmacologically similar drugsTrade/Brand name- name designated by drug company which makes and markets it

7. What are the characteristics of over-the-counter drugs? for a drug to be available OTC, it must be safe for self-medication, must clearly indicate the contents, dosage, precautions and possible drug interactions.low doses (sometimes less than therapeutic amounts)combinations of ingredients - fixed combination products. Thus if an increase in one

ingredient is needed, more of the other ingredients must be consumed as well, even if they are not needed.

• their benefits outweigh their risks • the potential for misuse and abuse is low • consumer can use them for self-diagnosed conditions • they can be adequately labeled • health practitioners are not needed for the safe and effective use of the product

What determines whether a drug will be available over the counter? For a drug to be available OTC, it must be safe for self-medication, must clearly indicate the contents, dosage, precautions and possible drug interactions.

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PHARMACODYNAMICS

PHARMACODYNAMICS: Biochemical and physiological effects of drugs and their mechanisms of action i.e. what they do to you. Determines 1) primary action of a drug, 2) its chemical interaction with the cell and 3) characterizes its actions and effects which can provide a basis for rational therapeutic use and design of new therapeutic agents.

RECEPTORS are reactive sites with which drugs interact. Activation of receptors by drugs mediates the drug’s effects. Drugs change the RATE of a given function, or modulate ongoing functions; they DO NOT confer new functions on cells. There are two general categories of drugs that bind to receptors.

1) agonists: drugs which bind to receptors and mimic at least some of the effects of the endogenous regulatory compound.

full: Drugs which produce all the possible responses associated with activating that receptorpartial: produce only some of those responses i.e. are partly as effective as a full agonistinverse: Produce effects opposite of those produced by a full agonist

2) antagonists: bind to agonist receptors, have no pharmacological activity of their own and cannot activate the receptors. However, when antagonists bind to receptors agonists cannot. So antagonists can prevent the effects of agonists.

competitive: Effects can be reversed by high concentrations of agonistnon-competitive: Effects are essentially irreversible

RECEPTORS CHARACTERISTICS: Receptors are selective not specific for the ligand they bind. 1) chemical properties: protein, DNA, membrane lipids, transporters, etc.... 2) structure-activity relationships: the affinity of a drug for its receptor and its intrinsic activity are

closely related to its structure such that even small changes in a drug’s structure can alter its agonist properties or even convert it to an antagonist.

3) cellular sites of drug action include: a. common molecules present in most cells (i.e., Na pump, DNA/RNA, AChE).

Drugs interacting with these molecules cause wide-spread effects and if that function is vital, the drug may be dangerous and difficult to use (e.g., cardiac glycosides)

b. receptors for physiological regulatory molecules (hormones and neurotransmitters) c. actions not mediated by receptors (e.g., antacids) 4) drug-receptor interactions

a. covalent interactions - characterized by the sharing of pairs of electrons between atoms and are not easily reversible e.g. phosphorylation

b. electrostatic interactions - include strong interactions between + and – charges, H+ bonds and weak dipole interactions

c. hydrophobic bonds – weak interactions of lipid-soluble drugs with membrane lipid

DOSE-RESPONSE RELATIONSHIPS: The easiest way to increase the response to any drug is to increase the dose. Thus, of all of the controllable variables in drug action, dose is crucially important. The magnitude of a drug effect is proportional to the dose administered; dose-response curves are ways of quantitating drug responses and help define drug responses by illustrating the effects of a drug as a function of its concentration. Semi-log dose-response curves have two advantages: (1) the response to a wide concentration of a drug can be illustrated and (2) the response is linear over a wide portion of the curve.

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Maximal response is 100% andis the maximum number ofreceptors activated

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Increasing concentrationsof prazosin produce noresponse while decreasingEPI'spotency (not itsefficacy).

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receptors no longeravailable for EPIactivation

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Fig. 1 represents a linear dose response curve. Notice that this graph is very difficult to read at low doses, and at high doses, it is difficult to see small changes in drug response. In the graph on the right, drug dose has been converted to a log scale. Thus, 3 g = 100.5, 10 g =101, 30 g=101.5, 100 g is 102 g, 300 g = 102.5, 300 g = 102.5, etc… Converting doses to log doses makes a portion of the graph easy to read (i.e. makes it linear). Thus we can easily compare the response to 100 g; log=2.0, 500 g, log=2.7, and 1000g, log=3.

CHARACTERISTICS OF DOSE-RESPONSE CURVES (fig. 2)1. EC50: Effective Concentration50 (EC50) is that concentration of a drug producing a 1/2 maximal (or

50% of the maximal) response. In Fig 2, each drug produces the same maximal effect, but the concentrations producing that increase are different. Since it is hard to compare drug concentrations producing a maximal response, we instead compare the doses producing a half-maximal (50% response).These concentrations are different for each drug.

2. POTENCY: A term used to compare concentrations of several drugs. The EC50 is used as an indication of potency; the smaller the EC50, the more potent the drug. Thus it takes 1 mg/kg of ISO, 3 mg/kg EPI 10 mg/kg NE and ~20 mg/kg dobutamine to produce a half-maximal response. Thus, ISO is the most potent drug while dobutamine is the least potent and ISO>EPI>NE>dobutamine (rank order of potency).REMEMBER: Potency is a comparative term.

3. EFFICACY: An indication of how well a drug works and reflects the maximum response a drug can produce. It is indicated by the height of the dose-response curve and is proportional to the number of receptors activated. This is also a comparative term and is more important clinically than POTENCY. Since ISO, EPI and NE produce the same maximal response, they are equally efficacious (they all produce the same maximal response) and are all full agonists. In contrast, dobutamine does not produce the same maximal response; it is a partial agonist.

4. SLOPE: The slope of the dose response curve reflects the degree of receptor occupancy. A steep slope indicates that very few receptors need to be occupied to produce a response. A drug with a steep slope may not be as safe to use as a drug with a shallow slope. Since the slopes of the ISO, EPI, and NE curves are about equal, in theory they are about equally safe to use.

DOSE-RESPONSE CURVES IN THE PRESENCE OF ANTAGONISTS (fig 3): Epinephrine (EPI) is an agonist which increases blood pressure. When 1 mg prazosin is used in the presence of EPI there is an apparent decrease in EPI’s potency (EC50 EPI = 0.1 mg/kg; EC50 EPI+1 mg/kg prazosin = 0.3 mg/kg). Increasing the dose of prazosin to 10 mg reduces EPI’s potency even further (to 1 mg/kg). Prazosin binds reversibly to the same site on EPI receptors that EPI does, but cannot activate these receptors (i.e. it has no efficacy). When EPI receptors are occupied by prazosin (notice that prazosin by itself produces no response), low concentrations of EPI cannot compete with prazosin for binding to EPI receptors. However, increasing concentrations of EPI can overcome the antagonism of

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Fig 6force force

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prazosin, Thus, prazosin is described as a COMPETITIVE ANTAGONIST. The maximal effect of the agonist (EPI) can still be achieved if the dose of agonist is high enough. Also notice that prazosin shifts the dose-response curve for EPI to the right. This shift depends ONLY on the concentration of the antagonist and its affinity for the receptor When EPI is used in the presence of phenoxybenzamine, there is an apparent decrease in EPI’s efficacy. This is because phenoxybenzamine covalently binds to EPI receptor’s preventing EPI from binding and does so irreversibly. Thus, EPI can’t bind, no matter how high the EPI concentration (notice that phenoxybenzamine by itself produces no response). Since EPI cannot compete with phenoxybenzamine, phenoxybenzamine is termed a NON-COMPETITIVE ANTAGONIST. This results in a decrease in the number of receptors available for agonist activation and thus a decrease in efficacy (REMEMBER:efficacy is proportional to the number of receptors activated).

Basal activities of agonists, antagonists and inverse agonists: Figure 4 compares receptor activation by agonists, antagonists and inverse agonists. Notice that agonists increase basal activity, antagonists have no activity and that inverse agonists produce the opposite effect of an agonist because there is some level of basal activity in the system in the absence of any drug. OTHER TYPES OF DOSE-RESPONSE CURVES: In Quantal Dose-Response Curves (fig 5a), an experiment was performed on 14 groups of rats with 100 rats/group (a total of 1400 rats) and an all-or-none

response is produced (e.g. a seizure is controlled or not). The dose of drug vs % of population responding at each dose is then plotted. From this, an Effective Dose50 (ED50) can be calculated and indicates the dose where 50% of the population is responding. Most individuals will respond to a drug dose lying between 0.5 and 2 x the ED50. Quantal dose-response curves can then be used to compare two drugs OR to define the therapeutic index of a drug. In Graded Dose-Response Curves (Fig 5b) a single animal receives increasing doses and a complete dose-response curve is produced in each animal. An EC50 is determined for each animal and variability is reflected in the family of

dose-response curves. Means of responses are calculated at each dose, then a mean EC50 is calculated.

QUANTAL DOSE-RESPONSE CURVES TO DETERMINE THERAPEUTIC INDEX (fig 6): Therapeutic index is a reflection of a drug’s selectivity or its margin of safety. It is determined by comparing the dose-response relationship for therapeutic effects and toxic effects. Therapeutic index = Lethal Dose50 (LD50)/Effective Dose50

(ED50) or better the ED50 for the side effects/ED50 for the therapeutic effects ) . The further apart the 2 curves,

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the safer the drug (i.e. the larger the ratio, the safer the drug). In fig. 6 the TI of two drugs used to treat heart failure are compared. Digoxin (left graph) has a TD50 of 5 and LD50 (or better Toxic dose50) where the appearance of arrhythmias is half-maximal of 17. 17/5=3.4 so digoxin has a TI of 3.4. Digitoxin (right graph) has a TD50 of 5 and a toxic dose50 of 80. So its TI= 80/5=16. Thus Digitoxin is safer to use.

DRUGS DO NOT HAVE A SINGLE THERAPEUTIC INDEX.

1. aspirin has a greater margin of safety for headache relief than arthritis relief (since lower doses are needed to relieve headache pain)

2. drugs can be both selective and non-selective; e.g. antihistamines block the effects of histamine and cause sedation (an anticholinergic effect)

3. margin of safety is a meaningless measurement in an individual allergic to the drug

TIME-COURSE OF DRUG ACTION (Fig 7)

1. onset - time it takes to achieve a concentration of a drug which produces a response

2. peak effect - time it takes a drug to achieve its highest concentration in the blood

3. duration - time during which there is sufficient drug in the circulation to produce a response

4. half-life (t1/2) - time it takes for elimination processes to decrease drug concentration in the body by 1/2

Study Questions:

1. Define pharmacodynamics. Define receptors.2. Describe the similarities and differences between agonists and antagonists.3. What does the ED50 of a drug indicate? The efficacy? The slope of a dose-response curve?4. Describe the relationship between the agonists and antagonists in the graph to the right.5. Differentiate between competitive and non-

competitive antagonists and inverse agonists6. Describe the similarities and differences between

quantal and graded dose-responses curves. What information can be obtained from each?

7. What does the therapeutic index of a drug indicate? How is it calculated?

8. Define the following characteristics of the time-course of a drug’s action.

onset of drug actiontime to peak effectduration of actionhalf-life

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PHARMACOKINETICS

For a drug to activate receptors and produce a response, it must be transported from its site of administration to its site of action. In addition, to produce a finite response, the drug must be inactivated and/or excreted to terminate its actions. The intensity of a biological response produced by a drug is related to the concentration of the drug at its site of action. Drug concentration actually attained at the site of action depends on many factors and the examination of these factors = PHARMACOKINETICS (drug movement throughout the body or what your body does to drugs). There are 4 phases:

1. ABSORPTION2. DISTRIBUTION 3. BIOTRANSFORMATION4. EXCRETION

ABSORPTION is the ability of a drug to enter the blood stream without chemical alteration. Absorption is expressed as a rate (amount/time) and indicates the speed with which a drug leaves its administration site and the degree to which this occurs. A number of factors affect drug absorption including:

1. physiochemical properties of the drug: In order to interact with its receptor, a drug must be the correct size, shape, charge, composition, and solubility. Distribution of a drug across membranes is determined by its pKa (i.e. relative acidity or alkalinity) and the pH gradient across the membrane. The term pH refers to the negative log of the hydrogen ion (H+) concentration. pH values range from 1 (extremely acidic) to a value of 14 (extremely basic). An acidic solution with a pH of 3 has a H + concentration of 10-3M (0.001 M) while a basic solution with a pH of 9 as a H+ concentration of 10-9 M (0.000000001 M).

Effect of pH on solubility: Most drugs are weak acids or weak bases. For weak acids and bases, the ability to move from an aqueous to a lipid environment varies with the pH of the medium because charged molecules attract water molecules. Acids are defined as H+ (proton) donors; a neutral molecule that can reversibly dissociate into an anion and a proton (H+). When weak acids are dissolved in water they lose a proton and become negatively charged.

Bases are defined as proton acceptors; a neutral molecule that forms a cation by combining with a proton (H+). When weak bases are dissolved in water they gain a proton and become positively charged. Why is this important? Because uncharged drugs are lipid soluble and able to move across membranes while charged drugs are water soluble and easier to excrete in the urine.

RCOOH RCOO- + H+RNH2 RNH3

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The excretion of a weakly acidic drug can be enhanced by keeping it in a charged, water soluble form. To keep the negative charge on an acidic drug we must prevent H+ from re-associating with RCOO-. This can be accomplished by adding H+ acceptors or bases (-OH) to the system. Thus, you enhance the excretion of a weakly acidic drug by increasing the pH (i.e. alkalinizing) of the urine with a base (e.g. sodium bicarbonate). Conversely, to enhance the excretion of a weakly basic drug you must prevent H+ dissociation from RNH3

+. This is accomplished by adding H+ donors or acids to the system (i.e. lowering urine pH or acidifying the urine with an acid such as ascorbic acid). Although not done therapeutically, you could enhance the absorption of a weakly acidic drug by making it more lipid soluble. This can be accomplished by reducing the drug’s charge by acidifying the system. Conversely to enhance the lipid solubility of a weakly basic drug, you reduce its charge (i.e. remove the H+) by alkalinizing the system with a H+ acceptor (i.e. a base).2. types of transport a. passive transport - no energy required; movement from an area of [high] to [low]; this is the

primary means of drug absorption b. carrier-mediated 1. active transport - energy-dependent moving from [low] to [high]

-selective(structural analogs can compete)-saturable-movement vs electrochemical gradients

2. facilitated diffusion - movement from [high] to [low] -no energy required -saturable -selective (structural analogs can compete)

-moves compounds whose rate of movement across membranes would otherwise be too slow

3. nature of the absorbing surface - the greater the surface area, the greater the absorption4. blood flow to the absorption site (i.e. perfusion) the greater the blood flow to the site of application, the greater the absorption5. drug concentration - in general, the higher the concentration, the more rapid the absorption. A loading dose is a single large dose used to rapidly increase blood concentrations into the therapeutic range. A loading dose is followed by repeated or continuous infusion to maintain blood concentrations.6. dose form - affects the rate of dissolution and drugs must be in solution to be absorbed (time release capsules; enteric coating). Regardless of the site, absorption depends on drug solubility.7. route of administration a. enteral - administered by any portion of the GI tract subject to 1. ORAL – most common, safest, cheapest convenient. Also most unreliable first pass and slowest absorption due to pH changes in the gut, GI motility, gastric metabolism enzyme and first pass metabolism in the liver. in the liver 2. GASTRIC

3. SMALL INTESTINE4. RECTAL-slow absorption5. SUBLINGUAL – rich vasculature under the tongue provide a large absorbing

surface and rapid absorption. b. parenteral - by injection. Absorption occurs by diffusion from the injection site.

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1. SUBCUTANEOUS (s.c. or sub q.) - small volume; slow sustained effect 2. INTRAMUSCULAR (i.m.) - larger volume; faster absorption due to larger

blood supply to skeletal muscle (compared to s.c.)3. INTRAVENOUS (i.v.) - immediate effect (within 1 circulation time)4. INTRATHECAL - into the subarachnoid space; cerebrospinal fluid

c. pulmonary - large surface area; primarily local effects. Hard to regulate dose.d. topical - skin and mucous membranes

8. bioavailability - fraction of unchanged drug reaching the systemic circulation following administration by any route (Compared with the amount absorbed after i.v. administration). Affected by solubility, incomplete absorption, rapid first pass metabolism. Differences in bioavailability of oral preps result from inactive ingredients and tableting process.

e.g., oral drug stomach small intestine hepatic portal liver blood bioavailable

DISTRIBUTION is the movement of drug throughout the body to various tissue sites. It depends on:1. physiochemical properties of the drug2. cardiac output and blood flow (Initially, the most well-perfused tissues receive most of drug brain, kidney, liver, etc…)3. drug reservoirs4. blood-brain barrier: distribution of drugs to the CNS is unique because drug entry is restricted by this barrier

Drug Reservoirs allow the accumulation of drugs by binding to specific tissues, primarily plasma protein (albumin) but also mineralized tissues such as bone and teeth, skeletal muscle and liver. Large reservoirs that fill rapidly can alter distribution to such an extent that large initial concentrations of a drug are required to produce a therapeutic effect. There are two general types of drug pooling: 1) plasma protein binding and 2) tissue binding. Binding is reversible and in dynamic equilibrium

albumin-drug albumin + drug drug-receptor

can’t cross blood vessels bound to albumin small enough to diffuse across blood vessels

Why is this important?1. only drug free in solution is therapeutically active; a drug bound to protein does not have access

to its sites of action2. small changes in the amount of free drug are not a concern with most drugs, but if a drug has a low TI

the small changes in free drug concentration can produce toxic effects3. binding of a drug in drug reservoirs allows a drug to be available for a long time4. several drugs can compete for protein binding, changing the therapeutically active concentration of both

drugs (see figure).5. most assays measure total drug concentration6. limits glomerular filtration and thus excretion

10

Competition for plasma protein binding (see figure): When warfarin is administered alone, 75% is bound to albumen and 25% is free in solution and available for therapeutic effects. Aspirin when administered alone it is also 75% bound/25% free. But when they are administered together, they compete for binding to a finite amount of plasma protein, increasing the free concentration of both from 25% to 50%. This effectively doubles the free concentration of each drug in the circulation. Reservoirs also include fat (storage for lipid soluble drugs), mineralized tissues such as bones and teeth (antibiotics like tetracyclines), and skeletal muscle (a large reservoir for digitalis).

Blood-brain barrier (BBB): The BBB is the result of endothelial cells lining blood vessels in the brain forming a

barrier between the circulation and the brain. A thin basement membrane surrounds the endothelial cells and associated pericytes, providing mechanical support and barrier function. The BBB prevents entrance of blood-borne immune cells, pathogens and charged chemicals into the CNS and protects the neuronal network from chemical and immune response damage.

Re-distribution is the movement a drug from its site of action into other sites. For example, the lipid-soluble barbiturate thiopental rapidly enters the brain (within 1 min following injection) due to the brain’s high perfusion. After the injection is completed the concentration of thiopental in the brain rapidly drops as it comes out of the brain, back into the circulation and distributes to other tissues like muscle.

BIOTRANSFORMATION is the alteration of the chemical structure of a drug. It occurs primarily in the liver, but also in plasma, lungs, and kidney. The majority of the changes occur as a result of interaction with enzyme systems in the liver. Phase I reactions (non-synthetic) are usually oxidation/reduction in the smooth endoplasmic reticulum. These reactions convert parent drugs to more polar metabolites by introducing/unmasking functional groups (e.g. –OH, -NH2, -SH) Phase II reactions (synthetic) couple endogenous substances to Phase I reaction products or parent drugs. These molecular are large and polar (acetate, sulfate, methyl, phosphate)

1. OXIDATIONintroduce new functional 2. REDUCTION may/ may not inactivate groups into the parent 3. HYDROLYSISdrug 4. CONJUGATION – causes inactivation. Joins polar (i.e. charged drug

with endogenous substances like glucuronic acid, acetate, sulfate

Biotransformation reactions can transform: 1) active drugs into inactive metabolites,

active barbiturates inactivate metabolites (produces a therapeutic response) (cause no therapeutic response)2) active drugs into active metabolites, and active benzodiazepine active metabolites (produces a therapeutic response) (each metabolite causes a response)

warfarin

aspirin

Warafin alone 75% bound 25% free

Aspirin alone 75% bound 25% free

Warafin and aspirin administeredtogether reduces the amountof each drug bound to 50% andincreases the free amount to 50%effectively doubling thetherapeutically effective dose.

albumen

BLOOD BLOOD

BLOOD

BRAINBLOOD

Blood-brain barrier

lipid-soluble drugs

water-soluble drugs

transporter-mediated influx

transporter-mediated efflux

11

3) inactive drugs into active metabolites. When a metabolite is active, the parent drug is said to be a prodrug. inactive aspirin active metabolite (produces no therapeutic deacetylation (produces a therapeutic response)

response)

Factors Modifying Biotransformation

1. genetically determined enzyme polymorphisms e.g. the enzyme metabolizing thiopurine used to treat some cancers are well-known to have mutations that greatly reduce their activity. In some patients only 1% of the normal dose is needed to produce a therapeutic response!

2. environmental influences including drug interactions3. liver disease

EXCRETION is the removal of drugs and biotransformation products from the body. Excretory organs eliminate unchanged drugs or drug metabolites. Excretory organs (except the lungs) eliminate polar (charged) compounds more easily than non-polar (uncharged) compounds. Excretion includes all processes that terminate the presence of a drug in the body (renal, biliary, lungs, sweat and saliva).

1. biliary excretion: enterohepatic cycle. Metabolites formed in the liver can be excreted in bile. Breakdown compounds in

liver, transport to gall bladder (into bile) resulting in fecal excretion.2 renal excretion: primary route, consisting of filtration, reabsorption, and active secretion.

a. filtration depends on free [drug], size of molecule and pH.b. reabsorption can be affected by pH.

1. increase pH with sodium bicarbonate (NaHCO3)2. decrease pH with NH4Cl or ascorbic acid3. changes in ionization change lipid solubility

and reabsorption

Study Questions:

1. Define pharmacokinetics. What are the 4 phases of pharmacokinetics?2. What factors alter the absorption of a drug?3. How would you increase the charge on a weakly acidic drug? On a weakly basic drug? How would you

enhance the excretion of a weakly acidic drug? A weakly basic drug?4. What are the characteristics of the 5 routes of enteral drug administration and which are affected by first

pass metabolism in the liver?5. What are the characteristics of the 4 parenteral routes of drug administration?6. Define drug distribution. What can affect drug distribution? What are drug reservoirs and how do they

affect drug distribution? What happens when 2 highly protein bound drugs are administered together?7. Define biotransformation. Do biotransformation reactions always inactivate drugs?8. Define excretion.

Filtration

reabsorption

TUBULEBLOOD

secretion

BLOOD

Filtration

reabsorption

TUBULEBLOOD

secretion

BLOOD

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ADVERSE EFFECTS AND DRUG INTERACTIONS

Drug responses are subject to individual variability and present the greatest challenge to using drugs therapeutically. All drugs have the potential for altering more than one function. These responses can be 1) PREDICTABLE, 2) IATROGENIC, or 3) UNPREDICTABLE.

PREDICTABLE ADVERSE RESPONSES: These adverse responses are extensions of a drug’s pharmacological actions. The best way to minimize predictable adverse responses is to minimize drug dosage. For example, barbiturates produce sleep by CNS depression. Since respiration is controlled in the CNS, respiratory depression is a predictable side effect of barbiturate use.1. Side effects vs toxic effects: Side effects are unavoidable secondary drug effects produced at

therapeutic doses. Toxic effects are adverse reactions caused by excessive levels of a drug.2. Factors allowing for the prediction of adverse responses

a. age: children and the elderly with differences in metabolism and excretion b. body mass and drug dose: dose is adjusted for body size, mass and water content. The mean adult dose is the amount which produces a response in 50% of people between 18-65 years old weighing 150 lbs.

c. sex: differences in size, percent body composition of fat and water, pregnancyd. time of administration: absorption is easier on an empty stomach but irritating drugs should be

taken with food. Often drugs are administered to mimic biorhythms (e.g. glucocorticoids in the morming).

e. disease states which alter pharmacokinetics: e.g., heart and kidney diseasef. genetic factors: inherited deficiencies in drug metabolism (e.g., lack of metabolizing enzymes producing prolonged effects).

IATROGENIC DRUG RESPONSES: Iatros (physician) genic (to produce). The best definition is a disease produced by drugs. For example, cortisol and other glucocorticoids are used as anti-inflammatories to control severe inflammation in patients with rheumatoid arthritis. This requires the use of high doses of these drugs which then mimics hypersecretion of cortisol from the adrenal cortex (CUSHING’S SYNDROME) a condition called iatrogenic CUSHING'S SYNDROME. This form of Cushing's is 1) drug-induced and 2) is nearly identical to the naturally-occurring disease caused by hypersecretion of cortisol from the adrenal cortex. Also:

1. antipsychotics and Parkinson's disease2. amphetamines and schizophrenia-like psychoses

UNPREDICTABLE RESPONSES:

1. hypersensitivity (allergy): requires prior sensitization and is largely independent of dose. It can be as simple as hives, runny nose, and mild hypotension to anaphylaxis (an immediate, severe allergic reaction). Mediated by the immune system.

2. hyper or hyporeactive: effects at unusually low or high concentrations of drugs, respectively.3. tolerance: a reduced response to repeated administration of a drug. This is drug-induced

hyporeactivity acquired as a result of continued drug exposure. Overcoming tolerance requires the administration of larger and larger drug doses. Tolerance does not usually develop equally to all effects of a drug. e.g. tolerance to the sedative effects of a barbiturate occur before tolerance develops to its anticonvulsant effects.

4. tachyphylaxis: rapid development of tolerance5. idiosyncratic: genetically determined abnormal reactivity to a chemical that results in extreme

sensitivity or insensitivity to a drug. e.g., succinylcholine and prolonged muscle paralysis in people who are "poor acetylators"

6. cumulative: drug is not metabolized before another dose is administered

DRUG INTERACTIONS: Concomitant use of drugs is often essential to produce the desired therapeutic effect. However, drugs often alter each others pharmacokinetic or pharmacodynamic properties.

13

0 .01 .03 .1 .3 1 3 100

20

40

60

80

100normal alpha receptorhetrozygous mutanthomozygous mutant

[EPINEPHRINE], mg/100 g body weight

% M

AX

IMA

L R

ES

PO

NS

E

0 .01 .03 .1 .3 1 3 100

20

40

60

80

100

NORMALDISEASE

[EPINEPHRINE], mg/100 g body weight

% M

AX

IMA

L R

ES

PO

NS

E

Pharmacokinetic Mechanisms

1. chemical/physical interactions: Drugs interact resulting in insoluble complexes (e.g., Ca and Mg antacids interact with tetracycline; antacids increase gastric pH enhancing the breakdown of enteric coatings and affecting drug absorption).

2. competition for plasma protein binding: Minor changes in the free concentration of a drug can result in large changes in its therapeutic effectiveness.

3. lack of specificity: Drugs are selective not specific for the receptors with which they interact. For example, some older antihistamines like diphenhydramine (BENADRYL) are also anticholinergic, making them useful as OTC sleep preparations.

4. enzyme induction: Exposure to a drug increases (i.e. induces) the amount or activity of biotransforming enzymes resulting in accelerated metabolism and a shorter t1/2. For example. the hyperforin in St John’s wort induces the activity of the enzyme CYP3A.

5. enzyme inhibition: a decrease in the amount or activity of biotransforming enzymes resulting in a reduction in drug metabolism and a longer t1/2. For example, the furanocumarins in grapefruit juice inhibit the activity of CYP3A.

6. changes in renal excretion: one drug may affect the excretion of a second by competing for the same transport mechanism

Pharmacodynamic Mechanisms

1. changes in receptor number: the magnitude of a drug response is proportional to the number of receptors it activates. Therefore changes in receptor number affect a drug’s efficacy.

2. genetic polymorphisms: small changes in the amino acid sequence of a receptor can affect ligand binding; it can increase or decrease affinity for the ligand. Increases in affinity would reduce the dose required to produce a particular effect while a reduction in affinity would increase the dose requirement

3. receptor mutations: mutations may change receptor- drug interaction (e.g. affinity of receptor for agonist/antagonist) and the ability of the receptor to initiate signaling important in the regulation of cellular function.

4. disease-related changes: Diseases and drug treatment of disease often produce changes in the expression and function of receptors (up- or down-regulation).

DRUG TRANSFER TO THE FETUS

1. Volume expansion (increases in extracellular fluid volume) during pregnancy results in a reduction in plasma protein and an increase free [drug] in circulation. Also metabolism decreases and excretion increases as the result of increases in glomerular filtration rate and increased renal blood flow. Finally, there are increases in body fat and cardiac output.

2. Although the placenta metabolizes drugs it is NOT a barrier to drug transference from maternal to fetal tissues. Transfer occurs primarily by diffusion, is greatest late in gestation due to increased blood flow, and continual exposure to drug is more important than the rate of exposure.

14

3. Consequences of prenatal exposure can include teratogenic effects [terato (monster) genic (to produce)] which are developmental abnormalities (e.g. thalidomide), and mutagenic effects which are genetic defects (e.g. DES and cervical cancer)

4. Critical periods include the first 2 weeks of rapid cell proliferation (often lethal at this stage but since these cells are pleuripotent (i.e. capable of developing into any tissue – embryonic stem cells) if a sufficient number survive, the embryo will survive undamaged) and the third to tenth weeks when development of the axial skeleton, muscles, limbs, and organs is occurring.

ADVERSE EFFECTS IN CHILDREN: Often occur because we do not consider the following;

1. Neonates lack protective mechanisms. They have thin skin, produce little gastric acid, their lungs secrete little mucous, they are poor thermoregulators, they have immature kidney and liver function, their plasma protein concentration is comparatively low and the blood-brain barrier is not fully developed.

2. The body mass of children is composed of a greater percentage of water and less fat as compared to adults and this can affect the distribution of drugs. Drug doses must be adjusted accordingly.

3. Breast feeding can transfer drugs to infants.

ADVERSE EFFECTS IN THE ELDERLY: Only 12.4% of the US population is 65 years old or older (as of the 2000 Census) but they use about 25% of the prescription drugs. Physical changes require changes in dosage. 1. There is a general decrease in body weight, accompanied by a reduction in extracellular water and an

increase in body fat. The concentration of plasma proteins decline affecting free [drug].2. Common physical ailments such as heart disease and reductions in kidney and liver function produce

pharmacokinetic changes in distribution, biotransformation and excretion.3. Stimulants tend to be less effective and depressants more effective and may in fact produce

paradoxical effects. In addition, confusion with therapy may result in compliance problems and medication errors.

Study Questions:

1. What is the difference between side effects and toxic effects?2. What are predictable adverse drug responses and what factors allow for the prediction of adverse

responses?3. What are iatrogenic drug responses? Give an example.4. Define the following unpredictable adverse drug responses.

allergy (hypersensitivity)hyperresponsivityhyporesponsivitytolerancetachyphylaxisidiosyncraticcumulative

5. What are the pharmacodynamic mechanisms leading to adverse drug reactions?6. How does the induction of biotransformation enzymes affect drug metabolism? Enzyme inhibition?7. What factors affect fetal exposure to drugs? What are the consequences of fetal drug exposure?8. What physiological characteristics of neonates, children and the elderly affect drug responses?

15

OVERVIEW OF THE AUTONOMIC NERVOUS

The nervous system is broadly divided into the CENTRAL NERVOUS SYSTEM (CNS) composed of the brain and spinal cord and the PERIPHERAL NERVOUS SYSTEM composed of the AUTONOMIC and SOMATIC NERVOUS SYSTEMS. The autonomic nervous system is "involuntary" or "self-governing" and is further subdivided into the PARASYMPATHETIC (PNS) and SYMPATHETIC (SNS) NERVOUS SYSTEMS. Autonomic nerves have ganglia outside the CNS and are composed of two neurons termed preganglionic and post-ganglionic, named with respect to their location relative to the ganglion. Preganglionic fibers exit the CNS, form a synapse with the cell body of post-ganglionic fibers which then send axons to effector organs. Somatic nerves innervate skeletal muscles and do not have ganglionic junctions. In autonomic ganglia (both PNS and SNS pathways), the neurotransmitter is acetylcholine (ACh) and the receptor on the cell body of the post-ganglionic fiber is nicotinic (RN). In the PNS, the post-ganglionic fiber is a cholinergic pathway, ACh is the neurotransmitter and ACh interacts with muscarinic (RM) or RN receptors. In the SNS, the post-ganglionic fiber is an adrenergic pathway, norepinephrine (NE) is the neurotransmitter and NE interacts with or receptors. One “ganglion” in the SNS does not have post-ganglionic fibers. Instead, activation of pre-ganglionic nerves innervating the adrenal medulla cause the release of the hormone epinephrine (adrenaline). In Fig 1. all autonomic cholinergic fibers are red and all adrenergic fibers are blue

PARASYMPATHETIC NERVOUS SYSTEM: This is the Rest and Digest nervous system. The pre-ganglionic fibers are long and the post-ganglionic fibers are short. The ratio of pre-ganglionic to post-ganglionic fibers is small (1:1 or 1:2). Activation causes a discrete, local response.

SYMPATHETIC NERVOUS SYSTEM: This is the Fight or Flight nervous system. The pre-ganglionic fibers are short and the post-ganglionic fibers are long. The ratio of pre-ganglionic to post-ganglionic fibers can be a great as 1:20 and activation produces a generalized response in many tissues.

SOMATIC NERVOUS SYSTEM: The somatic nervous system has no ganglia. Motor neurons arise in the spinal cord and terminate at special cholinergic synapses termed the neuromuscular junction (NMJ)

AChRNAChE

AChRNAChE

AChRNAChE

CNS

ACh

ACh

NE

NENE

NE

NE

NE

TA

RG

ET

TA

RG

ET

NM

JSOMATIC ACh

Pre-ganglionicPost-ganglionic

Adrenal medulla

epinephrine

PNS

SNS

ANS

Motor neuron

an

d

rece

pto

rsR

NR

MA

Ch

EA

Ch

E

re-uptake

SYNAPSE (ganglion)

SYNAPSE (ganglion) pre-synaptic post-synaptic

SYNAPSE (neuroeffector junction)

motor end plate

16

NEUROHUMORAL TRANSMISSION: passage of impulse across a synapse or neuroeffector junction with the use of a chemical. Sequence of events

1. biosynthesis of neurotransmitter2. storage in vesicles 3. release autonomic drugs affect one/more of these processes 4. action (interaction with receptor) 5. inactivation

CHOLINERGIC TRANSMISSION:

1. Synthesis choline acetyltransferaseacetyl CoA + choline acetylcholine + CoA

acetylcholinesterase (AChE)

2. Storage into vesicles at nerve terminal. Vesicular storage ensures regulated (quantal) release; i.e. a depolarization of a certain size releases a fixed number of synaptic vesicles containing a fixed amount of ACh.3. Release: depolarization results in the influx of Ca2+ and vesicles fuse with the synaptic membrane, releasing ACh. ACh binds to RN or RM postsynaptically, resulting in excitation/inhibition of post-synaptic cell4. Action by activation of ACh receptors: Nicotinic receptors (RN) are located at autonomic ganglia (both PNS and SNS), the neuromuscular junction (NMJ) and the adrenal medulla. Muscarinic receptors (RM) are located on smooth and cardiac muscle, glands etc... 5. Inactivation of ACh enzymatically by ACh esterase (AchE) and by diffusion away from the synapse. ACh’s t1/2 is very short.

MUSCARINIC and NICOTINIC

CHOLINERGIC SYNAPSES

ACh Receptors:muscarinic (G protein coupled)

M1: Ca2+ signalM2: inhibit cAMP productionM3: Ca2+ signal

nicotinic: ligand-gated ion channelsNG: opens Na+, K+ channelsNM: opens Na+, K+ channels

17

ADRENERGIC TRANSMISSION: catecholamines (norepinephrine, dopamine )

1. synthesis: rate-limiting step

tyrosine dopa dopamine methyl tyrosine Dopa DA NE EPI hydroxylase decarboxylase hydroxylase transferase

2. storage: DA taken up into vesicles where conversion to NE occurs3. release:depolarization results in Ca2+ influx, fusion of vesicles and release of NE into the

junction4. action: NE binds to , and receptors but not to 5. inactivation by re-uptake (primary), enzymatic transformation (monoamine oxidase-MAO and

catechol-O-methytransferase- COMT) and diffusion.-

Functional Organization: An understanding of the organization of the ANS activity is essential for understanding the actions of ANS drugs and the significant reflex responses they cause. For example:

ORGAN SNS RECEPTOR PNS RECEPTORHeart: SA node contractility

increased activityincreased force

1/21/2

decreased activitydecreased contractility

M2

M2

GI smooth muscle relaxes 2/2 contracts M3

bronchiole smooth muscle relaxes 2 contracts M3

eye (ciliary muscle) relaxes contracts M3

1. Integration of cardiovascular function: the primary controlled variable is mean arterial pressure. Any aspect of cardiovascular function that changes mean arterial pressure (e.g. heart rate, peripheral vascular resistance (PVR), venous return to the heart etc…)

a. 1 agonist causes increased heart rate resulting in reflex activation of PNS pathwaysb. 1 antagonist decreases heart rate cause?

cytoplasm vesicle

18

c. muscarinic agonist decreases heart rate causing SNS activationd. muscarinic antagonist increases heart causing?

2. presynaptic regulation: presynaptic receptors, when activated, reduce the rate of further neutortransmitter release (e.g. 2 receptors for NE). Also called auto-receptors since they regulate neurotransmitter release by being activated by that neurotransmitter.3. postsynaptic regulation: activity modulated by

a. prior history (i.e. desensitization/downregulation or upregulation). For example, cutting the nerve to a skeletal muscle fibers results in an increase in AChRN receptors over the whole muscle fiber

b. temporal events: the same neurotransmitter acting through two different receptors produced distinct responses due to the speed of receptor activation/signaling

Study Questions

1. Briefly describe the anatomy of the peripheral nervous system (i.e. what nervous systems are included, which have ganglia, etc…)

2. Where are nicotinic ACh receptors located? Where are muscarinic receptors located? What terminates ACh actions at all cholinergic synapses?

3. NE is the neurotransmitter at what synapses (i.e. ganglionic or post-ganglionic ) and what kind of receptors are present at these synapses. What is the primary way NE actions are terminated?

4. How is autonomic nervous system function (i.e. SNS and PNS function) integrated? Why is this important?

19

motility

tone

increased motility

increased tone

Fig. 1: changes in tone and motility

CHOLINERGIC AGONISTS AND ANTAGONISTS

PARASYMPATHOMIMETICS: drugs producing acetylcholine (ACh)-like effects. ACh is not used therapeutically due to its lack of selectivity, its very short half-life, and its susceptibility to breakdown by acetylcholinesterase (AChE) and plasma cholinesterases. Responses to PNS activation are all related to Rest and Digest. The direct effects of ACh are mediated by AChRM and AChRN. ACh can also work indirectly by inhibiting the release of other neurotransmitters.

Receptors: The actions of ACh are mediated by muscarinic and nicotinic receptors. 1. nicotinic ACh receptors (ACh RN): Nicotinic receptors mediate ACh action at autonomic ganglia,

the NMJ and some sites in the CNS. Activation of ganglionic receptors results in increased heart rate and blood pressure (via the SNS), increased GI tone and motility and acid secretion (via the PNS), vomiting and CNS stimulation. At the NMJ AChRN receptor activation causes skeletal muscle contraction.

2. muscarinic ACh receptors (ACh-RM): Muscarinic receptors are found on most cells innervated by PNS post-ganglionic fibers. They are also found in the brain, ganglia, blood vessels and the adrenal medulla. All organs are regulated by the PNS, and in general, activation of muscarinic receptors results in the modulation of ongoing mechanical and/or electrical activity.

Activation of muscarinic receptors produces the following: 1) increases in gastrointestinal (GI) smooth muscle tone and motility and gastric acid secretion 2) increases in urinary bladder smooth muscle tone and motility 3) increases in exocrine gland secretion including increased salivation, sweating (diaphoresis), lacrimation and increased

tracheobronchial secretions4) in the cardiovascular system, RM cause vasodilation (decreased

blood pressure),decrease heart rate ( - chronotropic) and conduction velocity at the SA/AV nodes (-dromotropic) and decrease the force of contraction

5) in the respiratory system, RM cause bronchiole smooth muscle

contraction and increased tracheobronchial secretions.

DIRECT-ACTING MUSCARINIC RECEPTOR AGONISTS: Drugs that interact with and activate muscarinic receptors. Most produce effects very similar to ACh with the primary differences lying in their potency and durations of action. The best-studied members are highly charged molecules that have long t1/2 due to resistance to AChE and plasma cholinesterases [e.g. bethanechol (URECHOLINE) and pilocarpine (PILOPTIC)]. Most have little or no effect at AChRN at therapeutic doses.

Uses: delivered subcutaneously for acute responses and orally for chronic responses..1. GI disorders - post-operative decreases in tone and motility; atony2. urinary bladder disorders - urine retention/inadequate emptying3. xerostomia - dry mouth due to disease or radiation therapy4. eye - glaucoma; stimulates contraction of the ciliary body and the outflow of aqueous humor5. CNS - Alzheimer’s disease

INDIRECT-ACTING CHOLINERGIC AGONISTS inhibit AChE, prolonging the effect of ACh at virtually all cholinergic synapses (i.e. AChRM and AChRN ) to which they have access. Thus they can cause muscarinic AND nictotinic effects and are used to treat conditions where muscarinic or nicotinic activation can contribute to controlling symptoms.

Pharmacological Effects:1. In the CNS: if accessible, these drugs cause stimulation followed by depression 2. at AChRM: increased exocrine gland secretion, increased GI and urinary bladder tone and motility,

20

Fig 2: AChE inhibitors mechanisms of action A= acetate; Ch=choline

AChE

A

AChE AChE

ChA

AChE

A

ChChA deacylation

AChE

reversible

AChE

ChA ChA

ChA ChA

ChA ChAChA ChA

AChE AChE

ChA ChA ChA ChA

deacylation

ChA ChA

AChE AChE

PO4

ChA ChA

ChA ChAirreversibleChA ChA

ChA ChA

AChE

PO4

ChA ChA

ChA ChA

ChA ChA

ChA ChA

ChA ChA

AChE

PO4

ChA ChA

AChE

PO4

ChA ChA

AChE

PO4

CA CA

ChA ChA

ChA ChA

ChA ChA

ChA ChA

ChA ChA

ChA ChA

ChA ChA

ChA ChA

ChA ChA

ChA ChAdeacylation

ChA ChA

AChE AChE

PO4

ChA ChA

ChA ChAirreversibleChA ChA

ChA ChA

AChE

PO4

ChA ChA

ChA ChA

ChA ChA

ChA ChA

ChA ChA

AChE

PO4

ChA ChA

AChE

PO4

ChA ChA

AChE

PO4

CA CA

ChA ChA

ChA ChA

ChA ChA

ChA ChA

ChA ChA

ChA ChA

ChA ChA

ChA ChA

ChA ChA

ChA ChAdeacylation

irreversible

reversible

time

bradycardia and bronchial constriction.

3. at NMJ nicotinic receptors: low doses moderately prolong and intensify ACh actions and strengthen

muscle contractions, high doses cause muscle fibrillation, fasciculation and paralysis.4. at ganglionic RN: stimulation followed by depression

Types of Acetylcholinesterase Inhibitors (AChE-I): The difference between reversible and irreversible AChE-I is a function of the raye of AChE deactylation. 1) Reversible Cholinesterase Inhibitors bind to the active site of AChE and thus prevent ACh from binding (Fig. 2). They are themselves acted upon by AChE and when they are broken down, their effects are terminated. They affect activity at AChRM and the NMJ. Those that are highly charged have little effect at autonomic ganglia or in the CNS. They are used to treat myasthenia gravis, an autoimmune disease where antibodies develop against RN at the NMJ resulting in a decrease in RN and thus a decrease in force of skeletal muscle contraction.

Uses: 1. post-operative and drug-induced atony of GI and UB smooth muscle2. glaucoma e.g. physostigmin (ESERINE) - glaucoma3. myasthenia gravis: an autoimmune disease where antibodies develop against AChRN at the NMJ and cause accelerated turnover of AChRs, blockade of the active site of the AChR and damage to the postsynaptic muscle membrane. The loss of receptors results in muscle weakness, rapid fatigue and severe cases can result in respiratory difficulties. e.g. neostigmine (PROSTIGMIN)

Myasthenia Crisis: inadequately medicatedcholinergic crisis: overmedicated

4. Alzheimer’s disease e.g. donepezil (ARICET)

2) Irreversible Cholinesterase Inhibitors: organophosphates that irreversibly inactivate AChE activity by phosphorylating the active site of the enzyme (Fig. 2). The longer the reaction is allowed to “age” the stronger is the interaction between the enzyme and the phosphate . Before aging occurs, strong nucelophiles like pralidoxime (PROTOPAM) which is a AChE reactivator can split the phosphate-enzyme bond. Organophosphates are non-ionized and thus readily penetrate the blood-brain barrier.

isoflurophate (DFP- diisopropylfluorophosphate)malathion/parathion - insect poisonssoman - a nerve gasToxic Effects: poisoning with insecticides is not uncommon and results in cholinergic crises causing

excessive secretions from nose, eyes, mouth, airways, and intestines, urination and defecation (RM), muscle fasiculations, twitching, weakness and paralysis (RN) as well as generalized seizures (CNS). The skeletal muscle paralysis results from ACh buildup at the NMJ and the subsequent loss of synchrony between depolarization and the action potential. This results in fibrillation and ultimately constant depolarization and NMJ blockade. Treatment includes mechanical ventilation, use of the muscarinic receptor antagonist atropine and pralidoxime (PROTOPAM) to prevent "aging" of the bond between organophosphate and AChE. AChRN

antagonists are NOT used to treat cholinergic crises (Why do you suppose?).

MUSCARINIC RECEPTOR ANTAGONISTS (Parasympatholytic) are competitive antagonists which produce no effects of their own, but block the effects of ACh at AChRM. They are also referred to as antimuscarinics, anticholinergics, and parasympatholytic. The prototypical drug is the belladonna alkaloid

21

atropine (Atropine sulfate). Derived from Atropa belladonna, the deadly nightshade and Datura stramonium (jimsonweed) . Also important are scopolamine (TRANS-DERM SCOP) and ipratoprium (ATROVENT). Their pharmacological effects are opposite to those produced by muscarinic agonists. They have little effect at ganglionic ACh RN except at high doses or at NMJ ACh RN except at extremely high doses. Most are more effective at blocking the effects of exogenously administered muscarinic agonists than in preveting the effects of endogenous ACh release. The tissues most sensitive to the effects of AChRM antagonists are the salivary, lacrimal and sweat glands.

Dose-dependent Effects: low doses (0.5 mg) atropine can reduce salivation, decrease heart rate (transient and seems to be related to blockade of post-ganglionic fibers that release Ach) and reduce sweating. 1.0 mg atropine causes dry mouth, increased heart rate and pupil dilation. Moderate doses (2.0 mg) cause rapid heart rate, markedly reduce salivation, dilate pupils and blur near vision, decrease acid secretion and produce bronchodilation. High doses (5.0 mg) can produce all of the above as well as disturbed speech, swallowing difficulty, hot dry skin, difficult urination and decreased intestinal peristalsis. Therefore, even though hypersecretion of acid can be reduced by atropine, people with gastric ulcers do not routinely receive this drug because at the doses which must be used, there would be effects on glandular secretion and cardiovascular function.

Uses: The primary limitation to atropine use is the failure to achieve a therapeutic effect without producing side effects.

1. ocular exams - mydriasis (dilation) and cycloplegia (paralyzes accommodation)2. MI-induced bradycardia (increases rate without affecting pressure)3. antispasmodic, antidiarrheal, anti-emetic (motion sickness)4. Parkison’s disease5. chronic obstructive pulmonary diseases (COPD; asthma, emphysema)

GANGLIONIC AChRN AGONISTS AND ANTAGONISTS: Ganglionic receptors are nicotinic. Ganglionic stimulation influences nerve impulses in the PNS and the SNS and therefore ganglionic drugs have limited

therapeutic value.

Ganglionic Agonist: nicotine, a plant alkaloid with no therapeutic uses except for withdrawal of smoking.

Pharmacological Effects: Peripherally, virtually all of the drugs cause transient stimulation and subsequent persistent depression of ANS ganglia. At the NMJ, they cause contraction followed by paralysis due to persistent depolarization and receptor desensitization.1. low doses result in stimulation, high doses

in receptor blockade.2. increase blood pressure due to NE

release (SNS ganglia) and EPI release from the adrenal gland3. increased GI T/M and activation secretion

(PNS ganglia) 4. CNS stimulation: low doses produce a

weak analgesia and high doses cause tremor and convulsions and vomiting due to activation of the emetic center

(chemoreceptor trigger zone).

AChRNAChE

AChRNAChE

AChRNAChE

CNS

ACh

ACh

NE

NENE

NE

NE

NE

TA

RG

ET

TA

RG

ET

NM

JSOMATIC ACh

Pre-ganglionicPost-ganglionic

Adrenal medulla

epinephrine

PNS

SNS

ANS

Motor neuron

an

d

rec

epto

rsR

NR

MA

Ch

EA

Ch

E

re-uptake

SYNAPSE (ganglion)

SYNAPSE (ganglion) pre-synaptic post-synaptic

SYNAPSE (neuroeffector junction)

22

nerve

muscleAChRN

AChE

motor end plate

myelin

contraction

contraction contraction

PHASE I PHASE II

Non-depolarizing

Depolarizing

Fig 4: Effects of neuromuscular blocking agents on the neuromuscular junction. (A) The structure of the neuromuscular junction. (B) mechanism of action of neuromuscular blocking agents.

AB

Ganglionic Antagonists (Blockers): These drugs work as receptor antagonists or as ion channel blockers. The responses to these drugs depends upon whether the PNS or the SNS is the dominant controller of various organs. For example, blood pressure is primarily under the control of SNS thus ganglionic blockade causes vasodilation and decreased blood pressure. These drugs are of limited therapeutic usefulness

because 1) the net effect depends upon the SNS/PNS balance prior to use, 2) orthostatic hypotension that they cause, 3) decreased GI T/M and 4) impaired micuritionMechanism of Action: competitive antagonist at ACh RN at autonomic ganglia affecting both PNS and SNS.Pharmacological Effects: majority of organs are under the influence of PNS tone. Ganglionic blockers produce effects similar to muscarinic antagonists.

Therapeutic Uses: initial control of blood pressure in patient with dissecting aortic aneurysms because they reduce blood pressure and limiting further tearing and they also block reflex increases in SNS activity. They provide acute control only.

NEUROMUSCULAR BLOCKING AGENTS (interact with AChRN) are used primarily to produce muscle relaxation for surgery. All can produce some effect at autonomic ganglia and the adrenal medulla.

Control of muscle contraction: an action potential (wave of depolarization) arrives at the terminal of a motor neuron, causing the influx of Ca2+ and the subsequent release of ACh. ACh binds to AChRN on the motor end plate (MEP) of the muscle, opening channels and allowing Na+, K+ movement and end plate depolarization. End plate depolarization causes an action potential in the muscle, the release of Ca2+ and muscle contraction (fig 4a). There are 2 classes of NMJ blocking drugs

1. Non-depolarizing agents are curare-like drugs such as pancuronium (PAVULON) and doxacurium (NUROMAX). These drugs are highly charged competitive antagonists. These drugs bind to ACh RN at MEPs without stimulating an action potential or initiating a contraction (see Fig 4b). Since the drug binds to the receptor but produces no response (i.e. no contraction) it is a receptor antagonist. The muscle remains relaxed as long as pancuronium remains at the NMJ in sufficient quantities to prevent ACh binding. At high concentrations they may also block the channels. These drugs cause flaccid paralysis with the smallest muscles affected first (eyelids, fingers, jaws) followed by the trunk (limbs and abdomen) and finally the

anhidrosis

Dry mouth (xerostomia)

Urine retention

Reduced T/M

Tachycardia

Dilation

Vasodilation

Effect of

ganglionic blockers

SNSSweat glands

PNSSalivary glands

PNSUB

PNSGI tract

PNSHeart

SNSVeins

SNSAterioles

Dominant

ToneSite

anhidrosis

Dry mouth (xerostomia)

Urine retention

Reduced T/M

Tachycardia

Dilation

Vasodilation

Effect of

ganglionic blockers

SNSSweat glands

PNSSalivary glands

PNSUB

PNSGI tract

PNSHeart

SNSVeins

SNSAterioles

Dominant

ToneSite

23

respiratory muscles (intercostals and then the diaphragm). Recovery occurs in the reverse order. These drugs produce paralysis but not unconsciousness nor analgesia.

Uses: The margin of safety between therapeutic doses and dose-induced respiratory paralysis is small. 1. produce surgical muscle relaxation2. muscle relaxation for mechanical ventilation3. muscle relaxation for electroconvulsive therapy (weakens muscle contractions in seizures)

2. Depolarizing Blocking Agents are receptor agonists (e.g. succinylcholine (ANECTINE). They bind to ACh RN at NMJ, depolarizing the MEP (Phase I). They also enters the channel and causes channel flickering. Since these drugs bind to receptors and produce a response (an initial contraction), they are receptor agonists. Drugs remain bound producing long-lived depolarization resulting in transient muscle fasiculations followed by blockade of transmission and flaccid paralysis (Phase II) due to receptor desensitization. These drugs have a higher affinity for RN than does ACh and is more resistant to AChE than ACh, causing more prolonged depolarization. Plus, released ACh binds to AChRN on an already depolarized end plate.

Uses: These drugs cause paralysis within minutes and recovery within 4-10 min and are most valuable when a short-lived paralysis is required They are rapidly degraded by plasma pseudocholinesterases (most people have high levels of plasma cholinesterase; those that don't can be paralyzed for much longer -an IDIOSYNCRATIC response).

1. produce surgical muscle relaxation2. muscle relaxation for mechanical ventilation3. muscle relaxation for electroconvulsive therapy (weakens muscle contractions in seizures)4. orthopedic - fracture reduction5. insertion of endotracheal tubes

Study Questions

1. What are the 4 general responses to activation of muscarinic ACh receptors? What could a muscarinic receptor agonist be used for therapeutically? What side effects would be associated with its use?

2. What are the physiological responses to a muscarinic ACh receptor antagonist? What could it be used for therapeutically? What would its side effects be?

3. How do indirect-acting cholinergic agonists work? Do they affect muscarinic synpases, nicotinic synapses or both? What are they used for and what are the signs of overdose?

4. Drugs acting at autonomic ganglia affect what type of ACh receptor? How selective are these drugs for parasympathetic vs sympathetic ganglia? What are these drugs used for?5. Describe how non-depolarizing and depolarizing neuromuscular blocking agents cause muscle paralysis.

24

Post-synaptic cell(neuron or neuroeffector)

Pre-synaptic cell(post-ganglionic fiber)

synapse

Re-uptaketransporter

Pre-synaptic2 receptor

Neurotransmitter(NE, DA, 5HT) Po

st-s

ynap

tic

rece

ptor

s

1

2

5

4

3

5

4

Fig 1: sites for SNS drug action

cathecol

ADRENERGIC AGONISTS AND ANTAGONISTS

SYMPATHOMIMETIC DRUGS: mimic the effects of SNS stimulation. Three classes1. direct-acting (receptor agonists; EPI, NE, DA) 2. indirect-acting (cause NE release prevent NE reuptake; amphetamine)3. dual acting(bind to receptors AND cause NE release; ephedrine)

CATECHOLAMINES are direct-acting adrenergic agonists which are released from sympathetic nerves (the neurotransmitters NE and DA), the adrenal medulla (the hormone

EPI) and also includes the synthetic catecholamine isoproterenol. They are particularly important in integrating stresses that threaten homeostasis. All catecholamines: 1) have short durations of action, 2) are ineffective orally, 3) are subject to first-pass metabolism in the liver (MAO and COMT) and to degradation by MAO and COMT in the intestine and 4) are highly charged and do not cross the blood-brain barrier. The actions of catecholamines are mediated by adrenergic receptors. Their actions include:

1. peripheral excitation of vascular smooth muscle and glands2. peripheral inhibition of GI, bronchial and skeletal muscle arteriole smooth muscle3. cardiac excitation [increase force (+ inotropic) and rate (+chronotropic)]4. metabolic actions including glycogenolysis and lipolysis (mobilization of energy)5. endocrine effects on insulin secretion, renin production and pituitary hormone secretion6. CNS effects including respiratory stimulation, enhanced wakefulness, appetite suppression (peripheral catecholamines do not cross the blood-brain barrier)

7. presynaptic enhancement or inhibition of neurotransmitter release

ADRENERGIC RECEPTORS AND RESPONSES: Net effect of a given adrenergic agonist depends on:

1. relative receptor affinity: NE is primarily an agonist causing vasoconstriction (1) and has little effect on bronchial smooth muscle or skeletal muscle arterioles (where receptors predominate); EPI interacts with both and receptors therefore causing vasoconstriction and vasodilation and dilation of bronchiole smooth muscle; ISO interacts only with receptors. Also, most vascular smooth muscle has adrenergic receptors- thus EPI and NE cause vasoconstriction while the selective agonist ISO has no effect.

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RECEPTOR and SIGNAL LOCATION/RESPONSE

Ca2+

EPI > NE >> DA >>>ISO

vascular smooth muscle (nerve ending)/ vasoconstrictionradial smooth muscle/ pupil dilationuterine smooth muscle/ contractionGI smooth muscle/decreased tone and motility

2 - cAMPEPI > NE >> DA >>>ISO

vascular smooth muscle (blood-borne (EPI)/vasoconstrictionpre-synaptic/ inhibits NE releasepancreas/ inhibits insulin secretion

1 - cAMPISO > EPI = NE >DA

Hear/ increase rate, force, conduction velocityadipose tissue/ lipolysis

2 - cAMPISO> EPI >>>NE>DA

bronchiole smooth muscle/ bronchiole dilationskeletal muscle arterioles/ vasodilationuterine smooth muscle/relaxationGI smooth muscle/ relaxationLiver/ stimulates glycogenolysis

DAD1, D5 - cAMP; D2-D4 - cAMP

vasculature (kidney, coronary, mysentary)/ vasodilation

2. relative density of and receptors in a given tissue. For example, the pancreas has and receptors, but EPI decreases insulin secretion because there are more receptors present (What effect would ISO have?)3. compensatory reflexes evoked (see Fig 2). EPI causes vasoconstriction and elevates blood pressure. This results in decreased SNS tone and increased PNS (vagal) tone caused by the heart’s baroreceptor system. (This would not occur in heart transplant recipients - why?)

SYMPATHOMIMETIC DRUGS: SNS AGONISTS

1. CATECHOLAMINES: All have rapid onsets, short durations of action and are metabolized in the liver by MAO (monoamine oxidase) and COMT (catecho-O-methyltransferase). Based on these properties, none are administered orally but can be administered i.v., s.c., topically or by inhalation (EPI).

a. epinephrine (adrenaline2, 1 and 2. A non-selective adrenergic agonist. Activation of 1, 2 and 1 receptors all contribute to the increase in blood pressure.

1. 1 effects: vasoconstriction resulting in increased blood pressure, nasal decongestion, mydriasis (pupil dilation), decreased insulin secretion (predominates) and contraction of

uterine smooth muscle.2. 2 effects: vasoconstriction, inhibition of insulin secretion3. 1 effects: increased heart rate and force of contraction and increased lipolysis4. 2 effects: bronchiole dilation, arteriole dilation in skeletal muscle, increased insulin

secretion, relaxation of uterine smooth muscle and stimulation of liver glycogenolysis.. EPI is

used as a bronchiole dilator, in the treatment of anaphylaxis, as a topical hemostatic agent and to delay absorption of local anesthetics

b. norepinephrine (noradrenalin, LEVARTERENOL) Acts at1, 2 and1. It differs from EPI in its efficacy at and 2 receptors. Used for acute hypotension when a potent and effective vasoconstrictor is needed and to limit the absorption of local anesthetics.

Toxicity of EPI and NE: hypertensive crises, arrhythmias, anginal pain, necrosis and sloughing of tissues at injection site, hyperglycemia. Responses to EPI are more severe then those of NE.

c. dopamine (INOTROPIN, DOPASTAT): at low concentrations, DA binds to vascular D1 receptors (kidney, coronary and mysenteric vessels) resulting in vasodilation as well as increased glomerular filtration rate (GFR) and renal blood flow (RBF). At high concentrations it also binds to 1 producing increased force. At even higher concentrations, it binds to resulting in vasoconstriction. Used to treat hypovolemic shock (to maintain renal blood flow), to prevent renal failure, increase cardiac output and blood pressure.d. isoproterenol (ISUPREL): a non-selective agonist (1 and2). Increases heart rate and force

of contraction, stimulates lipolysis (1), dilates arterioles in skeletal muscle, increases insulin secretion , relaxes uterine and GI smooth muscle, stimulates liver glycogenolysis. Used primarily as a cardiac stimulant where it prevents heart block by shortening conduction time. Its use as a bronchial dilator has largely been supplanted by 2 selective agonists. It can cause tachycardia, cardiac insufficiency, arrhythmias and hyperglycemia.

2. SELECTIVE AGONISTS: used primarily to control blood pressure and vascular perfusion (e.g. nasal decongestion)

a. 1-selective agonist: phenylephrine (NEO-SYNEPHRINE) - may also cause NE release. Used to treat hypertensive emergencies, as a nasal decongestant and as a mydriatic agent.b. centrally acting 2-selective agonist: clonidine (CATAPRES): primary use is to treat systemic hypertension. Peripherally, it causes transient vasoconstriction due to activation of vascular receptors. But centrally, it inhibits NE release and reduces SNS tone thus producing long-lived drops in

26

blood pressure. This latter effect predominates. It can cause dry mouth, sedation, bradycardia, sexual dysfunctionc. peripheral 2 agonist: oxymetazoline (AFRIN): nasal decongestant. Large dose can produce CNS effects.

3. SELECTIVE AGONISTS: Selectivity of a drug for or or even receptors in general is NOT absolute and selectivity is generally lost at high concentrations. Used primarily as cardiac stimulants or to treat asthma.

a.1-selective agonist: dobutamine (DOBUTREX). This drug has 1 effects but also interacts with 1

and 2 receptors. Increases force with little effect on heart rate. Improves inotropic activity following heart surgery, congestive heart failure or myocardial infarction (MI). Can cause tachycardia, increased blood pressure, ectopic ventricular beats and exacerbates MI. b. 2-selective agonist-albuterol (PROVENTIL, VENTOLIN) orally effective; not a substrate for COMT (it is not a catecholamine). Long-lived bronchodilation; aerosols (inhalers) can limit 1 effects. Can cause skeletal muscle tremor and systemic administration can increase heart rate.

4. INDIRECT- ACTING ADRENERGIC AGONISTS: cause release of NE (and often DA in the CNS)

a. ephedrine: found in plants. Causes NE release but also has activity at AR (it is DUAL-ACTING) and thus mimics EPI in its effects. Used primarily as a decongestant and as a pressor agent.b. amphetamine: CNS stimulant used for treatment of ADHD, narcolepsy, weight control. Abused because of the euphoriant effect associated with elevated catecholamine levels in the brain. c. methylphenidate (RITALIN): CNS stimulant used for treatment of ADHD, narcolepsy, weight controld. cocaine: a local anesthetic that still has medical uses. Peripherally it produces SNS-like effects by inhibiting NE re-uptake (predominant effects are on cardiovascular function). Centrally, it acts much like amphetamine, but its effects are shorter lived and more intense. It also inhibits DA re-uptake in the “pleasure centers” of the brain, contributing to abuse potential. e. methamphetamine: Methamphetamine is closely related chemically to amphetamine, but has a greater effect in the CNS. It has some limited therapeutic uses, primarily in the treatment of obesity.

f. ecstasy: MDMA (3-4 methylenedioxymethamphetamine) is a synthetic drug chemically similar to methamphetamine and the hallucinogen mescaline. MDMA exerts its primary effects on serotonergic neurons which are important in regulating mood, aggression, sexual activity, sleep, and sensitivity to pain.

SYMPATHOLYTIC DRUGS - SNS ANTAGONISTS:

1. ADRENERGIC ANTAGONISTS (BLOCKERS): receptors mediate many of the important responses to EPI and NE. Particularly important are 1-mediated vasoconstriction and 2-mediated suppression of SNS tone, inhibition of NE release from nerve terminals and vasoconstriction in some vascular beds. Their use is limited almost exclusively to the treatment of cardiovascular disorders although some are now being used to treat benign prostate hyperplasia

a. phenoxybenzamine (DIBENZALINE): somewhat 1-selective, binding covalently and irreversibly (i.e. non-competitively) to receptors. Blocks and reverses the effects of NE/EPI, decreases PVR and increases cardiac output due to reflex SNS stimulation. Used to treat severe hypertension, particularly that associated with pheochromocytomas (epinephrine-secreting tumor of the adrenal gland). Can cause postural hypotension and reflex tachycardia.b. prazosin (MINIPRESS): competitive 1-selective antagonist, causing arterial and venous dilation and a drop in blood pressure. Causes arterial and venous dilation and is used to treat hypertension. Can cause postural hypotension and syncope (fainting) with administration of the first dose and reflex tachycardia.

2. ADRENERGIC ANTAGONISTS (BLOCKERS): used to manage cardiovascular disorders, primarily 1

antagonists, blocking effects of catecholamines on heart action. Consequences of blockade include a

27

reduction in heart rate, decreased force of contraction and a reduction in conduction velocity through the atrioventricular (AV) node. antagonists are use to treat hypertension (decreases force and rate resulting in decreased cardiac output and blood pressure), angina, cardiac arrhythmias. antagonists have little effect on normal heart rate of an individual at rest, but has marked effects when SNS tone is high. Also with little effect on heart rate or blood pressure in people with normal cardiac function and blood pressure.

a. propranolol (INDERAL): non-selective antagonist. Propranolol decreases force, rate and cardiac output (1). It also decreases renin secretion (1), cause vasoconstriction and reduced glycolysis in skeletal muscle and bronchial constriction (2). Used to treat hypertension, angina and cardiac arrhythmias. Can cause bradycardia, rebound cardiac excitation, AV heart block and CHF, masks diabetic hypoglycemic tachycardia and bronchial constriction in asthmatics.b. metoprolol (LOPRESSOR): 1-selective antagonist that decreases force, rate and cardiac output and renin secretion. Used to treat hypertension, angina and cardiac arrhythmias. Can cause bradycardia, rebound cardiac excitation, AV heart block and CHF, masks diabetic hypoglycemic tachycardiac. labetalol (NORMODYNE): A 1 and 1 antagonist with some sympathomimetic 2 activity. 1

blockade blocks SNS reflex increases in heart rate. 2 agonist effects may contribute to vasodilation. Used to treat hypertension due to its multiple sites of action.

Study Questions:

1. What are the four catecholamines? What characteristics do all catecholamines possess?2. The net result of using an adrenergic agonist depends on what 3 factors?3. Where are andreceptors located and what responses occur when each is activated?4. What type(s) of adrenergic receptors does EPI activate? What are the therapeutic uses and adverse

effects associated with the use of EPI? Answer these questions with regards to NE, DA and ISO (REMEMBER: If you know what receptors are activated by each catecholamine you’ll know what responses they produce and the adverse responses they cause)

5. Describe the responses to selective and non-selective agonists. Based on their effects, for what purposes might they be used therapeutically?

6. Describe the responses to selective and non-selective adrenergic agonists. What are they used for therapeutically? What are their side effects?

7. How do indirect-acting adrenergic agonists produce their responses?

28

Post-synaptic cell(neuron or neuroeffector)

Pre-synaptic cell

Y Y Y

Y Y

Y Y

Y Y

synapse

ACh

ACoA + choline

AChE

AChE

Post-s

ynap

tic

rece

ptor

s

Acetate+ choline

1

2

43

5

Fig 1: Steps in neural transmission

INTRODUCTION TO CNS PHARMACOLOGY

Nearly all CNS drugs act directly or indirectly on specific receptors that modulate synaptic transmission. Drugs used therapeutically that affect CNS function include: 1) anesthetics, 2) analgesics, 3) anti-pyretics, 4) anti-Parkinson’s and Alzheimer’s drugs, 5) anticonvulsants, 6) sedatives/hypnotics, 7) treatments for ADHD, 8) anti-psychotics and anti-depressants and more. While the mechanisms of action of most CNS drugs are not well understood, these drugs have been extremely useful in defining CNS physiology. Using agonists and antagonists and observing the consequences of their use have provided insights into the disease mechanism and the role neurotransmitters play in the disease process. For example, many antipsychotic drugs are dopamine receptor antagonists. Since these drugs relieve the symptoms of schizophrenia, this suggests changes in dopamine levels in the brain contribute to the appearance of schizophrenia.

Macroanatomy and functionality of the CNS:

1. cerebral cortex: sensory information is processed in the cerebral cortex is including somatosensory (touch), visual, auditory, olfactory and motor. The cerebral cortex can also be subdivided on an anatomical basis, including frontal, temporal, parietal and occipital lobes.

2. limbic “system”: regulates complex emotional and motivational function. The extrapyramidal motor system helps control the function of the voluntary (pyramidal) motor systems. This region is damaged in Parkinson’s disease and in Huntington’s disease. The hippocampus controls the formation of recent memory and is the site of damage in amnesia and in Alzheimer’s disease.

3. diencephalon: houses the thalamus which regulates eating and drinking and relays information between incoming sensory pathways and the cortex. The hypothalamus regulates body temperature, water balance, blood pressure, sex and circadian cycles, sleep, etc…

4. midbrain/brain stem: composed of the mesencephalin, the pons and the medulla oblongata. These regions of the brain contain the reticular activating system which controls sleep, wakefulness, levels of arousal, and sensory filtering by linking sensory input to the interpretive centers of the brain. Monoamines (NE, DA, 5-HT) are important here. Coordination of reflex acts like swallowing and vomiting are also located here.

5. cerebellum: regulates balance in “anti-gravity” or postural muscles and during movement.

The Basics of Nerve function: A common misconception is that all neurotransmitters and all nerves produce excitatory responses. However, there are inhibitory neurotransmitters that suppress the activity of post-synaptic nerves. In figure 1, the depolarization associated with an action potential results in Ca2+-mediated release of neurotransmitter at the synapse (3), the interaction of the neurotransmitter with receptors on the membrane of the second (post synaptic) neuron (4) and a local change in ion composition and potential difference. This post-synaptic potential (PSP) can be a) depolarizing (excitatory PSP = EPSP) and if large enough can generate an action potential in the second neuron or b) hyperpolarizing (inhibitory PSP =IPSP) and reduce the likelihood of action potential generation.

Drugs affecting CNS function can affect the same 5 steps in neurochemical transmission that were discussed with regard to the autonomic nervous system 1) synthesis, 2) storage, 3) release, 4) action and 5) inactivation.

NEUROTRANSMITTER SIGNALING/ACTION RESPONSE NOTESACh RM - GPCR excitatory may be involved in cognitive

29

RN - ligand-gated ion channel disorders like Alzheimer’s.

GABA (GABAA) increase Cl- permeability inhibitory

major inhibitory neurotransmitter in the CNS. Target for barbiturates, benzodiazepines and general anesthetics

glycine increase Cl- permeability inhibitoryglutamate ligand-gated ion channels and GPCR excitatory

monoamines

NE GPCRexcitatoryinhibitory

target for TCADs like amitriptylline in treating affective disorders; target in treatment of ADHD (?)

DA GPCRgenerally inhibitory

target for antipsychotics like chlorpromazine; also important in Parkinson’s disease and regulation of pituitary function

5HT (serotonin)

GPCR and ligand-gated ion channelsinhibitoryexcitatory

target for SSRIs like fluoxetine. regulation of behaviors (sleep, pain perception. depression, sexual activity, aggressiveness.

peptides: substance P, opioids, neurotensin, cholecystokinin, vasoactive intestinal peptide, thyrotropin releasing hormone

Table 1: CNS neurotransmitter pharmacology

Study Questions:

1. How do most/all CNS drugs produce their effects?2. In general terms, define the function of the a. cerebral cortex b. the limbic system c. the diencephalons d. the midbrain/brainstem e. cerebellum3. Define excitatory and inhibitory post-synaptic potentials (EPSPs and IPSPs, respectively)4. What are the major neurotransmitters in the CNS? Are they excitatory or inhibitory?

30

PAIN AND THE TREATMENT OF PAIN

Pain is a reaction of the body to harmful stimuli and thus serves a protective function. However, pain associated with cancer or chronic disease such as rheumatoid arthritis does not serve a useful function and can have harmful effects on the body; the stress response to pains can increase SNS activity, produce changes in blood flow to tissues and organs and alter immune function and healing responses. Pain is both an objective (sensory) and subjective (emotional/interpretive) experience. The objective response is the result of nerve activation and can be diminished with NSAIDs (non-steroidal anti-inflammatory drugs) like aspirin and ibuprofen. The subjective response involves the perception of pain which involves emotion and can be diminished with opioids like morphine. Nociceptive pain is caused by stimulating nociceptive receptors and is transmitted over intact neural pathways. Both NSAIDs and opioids can control this pain. In contrast, neuropathic pain is caused by damage to nerves and responds poorly to NSAIDs and opioids (e.g. diabetic neuropathies, shingles, phantom limb pain). Analgesics work by 1) reduced the underlying cause of pain (e.g. NSAIDs inhibiting the production of inflammatory mediators) and 2) inhibiting the transmission of pain impulse and pain perception (opioids).

NON-OPIOID ANALGESICS: Antiflammatories/Antipyretics

INFLAMMATION occurs when the immune response is activated. It is defined as the reaction of vascularized tissue to local injury. Inflammation consists of heat, redness, swelling/pain due to changes in vascular diameter and blood flow, increased vascular permeability and exudation of leukocytes. The inflammatory response can be beneficial (invading organisms are phagocytosed and neutralized) or deleterious (i.e. harmful as in rheumatoid arthritis when the inflammatory process is associated with destruction of cartilage and bone and limitation of joint function).

NSAIDs Mechanism of Action - all NSAIDs inhibit the activity of the enzyme cyclooxygenase (COX). There are at least two forms of COX; COX1 and COX2. COX1 is active all the time (constitutively active) while COX2 seems to be active only during inflammatory responses. Older NSAIDs (e.g. aspirin and ibuprofen) inhibit both COX1 and COX2, while the newest NSAIDs celecoxib (CELEBREX) and rofecoxib (VIOXX; removed from the market in 2004) appear to inhibit only COX2. Since COX1 regulates the production of gastric prostaglandins which in turn inhibit gastric acid production, aspirin and ibuprofen can increase gastric acid secretion while the COX2 inhibitors celecoxib and rofecoxib appear not to affect gastric acid production. The products of the lipoxygenase and cyclooxygenase pathways are termed eicosanoids or local hormones and are the mediators of the inflammatory process.

Most NSAIDs are similar in a number of ways and in fact there are no substantive differences in the response to average doses of NSAIDs among patients with rheumatoid or osteoarthritis. However, the proportion of NSAIDs not ionized at a particular pH is very important since it influences the distribution of these drugs in tissues. Acidic NSAIDs sequester preferentially in synovial fluid of inflamed joints. With increasing doses, aspirin, newer NSAIDs, and acetaminophen (which is not an NSAID) reach a limit to their maximum analgesic effects.

SP

INA

L C

OR

D

BRAIN

nociceptiveprimary afferent

presynaptic terminal reduce Ca2+ influx and neurotransmitter release

postsynaptic neuron increase K+ entrance, hyper-polarization and IPSPs

spinal pain trans-mission neuron

inflammatorymediatorsirritate nerves

NSAIDs

OPIOIDS

31

All NSAIDs1. inhibition of cyclooxygenase2. inhibit platelet function3. are antiinflammatory, analgesic, and antipyretic (inhibit the release of pyrogens--fever producing

chemicals--released by white blood cells. These chemicals act on the hypothalamus (increasing the set-point of the body's thermostat)

4. have similar toxicities including GI ulcers (with perforation), bleeding and blood dyscrasies, changes in kidney and liver function

5. are extensively plasma protein-bound6. can be administered orally and tend to be used chronically

ASPIRIN (acetylsalicylic acid) is the prototypical NSAID. It was originally derived from willow bark and is still the standard by which all antiinflammatory agents are measured. It remains the drug of choice for articular and musculoskeletal disorders due to its low cost and long history of safety. In addition, high concentrations are as effective as other NSAIDs in those people who can tolerate its GI toxicity. Aspirin is a weak organic acid, absorbed from the stomach and upper small intestine and is highly bound to plasma proteins. It is excreted by the kidney and alkalinization of the urine can enhance its excretion. The principle therapeutic action of aspirin (and all NSAIDs) results from the inhibition of prostaglandin synthesis.

Analgesia is produced peripherally through its inhibition of inflammation and centrally through subcortical suppression of painAntiinflammatory effects are mediated by the acetylation and irreversible inactivation of cyclooxygenase which results in the inhibition of prostaglandin, thromboxane and prostacyclin productionAntipyretic effects are produced by enhanced heat dissipation (vasodilation) and direct effects on the hypothalamus temperature control center to control the fever-inducing effects of pyrogens released by leukocytes in response to infection.Platelet effects result from the inhibition of thromboxane production which prevents platelet aggregation. Aspirin is thus an anticoagulant or more correctly, an antiplatelet drug. A single therapeutic dose results in irreversible platelet inhibition for the 7-day lifetime of the platelet and thus persists for 4-7 days. This results in a reduction of transient ischemic attacks and unstable angina and may reduce thrombosis associated with coronary by-pass

Adverse Effects - aspirin has an enormous potential for drug interaction. At usual doses, the primary effect is gastric intolerance which can be minimized with food, water, antacids. In kidney, the inhibition of prostaglandin production can affect autoregulation of renal blood flow, glomerular filtration rate and alter the transport of ions and water. Some diuretics may produce their effects on water/electrolytes and blood pressure by increasing prostaglandin synthesis (e.g. furosemide [LASIX]). In the CNS, the adverse effects are dose-dependent and include:

1. high doses (50-80 mg/dl) - tinnitus, decreased heart rate, vertigo (reversible)2. higher doses (50-80 mg/dl) - hyperpnea, respiratory alkalosis3. moderate toxicity (80-110 mg/dl) - fever, dehydration, acidosis4. severe toxicity (110-160 mg/dl) - cardiovascular depression, renal failure and coma5. over 160 mg/dl - lethal, primarily the result of respiratory failure.

OTHER NSAIDs: The newer NSAIDs tend to be more expensive, do not irreversibly inactivate cyclooxygenase and may possibly have fewer side effects. Ceiling for maximum analgesic effect may be greater than aspirin and duration of analgesia may be longer. However, they are still associated with GI irritation resulting in peptic ulcers. In addition, all NSAIDs reduce renal blood flow, cause fluid retention and may cause renal failure. All can cause hepatitis and pancreatitis. Ibuprofen (ADVIL, NUPRIN, MOTRIN IB) is as effective an analgesic but is less effective than aspirin as an antiinflammatory agent. Naproxin sodium (ALEVE) is a long-lived NSAID formulated in a disintegrating tablet system combining an immediate release component and a sustained release component of microparticles that are widely dispersed. This allows absorption of the active ingredient throughout the gastrointestinal (GI) tract, maintaining blood levels over 24 hours. COX2 INHIBITORS (celecoxib [CELEBREX]; rofecoxib [VIOXX]) have been under scrutiny for increasing the risk

32

of heart problems and the ability of CELEBREX to reduce the risk of ulcers also has been questioned. VIOXX was removed from the market by its manufacturer (Merck) in September 2004.

NON-NSAID NON-OPIOID ANALGESICS

acetaminophen (TYLENOL): Acetaminophen inhibits COX activity (perhaps COX3?) but does not reduce inflammation. Therefore, although it is analgesic and antipyretic it is NOT antiinflammatory and is not an NSAID. Acute overdoses can lead to fatal hepatic damage (ingestion of 15 g - less then the contents of 1 50 tablet bottle - can be fatal). Acetaminphen lacks platelet inhibiting effects, is useful in mild to moderate pain and is preferred in patients allergic to aspirin, those who cannot tolerate its GI effects and in children to avoid complications of Reye's Syndrome.

OPIOIDS ANALGESICS

OPIOIDS AND ALKALOID DERIVATIVES: Opioids in many cases are still derived from plants such as the poppy Papaver somniferum. Morphine is the prototypical opioid analgesic and is still derived from opium. It remains the standard against which new analgesics are measured. There is no ceiling on effects of morphine to relieve pain except that imposed by its adverse effects. Opioids relieve the subjective aspects of pain and the sensing of pain so that people become less attentive to pain. Endogenous opioids include endorphin, met- and leu-enkephalin and dynorphens.

Terminology

1. narcotic analgesic - any drug which induces sleep but most commonly associated with opioid analgesics. A relatively obsolete term pharmacologically but not leaglly.

2. opiates – drugs derived from opium3. opioids - all drugs (including endogenous opioids)

which act at opioid receptors. A large family of drugs which were developed with the hope of reducing adverse effects of morphine

Opioid receptors: All are G protein-coupled receptors which inhibit cAMP production. This in turn reduces the phosphorylation state of channels and reduces channel opening.1. mu () - involved with analgesia (supraspinal

meaning above the spine i.e. CNS; subcortical and limbic regions where discrimination and sensory aspects of pain are interpreted), respiratory depression, euphoria, constipation, miosis, dependence. Most chemically

useful opioids are agonists (e.g. morphine and codeine as well as endorphins and

enkephalins).2. kappa () - analgesia (spinal; nociceptive nerves), sedation, dysphoria3. delta () - hallucinogenic and cardiac effects as well as spinal analgesia.

Pharmacological Effects of Morphine in the CNS1. analgesia: increases threshold of perception without producing unconsciousness (hypnosis),

reduces anxiety, sedates without affecting the other senses. Opioid binding in the brain stimulates the release of 5HT which inhibits the activity of dorsal horn neurons.

2. sedation: drowsiness without amnesia (lack not loss of memory). In analgesic doses, morphine upsets REM and NREM sleep patterns.

3. euphoria and dysphoria: pleasant “high” or unpleasant “low” (feeling of restlessness and malaise)

SP

INA

L C

OR

D

BRAIN

nociceptiveprimary afferent

presynaptic terminal reduce Ca2+ influx and neurotransmitter release

postsynaptic neuron increase K+ entrance, hyper-polarization and IPSPs

spinal pain trans-mission neuron

33

4. miosis: telltale effect of agonists. Limited tolerance develops, but addicts still have pin-point pupils. However, when OD results in near-death, pupils dilate due to increased EPI release and increased levels of CO2. CHARACTERISTIC SIGN OF OVERDOSE.

5. respiratory depression: direct action on brain stem (medullary) respiratory center where it reduces responsiveness to increases in H+ and CO2 concentrations in the blood and reduces respiratory rate. The primary cause of OD death is respiratory depression (diminished response to increased PCO2) and is the primary limiting factor in dosing. CHARACTERISTIC SIGN OF OVERDOSE.

6. cough suppression (antitussive): inhibits the cough reflex. May result in the accumulation of secretions and airway obstruction. D- and L-isomers both reduce cough but D-isomers do not cause dependence, have no analgesic properties and are not addictive. e.g. dextromethorphan (BENYLIN) is the D-isomer of codeine.

7. emesis (nausea and vomiting): direct stimulation of the chemoreceptor trigger zone, especially prominent in first-time use

Pharmacological Effects of Morphine in the periphery

1. GI tract - reduces tone and motility resulting in constipation. Also decreases gastric, biliary and pancreatic secretions 2. urine retention - due to increased secretion of antidiuretic hormone. 3. cardiovascular - causes vasodilation resulting in orthostatic hypotension (no effect on blood

pressure in the supine patient) and histamine release (which can contribute to vasodilation and decreased blood pressure), which may be mistaken for an allergic reaction.

Uses: Forms of delivery1. analgesia 1. timed release - oxycodone (OXYCONTIN) and2. acute pulmonary edema morphine (MS-CONTIN)3. cough 2. oral/parenteral4. diarrhea 3. fixed interval5. anesthesia 4. transdermal - especially fentanyl

Adverse Effects: extensions of their pharmacological actions. The major danger is respiratory depression. 1. common responses include nausea, vomiting, constipation, urine retention, hypotension 2. tolerance - to analgesia, euphoria (develops rapidly) and respiratory depression. Tolerance begins with the first dose, but is not usually manifest for 2-3 weeks. Tolerance to all aspects of an opioid’s action does not develop at the same rate and people do not develop a tolerance to all of an opioid’s effects. e.g. respiratory depression in an opioid-naïve person may appear at 60mg administered over 2 hours whereas someone taking opioids over a longer period may require 2000 mg before respiratory depression is observed. Cross-tolerance occurs but is not complete and switching to other opioids may be helpful 3. dependence - should not deter use in cases of severe pain. ABSTINENCE SYNDROME -

readjustment to loss of drug generally producing opposite of drug effects. Chemical dependence after several weeks of therapy. Symptoms of withdrawal include rhinorrhea, diarrhea, lacrimation, chills

These drugs should be used with caution in patients with reduced respiratory reserve, decreased blood volume(shock) and head injury. In head injuries, opioids can increase intracranial pressure as a results of vasodilation and increased cerebrospinal fluid volume. In addition, opioid-induced miotic responses can mask the papillary responses of brain injury.

OPIOIDS FOR SEVERE PAIN: morphine is the prototypical drug; all are Schedule II drugs.

meperidine (DEMEROL) is among the most commonly prescribed opioids and is used for moderate to severe pain. Compared to morphine it has a shorter duration of action and is not antitussive. It may be administered to morphine-allergic patients since its structure is different. It is not used as an antidiarrheal or an antitussive. oxycodone (OXYCONTIN) as a time-release formula was designed for controlled delivery over 12 hours.

seen in all patients;

not a predictor of

addiction

34

Time-release forms provide 60-87% of the bioavailability of parenteral forms, while immediate release formulations provide 100% biovailability. However, crushing, cutting, or chewing the time-release forms increases their bioavailability to ~100%. Similar issues have arisen with fentanyl (SUBLIMAZE) transdermal patches from which people remove all of the fentanyl to inject it all at once. fentanyl (SUBLIMAZE): i.v. anesthetic/analgesic with little hypnotic effect. It is approximately 80 x more potent than morphine, but has a short half-life (~30 min) and a duration of 1-2 hours.methadone (DOLOPHINE): synthetic, oral opioid. Analgesic with extended duration of action and without euphoric effects. The t1/2 is 4-6 h, but can be extended to 22-48 h with repeated injection. This is in comparison to morphine's t1/2 of ~2 h. The long t1/2 is useful in detoxification (ABSTINENCE SYNDROME) since doses can be gradually reduced with tolerable withdrawal symptoms. It is sometimes used as analgesic in cancer patients but repeated doses can cause cumulative drug effects and progressive CNS depression. Methadone is highly protein bound which also contributes to cumulative drug effects.

OPIOIDS FOR MILD TO MODERATE PAIN: Effectiveness of these opioids overlaps with aspirin and other NSAIDs

codeine: Schedule II drug often used in combination with another drug (e.g. aspirin and codeine, a Schedule III drug). In such a combination, 30 mg codeine + aspirin has the same analgesic effect of 65 mg of codeine alone. At antitussive doses, codeine has few side effects. Its conversion to morphine is thought to account for its analgesic effects.Oxycodone + aspirin (PERCODAN) or oxcodone + acetaminophen (PERCOCET), also hydrocodone + acetaminophen (VICODIN). Because the two analgesics have different mechanisms of action, the combination can produce an analgesic effect that would otherwise require a greater dose of opioid.

OPIOID ANTAGONISTS: primarily antagonists. They have little effect in the absence of agonists. Can precipitate withdrawal in opioid abusers. They are used to treat opioid-induced respiratory depression and for detoxification.

naloxone (NARCAN): i.v. treatment of opioid OD. Has a very short t1/2 (minutes) therefore repeated doses may be necessary due to reverse the effects of opioids with the longer t1/2 (hours). Used for known/suspected opioid-induced respiratory depression and post-operative opioid depression. May cause acute ABSTINENCE SYNDROME.naltrexone (TREXAN): orally effective, long-acting. Adjunct for maintenance of an opioid-free state in detoxified individuals. May also be useful in treating alcoholism.

Study Questions1. What is the difference between the objective and subjective aspects of pain? Which is targeted by

NSAIDs? By opioids?2. What is nociceptive pain? Neuropathic pain? Which pain responds best to NSAIDs and opioids?3. What is inflammation?4. How do NSAIDs work? What types of COX enzymes are present in the body? Which drugs target which

COX isoforms?5. What effects do older NSAIDs all have in common?6. Why is/isn’t acetaminophen (TYLENOL) an NSAID?7. What is an opioid?8. Differentiate between subjective and objective pain.9. What are the physiological effects of morphine in the CNS? In the peripihery?10. Methadone has a very long half-life following repeated administration. What are the advantages and

disadvantages of methadone use? What can it be used for?11. What are the adverse effects associated with the use of morphine?12. What are the advantages of combining an opioid and a non-opioid analgesic to treat pain?13. What are opioid antagonists? What are they used for? What kinds of effects can they produce?

35

CNS DEPRESSANTS

SEDATIVES and HYPNOTICS: A number of agents can reduce CNS function to produce drowsiness including barbiturates, benzodiazepines, azapirones, ethanol, and antihistamines. The principle use of sedatives/hypnotics is to produce drowsiness and promote sleep. Sedatives reduce activity and anxiety without affecting motor or mental function while hypnotics produce drowsiness and facilitate the onset/maintenance of sleep. This can be achieved by increasing the dose of any sedative. Sedative/hypnotics cause dose-dependent CNS depression that progresses from sedation sleep (hypnosis) unconsciousness surgical anesthesia coma fatal respiratory depression.

Two primary classes of drugs 1. benzodiazepines e.g. diazepam (VALIUM), alprazolam (XANAX) and triazolam (HALCION)2. barbiturates e.g. phenobarbital (LUMINAL)

Pharmacodynamics (Mechanism of Action): both benzodiazepines and barbiturates appear to act on the limbic, thalamic and hypothalamic (reticular activating system which filters incoming information) regions of the CNS. Both modify the actions of the inhibitory neurotransmitter gamma aminobutyric acid (GABA).1. benzodiazepines intensify GABA actions by increasing

GABA receptor affinity for GABA and decreasing the firing rate of critical neurons in many regions of the brain. They bind to GABA receptors on a site distinct from the GABA site on GABA the GABA receptors which control Cl- entry into cells.

2. barbiturates prolong GABA actions and also reduce the actions of most excitatory neurotransmitters. This latter effect indicates they are not as selective as benzodiazepines. The multiplicity of actions may also explain why barbiturates produce full surgical anesthesia and benzodiazepines do not.

BENZODIAZEPINES are Schedule IV drugs; the prototypical drug is diazepam (VALIUM). The class includes alprazolam (XANAX) which is among the most prescribed drugs in the country and triazolam (HALCION). Most are anxiolytic, sedative/hypnotic and anticonvulsant and the clinical indications for one versus another are not absolute. Benzodiazepines are most commonly used to treat anxiety disorders and stress secondary to organic disease, control seizure disorders, treat insomnia, control alcohol and other sedative/hypnotic withdrawal states and relax skeletal muscle. However, skeletal muscle has no benzodiazepine receptors and high doses are required, suggesting this is a function of generalized CNS depression. In most circumstances the pharmacokinetic properties of a benzodiazepine will determine its use. For example, mimicking a “good night sleep” would require a rapid onset and short half-life. Benzodiazepines are preferred over barbiturates because they have 1) higher therapeutic indices (wide separation between the sedative dose and the lethal dose), 2) low risk of drug interaction, 3) low and slow elimination rates (most are converted into active metabolites) and 4) low risk of physical dependence.

(active) (active) (active)e.g. diazepam desmethyldiazepam oxazepam conjugation, inactivation and excretion

Adverse reactions: are related to dose-dependent CNS depression and include drowsiness, impaired judgment, diminished motor skills and hangovers, especially those drugs with long t1/2. Discontinuation can

Fig. 1: Benzodiazepines and barbiturates alter GABA-mediated Cl- channel opening

Cl-

Cl-

benzo

bar

b

GABA

BNZ GABA

BA

RB

36

DRUG TIME TO PEAK ELIMINATION t1/2

chlordiazepoxide (LIBRIUM) 0.5-2.0 hours 8-20 hoursdiazepam (VALIUM) 0.5-1.5 hours 20-60 hoursflurazepam (DALMANE) 0.5-1.0 hours 24-120 hoursalprazolam (XANAX) 1.0-2.0 hours 12-15 hoursoxazepam (SERAX) 2.0-4.0 hours 4-12 hourstriazolam (HALCION) 1.5-2.0 hours 3-5 hours

produce withdrawal symptoms and REBOUND INSOMNIA. Cross-tolerance can occur with other sedative/hypnotics and with ethanol.

BARBITURATES are derivatives of barbituric acid and have long been used as sedatives/hypnotics They have largely been replaced by the safer benzodiazepines. They are NOT analgesics, but do reinforce the actions of analgesics. All depress the motor cortex in large doses, however phenobarbital, mephobarbital and others depress the motor cortex a low doses making them useful as anticonvulsants. They are classified according to their durations of action which contributes to what they are used for therapeutically.

1. ultra-short acting: act within minutes, used as i.v. anestheticse.g. thiopental (PENTOTHAL)

2. short-acting: onset within 10-15 min, peak over 4 h; used for anesthesia and hypnosise.g. pentobarbital (NEMBUTAL), secobarbital (SECONAL)

3. intermediate-acting: onset in 45-60 min, peak at 6-8 he.g. amobarbital (AMYTAL)

4. long-acting: onset within 60 min, peak at 10-12 h, used to treat epilepsy and as sedatives to treat high anxiety.

e.g. phenobarbital (LUMINAL)Adverse Reactions include cross-tolerance with CNS depressants and ethanol and the induction of

enzymes metabolizing anticoagulants. Also after-effects of drowsiness and CNS depression (hangover), paradoxical excitement and pain (neuralgia, arthritis). Tolerance develops to all but the rates are unpredictable and abrupt withdrawal may result in seizures in epileptics. Barbiturate poisoning (those with short t1/2 and high lipid solubility are more potent and more toxic than those that are polar and have a long t1/2)

Study Questions

1. What are the definitions of sedative and hypnotic (sedation and hypnosis)?2. compare and contrast the pharmacokinetic and pharmacodynamic properties of benzodiazepines and barbiturates3. What are benzodiazepine used for therapeutically? What side effects are associated with their use? What determines the benzodiazepine chosen?4. Why have benzodiazepine largely replaced barbiturates for most uses?5. How are barbiturates classified? What are they used for?6. What kinds of side effects are associated with barbiturate use?

37

Fig. 1: genetic changes in transporters and receptors in ADHD

Data Table-2

normal ADHD0

100

200

300

400

# D

A r

e-u

pta

ke t

ran

spo

rter

s

Data Table-4

normalSNP

DA

Sig

na

lin

g

# D

A r

e-u

pta

ke t

ran

spo

rter

s

CNS STIMULANTS

CNS stimulants (Analeptics) are a diverse group of drugs and CNS stimulation is an adverse response associated with an even larger group of drugs. In general, all CNS stimulants produce their effects by: 1) potentiating/enhancing neurotransmission, 2) decreasing the amount or activity of an inhibitory neurotransmitter or 3) altering presynaptic control of neurotransmitter release. Any hyperexcitablity due to a drug is the result of a change in the balance between excitatory and inhibitor influences. CNS stimulants produce the following effects in humans.

1. psychomotor activation - cerebral cortex and the RAS2. anorexia - hypothalamus3. decreased sleep/fatigue (increased alertness) - cerebral cortex4. hypodypsia - hypothalamus5. respiratory stimulation (analepesis ) – medulla6. euphoria (cerebral cortex)

CNS stimulants are used therapeutically to treat 1. ATTENTION DEFICIT AND HYPERACTIVITY DISORDER (ADHD): excessive motor activity,

inattention, distractibility and short attention span. Cause? Used to think ADHD was problem in filtering sensory inputs. Now it seems more likely that its related to an inability to inhibit impulsive motor responses to sensory input. The CNS stimulants used to treat ADHD are considered psychomotor stimulants (amphetamine [DEXEDRINE, BENZEDRINE, ADDERAL], methylphenidate [RITALIN]). Both amphetamine and methylphenidate are indirect-acting adrenergic agonists which work by stimulating the release and reducing the re-uptake of neural and peripheral amines (NE, DA and 5-HT). Effects are most pronounced on DA (especially with methylphenidate) but amphetamines also stimulate NE and 5-HT release.

2. NARCOLEPSY: hypersomnia (excessive drowsiness) and uncontrolled sleep attacks under conditions not usually promoting sleep. Psychomotor CNS stimulants like dextroamphetamine (DEXEDRINE)are used to treat narcolepsy.

Uses for the following purposes is more or less obsolete.

3. APPETITE (weight) CONTROL: promotes weight loss by suppressing appetite not by increasing energy expenditure. Drugs such as phenylpropanolamine (DEXATRIM) used to suppress appetite are defined as anorexiants. Tolerance rapidly develops. Also require some form of diet and exercise in addition to drug therapy

4. RESPIRATORY STIMULANT(Analeptic): e.g. strychnine and doxapram (DOPRAM) Historically, these drugs have been used to counteract the effects of CNS depressants. However, this is obsolete for the following reasons: 1) they are not specific antagonists, 2) they have a narrow margin of safety, 3) their duration of action is shorter than that of most CNS depressants 4) doses required are very close to those causing convulsions (analepsis superimposed on CNS depression may cause neuronal instability and seizures) and cardiac arrhythmias. Thus it is safer to treat respiratory depression with antagonists where available (e.g. opioid antagonists) and by supportive measures. Some analeptics closes the Cl - channel while others and perhaps the methylxanthines are GABAAR antagonists. In contrast, strychnine inhibits the actions of another inhibitory neurotransmitter glycine (whose actions are more prominent in the spinal cord).

ATTENTION DEFICIT AND HYPERACTIVITY DISORDER (ADHD): Often with co-occurring anxiety, mood and disruptive disorders and substance abuse. ADHD is not a disorder of attention per se but seems to be a developmental failure in brain circuitry that regulates inhibition and self control.

Neurobiology: ADHD is associated with decreases in the volume of the total brain, corpus callosum, caudate (which coordinates input among several regions of the cortex), reduced prefrontal cortex metabolism (prefrontal cortex edits behavior, resists distraction [delays gratification] and is the site where awareness of self and time

38

develops). Genetic differences in a) the number of DA re-uptake transporters and SNPs in D4 DA receptors that reduce DA signaling (see Fig. 1) (How would either of these changes affect affect DA responsiveness?)

Treatment of ADHD: 1. Amphetamines: There is some evidence that they also suppress the activity of MAO. Low doses decrease serotonin levels which can produce calming effects and may explain their effectiveness in ADD and ADHD. They stimulate the RAS and the higher thought centers (cortex), resulting in increased alertness and increased response to incoming stimuli. Amphetamines can cause a marked euphoria (addictive) and their abuse potential makes them Schedule II drugs. Chronic use results in tolerance due to reductions in newly synthesized stores of NE. Amphetamine side effects include:

a. increased systolic blood pressure with reduced heart rate (increases in bp cause reflex bradycardia)

b. hyperthermiac. growth suppressionc. Toxicity: restlessness and irritability, anorexia, tremor, insomnia and mood changes

(these changes in mood can be severe, causing TOXIC PSYCHOSES). Treatment of intoxication: acidify the urine with ammonium chloride and use chlorpromazine

(THORAZINE) to treat the toxic psychoses.2. methylphenidate (RITALIN): similar to amphetamines in that it causes DA and NE release. It is a mild CNS stimulant with greater effect on mental than motor activity. Same abuse potential of amphetamines. Methylphenidate is also used to treat narcolepsy. It can suppresses growth but not as severely as amphetamines. Can produce euphoria in children when used at high doses

METHYLXANTHINES: Caffeine (coffee and tea) and theophylline (tea) are plant alkaloids. Dietary sources of caffeine include beverages, food and OTC and prescription drugs. Caffeine has been implicated (anecdotal evidence) as a causative agent in cancer, fibrocystic breast disease and birth defects. Per capita intake in the USA is 170-200 mg per day.

coffee - 100 mg/5 oz tea 50 mg/5 oz Coca cola 70 mg/5 oz Vivarin 200 mg/tabletPharmacodynamics: increase intracellular cAMP by preventing its breakdown, and are adenosine receptor antagonists which alters intracellular Ca2+. Most effects appear related to their adenosine antagonist properties. Methylxanthines (especially caffeine) are present in OTC analgesics and cold medications while theophylline was used to treat asthma (this use has declined due to the use of agonists and glucocorticoids)

1. in the CNS they cause cortical stimulation resulting in increased awareness2. in the cardiovascular system they increase heart rate, cardiac output and overstimulation can

result in tachycardia, arrhythmia and ectopic beats.3. constrict cerebral blood vessels (relief of vascular headaches)4. increases GI pepsin and acid secretion5. mild diuretic6. relaxes bronchiole smooth muscle (theophylline is most effective)7. can cause focal and generalized seizures (theophylline causes a more profound abd potentially

dangerous CNS stimulation)8. nausea and vomiting

Adverse Effects/Toxicities: fatal poisoning with caffeine is rare; poisoning is more common with theophylline. Symptoms include headache, palpitations, dizziness, nausea, vomiting, hypotension, tachycardia, restlessness, agitation, seizures, coma and death.

Study Questions:1. What effects do CNS stimulants produce in humans?2. What are CNS stimulants used for therapeutically?3. What genetic differences in DA inactivation and receptor activation may contribute to ADHD? How do

amphetamines and methylphenidate control these problems?4. What are the other uses for amphetamines and methylphenidate? What are their side effects and

toxicities?5. How do methylxanthines cause CNS stimulation? What are their pharmacological effects? Their side

effects and toxic effects?

39

Fig. 1: Bases for neurodegenerative disorders and possible interventions

OXIDATIVE STRESSproduction of reactive free radicals

vitamin E, ascorbate, Fe chelatorsEXCITOTOXICITY

excess glutamate activating NMDA receptorsNMDA receptor antagonists

MITOCHONDRIAL DYSFUNCTIONinhibition of mitochondrial electron transport

CoEnzyme Q10, creatinineINFLAMMATION

injury-related inflammatory responseCOX2 inhibitors

PROTEIN AGGREGATION

APOPTOSIS/NECROSIS

GENES ENVIRONMENTETIOLOGY

PATHOGENESIS

CELL DEATH

NEURODEGENERATIVE DISORDERS

Neurodegenerative diseases are a group of distinct disorders with a unifying feature of characteristic patterns of neuronal degeneration in anatomically or functionally related areas. These include: 1. Parkinson’s Disease (PD) - basal

ganglia (extrapyramidal areas) controlling

movement 2. Alzheimer’s Disease (AD) -

hippocampal and cortical neurons involved in

memory/cognitive ability 3. Huntington’s Disease (HD) - basal

ganglia areas controlling movement 4. Amyotrophic Lateral Sclerosis (ALS

or Lou Gehrig’s disease) degeneration of nerve cells in the CNS controlling voluntary muscle movement. causing muscle weakness and atrophy. Symptoms appear in middle to late adulthood, with death in two to five years. The cause is unknown, and there is no known cure.

Potential underlying disease processes are diagrammed in fig. 1. The nerves involved are subject to oxidative stress (production of reactive free radicals; H2O2 and oxygen radical causing DNA damage and lipid peroxidation), excitotoxic injury by excessive glutamate activation of NMDA (N-methyl-D-aspartate) receptors (NMDA receptors gate Ca2+ rather than Na+, and excessive intracellular Ca2+ can be toxic), mitochondrial dysfunction (inhibition of the mitochondrial electron transport chain and possible energy failure) and underlying inflammatory responses to injury.

For example, normal dopamine metabolism can lead to the production of free radicals. The primary metabolic pathway of dopamine to 3,4-dihydroxyphenylacetic acid (DOPAC) is catalyzed by monoamine oxidase B (MAO-B) and generates hydrogen peroxide (H2O2) (see reaction below). H2O2 in the presence of ferrous ion (Fe2+) which is abundant in basal ganglia may generate hydroxyl free radical (•OH). If protective mechanisms are inadequate (insufficient amounts of reducing compounds such as ascorbate or glutathione or enzymes for degradation such as superoxide dismutase), the oxyradicals could damage dopamine neurons and lead to the symptoms associated with Parkinson’s disease.

PARKINSON’S DISEASEParkinson's disease is a progressive, debilitating disorder of the CNS whose precise initiating cause is unknown. Characteristic changes in the CNS involve the degeneration of the pigmented dopaminergic neurons in the substantia nigra pars compacta (part of the striatal tracts of the motor cortex involved in coordinating muscle contraction/function). Theses neurons inhibit the excitable cholinergic neurons on the corpus striatum and under normal circumstances, there is a balance between dopaminergic inhibitory control of muscle function and cholinergic excitatory control of muscle function. When dopamine neurons are lost, there is a corresponding loss of coordinated muscle contraction, resulting in disorders of movement. Loss of DA

DA + O2 + H2OMAO-B

DOPAC + NH3 + H2O2

Fe2+

•OH +OH- + Fe3+

40

periphery brain

L-Dopa

DA

L-Dopa DA

AADcarbidopa

3-MD

AAD

3-MT

COMT

COMT

MAOtolcapone

Fig 3: Effects of AAD and COMT inhibitors

neurons is a normal part of aging, but not the 70-80% loss seen in symptomatic PD. There are 4 cardinal features of Parkison’s disease.

1. tremor at rest; often unilateral early in the disease

2. bradykinesia (slowness/lack of movement and difficulty initiating movement) which results in a shuffling gait. This is followed by late-appearing akinesia (no movement)

3. muscle rigidity (increased muscle tone with reduced reflex activity)

4. impaired balance with falling and gait and posture disturbances.

(5. sometimes dementia late in the disease process).Approaches to treatment: Treatment involves 1) increasing dopaminergic activity or 2) reducing cholinergic activity in the brain. There may also be a role for 3) drugs/chemicals that can limit oxidative or excitotoxic damage and surgical procedures including 4) removal of certain areas of the brain (pallidotomy). Finally, 5) transplantation of fetal nigral tissue, autologous adrenal medullary tissue or stem cells may prove useful. There is no cure; the current treatments available alleviate symptoms, but Parkinson's disease is ultimately fatal, most often due to complications of immobility such as embolism and aspiration pneumonia

1. Increasing DA activity (see fig 2) a. L-DOPA (levodopa): levodopa (L-DOPA) and levodopa + carbidopa (SINEMET). L-Dopa is the immediate precursor of dopamine, relatively inert by itself. It must bedecarboxylated to dopamine to produce an effect in the CNS. Unfortunately it can be converted peripherally by plasma decarboxylase, resulting in significant side-effects. To insure that sufficient amounts of levodopa cross the blood-brain barrier, it is

adminisitered with inhibitors of decarboxylases (e.g. carbidopa) to increase the fraction of levodopa reaching the brain (carbidopa-levodopa [SINEMET]). Carbidopa prevents peripheral conversion of levodopa, allowing the effective dose of levodopa to be reduced by ~75% (see fig 3). Therapeutic levels of levodopa are achieved more quickly and the percentage of patients improved and the degree of improvement is greater than with levodopa alone. Carbidopa also reduces the systemic side-effects of levodopa since less is converted into dopamine. There are also controlled release formulations which take

longer to reach peak levels but they maintain a relatively steady plasmalevel for 4-6 hours. (levodopa-carbidopa (SINEMET CR). The majority of patients using levodopa experienceside-effects and continued treatment results in reduced effectiveness.

Acute Adverse Effects: nausea, vomiting, anorexia, postural hypotension (a2 effect?)Long-term Adverse Effects: Long-term therapy causes motor complications that limits its effectiveness1. wearing off effect: shortening of the duration of action2. On-Off Effect: unpredictable fluctuations between mobility and immobility3. Dyskinesia: excessive and choreiform (involuntary) movements of the limbs, hands, trunk and tongue. Long-term high dose therapy produces these symptoms in more than 40% of patients. It may be related to fluctuating levels of DA in face of constant DA receptor number. Constant plasma DA levels do not result in dyskinesia and sustained release formulations (SINEMET CR) or levodopa every 2 hours may minimize dyskinesia.

b. dopamine receptor agonists direct activation of DA receptors without the need for L-DOPA to DA conversion. They are potentially more selective in their actions and have longer durations of action which may

Tyrosine

L-DOPA

DA

DA D

AD

AD

A DA

DADOPAC

MAO

DA

3-methoxytyramine

Homovanillicacid

MAO

COMT

1

2

3

1. levodopa2. DA agonists3. MAO-B Inhibitor

3

41

make them less likely to cause On-Off effects and dyskinesia. These drugs include bromocriptine (PARLODEL), pergolide (PERMAX), pramipexole (MIRAPEX) and ropinivole (REQUIP). The primary differences are the adverse effects (postural hypotension, nausea, somnolence and fatigue) and tolerability. Dose adjustment of bromocriptine and pergolide takes weeks to months, days to weeks with pramipexole and ropinivole. c. monoamine oxidase inhibitors: Selegiline (ELDEPRYL) is an irreversible inhibitor of MAO-B, the form which predominates in the CNS. Selegiline increases DA availability at its receptor, and is most useful early in drug regimen when there are still some residual DA neurons. At therapeutic doses there is little or no effect on MAO-A and this does not produce adverse interactions with foods containing tyramine. Since it slows, prevents DA metabolism, it may also serve a neuroprotective function. d. COMT inhibitor: Inhibit the peripheral conversion of COMT thus increasing the plasma t1/2 of L-Dopa (see fig 3). Tolcapone (TASMAR) is used in conjunction with carbidopa to more completely prevent the peripheral conversion of L-Dopa.

2. reducing cholinergic activity: At one time, antimuscarinic agents were the primary means of treatment. They are useful in patients with minimal symptoms, those who can't tolerate levodopa and those not benefitted by levodopa. They are sometimes used in conjunction with levodopa to reduce cholinergic influences and enhance the effect of levodopa. Drugs include: atropine and scopolamine and the more CNS selective trihexyphenidate (ARTANE), benzotropine mesylate (COGENTIN), biperiden (AKINETON) and procyclidine (KEMADRIN). Side effects: encountered in nearly all patients including dry mouth urine retention, constipation, blurred vision.

Study Questions

1. What are the hypotheses concerning the causes of PD? How many neurons must be lost before people suffer symptoms?

2. What are the 4 cardinal features of PD?3. How does L-Dopa alleviate the symptoms of PD? How does it enter the brain and what roles do the

AAD inhibitor carbidopa and the COMT inhibitor tolcapone (TASMAR) play in L-Dopa delivery to the brain? Why isn’t DA used to treat PD?

4. What are the acute and long term effects of L-Dopa use?5. What role do

a. DA receptor agonistsb. DA releasersc. MAO and COMT inhibitors

play in treatment of PD? How does each produce its effect? Are they better/worse than L-Dopa?

6. What role do AChRM antagonists play in treating PD? What are their side effects?

42

PSYCHOSES (SCHIZOPHRENIA) and ANTIPSYCHOTICS

Psychoses like schizophrenia are major disorders of thought processes, behavior, and perceptions of reality. There is a diminished capacity to process information, draw logical conclusions, and there may be hallucinations, delusions and disorganized behavior. It is treated with typical antipsychotics (neuroleptics) like chlorpromazine and haloperidol and atypical antipsychotics like clozapine and risperadone. Schizophrenia is a heterogeneous disease that manifests late in adolescence or early adulthood and has a poor outcome progressing from social withdrawal and perceptual distortions to chronic hallucinations and delusions. Patients may have positive symptoms (conceptual disorganization, delusions, hallucination) which respond reasonably well to drugs or negative symptoms (decreased affect (mood), impaired concentration, reduced social interaction) which do not respond well to drug treatment.

Risk factors for schizophrenia1. genetic susceptibility - family, twin and adoption studies2. early developmental insults -Rh factor, prenatal exposure to influenza during 2nd trimester, prenatal

nutritional deficiency, localized hypoxia during fetal development3. winter birth?

Structural and functional abnormalities: The changes in brain suggest there is disturbed sensory filtering, impairments in attention and information processing, autonomic nervous system activation. There is (1) enlargement of the lateral and third ventricles and cortical atrophy, (2) reduced volume of the amygdala, hippocampus, right prefrontal cortex and thalamus and (3) decreased neuronal metabolism in the thalamus and prefrontal cortexThe dopamine hypothesis of overstimulation of dopamine receptors is still used to help explain the cause of schizophrenia. There are multiple lines of evidence that changes in DA levels are important. 1) drugs which increase DA levels in the brain (L-Dopa, amphetamines) aggravate schizophrenia in schizophrenics or cause schizophrenia-like symptoms in non-schizophrenics. 2) typical antipsychotics used to treat schizophrenia block DA receptors (D2 receptors), 3) there are increased numbers of DA receptors in the schizophrenic brain, 4) antipsychotic drugs initially increase the rate of production of DA metabolites, the rate of conversion of tyrosine to L-Dopa and the rate of firing of DA cells in the midbrain representing an adaptive response to the interruption of DA transmission and 5) reduce the metabolism of homovanillic acid, a major DA metabolite. Thus, increases in the basal occupation of receptors or an increase in the release of dopamine (or both) may contribute to the symptoms of schizophrenia.

Virtually all of the drugs used to treat schizophrenia are D2 DA receptor antagonists (anti-dopaminergic) including the typical antipsychotics chlorpromazine (THORAZINE) and haloperidol (HALDOL]). Even those with greater effects at serontonin (5-HT) receptors [atypical antipsychotics like clozapine (CLOZARIL) or risperidone (RISPERDAL)] have DA antagonist effects. Some drugs also interact with D1 and D4 receptors, 5-HT2 serotonin receptors and 1-adrenergic receptors. Drugs with high potency for DA receptors tend to have more adverse extrapyramidal neurological effects while low potency drugs are more sedating and have more hypotensive and autonomic side effects (See TABLES 1and 2). There is no cure agents and drug treatment tends to be chronic. These drugs have had a revolutionary impact on treatment of severe psychoses, but also have a relentless association with extrapyramidal side effects in those regions of the brain involved with control of posture and involuntary aspects of movement resulting in iatrogenic Parkinson's disease. Chronic schizophrenia requires prolonged therapy but the risk of TARDIVE DYSKINESIA must be kept in mind when prescribing these drugs. These drugs have high therapeutic indices and lethal doses are extraordinarily high.

Antipsychotic mechanisms of action1. three DA pathways are targeted. Clinical

potencies parallel their affinities for D2 receptors and even the newer atypical antipsychotics have a measurable affinity for D2 receptors. a. nigrostrial pathways (basal ganglia) which control of posture and voluntary movement and lead to the extrapyramidal effects (Parkinsonian)

TABLE 1: Examples of the potencies of typical and atypical antipsychotics at neurotransmitter receptors. Affinities reported in nM

DRUG type D2 D1 D4 5-HT2 AChRM 1 2 H1

Risperidone (a)typical 3.3 750 16.6 0.16 >10,000 2 55.6 58.8Haloperidol typical 4 45 10.3 36 >20,000 6.2 3800 1890

chlorpromazine typical 19 56 12.3 1.4 60 0.6 750 9.1clozapine aytpical 180 38 9.6 1.6 7.5 9 160 2.75

43

b. mesolimbic/mesocortical which controls higher mental and emotional motional functions. These regions are the therapeutic target areas and contain high levels of the D4 receptor which is a subtype of the D2 receptor. c. tuberoinfundibular which connect hypothalamus to anterior pituitary. DA tonically inhibits prolactin secretion and antipsychotics cause hyperprolactinemia. The hypothalamus is also intimately involved in the regulation of body temperature.2. not simply DA receptor blockade as blockade takes place within hours while symptomatic relief takes weeks. This suggests there may be drug-induced changes in DA activity. Perhaps at the start of therapy, DA turnover is enhanced while later metabolism returns to normal (this is consistent with the changes seen in homovanillic acid concentrations. 3. other neutrotransmitters must be important, as the atypical drugs like clozapine have a lower afinity for D2

receptor and a greater affinity for 5-HT2 receptors (see Table 1). Adverse Effects: While all have high therapeutic indices, they also have significant side effects at therapeutic doses. All but clozapine cause Tardive dyskinesia. However, clozapine is reserved for those refractory to other antipyschotics. Its second line status is due to its seizure-inducing effects and its high risk of causing agranulocytosis (1 in 100) which is a severe reduction in white blood cells (neutrophils, eosinophils, and basophils) in the immune and inflammatory responses.

1. extrapyramidal effects which usually follow chronic treatment but sometimes occur following acute administration. More prevalent with high potency antipsychotics (see Tables 1 and 2)a. Iatrogenic Parkinsonism, which results from their antidopaminergic activity; can be

managed with anticholinergics. It includes symptoms like bradykinesia, rigidity, tremor, shuffling gait similar to and difficult to differentiate from Parkinson's disease. It is NOT treated with L-Dopa, but rather with anti-AChRM or DA releasers. (Why would L-Dopa be a bad idea?)

b. Akathesia: motor restlessness and agitation and strong feelings of distress which can be confused with agitation due to psychoses.

c. Acute Dystonia: facial grimacing due to spasms of the muscles of the tongue, face, neck and back.

d. Tardive Dyskinesia: usually late-appearing. Stereotypical involuntary movement, smacking and sucking of lips, lateral jaw movements, pushing and twisting of tongue. Persists for a long time and may persist for life even after discontinuing the drug. Associated with upregulation of D2 receptors (i.e. supersensitivity).

2. sedation: tolerance develops; more prevalent with low potency antipsychotics and is probably related to their antagonist effects as 1, AChRM and H1 receptors (see Tables1and 2)

3. anticholinergic effects: blurred vision, dry mouth, constipation and urine retention, sedation

4 1 antagonist, resulting in postural hypotension (which may lead to syncope and falls) and sedation

5. poor thermoregulation: effect on the hypothalamic thermoregulator center. Also the site of alteration in hypothalamus-dependent regulation of prolactin release from the anterior pituitary which results in hyperprolactinemia.

Study Questions

1. What is(are ) the major differences between typical antipsychotics and the atypical antipsychotics like clozapine (CLOZARIL) - particularly with regards to their interactions with neurotransmitter receptors?

2. What is the Dopamine hypothesis of schizophrenia? What is the evidence that DA plays a crucial role in the development of schizophrenia?

3. What side effects are associated with the use of typical and atypical antipsychotics? What determines which side effects appear (i.e. high vs low potency, receptor activation, etc…)

TABLE 2: Receptor-mediated side effects

TYPE SIGNS MECHANISMS

Sedation Drowsiness, lethargy a1 and H1 histamine receptor blockade

Extrapyramidal Side effects

Dystonia, akathisia, parkinsonism Tardive’s dyskinesia

D2 receptor blockade

D2 receptor upregulation

Autonomic Dry mouth, blurred vision, urine retention, constipation Orthostatic hypotenison, impotence

AChRM blockade

a1 receptor blockade

Endocrine Amenorrhea, galactorrhea, infertility,

impotence

D2 receptor blockade causing yperprolactinemia

associated with D2

receptor blockade

44

4. Describe the extrapyramidal side effects of typical antipsychotics. What property of these drugs causes these effects on muscle control and posture?

5. How are the parkinsonian symptoms associated with antipsychotic use treated? Why is the use of L-Dopa a bad idea?

45

a

b

c

Fig 1: Mechanism of SSRI action. modified from Craig and Stitzel’s Modern Pharmacology, 6th edition

MOOD (AFFECTIVE) DISORDERS MAJOR DEPRESSION AND BIPOLAR DISORDER

Mood disorders (major depression(unipolar, endogenous) and bipolar disorder (manic, manic-depression, manic-normal) are characterized by exaggerated mood associated with physiological, cognitive and psychomotor disturbances. While uni- and bipolar disorders are entities in and of themselves, they can occur secondary to medical problems (hypothyroidism), neurological disorders (PD) or as secondary effects associated with certain drugs (antihypertensive drugs like antagonists and depression; amphetamines and mania).

Causes of Affective disorders - The monoamine theory: A reduction in CNS monoamines (NE, DA, serotonin etc..., but particularly NE) results in depression, whereas an increase in CNS NE content results in mania. In fact, centrally activating drugs which inhibit NE actions can cause depression (e.g. antihypertensive) while anti-depressants seem to enhance the biological activity of monoamine neurotransmitters in the CNS. While this is an attractive hypothesis, direct evidence is limited and inconsistent.

DEPRESSION AND ANTIDEPRESSANTS: Depression is quite different from “the blues”. The symptoms include depressed mood most of the day, decreased interest and pleasure in daily activities, changes in appetite (increased or decreased), insomnia or excessive sleeping, restlessness, fatigue, feelings of worthlessness, decreased ability to concentrate, frequent thoughts of death or suicide.

All the drugs used to treat depression increase the availability of NE, DA, or serotonin (5-HT) (or a combination of neurotransmitters) Surprisingly, mood-elevating drugs do not act as CNS stimulants and they have limited effects in non-depressed persons. None of these drugs can be taken on an “as needed” basis. In the past, tricyclic antidepressants (TCADs) were the drug of choice for treatment of depression and monoamine oxidase (MAO) inhibitors were second line drugs. Recently, selective serotonin reuptake inhibitors (SSRI) like fluoxetine (PROZAC) have become the drugs of first choice. All three groups of drugs require several weeks to produce mood elevation and all should be cleared from the system before starting

a different therapeutic agent. As a rule of thumb, 5 half-lives should be allowed for a drug to clear; for an SSRI like fluoxteine (PROZAC), that could be 5 weeks!

Therapeutic Agents

1. Selective Serotonin Re-uptake Inhibitors

(SSRIs): SSRIs are the dominant therapeutic agents not because they are superior to other anti-depressants, but they are much safer and their side effects are more tolerable. In addition, lethal overdoses are rare, although suicide ideation seems a more significant problem in children and teenagers than in adults (Why do you suppose this is true?). Drugs in this class include the prototypical drug

Post-synaptic ce ll(neuron or neuroeffector)

Pre-synaptic cell(post-ganglionic fiber)

Y Y Y

Y Y

Y Y

Y Y

synapse

Re-uptaketransporter

U

Pre-synaptic2 receptor

MAOCOMT

Neuro transmitter(NE, DA, 5HT) Po

st-s

ynap

tic

rece

ptor

s

1

2

5

4

3

5

4TCADs canblock NE,DA or 5-HT

SSRIs affect onlyserotonin (5-HT)

46

a.

b.

c.

Fig 2: TCAD mechanism of action

fluoxetine (PROZAC) as well as sertraline (ZOLOFT), fluvoxamine (LUVOX), paroxetine (PAXIL) and citalopram (CELEXA).

Pharmacodynamics: SSRIs selectively bind to the 5-HT re-uptake transporter, reduce the re-uptake of 5-HT and initiate a cascade of events (Fig. 1). Normal activity (a) is inhibited when cell body 5-HT1A receptors are activated by 5-HT (b). This is a result of the increase in 5-HT levels caused by inhibition of re-uptake. Desensitization of cell body 5-HT1A receptors results in enhanced 5-HT release (c) and desensitization of the terminal 5-HT1B receptors which normally inhibit 5-HT release.

Adverse Effects: Unlike TCADs and MAO inhibitors, SSRIs have no effect on ACh RM or 1 and do not alter cardiovascular function nor cardiac conduction. They are initially mood-elevating and may cause anxiety. Nevertheless, it still takes several weeks to achieve therapeutic effects. Common side effects include nausea and vomiting, headache and fully ½ of those taking SSRIs may complain of sexual dysfunction. The major differences between SSRIs are their durations of action, their rates of elimination half-lives, the production of active metabolites, the intensity of their side effects and potential to cause extrapyramidal side effects.

2. Tricyclic Antidepressants (TCADs): Their name comes from their chemical structure. TCADs have significant side effects and overdoses can be lethal; thus doses should be limited to the depressed with suicidal thoughts. Prototypical drugs are imipramine (TOFRANIL) and amitriptyline (ELAVIL).

Pharmacodynamics (Fig 2): Normal activity (A) is altered by TCADs which inhibit the re-uptake of NE and allow NE to accumulate at the synapse (B). This leads to the desensitization of presysnaptic 2 receptors, preventing their inhibitory effect on NE release. This leads to a further increase in NE release and the desensitization of postsynaptic receptors (C) with no change in post-synaptic 1 receptors. TCADs also have effects on 5-HT neurotransmission, with TCAD use increasing the number of post-synaptic 5-HT1A receptors. This time-dependent increase in receptor upregulation parallels the time to onset of drug action.

Adverse Effects: postural hypotension (1), anti-muscarinic, sedation and weight gain (H1 receptor antagonists), heart block as a result of slowed conduction velocity, arrhythmia, seizures, extrapyramidal effects, potentiate effects of NE and EPI and block the effects of indirect-acting adrenergic agonists.

3. Monoamine Oxidase Inhibitors: The use of these drugs have largely been supplanted by the TCADs because MAO-I have complex and sometimes severe interactions with other drugs and food-derived amines. They are generally reserved for treatment of depression resistant to treatment with SSRIs. Pharmacodynamics: MAO-I like phenelzine (NARDIL) irreversibly inhibit the action of monoamine

oxidase A and B allowing levels of catecholamines to rise. While both MAO-A and MAO-B are affected, the antidepressant effects seem related to the inhibition of MAO-A. Inhibition of MAO at NE or 5-HT synapses or both appears responsible for the actions of these drugs. Complete inhibition of MAO occurs within several days, but the effects on mood take several weeks. Thus it seems unlikely that inhibition of NE and 5-HT breakdown is the sole effect of these drugs. Like TCADs and SSRIs, there appear to be adaptive changes in NE and 5-HT synapses. 2 and receptors downregulate at NE synapses without affecting 1 postsynaptic receptors while 5-HT1A receptors upregulate at 5-HT synapses, similar to the responses seen with SSRIs.

Adverse Effects: Two life-threatening forms of toxicity are associated with their chronic use and limit their usefulness: 1) hepatoxicity (due to biotransformation products) and 2) dietary tyramine-induced hypertensive crises (associated with ingesting foods containing like cheeses and red wines which contain tyramine. These compounds are usually rapidly metabolized in the gut). These drugs also have serious drug interactions with OTC cold medications containing sympathomimetic anmines (e.g. pseudoephedrine, phenylepherine, etc… Co-administration of MAOI and SSRIs can lead to overstimulation of 5-HT receptors in the brainstem (remember, both upregulate post-synaptic 5-HT1A receptors).

MANIA AND BIPOLAR DISORDER: Mania is marked by expansive mood, dysphoria, severe insomnia, rapid speech, delusions of grandeur, impaired judgment, inflated self-esteem, self-destructive

47

behavior (e.g. promiscuous sex, reckless driving, spending sprees). Manic episodes typically emerge over days-weeks, but onset within hours is possible. An untreated episode of either depression or mania can last several weeks or many months. Rapid cycling occurs when patients have four or more episodes of either depression or mania in a given year. There is evidence for genetic predisposition but the underlying mechanism(s) are not clear. Cellular models of changes in membrane Na+/K+-ATPase (Na+-pump) and dysfunctional signal transduction via phospholipase C (PLC) and G proteins may be involved. This latter suggestion is consistent with the ability of lithium to control the manic phase of bipolar disorder as it interferes with receptor-G protein interactions and with second messenger production by phospholipase C (PLC) (see fig. 3).

Therapeutic Agents

1. Lithium Carbonate: Lithium is a monovalent cation which has FDA approval for the treatment of the manic phase of manic-depression, but is also used to treat cluster headaches and aggression.

Pharmacodynamics: Lithium enters nerves tissues with Na+ but can't be pumped out by Na/K ATPase and nerves cannot maintain membrane potential. While this clearly happens in response to Li, it cannot be the underlying mechanism of action as there would be no selectivity in the response. It is more likely that Li’s ability to interfere with receptor-G protein interactions and the production of PLC-generated second messengers mediate its effects on mania. Since several neurotransmitter receptors share common G protein-coupled signal transduction pathways, Li could alter the activities of several neurotransmitters at one time.

Adverse Effects: Lithium has a very low therapeutic index (2-3), thus plasma concentrations must be monitored to facilitate safe use. There is no specific antidote and toxicity is dose-dependent; treatment of toxicity is supportive and includes dialysis, diuretics, i.v. sodium bicarbonate. It is excreted unchanged by the kidney and since it competes with Na+ for many transport mechanisms, careful control of dietary Na+ intake is required. Like Na+, Li is freely filtered and actively reabsorbed in the proximal tubule at sites where Na+ is reabsorbed. Thus Na+ loading can increase Li excretion while Na+ depletion causes Li retention. There is a 1-3 week lag time before effects appear. It can cause transient increases in urine K, Na, water and 17 hydroxycorticosteroids. Typical side effects of high Li levels include polydipsia (increased water intake; increased drinking) and polyuria (frequent urination) as well as hypothyroidism (which can cause depression). Toxicity is indicated by mental confusion, gross tremors and seizures progressing to coma and death. It is potentially teratogenic (causing cardiovascular anomalies) and its use during pregnancy must be carefully considered.

2. Others: Other drugs used for treatment of bipolar disorder include the anticonvulsants carbamazepine (TEGRETOL)--chemically similar to TCAD, clonazepam (KLONOPIN) and valproic acid (DEPAKENE)--may be best alternative for those who cannot tolerate Li

Study Questions

1. How do TCADs relieve depression? What are their pharmacological actions? What are their side effects? What are their effects on non-depressed individuals?

2. How do SSRI relieve depression? What are their pharmacological actions? What are their side effects? Do they affect non-depressed persons?

3. How do MAO inhibitors relieve depression? What are their pharmacological actions? What are their side effects? Do they affect non-depressed persons?

4. How does lithium relieve mania? What are its side effects? How safe is it to use?

48

RENAL SYSTEM OVERVIEW

Nephrons, the individual filtering units of the kidney, consist of a glomerulus and a tubular system. The glomerulus consists of a tuft of capillaries which lies in close proximity to Bowman’s capsule. The capillaries are supplied by an afferent arteriole and drained by an efferent arteriole. In the kidneys, filtration of blood at the glomerulus produces a fluid that is basically a protein- and cell-free plasma (filtrate). Filtration occurs as a result of pressure generated by the heart and constriction of efferent arterioles. GFR is reported in volume or mass/time. The glomerular membrane does not filter proteins larger than 100 Å (10 nm; 0.00001 mm) otherwise, the glomerular filtrate is almost same as plasma. As the filtrate passes through the nephron, its composition is modified and its volume is reduced by tubular reabsorption and tubular secretion. Tubular reabsorption can be passive or active. For example Na+ is actively reabsorbed in the proximal tubule, followed passively by Cl and H2O. Active transport processes express a tubular transport maximum, the maximum rate at which a transport mechanism can function. If the tubular load exceeds the transport maximum, the excess will appear in the urine. e.g. Tm glucose = 320 mg/min; if FL > 320 mg/min, excess appears in urine. Tubular secretion involves the movement of a substance from the blood into the urine. It allows for more of a substance to be excreted in the urine than is filtered at the glomerulus and is an important way for excreting foreign substances. Specific transport mechanisms exist for organic acids like PAH (aspirin, penicillin and diuretics can be transported on these) and organic bases like ammonia (NH4

+) (amphetamines are transported on these proteins).

Regulation of renal blood flow (RBF) is important in filtration and in the final composition of the urine: Norepinephrine constricts the renal vessels, while dopamine made in the kidney causes renal vasodilation and natriuresis. Angiotensin II (Ang II) is a potent and effective vasoconstrictor which has greater effects on the efferent than the afferent arterioles. Renin, which is made in the kidney, is responsible for the periperhal conversion of angiotensinogen (which is inactive) to angiotensin I (Ang I). Ang I is then converted to Ang II via the action of angiotensin converting enzyme (ACE). When the kidney is perfused at moderate pressures, the renal vascular resistance varies with the pressure so that renal blood flow is relatively constant

Na+ and Cl- reabsorption play major roles in body electrolyte and water metabolism. In addition, the Na+

gradient generated by the activity of the Na+/K+-ATPase (i.e. the Na+ pump) is used to drive the movement of H+, phosphate, Ca2+, glucose, amino acids, organic acids, bicarbonate and other substances across the tubule walls (secondary active transport).

Transport along the nephron

1. Proximal Tubule While a number of substances are actively transported out of the proximal tubular fluid, the fluid is essentially isosmotic to the end of the proximal tubule and water moves passively out of the tubule along the osmotic gradients set up by active transport of solutes. 60-70% of the filtered solute and filtered water are removed by the end of the proximal tubule.

1

2

Tubule

SOLUTE

reabsorption

secretion

Na KCl

reabsorption secretion

1. Cross-section of a tubule. Reabsorption removes solutes (I.e. Na, K, Cl, etc…) from the tubular fluid through tubular cells and back into the blood. Secretion removes toxins, metabolic by-products from the blood and ads them directly to the tubular fluid2. Close-up of renal tubular cells

transporters

blood vessels

49

2. The loop of Henle: The urine is concentrated in the Loop of Henle through changes in membrane permeability and by the activity of the Na+/K+/2Cl cotransporter. The descending limb of the loop of Henle is permeable to water, but the ascending limb is not. When Na+, K+, and Cl- are cotransported out of the thick segment of the ascending limb by the Na+/K+/2Cl cotransporter, water moves into the hypertonic interstitium. Thus, fluid in descending limb of the loop of Henle becomes hypertonic and that in the ascending limb becomes more dilute. In passing through the loop of Henle, another 15% of the filtered water is removed.

3. Distal Tubule: the early distal tubule is an extension of the thick segment of the ascending limb and is relatively impermeable to water. Continued removal of solute by the Na+/Cl- cotransporter further dilutes the tubular fluid. About 5% of the filtered water is removed in this segment. In the late distal tubule ~ 5% of the remaining Na+ is reabsorbed and K+ and H+ are secreted. These processes are under the control of the mineralocorticoid steroid hormone aldosterone.

4. Collecting Ducts: The changes in osmolality and volume of the tubular fluid in the collecting ducts

are controlled by vasopressin (AVP) also known as antiduretic hormone (ADH). AVP increases the permeability of the collecting ducts to water by inserting water channels (aquaporin-2) into the membrane. In the presence of AVP, water moves out of the hypotonic fluid entering the cortical collecting ducts and into the interstitium of the cortex. In times of dehydration, AVP secretion increases, water is conserved and a concentrated urine is excreted. When vasopressin is absent, the collecting duct epithelium is relatively impermeable to water and a dilute urine is excreted

CARDIOVASCULAR SYSTEM OVERVIEW

Although the heart is a pump, it would be better described as TWO pumps. The right pump is a low pressure system delivering deoxygenated blood to the lungs via the pulmonary artery. The left heart is a high pressure system delivering blood systemically through the aorta. Drugs used to modify cardiac performance work primarily in 3 tissues: 1) the cardiac muscle (myocardium), 2) the conduction system (SA and AV nodes, bundles of His and Purkinje fibers) and the coronary blood vessels.

1. CARDIAC MUSCLE (myocardium): under normal circumstances, the heart can adapt its performance to meet the demands. Normally, the greater the length of the muscle fibers, the greater the force of contraction (within limits). This is called Frank-Starling's Law of the Heart. The overall process for controlling cardiac muscle contraction involves electrical excitation, mechanical activation and contractile mechanisms.

50

1 2

3 4

Figure 2: conduction system

a. regulation of contraction: Contraction begins with a rapid change in membrane potential (electrical current) which spreads inside the cell due to movement of Na+, K+, Ca2+. This, in turn, causes the release of Ca2+ from the SARCOPLASMIC RETICULUM producing contraction (excitation-contraction coupling). Ca2+ is the primary component coupling excitation of the action potential with contraction of the myofibrils (couples electrical and mechanical activity.

1. contractile mechanism- Ca2+ causes the interaction of actin and myosin filaments, producing contraction (systole). 2. relaxation: depends on the removal of Ca2+ from the muscle fibers back into the sarcoplasmic reticulum by the Ca2+ pump (Ca2+ ATPase)

b. cardiac action potential: Resting potential is approximately -90mV. The membrane slowly depolarizes (4) until threshold is reached, producing a rapid depolarization due to the fast

inward movement of Na+ and an action potential (0) is generated. A peak depolarization is achieved (1) and slow repolarization begins due to the slow influx of Ca2+ (2) and the efflux of K+ (3). A rapid efflux of K+ produces a rapid repolarization due to the active transport of Na+ out of the cell and K+

into the cell using the Na/K-ATPase (Na pump) (figure 1).2. CARDIAC CONDUCTION SYSTEM: Action potentials travel from the SA node (pacemaker), down

the internodal pathways to the AV node and bundle of His (AV junction), to the right and left bundle branches and down the Purkinje fibers, which end in myocardial cells (Figure 2). There are several importance

characteristics of the conduction system including:a. Automaticity: The ability to spontaneously initiate an

electrical impulse without external stimuli. The pacemaker is the SA node because it has the highest frequency of depolarization, producing the greatest number of action potentials/time. Phase 4 depolarization is referred to as the pacemaker potential. Rate of depolarization then determines when APs are fired and when heart beats. Under normal circumstances, there is only 1 pacemaker.b. Conductivity: The ability to transmit an action potential

from cell to cell, including the myocardial cells. Slow velocity in AV node allows ventricular filling. Fast velocity through Purkinje fibers allows for coordinated contraction of ventricles.c. Refractoriness: Inability to respond to a stimulus.

Consists of the 1) ERP--effective or absolute refractory period which is that period of the cardiac cycle when a stimulus, no matter how strong, cannot produce an action potential and 2).relative refractory period which is that period of the cardiac cycle when a larger than normal

stimulus produces a smaller response than normal-premature contraction

figure 1: cardiac AP

51

3. CORONARY VESSELS-right and left coronary artery supply the entire myocardium with O2 and coronary artery disease causes ischemia. These are the vessels "by-passed" in bypass surgery.

CARDIAC PERFORMANCE IS A FUNCTION OF FOUR FACTORS

1. PRELOAD: blood volume returned to the heart (venous return or the amount of blood in the heart before it pumps)

2. AFTERLOAD: resistance that must be overcome to open aortic valve and pump blood out of the heart. Also resistance to flow in the arteries (i.e. peripheral vascular resistance –PVR)

3. CONTRACTILITY: vigor of heart muscle contraction. Related to elasticity of each muscle fiber. The primary defect in Cogestive Heart Failure (CHF).

4. HEART RATE: the major determinant of cardiac output (C.O). A decrease in heart function results in a decrease in stroke volume. This is perceived as a decrease in blood pressure, and the reflex response to a drop in blood pressure is a reflex tachycardia.

.

.

Study Questions:

1. Define filtration. What determines if a molecule is filtered? What regulates glomerular filtration rate (GFR)?

2. Define reabsorption. Where is most of the solute and water reabsorbed? What is a tubular transport maximum (Tm)?

3. Define secretion. Why is secretion important in urine production?4. What transport events are occurring in the proximal tubule? The loop of Henle? The distal tubule and

collecting ducts?5. What are angiotensin II and AVP? What role do they play in controlling the final composition of the

urine?6. Describe the events at each phase of the cardiac action potential. 7. What is meant by the term “excitation-contraction coupling”?8. Define automaticity, conductivity and refractoriness (including effective and relative refractory periods).9. What 4 factors determine cardiac performance?

52

RENAL PHARMACOLOGY: DIURETICS

About 120ml/min of filtrate is formed by the nephron but only 1 ml/min of urine is produced. Thus >99% of the glomerular filtrate is reabsorbed - ~65% in the proximal tubule and ~25 % in the Loop of Henle. Diuretics are drugs which aid in the removal of excess fluid and electrolytes by decreasing the reabsorption of salt and water and/or increasing the glomerular filtration rate. The therapeutic actions of diuretics are closely associated with changes in renal electrolyte reabsorption or secretory capacity. These drugs are used to adjust volume and/or composition of the body fluids as a means of treating hypertension, heart failure, renal failure and cirrhosis.

Figure 1a shows, in general, how diuretics enhance salt and water excretion. Diuretics (blue triangles) interact with transporters (green circles) and prevent them from transporting solutes into and across cells and finally into the blood. When solutes are retained in the tubular fluid, water is also retained. Together, this leads to an increase in the salt content of the urine and in the amount of water excreted.

1. PROXIMAL TUBULE DIURETICS: The proximal tubule reabsorbs 60-70% of the filtered solute and a similar amount of the filtered water. Although this would seem to suggest that drugs altering solute reabsorption here would be extremely effective diuretics, in reality, Na+ rejected here is simply reabsorbed in the Loop of Henle and the distal tubule. Thus these diuretics have limited usefulness in mobilizing Na+ and water..

Pharmacodynamics: The Na gradient generated by the Na pump (on the blood or basaolateral side of the cell) drives Na/H exchange on the luminal side of the proximal tubule (1). Catalyzed by carbonic anhydrase (CA) H+ reacts with HCO3

- in the lumen producing H2CO3 (2; carbonic acid) which breaks down into CO2 and H2O (3). CO2 enters the cell and recombines with H2O (4) catalyzed by CA. which subsequently dissociates into HCO3

- (5a) and H+ (5b). The net effect is reabsorption of Na+ and HCO3

-. By inhibiting CA, proximal tubule diuretics inhibit the formation of carbonic acid. HCO3

- is retained in the proximal tubule accompanied by Na+

transporter

solutes

diuretic

Figure 1: General mechanism of action (A) and (B) types and sites diuretic action.

A B

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and water follows Na+. Na+/H+ exchange is also inhibited. Altogether, this results in increased urine HCO3 (and urine pH), decreased Na+ reabsorption and an osmotic diuresis.

Therapeutic Uses: Drugs like acetazolamide (DIAMOX) are of limited value therapeutically. However, they are used to 1) treat glaucoma (decreases the formation of the aqueous humor which has a high content of HCO3

-) 2) alkalinize the urine to increase excretion of acidic drugs and 3) treat altitude sickness by shortening the period of high altitude acclimatization; by decreasing the conversion of CO2 to HCO3 it may increase CO2 tension in the tissues and stimulate respiration due to the reflex response to hypoxia.

2. LOOP (HIGH CEILING) DIURETICS: Urine is concentrated in the loop of Henle through changes in membrane permeability and by activity of the Na+/K+/2Cl-

cotransporter. The descending limb of the loop is permeable to water but the ascending limb is not. When Na+, K+, and Cl- are cotransported out of the thick segment of the ascending limb by the Na+/K+/2Cl cotransporter, water moves into the hypertonic interstitium. 25% of the filtered Na+ is reabsorbed here and the amount increases with increases in Na delivery. Fluid in descending limb of the loop of Henle becomes hypertonic and that in the ascending limb becomes more dilute. In passing through the loop of Henle, another 15% of the filtered water is removed.

Pharmacodynamics (Mechanism of Action): The peak diuresis produced by these drugs (e.g. furosemide, [LASIX]) is much greater than that observed with other agents They inhibit the Na+/K+/2Cl-

exchanger in the thick ascending limb of the loop of Henle, resulting in an inhibition of Na+ reabsorption and an increase in Na+ excretion. Even though Na can be reabsorbed in the distal tubule, the amount of Na present in the tubule of persons diuresed with loop diuretics is much greater than the Na transporter capacity in the distal tubule. Therefore lots of Na is excreted accompanied by Cl and water. These drugs thus interfere with the concentrating ability of the loop of Henle. They are HIGH CEILING diuretics since increasing doses continue to increase the diuretic effect and can give a response in patients even if they are maximally diuresed with another drug. This is due to the ability of loop diuretics to inhibit the large Na+ Cl- absorptive capacity of the loop. Loop diuretics are highly protein bound, but must be in the tubular fluid to work. They gain access via the organic acid secretory pathway. 3. DILUTING SEGMENT (THIAZIDE) DIURETICS: The early distal tubule is an extension of the thick segment of the ascending limb and is relatively impermeable to water. Continued removal of solute by the Na+/Cl- cotransporter further dilutes the tubular fluid. About 5% of the filtered water is removed in this segment. In the late distal tubule ~ 5% of the remaining Na+ is reabsorbed and K+ and H+ are secreted. Increased Na+ delivery to the distal tubule enhances K+ secretion. Na+ reabsorption and K+ secretion are regulated by the mineralocorticoid steroid hormone aldosterone.

USESDIURETIC

LOOP DILUTING SEGMENTAcute pulmonary edema Yes PossiblyHeart failure with edema Yes Yes (preferred)Hypertension Yes Yes (preferred)Cirrhosis with ascites Yes Yes

SIDE EFFECTSHyponatremia, hypokalemia, hypovolemia, hypotension Yes; hypovolemia can be severe yesHyperuricemia, hyperlipidemia Yes YesOtotoxic, hypercalciuria Yes Nohypercalcemia No Yes

Pharmacodynamics: Inhibit electroneutral Na+/Cl- cotransport in the diluting segment of the distal tubule. They are less effective than loop diuretics because > 90% of the tubular fluid content of Na+ is reabsorbed in the Loop of Henle before reaching the site where these diuretics work. They increase Na +, and Cl- excretion. The increased delivery of Na+ to the late distal tubule increases K+ secretion and can result in

54

hypokalemia. These drugs must be in the tubular fluid in order to work and gain access by occupying the organic acid secretory transporter in the proximal tubule.

4. POTASSIUM-SPARING DIURETICS: The hypokalemia caused by both Loop and Diluting segment diuretics can be controlled by 1) limiting the dose of the diuretic or 2) administering K+ sparing diuretics. The K+ “wasting” that occurs in response to Loop and Diluting segment diuretics is a direct result of the increased delivery of Na+ to the distal tubule causing increased K+ secretion. In addition, Na+ reabsorption and K+ secretion are stimulated by the mineralo-corticoid steroid hormone aldosterone. Thus, K+ sparing diuretics are used to avoid K+ wasting (i.e. hypokalemia/hyperkaliuria). These are weak diuretics acting at the distal tubule and there are two types: 1) those that act as Na+ channel blockers (e.g. amiloride[MIDAMOR]) and 2) aldosterone receptor antagonists (e.g. spironolactone [ALDACTONE]).

a) Na channel blockers. By preventing Na entry into the distal tubule, they prevent the increase in K+

secretion that occurs when loop diuretics and distal tubule diuretics increase the Na concentration in the tubular fluid. These drugs are seldom used alone but rather are given as adjuncts with other antidiuretics. In fact, fixed dose mixtures of diluting segment diuretics and non-steroidal K+ sparing diuretics are available. Their site of action is the late distal tubule where they increase Na+ and Cl- excretion, with little change in K+. They block Na+ reabsorption by blocking Na+ channel activity which in turn prevents K+ secretion. When K+

excretion is high, they markedly decrease urine K+ excretion by inhibiting electrogenic Na+ entry, decreasing the potential difference across the renal tubular epithelium. The secretion of K+ decreases due to the loss of the Na+ driving force and K+ is conserved. They also inhibit Na+/H+ exchange, increasing urine pH. Both diuretics can cause hyperkalemia, therefore it is necessary to reduce K+ intake and serum electrolytes should be monitored. Also increase plasma K+ when administered with other K+-sparing diuretics, ACE inhibitors, K+

supplements, K+-containing medications (e.g. penicillin G) or salt substitutes.b) aldosterone antagonists: [e.g. spironolactone (ALDACTONE)] Aldosterone is a steroid hormone

(mineralocorticoid) which enhances distal tubule Na and water reabsorption and stimulates K secretion. Spironolactone blocks aldosterone-induced reabsorption of Na+ and the secretion of K+. Its effects are proportional to the concentration of aldosterone in the circulation

5. OSMOTIC DIURETICS Osmotic work throughout the nephron, but have prominent effects in the proximal tubule where 60-70% of solute and water are removed. They produce their effects by causing osmotic retention of water rather than inhibiting transport function. Osmotic diuretics (e.g. mannitol [OSMITROL]) are freely filtered but are neither reabsorbed nor secreted. They increase the tonicity of the tubular fluid, hindering tubular reabsorption of solutes and H2O, promoting excretion of H2O, Na, K, Cl-, PO4

2-, Mg2+ and uric acid. Also increase blood tonicity, promoting shift of intracellular H2O into blood. The degree of diuresis is proportional to the quantity of diuretic administered. Over-expansion of the vascular compartment can result in pulmonary edema. Therapeutic Uses: 1) maintain kidney function and urine flow rate during hypotension (increased volume results in increased blood pressure which in turn increases the glomerular filtration rate). Sufficient amounts are filtered at reduced GFRs to exert an osmotic effect in the tubules and continue urine formation, 2) treat cerebral edema by increasing plasma tonicity with draws water out of the CSF decreasing pressure and 3) control intraocular pressure during acute glaucoma attacks

Adverse Responses: Too rapid an administration may result in an excessive shift of fluid from the intra- to the extracellular compartment and cause congestive heart failure.

Study Questions:

1. For each of the classes of diuretic (proximal tubule diuretics, distal tubule diuretics, loop diuretics, K sparing diuretics and osmotic diuretics) describe their mechanisms of action, their therapeutic uses and their side effects.

2. Why are loop diuretics more effective at enhancing salt and water excretion than distal tubule diuretics?

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TREATMENT OF HEART FAILURE

Heart failure occurs when the heart cannot pump enough blood to meet the oxygen demands of the heart muscle. Cardiac output (C.O.) is reduced as is myocardial contractility. These changes cause reflex increases in cardiac pre- and afterload in an attempt to compensate for the decrease in output. The net result is that CO is insufficient to meet O2 demands of the body. Treatment of heart failure is targeted to increasing contractility, decreasing preload and/or decreasing afterload.

REMEMBER: Cardiac performance is a function of four factors

1. PRELOAD: blood volume returned to the heart (venous return or the amount of blood in the heart before it pumps)

2. AFTERLOAD:resistance that must be overcome to open aortic valve and pump blood out of the heart. Also resistance to flow in the arteries (i.e. peripheral vascular resistance –PVR)

3. CONTRACTILITY: vigor of heart muscle contraction. The primary defect in congestive heart failure (CHF).

4. HEART RATE: the major determinant of C.O. A decrease in heart function results in a decrease in stroke volume. This is perceived as a decrease

in blood pressure, and the reflex response to a drop in blood pressure is a reflex tachycardia.

DEFECTS IN CHF

COMPENSATORY RESPONSES

SIGNS/SYMPTOMSDRUG

INTERVENTION

Decreased contractility

decreased cardiac output

Reflex increase in SNS tone

Tachycardia

Increased PVR

Attempts to increase contractility

Digitalis glycosides (1 antagonist)

Nitrovasodilators and ACE inhibitors

Digitalis glycoside and 2 agonists

Activation of RAAP

Salt and water retention peripheral/pulmonary edema

Increased vascular toneIncreased blood volume Increased venous return

Diuretics and ACE -I

Nitrovasodilators and ACE-I

Diuretics and ACE-IISSUES WITH CHF: The decrease in contractility and cardiac output (C.O.) causes an initial increase in heart rate (tachycardia). The initial response to a decreased C.O. is an increase in heart-rate. In addition, since the decrease in C.O. is perceived as a drop in blood pressure, the renin-angiotensin-aldosterine pathway (RAAP) is activated leading to salt and water retention (due to aldosterone) and increased PVR (Ang II) in an attempt to increase blood pressure. Blood backs up into capacitance vessels (veins) and there is an increase in intracapillary pressure which results in the movement of fluids into the extravascular space (edema). The end result is peripheral and pulmonary edema. The increase in venous return is greater than the ability of the heart to pump. Thus some blood remains in the chamber with each stroke. This stretches cardiac muscle and ultimately the heart is stretched beyond mechanical limits resulting in a decrease in the strength of contraction. The increased volume coupled with reduced CO results in enlargement of the heart. The combination of all of these problems leads to inadequate blood oxygenation due to decreased lung perfusion resulting in decreases in exercise tolerance and shortness of breath as well as cyanosis

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Three basic goals in treating heart failure1. Increase contractility--positive inotropic agents like cardiac glycosides, agonists 2. reduce afterload—vasodilators like nitroprusside and ACE inhibitors3. reduce preload—diuretics and ACE inhibitors

1. INCREASING CONTRACTILITY: Positive inotropic drugs increase the force of cardiac contraction and include a) digitalis glycosides and b) agonistsa) AGONISTS (dobutamine and dopamine) - + inotropic agents that provide short-term

support to the failing heart. b) Digitalis glycosides are steroid-like molecules with sugar moieties. These drugs (e.g. digoxin

(LANOXIN) and digitoxin (CRYSTODIGIN)) have complex actions on the mechanical and electrical functions of the heart. The effects of both are dose-related and include direct and indirect actions.

direct actions on the heart (inhibits the Na+/K+-ATPase): The Na pump maintains [Na] high outside the cell and low inside the cell. Because [Na] is high outside, it will diffuse into the cells. When Na outside binds to the Na/Ca exchanger, Na movement into the cell drives Ca out of the cell. When cardiac glycosides bind to the Na pump (1), Na can’t be pumped out of the cell and gradually the [Na] inside = the [Na] outside and Na no longer diffuses into the cell (2). If Na doesn’t diffuse into the cell, Ca can’t leave the cell and the [Ca] inside the cell increases (3) . The increase in Ca allows more actin and myosin cross bridges to form and the force of muscle contraction increases (4). Thus, the increases in contractility increase C.O., which causes a decrease in SNS tone and leads to decreased heart rate and PVR, reduces activity of RAAP, increases renal blood flow causing increased GFR, decreasing blood volume and resolving edema.

indirect actions on cardiac function: parasympathomimetic at low doses (vagal enhancement), sensitizes SA node to effects of ACh and slows AV conduction velocity. These actions are useful in CHF but also in atrial fibrillation (randomized contractions of the atria, producing an irregular and often rapid ventricular rate; tachyarrhythmias) where digitalis glycosides do not halt atrial fibrillations, but rather prevent passage of supraventricular arrhythmias to the ventricles by decreasing AV conduction velocity, increasing ERP in ventricles, and slowing ventricular rate In order for digitalis glycosides to work, the body’s reservoir for the drug must be loaded. The Na+ pump is in many places in the body, but especially skeletal which serves as a large reservoir. Therefore, people must receive sufficient doses of digitalis glycosides to make the signs and symptoms of heart failure disappear. This process is termed digitalization. It takes 3-4.5 half-lives to produce saturation; for digoxin this takes 1-2 days and for digitoxin ~ 1 month. Patients receive an initial loading (digitalizing) dose to rapidly increase blood levels followed by a maintenance dose which replaces the daily loss of drug. Since the therapeutic index is quite low for both drugs, slow digitalization would be safer but if time is of the essence, rapid digitalization can be performed in the hospital.

Digitalis Toxicity: These drugs have low therapeutic indices (1.6 - 2.5) and toxic reactions are frequent. Thus toxicities are well-known and easily predictable. 1. predisposing factors: hypokalemia, hypercalcemia, kidney, liver and heart disease. The most

common is the concurrent use of K+ wasting diuretics (diluting segment and loop diuretics).2. cardiac dysrhythmias including PVC, bigeminy, fibrillations and complete SA and AV block.

Treated with antiarrhythmic drugs and K+ to decrease glycoside binding to the heart.3. disturbances in color vision (green/yellow images), flashing lights, blind spots and double vision

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4. anorexia, nausea, vomiting (CNS- and GI-mediated), polyuria, diarrhea5. severe OD can inhibit Na/K-ATPase throughout the body resulting in a progressive increase in

plasma K. Severe ODs are treated with digoxin immune FAb (DIGIBIND) 2. REDUCING PRELOAD with diuretics: In the failing heart, the reduction in contractility causes

reflex increases in heart rate and Na and water retention. The increase in Na and water retention results in volume expansion, increased preload, increased stretch of the ventricles. The use of diuretics can reduce blood volume and thus preload. The use of diuretics is reserved for those with advanced disease since chronic use of diuretics is problematic. Thiazide (diluting segment) diuretics are used for mild heart failure, loop diuretics where more rapid and effective reductions in blood volume are required and K sparing diuretics are used in combination with loop or diluting segment diuretics.

3. REDUCING AFTERLOAD with vasodilators: Increases in SNS tone accompany heart failure as the body tries to compensate for the reduction in contractility. The increase in SNS not only increases heart rate and activation of the renin-angiotensin-aldosterone system, it also causes increases in afterload (PVR). Vasodilators can be used to reverse the vasoconstriction due to long-term SNS stimulation common in congestive heart failure..

a). Angiotensin Converting Enzyme (ACE) Inhibitors: ACE is activated by renin and catalyzes the conversion of inactive angiotensinogen to angiotenin I and then angiotensin II. Angiotensin II is a very potent vasoconstrictor which acts on both arteries (inc. PVR) and veins (preload). In addition, angiotensin II stimulates the production of the hormone aldosterone. Aldosterone increases Na+ and water reabsorption from the distal nephron and increases in aldosterone-mediated Na+ and water reabsorption can increase blood volume and preload. ACE inhibitors can thus decrease preload and afterload.

b). Nitrovasodilators: dilate both arteries and veins thus decreasing both preload and afterload.

Study Questions:

1. What 4 factors determine cardiac performance?2. What are the signs and symptoms of heart failure? What compensatory mechanisms are activated in response to heart failure?3. What are the therapeutic goals in treating heart failure? What drugs are used to achieve these goals?4. How do cardiac glycosides increase cardiac contractility? How does this relieve the signs and symptoms of heart failure?5. Define the process of digitalization. 6. What toxicities are associated with the use of cardiac glycosides? How are these symptoms treated?

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ANTIARRHYTHMIC DRUGS

CARDIAC ARRHYTHMIAS are any deviation from the normal rhythm of the heart beat by modification of the electrophysiological properties of the conducting system or the cardiac muscle cells. Cardiac rhythm can be affected by acute ischemia (oxygen deprivation), SNS stimulation and myocardial scarring. Several types of disorders in cardiac electrophysiology lead to arrhythmias including:

1. changes in automaticity: overstimulation by the SNS can result in shortening of phase 4 of thecardiac action potential and a lowering of the threshold of atrial and ventricular cells and Purkinje fibersresulting in more rapid spontaneous firing. Thus, enhanced automaticity in normal pacemaker cells or the appearance of latent pacemakers elsewhere in the heart can result in tachyarrhythmias.

2. changes in conductivity: damage to the heart may result in failure to conduct the action potential causing premature contractions and/or missed beats. The most common cause of PSVTs is AV nodal re-entry. SA nodal re-entry can also result in tachyarrhythmias.REENTRY PHENOMENON: one impulse re-enters and excites the heart more than once. In order for this to happen, the following must occur.

1. normal conduction must be slowed and/or the effective refractory period must be shortened2. there must be an "obstacle" to conduction which can provide a circuit around which the re-

entrant impulse can travel3. there must be a unidirectional block; i.e. impulse propagation should be blocked only in

one pathway, and conduction velocity must be reduced in another region of the heart The re-entrant impulse can be abolished by changing 1) conduction velocity or 2) refractory periods.

myocardium

Purkinje fiber

1 2

Purkinje fiber

1

2

Uni-directionalblock

Re-entry

NORMAL - in normal fibers, the impulsestraveling in branches 1 and 2 travel both leftand right in the myocardium. The impulses extinguish when they meet.

Impulsesextinguish

INJURED - injury in branch 2 results in adecrease in resting potential, the impulseconducts slowly and decrementally and isfinally blocked in the injured area. Thus theimpulse in branch 1 is not extinguished andcan travel backwards (re-entering) throughbranch 1 and exciting the myocardium.

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Effects of group II drugsEffects of group I drugs

Effects of group III drugs

Antiarrhythmic drug therapy has two goals: (1) termination of on-going arrhythmias and (2) prevention of recurrence. Unfortunately, anti-arrhythmic drugs can cause arrhythmias especially with long-term therapy. Thus treatment of arrhythmia should have the following goals:

1. identify and remove the precipitating causes (e.g. electrolyte imbalances, myocardial infarctions and some drugs)

2. set treatment goals: a. some arrhythmias should not be treatedb. initiate drug therapy only when there is some clear benefitc. some arrhythmias are asymptomatic

3. choose a therapy based on symptoms and type/extent of heart damage4. minimize the risks by monitoring drug concentrations and designing patient-specific therapy

Antiarrhythmic drugs are grouped according to their similarity of action and the part of the cardiac cycle they effect, not their chemical relatedness.

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GROUP EFFECT CHANGES IN CARDIAC ACTION POTENTIAL

1A

Na+ channel blockers

Prolong phase 0, decreases rate phase 4 depolarization, prolongs ERP and duration of the AP

1B Shorten ERP and the duration of the AP

1CMarkedly reduce phase 0 and profoundly slow conduction velocity

II antagonists Decrease phase 4 depolarization, decrease SA and AVC node

conduction velocity, prolongs the ERP

IIIMost are K+ channel

blockersMarkedly prolong phase 3 repolarization and thus AP duration

IVCa2+ channel

blockers

Slow Ca2+ entry during phase 2, slow conduction velocity at the AV node, thus reducing conduction of supra-ventricular arrhythmias, lengthen ERP of the AV node

Study Questions:

1. What can cause arrhythmias?2. What are the goals of antiarrhythmic drug therapy? Describe how groups I, II, III and IV antiarrhythmic drugs control arrhythmias (i.e. what phase of the cardiac

do they affect?).

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ANTIHYPERTENSIVES

HYPERTENSION is a sustained elevation in blood pressure which can cause vessel damage in the kidney (resulting in kidney failure), the heart (coronary artery disease and dissecting aortic aneurysms) and the brain (resulting in stroke). Hypertension is defined as a resting blood pressure of > 140 systolic or > 90 diastolic. Treatment continues to change with new drugs and the prevalence of non-pharmacological intervention. Even when drugs are individualized, responses vary. Hypertension is classified as 1) essential (cause unknown (~ 90%) or 2) secondary as the result of a disease state (toxemia, pheochromocytoma and renal artery disease ~ 10%). The major factors regulating blood pressure include: 1) body salt and water content controlled by the renin-antiotensin- aldosterone pathway (RAAP), 2) cardiac output and 3) peripheral vascular resistance (PVR). The figure below illustrates sites of drug action and approaches (drugs) used for control.

NOTE: A reduction in

both PVR (afterload) and venous return (preload) will result in postural hypotension. If venous circulation is not affected, then the drug in question should not cause postural hypotension.

Diuretics: These drugs are used alone in mild hypertension and in combination with other drugs to handle severe hypertension. The increase in salt and water excretion results in a decrease in blood volume and cardiac output, the reduction in cardiac output reduces blood pressure. High Na+ intake or low GFR will result in the loss of the antihypertensive effects of diuretics. The diuretics of choice are THIAZIDE (DILUTING SEGMENT) DIURETICS (e.g.hydrochlorothiazide [DYAZIDE]). Low doses result in a small natriuretic effect, whereas large doses result in an obvious diuresis and increased urine K+ loss. The use of large doses can be avoided by restricting salt intake (also reduces K loss). Loop diuretics have shorter durations of action and are generally less effective in treating hypertension, but are useful in those with renal failure since they increase GFR.

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Angiotensin II Converting Enzyme (ACE) Inhibitor: ACE inhibitors reduce the activity of the renin-angiotensin-aldosterone system by inhibiting the enzymatic conversion of ANG I to ANG II. ANG II is a potent vasoconstrictor and it stimulates aldosterone production which in turn increases Na+ and water retention. The net result of the use of ACE inhibitors is to reduce PVR and increase Na+ and water excretion. Adverse effects include extensive hypotension associated with volume or salt depletion and all can cause a dry hacking cough and angioedema. These drugs tend to be less effective in elderly African-Americans due to their low renin levels. In contrast, patients with high plasma renin levels may experience excessive hypotension.

Calcium Channel Blockers: include nifedipine (PROCARDIA) and diltiazem (CARDIZEM). A major advance has been the development of sustained release preparations. Reflex increases in heart rate occur with nifedipine but not with verapamil or diltiazem. These drugs reduce blood pressure due to their capacity to dilate systemic arteries (decrease PVR). The side effects of their use are primarily the result of excessive vasodilation. They should be used carefully in those taking antagonists (both decrease heart rate) or those with heart failure (they reduce contractility). These drugs are particularly useful in treating hypertension in persons with low renin levels.

DRUGS THAT IMPAIR SNS FUNCTIONING: ALL of the drugs in this broad category elicit compensatory responses through mechanisms not dependent on adrenergic nerves. They are used for moderate to severe hypertension.

antagonists: vasodilators which affect both veins (preload; venous return) and arteries (afterload; PVR). Drugs like the 1-selective antagonist prazosin (MINIPRESS)which causes tachycardia and postural hypotension. These drugs can be used alone to to treat mild hypertension or with diuretics and antagonists for severe hypertension.

antagonists: All changes in blood pressure occur through reductions in contractility and C.O. and plasma renin levels. e.g. the non-selective antagonist propranolol (INDERAL) and the 1-selective altenolol (TENORMIN) which

1. block reflex tachycardia induced by vasodilation2. reduce cardiac output and heart rate3. reduce renin production4. can cause depression, aggravate congestive heart failure and increase bronchospasms

in asthmatics. Insulin-dependent diabetics are also better treated with other drugs.

Centrally-acting 2 agonists: bind to presynaptic receptors in the brainstem and INHIBIT NE RELEASE. This decreases SNS outflow resulting in decreased blood pressure and heart rate. Severe rebound increases in blood pressure occur with abrupt cessation of clonidine use. Clonidine (CATAPRES) inhibits NE release in the medulla, reducing SNS outflow. It does bind to receptors in vascular smooth muscle resulting in transient increases in blood pressure, but the CNS effects predominate. It can cause salt and water retention so a diuretic is required. It is used to treat mild-moderate hypertension and it DOES NOT cause reflex tachycardia (why not?)

DIRECT VASODILATORS: Drugs which produce vasodilation independent of the adrenergic nervous system and adrenergic receptors. All produce arterial dilation (reduce afterload); Organic nitrates like nitroprusside (NITROPRESS) also cause venous dilation (reduce preload). All produce their effects directly on vascular smooth muscle. Their chronic use is limited by SNS reflex responses (reflex tachycardia and activation of the renin-Ang II-

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aldosterone system), therefore they are not used as sole therapy but in combination with antagonists and diuretics.

minoxidil (LONITEN): Opens K+ channels which in turn decreases Ca entry and causes arterial dilation with little effect on venous circulation. It MUST be given with a antagonists and a diuretic. It is used to treat severe hypertension, hypertension with renal failure, hypertension resistant to other therapy and is best reserved for these purposes and/or those that respond poorly to other drugs. Interestingly, it causes hypertrichosis (excessive hair growth)

sodium nitroprusside (NITROPRESS): i.v. use only because its half-life is very short. Causes venous dilation (decreased preload and decreased CO) and arterial dilation (decreases PVR-afterload). Used in hypertensive emergencies to rapidly reduce blood pressure. Acts within seconds, and can reduce blood pressure in all patients regardless of the cause of hypertension. Causes dilation by increasing intracellular cGMP levels.

Combination Products: Some antihypertensive agents are available as combination products. Combination products are convenient and may enhance compliance, but individual adjustment of the dosage of any one ingredient is not possible.

hydrochlorothiazide (25,50 mg) + spironolactone (25,50 mg) (ALDACTONE) (diluting segment diuretic) + (K sparing diuretic)

propranolol (40,80 mg) + hydrochlorothiazide (25 mg) (INDERIDE) (non-selective antagonist) + (diluting segment diuretic)

Choice of Drugs: in some patient categories, one drug may prove more effective than others. In general, diuretics, antagonists, ACE inhibitors and Ca channel blockers are the best tolerated antihypertensive agents.

1. African Americans - diuretics and Ca-channel blockers are more effective than antagonists or ACE-inhibitors

2. Diabetics - ACE inhibitors3. Hyperlipidemic patients - ACE-inhibitor, antagonists, or Ca channel blocker4. CHF - ACE inhibitors5. Patients with angina, migraines or those who have had a MI-- antagonists

Study Questions:

1. Define hypertension and describe the 2 classifications.2. Describe the mechanism(s) of action, uses and side effects of each of the following anti-hypertensive

drugs. ACE inhibitors diuretics Ca channel blockers antagonists antagonists direct vasodilators3. What advantages are there to administering anti-hypertensive agents as combinations products? What are

the disadvantages?4. What determines which drug(s) is used in a particular patient?

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ANTICOAGULANTS AND THROMBOLYTIC DRUGS

A thrombus is a clot in an artery or vein. Arterial thrombi result in occlusions that cause ischemic damage (i.e. decreased oxygen delivery) to the tissue it supplies, while venous thrombi cause tissues drained by veins to become edematous (swollen) and inflamed. Venous thrombi often give rise to emboli which are masses of undissolved clots that break off a thrombus, travel in the blood stream and lodge in blood vessels in other areas of the body. Emboli from the venous circulation tend to lodge in pulmonary vessels while arterial emboli tend to lodge in cerebral or extremity circulation.

BLOOD COAGULATION is the transformation of soluble fibrin to insoluble fibrin which occurs by a cascading series of limited proteolytic reactions. The cascade results in amplification at each step, thus a small stimulus can rapidly produce a maximal response. The earlier in the cascade a step can be blocked, the more efficient is the anticoagulant (thrombin = final protease). Formation of a blood clot is the end result of hemostasis, a spontaneous arrest of blood flow from a damaged area. The sequence of events include: 1. vasospasm of damaged blood vessel

and exposure of collagen2. platelet adhesion to exposed collagen3. platelet aggregation where platelets stick to

one another and release thromboxane A2, resulting in further aggregation (aspirin prevents the release of thromboxane A2)

4. platelet plug forms5. reinforcement of the plug with fibrin

REGULATION OF COAGULATION AND FIBRIN-OLYSIS confines a clot to smallest possible area by:

1. fibrin inhibition with antithrombin III (naturally occurring anticoagulant)

2. fibrinolysis occurs via conversion of plasminogen to plasmin via a naturally occurring tissue plasminogen activator.

ANTICOAGULANTS: prevent clot formation they do not dissolve clots. Anticoagulants include parentral drugs such as heparin and oral drugs like warfarin.

1) Parentral anticoagulants - Heparin is found in mast cells and is commonly extracted from porcine intestinal mucosa and bovine lung. Heparin is a very large molecule and is not absorbed orally, therefore it is administered parenterally (i.v. infusion, i.v. injection and deep s.c. injection). Heparin requires antithrombin III to work (some people with a genetic defect resulting in the loss of antithrombin III). Antithrombin III inhibits the activation of thrombin and thus prevents thrombin from producing fibrin to reinforce clots. Heparin binds to antithrombin III, producing a confirmational change which accelerates antithrombin III's anticoagulant activity. The result is a blockade of activation of clotting factors IX, X, XI and XII and prevents the conversion of prothrombin (factor II) to thrombin (factor IIa). Thrombin and factor X are most sensitive to the actions of heparin. Heparin also prevents the activation of factor XIII and the conversion of soluble fibrin to insoluble fibrin (fibrin bound thrombin is relatively resistant to heparin which may explain why preventing the extension of clots requires greater concentrations of heparin than preventing clot formation. Heparin (low doses administered s.c.) provides a slow, continual release for prophylactic anticoagulation, high doses are administered i.v. when rapid anticoagulation is needed. It is the drug of choice for acute thromboembolic disease. It is also used to prevent/treat venous and pulmonary emboli, to treat mural

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thrombi after MI, to prevent coronary artery re-occlusion after thrombolysis and to prevent clot formation during hemodialysis and heart-lung bypass surgery

Hemorrhage is most common side effect and allergic reactions can occur with heparin derivedfrom non-human sources (e.g. bovine lung). More rarely, heparin causes thrombocytopenia (decrease in the number of platelets, requires frequent blood counts – mechanism?). It should not be used in those with hemophilia, ulcerative lesions of the GI tract, or recent CNS trauma or in pregnancy except when clearly indicated (even though it does not cross the placenta nor enter breast milk)

2) Oral anticoagulants - especially the coumarin warfarin (COUMADIN). Warfarin is most commonly used in the USA due to its predictable onset and duration of action and its excellent bioavailability. Warfarin inhibits synthesis of vitamin K-dependent clotting factors in the liver (factors X, IX, VII and II) by interfering with the regeneration of active vit. K. Vit. K is an essential cofactor in the post-translational carboxylation of vit. K-dependent proteins. Warfarin prevents vit. K reduction from its epoxide form back to its active form, thus limiting the carboxylation of the vit. K-dependent clotting factors. The effect on clotting is not immediate since it takes some time for the clotting factors made prior to administration of warfarin to be cleared from the blood. Likewise, it takes sometime for recovery since new clotting factors must be made. There can be a marked variability in response from person to person which may reflect differences in receptor affinity, the concentration of available vit. K clotting factors or vit. K availability. In fact diets high in vit. K (green leafy vegetables etc..) can reduce the response to warfarin while malabsorption of the vitamin can result in an enhanced response Warfarin readily crosses the placenta and can cause fetal hemorrhagic disorder.

Oral drugs are the drugs of choice for long-term anticoagulant therapy and are used to prevent venous thromboembolism, treat deep venous thrombosis, and prevent clots following artificial heart valves. As with heparin, hemorrhage is the most common side effect.

THROMBOLYTIC (fibrinolytic) DRUGS (“Clot busters”): All thrombolytic drugs dissolve clots by enhancing the conversion plasminogen to plasmin. Plasmin then breaks down fibrin and fibrinogen as well as factors V and VIII with the end result being the breakdown of emboli AND protective clots. All are infused due to their short durations of action and bleeding is common to all. All convert plasminogen to plasmin. They are used for acute intra-arterially for acute coronary thrombosis (best results if administered 2-4 hrs after MI), 2) pulmonary emboli too small for surgery or cenral deep venous thrombi (e.g. in vena cava, ileofemoral vein). If given within 7 days, approximately 65% of the clots can be broken down. Therapy is usually followed up with heparin then warfarin. The drugs are expensive - but what is the cost of long-term care following a stroke?

1. streptokinase (STREPTASE) - from streptococci; t1/2 of ~23 min 2. urokinase (ABBOKINASE) - a renal enzyme; t1/2 ~16 min3. tissue plasminogen activator (tPA; ACTIVASE) - selective for fibrin4. anistreplase (EMINASE) - streptokinase (inactive) + lys-plasminogen (streptokinase activated

after injection; has a longer t1/2 than 1-3; ~90 min)ANTIPLATELET THERAPY: Platelets provide the initial plug at the site of vascular injury and they can contribute to the pathology of atherosclerosis and thrombosis. Cyclooxygenase inhibitors like aspirin prevent the production of thromboxane A2 which is responsible for platelet aggregation. Since aspirin irreversibly inactivates cycloxygenase and platelets cannot synthesize new protein, the effect of aspirin is for the life of the platelet (7-10 days).Uses:

1. prevention of transient ischemic attachs (TIA) and MI in patients with histories of such events2. prevention of TIA/MI in those without history1. improvement in blood flow in post-operative coronary bypass

Study Questions:1. What steps are involved in hemostasis?2. What are the naturally-occuring anticoagulant and fibrinolytic agents?3. How does heparin inhibit coagulation? What is it used for? What are its side effects and contraindications

for its use?4. How do oral anticoagulants work? What are they used for? What are their side effects and

contraindications for their use? How rapidly do they produce their effects?5. How do thrombolytic (fibrinolytic) drugs work? What are they used for? What are their side effects and

when is their use contraindicated?

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DRUGS AFFECTING THE REPRODUCTIVE SYSTEM

ESTROGENS AND PROGESTERONES are steroid hormones. Naturally occurring forms of estrogen and progesterone are not effective orally, but conjugated natural forms and synthetic estrogens (e.g. DES) and synthetic progestins are effective orally.

Estrogen is secreted from the ovary; the circulating form is estradiol. The role of estradiol is to:

1. induce growth of the uterus, fallopian tubes and vagina 2. induce the expression of secondary sexual

characteristics at puberty (breast tissue, fat distribution, pubic hair)

3. stimulate the closure of epiphyseal plates of long bones

4. stimulates uterine and mammary gland development during pregnancy

Progesterone is produced by the corpus luteum of the follicle during the post-ovulatory phase of the cycle. The circulating form is 17-hydroxyprogesterone

1. suppresses ovulation during pregnancy 2. prepares the endometrium for implantation

THE GONADOTROPINS are peptide hormones that regulate the growth and secretory status of the ovary and testes. These include the pituitary gonadotropins leutinizing hormone (LH) and follicle stimulating hormone (FSH), the placental pregnancy hormone

human chorionic gonadotropin (hCG) (maintains the corpus luteum when LH levels decline and supports the continuing secretion of estrogen and progesterone during pregnancy and prevents ovulation during pregnancy. Human CG and human menopausal gonadotropins (LH and FSH present in the urine of post menopausal women due to the loss of negative feedback control provided by estrogen and progesterone) produces LH-like effects in females and males and.

LH (steroidogenesis) FSH (gametogenic) FEMALES binds to ovarian thecal, granulosa, binds to and induces the

luteal cells, increasing ovarian development of ovarian folliclesestrogen and luteal progesteroneproduction

MALES binds to testicular Leydig cells, binds to gametes and seminiferousincreasing testosterone production tubules, initiating the development

of gametes, maintenance ofseminiferous tubules and increases the number of LH receptors on Leydig cells

Clinical Uses of Estrogens and Progesterone1. oral contraception - contain preparations of estrogen and progesterone. Taken for 20-22 days,

followed by 7 days pill (and hormone) free. Withdrawal results in bleeding 2-3 days later. Work by inhibiting mid-cycle surges of LH and FSH.

types of pills--

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stimulatesinhibits

a. combined low dose: lowest available doses of estrogen and progesterone b. phasic: designed to reduce total intake of hormone; first 6 days, receive lowest dose,

higher dose for next 5 days, and highest dose last 10 days c. minipills: contain progesterone only; used to provide contraception where use of estrogen

is contraindicated d. post-coital: high doses of estrogen/ progesterone in combination, used as soon as

possible

Others--

levonorgestrel (NORPLANT)mifepristone (RU486) - an antiprogesterone which may

also be used as an abortifactant

2. treatment of menopausal symptoms - vasomotor symptoms (hot flashes) and atrophic changes in uterus and vagina, osteoporosis and to prevent cardiovascular disease

3. replacement therapy - hypogonadism or following oophrectomy

4. infertility - provided the reasons for infertility are known

Drugs Used to Treat Infertility:

HMG (Menotropins, PERGONAL) - human menopausal gonadotropins. 1. used in women with low endogenous estrogen but not in those with primary ovarian failure

as it can cause can cause o ovarian hyperstimulation and enlargement of the ovaries,

thrombotic emboli and multiple births 2. used in males with hypopituitary hypogonadism

GnRH [leuprolide (LUPRON)] - synthetic gonadotropin-releasing hormone analogs1. treatment of hypothalamic hypogonadism2. endometriosis, treatment of some cancers

hCG (PREGNYL) - derived from pregnancy urine1. substituted for LH since they are virtually identical in structure 2. usually used in conjunction with HMG to induce follicular development. HCG is administered to

mimic the LH surge which induces ovulation.3. used in males to treat cryptorchidism and in some cases hypopituitary hypogonadism.

Drugs Used to Treat Cancers

1. breast cancer - breast growth is estrogen-dependent, therefore antiestrogens can be used to treat breast cancer. e.g. tamoxifen citrate (NOLVADEX) - an estrogen antagonist paradoxically high doses of diesterstilbesterol (DES), a synthetic estrogen2. endometrial cancer - progesterone can cause remission in ~1/3 of those with metastatic cancer, but the mechanism is unknown.3. prostate cancer - estrogen can produce remissions in 50-80% of those with prostate carcinomas. Acts as an anti-androgen, reducing serum LH and thus serum testosterone levels.

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Adverse Reactions

1. common side effects of estrogen and progesterone include nausea, weight gain edema2. cancers have been associated with long-term use (anecdotal evidence) These include an estrogen-induced increased risk of endometrial cancer (can be counteracted by coadministration of progesterone), estrogen-induced increased/decreased risk of breast cancer, 3. prolonged use can result in cardiovascular disease; estrogen can cause thromboembolism and hypertension4. teratogenic: DES has been associated with an increased risk of cervical cancer in daughters of women taking DES to prevent miscarriage

ANDROGENS AND ANABOLIC STEROIDS

Testosterone regulates the differentiation and secretory function of male accessory sex organs and has growth-promoting effects on muscle, bone and kidney. Anabolic androgenic steroids were developed as synthetic testosterone analogs to minimize the androgenic properties of testosterone while maintaining their anabolic (growth-promoting) effects. The FDA regulates anabolic steroids distribution under the Food, Drug and Cosmetic Act, and under the Controlled Substance Act (Schedule III). They include drugs such as stanozolol (WINSTROL), methandrostenolone (DIANABOL) and nandrolonephenproprionate (DURABOLIN).

Therapeutic Uses

1. treatment of testicular deficiency (hypogonadism)2. delayed puberty/short stature3. treatment of endometrial cancer and metastatic breast

cancer4. anabolic effects are exploited to increase free amino acid

incorporation into protein, enhancing protein synthesis (i.e., catabolic states), which is useful in treating conditions of severe negative nitrogen balance (burn victims, premature infants,

corticosteroid-induced negative nitrogen balance and osteoporosis (?)) 5. anemia (controversial)- androgens stimulate renal production of erythropoietin which in turn stimulates

RBC production by bone marrow. Also produces non-specific increases in hemoglobin (one reason hemoglobin content in blood is greater in males than females); use is controversial

6. athletic use - to increase muscle mass and strength. Androgens increase training effort and enhance performance, although the changes in some cases may be more perceived than real. The risk is in the associated side effects produced by the large doses (often 100 times the therapeutic dose) and prolonged use of these drugs (months-years). These toxic effects include

a. fluid retention and edema (kidney damage)b. liver abnormalities (changes in both structure and function)c. changes in cardiovascular function (hypertension resulting in heart attack, stroke, renal

failure), increased LDLsd. endocrine effects - reduction in LH and FSH can result in testicular atrophy and sterility,

gynecomastia in males while causing virilization, anovulation and alopecia in females. Virtually abolishes circulating LH and FSH.

e. psychological changes - severe mood swings (steroid psychoses) and changes in libido

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Anabolic steroids are traditionally taken in cycles (6-12 weeks duration), but some take drugs continually and often take more than 1 steroid at a time (stacking). Rationale is that multiple steroids activate more receptor sites and/or a synergistic effect can be achieved with certain combinations of steroids.

In pre- and peripubertal children, anabolic steroids can advance development of skeleton (cause epiphyseal plate closure) out of proportion of the ability to increase length and inhibit children and adolescents from reaching genetic height potential.

Study Questions:

1. What physiological functions are regulated by estrogen? By progesterone? Where are each of these hormones produced?

2. What are the gonadotropins? Where are they synthesized? What regulates their secretion? What physiological functions do they regulate in males and females?

3. Where is human chorionic gonadotropin (hCG) synthesized? What are human menopausal gonadotropins?

4. What are estrogen and progesterone used for clinically?5. What drugs are used to treat infertility? Why?6. What are anabolic steroids? Why were they developed? What are they used for therapeutically?

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DRUGS FOR TREATING DIABETES MELLITUS

Carbohydrates are important sources of energy; glucose is the primary energy source used by most cells and is the only energy source utilized by nervous tissue. There are two major sources of plasma glucose: 1) exogenous glucose derived from dietary sources and 2) endogenous glucose derived from glycogenolysis (breakdown of glycogen) and gluconeogenesis (production of glucose from non-carbohydrate sources - fat and protein). Glucose enters cells slowly via a glucose transporter, but its transport is accelerated by insulin. Insulin and glucagon are the 2 principal hormones involved in regulating glucose metabolism. Both are made in and released from specific cell types in the pancreatic islets of Langerhans. Insulin is produced in cells and enhances glucose uptake into cells (i.e. it is a hypoglycemic agent). In

contrast, glucagon is made in cells and enhances glycogen breakdown and glucose release (i.e. it is a hyperglycemic agent).

INSULIN: Insulin is a 51 amino acid protein composed of 2 polypeptide chains ( and ) joined by disulfide bonds. The disulfide bonds are required to maintain tertiary structure and for biological activity. Insulin is synthesized as a large precursor molecule (preproinsulin) which is processed intro proinsulin and finally into inulin and packaged in secretory granules. Insulin is continuously secreted at a low basal level during fasting but its secretion is markedly elevated in response to post-prandial increases in plasma glucose. In addition, the SNS inhibits insulin secretion while the PNS stimulates insulin secretion. The primary stimulus for insulin secretion is an increase in blood glucose Thus, carbohydrate-rich meals cause a 2-fold increase in insulin secretion. In addition amino acids (arginine and leucine) increase insulin secretion as do the hormones glucagon, ACTH and GH. Somatostatin, produced by the cells of the pancreatic islet, inhibits insulin secretion. Insulin produces its effects by binding to and activating a receptor tyrosine kinase. Signaling by this activated receptor promotes anabolism, growth and energy storage by:

1. decreasing glucose efflux from the liver (inhibits liver gluconeogenesis and glycogenolysis and increases glycogen storage)

2. increasing glucose uptake, storage and use in insulin-sensitive cells (especially skeletal muscle and fat)

3. enhancing cellular amino acid uptake/incorporation into protein (results in a (+) nitrogen balance)

4. antilipolytic (inhibits lipolysis)

DIABETES MELLITUS: Diabetes mellitus is a group of disorders of carbohydrate metabolism resulting from defects in insulin processing (proinsulin to insulin), reduced affinity of receptor for hormone, mutations in the insulin receptor, reduced insulin excretion, secretion, lack of insulin secretion, etc...

Type 1 (Insulin-dependent Diabetes Mellitus - IDDM): Usually occurs in people younger than 30 years old. Persons with this form make little/no insulin and therefore require insulin administration. This is an autoimmune disease where patients have anti-islet cell antibodies and it is brought about by a viral infection or other pancreatic disorders.

Type 2 (Non-insulin-dependent Diabetes Mellitus - NIDMM): Usually occurs in people older than 40 years. However, type 2 diabetes is now appearing at a younger and younger age as the American population becomes more obese. Persons with this form of diabetes have a pancreas with some capacity to synthesize insulin and hyperglycemia can be controlled with diet and oral hypoglycemics. This is a relatively heterogeneous disease as people can have defects in insulin binding to its receptor, defective insulin receptor signaling, reductions in insulin receptor number, etc… People often show some degree of insulin resistance (a subnormal biological response to a give concentration of insulin). There is clearly a genetic component as diabetes “runs” in families, but its most likely a polygenic disease with no one gene being associated with all of its symptoms.

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Metabolic derangements associated with diabetes

1. increased blood glucose (hyperglycemia) due to the reduced transport into cells2. muscle cells become gluconeogenic (using amino acids to make glucose)3. constant fatigue4. polyuria due to the osmotic effect of increased glucose in the tubular fluid; this results in

polydipsia5. adipose tissue becomes gluconeogenic resulting in increased free fatty acids, ketosis

and acidosis = diabetic ketoacidosis, which is potentially fatal (seen primarily in type 1)

Complications associated with diabetes include 1) microvascular damage leading to retinopathy, nephropathy and neuropathy (diabetes is the 2nd leading cause of blindness and the 2nd leading cause of renal failure in the USA) and 2) macrovasular damage as a result of hyperlipidemias and cardiovascular disease

Treatment of type 1 diabetes: insulin replacement therapy, diet (the cornerstone of all treatments) and exercise (which sensitizes insulin-responsive tissues to the effects of insulin). There are a variety of insulin preparations differing primarily in onset of action, maximal activity and duration of action. In the past, animal sources of insulin were the primary forms available, but now most diabetics use human recombinant insulin in one of its many forms. All preparations must be administered parenterally, most often subcutaneously. There are a variety of conjugated forms of insulin where amino acid modification or conjugation with protamine (a polyvalent cation) and/or zinc alters the onset and duration of action. Often patients will take more than one form of insulin to control their blood glucose levels throughout the day. Individualized schemes can take into account variations in physical activity, eating schedules etc... in an attempt to provide the appropriate amount of insulin at the appropriate time. In addition, administering exogenous insulin can only approximate normal insulin secretion. Therefore, using multiple forms can also more closely mimic normal insulin secretion.

Indications for insulin use:

1. low plasma insulin and low body weight2. type 2 diabetes not responding to diet, exercise and oral hypoglycemics

3. diabetic ketoacidosis and diabetic coma (distinct from coma associated with insulin OD ; insulin shock)

4. diabetes in pregnancy (gestational diabetes associated with increases in glucocorticoids and placental lactogens)

Adverse Reactions to Insulin therapy

1. Hypoglycemia is the single most common side effect, especially now with the therapeutic goal of stricter control of plasma glucose. Modest reductions in plasma glucose can be treated by drinking orange juice or another glucose source. More significant hypoglycemia can be treated with glucose injection or with glucagons. Insulin OD (Insulin shock) causes severe hypoglycemia and coma (can result in permanent brain damage), requiring a source of glucose.

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TYPE OF INSULIN ONSET PEAK ACTION DURATION

Rapid ActingLispro (Humalog - human recombinant insulin

where position of lys28 and pro29 switched)15 min 0.5-1.5 hours 3.5 hours

Regular Insulin 0.5 hours 2-4 hours 6-8 hours

Intermediate ActingNPH (Isophane Insulin)

Lente (Insulin Zn)1-3 hours 6-12 hours 18-24 hours

Long-ActingUltralente

(extended Zn suspension)4-8 hours 12-18 24-28 hours

2. hypokalemia which can cause cardiac arrhythmias. This is due to insulin’s ability to activate the Na+/K+-ATPase.

3. insulin resistance in long-term use (where resistance is a subnormal response to a given concentration of insulin). Insulin antibodies used to be a significant problem. Antibodies to the insulin receptor also occur, often in a setting of other features of an autoimmune problem.

Treatment of Type 2 diabetes with oral agents: Oral agents are used to treat milder forms of NIDDM that do not respond to diet management alone. There are a variety of drugs with distinct mechanisms of action that are used to control type 2 diabetes. NONE are useful in the treatment of type 1 diabetes.1. Insulin releasers (sulfonylureas and megletinides): the first sulfonylureas were introduced ~50 years ago. These drugs work by stimulating insulin release from residual pancreatic cells. This is accomplished by sulfonylureas binding to and closing ATP-gated K+ channels. This results in depolarization of the cells, Ca2+ entry, the fusion of secretory granules with cell membranes and insulin release. sulfonylurease1st generation:

acetohexamide (DYMELOR)tolbutamide (ORINASE)

2nd generation (higher affinity/ specificity for the ATP-gated K+ channel):

glyburide (DIAETA) glipizide (GLUCOTROL) meglitinides repaglinide (PRANDIN)

2. Insulin Sensitizers (thiazolidinediones or glitazones): insulin sensitizers that reduce insulin resistance and enhance insulin action in target tissues. Agonists for peroxisome proliferators activated receptor (PPAR) which in turn activate insulin-responsive genes regulating carbohydrate and lipid metabolism. PPAR seem especially abundant in adipose tissue and fewer are expressed in muscle, liver and other tissues.

pioglitazone (ACTOS)rosiglitazone (AVANDIA)(troglitazone (REZULIN)- removed from the market due to significant liver toxicity

3. Anti-hyperglycemics (biguanides): decreases hepatic glucose production by inhibiting gluconeogenesis and enhances glucose uptake. Requires the presence of insulin to work.

metformin (GLUCOPHAGE)4. glucosidase inhibitors: inhibit the activity of glucosidases which slow the rate at which carbohydrates are absorbed after a meal. This in turn causes a blunted insulin response.

acarbose (PRECOSE)5. Combination products: glyburide + metformin (GLUCOVANCE) (insulin releaser + anti-hyperglycemic)

rosiglitazone + metformin (AVANDOMET) (insulin sensitizer + anti-hyperglycemic)Study Questions:

1. What hormones are synthesized and secreted from the endocrine pancreas?2. What are the characteristics of type 1 and type 2 diabetes? How are each treated?3. How does diabetes mellitus affect metabolism? Why does insulin deficit cause hyperglycemia and ketoacidosis?4. What stimulates insulin secretion? What are the pharmacological actions of insulin?5. What are the major differences between insulin preparations? Why do some diabetics take more than one form of insulin?

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6. What are the adverse responses associated with the use of insulin? What causes diabetic coma? What causes insulin shock?7. How do oral hypoglycemic agents reduce plasma glucose levels? What type of diabetes are they used to treat? What are the adverse effects associated with their use?

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CHEMOTHERAPY

Chemotherapy is the use of any chemical compound that selectivity acts on microbes or cancer. Success requires exploiting metabolic or structural differences between normal human cells and disease-producing cells. The more closely related the undesirable cells are to normal human cells, the more difficult the task of SELECTIVE TOXICITY.

e.g. 1. viruses use host replicating enzymes so virally transformed cells are not that different from normal cells2. fungi are eukaryotes so fungal infections are difficult to treat as there are few selective targets present in fungi that are absent in mammalian cells.

ANTIMICROBIAL THERAPY: The ideal drug would have selective toxicity (i.e. drug would be harmful to microorganisms with little/no effect on hosts). In addition, the ideal pharmacodynamic response would be no pharmacodynamic response (i.e. the target is not present in host cells). The less selective the drug, the greater the severity of the adverse effects. These adverse effects can include:

1. allergic reactions - hypersensitivity, cross -sensitivity2. toxic reactions at high doses (e.g. gentamicin and streptamicin are polycations and their

interactions with lipids of the proximal tubule can lead to kidney damage)3. drug interactions. 4. alterations in normal body flora (particularly in the GI tract). Antibiotics reduce/eradicate normal

flora which are replaced by exogenous or endogenous resistant bacteria resulting in superinfections. The risk is greater with large doses, multiple antibiotics and broad spectrum antibiotics.

5. idiosyncratic reactions most often related to single nucleotide polymorphisms in p450s

CLASSIFICATION OF ANTIBIOTICS: based on 1. bacteriocidal (lethal -causing bacteriolysis ) vs bacteriostatic (inhibitory - inhibiting growth and relying on the immune system to get rid of bacteria). This is somewhat misleading as there is a continuous spectrum depending upon dose.

OR2. mechanism of action (see fig)

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a. cell wall disrupters inhibit the synthesis of cell walls. Viability of bacteria depends on integrity of cell wall to maintain hypertonic interior. Injury or inhibition of synthesis results in bacteriolysis. Bacteriocidal. lactams like the penicillins and cephalosporins are among the most widely used antibiotics and have many properties in common. Bacterial cell wall production requires the cross-linking of adjacent peptidoglycans strands through a transpeptidase reaction. Bacteria cleave the terminal D-alanine from a pentapeptide on one strand and cross link it with the pentapeptide of another. These cross-linked peptidoglycan strands give the cell wall strength and protect bacteria from changes in osmotic pressure of their external environment. -lactams structurally resemble the terminal D-alanyl-D-lanine (D-Ala-D-Ala) in the pentapeptides on peptidoglycans Bacterial transpetidases (penicillin binding protein) bind the antibiotics at their active site which inactivates the enzyme. This inhibits cell wall synthesis, resulting in bacteriolysis. These antibiotics are most effective on rapidly multiplying bacteria; don't affect cell walls already synthesized. Persons allergic to penicillins are allergic to cephalosporins and vice versa. Allergic reactions can range from rashes to anaphylaxis. Some bacteria have inherent resistance and some acquire resistance through the production of lactamase (penicillinase) [e.g. Staphylococcus aureus and Neisseria gonorrhea]. In an attempt to overcome the actions of -lactamases, -lactamase inhibitors are included in the formulations (e.g. clavulanic acid). Resistance may also involved alteration of additional targeted penicillin binding proteins. In these circumstances, addition of a lactamse inhibitor is of no value. b. inhibition of cell membrane function: bacteriostatic or bacteriocidal. Changes in membrane permeability result in the loss of essential ions and metabolic substrates. c. ribosomal inhibitors: inhibit protein synthesis resulting in the production of defective proteins or the loss of specific proteins required for cell growth. These drugs can be bactriostatic or bacteriocidal. Aminoglycosides like streptomycin drugs used to treat life-threatening infections with gram (-) bacteria. They are composed of 3-4 amino sugars joined by a glycoside linkage. The polycationic aminoglycoside structure allows for binding to the anionic outer bacterial membrane (bacteriocidal) and to anionic phospholipids of mammalian cell membrane (which contributes to their toxicity). All bind to ribosomes, inhibiting protein synthesis or causing the production of defective proteins. In addition, their binding to the bacterial outer membrane disrupts membrane integrity. Resistance occurs by reducing the uptake of the drug, changes in protein target on ribosomes and enzymatic destruction of the drug (most common). All are potentially nephro- and ototoxic and can cause neuromuscular blockade. d. inhibition of nucleic acid synthesis: bacteriostatic or bacteriocidal. Drugs complex with DNA or RNA, blocking DNA replication or RNA formation (e.g. quinolones like ciprofloxacin which inhibit DNA gyrase (a topoisomerase that relieves supercoiling in DNA by creating a transient break in the double helix) and topoisomerase IV (which separates daughter cells following replication). Also inhibition of folic acid synthesis - folic acid is a coenzyme required for the production of nucleotide bases which are used in DNA and RNA synthesis. Folic acid is composed of pteridine, PABA and glutamate.(e.g. sulfonamides like sulfamethazole which are structural analogs of para-amino benzoic acid). ). Susceptible microorganisms require PABA to make folic acid and subsequently to make nucleic acids. Thus, sulfonamide antibiotics inhibit DNA synthesis by competing with PABA for essential enzymes like dihydrofolic acid synthetase (DHFS). Humans are not susceptible because we do not synthesize folic acid but rather obtain it from dietary sources.

RESISTANCE: occurs when antibiotics do not affect bacteria. Inherent or innate (natural resistance and the bacteria were never sensitive) and acquired (prolonged exposure to low doses selects for mutant bacteria with a changed antibiotic target). Mechanisms of Resistance: The risk for resistance is also greater with large doses, multiple antibiotics and broad spectrum antibiotics. In addition, the prevalence of antibiotics in everyday use (handsoaps, sponges, dishwashing liquid) and in animal feeds has contributed to the appearance of resistant bacteria.

1. alteration in drug transport: causes changes in membrane permeability a. altering the glycocalyx to prevent entrance of lipophilic drugs (e.g.

Pseudomonas sp) b. changes in porins which affect the uptake of hydrophilic drugs

2. enzyme inactivation: production of enzymes which breakdown antibiotics (e.g. Staphylococci sp. resistant to penicillin G make lactamase or penicillinase)

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3. expression of pumps to expel drugs4. alterations in targets: genetic changes where bacteria no longer make target protein or make it in a different form (e.g. erythromycin-resistant bacteria change ribosomal protein target of the drug)5. gene exchange with other bacteria through plasmids (loops of DNA that are independent of bacterial chromosomal DNA) or gene cassettes inserted directly into the chromosomal DNA.

ANTIFUNGAL DRUGS: Fungal infections are termed MYCOSES. Infecting organisms are ingested, inhaled or implanted under the skin. Antibiotics are ineffective as fungi are eukaryotes. In addition, antifungal drugs tend to be toxic because of the lack of selective toxicity; both mammals and fungi are eukaryotic and the only major difference is that mammalian cell membranes contain cholesterol while those of fungi contain ergosterol.

Common fungal infections

1. candidiasis: Candida albicans. Part of the normal flora of the skin, mouth intestine, vagina. Opportunistic infections arise in immunosuppressed people and those taking antibiotics (women often acquire vaginal yeast infections this way)

2. aspergillosis: Aspergillus sp. Most commonly cause pneumonia in immunosuppressed people. 3. histoplasmosis: Histoplasma sp. Yeast-like organisms; not spread person-to-person, but through soil

contaminated by fecal material of birds, causing pulmonary or disseminated infections. 4. blastomycoses: Blastomyces sp. Yeast-like organisms, causing skin and respiratory infections. 5. coccidiomycoses: Coccidioides sp. causing pulmonary and skin infections.

Systemic Drugs:- amphotericin B (FUNGIZONE): fungicidal/fungistatic and reserved for severe systemic fungal infections (e.g. deep candidiasis and aspergillosis). Binds to membrane ergosterol causing the formation of pores. This increase the membrane permeability, resulting in a change in distribution of ions and substrates. - miconazole (MONISTAT I.V.; MONISTAT 7): Broad-spectrum; may be fungicidal or fungistatic, depending upon dose and the organism. Used to treat dermatophytosis, vaginal candidiasis, vaginal yeast infections.

AIDS: Viruses are intracellular parasites whose replication depends upon using the metabolic processes of the host cells. The hallmark of Human Immunodeficiency virus (HIV) infection is the depletion of CD4 lymphocytes which results in immunodeficiency. Development of AIDS is characterized by susceptibility to infection and certain types of malignancies. The virus is a single-stranded RNA retrovirus and it is the causative agent of acquired immunodeficiency syndrome (AIDS). The virus is found in two major forms, HIV-1(major form world-wide) and HIV-2 (most prevalent in western Africa). Like all retroviruses, HIV contains 3 major genes (gag, pol and env) and while HIV-1 and HIV-2 have ~50% homology, some anti-retroviral drugs are more effective against one than the other. In fact, a whole class of drugs (nonnucleoside reverse

transcriptase inhibitors) has no effect on HIV-2 infections. Although much information has been gathered about the virus in the 20+ years since it was identified, AIDS is a significant world health issue because of: 1) the expense and inaccessibility of AIDS drugs in developing nations and 2) the emergence of drug-resistant forms of the virus. In addition, the extensive

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heterogeneity of HIV will make vaccine development difficult, plus drug-resistant forms of the virus have and will continue to appear.

Retroviruses are RNA viruses which replicate through a DNA intermediate; RNA as its genetic material and the virus must convert RNA to DNA for replication. This event is catalyzed by reverse transcriptase (viral DNA polymerase). Fig 1 shows the HIV infection cycle. HIV infects CD4+ T lymphocytes through their interactions with HIV envelope gp120 and gp41 glycoproteins and cell CD4 and chemokine receptors (Chemokines are soluble factors secreted by immune system cells to stimulate activity of other cells through their chemoattractant properties). gp41 binding to cell membranes causes fusion and entry of viral core into the cell. Viruses uncoat, viral RNA is reverse transcribed into DNA using RNA-dependent DNA polymerase (reverse transcriptase). Double stranded DNA (dsDNA) circularizes, enters the host cell nucleus and is integrated into the host genome via integrase. The proviral DNA is then transcribed by host cell machinery into viral RNA which is translated to make viral proteins and progeny viral RNA for new virons. Virons bud and are released; maturation requires protease-dependent cleavage of viral polypeptide (gag-pol) into active enzymes (reverse transcriptase, protease and integrase) and structural proteins.

PRINCIPLES OF DRUG THERAPY: HIV reverse transcriptase (RT) is one of the few selective targets for drug intervention. However, it is highly prone to making errors in transcribing RNA into DNA and thus leading to mutations in protein target including the RT itself. The HIV genome is ~104 base pairs and mutations at every nucleotide occur each day in untreated patients and every double mutation occurs within 100 days. Since only replicating HIV can accumulate mutations, complete suppression of replication can reverse CD4 lymptocyte depletion and prevent the appearance of resistance. Thus, the goal of therapy is to inhibit viral replication as completely and durably as possible while minimizing toxicity. This requires the administration of multiple drugs simultaneously. Each drug drug have a different mechanism of action in order to counter rapid mutation and to minimize drug toxicity (combinations allow for lower doses of each drug)

Four Classes of drugs

1. nucleoside reverse transcriptase inhibitors (NRTIs): competitive inhibitor of RT action. They are converted by host cell kinases into ddNTP (dideoxynucleotide trisphosphates like ddATP,ddCTP, ddTTP) which can bind to RT, but lack the 3’ hydroxyl group required for extension of the DNA chain. Thus, after they are incorporated into DNA they cause termination of elongation.

e.g. azidodideoxythymidine; zidovudine (AZT; RETROVIR) - a thymidine analog didanosine (VIDEX) (or dideoxyinosine) - an adenosine analog lamivudine (EPIVIR) - a cytosine analog abaracavir (ZIAGEN) - a guanosine analog

2. non-nucleoside reverse transcriptase inhibitors (NNRTIs): inhibit viral RT by binding adjacent to the enzyme’s active site and inducing a conformational change in the enzyme resulting in inhibition of activity. These drugs have NO effect on HIV-2 infections.

e.g. efavirenz (SUSTIVA)3. nucleotide reverse transcriptase inhibitors (NTRTIs): the only member of this class approved for use is tenofovir (VIREAD). It is a phosphorylated adenosine analog (tenofovir phosphate) converted by kinases to tenofovir diphosphate. Tenofovir diphosphate then competes with dATP for binding on RT and causes termination following its incorporation into DNA.4. protease inhibitors: HIV protease processes viral precursor polypeptide into active viral enzymes (RT, protease and integrase) and structural proteins. Inhibition of protease activity prevents the maturation newly released virons. Protease inhibitors bind reversibly to the active site of the enzyme, preventing access by viral polypeptide.

Study Questions

1. What is chemotherapy? What determines the success of chemotherapy?

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2. What kinds of adverse responses can be caused by antibiotics? What are superinfections and what increases the risk of causing them?

3. What is resistance? What 4 general mechanism lead to resistance? What enhances the risk of bacterial resistance?

4. How are antibiotics classified? Distinguish between bacteriocidal and bacteriostatic.5. How do penicillins and cephalosporins work? Re they bacteriocidal or -static? What kind of resistance

can develop?6. Why are fungal infections particularly difficult to treat?7. What are retroviruses? What aspect of HIV reverse transcriptase activity contributes to the appearance

of resistance? How are drug therapies designed to overcome this problem?8. Why is AIDS such a significant world health problem

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ANTINEOPLASTIC DRUGS (CANCER CHEMOTHERAPY)

CANCER is a disease of cells characterized by a shift in the control mechanisms governing cell growth and proliferation. Normal cells grow in an orderly fashion. Cancer cells 1) proliferate excessively, 2) are not contact-inhibited, 3) lack cell adhesiveness allowing for metastases and 4) are "immature" or undifferentiated cells.

Modern chemotherapy started with the observation that nitrogen mustards could inhibit human lymphomas and leukemias. Some cancers have a 40-80% “cure” rate using chemotherapy or hemotherapy plus surgery or radiation. Some tumors are controllable with chemotherapy (prolonged life, tumor shrinkage, improvement in symptoms. Some are resistant to most currently available types of intervention.

Types of neoplasms1. adenoma: a benign epithelial neoplasm forming a gland or gland-like structure. These growths tend

to compress adjacent structures, but do not invade the surrounding tissue2. carcinoma: a malignant (i.e. life-threatening) epithelial neoplasm3. sarcoma: a highly malignant mesodermal connective tissue neoplasm

Principles of Cancer Chemotherapy1. the ideal drug would only kill cancer cells. Cancer cells are rapidly dividing cells and thus are more

sensitive to chemotherapeutic drugs. However, tissues like bone marrow (anemia and leucopenia), GI mucosa and hair cells are also rapidly dividing and therefore likely sites for toxic side effects

2. drugs are most effective against small tumors since they have more proliferating cells and an adequate blood supply. 3. the neoplastic cell burden is important; a patient with widespread cancer may have 1012 (1 trillion) cells

throughout the body. At a given drug dose, anti-cancer drugs kill a constant fraction of the tumor cells rather than a fixed number of cells. Thus, a tolerable dose of an antineoplastic drug may produce a 3 -log cellkill ( 99.9% cytotoxicity) but still leave 109 (1 billion) cells untouched 99.9% killed means that 0.1% or 109 cells remain). This is the LOG CELL KILL HYPOTHESIS.

4. tumor removal and chemotherapy can eradicate micrometastases5. combinations of chemotherapeutic drugs are more effective than any one drug alone

(COMBINATION CHEMOTHERAPY). Drugs should have different organs of toxicity or different time courses for the onset of toxicity.

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CURE RATE TYPE OF CANCER

40-80% - children

acute lymphoblastic leukemiaBurkitt’s sarcomaEwing’s sarcomaretinoblastoma

rhabdomyosaromaWilms’ tumor

40-80% - adults

Hodkin’s diseaseNon-Hodkin’s disease

trophoblastic choriocarcinomatesticular and ovarian germ cell carcinoma

survivableovarian epithelial and breast carcinomas

oat cell carcinomas of the lungacute myelocytic leukemia

resistant

melanomacolorectal carcinomas

renal carcinomasnon-oat cell cancers of the lung

The major limiting factor in the use of cancer chemotherapeutic agents is their lack of specificity. Common toxic side-effects include 1) alopecia (hair loss), 2) nausea, vomiting and diarrhea and 3) bone marrow suppression (thrombocytopenia and leukopenia)

Classification of Drugs:

Scheme I: Effects on the cell cycle1. Cell Cycle Specific: effective during particular phases of the cell cycle. Thus scheduling of drug administration becomes important (e.g. methotrexate)2. Cell Cycle Non-specific: affect proliferating and resting cells alike (e.g. alkylating agents like cyclophosphamide)

Scheme II- Mechanism of Action

1. antimetabolites have structures similar to purine and pyrimidine bases which compose DNA and RNA i.e. they are structural analogs). They interfere with synthesis of nucleic acids.

a. fluorouracil (ADRUCIL): cell cycle-specific pyrimidine antagonist which inhibits the enzymatic incorporation of thymidine into DNA and into RNA.

b. methotrexate (MEXATE; MTX): cell-cycle specific folic acid antagonist which binds to the enzyme dihydrofolate reductase (DHFR), reducing the synthesis of purine nucleotides, inhibiting

DNA synthesis. Prevents the conversion of the vitamin (folic acid) to its active metabolite, tetrahydrofolate (THF). Resistance can develop as the result of reduced drug transport, changes in DHFR (lower affinity for MTX) or increased synthesis of DHFR (gene amplification resulting in increased mRNA for DHFR and increase amount of the enzyme produced)

2. alkylating agents transfer alkyl groups to DNA, cross-linking DNA strands and preventing DNA replication. Alkylating agents were the first class of drugs used in cancer chemotherapy. They are related to the mustard gases used in WW I. Cell cycle non-specific

cyclophosphamide (CYTOXAN): Some degree of leukopenia is necessary to indicate that the drug is working and is used as a guide for adjusting dosage. Severe leukopenia necessitates

interruption of therapy. mechlorethamine (MUSTARGEN): nitrogen mustard compound very toxic, has a very low

therapeutic index, and is a very potent vesicant (blister-former). 3 alkylator-like drugs cross-link using platinum complexes Cell cycle-nonspecific. Significant effects on

renal function (platinum is a metal) and occasional acoustic nerve dysfunction. There is little/no bone marrow suppression

cisplatin (PLATINOL)carboplatin (PARAPLATIN))

4. antibiotics block DNA to RNA transcription, inhibiting RNA and protein synthesis. These include the anthracyclines: doxorubicin (ADRIAMYCIN) and daunorubicin (CERABIDINE) actinomycins: dactinomycin (ACTINOMYCIN D), bleomycin, mitomycin and plicamycin)

They also bind to membranes, changing fluidity and ion transport and may also generate free radicals which damage cell membranes.

5. mitotic inhibitors block cell division in metaphase by disrupting the cytoskeletal microtubules. Mitotic inhibitors are plant alkaloids with similar mechanisms of actions. They inhibit cell division by causing depolymerization of cytoskeletal elements like microtubules, arresting cell division at metaphase.

vinblastine (VELBAN) and vincristine (ONCOVIN) cause bone marrow depression, alopecia and neurotoxicity.

6. hormones are used to treat neoplasm whose growth is hormone-dependent. These include the sex hormone estrogen and testosterone and adrenocortical hormones like cortisol (and its synthetic forms).

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These agents are not effective in cancerous tissues without receptors for these hormones. However, it is relatively easy to determine if receptors are present and this can predict responsiveness to hormone or ablation therapy.

Treatment of bone marrow suppression1. filgrastim (NUPOGEN): recombinant human Granulocyte-Coloy Stimulating Factor (rhG-CSF) used to accelerate the recovery of neutrophils)2. sargramostin (PROKINE: Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) used to increase the production and function of ganulocytes and macrophages and accerelate bone marrow repopulation3. epoietin (PROCRIT): recombinant erythropoietin used to stimulate the production of red blood cells and treat anemia

New Target Therapeutics1. imantinib (GLEEVEC): a rationally designed inhibitor of rationally designed inhibitor of bcr-abl kinase found in chronic myelogenous leukemia (CML). Rearrangement of Philadelphia chromosome links tyrosine kinase bcr to tyrosine kinase abl which provides unique target in CML. Resistance is already emerging

2. herceptin (TRASTUZUMAB: a humanized monoclonal antibody against HER2 (the EGF receptor).

HER2 over-expressed in ~25% of breast cancers. HER2/neu/erbB2 overexpression is an aggressive form of estrogen receptor deficient breast cancer 3. irressa (ZD1839): an EGF receptor tyrosine kinase inhibitor in clinical trials

Study Questions

1. Describe the three types neoplasms2. What are the 5 principles of cancer chemotherapy? What is the log cell kill hypothesis?3. What are the most common sites for cancer drugs toxicity? Why are they susceptible? What drugs

can be used to treat bone marrow suppression?4. what are the 6 “traditional” classifications of anti-neoplastic drugs?5. What is mean by the term targeted therapeutics?

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