General Principles ofPharmacology and Toxicology

Parisa Gazerani, Pharm D, PhDAssistant Professor

Center for Sensory-Motor Interaction (SMI)Department of Health Science and TechnologyAalborg University

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Pharmacodynamic II

• Today, we’ll explore the Dose response curves, Affinity, Efficacy,Potency, long term drug effects and Drug Interactions and a bitmore!

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Drug-Receptor Interactions

What is the importance?

• Most drugs interact with receptors that will determine therapeutic and toxiceffects of the drug.

• Receptors largely determine the quantitative relations between dose of adrug and pharmacologic effect.

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Dose --- Concentration, make it clear Doc!

Check it out!http://homepage.mac.com/mattocks/morfz/rx/drugcalc.html

• The term "dose" is often used loosely. The term "dose" strictly onlyapplies to experiments performed with animals or people, where youadminister various doses of drug. You don't know the actualconcentration of drug -- you know the dose you administered.

• Term "dose-response curve" is also used more loosely to describe in vitroexperiments where you apply known concentrations of drugs. The term"concentration-response curve" is a more precise label for the results ofthese experiments.

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Dose - Response Curves

Two important properties of drugs can be determined by dose - response curves:

• Efficacy of a drug

• Potency of a drug

However first the drug needs to bind... (affinity)

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Drug–receptor binding

• We can mathematically express the relationship between the percentage (orfraction) of bound receptors and the drug concentration:

[D] = the concentration of free drug;[DR] = the concentration of bound drug[Rt] = the total concentration of receptors (sum of the concentrations of unbound

(free) receptors and bound receptors)Kd = the dissociation constant for the drug from the receptor.

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Affinity and Intrinsic Activity

• All ligands have affinity for a receptor/target

• Remember that ligand is an agonist or an antagonist, if it binds, it has affinity

• A drug's action is affected by the quantity of drug that reaches the receptor and thedegree of attraction (affinity) between it and its receptor.

• Once bound to their receptor, drugs vary in their ability to produce an effect (intrinsicactivity).

• Drugs vary in their affinity and intrinsic activity:

• Drugs that activate receptors (agonists) must have both great affinity and intrinsicactivity: They must bind effectively to their receptors, and the drug bound to itsreceptor (drug-receptor complex) must be capable of producing an effect in thetargeted area.

• Drugs that block receptors (antagonists) must bind effectively but have little or nointrinsic activity, because their function is to prevent an agonist from interactingwith its receptors.

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How to determine the affinity? Dissociation Constant (Kd)

• The dissociation constant is commonly used to describe the affinity betweena ligand (D) and its target/Receptor (R) i.e. how tightly a ligand binds to aparticular receptor.

D+R DR Kd =

[D], [R] and [DR] represent the concentrations of the ligand (drug), target andcomplex, respectively.

[DR]

[D] x [R]

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Kd

• The value of Kd can be used to determine the affinity of a drug for its receptor.

• Affinity describes the strength of the interaction (binding) between a ligand andits receptor.

• The higher the Kd value, the weaker the interaction and the lower the affinity.

• The converse occurs when a drug has a low Kd. The binding of the ligand to thereceptor is strong, and the affinity is high.

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Both of these drugs have comparable affinity for μ opioid receptors

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Are you interested??

Take a look at the following review article...

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Efficacy and Potency

• A drug's effects can be evaluated in terms of:

• strength (potency)or

• effectiveness (efficacy)

• Efficacy refers to the potential maximum therapeutic response that a drug canproduce.

• For example, the diuretic furosemide (LASIX) eliminates much more saltand water through urine than does the diuretic chlorothiazide (DIURIL).Thus, LASIX has greater efficacy than DIURIL.

• Potency refers to the amount of drug (usually expressed in milligrams) needed toproduce an effect, such as relief of pain or reduction of blood pressure.

• For instance, if 5 milligrams of drug A relieves pain as effectively as 10milligrams of drug B, drug A is twice as potent as drug B.

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However….

• Greater potency or efficacy does not necessarily meanthat one drug is preferable to another.

• When judging the relative merits of drugs for a patient,doctors consider many factors, such as side effects,potential toxicity, duration of effect (which determinesthe number of doses needed each day), and cost.

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Relationship of binding to effect ---- Efficacy

• The binding of the drug to its receptor initiates events that ultimately lead toa measurable biologic response.

[E] = the effect of the drug at concentration [D][Emax] = the maximal effect of the drugKd = the dissociation constant for the drug from the receptor.

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Efficacy

• Efficacy refers to the potential maximum therapeutic response that a drugcan produce.

• So by definition, antagonists have no efficacy. Efficacy is a function ofreceptor activation, and antagonist binding does not change receptoractivation.

Heroin is a full agonistNaloxone (antagonist) has no efficacy

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Efficacy

Heroin is a full agonistCodeine is a partial agonist

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Efficacy

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The concentration-response curve is shown here for a full agonist and a partial agonist.The partial agoinst, in this case, can only produce 60% of the maximal response.

Efficacy

Partial agonists (e.g. buspirone, aripiprazole, buprenorphine, or norclozapine)

In general, a full agonist has a strong affinity for its receptor and good efficacy.

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Potency

Potency refers to the amount of drug needed to produce an effect. It is anexpression of the activity of a drug, in terms of the concentration or amountneeded to produce a defined effect.

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Potency – EC50 or ED50

• The concentration producing an effect that is fifty percent of the maximum isused to determine potency (EC50 or ED50).

• EC50 or ED50 = drug dose/concentration that shows fifty percent of maximalresponse.

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Potency vs Efficacy

• Drug A has greater biologicactivity per dosing equivalentand is thus more potent thandrug B or C.

• Drugs A and C have equalefficacy, indicated by theirmaximal attainable response(ceiling effect).

• Drug B is more potent thandrug C, but its maximal efficacyis lower.

C

B

A

Log Drug

Resp

on

se

´%)

100

50

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Which drug is more potent?

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Real Scenario!

• Candesartan and irbesartan are angiotensin–receptor blockers that are usedalone or in combination to treat hypertension.

• Candesartan is more potent than irbesartan because the dose range forcandesartan is 4 to 32 mg, as compared to a dose range of 75 to 300 mg forirbesartan.

Candesartan Irbesartan

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Test Yourself!

1. Which drug has the highest potency?2. Which drugs has the biggest maximal effect?3. Which drug has the lowest potency?

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Therapeutic Index or Therapeutic ratio

• The therapeutic index of a drug is the ratio of the dose that produces toxicity tothe dose that produces a clinically desired or effective response in a population ofindividuals:

Therapeutic ratio = TD50 / ED50

• TD50 = the drug dose that produces a toxic effect in half the population

• ED50 = the drug dose that produces a therapeutic response in half the population.

• The therapeutic index is a measure of a drug's safety, because a larger valueindicates a wide margin between doses that are effective and doses that aretoxic.

• You may see LD50 instead of TD50 in some text books.

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Determination of therapeutic index

• In humans, the therapeutic index of a drug is determined using drug trials andaccumulated clinical experience. These usually reveal a range of effectivedoses and a different (sometimes overlapping) range of toxic doses.

Log Drug

Resp

on

se

´%)

100

50ED50 = 0.4TD50 = 40TI = 40/0.4

Toxicity

Efficacy

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Small and Large Therapeutic Index

warfarin, an oral anti-coagulant with a narrow therapeutic index (A)penicillin, an antimicrobial drug with a large therapeutic index (B)

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Warfarin

• Variation in patient response is mostlikely to occur with a drug showing anarrow therapeutic index, because theeffective and toxic concentrations aresimilar.

• For agents with a low therapeutic doseis critically important

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• For drugs such as penicillin, it is safeand common to give doses in excess(often about ten-fold excess) of thatwhich is minimally required to achievea desired response.

• In this case, bioavailability does notcritically alter the therapeutic effects.

Penicillin

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Some drugs with a low therapeutic index

LithiumDigoxinCarbamazepineCyclosporinPhenytoinPhenobarbitoneTheophylline (Aminophylline)

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Therapeutic window

• Do not confused this with therapeuticindex!

• Therapeutic window is the range ofplasma concentrations of a drug thatwill elicit the desired response in apopulation of patients.

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Selectivity in drug action

• It is related to the structural specificityof drug binding to receptors.

• Propranolol binds equally well to β1

and β2 adrenoreceptors, while Atenololand Metoprolol bind selectively to andblock β1 adrenoreceptors.

• Salbutamol is a selective β2

adrenoreceptor agonist andselectiveity could be achived byinhaling the drug to reach to the site ofaction in lungs.

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Real Scenario? --- Have a look at the following article!

Paccaly et al. J Clin Pharmacol .2006; 46: 45-51

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• Tolerance is a person's diminished response to a drug, which occurs whenthe drug is used repeatedly.

• When morphine or alcohol is used for a long time, larger and larger dosesmust be taken to produce the same effect.

• Usually, tolerance develops because metabolism of the drug speeds up(often because the liver enzymes involved in metabolizing drugs becomemore active) and because the number of sites (cell receptors) that the drugattaches to or the strength of the bond (affinity) between the receptor anddrug decreases.

Tolerance

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Dependence

• Tolerance is not the same as dependence or addiction.

• Dependence, which may be physical or psychologic, refers to a strongdesire to experience the effects of the drug.

• In physical dependence, the person may experience symptoms ofwithdrawal when the drug is stopped.

• Addiction is compulsive use and overwhelming involvement with a drug.

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• Strains of microorganisms (bacteria or viruses) are said to developresistance when they are no longer killed or inhibited by the antibiotics andantiviral drugs that are usually effective against them (or, in practice, whensignificantly higher than normal doses are required to have an effect).

• Cancer cells may develop resistance to chemotherapy drugs.

• Resistance appears because of the mutations that take place spontaneouslyin any group of growing cells, whether exposed to drugs or not. Most suchmutations change the cell's structure or biochemical pathways in a harmfulway. But some mutations change the parts of the cell that are affected bydrugs, decreasing the drug's ability to work (that is, causing resistance).

• Once tolerance or resistance has developed to a drug, doctors may increasethe dose or use a different drug.

Resistance

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Drug Interaction - Mechanisms

Interactions can be pharmacodynamic or pharmacokinetic. Some druginteractions are due to a combination of mechanisms. There are alsopharmaceutical interactions.

Pharmaceutical Interactions• These can be classified as those interactions that occur prior to systemic

administration. For example incompatibility between two drugs mixed in anIV fluid. These interactions can be physical (e.g. with a visible precipitate) orchemical with no visible sign of a problem.

Pharmacokinetic Interactions• This is when one drug affects the availability (absorption), distribution,

metabolism or excretion of another drug. A change in blood concentrationcauses a change in the drug’s effect.

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Pharmacodynamic Interactions

• These interactions are due to competition at receptor sites or activity of theinteracting drugs on the same physiological system. There is no change in theplasma concentrations of interacting drugs.

• Antagonist (Drugs with opposing pharmacological actions acting on the same receptor)

• E.g. salbutamol (a β2 agonist) with metoprolol (a β2 antagonist)

• Additive/synergistic (Drugs with a similar pharmacological action may have an additiveeffect)

• E.g. Fluoxetine (an SSRI) with clomipramine (a tricyclic antidepressantwith serotonergic activity) can cause serotonin syndrome in somepatients.

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Drug Interaction Resources

Dalhousie University:

http://dir.pharmacy.dal.ca/drugprobinteraction.php

Drug Interactions Checker:

http://www.drugs.com/drug_interactions.html

P450 data:

http://medicine.iupui.edu/flockhart/table.htm

Grapefruit Juice:http://www.cop.ufl.edu/fdic/profe.php?interaction_category=9

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Stockley’s Drug Interactions, 8th Edition

Edited by Karen Baxter BSc MSc MRPharmS. Published by PharmaceuticalPress, London, UK, 2008. ISBN 978-0-85369-754-1. Clothbound,vii + 1464 pp. (28.5 × 22.5 cm), $250. www.pharmpress.com

Drug Interaction Resources

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Study Hours --- A group work!

Find at least one pharmacodynamic, one pharmacokinetic druginteraction for your drug of choice with related mechanism

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We’ll meet again on Friday... And will explore the term ”pharmacogenetics”together.

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Test your pharmacodynamic knowledge!

If agonists and antagonists occupy the same receptor site, an effective antagonistshould exhibit

1. High intrinsic activity and high affinity

2. Low intrinsic activity and low affinity

3. High intrinsic activity and low affinity

4. No intrinsic activity and high affinity

4

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Which of the following are necessary requirements for a chemical to be termed adrug? (more than one answer)

1. Must selectively localize at the receptor site

2. Must possess sufficient potency

3. Must change the basic function of a tissue or organ tissue

4. Must to some degree be lipid or water soluble

5. Must usually be reversible in action

2,4,5

Test …

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If drug A has a greater efficacy than drug B, then drug A

1. Is more toxic than drug B

2. Has a greater affinity for the receptor than drug B

3. Has a greater margin of safety than drug B

4. Is capable of producing a greater maximum effect than drug B

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Test …

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In Figure 1, three different doses of drug A are tested for activity. In Figure 2, threedoses of drug B are tested for activity in the same test system. In Figure 3, threedoses of drug A are tested in the presence of the high dose of drug B. Based upon theresponses seen, which of the following statements best describe drugs A and B?

1. Drug A is a partial agonist; drug B is an antagonist

2. Drug A is an antagonist; drug B is an agonist

3. Drug A is an agonist; drug B is an antagonist

4. Drug A is an agonist; drug B is a partial agonist

5. Drug A is an agonist; drug B is neither an agonist nor antagonist

Test …

5

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When comparing drugs with respect to intensity of response, the drug thatproduces the greatest maximum effect is the one with the highest

1. Affinity

2. Potency

3. Efficacy

4. Therapeutic index

Test …

3

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Which of the following is an action of a noncompetitive antagonist?

1. Alters the mechanism of action of an agonist

2. Alters the potency of an agonist

3. Shifts the dose-response curve of an agonist to the right

4. Decreases the maximum response to an agonist

5. Binds to the same site on the receptor as the agonist

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Test …

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All of the following statements regarding receptor classes are true EXCEPT

1. Ion channels are confined to excitable tissue

2. Each cell is capable of producing only one G protein

3. Steroids bind to intracellular receptors

4. A hormone or neurotransmitter receptor may be an ion channel

5. Certain growth factors interact with receptors that have tyrosine-specificprotein kinase activity

Test …

2

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The maximum effect (Emax) achieved by a drug is a measure of

1. Potency

2. Efficacy

3. The quantal response

4. Antagonist magnitude

5. The therapeutic index (TI)

Test …

2

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The ED50 of a drug is:

1. The effective dose of a drug in 50% of the subjects tested

2. Half of the effective or therapeutic dose

3. The dose that gives 50% of the maximum effect

4. Is a measure of toxicity

Test …

3

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In order to be therapeutically useful, the selective effect of drugs on cellularcomponents must be

1. Reversible

2. Irreversible

3. Rapid

4. Continuous

5. Sustained

Test …

1

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Two drugs, A and B, have the same mechanism of action. Drug A in a dose of 5mg produces the same magnitude of effect as drug B in a dose of 500 mg.

1. Drug B is less efficacious than drug A

2. Drug A is 100 times more potent than drug B

3. The toxicity of drug A is lower than that of drug B

4. Drug A is a better drug if maximal efficacy is needed

5. Drug A has a shorter duration of action

Test …

2

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