dr. steven i. dworkin pharmacology for the health sciences lecture 2b

Dr. Steven I. Dworkin

Pharmacology for the Health Sciences

Lecture 2b


Dose-response curve The classic S-shape describes the gradual increase in biological response that occurs with increasing doses of a dose (dose—receptor activation).Threshold is the dose producing the smallest measurable response.The dose at which the maximum response is achieved is the ED 100 (100% effective dose), while the ED50 is the dose that effectively produces 50% of the maximum response


Dose-Response Curve

• Allows for the comparison of different drugs– The relative position the curves for a drug on the x-axis indicates potency

• Reflects the affinity of each drug for the receptor that mediates the measured response.

• Drugs may differ in affinity for the receptor but reaches the same maximum on the y-axis, indicating that they have identical efficacy.

• Drugs that work by the same mechanism produce parallel curves.• Curves that are shifted to the right are less potency.

– A lower-potency drug is frequently just as effective when a higher dose is administered.

– The dose-response curve depends on the response that is being measured.– A drug may be less potent for one response and more potent on

another.


Dose—response curves for four analgesic agents Each curve represents the increase in pain threshold (the magnitude of painful stimulus required to elicit a with drawal response) as a function of dose.The ED50 for hydromorphine, morphine,and codeine help compare potency.The linear portions of the curves for the opiate analgesics are parallel, sug gesting they work through the same mechanism. Aspirin is not an opiate and relieves pain by a very different mechanism of action, so the shape of the curve is distinct. In addition, aspirin's maximum effectiveness never reaches the level of the opiates


The therapeutic index calculates drug safety

• Among the multiple responses to any drug, some are undesirable or even dangerous side effects and need to be evaluated carefully in a therapeutic situation. For example, by drug A, which is prescribed to reduce anxiety. The blue curve shows the number of individuals who experience reduced anxiety at various doses of the drug.

• The purple curve shows the number of persons suffering respiratory depression (a toxic effect) from various doses of the same drug.

• Comparing the ED50 for relieving anxiety (i.e., the dose at which 50% of the population show reduced anxiety) and the TD50 (50% toxic dose; the dose at which 50% of the population experiences a particular toxic effect) for respiratory depression.

• The dose needed to provide significant clinical relief to many patients (50%), almost none of the patients would be likely to experience respiratory depression.

• The drug has a relatively favorable therapeutic index (TI = TD50/ED50).

• In contrast, the dose of drug A that produces sedation and mental clouding (red curve) is not very different from the ED 50.

• That small difference means that there is a high probability that a dose effective in reducing anxiety is likely to also produce significant mental clouding and sedation, which may represent serious side effects for many people who might use the drug


Receptor antagonists compete with agonists for binding sites

• Competitive antagonists– Can be displaced from those sites by an excess of the agonist.

• Increased concentration of active drug can compete more effectively for the fixed number of receptors.

– If the agonist and antagonist have similar affinities for the receptor, then if 100 molecules of drug and 100 molecules of antagonist were both present at the receptor, the probability of an agonist acting on the receptor would be 1 to 1.

– If drug molecules were increased to 1000, the odds of agonist binding rise to 10 to 1; at 1,000,000 agonist molecules.

» The presence of the antagonist is of no consequence to the biobehavioral effect measured.



• Non-competitive antagonists are drugs that reduce the effect of agonists in ways other than competing for the receptor.

– A noncompetitive antagonist may impair agonist action by:

• Binding to a portion of the receptor other than the agonist binding site

• Disturbing the cell membrane supporting the receptor

• By interfering with the intracellular processes that were initiated by the agonist-receptor association.

– In general, the shape of the dose-response curve will be distorted and the same maximum effect is not likely to be reached.

• Biobehavioral interactions can also result in several different possible outcomes


Drug antagonism (A) The effect of a competi tive antagonist (naloxone) on the analgesic effect of morphine. The addition of a competitive antagonist essentially reduces the agonist's potency, as shown by the parallel shift of the dose-response curve to the right. (B) In contrast, adding a non-competitive antagonist usually produces a distinct change in the shape of the dose-response curve, showing that it does not act at the same receptor site. Also, regardless of the increase in morphine, the maximum efficacy is never reached.



• Biobehavioral interactions can also result in several different possible outcomes.– Physiological antagonism involves two drugs that act in two distinct

manners but interact in such a way that they reduce each other's effectiveness in the body.

• One drug may act on receptors in the heart to increase heart rate, while the second may act on distinct receptors in the brain stem to slow heart rate.

• Two agents may have additive effects if the outcome equals the sum of the two individual effects.

• Finally, potentiation refers to the situation in which the combination of two drugs produces effects that are greater than the sum of their individual effects.

– Potentiation often involves issues of pharmacokinetics such as altered metabolic rate or competition for depot binding, which may elevate free drug blood levels in unexpected ways.


Possible results of the interac tion of two drugs (A) Physiological antago nism results when two doses produce opposite effects and reduce each other's effectiveness. (B) Additive effects occur when the combined dose effect equals the sum of each alone. (C) Potentiation is said to occur when the combined dose effects are greater than the sum of the individual dose effects


Biobehavioral Effects of Chronic Drug Use

• Many prescription and over-the-counter drugs are taken on a regular basis for chronic medical or psychiatric conditions.

• Drugs are taken for periods of weeks, months, or even years.• Recreational drugs also are most often used repeatedly rather than on only a

single occasion.• When a drug is used on several occasions (i.e., chronically administered),

changes in the magnitude of response to the drug frequently occur.• Most often the response diminishes with chronic use (tolerance), but

occasionally the effects are increased (sensitization).• In some cases, selected effects of a particular drug decrease while others

increase in magnitude.– A good example is amphetamine

• Tolerance to decrease in food intake• Sensitization to locomotor activity


Repeated drug exposure can cause tolerance

• Tolerance is defined as a diminished response to drug administration or a shift to the right in the dose effect-curve.

– In other words, tolerance has developed when increasingly larger doses of a given drug must be administered to obtain the same magnitude of biological effect that occurred with the original dose.

• Cross-tolerance is defined as the development of tolerance to one drug that diminish the effectiveness of a second drug.

– For example, the effective anticonvulsant dose of phenobarbital is significantly larger in a patient who has a history of chronic alcohol use than in a patient who has not developed tolerance to alcohol.


Drug Tolerance

• Some drugs induce tolerance relatively rapidly (LSD), while others take weeks of chronic use (barbiturates) or never cause significant tolerance (antipsychotics).

• In some cases tolerance even develops during a single administration, as when an individual experiences significantly greater effects of alcohol as her blood level rises than she experiences several hours later when his blood level has fallen to the same point.

• This form of tolerance is called acute tolerance.

• Also, it is important to be aware that not all biobehavioral effects of a particular drug demonstrate tolerance equally.


Tolerance

• Biobehavioral effects of a particular drug do not demonstrate tolerance equally.

• Behavioral or context specific tolerance disappears in a novel environment.

– Indicating the importance of behavioral and drug history in the development of biobehavioral tolerance.


Classical conditioning of drug-related cues Although dose-taking equipment and the immediate environment is initially a meaningless stimulus to the individual, its repeated pairing with the dose (unconditioned stimulus; US), which naturally elicits euphoria, arousal, or other desirable effects (unconditioned response; UR), gives the dose-taking equipment new meaning. Ultimately the equipment and environment alone (now a conditioned stimulus; CS) could elicit dose effects (conditioned response; CR) in the

absence of the dose.

Tolerance to morphine-induced hyper thermia Following an identical series of prior morphine injec tions (5 mg/kg SC for 10 days), rats were tested with a morphine injection and changes in body temperature were measured for the next two hours. One group of rats was given the morphine in the same environment in which they were previously treated ("Same"), and the second group were tested in a novel environ ment ("Different").The animals treated in the same environ ment show much less hyperthermia, which indicates tolerance


Chronic drug use can cause sensitization

• Sensitization, sometimes called reverse tolerance, is the enhancement of particular drug effects following repeated administration of the same dose of drug.– Prior administration of cocaine to animals significantly increases

motor activity and stereotypy (continuous repetition of a simple action such as head bobbing) produced by subsequent stimulant administration.

– Chronic administration of higher doses of cocaine has also been shown to produce an increased susceptibility to cocaine-induced catalepsy, in which the animal remains in abnormal or distorted postures for prolonged intervals, as well as hyperthermia and convulsions.

– Cocaine and amphetamine are examples of drugs that induce tolerance for some effects (euphoria) and sensitization for others.


Chapter Questions• 1)What are the basic differences between pharmacokinetics and

pharmacodynamics?

• 2)What process are involved in the initiation of a drug effect?

• 3)Why do drugs have an effect on biologic systems or why are we influenced by exogenous substances?

• 4)What are some of the differences between agonists and antagonists?

• 5)What is the importance of a curve that is shifted to the left on a dose-effect curve?

• 6)What is the therapeutic index and why is it important?

• 8)When dose tolerance occur?

• 9)What is the difference between tolerance and sanitization?

• 10) Draw the dose–response curves for two drugs with the same efficacy, given that drug A is twice as potent as drug B.


Lecture Summary

• The concept of the receptor is vital to pharmacology, as drugs have biological effects only because they interact with receptors on target tissues.

• Drugs or ligands that bind and are capable of changing the shape of the receptor protein and subsequently alter cell function are called agonists.

• The ligands that attach most readily are said to have high affinity for the receptor. Antagonists, in contrast, are capable of binding and may have high affinity, but they produce no physiological change, that is, they have little or no efficacy. Antagonists also prevent agonists from binding to the receptor at the same moment, hence "blocking" agonist activity.

• Rather than being fixed, the number of receptors changes to compensate for either prolonged stimulation (causing down-regulation) or absence of receptor stimulation (up-regulation of recep tors). Pharmacologists study the relationship between drug, receptor, and biobehavioral effect by analyzing dose–response curves.

• The curves show the threshold dose at which biobehavioral effects can first be measured. With increasing doses, the effect also increases in a linear fashion until the maximum effect is reached. The ED50 is the dose that produces a half-maximal (50%) effect and is used to compare the potency of drugs that produce similar biobehavioral effects. The more potent drug is the one that has the lower ED50. Comparison of the ED50 with the TD50 (50% toxic dose) for a single drug helps us calculate the therapeu tic index. A large therapeutic index suggests that the drug is effective at low doses but the toxic dose is high, making the drug relatively safe. A small TI suggests that there is not much difference between the effective and toxic doses, so the drug is potentially dangerous.


Lecture Summary

• Pharmacologists study the relationship between drug, receptor, and biobehavioral effect by analyzing dose–response curves.

• The curves show the threshold dose at which biobehavioral effects can first be measured.

• With increasing doses, the effect also increases in a linear fashion until the maximum effect is reached. The ED50 is the dose that produces a half-maximal (50%) effect and is used to compare the potency of drugs that produce similar biobehavioral effects.

• The more potent drug is the one that has the lower ED50. Comparison of the ED50 with the TD50 (50% toxic dose) for a single drug helps us calculate the therapeutic index.

• A large therapeutic index suggests that the drug is effective at low doses but the toxic dose is high, making the drug relatively safe.

• A small TI suggests that there is not much difference between the effective and toxic doses, so the drug is potentially dangerous.


Lecture Summary

• Receptor antagonists are competitive if they reduce the effects of an agonist by binding to the same receptor and reducing agonist–receptor interaction.

• This type of interaction reduces the potency of the agonist, as shown by a parallel shift of the dose–response curve to the right. However, the maximum effect is not altered, because raising the agonist concentration can overcome the action of the antagonist.

• Noncompetitive antagonists impair agonist function by altering the receptor at a modulatory site, by impeding the initiation of intracellular processes, or by disturbing the membrane surrounding the receptor.

• Drugs can also interact by altering the biological effects beyond the receptor's site of action. Drugs can produce physiological antagonism, additive effects, or potentiation. In potentiation, the two drugs produce effects greater than the sum of their individual effects.


Lecture Summary

• When drugs are administered on more than one occasion, the magnitude of drug response often changes.

• Most often chronic drug use leads to tolerance, that is, a diminished effect, but in some circumstances drug effects increase with repeated use, a phenomenon called sensitization.

• Cross-tolerance may occur if repeated use of one drug reduces the effectiveness of a second drug.

• Although there are several types of tolerance, with distinct mechanisms, tolerance in general is a reversible condition.

• Tolerance is dependent on the dose and frequency of use, although some drugs induce tolerance rapidly while others require longer treatment or never cause tolerance at all.

• Further, not all effects of a drug undergo tolerance to the same extent or at the same rate.

• Drug-disposition tolerance occurs when drugs induce the formation of the liver's metabolizing enzymes. Increased enzyme action reduces the effective blood level of the drug more rapidly, so the biobehavioral effect is reduced.


Lecture Summary

• Pharmacodynamic tolerance depends on the compensation of the nervous system to the continued presence of the drug.

• Changes may include increases or decreases in receptor number or other compensatory intracellular processes.

• Behavioral tolerance occurs when learning processes and environmental cues contribute to the reduction in drug effectiveness.

• Habituation, Pavlovian conditioning, and operant conditioning can contribute to the change in drug response.

dr. steven i. dworkin pharmacology for the health sciences lecture 2b

Documents

dose of drug

toxic dose

effective dose

dose effective

function of dose

higher dose

drug safetyamong

measured response