Pharmacodynamics 2

Question 1

1. What are the major types of dose-response curves?

Answer 1

1. Graded → effect of various doses of a drug on a whole animal or human or an in vitro experiment
2. Quantal → effect of various doses of a drug on a population of animal or human subjects (in vitro plots concentrations EC50, in vitro plots doses ED50)

Question 2

2. How would you describe the graphic relationship of a drug concentration and effect curve?

Answer 2

Hyperbolic

Question 3

3. What is the equation of the drug concentration v effect curve?

Answer 3

E= (Emax*C)/(C+EC50)
E = effect observed at concentration C
Emax = max response produced by the drug
EC50 = concentration of drug that produces 5-% of the maximal effect

Question 4

4. What is the equation of the drug-receptor binding curve?

Answer 4

B = (Bmax*C)/(C+Kd)
B = drug bound to receptor
C = concentration of free drug
Bmax = total concentration of receptor sites
Kd =concentration of free drug at which half of the receptors are occupied (receptor affinity – if Kd is low, binding affinity is high!)
*This is the equation where when the drug concentration increases the number of receptors occupied by drug increases

Question 5

5. What is the relationship b/t the dose-response curve and drug-receptor binding curve?

Answer 5

The shape of both of these curves are analogous. This is because as the drug binds the receptor, the drug will elicit its effect. Therefore they will both increase together. These graphs are generally represented in the logarithm of the dose of the drug therefore the curve changes from a hyperbolic state to a signmoid curve with a linear midpoint.
*binding curve has Kd and the effect curve has EC50 → Kd is usually larger than the EC50 because you do not need to activated 50% of the receptors to get half the maximal effect – this is due to signal amplification (large response with minimal receptor activation)

Question 6

6. What are spare receptors?

Answer 6

Receptors that do not need to be activated to produce a full effect of the drug. There are spare receptors present when the EC50 is less than the Kd. The presence of spare receptors indicates signal amplification.

Question 7

7. Define efficacy.

Answer 7

Efficacy (aka maximal efficacy) is the maximal effect (Emax) a drug can produce. It is determined mainly by the nature of the receptor and its associated effector system. Clinical effectiveness of a drug depends on maximal efficacy. Efficacy is the measure of the intrinsic ability of a drug to produce an effect.

Question 8

8. Define potency.

Answer 8

Potency is a measure of the concentration of amount of drug necessary to produce an effect of a given magnitude. The EC50 is usually used to determine the potency, therefore the potency depends on the affinity (Kd) and the efficiency with which the drug-receptor interaction is coupled to the response. Potency is generally only clinically important when a drug is administered in inconveniently large amounts.

Question 9

9. Define agonist and antagonist.

Answer 9

Agonist – drug that binds to and activates a receptor bringing about an effect
Antagonist – drug that inhibits the action of an agonist but has no effect in the absence of the agonist

Question 10

10. What are the different types of receptor antagonists?

Answer 10

1. competitive
2. noncompetitive
3. uncompetitive
   * receptor antagonist binds to the same receptor to which the agonist binds (same site!)

Question 11

11. What are the different types of nonreceptor antagonists?

Answer 11

1. functional antagonism
2. chemical antagonism
   * this is an antagonist that does not bind to the receptor which the agonist binds but rather inhibits the response to the agonist

Question 12

12. What is a competitive antagonist?

Answer 12

A competitive antagonist binds to the same site that the agonist binds. By binding this site, it prevents the binding of the agonist to the receptor therefore inhibits the function of the cell. These antagonists can be reversible where when the amt of agonist can be increased exponentially to overcome the antagonist or irreversible where a covalent bond is formed with the antagonist and active site preventing any more binding of the agonist. Emax remains the same for reversible antagonists and there is a right shift. The Emax is reduced with irreversible competitive antagonists and is insurmountable.

Question 13

13. Give an example of an irreversible competitive antagonists.

Answer 13

Phenoxybenzamine is an irreversible alpha-adrenoceptor blocker used to treat pheochromocytoma.

Question 14

14. What is a noncompetitive antagonist?

Answer 14

This is an allosteric antagonist. The antagonist binds to the receptor at a site different from the agonist binding site and prevents agonist binding without actually binding to the agonist site. This type of antagonism is insurmountable and leads to a decrease in Emax. Ex. ketamine which is a dissociative anesthetic as a noncompetitive antagonist at the NMDA receptor

Question 15

15. What are the different types of functional antagonism?

Answer 15

1. indirect antagonism → binds an intermediate macromolecule in the pathway that links the receptor to the physiological effect (ex. drug that inhibits protein kinase A blocks effect of B-adrenoceptor agonist)
2. Physiological antagonism → agonist opposes another agonist through different receptors. Ex. epinephrine increases blood pressure and bronchodilation whereas histamine decreases blood pressure and bronchoconstriction

Question 16

16. What is chemical antagonism?

Answer 16

Drug reacts chemically with an agonist to form a product that cannot activate a receptor. Ex. protamine is a protein which is positively charged at physiologic pH which can be used to counteract the effects of heparin which is an anticoagulant that is negatively charged.

Question 17

17. What is the difference b/t a full and partial agonist?

Answer 17

Full agonist – produces a maximal response
Partial agonist – produces submaximal response (lower than the full receptor response) – aka lower Emax
**A partial agonist acts as a competitive antagonist in the presence of a full agonist by competing with the full agonist for receptor occupancy

Question 18

18. What is an inverse agonist?

Answer 18

Many receptor systems exhibit activity in the absence of an agonist suggesting that part of the receptor is always in the active state = constitutive activity. Inverse agonists revers the constitutive activity of a receptor behaving like a competitive antagonist. Ex. famotidine, losartan, metoprolol, risperidone

Question 19

19. How would you determine if a drug is said to be selective?

Answer 19

There is at least a 10-fold difference b/t its binding affinity for its first target (desired effects) versus its second target (mediates its adverse effects). The greater the difference the more selective the drug is. As binding affinity increases to a 100-fold difference from 10-fold difference, the involvement of a second target is virtually absent due to increased degree of separation from desired and adverse side effects.

Question 20

20. Define desensitization and tachyphylaxis.

Answer 20

These terms are synonymous describing the effect of a drug that gradually diminishes when it is given continuously or repeatedly. This decrease develops in the course of a few minutes.

Question 21

21. Define tolerance, refractoriness, and drug resistance.

Answer 21

Tolerance → more gradual decrease in responsiveness to a drug taking days or weeks to develop
Refractoriness → loss of therapeutic efficacy
Drug resistance → loss of effectiveness of antimicrobial or anticancer drugs.

Question 22

22. What are different mechanisms that lead to desensitization and tolerance?

Answer 22

1. change in receptors – activation of ion channel receptors
2. internalization of receptors – decrease in receptors expressed on cell surface
3. exhaustion of mediators – decrease in neurotransmitter stores
4. increased metabolic degradation of the drug – repeated administration produces lower plasma concentration
5. physiological adaptation – drugs effect is nullified by a homeostatic response (ex. blood pressure lowering effect of thiazide diuretics is limited b/c of gradual activation of renin-angiotensin system)

Question 23

23. Discuss quantal dose-effect curves.

Answer 23

A quantal dose-effect curve is an all-or-nothing response where the relationship of a dose is plotted against the fraction of the population who responds. The response is either present or not present. The curve will be sigmoid shape but the slope of the quantal dose-effect curve is an expression of the pharmacodynamics variability in the population.

1. ED50 – median effective dose (50% of individuals exhibit the specified quantal effect)
2. TD50 – dose required to produce a particular toxic effect in 50% of animals
3. LD50 – if the dose effect is death of the animals
   * These curves provide potency and selectivity for the drug
   * Only graded dose-response curves indicate max efficacy of drug and quantal dose-response curves indicate potential variability of responsiveness among individuals

Question 24

24. What is the therapeutic index?

Answer 24

The therapeutic index is defined as the ratio of the TD50 to the ED50. TI represents the safety of a drug. The larger the ratio the more dangerous the drug.
TI = (TD50/ED50) or TI = (LD50/ED50)

Question 25

25. What is the therapeutic window?

Answer 25

The dosage range b/t the min effective therapeutic concentration and the min toxic concentration [ex. 8-18 mg/L]