Example short answer (10 minute) questions for PHA3801 Introduction to Drug Action theme

1. Write brief notes to explain the differences between (i) affinity, efficacy and potency (ii) full agonist, partial agonist and antagonist

2. Use diagrams to illustrate the following statements.

(i) Agonist A is more potent than agonist B in producing contractions of an isolated tissue preparation of smooth muscle. (ii) On an isolated preparation of guinea-pig ileum, antagonists X and Y are both competitive antagonists of histamine, but antagonist X is more potent than antagonist Y.

3. List the 4 receptor superfamilies.

(ii) For each of these families, indicate the main events that occur following activation of the receptor by an agonist drug, highlighting the time scale of the response. (iii) For each of the superfamilies, give an example of a receptor type, as well as an example of an agonist, an antagonist and a resultant response.

4. (i) Identify two (2) major pathways that lead to the generation of second messengers, giving an example of each (ii) Describe ONE of these pathways in more detail, indicating the processes that occur subsequent to receptor activation to alter the activity of the cell. (iii) How is the specificity of the second messenger effect determined?

5. Membrane phospholipids are important precursors for the prostaglandins and leuckotrienes. a. Illustrate the main synthetic pathways for leukotrienes, prostacyclin and thromboxane A2,

giving the main synthetic enzymes, and intermediate metabolites. b. Using these pathways, discuss how inhibiting the synthesis of prostaglandins could be

detrimental to asthmatics.

6. There are a number of similarities between the steps involved in the synthesis, storage, release and termination of action of catecholamines (such as noradrenaline) and 5-hydroxytryptamine. Describe these similarities, highlighting how drugs such as reserpine, imipramine and moclobemide can influence the levels of both NA and 5HT within the body.

7. Choose TWO of the following mediators:

• histamine • angiotensin II • prostaglandins and indicate (with the aid of a diagram if appropriate): (i) the pathway responsible for the synthesis of each of your chosen mediators (ii) one physiological role for each of your chosen mediators (iii) one pathophysiological role for each of your chosen mediators

(iv) one drug which is currently used clinically that interferes with the synthesis/action of each of your chosen mediators, highlighting the condition it is used to treat and the rationale for its use in this condition.

8. The intravenous injection of tyramine produces a rise in blood pressure.

a. How does it produce this effect? b. Repeated injections result in smaller and smaller responses. Explain how this might

happen and how the original response can be restored.

9. Describe the main therapeutic uses of α-adrenoceptor antagonists.

10. a. With the aid of a diagram, describe the process involved in cholinergic neurotransmission. b. Give examples of at least 1 drug which acts to inhibit or activate each step of this process

and state the consequences of the actions of each drug.

11. Give examples of drugs which have the following properties and where relevant indicate their clinical use. a. An agonist which displays selectivity for α1-adrenoceptors b. An antagonist that irreversibly blocks α-adrenoceptors c. An antagonist that blocks both β1 and β2-adrenoceptors d. An agonist that selectively stimulates α2-adrenoceptors e. An agonist that stimulates all known adrenoceptor subtypes

12. Briefly discuss the main therapeutic uses of :

a. β-adrenoceptor agonists (selective and/or non selective) b. β-adrenoceptors antagonists (selective and/or non selective) c. With the aid of a diagram, describe the process involved in noradrenergic

neurotransmission. d. Give examples of at least 1 drug which acts to inhibit or activate each step of this process

and state the consequences of the actions of each drug.

13. Write an account of the actions of THREE drugs that act at receptors for acetylcholine, indicating, where relevant, their clinical uses.

14. Explain the rationale for using sodium bicarbonate to enhance the excretion of weak acids

(e.g. aspirin) from the body when an overdose has been taken.

15. a. What does the half-life (t½) of a drug mean? b. Briefly discuss the importance of this parameter in therapeutics. c. Can the t½ of a drug always be determined? Why or why not?

16. Mr Average (70kg) is given a 500µg dose of digoxin and his plasma digoxin concentration is

measured to be 0.78ng/ml. a. From this data, calculate the Vd for digoxin.

b. What does this calculated Vd tell you about the distribution of digoxin? c. What are the implications of this Vd for obtaining a steady state level of digoxin with repeat dosing?

17. Studies of the pharmacokinetics of a new drug show that it has a variable t½ (ie the t½ varies

with the dose administered). a. What is a possible explanation for the variable t½ of the drug? b. What does this suggest about the likely route of clearance of the drug? c. What are the implications of this variable t½ for repeated dosing with this drug?

18. With reference to specific examples, discuss how differences in genetics can influence the clinical response to a drug.

19. Briefly discuss the advantages and disadvantages of the intravenous and oral routes of administration, highlighting situations where each might be used preferentially

20. Briefly discuss why the plasma concentrations of drugs such as alcohol (which exhibit 'saturation elimination kinetics') may increase dramatically with repeated short interval dosing.

21. Your grandmother, who has been on a number of different medications for many years, has been recently diagnosed with renal failure. Her doctor explains that this is likely to require changes in the dosage schedules for some of her medications. From your knowledge of pharmacokinetics, can you explain why this may be so and what types of drugs are most likely to be affected?

22. In doing an experiment investigating the action of an unknown drug (ZZZ), you find that it blocks the response of the guinea-pig isolated ileum caused by electrical stimulation of the postganglionic parasympathetic nerve that innervates the ileal smooth muscle (ie the response to endogenous acetylcholine). However, ZZZ has no significant effect on the response of the preparation to exogenously added acetylcholine.

Write a brief summary indicating which of the following is MOST likely to be the site of action of ZZZ and outlining your reasoning.

A. inhibition of acetylcholinesterase B. inhibition of muscarinic receptors C. inhibition of acetylcholine reuptake into the nerve terminal D. inhibition of acetylcholine release from the nerve terminal

Drugs & Society Theme

1. Using examples, discuss 3 factors which could be used to decide whether a drug should be available over the counter.

2. Briefly, and using examples, outline how modification of risk factors can be used in the treatment and prevention of cardiovascular disease.

3. Describe the mechanism of action of 2 drugs used in the treatment of cardiovascular disease,

highlighting the risk factor they target.

4. Describe the basic mechanisms by which selective toxicity can be achieved in antiviral chemotherapy, highlighting the spectrum of activity of antiviral drugs.

5. Describe two targets for selective toxicity of antibiotic drugs indicating the basis for their

selectivity for the bacteria over the host cells.

6. Discuss the problems which can arise if resistance to antimicrobial agents occurs.

7. Describe the processes involved in an allergic reaction, indicating why antihistamines are useful in the treatment of these conditions.

8. Discuss what type of evidence is most useful in assessing whether or not a particular herbal medicine is effective and safe. Give an example of a particular herbal medicine for which there is strong evidence for effectiveness, and briefly discuss its mechanism of action (if known), any possible adverse effects and the condition(s) for which it has been shown to be effective.

9. Define the term ‘functional food’. 1. Briefly describe the difference between a ‘natural’ and a ‘fortified’ food, giving an example of

each. 2. For the examples given, discuss the proposed benefits and mechanisms of action.

10. With the aid of a diagram, identify the major components of the renin-angiotensin system

(RAS). o Using this diagram, indicate the sites of action of drugs which are used clinically

to alter the activity of the RAS. o Describe the main differences in the effects and side-effects of the ACE

inhibitors and AT1 receptor antagonists.

11. Discuss the major clinical uses of histamine antagonists, highlighting the subtypes of

receptor involved, the rationale for their use and any problems that maybe associated with their use.

Drug development theme

1. Briefly describe the major steps involved in taking a NCE from discovery of a likely therapeutic indication to the market place.

2. Identify and discuss four factors that would lead a drug company to abandoning further development of a new drug, indicating at which stage of the development process these are likely to be apparent.

3. Discuss the factors which contribute to the time delay between drug discovery and its

entry into the marketplace.