Understanding Drugs' Interactions with Living Systems

1. HOW DRUGS ACT: GENERAL PRINCIPLES 24th of Nov 2011

2. The emergency of pharmacology as a science came when the emphasis shifted from describing what drugs do; to explaining how they work

3. Learning Objective • At the end of this session the student should be able to: • identify some important general principles underlying the interaction of drugs with living systems • Describe the interaction between drugs and cells • Examine the different types of drug-receptor interaction

4. Introduction Pharmacology can be defined as: • The study of the manner in which the functions of living systems is affected by chemical agents • Knowledge of the normal & abnormal functioning of the body is necessary

5. Introduction… • Pharmacology comprises two broad divisions, which are: • 1. Pharmacodynamics-the biological and therapeutic effects of drugs • 2. Pharmacokinetics-the absorption, distribution, metabolism and excretion of drugs

6. The distinction can be put crudely thus • Pharmacodynamics is what drugs do to the body while • Pharmacokinetics is what the body does to the drugs

7. Introduction… • It is self evident that knowledge of pharmacodynamics is essential to the choice of drug therapy. • But the well-chosen drug may fail (or be poisonous) because too little or too much is present at the site of action for too short or too long a time. • Drug therapy can fail for pharmacokinetic as well as for pharmacodynamic reasons.

8. Pharmacodynamics • Understanding the mechanisms of drug action is not only an objective of the pharmacologist who seeks to develop better drugs , but also permits a more intelligent use of medicines

9. Pharmacodynamics… • Consider the treatment of hypertension or asthma for e.g.- • Using combinations of drugs with the same mode of action will not only provide additive therapeutic effect but also additive adverse effects. • Selection of combinations of drugs having different modes of action will also provide additive therapeutic efficacy and reduce the risk of additive adverse effects

10. BINDING OF DRUG MOLECULES TO CELLS

11. How do drugs act/work? • Body functions are mediated through control systems that involve receptors, enzymes, carrier molecules and specialized macromolecules such as DNA. • Most drugs act by altering the body’s control systems

12. Majority of drugs act by binding to cells • To produce a biological response drug molecules must exert some chemical influence on one or more constituents of the cell OR • Drug molecules must get very close to these constituent cellular molecules for their function to be altered

13. molecules in the organism greatly outnumber the drug molecules and if the drug molecules were merely distributed at random, the chance of interaction with any particular class of cellular molecule would be negligible. • Pharmacological effects, therefore, require in general, the non-uniform distribution of the drug molecule within the body or tissue, which is the same as saying that:

14. Drug molecules must be “bound” to particular constituents of cells and tissues in order to produce an effect • Paul Ehrlich summed it up as follows: “Corpora non agunt nisi fixata” - (in this context, ‘a drug will not work unless it is bound’).

15. Exceptions to Ehrlich’s dictum: A few drugs act by simple mechanisms related to their chemical or physical properties, without being bound to any tissue constituent e.g.: • EDTA (EthyleneDiamineTetraAcetate) is a metal chelating agent with high affinity for Pb2+. It is used for treatment of lead intoxication • Antacids such as Mg(OH)2 & Al(OH)3 are bases and act by neutralizing acid after oral administration • Mannitol: an osmotic diuretic, biologically inert, does not penetrate into cells. Given IV it is filtered in the glomerulus but not reabsorbed. - Diuresis

16. The major aim of pharmacological research is: • To understand the nature of these binding sites • To understand the mechanism by which the association of a drug molecule with a binding site leads to a physiological/biological response

17. Most drugs produce their effects by binding, in the first instance, to protein molecules-often called targets

18. What are these binding sites? • Mainly proteins • The only exception to protein as target sites is DNA (site of action for some anticancer drugs, some antimicrobials, mutagenic & carcinogenic agents; these interact directly with DNA)

19. PROTEIN TARGETS FOR DRUG BINDING • Four main kinds of regulatory protein are commonly involved as primary drug targets, namely: • Enzymes • Ion channels • Carrier molecules (transporters) • Receptors NB: there are still many drugs whose binding sites are still unknown

20. A few other types of protein are known to function as drug targets. • Many drugs are known to bind (in addition to their primary targets) to plasma protein ( see in cell proliferation & apoptosis) as well as to cellular constituents, without producing any obvious physiological effect • In general most drugs act on one or other of the four types of protein listed . • (The mechanisms by which such binding leads to cellular responses will be discussed later)

21. a) ENZYMES • In common with all catalysts, enzymes speed up a reaction by providing an alternative route of lower activation energy. • They do this by the reactant molecule called the substrate and holding it in a favorable orientation for the reaction

22. a) ENZYMES… There are many drugs which act by targeting enzymes: often the drug molecule; Act as substrate analoguethat acts by • competitively inhibit the enzyme e.g. captopril, acting on angiotensin-converting enzyme • reversibly e.g. neostigmine which inhibits acetyl cholinesterase • irreversibly and non-competitive e.g. inhibition of cyclo-oxygenase by aspirin

23. Act as false substrates -where the drug molecule undergoes chemical transformation to form an abnormal product that inhibit the normal metabolic pathway e.g.: - fluorouracil (anticancer) replaces uracil as an intermediate in purine biosynthesis BUT - it can not be converted into thymidylate thus - blocks DNA synthesis and hence prevents cell division

24. Activation of drugs by enzymes - some drugs require enzymic degradation to convert them from an inactive form to the active form - such drugs are called prodrugs e.g.: Proguanil cycloguanil

25. b) ION CHANNELS • These are pores which are situated on the cell membrane • On the outer part of the pores are situated ions: - K+ (potassium channels) - Ca2+ (Calcium channels) - Na+ (sodium channels) - Cl- (chloride channels)

26. Some ion channels are directly linked to a receptor and open only when the receptor is occupied by an agonist (Ligand-gated ion channels) • Some are direct targets of drug action - the simplest type of interaction is physical blockade of the ion channel by a drug: e.g.: (1)the blockade of the voltage gated sodium channels by local anesthetics (2) the blockade of sodium entry into renal tubular cells by the diuretic amiloride

27. Channel function can also be modulated by drugs which bind to accessory (allosteric) sites on the channel protein • The binding of such drugs influence the gating of the channel examples • Dihydropyridines (vasodilators) which inhibit the opening of L-type calcium channels • Ca2+ channels open in response to depolarization of the cell membrane • The binding of dihydropyridines to the channel may inhibit or facilitate the opening depending on the structure of the dihydropyridine

28. (2) ATP-dependent K+-channels of the pancreatic β-cells • pancreatic β-cells secrete insulin when [plasma glucose] • [intracellular ATP] channels open • Channels blocked by sulphonylureas • Blocking the K+-channels β-cell depolarization insulin secretion • Sulphonylureas do not block the channel physically • They modulate its gating by binding to an associated protein, the Sulphonylureas -receptor

29. GABA receptor/chloride-channel complex • GABA-Gamma Amino Butyric Acid (natural substrate) • Stimulation of the receptor by GABA opens the associated Cl- channel leading to inhibition of neurotransmission in the CNS • Benzodiazepines/barbiturates - act on sites which are different to the GABA binding site • Facilitate opening of the Cl- channel by GABA

30. c) CARRIER MOLECULES • Ions and small molecules (glucose) are not sufficiently lipid soluble to cross the cell membrane and get into the cells • Transport into the cells requires carriers • Types of carriers: -for transport of glucose & amino acids in the gastro-intestinal tract -for transport of ions & organic molecules by renal tubules - for transport of Na+, Ca2+ ions out of the cell etc. • These carriers belong to a family of very well defined transporter systems

31. d) RECEPTORS • Are recognition sites for drugs (recognition molecule for a chemical mediator) • A receptor produces an effect only when a particular drug is bound to it; otherwise it is functionally inert • There is an important distinction between agonists and antagonists Agonists: drugs which activate receptors Antagonists: (a) drugs which on their own do not activate receptors (b) displace agonists from their receptors and reduce their biological effect

32. Receptors in Physiological Systems • Receptors form a key part of the system of chemical communication that all multi-cellular organisms use to coordinate the activities of their cells and organs • The term receptor is, therefore, reserved for interactions of the regulatory type, where a ligand (chemical molecule) may function as an agonist or antagonist • It is limited to molecules/structures which have a physiological regulatory function

33. Drug specificity • For a chemical agent/drug to be useful as a therapeutic or scientific tool it must act selectively on particular cells and tissues i.e. it must show a high degree of binding-site specificity • Conversely: proteins that function as drug targets generally show a high degree of ligand specificity • They will recognize only ligands of a certain precise type and ignore closely related molecules

34. Drug specificity… • These principles of binding site and ligand specificity can be clearly recognised in the actions of a mediator such as angiotensin • This peptide acts strongly on vascular smooth muscle, and on the kidney tubule, but has very little effect on other kinds of smooth muscle or on the intestinal epithelium

35. NO DRUGS ARE COMPLETELY SPECIFIC IN THEIR ACTIONS In many cases, if you increase thedose, a drug will affect targets other than the principal one, and lead to side effects

36. Emphasis is that No drugs acts with complete specificity… • Thus tricyclic antidepressant drugs act by blocking monoamine transporters but are notorious for producing side effects (e.g. dry mouth) related to their ability to block various receptors. • In general, the lower the potency of a drug, and the higher the dose needed, the more likely it is that sites of action other than the primary one will assume significance. • In clinical terms, this is often associated with the appearance of unwanted side effects, of which no drug is free.

37. Understand clearly these Terminologies: • Dose • Concentration • Potency • Efficacy • Sensitivity • Selectivity • Therapeutic index • Dose response curves

38. Terminologies • Dose: is a specified quantity of a therapeutic agent, such as a drug or medicine, prescribed to be taken at one time or at stated intervals. It has dimension mass (e.g units ng, ug, mg, gm, pmole,nmole,umole) • A concentration of a drug is an amount per unit volume and has the dimension mass/volume (e.g. units ng/ml, umole/L) • People and animals are given doses of drugs and concentrations are achieved in bodily fluids (see Drug Disposition and metabolism)

39. Potency • Potency of a drug is a measure of the dilution in which it causes a specified effect; OR the amount (weight) of drug in relation to its effect • thus a drug that evokes the specified effect when present in great dilution (i.e. small concentration) is said to be highly potent.

40. Efficacy • Efficacy is the capacity of a drug to produce an effect and refers to the maximum such effect • E.g. if drug A can produce a therapeutic effect that cannot be obtained with drug B, however much of drug B is given, then drug A has the higher therapeutic efficacy • Differences in therapeutic efficacy are of great clinical importance

41. Sensitivity • Sensitivity is the tissue or target equivalent of potency. In other wordspotency is the property of the drug that describes how little of it is needed. Sensitivity is the property of the responding system that describes the concentration at which it responds to a drug. The units of measurement are the same in both cases (e.g nmole/L)

42. Selectivity • Selectivity is the central theme of pharmacology and is the phenomenon that allows drugs to be useful. No drug is absolutely specific-that is produces only one (desirable) effect at very high potency. • Selectivity is the term used to describe the ability of a given dose or concentration of a drug to produce one effect rather than another.

43. Dose response curves • A pharmacological response is a function of the dose/concentration • The relationship between dose & response is represented graphically by dose-response curves

44. There are two types of responses: (a) quantal or ‘all-or-none responses (b) graded responses • Quantal responses: - analgesia for headache -digitalis to stop heart - sleep or lethal dose for anaesthetics

45. Responses are represented as cumulative percentage of subjects exhibiting a defined effect • Quantal relationships can be defined for both toxic & therapeutic effects • This allows the calculation of therapeutic index • A safe drug has a large therapeutic index.

46. Frequency distribution Curve Y axis = number responding X-axis = conc (mg/L) Cumulative frequency distribution Frequency distribution

47. Quantal conc-effect & dose-effect curves Y-axis = percent of individuals responding X-axis = dose Hypnosis death

48. Therapeutic Index • When the dose of a drug is increased progressively, the response in the patient usually rises to a maximum beyond which further increases in dose do not elicit a greater effect but induce only unwanted effects. • This is because a drug does not have a single dose-response curve, but a different curve for each action, so that new and unwanted actions are recruited if dose is increased after the maximum therapeutic effect has been achieved

49. Therapeutic index • Ehrlich introduced the concept of the therapeutic index as the maximum tolerated dose divided by the minimum curative dose, but since there are no single such doses that apply to all individuals, the index is never calculated in this way.

50. Therapeutic index… • The index can be calculated for animals by using the ratio: Median lethal dose Median effective dose OR LD50/ED50 = 400/100 = 4 i.e. the dose that is lethal to 50% of animals LD50 divided by the dose that has the desired effect in 50% of animals (ED50)