General pharmacology How drugs act and interact, how they enter the body, what happens to them inside the body, how they are eliminated from it; the effects of genetics, age, and disease on drug action — these topics are important for, although they will generally not be in the front of the conscious mind of the prescriber, an understanding of them will enhance rational decision taking Knowledge of the requirements for success and the explanations for falure and for adverse events will enable the doctor to maximise the benefits and minimise the risks of drug therapy. Pharmacodynamics © Qualitative aspects: Receptors, Enzymes, Selectivity © Quantitative aspects: Dose response, Potency, Therapeutic efficacy, Tolerance Pharmacokinetics 10 of drug concaneration: © Time cou rag passage across cell membranes; Order of reaction; Plasma halflife and steady-state concentration; Therapeutic drug monitoring « Individual processes: Absorption, Distribution, Metabolism, Elimination ‘* Drug dosage: Dosing schedules '* Chronic pharmacology: the consequences of prolonged drug administration and drug discontinuation syndromes « Individual or biological variation: Variability due to inherited influencas, enviranmantal and host influences ‘* Drug interactions: outside the body, at site of absorption, during distribution, directly on receptors, during metabolism, during excretion _ Pharmacodynamics what drugs do to the body: pharmacokinetics is what che body does. It is selfevident that knowledge of pharmaco- dynamics is essential to the choice of drug therapy. But the well-chosen drug may fail to produce benefit or may 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 pharmaco- Kinetic as well as for pharmacodynamic reasons The practice of drug therapy entails more than remembering an apparently arbitrary list of actions or indications. cI ZNOILDaSSECTION 2 [TZ cenenae ruannacotoey ‘Technical incompetence in the modem doctor is inexcusable and technical competence and a humane approach are not incompatible as is sometimes suggested, It is appropriate to begin by considering what drugs do and how they do it, ie, the nature of drug action. Body functions are mediated through control systems that involved chemotransmitters or local hormones, receptors, enzymes, carrier molecules and other specialised macromolecules such as DNA. Most medicinal drugs act by altering the body's control systems; in general they do so by binding to some specialised constituent of the cell selectively to alter its function and consequently that of the physiological or pathological system to which it contributes. Such drugs are structurally specific in that small modifications to their chemical structure may profoundly alter their effect. MECHANISMS ‘An overview of the mechanisms of drug action shows that drugs act on the cell membrane by: © Action on specific receptors,” e.g, agonists and antagonists on adrenoceptors, histamine receptors, acetylcholine receptors © Interference with selective passage of ions across membranes, e.g, calcium entry (or channel) blockers ‘© Inhibition of membrane bound enzymes and A receptor mediates a biological effect, eg. adrenocoeptor; a binding site, e.g, on plasma albumin, does not pumps, e.g. membrane bound ATPase by cardiac glycoside; tricyclic antidepressants block the pump by which amines are actively taken up from the exterior to the interior of nerve cells. Drugs act on metabolic processes within the cell by: © Enzyme inhibition, e.g. platelet cyclo-oxygenase by aspirin, cholinesterase by pyridostigmine, xanthine oxidase by allopurinol © Inhibition of transport processes that carry substances across cells, e.g, blockade of anion transport in the renal tubule cell by probenecid can be used to delay excretion of penicillin, and to enhance elimination of urate ‘© Incorporation into larger molecules, e.g. 5- fluorouracil, an anticancer drug, is incorporated into messenger-RNA in place of uracil © In the case of successful antimicrobial agents, altering metabolic processes unique to microorganisms, e.g. penicillin interferes with formation of the bacterial cell wall, or by showing enormous quantitative differences in affecting a process common to both humans and microbes, ¢g. inhibition of folic acid synthesis by trimethoprim. Drugs act outside the cell by: ‘© Direct chemical interaction, e.g. chelating agents, antacids ‘© Osmosis, as with purgatives, e.g. magnesium sulphate, and diuretics, e.g. mannitol, which are active because neither they nor the water in Which they are dissolved are absorbed by the cells lining the gut and kidney tubules respectively. RECEPTORS Most receptors are protein macromolecules. When the agonist binds to the receptor, the proteins undergo an alteration in conformation which induces changes in systems within the cell that in ‘turn bring about the response to the drug. Different types of effector-response exist. (1) The most swift are the channel-linked receptors, i.e. receptors coupled directly to membrane ion channels; neurotransmittersquatizarive nsrecrs |Z) act on such receptors in the postsynaptic membrane of a nerve or muscle cell and givea response within milliseconds. (2) Another type of response involves, receptors bound to the cell membrane and coupled to intracellular effector systems by a G-protein. Cate- cholamines (the first messenger) activate fadreno- ceptors to increase, through a coupled G-protein system, the activity of intracellular adenylate cyclase which raises the rate of formation of cyclic AMP (the second messenger), a modulator of the activity of several enzyme systems that cause the cell to act; the process takes seconds. (3) A third type of membrane- bound receptor is the kinase-linked receptor (so called because a protein kinase is incorporated within the structure), which is involved in the control of cell growth and differentiation, and the release of inflammatory mediators. (4) Within the cell itself, steroid and thyroid hormones act on nuclear receptors which regulate DNA transcription and, thereby, protein synthesis, a process which takes hours. Radioligand binding studies’ have shown that the receptor numbers do not remain constant but change according to circumstances. When tissues are continuously exposed to an agonist, the number of receptors decreases (down-regulation) and this may be a cause of tachyphylaxis (loss of efficacy with frequently repeated doses), e.g. in asthmatics who use adrenoceptor agonist bronchodilators excessively. Prolonged contact with an antagonist leads to formation of new receptors (up-regulation). Indeed, one explanation for the worsening of angina pectoris or cardiac ventricular arrhythmia in some patients following abrupt withdrawal of a Bradrenoceptor blocker is that normal concentrations of circulating catecholamines now have access to an increased (up-regulated) population of f-adreno- ceptors (see Chronic pharmacology, p. 119). Agonists. Drugs that activate receptors do so because they resemble the natural transmitter or hormone, but their value in clinical practice often rests on their greater capacity to resist degradation "The extraordinary discrimination ofthis technique is shown by the calculation that the total Bradrenoceptor protein in a large cow amounts to 1 mg (Maguire ME et al 1977 In: Greengard P Robison GA (eds) Advances in Cyclic ‘Nucleotide Research. Raven Press, New Yorke 8:1.) and so to act for longer than the natural substances (endogenous ligands) they mimic; for this reason bronchodilation produced by salbutamol lasts longer than that induced by adrenaline (epinephrine). Antagonists (blockers) of receptors are sufficiently similar to the natural agonist to be ‘recognised’ by the receptor and to occupy it without activating a response, thereby preventing (blocking) the natural agonist from exerting its effect, Drugs that have no activating effect whatever on the receptor are termed, pure antagonists. A receptor occupied by a low efficacy agonist is inaccessible to a subsequent dose of a high efficacy agonist, so that, in this specific situation, a low efficacy agonist acts as an antagonist. This can happen with opioids. Partial agonists. Some drugs, in addition to blocking access of the natural agonist to the receptor, are capable of a low degree of activation, ie. they have both antagonist and agonist action. Such substances are said to show partial agonist activity (PAA). The B- adrenoceptor antagonists pindolol and oxprenolol have partial agonist activity (in their case it is often called intrinsic sympathomimetic activity) ISA), whilst propranolol is devoid of agonist activity, ie. itis a pure antagonist. A patient may be as extensively ‘B- blocked” by propranolol as by pindolol, ie. exercise tachycardia is abolished, but the resting heart rate is lower on propranolol; such differences can have clinical importance Inverse agonists. Some substances produce effects that are specifically opposite to those of the ago- nist. The agonist action of benzodiazepines on the benzodiazepine receptor in the CNS produces sedation, anxiolysis, muscle relaxation and controls convulsions; substances called B-carbolines which also bind to this receptor cause stimulation, anxiety, increased muscle tone and convulsions; they are inverse agonists. Both types of drug act by modu- lating the effects of the neurotransmitter gamma- aminobutyric acid (GABA). Receptor binding (and vice versa). If the forces that bind drug to receptor are weak (hydrogen bonds, van der Waals bonds, electrostatic bonds), the binding will be easily and rapidly reversible; if the forces involved are strong (covalent bonds), 1 ZNOILDaS