General Principles of Pharmacology

HOW DO DRUGS ACT?

Drugs produce their effects on biological systems by several mechanisms; these include physicochemical action, activity at receptors and inhibition of reactions mediated by enzymes.

Physicochemical Properties

Sodium citrate is an alkali and neutralizes acid; it is often administered orally to reduce the likelihood of pneumonitis after regurgitation of gastric contents. Chelating agents (chel is the Greek word for a crab’s claw) combine chemically with metal ions, reducing their toxicity and enhancing elimination, usually in the urine. Such drugs include desferrioxamine (chelates iron and aluminium), dicobalt edetate (cyanide toxicity), sodium calcium edetate (lead) and penicillamine (copper and lead). Stored blood contains a citrate-based anticoagulant which prevents clotting; this chelates calcium ions and may cause hypocalcaemia after massive blood transfusion. Phenol and alcohol denature proteins; they are used occasionally to produce prolonged or permanent nerve blockade.

Action on Receptors

A receptor is a complex structure on the cell membrane which can bind selectively with endogenous compounds or drugs, resulting in changes within the cell which modify its function. These include changes in selective ion channel permeability (e.g. acetylcholine, glutamate, GABA receptors), cyclic adenosine monophosphate (e.g. opioid, β, α₂ and dopamine receptors), cyclic guanosine monophosphate (e.g. atrial natriuretic peptide receptor), inositol phosphate and diacylglycerol (e.g. α₁, angiotensin AT₁, endothelin, histamine H₁ and vasopressin V₁ receptors) and nitric oxide (e.g. muscarinic M₃ receptor).

A compound which binds to a receptor and changes intracellular function is termed an agonist. The classic dose–response relationship of an agonist is shown in Figure 1.1. As the concentration of the agonist increases, a maximum effect is reached as the receptors in the system become saturated (Fig. 1.1A). Conventionally, log dose is plotted against effect, resulting in a sigmoid curve which is approximately linear between 20 and 80% of maximum effect (Fig. 1.1B). Three agonists are shown in Figure 1.2. Agonist A produces 100% effect at a lower concentration than agonist B. Therefore, compared with A, agonist B is less potent but has similar efficacy. Drug C is termed a partial agonist as the maximum effect is less than that of A or B. Buprenorphine is a partial agonist (at the μ-opioid receptor), as are some of the β-blockers with intrinsic activity, e.g. oxprenolol, pindolol, acebutalol, celiprolol.

FIGURE 1.1 (A) The effect of an agonist peaks when all the receptors are occupied. (B) A semilog plot produces a sigmoid curve which is linear between 20 and 80% effect. ED₅₀ is the dose which produces 50% of maximum effect.

FIGURE 1.2 Agonist B has a similar dose–response curve to A but is displaced to the right. A is more potent than B (smaller ED₅₀) but has the same efficacy. C is a partial agonist which is less potent than A and B and less efficacious (maximum effect 50% of A and B).

Antagonists combine selectively with the receptor but produce no effect. They may interact with the receptor in a competitive (reversible) or non-competitive (irreversible) fashion. In the presence of a competitive antagonist, the dose–response curve of an agonist is shifted to the right but the maximum effect remains unaltered (Fig. 1.3A). Examples of this effect include the displacement of morphine by naloxone and endogenous catecholamines by β-blockers.

FIGURE 1.3 (A) The dose–response curve of an agonist is displaced to the right in the presence of a reversible antagonist. There is no change in maximum effect but the ED₅₀ is increased. (B) The dose–response curve is displaced to the right also in the presence of an irreversible antagonist but the maximum effect is reduced.

A non-competitive (irreversible) antagonist also shifts the dose–response curve to the right but, with increasing concentrations, reduces the maximum effect (Fig. 1.3B). For example, the α₁-antagonist phenoxybenzamine, used in the preoperative preparation of patients with phaeochromocytoma, has a long duration of action because of the formation of stable chemical bonds between drug and receptor.

The relationship between drug dose and response is often described by a Hill plot (Fig. 1.4). A typical agonist such as that shown in Figure 1.1 produces a straight line with a slope (i.e. Hill coefficient) of + 1.

FIGURE 1.4 A Hill plot. The Hill coefficient is the slope of the line (+ 1 for this drug). E_max = maximum effect, E = effect at different doses.

Action on Enzymes

Drugs may act by inhibiting the action of an enzyme or competing for its endogenous substrate. Reversible inhibition is the mechanism of action of edrophonium (acetylcholinesterase), aminophylline (phosphodiesterase) and captopril (angiotensin-converting enzyme). Irreversible enzyme inhibition occurs when a stable chemical bond is formed between drug and enzyme, resulting in prolonged or permanent inactivity e.g. omeprazole (gastric hydrogen-potassium ATPase), aspirin (cyclo-oxygenase) and organophosphorus compounds (acetylcholinesterase).

However, the interaction between drug and enzyme may be more complex than this simple classification implies. For example, neostigmine inhibits acetylcholinesterase in a reversible manner, but the mechanism of action is more akin to that of an irreversible drug because neostigmine forms covalent chemical bonds with the enzyme.

THE BLOOD–BRAIN BARRIER AND PLACENTA

Many drugs used in anaesthetic practice must cross the blood–brain barrier in order to reach their site of action. The brain is protected from most potentially toxic agents by tightly overlapping endothelial cells which surround the capillaries and interfere with passive diffusion. In addition, enzyme systems are present in the endothelium which break down many potential toxins. Consequently, only relatively small, highly lipid-soluble molecules (e.g. intravenous and volatile anaesthetic agents, opioids, local anaesthetics) have access to the central nervous system (CNS). Compared with most opioids, morphine takes some time to reach its site of action because it has a relatively low lipid solubility. Highly ionized drugs (e.g. muscle relaxants, glycopyrronium) do not cross the blood–brain barrier.

The chemoreceptor trigger zone is situated in the area postrema near the base of the fourth ventricle (see Ch 42). It is not protected by the blood–brain barrier because the capillary endothelial cells are not bound tightly in this area and allow relatively free passage of large molecules. This is an important afferent limb of the vomiting reflex and stimulation of this area by toxins or drugs in the blood or cerebrospinal fluid often leads to vomiting. Many antiemetics act at this site.

The transfer of drugs across the placenta is of considerable importance in obstetric anaesthesia (see Ch 35). In general, all drugs which affect the CNS cross the placenta and affect the fetus. Highly ionized drugs (e.g. muscle relaxants) pass across less readily.

PLASMA PROTEIN BINDING

Many drugs are bound to proteins in the plasma. This is important because only the unbound portion of the drug is available for diffusion to its site of action. Changes in protein binding may have significant effects on the active unbound concentration of a drug, and therefore its actions.

Albumin is the most important protein in this regard and is responsible mainly for the binding of acidic and neutral drugs. Globulins, especially α₁-glycoprotein, bind mainly basic drugs. If a drug is highly protein bound (> 80%), any change in plasma protein concentration or displacement of the drug by another with similar binding properties may have clinically significant effects. For example, most NSAIDs displace warfarin, phenytoin and lithium from plasma binding sites, leading to potential toxicity.

Plasma albumin concentration is often decreased in the elderly, in neonates and in the presence of malnutrition, liver, renal or cardiac failure and malignancy. α₁-Glycoprotein concentration is decreased during pregnancy and in the neonate but may be increased in the postoperative period and other conditions such as infection, trauma, burns and malignancy.

METABOLISM

Most drugs are lipid-soluble and many are metabolized in the liver into more ionized compounds which are inactive pharmacologically and excreted by the kidneys. However, metabolites may be active (Table 1.1). The liver is not the only site of metabolism. For example, succinylcholine and mivacurium are metabolized by plasma cholinesterase, esmolol by erythrocyte esterases, remifentanil by tissue esterases and, in part, dopamine by the kidney and prilocaine by the lungs.

TABLE 1.1

Examples of Active Metabolites

Drug	Metabolite	Action
Morphine	Morphine-6-glucuronide	Potent opioid agonist
Diamorphine	6-Monoacetylmorphine Morphine	Opioid agonist
Meperidine (pethidine)	Normeperidine (norpethidine)	Epileptogenic
Codeine	Morphine	Opioid agonist
Diazepam	Desmethyldiazepam Temazepam Oxazepam	Sedative
Tramadol	O-desmethyltramadol	Opioid agonist
Parecoxib	Valdecoxib	COX-2 specific inhibitor