General pharmacology

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Chapter 8 General pharmacology

The practice of drug therapy entails more than remembering an apparently arbitrary list of actions or indications. Scientific incompetence in the modern doctor is inexcusable and, contrary to some assertions, scientific competence is wholly compatible with a humane approach.

Pharmacodynamics

Qualitative aspects

The starting point is to consider what drugs do and how they do it, i.e. the nature of drug action. The body functions through control systems that involve 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 and, 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 specific receptors in the cell membrane and interior by:

Drugs also act on processes within or near the cell by:

Outside the cell drugs act by:

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 over differing time courses. Many kinds of effector response exist, but those indicated above are the four basic types.

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 β-adrenoceptor blocker is that normal concentrations of circulating catecholamines now have access to an increased (up-regulated) population of β-adrenoceptors (see Chronic pharmacology, p. 98).

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), then binding will be effectively irreversible.

An antagonist that binds reversibly to a receptor can by definition be displaced from the receptor by mass action (see p. 81) of the agonist (and vice versa). A sufficient increase of the concentration of agonist above that of the antagonist restores the response. β-blocked patients who increase their low heart rate with exercise are demonstrating a rise in sympathetic drive and releasing enough catecholamine (agonist) to overcome the prevailing degree of receptor blockade.

Raising the dose of β-adrenoceptor blocker will limit or abolish exercise-induced tachycardia, showing that the degree of blockade is enhanced, as more drug becomes available to compete with the endogenous transmitter.

As agonist and antagonist compete to occupy the receptor according to the law of mass action, this type of drug action is termed competitive antagonism.

When receptor-mediated responses are studied either in isolated tissues or in intact humans, a graph of the logarithm of the dose given (horizontal axis) plotted against the response obtained (vertical axis) commonly gives an S-shaped (sigmoid) curve, the central part of which is a straight line. If the measurements are repeated in the presence of an antagonist, and the curve obtained is parallel to the original but displaced to the right, then antagonism is said to be competitive and the agonist to be surmountable.

Drugs that bind irreversibly to receptors include phenoxybenzamine (to the α-adrenoceptor). Because the drug fixes to the receptor, increasing the concentration of agonist does not fully restore the response, and antagonism of this type is described as insurmountable.

The log dose–response curves for the agonist in the absence of, and in the presence of, a non-competitive antagonist are not parallel. Some toxins act in this way; for example, α-bungarotoxin, a constituent of some snake and spider venoms, binds irreversibly to the acetylcholine receptor and is used as a tool to study it.

Restoration of the response after irreversible binding requires elimination of the drug from the body and synthesis of new receptor, and for this reason the effect may persist long after drug administration has ceased. Irreversible agents find little place in clinical practice.

Enzymes

Interaction between drug and enzyme is in many respects similar to that between drug and receptor. Drugs may alter enzyme activity because they resemble a natural substrate and hence compete with it for the enzyme. For example, enalapril is effective in hypertension because it is structurally similar to the part of angiotensin I that is attacked by angiotensin-converting enzyme (ACE); enalapril prevents formation of the pressor angiotensin II by occupying the active site of the enzyme and so inhibiting its action.

Carbidopa competes with levodopa for dopa decarboxylase, and the benefit of this combination in Parkinson’s disease is reduced metabolism of levodopa to dopamine in the blood (but not in the brain because carbidopa does not cross the blood–brain barrier).

Ethanol prevents metabolism of methanol to its toxic metabolite, formic acid, by competing for occupancy of the enzyme alcohol dehydrogenase; this is the rationale for using ethanol in methanol poisoning. The above are examples of competitive (reversible) inhibition of enzyme activity.

Irreversible inhibition occurs with organophosphorus insecticides and chemical warfare agents (see Chap. 10), which combine covalently with the active site of acetylcholinesterase; recovery of cholinesterase activity depends on the formation of new enzyme. Covalent binding of aspirin to cyclo-oxygenase (COX) inhibits the enzyme in platelets for their entire lifespan because platelets have no system for synthesising new protein; this is why low doses of aspirin are sufficient for antiplatelet action.

Selectivity

The pharmacologist who produces a new drug and the doctor who gives it to a patient share the desire that it should possess a selective action so that additional and unwanted (adverse) effects do not complicate the management of the patient. Approaches to obtaining selectivity of drug action include the following.

Stereoselectivity

Drug molecules are three-dimensional and many drugs contain one or more asymmetrical or chiral1 centres in their structures, i.e. a single drug can be, in effect, a mixture of two non-identical mirror images (like a mixture of left- and right-handed gloves). The two forms, which are known as enantiomorphs, can exhibit very different pharmacodynamic, pharmacokinetic and toxicological properties.

For example, (1) the S form of warfarin is four times more active than the R form,2 (2) the peak plasma concentration of S fenoprofen is four times that of R fenoprofen after oral administration of RS fenoprofen, and (3) the S, but not the R, enantiomorph of thalidomide is metabolised to primary toxins.

Many other drugs are available as mixtures of enantiomorphs (racemates). Pharmaceutical development of drugs as single enantiomers rather than as racemic mixtures offers the prospect of greater selectivity of action and lessens risk of toxicity.

Quantitative aspects

That a drug has a desired qualitative action is obviously all important, but is not by itself enough. There are also quantitative aspects, i.e. the right amount of action is required, and with some drugs the dose has to be adjusted very precisely to deliver this, neither too little nor too much, to escape both inefficacy and toxicity, e.g. digoxin, lithium, gentamicin. While the general correlation between dose and response may evoke no surprise, certain characteristics of the relation are fundamental to the way drugs are used, as described below.

Potency and efficacy

A clear distinction between potency and efficacy is pertinent, particularly in relation to claims made for usefulness in therapeutics.

Therapeutic index

With progressive increases in dose, the desired response in the patient usually rises to a maximum beyond which further increases elicit no greater benefit but induce unwanted effects. This is because most drugs do not have a single dose–response curve, but a different curve for each action, wanted as well as unwanted. Increases in dose beyond that which gives the maximum wanted response recruit only new and unwanted actions.

A sympathomimetic bronchodilator might exhibit one dose–response relation for decreasing airway resistance (wanted) and another for increase in heart rate (unwanted). Clearly, the usefulness of any drug relates closely to the extent to which such dose–response relations overlap.

Ehrlich (see p. 162) introduced the concept of the therapeutic index or ratio as the maximum tolerated dose divided by the minimum curative dose, but the index is never calculated thus as such single doses cannot be determined accurately in humans. More realistically, a dose that has some unwanted effect in 50% of humans, e.g. in the case of an adrenoceptor agonist bronchodilator a specified increase in heart rate, is compared with that which is therapeutic in 50% (ED50), e.g. a specified decrease in airways resistance.

In practice, such information is not available for many drugs but the therapeutic index does embody a concept that is fundamental in comparing the usefulness of one drug with another, namely, safety in relation to efficacy. Figure 8.1 expresses the concept diagrammatically.

Pharmacokinetics

Dosage regimens of long-established drugs grew from trial and error. Doctors learned by experience the dose, the frequency of dosing and the route of administration that was most likely to benefit and least likely to harm. But this empirical (‘suck it and see’) approach is no longer tenable. We now have an understanding of how drugs cross membranes to enter the body, how they are distributed round it in the blood and other body fluids, how they are bound to plasma proteins and tissues (which act as stores), and how they are eliminated from the body. Quantification of these processes paves the way for efficient development of dosing regimens.

Pharmacokinetics3 is concerned with the rate at which drug molecules cross cell membranes to enter the body, to distribute within it and to leave the body, as well as with the structural changes (metabolism) to which they are subject within it.

The discussion covers the following topics:

Drug passage across cell membranes

Certain concepts are fundamental to understanding how drug molecules make their way around the body to achieve their effect. The first concerns the modes by which drugs cross cell membranes and cells.

Our bodies are labyrinths of fluid-filled spaces. Some, such as the lumina of the kidney tubules or intestine, connect to the outside world; the blood, lymph and cerebrospinal fluid are enclosed. Sheets of cells line these spaces, and the extent to which a drug can cross epithelia or endothelia is fundamental to its clinical use, determining whether a drug can be taken orally for systemic effect, and whether within the glomerular filtrate it will be reabsorbed or excreted in the urine.

Cell membranes are essentially bilayers of lipid molecules with ‘islands’ of protein, and they preserve and regulate the internal environment. Lipid-soluble substances diffuse readily into cells and therefore throughout body tissues. Adjacent epithelial or endothelial cells are linked by tight junctions, some of which are traversed by water-filled channels that allow the passage of water-soluble substances of small molecular size.

The jejunum and proximal renal tubule contain many such channels and are leaky epithelia, whereas the tight junctions in the stomach and urinary bladder do not have these channels and water cannot pass; they are termed tight epithelia. Special protein molecules within the lipid bilayer allow specific substances to enter or leave the cell preferentially, i.e. energy-utilising transporter processes, described later. The natural processes of passive diffusion, filtration and carrier-mediated transport determine the passage of drugs across membranes and cells, and their distribution round the body.

Drugs that ionise according to environmental pH

Many drugs are weak electrolytes, i.e. their structural groups ionise to a greater or lesser extent, according to environmental pH. Most such molecules are present partly in the ionised and partly in the un-ionised state. The degree of ionisation influences lipid solubility (and hence diffusibility) and so affects absorption, distribution and elimination.

Ionisable groups in a drug molecule tend either to lose a hydrogen ion (acidic groups) or to add a hydrogen ion (basic groups). The extent to which a molecule has this tendency to ionise is given by the dissociation (or ionisation) constant (Ka), expressed as the pKa, i.e. the negative logarithm of the Ka (just as pH is the negative logarithm of the hydrogen ion concentration). In an acidic environment, i.e. one already containing many free hydrogen ions, an acidic group tends to retain a hydrogen ion and remains un-ionised; a relative deficit of free hydrogen ions, i.e. a basic environment, favours loss of the hydrogen ion from an acidic group, which thus becomes ionised. The opposite is the case for a base. The issue may be summarised:

This in turn influences diffusibility because:

Quantifying the degree of ionisation helps to express the profound effect of environmental pH. Recall that when the pH of the environment is the same as the pKa of a drug within it, then the ratio of un-ionised to ionised molecules is 1:1. But for every unit by which pH is changed, the ratio of un-ionised to ionised molecules changes 10-fold. Thus, when the pH is 2 units less than the pKa, molecules of an acid become 100 times more un-ionised and when the pH is 2 units more than the pKa, molecules of an acid become 100 more ionised. Such pH change profoundly affects drug kinetics.

pH variation and drug kinetics

The pH partition hypothesis expresses the separation of a drug across a lipid membrane according to differences in environmental pH. There is a wide range of pH in the gut (pH 1.5 in the stomach, 6.8 in the upper and 7.6 in the lower intestine). But the pH inside the body is maintained within a limited range (pH 7.46 ± 0.04), so that only drugs that are substantially un-ionised at this pH will be lipid soluble, diffuse across tissue boundaries and so be widely distributed, e.g. into the central nervous system (CNS). Urine pH varies between the extremes of 4.6 and 8.2, and the prevailing pH affects the amount of drug reabsorbed from the renal tubular lumen by passive diffusion.

In the stomach, aspirin (acetylsalicylic acid, pKa 3.5) is un-ionised and thus lipid soluble and diffusible. When aspirin enters the gastric epithelial cells (pH 7.4) it will ionise, become less diffusible and so will localise there. This ion trapping is one mechanism whereby aspirin is concentrated in, and so harms, the gastric mucosa. In the body aspirin is metabolised to salicylic acid (pKa 3.0), which at pH 7.4 is highly ionised and thus remains in the extracellular fluid. Eventually the molecules of salicylic acid in the plasma are filtered by the glomeruli and pass into the tubular fluid, which is generally more acidic than plasma and causes a proportion of salicylic acid to become un-ionised and lipid soluble so that it diffuses back into the tubular cells. Alkalinising the urine with an intravenous infusion of sodium bicarbonate causes more salicylic acid to become ionised and lipid insoluble so that it remains in the tubular fluid, and passes into the urine. Treatment for salicylate (aspirin) overdose utilises this effect.

Conversely, acidifying the urine increases the elimination of the base amfetamine (pKa 9.9) (see Acidification of urine, p. 126).

Permanently ionised drugs

Drugs that are permanently ionised contain groups that dissociate so strongly that they remain ionised over the range of the body pH. Such compounds are termed polar, for their groups are either negatively charged (acidic, e.g. heparin) or positively charged (basic, e.g. ipratropium, tubocurarine, suxamethonium) and all have a very limited capacity to cross cell membranes. This is a disadvantage with heparin, which the gut does not absorb, so that it is given parenterally. Conversely, heparin is a useful anticoagulant in pregnancy because it does not cross the placenta (which the orally effective warfarin does and is liable to cause fetal haemorrhage as well as being teratogenic).

The following are particular examples of the relevance of drug passage across membranes.

The order of reaction or process

In the body, drug molecules reach their sites of action after crossing cell membranes and cells, and many are metabolised in the process. The rate at which these movements or changes take place is subject to important influences called the order of reaction or process. In biology generally, two orders of such reactions are recognised, and are summarised as follows:

First-order (exponential) processes

In the majority of instances, the rates at which absorption, distribution, metabolism and excretion of a drug occur are directly proportional to its concentration in the body. In other words, transfer of drug across a cell membrane or formation of a metabolite is high at high concentrations and falls in direct proportion to be low at low concentrations (an exponential relationship).

This is because the processes follow the Law of Mass Action, which states that the rate of reaction is directly proportional to the active filtration masses of reacting substances. In other words, at high concentrations there are more opportunities for crowded molecules to interact with one another or to cross cell membranes than at low, uncrowded concentrations. Processes for which the rate of reaction is proportional to the concentration of participating molecules are first-order processes.

In doses used clinically, most drugs are subject to first-order processes of absorption, distribution, metabolism and elimination, and this knowledge is useful. The current chapter later describes how the rate of elimination of a drug from the plasma falls as the concentration in plasma falls, and the time for any plasma concentration to fall by 50% (t½, the plasma half-life) is always the same. Thus, it becomes possible to quote a constant value for the t½ of the drug. This occurs because rate and concentration are in proportion, i.e. the process obeys first-order kinetics.

Knowing that first-order conditions apply to a drug allows accurate calculations that depend on its t½, i.e. time to achieve steady-state plasma concentration, time to elimination, and the construction of dosing schedules.

Zero-order processes (saturation kinetics)

As the amount of drug in the body rises, metabolic reactions or processes that have limited capacity become saturated. In other words, the rate of the process reaches a maximum amount at which it stays constant, e.g. due to limited activity of an enzyme, and any further increase in rate is impossible despite an increase in the dose of drug. In these circumstances, the rate of reaction is no longer proportional to dose, and exhibits rate-limited or dose-dependent5 or zero-order or saturation kinetics. In practice, enzyme-mediated metabolic reactions are the most likely to show rate limitation because the amount of enzyme present is finite and can become saturated. Passive diffusion does not become saturated. There are some important consequences of zero-order kinetics.

Alcohol

(ethanol) (see also p. 142) is a drug whose kinetics has considerable implications for society as well as for the individual, as follows:

Alcohol is subject to first-order kinetics with a t½ of about 1 h at plasma concentrations below 10 mg/dL (attained after drinking about two-thirds of a unit (glass) of wine or beer). Above this concentration the main enzyme (alcohol dehydrogenase) that converts the alcohol into acetaldehyde approaches and then reaches saturation, at which point alcohol metabolism cannot proceed any faster than about 10 mL or 8 g/h for a 70-kg man. If the subject continues to drink, the blood alcohol concentration rises disproportionately, for the rate of metabolism remains the same, as alcohol shows zero-order kinetics.

An illustration. Consider a man of average size who drinks about half (375 mL) a standard bottle of whisky (40% alcohol), i.e. 150 mL alcohol, over a short period, absorbs it and goes drunk to bed at midnight with a blood alcohol concentration of about 250 mg/dL. If alcohol metabolism were subject to first-order kinetics, with a t½ of 1 h throughout the whole range of social consumption, the subject would halve his blood alcohol concentration each hour (see Fig. 8.2). It is easy to calculate that, when he drives his car to work at 08.00 hours the next morning, he has a negligible blood alcohol concentration (less than 1 mg/dL) though, no doubt, a hangover might reduce his driving skill.

But at these high concentrations, alcohol is in fact subject to zero-order kinetics and so, metabolising about 10 mL alcohol per hour, after 8 h the subject has eliminated only 80 mL, leaving 70 mL in his body and giving a blood concentration of about 120 mg/dL. At this level, his driving skill is seriously impaired. The subject has an accident on his way to work and is breathalysed despite his indignant protests that he last touched a drop before midnight. Banned from the road, on his train journey to work he will have leisure to reflect on the difference between first-order and zero-order kinetics (though this is unlikely!).

In practice. The example above describes an imagined event but similar cases occur in everyday therapeutics. Phenytoin, at low dose, exhibits a first-order elimination process and there is a directly proportional increase in the steady-state plasma concentration with increase in dose. But gradually the enzymatic elimination process approaches and reaches saturation, the process becoming constant and zero order. While the dosing rate can be increased, the metabolism rate cannot, and the plasma concentration rises steeply and disproportionately, with danger of toxicity. Salicylate metabolism also exhibits saturation kinetics but at high therapeutic doses. Clearly saturation kinetics is a significant factor in delay of recovery from drug overdose, e.g. with aspirin or phenytoin.

Order of reaction and t½. When a drug is subject to first-order kinetics, the t½ is a constant characteristic, i.e. a constant value can be quoted throughout the plasma concentration range (accepting that there will be variation in t½ between individuals), and this is convenient. But if the rate of a process is not directly proportional to plasma concentration, then the t½ cannot be constant. Consequently, no single value for t½ describes overall elimination when a drug exhibits zero-order kinetics. In fact, t½ decreases as plasma concentration falls and the calculations on elimination and dosing that are so easy with first-order elimination (see below) become more complicated.

Zero-order absorption processes apply to iron, to depot intramuscular formulations and to drug implants, e.g. antipsychotics and sex hormones.

Time course of drug concentration and effect

Plasma half-life and steady-state concentration

The manner in which plasma drug concentration rises or falls when dosing begins, alters or ceases follows certain simple rules, which provide a means for rational control of drug effect. Central to understanding these is the concept of half-life (t½) or half-time.

Increase in plasma concentration with constant dosing

With a constant rate infusion, the amount of drug in the body and with it the plasma concentration rise until a state is reached at which the rate of administration to the body is exactly equal to the rate of elimination from it: this is called the steady state. The plasma concentration is then on a plateau, and the drug effect is stable. Figure 8.3 depicts the smooth changes in plasma concentration that result from a constant intravenous infusion. Clearly, giving a drug by regularly spaced oral or intravenous doses will result in plasma concentrations that fluctuate between peaks and troughs, but in time all of the peaks will be of equal height and all of the troughs will be of equal depth; this is also called a steady-state concentration, as the mean concentration is constant.6

Change in plasma concentration with change or cessation of dosing

The same principle holds for change from any steady-state plasma concentration to a new steady state brought about by increase or decrease in the rate of drug administration. Provided the kinetics remain first order, increasing or decreasing the rate of drug administration (b and c in Fig. 8.3) gives rise to a new steady-state concentration in a time equal to 5 × t½ periods.

Similarly, starting at any steady-state plasma concentration (100%), discontinuing the dose (d in Fig. 8.3) will cause the plasma concentration to fall to virtually zero in 5 × t½ periods, as described in Figure 8.2.

Note that the difference between the rate of drug administration (input) and the rate of elimination (output) determines the actual level of any steady-state plasma concentration (as opposed to the time taken to reach it). If drug elimination remains constant and administration increases by 50%, in time the plasma concentration will reach a new steady-state concentration, which will be 50% greater than the original.

The relation between t½ and time to reach steady-state plasma concentration applies to all drugs that obey first-order kinetics. This holds as much to dobutamine (t½ 2 min), when it is useful to know that an alteration of infusion rate will reach a plateau within 10 min, as to digoxin (t½ 36 h), when a constant daily oral dose will give a steady-state plasma concentration only after 7.5 days. This book quotes plasma t½ values where they are relevant. Inevitably, natural variation within the population produces a range in t½ values for any drug and the text quotes only single average t½ values while recognising that the population range may be as much as 50% from the stated figure in either direction.

Some t½ values appear in Table 8.1 to illustrate their range and implications for dosing in clinical practice.

Table 8.1 Plasma t½ of some drugs

Drug t½
Adenosine < 2 s
Dobutamine 2 min
Benzylpenicillin 30 min
Amoxicillin 1 h
Paracetamol 2 h
Midazolam 3 h
Tolbutamide 6 h
Atenolol 7 h
Dosulepin 25 h
Diazepam 40 h
Piroxicam 45 h
Ethosuximide 54 h

Therapeutic drug monitoring

Patients differ greatly in the dose of drug required to achieve the same response. The dose of warfarin that maintains a therapeutic concentration may vary as much as five-fold between individuals. This is a consequence of variation in rates of drug metabolism, disposition and tissue responsiveness, and it raises the question of how optimal drug effect can be achieved quickly for the individual patient.

In principle, drug effect relates to free (unbound) concentration at the tissue receptor site, which in turn reflects (but is not necessarily the same as) the concentration in the plasma. For many drugs, correlation between plasma concentration and effect is indeed better than that between dose and effect. Yet monitoring therapy by measuring drug in plasma is of practical use only in selected instances. The underlying reasons repay some thought.