Prescribers need to understand what the drug does to the body (pharmacodynamics) and what the body does to the drug (pharmacokinetics) (Fig. 2.1). Although this chapter is focused on the most common drugs, which are synthetic small molecules, the same principles apply to the increasingly numerous ‘biological’ therapies (sometimes abbreviated to ‘biologics’) now in use, which include peptides, proteins, enzymes and monoclonal antibodies (p. 74).

Pharmacodynamics

Drug targets and mechanisms of action

Modern drugs are usually discovered by screening compounds for activity either to stimulate or to block the function of a specific molecular target, which is predicted to have a beneficial effect in a particular disease (Box 2.2). Other drugs have useful but less selective chemical properties, such as chelators (e.g. for treatment of iron or copper overload), osmotic agents (used as diuretics in cerebral oedema) or general anaesthetics (that alter the biophysical properties of lipid membranes). The following characteristics of the interaction of drugs with receptors illustrate some of the important determinants of the effects of drugs:

2.2 Examples of target molecules for drugs

Drug target	Description	Examples
Receptors
Channel-linked receptors	Ligand binding controls a linked ion channel, known as ‘ligand-gated’ (in contrast to ‘voltage-gated’ channels that respond to changes in membrane potential)	Nicotinic acetylcholine receptor γ-aminobutyric acid (GABA) receptor Sulphonylurea receptor
G-protein-coupled receptors (GPCRs)	Ligand binding affects one of a family of ‘G-proteins’ that mediate signal transduction either by activating intracellular enzymes (such as adenylate or guanylate cyclase, producing cyclic AMP or GMP, respectively) or by controlling ion channels	Muscarinic acetylcholine receptor β-adrenoceptors Dopamine receptors Serotonin receptors Opioid receptors
Kinase-linked receptors	Ligand binding activates an intracellular protein kinase that triggers a cascade of phosphorylation reactions	Insulin receptor Cytokine receptors
Transcription factor receptors	Intracellular and also known as ‘nuclear receptors’; ligand binding promotes or inhibits gene transcription and hence synthesis of new proteins	Steroid receptors Thyroid hormone receptors Vitamin D receptors Retinoid receptors PPARγ and α receptors
Other targets
Voltage-gated ion channels	Mediate electrical signalling in excitable tissues (muscle and nervous system)	Na⁺ channels Ca²⁺ channels
Enzymes	Catalyse biochemical reactions. Drugs interfere with binding of substrate to the active site or of co-factors	Cyclo-oxygenase Angiotensin converting enzyme (ACE) Xanthine oxidase
Transporter proteins	Carry ions or molecules across cell membranes	Serotonin re-uptake transporter Na⁺/K⁺ ATPase

(AMP = adenosine monophosphate; ATPase = adenosine triphosphatase; GMP = guanosine monophosphate; PPAR = peroxisome proliferator-activated receptor)

• Affinity describes the propensity for a drug to bind to a receptor and is related to the ‘molecular fit’ and the strength of the chemical bond. Some drug–receptor interactions are irreversible, either because the affinity is so strong or because the drug modifies the structure of its molecular target.

• Selectivity describes the propensity for a drug to bind to one target rather than another. Selectivity is a relative term, not to be confused with absolute specificity. It is common for drugs targeted at a particular subtype of receptor to exhibit some effect at other subtypes. For example, β-adrenoceptors can be subtyped on the basis of their responsiveness to the endogenous agonist noradrenaline (norepinephrine): the concentration of noradrenaline required to cause bronchodilatation (via β₂-adrenoceptors) is ten times higher than that required to cause tachycardia (via β₁-adrenoceptors). ‘Cardioselective’ β-blockers have anti-anginal effects on the heart (β₁) but may still cause bronchospasm in the lung (β₂) and are contraindicated for asthmatic patients.

• Agonists bind to a receptor to produce a conformational change that is coupled to a biological response. As agonist concentration increases, so does the proportion of receptors occupied, and hence the biological effect. Partial agonists activate the receptor, but cannot produce a maximal signalling effect equivalent to that of a full agonist even when all available receptors are occupied.

• Antagonists bind to a receptor but do not produce the conformational change that initiates an intracellular signal. A competitive antagonist competes with endogenous ligands to occupy receptor binding sites, with the resulting antagonism depending on the relative affinities and concentrations of drug and ligand. Non-competitive antagonists inhibit the effect of an agonist by mechanisms other than direct competition for receptor binding with the agonist (e.g. by affecting post-receptor signalling).

Dose–response relationships

Plotting the logarithm of drug dose against drug response typically produces a sigmoidal dose–response curve (Fig. 2.2). Progressive increases in drug dose (which for most drugs is proportional to the plasma drug concentration) produce increasing response, but only within a relatively narrow range of dose; further increases in dose beyond this range produce little extra effect. The following characteristics of the drug response are useful in comparing different drugs:

Fig. 2.2 Dose–response curve.
The green curve represents the beneficial effect of the drug. The maximum response on the curve is the E_max and the dose (or concentration) producing half this value (E_max/2) is the ED₅₀ (or EC₅₀). The red curve illustrates the dose–response relationship for the most important adverse effect of this drug. This occurs at much higher doses; the ratio between the ED₅₀ for the adverse effect and that for the beneficial effect is the ‘therapeutic index’, which indicates how much margin there is for prescribers when choosing a dose that will provide beneficial effects without also causing this adverse effect. Adverse effects that occur at doses above the therapeutic range (yellow area) are normally called ‘toxic effects’, while those occurring within the therapeutic range are ‘side-effects’ and those below it are ‘hyper-susceptibility effects’.

• Efficacy describes the extent to which a drug can produce a target-specific response when all available receptors or binding sites are occupied (i.e. E_max on the dose–response curve). A full agonist can produce the maximum response of which the receptor is capable, while a partial agonist at the same receptor will have lower efficacy. Therapeutic efficacy describes the effect of the drug on a desired biological endpoint, and can be used to compare drugs that act via different pharmacological mechanisms (e.g. loop diuretics induce a greater diuresis than thiazide diuretics and therefore have greater therapeutic efficacy).

• Potency describes the amount of drug required for a given response. More potent drugs produce biological effects at lower doses, so they have a lower ED₅₀. A less potent drug can still have an equivalent efficacy if it is given in higher doses.

The dose–response relationship varies between patients because of variations in the many determinants of pharmacokinetics and pharmacodynamics. In clinical practice, the prescriber is unable to construct a dose–response curve for each individual patient. Therefore, most drugs are licensed for use within a recommended range of doses that is expected to reach close to the top of the dose–response curve for most patients. However, it is sometimes possible to achieve the desired therapeutic efficacy at doses towards the lower end of, or even below, the recommended range.

Therapeutic index

The adverse effects of drugs are often dose-related in a similar way to the beneficial effects, although the dose–response curve for these adverse effects is normally shifted to the right (see Fig. 2.2). The ratio of the ED₅₀ for therapeutic efficacy and for a major adverse effect is known as the ‘therapeutic index’. In reality, drugs have multiple potential adverse effects but the concept of therapeutic index is usually reserved for those requiring dose reduction or discontinuation. For most drugs, the therapeutic index is greater than 100 but there are some notable exceptions with therapeutic indices less than 10 (e.g. digoxin, warfarin, insulin, phenytoin, opioids). The doses of such drugs have to be titrated carefully for individual patients to maximise benefits but avoid adverse effects.

Desensitisation and withdrawal effects

Desensitisation refers to the common situation in which the biological response to a drug diminishes when it is given continuously or repeatedly. It may be possible to restore the response by increasing the dose of the drug but, in some cases, the tissues may become completely refractory to its effect.

• Tachyphylaxis describes desensitisation that occurs very rapidly, sometimes with the initial dose. This rapid loss of response implies depletion of chemicals that may be necessary for the pharmacological actions of the drug (e.g. a stored neurotransmitter released from a nerve terminal) or receptor phosphorylation.

• Tolerance describes a more gradual loss of response to a drug that occurs over days or weeks. This slower change implies changes in receptor numbers or the development of counter-regulatory physiological changes that offset the actions of the drug (e.g. accumulation of salt and water in response to vasodilator therapy).

• Drug resistance is a term normally reserved for describing the loss of effectiveness of an antimicrobial (p. 151) or cancer chemotherapy drug.

• In addition to these pharmacodynamic causes of desensitisation, reduced response may be the consequence of lower plasma and tissue drug concentrations as a result of altered pharmacokinetics (see below).

When drugs induce chemical, hormonal and physiological changes that offset their actions, discontinuation may allow these changes to cause ‘rebound’ withdrawal effects (Box 2.3).

2.3 Examples of drugs associated with withdrawal effects

Drug	Symptoms	Signs	Treatment
Alcohol	Anxiety, panic, paranoid delusions, visual and auditory hallucinations	Agitation, restlessness, confusion, tremor, tachycardia, ataxia, disorientation, seizures	Treat immediate withdrawal syndrome with benzodiazepines
Barbiturates, benzodiazepines	Similar to alcohol	Similar to alcohol	Transfer to long-acting benzodiazepine then gradually reduce dosage
Corticosteroids	Weakness, fatigue, decreased appetite, weight loss, nausea, vomiting, diarrhoea, abdominal pain	Hypotension, hypoglycaemia	Prolonged therapy suppresses the hypothalamic–pituitary–adrenal axis and causes adrenal insufficiency requiring corticosteroid replacement. Withdrawal should be gradual after prolonged therapy (p. 776)
Opioids	Rhinorrhoea, sneezing, yawning, lacrimation, abdominal and leg cramping, nausea, vomiting, diarrhoea	Dilated pupils	Transfer addicts to long-acting agonist methadone
Selective serotonin re-uptake inhibitors (SSRIs)	Dizziness, sweating, nausea, insomnia, tremor, confusion, nightmares	Tremor	Reduce SSRIs slowly to avoid withdrawal effects

Pharmacokinetics

Understanding ‘what the body does to the drug’ (Fig. 2.3) is extremely important for prescribers because this forms the basis on which the optimal route of administration and dose regimen are chosen and explains the majority of inter-individual variation in the response to drug therapy.

where D is the amount of drug given and C₀ is the initial plasma concentration (Fig. 2.4A). Drugs that are highly bound to plasma proteins may have a V_d below 10 L (e.g. warfarin, aspirin), while those that diffuse into the interstitial fluid but do not enter cells because they have low lipid solubility may have a V_d between 10 and 30 L (e.g. gentamicin, amoxicillin). It is an ‘apparent’ volume because those drugs that are lipid-soluble and highly tissue-bound may have a V_d of greater than 100 L (e.g. digoxin, amitriptyline). Drugs with a larger V_d are eliminated more slowly from the body.

Fig. 2.4 Drug concentrations in plasma following single and multiple drug dosing.
A In this example of first-order kinetics following a single intravenous dose, the time period required for the plasma drug concentration to halve (half-life, t_1/2) remains constant throughout the elimination process. B After multiple dosing, the plasma drug concentration rises if each dose is administered before the previous dose has been entirely cleared. In this example, the drug’s half-life is 30 hours, so that with daily dosing the peak, average and trough concentrations steadily increase as drug accumulates in the body (black line). Steady state is reached after approximately 5 half-lives, when the rate of elimination (the product of concentration and clearance) is equal to the rate of drug absorption (the product of rate of administration and bioavailability). The long half-life in this example means that it takes 6 days for steady state to be achieved and, for most of the first 3 days of treatment, plasma drug concentrations are below the therapeutic range (yellow-shaded area). This problem can be overcome if a larger loading dose (red line) is used to achieve steady state drug concentrations more rapidly.

Drug elimination

Drug metabolism

Metabolism is the process by which drugs are chemically altered from a lipid-soluble form suitable for absorption and distribution to a more water-soluble form that is necessary for excretion. Some drugs, known as ‘pro-drugs’, are inactive in the form in which they are administered, but are converted to an active metabolite in vivo.

Phase I metabolism involves oxidation, reduction or hydrolysis to make drug molecules suitable for phase II reactions or for excretion. Oxidation is much the commonest form of phase I reaction and chiefly involves members of the cytochrome P450 family of membrane-bound enzymes in the endoplasmic reticulum of hepatocytes.

Phase II metabolism involves combining phase I metabolites with an endogenous substrate to form an inactive conjugate that is much more water-soluble. Reactions include glucuronidation, sulphation, acetylation or methylation, and conjugation with glutathione. This is necessary to enable renal excretion because lipid-soluble metabolites will simply diffuse back into the body after glomerular filtration (p. 430).

Drug excretion

Excretion is the process by which drugs and their metabolites are removed from the body.

Renal excretion is the usual route of elimination for drugs or their metabolites that are of low molecular weight and sufficiently water-soluble to avoid reabsorption from the renal tubule. Drugs bound to plasma proteins are not filtered by the glomeruli. The pH of the urine is more acidic than that of plasma, so that some drugs (e.g. salicylates) become un-ionised and tend to be reabsorbed. Alkalination of the urine can hasten excretion (e.g. after a salicylate overdose). For some drugs, active secretion into the proximal tubule lumen, rather than glomerular filtration, is the predominant mechanism of excretion (e.g. methotrexate, penicillin).

Faecal excretion is the predominant route of elimination for drugs with high molecular weight, including those that are excreted in the bile after conjugation with glucuronide in the liver, and any drugs that are not absorbed after enteral administration. Molecules of drug or metabolite that are excreted in the bile enter the small intestine, where they may, if they are sufficiently lipid-soluble, be reabsorbed through the gut wall and return to the liver via the portal vein (see Fig. 2.3). This recycling between the liver, bile, gut and portal vein is known as ‘enterohepatic circulation’ and can significantly prolong the residence of drugs in the body.

Elimination kinetics

The net removal of drug from the circulation results from a combination of drug metabolism and excretion, and is usually described as ‘clearance’, i.e. the volume of plasma that is completely cleared of drug per unit time.

For most drugs, elimination is a high-capacity process that does not become saturated, even at high dosage. The rate of elimination is therefore directly proportional to the drug concentration because of the ‘law of mass action’, whereby higher drug concentrations will drive faster metabolic reactions and support higher renal filtration rates. This results in ‘first-order’ kinetics, when a constant fraction of the drug remaining in the circulation is eliminated in a given time and the decline in concentration over time is exponential (see Fig. 2.4A). This elimination can be described by the drug’s half-life (t_1/2), i.e. the time taken for the plasma drug concentration to halve, which remains constant throughout the period of drug elimination. The significance of this phenomenon for prescribers is that the effect of increasing doses on plasma concentration is predictable – a doubled dose leads to a doubled concentration at all time points.

For a few drugs in common use (e.g. phenytoin, alcohol), elimination capacity is exceeded (saturated) within the usual dose range. This is called ‘zero-order’ kinetics. Its significance for prescribers is that, if the rate of administration exceeds the maximum rate of elimination, the drug will accumulate progressively, leading to serious toxicity.

Repeated dose regimens

The goal of therapy is usually to maintain drug concentrations within the therapeutic range (see Fig. 2.2) over several days (e.g. antibiotics) or even for months or years (e.g. antihypertensives, lipid-lowering drugs, thyroid hormone replacement therapy). This goal is rarely achieved with single doses, so prescribers have to plan a regimen of repeated doses. This involves choosing the size of each individual dose and the frequency of dose administration.

As illustrated in Figure 2.4B, the time taken to reach drug concentrations within the therapeutic range depends on the half-life of the drug. Typically, with doses administered regularly, it takes approximately 5 half-lives to reach a ‘steady state’ in which the rate of drug elimination is equal to the rate of drug administration. This applies when starting new drugs and when adjusting doses of current drugs. With appropriate dose selection, steady state drug concentrations will be maintained within the therapeutic range. This is important for prescribers because it means that the effects of a new prescription, or dose titration, for a drug with a long half-life (e.g. digoxin – 36 hours) may not be known for a few days. In contrast, drugs with a very short half-life (e.g. dobutamine – 2 minutes) have to be given continuously by infusion but reach a new steady state within minutes.

For drugs with a long half-life, if it is unacceptable to wait for 5 half-lives until concentrations within the therapeutic range are maintained, then an initial ‘loading dose’ can be given that is much larger than the maintenance dose, and equivalent to the amount of drug required in the body at steady state. This achieves a peak plasma concentration close to the plateau concentration, which can then be maintained by successive maintenance doses.

‘Steady state’ actually involves fluctuations in drug concentrations, with peaks just after administration followed by troughs just prior to the next administration. The manufacturers of medicines recommend dosing regimens that predict that, for most patients, these oscillations result in troughs within the therapeutic range and peaks that are not high enough to cause adverse effects. The optimal dose interval is a compromise between convenience for the patient and a constant level of drug exposure. More frequent administration (e.g. 25 mg 4 times daily) achieves a smoother plasma concentration profile than 100 mg once daily but is much more difficult for patients to sustain. A solution to this need for compromise in dosing frequency for drugs with half-lives of less than 24 hours is the use of ‘modified-release’ formulations. These allow drugs to be absorbed more slowly from the gastrointestinal tract and reduce the oscillation in plasma drug concentration profile, which is especially important for drugs with a low therapeutic index (e.g. levodopa).

Inter-individual variation in drug responses

Prescribers have numerous sources of guidance about how to use drugs appropriately (e.g. dose, route, frequency, duration) for many conditions. However, this advice is based on average dose–response data derived from observations in many individuals. When applying this information to an individual patient, prescribers must take account of inter-individual variability in response. Some of this variability is predictable and good prescribers are able to anticipate it and adjust their prescriptions accordingly to maximise the chances of benefit and minimise harm. Inter-individual variation in responses also mandates that effects of treatment should be monitored (p. 39).

Some inter-individual variation in drug response is accounted for by differences in pharmacodynamics. For example, the beneficial natriuresis produced by the loop diuretic furosemide is often significantly reduced at a given dose in patients with renal impairment, while confusion caused by opioid analgesics is more likely in the elderly. However, differences in pharmacokinetics more commonly account for different drug responses. Examples of factors influencing the absorption, metabolism and excretion of drugs are shown in Box 2.4.

2.4 Patient-specific factors that influence pharmacokinetics

Age

• Drug metabolism is low in the fetus and newborn, may be enhanced in young children, and becomes less effective with advancing age

• Drug excretion falls with the age-related decline in renal function

Sex

• Women have a greater proportion of body fat than men, increasing volume of distribution and half-life of lipid-soluble drugs

Body weight

• Obesity increases volume of distribution and half-life of lipid-soluble drugs

• Patients with higher lean body mass have larger body compartments into which drugs are distributed and may require higher doses

Liver function

• Metabolism of most drugs depends on several cytochrome P450 enzymes that are impaired in patients with advanced liver disease

• Hypoalbuminaemia influences the distribution of drugs that are highly protein-bound

Kidney function

• Renal disease and the decline in renal function with ageing may lead to drug accumulation

Gastrointestinal function

• Small intestinal absorption of oral drugs may be delayed by reduced gastric motility

• Absorptive capacity of the intestinal mucosa may be reduced in disease (e.g. Crohn’s disease, coeliac disease) or after surgical resection

Food

• Food in the stomach delays gastric emptying and reduces the rate (but not usually the extent) of drug absorption

• Some food constituents bind to certain drugs and prevent their absorption

Smoking

• Tar in tobacco stimulates the oxidation of certain drugs

Alcohol

• Regular alcohol consumption stimulates liver enzyme synthesis, while binge drinking may temporarily inhibit drug metabolism

Drugs

• Drug–drug interactions cause marked variation in pharmacokinetics (see Box 2.11, p. 28)

It is hoped that a significant proportion of the inter-individual variation in drug responses can be explained by studying genetic differences in single genes (‘pharmacogenetics’) (Box 2.5) or the effects of multiple gene variants (‘pharmacogenomics’). The aim is to identify those patients most likely to benefit from specific treatments and those most susceptible to adverse effects. In this way, it may be possible to select drugs and dose regimens for individual patients to maximise the benefit:hazard ratio (‘personalised medicine’).

2.5 Examples of pharmacogenetic variations that influence drug response

Genetic variant	Drug affected	Clinical outcome
Pharmacokinetic
Aldehyde dehydrogenase-2 deficiency	Ethanol	Elevated blood acetaldehyde causes facial flushing and increased heart rate in ~50% of Japanese, Chinese and other Asian populations
Acetylation	Isoniazid, hydralazine, procainamide	Increased responses in slow acetylators, up to 50% of some populations
Oxidation (CYP2D6)	Nortriptyline	Increased risk of toxicity in poor metabolisers
Oxidation (CYP2D6)	Codeine	Reduced responses with slower conversion of codeine to more active morphine in poor metabolisers, 10% of European populations Increased risk of toxicity in ultra-fast metabolisers, 3% of Europeans but 40% of North Africans
Oxidation (CYP2C18)	Proguanil	Reduced efficacy with slower conversion to active cycloguanil in poor metabolisers
Oxidation (CYP2C9)	Warfarin	Polymorphisms known to influence dosages
Oxidation (CYP2C19)	Clopidogrel	Reduced enzymatic activation results in reduced antiplatelet effect
Sulphoxidation	Penicillamine	Increased risk of toxicity in poor metabolisers
HLA-B*1502	Carbamazepine	Increased risk of serious dermatological reactions (e.g. Stevens–Johnson syndrome) for 1 in 2000 in Caucasian populations (much higher in some Asian countries)
Pseudocholinesterase deficiency	Suxamethonium (succinylcholine)	Decreased drug inactivation leads to prolonged paralysis and sometimes persistent apnoea requiring mechanical ventilation until the drug can be eliminated by alternate pathways in 1 in 1500 people
Pharmacodynamic
Glucose-6-phosphate dehydrogenase (G6PD) deficiency	Oxidant drugs including antimalarials (e.g. chloroquine, primaquine)	Risk of haemolysis in G6PD deficiency
Acute intermittent porphyria	Enzyme-inducing drugs	Increased risk of an acute attack
SLC01B1 polymorphism	Statins	Increased risk of rhabdomyolysis
HLA-B*5701 polymorphism	Abacavir	Increased risk of skin hypersensitivity reactions
HLA-B*5801 polymorphism	Allopurinol	Increased risk of rashes in Han Chinese
HLA-B*1502 polymorphism	Carbamazepine	Increased risk of skin hypersensitivity reactions in Han Chinese