Drug targets and mechanisms of action
Drugs usually either stimulate or block the function of a specific molecu- lar target relevant to a particular disease (Box 2.2). Other drugs have less selective chemical properties, such as chelators (e.g. for iron overload), osmotic agents (for cerebral oedema) or general anaesthetics (which alter the biophysical properties of membranes). The interaction of drugs with receptors depends on:
• Affinity: how well the drug binds to a receptor, reflecting the ‘molecular fit’ and the strength of the bond. Some such interactions are irreversible, attributed to a strong affinity or because the drug modifies its target.
• Selectivity: how well the drug binds to one target relative to another.
Drugs that target one receptor subtype commonly also affect other subtypes. For example, ‘cardioselective’ β- blockers have antianginal effects (β1), but may also cause bronchospasm (β2).
• Agonists bind to receptors, producing a response proportional to the agonist concentration and the proportion of receptors occupied.
Partial agonists cannot produce a maximal response, even when all receptors are occupied.
• Antagonists bind to a receptor without initiating a response. Competi- tive antagonists compete with endogenous ligands to occupy recep- tors, and their potency depends on the relative affinities and concen- trations of drug and ligand. Noncompetitive antagonists inhibit agonist effects by affecting other mechanisms (e.g. postreceptor signalling).
Dosage regimen
Plasma concentration Concentration at the site of action
Pharmacological effects
Pharmacokinetics ‘what the body does to a drug’
Monitoring Measure plasma drug
concentration
‘what a drug does to the body’
Monitoring Measure clinical
effects
Concentration Time
Pharmacodynamics
Concentration
Effect
Fig. 2.1 Pharmacokinetics and pharmacodynamics.
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Dose–response relationships
Plotting the logarithm of drug dose against drug response typically pro- duces a sigmoidal dose–response curve (Fig. 2.2). Increases in dose produce increasing responses, but only within a particular range; further increases produce little extra effect. Drug responses are characterised by:
• Efficacy: the extent to which a drug produces a specific response when all available receptors are occupied. Efficacy is maximal for a full agonist; a partial agonist at the same receptor shows lower efficacy.
• Therapeutic efficacy: the effect of the drug on a desired biological end- point. Used to compare drugs acting via different mechanisms (e.g.
diuresis following loop diuretics versus thiazides).
• Potency: the amount of drug required for a given response. More potent drugs act at lower doses.
2.2 Examples of target molecules for drugs
Drug target Description Examples
Receptors Channel- linked receptors
Ligand binding controls a
‘ligand- gated’ ion channel
Nicotinic acetylcholine receptor
GPCRs Ligand binding affects a ‘G-
protein’ that mediates signal transduction
β- adrenoceptors Opioid receptors Kinase- linked receptors Ligand binding activates
intracellular protein kinase, triggering phosphorylation
Insulin receptor Cytokine receptors Transcription factor
receptors Intracellular; ligand binding promotes or inhibits gene transcription
Steroid receptors Retinoid receptors Other targets
Voltage- gated ion
channels Mediate electrical signalling in
muscle and nervous system Na+ and Ca2+ channels
Enzymes Catalyse biochemical
reactions; drugs interfere with binding of substrate
ACE
Xanthine oxidase Transporter proteins Carry ions or molecules across
cell membranes Na+/K+ ATPase Cytokines/other
signalling molecules Small proteins that are important in cell signalling, especially immune responses
Tumour necrosis factors Interleukins
Cell surface antigens Block recognition of cell
surface molecules CD20, CD80
ACE, Angiotensin-converting enzyme; GPCR, G-protein-coupled receptor.
The dose–response relationship varies between patients because of variations in pharmacokinetics and pharmacodynamics. The prescriber cannot know the dose–response curve for individuals, so most drugs are licensed within a dose range predicted to reach close to the top of the dose–response curve in most patients.
Therapeutic index
Adverse effects of drugs, like beneficial effects, are often dose- related, although the dose–response curve for adverse effects is shifted to the right (Fig. 2.2). The ratio of the dose effective in 50% of patients to the dose causing adverse effects in 50% is called the ‘therapeutic index’. Many drugs have multiple adverse effects, so the therapeutic index is usually based on those that require dose reduction or discontinuation. For most drugs, the therapeutic index is greater than 100, but some have therapeutic indices of less than 10 (e.g. digoxin, warfarin, insulin, phenytoin, opioids).
These must be titrated to maximise benefits while avoiding toxicity.
Desensitisation and withdrawal effects
Desensitisation means that the response to a drug diminishes with repeated dosing. Sometimes the response can be restored by increasing the dose;
however, the tissues may ultimately become completely refractory to the drug.
Hypersusceptibility Side-effects 100
80
60
40
20
0.00010 0.001 0.01 0.1 1 10 100 1000
Therapeutic index 100/0.1 = 1000
Drug dose (mg)
Response (% of maximum)
Toxic effects Adverse
effect ED50 = 100 mg Beneficial
effect ED50 = 0.1 mg Emax
ED50 ED50
Fig. 2.2 Dose–response curve. The green curve represents the beneficial effect of the drug. The dose or concentration producing half the maximum response (Emax/2) is the ED50 (or EC50). The red curve is the dose–response relationship for the key adverse effect, which occurs at higher doses. Adverse effects occurring above the therapeutic range are called ‘toxic effects’, whereas those occurring within the therapeutic range are ‘side effects’.
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• Tachyphylaxis describes very rapid desensitisation, sometimes with the initial dose. This implies depletion of chemicals necessary for the drug to act (e.g. a stored neurotransmitter) or receptor phosphorylation.
• Tolerance describes a gradual loss of response over days to weeks.
This implies changes in receptor numbers or counter- regulatory physi- ological changes offsetting the drug’s effect.
• Drug resistance means the loss of effectiveness of an antimicrobial or chemotherapy drug.
• A reduced response may also be caused by lower drug concentra- tions as a result of altered pharmacokinetics (see later).
When drugs induce chemical, hormonal and physiological changes that offset their actions, discontinuation may cause ‘rebound’ withdrawal effects (Box 2.3).
2.3 Examples of drugs with withdrawal effects
Drug Symptoms Signs Treatment
Alcohol Anxiety, panic, paranoid delusions, visual and auditory hallucinations
Agitation, delirium, tremor, tachycardia, ataxia, disorientation, seizures
Treat immedi- ate withdrawal syndrome with benzodiazepines Barbiturates,
benzodiazepines Similar to alcohol Similar to alcohol Substitute long- acting benzodiaze- pine, then gradually wean off Glucocorticoids Weakness, fatigue,
anorexia, weight loss, nausea, vom- iting, diarrhoea, abdominal pain
Hypotension, hypoglycaemia
Prolonged therapy suppresses the HPA axis, causing ad- renal insufficiency;
gradual withdrawal required
Opioids Rhinorrhoea,
sneezing, yawn- ing, lacrimation, abdominal and leg cramps, nausea, vomiting, diarrhoea
Dilated pupils Transfer addicts to long- acting agonist methadone
SSRIs Dizziness, sweat-
ing, nausea, insomnia, tremor, delirium, night- mares
Tremor Reduce slowly to
avoid withdrawal effects
HPA, Hypothalamic pituitary adrenal; SSRI, selective serotonin reuptake inhibitor.