Pharmacodynamics

Core

Introduction to Pharmacodynamics

Pharmacodynamics, often shortened to PD, is the study of how a drug exerts its effect on the body once it has reached its site of action. Where pharmacokinetics describes what the body does to the drug, pharmacodynamics describes what the drug does to the body.

The two are inseparable in clinical practice: a drug with the wrong pharmacokinetics never reaches a useful concentration, and a drug with the wrong pharmacodynamics produces nothing at the receptor even when it does. Together they define every drug in the formulary.

Almost all of pharmacodynamics can be reduced to two questions:

• What does the drug bind to? (its target)
• What happens when it binds? (the response)

Diagram: Pharmacokinetics governs drug concentration at the site of action; pharmacodynamics governs the response that concentration produces.

Drug Targets

The vast majority of clinically useful drugs act on one of four kinds of macromolecule. The principles of how each of these is built and regulated are covered in Structure of Proteins and Enzymes and Regulation of Protein Function.

Receptors

A receptor is a protein whose normal job is to recognise an endogenous chemical messenger; a hormone or a neurotransmitter, and translate that recognition into a cellular response. Drugs that target receptors do so by mimicking, blocking or modulating the action of the natural ligand.

There are four broad receptor superfamilies, each with a characteristic timescale of response:

• Ligand-gated ion channels: respond in milliseconds. Examples: the nicotinic acetylcholine receptor at the neuromuscular junction, the GABA_A receptor in the central nervous system.
• G-protein coupled receptors (GPCRs): respond in seconds. Examples: adrenergic receptors, muscarinic receptors, opioid receptors. These are by far the largest receptor family and are covered in detail in G-Protein Coupled Receptors.
• Kinase-linked receptors: respond in minutes to hours. Examples: the insulin receptor, growth factor receptors.
• Nuclear (intracellular) receptors: respond in hours to days because they act by altering gene transcription. Examples: glucocorticoid receptor, oestrogen receptor, thyroid hormone receptor.

Enzymes

Many drugs are enzyme inhibitors that block the conversion of a substrate into its product. The most heavily prescribed examples in UK practice include:

• ACE inhibitors (e.g. ramipril) block angiotensin-converting enzyme.
• Statins block HMG-CoA reductase, the rate-limiting enzyme of cholesterol synthesis.
• Proton pump inhibitors (e.g. omeprazole) inactivate the gastric H⁺/K⁺ ATPase.
• NSAIDs inhibit cyclo-oxygenase (COX-1 and COX-2), reducing prostaglandin synthesis.
• Phosphodiesterase-5 inhibitors (e.g. sildenafil) prevent the breakdown of cGMP.

A small number of drugs are false substrates, fed into a metabolic pathway to produce an inactive or harmful end-product; many cancer chemotherapeutics work this way.

Ion Channels

Drugs that act directly on ion channels modulate the flow of ions across the cell membrane. The principles of how channels generate the electrical activity of excitable cells are covered in Membrane Potentials and Action Potentials. Important examples:

• Calcium channel blockers (e.g. amlodipine, verapamil) block voltage-gated L-type calcium channels.
• Local anaesthetics (e.g. lidocaine) block voltage-gated sodium channels.
• Class III antiarrhythmics (e.g. amiodarone) block voltage-gated potassium channels.
• Sulphonylureas (e.g. gliclazide) close ATP-sensitive potassium channels in pancreatic β-cells, triggering insulin release.

Transporters

Transporters move ions and small molecules across membranes: sometimes against a concentration gradient (active transport) and sometimes down it (facilitated diffusion). Drugs that block transporters tend to have rapid and predictable effects:

• Loop diuretics (e.g. furosemide) block the Na⁺/K⁺/2Cl⁻ cotransporter in the thick ascending limb.
• Thiazide diuretics (e.g. bendroflumethiazide) block the Na⁺/Cl⁻ cotransporter in the distal convoluted tubule.
• SSRIs (e.g. sertraline) block the serotonin transporter in central neurons.
• SGLT2 inhibitors (e.g. empagliflozin) block sodium-glucose co-transporter 2 in the proximal tubule.

Drug-Receptor Binding

The interaction between a drug and its target has two independent properties: affinity (how readily the drug binds) and efficacy (what happens when it does). A useful drug needs both.

Affinity

Affinity is a measure of how tightly a drug binds its target. It is described quantitatively by the dissociation constant, K_d: the concentration of drug at which half the available receptors are occupied at equilibrium. A drug with a low K_d binds tightly and is said to have a high affinity. A drug with a high K_d binds loosely and has low affinity.

Low K_d  =  high affinity   (less drug needed to occupy receptors)

Affinity alone says nothing about whether a drug produces a response; an antagonist can have very high affinity and still cause no effect by itself.

Efficacy and Intrinsic Activity

Efficacy is the capacity of a drug to produce a response once bound to the receptor. It is sometimes called intrinsic activity. A full agonist has maximum efficacy, a partial agonist intermediate efficacy, and an antagonist zero efficacy.

The cleanest way to remember the distinction:

• Affinity: will the drug bind?
• Efficacy: once bound, will it switch the receptor on?

Selectivity and Specificity

No drug binds only one target. Selectivity describes the degree to which a drug prefers one target over others; the more selective a drug is, the smaller the dose required for therapeutic effect, and the fewer the off-target side effects. Specificity is sometimes used interchangeably with selectivity but is best reserved for the strict sense: a drug that interacts with only one receptor subtype is specific.

Selective β₁-blockers such as atenolol and bisoprolol illustrate the point. They have a higher affinity for cardiac β₁ receptors than for bronchial β₂ receptors, and so cause less bronchoconstriction than older non-selective agents like propranolol. Selectivity is dose-dependent; at high doses, even "cardioselective" beta-blockers begin to block β₂ receptors significantly.

Agonists and Antagonists

Drugs are classified by what happens when they bind. The basic division is between agonists (drugs that activate the receptor) and antagonists (drugs that block the receptor without activating it).

Diagram: Dose-response curves for a full agonist, partial agonist, antagonist and inverse agonist. The horizontal dashed line marks constitutive (background) receptor activity in the absence of drug.

Full Agonists

A full agonist binds the receptor and produces the maximum possible response. The endogenous ligand is, by definition, a full agonist at its own receptor, for example, acetylcholine at muscarinic receptors, or noradrenaline at α-adrenergic receptors. Drugs used as hormone replacement (e.g. levothyroxine in hypothyroidism, hydrocortisone in adrenal insufficiency) are full agonists, as are direct receptor mimics like salbutamol at the β₂-adrenergic receptor.

Partial Agonists

A partial agonist binds the receptor but produces a sub-maximal response no matter how high the dose. Partial agonists have intermediate efficacy. They behave as agonists when no full agonist is present, but as antagonists in the presence of a full agonist (because they occupy receptors that would otherwise be fully activated).

The classic example is buprenorphine, a partial agonist at the μ-opioid receptor used in opioid substitution therapy. It binds with high affinity but produces a sub-maximal response, which gives it two useful properties: it provides enough opioid effect to suppress withdrawal, and the ceiling on its effect makes respiratory depression in overdose less likely than with full agonists like heroin.

Inverse Agonists

Some receptors have constitutive activity: they generate a baseline response even when no ligand is bound. An inverse agonist binds the receptor and reduces this baseline activity below its resting level; the opposite effect to an agonist, but not the same as an antagonist. Antihistamines such as cetirizine are now believed to act as inverse agonists at the H₁ histamine receptor rather than as simple antagonists.

Competitive Antagonists

A competitive antagonist binds the same site on the receptor as the agonist (the orthosteric site) but produces no response. By occupying the binding site, it prevents the agonist from binding. Crucially, the agonist can outcompete the antagonist if its concentration is high enough, so a competitive antagonist shifts the agonist dose-response curve to the right but does not reduce E_max. Potency is reduced; maximal efficacy is preserved.

Examples include:

• Naloxone at the μ-opioid receptor (used to reverse opioid overdose).
• Atenolol at the β₁-adrenergic receptor.
• Losartan at the angiotensin II type 1 (AT₁) receptor.

Non-Competitive Antagonists

A non-competitive antagonist either binds the same site as the agonist irreversibly, or binds a different site (allosteric) and changes the receptor's shape so that the agonist can no longer activate it. Increasing the agonist concentration cannot overcome a non-competitive block, so the dose-response curve flattens: E_max is reduced, and increasing the dose of agonist will not restore the maximum response.

Phenoxybenzamine, an irreversible α-adrenergic antagonist used in the pre-operative management of phaeochromocytoma, is the classic receptor example. (Aspirin is sometimes called an "irreversible non-competitive inhibitor" too, but it acts on an enzyme; cyclo-oxygenase; rather than a receptor, and is best understood under enzyme inhibition.)

Diagram: Effect of competitive (rightward shift, same E_max) and non-competitive (lower E_max) antagonism on an agonist dose-response curve.

Dose-Response Relationships

The relationship between drug dose and biological response is rarely linear. Plotted on a logarithmic dose axis it forms the familiar sigmoid dose-response curve, from which two key parameters are read off: EC₅₀ and E_max.

EC₅₀ and Potency

EC₅₀ is the concentration of drug that produces 50% of the maximum response on a graded concentration-response curve. It is a measure of potency: the lower the EC₅₀, the more potent the drug. Potency tells you how much drug is needed, but says nothing about how good the response will be.

The closely related ED₅₀ is the dose that produces a defined response in 50% of a population (a quantal response, e.g. the dose at which half of patients have their migraine relieved). EC₅₀ describes the curve in an individual; ED₅₀ and TD₅₀ describe the spread across a population, and they are the values used in the therapeutic index calculation below.

This matters in practice mainly because it determines the dose: a more potent drug is given in smaller doses, but a more potent drug is not necessarily a better drug.

E_max and Efficacy

E_max is the maximum response a drug can produce, no matter how much is given. It is a measure of efficacy. A drug with high efficacy can produce a large effect; a drug with low efficacy cannot, regardless of dose.

A useful pair of memory hooks:

• Potency: how much drug is needed.
• Efficacy: how big the effect can be.

Fentanyl is around 100 times more potent than morphine (lower EC₅₀), and the two have similar maximum efficacy at the μ-opioid receptor; both are full agonists. Paracetamol, by contrast, has a much lower efficacy than morphine for severe pain; no dose of paracetamol will match a therapeutic dose of morphine, no matter how much is given. Potency simply tells you the dose; efficacy tells you the ceiling.

Therapeutic Index and Therapeutic Window

The therapeutic index (TI) is the ratio of the dose that produces toxicity to the dose that produces the desired effect:

Therapeutic Index  =  Toxic Dose (TD₅₀)  ÷  Effective Dose (ED₅₀)

A drug with a high therapeutic index has a wide margin of safety. A drug with a narrow therapeutic index has overlapping effective and toxic ranges and requires careful dosing: warfarin, digoxin, lithium, phenytoin, theophylline, gentamicin, and ciclosporin are the classic examples. The same group is discussed in more detail in the article on Pharmacokinetics.

The therapeutic window is the related concept expressed in terms of plasma concentration: the range over which the drug is both effective and not yet toxic.

Variability in Drug Response

Two patients given the same dose of the same drug can have markedly different responses. Identifying the reasons is one of the central skills of clinical prescribing. The major sources of variability are:

• Body weight and composition: lipophilic drugs distribute into adipose tissue, so the volume of distribution scales with body fat.
• Age: neonates have immature hepatic enzymes and renal function; the elderly have reduced renal clearance and lower lean body mass.
• Sex: differences in body composition and CYP enzyme expression produce small but measurable effects on plasma concentrations.
• Genetics: CYP2D6, CYP2C9 and CYP2C19 polymorphisms produce poor, intermediate, extensive and ultra-rapid metaboliser phenotypes. Acetylator status (fast vs slow) affects isoniazid and hydralazine. Pharmacogenetics is covered in detail in the SimpleMed article on Pharmacovigilance and Pharmacogenetics.
• Co-existing disease: renal, hepatic and cardiac failure all change drug handling, as does any acute illness with significant haemodynamic effect. Chronic Kidney Disease and Hepatic Pathology both have direct dosing implications.
• Drug interactions (see below).
• The placebo effect: expectation, the act of taking a tablet, and the patient-clinician relationship all influence symptomatic outcomes.

Drug-Drug Interactions

Drug interactions are conventionally split into pharmacokinetic interactions (one drug changes the concentration of the other: absorption, distribution, metabolism or excretion) and pharmacodynamic interactions (the two drugs combine at the level of the response itself).

Pharmacodynamic interactions fall into three patterns:

• Additive: the combined effect equals the sum of the individual effects. Alcohol and benzodiazepines, both CNS depressants, together produce additive sedation and respiratory depression; this is the mechanism behind many benzodiazepine-related deaths.
• Synergistic: the combined effect is greater than the sum. Co-trimoxazole (trimethoprim plus sulfamethoxazole) blocks two consecutive steps in folate synthesis and is more bactericidal than either component alone.
• Antagonistic: one drug reduces the effect of the other. Naloxone reverses opioid sedation; vitamin K reverses the anticoagulant effect of warfarin.

The classic teaching example of a dangerous pharmacodynamic interaction is sildenafil and nitrates. Both increase intracellular cGMP: nitrates by donating nitric oxide, sildenafil by inhibiting phosphodiesterase-5, the enzyme that breaks cGMP down. Given together, profound vasodilation can produce a fatal drop in blood pressure. The combination is contraindicated, and the BNF and product information for both drugs say so explicitly.

Adverse Drug Reactions

An adverse drug reaction (ADR) is an unwanted or harmful reaction occurring after the administration of a drug, suspected or known to be due to that drug. ADRs account for around 6.5% of UK hospital admissions and are a leading cause of preventable harm.

The standard classification, by Rawlins and Thompson, divides ADRs into five types remembered as A B C D E:

• A: Augmented. Predictable, dose-dependent extension of the drug's known pharmacological action. Hypoglycaemia from insulin; bradycardia from a beta-blocker; bleeding from warfarin. By far the most common type, accounting for around 80% of ADRs.
• B: Bizarre. Unpredictable, not dose-dependent, often immune-mediated. Anaphylaxis to penicillin; Stevens-Johnson syndrome from carbamazepine.
• C: Chronic. Reactions that emerge with prolonged use. Cushing's syndrome from long-term prednisolone; osteoporosis from corticosteroids; tardive dyskinesia from antipsychotics.
• D: Delayed. Effects that appear long after exposure. Secondary malignancies after alkylating chemotherapy; teratogenesis from antenatal exposure.
• E: End-of-treatment. Reactions on stopping the drug, often a withdrawal syndrome. Rebound hypertension or unstable angina from sudden beta-blocker cessation; benzodiazepine withdrawal seizures.

Risk factors for ADRs are worth knowing: polypharmacy, extremes of age, renal or hepatic impairment, narrow therapeutic index drugs, and female sex.

Suspected serious ADRs in the UK are reported to the Yellow Card Scheme, run by the MHRA. This is covered in detail in the article on Pharmacovigilance.

A useful illustration of a Type A reaction is beta-blockers in asthma. Beta-blockers act as antagonists at β₁ receptors in the heart, reducing rate and contractility. Non-selective agents also block β₂ receptors in bronchial smooth muscle, where they are normally tonically activated by circulating adrenaline. Removing that tonic input causes bronchoconstriction, and in an asthmatic patient this can be severe. Cardioselective beta-blockers are safer but still relatively contraindicated.

Tolerance, Tachyphylaxis and Receptor Regulation

The response to a drug often diminishes with repeated administration. This is called tolerance and matters clinically because it forces dose increases or treatment-free intervals.

Tolerance arises through several mechanisms:

• Receptor downregulation: chronic stimulation reduces the number of receptors expressed at the cell surface (e.g. β-receptor downregulation in heart failure).
• Receptor desensitisation: the receptor remains present but becomes uncoupled from its second messenger (e.g. desensitisation of the β₂-adrenergic receptor in patients on continuous high-dose salbutamol).
• Depletion of mediator: the drug works through release of an endogenous substance which is then exhausted (e.g. tachyphylaxis to indirectly acting sympathomimetics such as ephedrine, which depletes neuronal noradrenaline).
• Biochemical adaptation: tolerance to nitrates with continuous dosing is thought to involve sulfhydryl-group depletion, oxidative stress and pseudo-tolerance from neurohumoral activation; nitrate-free intervals are used to prevent it.
• Increased metabolism: the drug induces its own metabolism via CYP induction (e.g. carbamazepine).
• Physiological adaptation: the body counter-regulates the drug's effect (e.g. compensatory salt and water retention with vasodilators).

Tachyphylaxis is rapid tolerance: the response falls within minutes to hours of repeated dosing. It is a feature of indirectly acting sympathomimetics such as ephedrine, where repeated doses deplete the noradrenaline they release.

The opposite phenomenon is upregulation: chronic blockade of a receptor increases its expression. Sudden withdrawal of the blocker then exposes the patient to a hypersensitive system. This explains the rebound tachycardia and hypertension that can follow abrupt cessation of beta-blockers, and the rebound psychosis that can follow abrupt antipsychotic withdrawal.

Summary

Pharmacodynamics is the science of the drug-target interaction and the response that follows.

• Drugs act on receptors, enzymes, ion channels and transporters.
• Drug binding is described by affinity (how tightly it binds, K_d) and efficacy (the response it produces).
• Agonists activate receptors (full, partial or inverse). Antagonists block them (competitive or non-competitive).
• The dose-response curve gives EC₅₀ (potency) and E_max (efficacy).
• Variability between patients comes from genetics, age, weight, disease and interactions.
• Adverse drug reactions are classified A-E (Augmented, Bizarre, Chronic, Delayed, End-of-treatment).
• Repeated dosing produces tolerance through receptor downregulation, desensitisation, induced metabolism or physiological adaptation.

Together with pharmacokinetics, these principles explain almost everything that follows in a pharmacology course; every drug class in the rest of this series is best understood as a particular combination of target, binding behaviour and dose-response.

Reviewed by: Dr. Marcus Judge

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