Pharmacodynamics

1. Introduction to Pharmacodynamics
2. Drug Targets
   • Receptors
   • Enzymes
   • Ion Channels
   • Transporters
3. Drug-Receptor Binding
   • Affinity
   • Efficacy and Intrinsic Activity
   • Selectivity and Specificity
4. Agonists and Antagonists
   • Full Agonists
   • Partial Agonists
   • Inverse Agonists
   • Competitive Antagonists
   • Non-Competitive Antagonists
5. Dose-Response Relationships
   • EC₅₀ and Potency
   • E_max and Efficacy
   • Therapeutic Index and Therapeutic Window
6. Variability in Drug Response
7. Drug-Drug Interactions
8. Adverse Drug Reactions
9. Tolerance, Tachyphylaxis and Receptor Regulation
10. Summary
11. Quiz

• Pharmacodynamics is the study of what the drug does to the body: the molecular interaction between a drug and its target, and the dose-response relationship that follows.
• Drugs act predominantly on four classes of target: receptors, enzymes, ion channels and transporters. Drug-target binding is described by affinity (how tightly the drug binds) and efficacy (the response that binding produces).
• Drugs that activate a receptor are agonists (full or partial). Inverse agonists reduce a receptor's baseline activity. Drugs that block a response are antagonists (competitive or non-competitive). The dose-response curve summarises these properties through EC₅₀ (potency) and E_max (maximum effect).
• The space between effective and toxic concentrations is the therapeutic window. Adverse drug reactions are classified A-E (Augmented, Bizarre, Chronic, Delayed, End-of-treatment). This extends the original Rawlins-Thompson classification, which had only types A and B.

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. A drug with the wrong pharmacodynamics produces no useful response even when it does reach its target. 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 (a large molecule, usually a protein). 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 (made by the body) chemical messenger, such as 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 (the molecule that normally binds to the receptor).

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 (where a motor nerve meets a muscle fibre), the gamma-aminobutyric acid type A (GABA_A) receptor in the central nervous system.
• G-protein coupled receptors (GPCRs): receptors that signal inside the cell through a G-protein (a molecular switch), so they respond in seconds. Examples: adrenergic (adrenaline-responsive) receptors, muscarinic (acetylcholine-responsive) receptors and opioid receptors (which respond to morphine-like drugs). These are by far the largest receptor family and are covered in detail in G-Protein Coupled Receptors.
• Kinase-linked receptors: linked to a kinase (an enzyme that adds phosphate groups to other proteins), they 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 (the target of steroid hormones such as cortisol), oestrogen receptor, thyroid hormone receptor.

Enzymes

Many drugs are enzyme inhibitors that block the conversion of a substrate into its product. Important examples include:

• ACE inhibitors (e.g. ramipril) block angiotensin-converting enzyme.
• Statins block HMG-CoA reductase (3-hydroxy-3-methylglutaryl-coenzyme A reductase), the rate-limiting enzyme (the step that sets the pace) of cholesterol synthesis.
• Proton pump inhibitors (e.g. omeprazole) inactivate the gastric H⁺/K⁺ ATPase (the proton pump, an enzyme that uses ATP to swap hydrogen ions for potassium ions).
• NSAIDs (non-steroidal anti-inflammatory drugs) inhibit cyclo-oxygenase (COX-1 and COX-2), reducing the synthesis of prostaglandins (local chemical signals in inflammation and pain).
• Phosphodiesterase-5 inhibitors (e.g. sildenafil) prevent the breakdown of cyclic guanosine monophosphate (cGMP), a signalling molecule that relaxes smooth muscle.

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 (channels of a long-lasting subtype that open when the membrane voltage changes).
• Local anaesthetics (e.g. lidocaine) block voltage-gated sodium channels.
• Class III antiarrhythmics (drugs that correct abnormal heart rhythm, e.g. amiodarone) block voltage-gated potassium channels.
• Sulfonylureas (e.g. gliclazide) close ATP-sensitive potassium channels in pancreatic β-cells (the insulin-producing 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, which is passive movement through a carrier protein). Important examples of drugs that block transporters:

• Loop diuretics (e.g. furosemide) block the Na⁺/K⁺/2Cl⁻ cotransporter in the thick ascending limb of the loop of Henle (a segment of the nephron).
• Thiazide and thiazide-like diuretics (e.g. bendroflumethiazide and indapamide) block the Na⁺/Cl⁻ cotransporter in the distal convoluted tubule (the coiled part of the nephron after the loop of Henle). NICE advises a thiazide-like diuretic (one with a different chemical structure but the same target), such as indapamide, in preference to a conventional thiazide such as bendroflumethiazide when starting or changing diuretic treatment for hypertension.
• SSRIs (selective serotonin reuptake inhibitors, 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 tightly the drug binds) and efficacy (what happens once it has bound). 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

Few drugs bind only one target. Selectivity describes the degree to which a drug prefers one target over others; a more selective drug tends to cause fewer off-target side effects (effects at targets other than the intended one). 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 (narrowing of the airways) 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 can produce the maximum response available in the receptor system being studied. Full agonism depends on the receptor system and the response measured. A ligand made by the body is not automatically a full agonist. In systems with spare receptors, the maximum response can be reached without occupying every 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. It is a partial agonist at the μ-opioid receptor and is 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. The ceiling on its effect also limits respiratory depression (slow, shallow breathing), so overdose is less likely to stop breathing than with full agonists like heroin. The ceiling is not a guarantee of safety: buprenorphine can still cause severe respiratory depression, especially when it is taken with benzodiazepines (sedatives such as diazepam) or other sedatives, or misused by injection.

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. This is the opposite effect to an agonist, but it is 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 blocks the receptor in one of two ways. It binds the same site as the agonist irreversibly, or it binds a different site (an allosteric site) 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 (an adrenal tumour that releases adrenaline), 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 (S-shaped) 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, or all-or-none, response, e.g. the dose at which half of patients have their migraine relieved). EC₅₀ describes the curve in an individual. ED₅₀ and TD₅₀ (the dose that is toxic in 50% of a population) describe the spread across a population. They are the values used in the therapeutic index calculation below.

Potency 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 roughly 50 to 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. It is used for mild to moderate pain, and giving more paracetamol does not make it match a therapeutic dose of morphine. The dose cannot be pushed higher in any case: the adult maximum is 4 g per day, and overdose can cause liver damage. 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. These drugs are 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.

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