General Pharmaceutical Council Registration Assessment (GPhC Assessment) Clinical Pharmacology and Pharmaceutical Science Syllabus

What is the structure of renal drug excretion (the three processes)?

Renal handling involves: (1) glomerular filtration of free drug; (2) active tubular secretion (e.g. via OAT/OCT transporters in the proximal tubule); and (3) passive tubular reabsorption (favoured for non-ionised, lipid-soluble drug). Net renal excretion = filtration + secretion − reabsorption.

How can urinary pH be manipulated to enhance elimination of acidic versus basic drugs in overdose?

Ion trapping: alkalinising the urine (e.g. with sodium bicarbonate) ionises weak acids, reducing their reabsorption and enhancing excretion — used for aspirin/salicylate overdose. Acidifying the urine would similarly trap weak bases. The ionised, water-soluble form cannot be reabsorbed and is excreted.

Define an agonist and an antagonist in drug–receptor interactions.

An agonist binds a receptor and activates it to produce a biological response (it has affinity and intrinsic efficacy). An antagonist binds the receptor but produces no response itself (affinity but no efficacy); it blocks the action of agonists. A partial agonist produces a submaximal response even at full receptor occupancy.

Distinguish competitive from non-competitive (irreversible) antagonism, including effect on the agonist dose–response curve.

Competitive antagonist binds reversibly to the same (orthosteric) site as the agonist; it shifts the agonist dose–response curve to the right (increased $EC_{50}$) but $E_{max}$ is unchanged and surmountable by more agonist. Non-competitive/irreversible antagonist binds irreversibly or to a separate site; it reduces $E_{max}$ and cannot be overcome by increasing agonist.

Define affinity, intrinsic efficacy, and potency.

Affinity is the strength of binding of a drug to its receptor (how readily it binds). Intrinsic efficacy is the ability of a bound drug to activate the receptor and produce a response. Potency is the amount of drug needed to produce a given effect (related to $EC_{50}$ / $ED_{50}$ — a more potent drug needs a lower dose).

Define $EC_{50}$, $ED_{50}$, $LD_{50}$ and the therapeutic index. Give the therapeutic index formula.

$EC_{50}$ = concentration producing 50% of maximal effect; $ED_{50}$ = dose producing the desired effect in 50% of the population; $LD_{50}$ = dose lethal in 50%. Therapeutic index measures safety: $$TI = \frac{LD_{50}}{ED_{50}}$$ A larger TI means a wider safety margin. A narrow TI (e.g. warfarin, digoxin, lithium, phenytoin) requires monitoring.

What is the typical shape of a dose–response curve, and why is a logarithmic dose axis used?

Plotting response against the linear dose gives a hyperbolic curve; plotting response against the logarithm of dose gives a characteristic sigmoidal (S-shaped) curve. The log axis linearises the central portion, allows a wide range of doses to be displayed, and makes $EC_{50}$ and curve shifts easy to read.

Define a partial agonist and explain how it can act as an antagonist in the presence of a full agonist.

A partial agonist has affinity but only sub-maximal intrinsic efficacy, so it cannot produce the full $E_{max}$ even at 100% occupancy. When a full agonist is present, the partial agonist competes for receptors and, having lower efficacy, lowers the overall response — thus behaving as a functional antagonist (e.g. buprenorphine at opioid receptors).

List the four main types of molecular targets (mechanisms) for drug action.

(1) Receptors (e.g. GPCRs, ligand-gated ion channels, kinase-linked receptors, nuclear receptors); (2) Ion channels (e.g. voltage-gated Na⁺/Ca²⁺ channels); (3) Enzymes (inhibition or false-substrate action, e.g. ACE inhibitors, statins); (4) Transporters/carrier proteins (e.g. SSRIs blocking serotonin reuptake, PPIs blocking the H⁺/K⁺-ATPase).

What is the difference between a pharmacokinetic and a pharmacodynamic drug interaction?

A pharmacokinetic interaction alters the ADME of a drug, changing the concentration that reaches its site of action (e.g. enzyme induction/inhibition, altered absorption, displaced protein binding, altered renal excretion). A pharmacodynamic interaction occurs at the site of action without changing plasma concentration — drugs produce additive, synergistic, or antagonistic effects.

Give two examples of pharmacodynamic synergism/additive interactions that increase risk of harm.

Examples: (1) additive CNS depression with alcohol + benzodiazepines/opioids; (2) increased bleeding risk with warfarin + aspirin/NSAIDs (and additive on the same pathway); (3) increased nephrotoxicity with ACE inhibitor + NSAID + diuretic (the 'triple whammy'); (4) serotonin syndrome with SSRI + MAOI/tramadol.

Define an adverse drug reaction (ADR) and the WHO classification into types A and B.

An ADR is a response to a drug that is noxious and unintended, occurring at doses normally used. Type A (Augmented) reactions are dose-dependent, predictable extensions of the drug's pharmacology, common, low mortality (e.g. bleeding with warfarin). Type B (Bizarre) reactions are unpredictable, not dose-related, often immunological/idiosyncratic, rarer but higher mortality (e.g. anaphylaxis).

List the full DoTS / Rawlins–Thompson extended ADR classification (Types A–F).

A = Augmented (dose-related, predictable); B = Bizarre (idiosyncratic/immune); C = Chronic (dose- and time-related, e.g. steroid osteoporosis); D = Delayed (e.g. carcinogenesis, teratogenesis); E = End-of-use/withdrawal (e.g. rebound on stopping beta-blockers, opioid withdrawal); F = Failure of therapy (unexpected, e.g. inadequate dose, interaction reducing efficacy).

What is the Yellow Card Scheme and what should be reported to it?

The UK MHRA's spontaneous reporting system for suspected ADRs. Report: all suspected reactions to black triangle (▼) drugs and newer medicines; all serious suspected reactions to established drugs (fatal, life-threatening, disabling, hospitalising, congenital abnormality); and reactions in children. Reporting can be by professionals or patients.

Which drug classes commonly require therapeutic drug monitoring (TDM), and why?

Drugs with a narrow therapeutic index, where plasma concentration correlates with effect/toxicity: digoxin, lithium, phenytoin, theophylline/aminophylline, aminoglycosides (gentamicin, amikacin), vancomycin, ciclosporin/tacrolimus, and methotrexate (toxicity). Monitoring optimises efficacy and avoids toxicity.

State the approximate therapeutic plasma ranges for lithium and digoxin and key toxicity signs.

Lithium target ~$0.4$–$1.0\ \text{mmol/L}$ (taken ~12 h post-dose); toxicity >$1.5\ \text{mmol/L}$ — tremor, ataxia, seizures, renal impairment. Digoxin therapeutic ~$1$–$2\ \mu\text{g/L}$ (sample ≥6 h post-dose); toxicity causes nausea, visual (yellow) disturbance, confusion, arrhythmias — worsened by hypokalaemia.

Why does hypokalaemia increase the risk of digoxin toxicity?

Digoxin and potassium compete for binding to the same site on the Na⁺/K⁺-ATPase. When plasma K⁺ is low, more digoxin binds the pump, enhancing its inhibitory effect and increasing toxicity. Hence diuretics that cause hypokalaemia (e.g. loop/thiazide) predispose to digoxin toxicity.

What monitoring is required for warfarin, and what is the antidote?

Warfarin (a vitamin K antagonist, narrow TI) is monitored by the INR (International Normalised Ratio), typically targeting $2.0$–$3.0$ (or $2.5$–$3.5$ for higher-risk indications e.g. mechanical valves). Reversal: vitamin K (phytomenadione) for high INR/minor bleeding; prothrombin complex concentrate (or FFP) for major bleeding.

Compare unfractionated heparin and low-molecular-weight heparin (LMWH): monitoring and antidote.

Unfractionated heparin acts via antithrombin to inhibit thrombin and factor Xa, is given IV, and is monitored by APTT. LMWH (e.g. enoxaparin) preferentially inhibits factor Xa, is given subcutaneously, has more predictable kinetics and usually needs no routine monitoring (anti-Xa if required, e.g. renal impairment/pregnancy). Antidote for both: protamine sulfate (less effective for LMWH).

List the common solid and liquid oral dosage forms.

Solid oral forms: tablets (immediate-release, modified/sustained-release, enteric-coated, dispersible, effervescent, chewable, sublingual/buccal), capsules (hard and soft gelatin), granules, powders, lozenges/pastilles. Liquid oral forms: solutions, syrups, elixirs, suspensions, emulsions, and linctuses.

What is the difference between a solution, a suspension, and an emulsion?

A solution is a single-phase homogeneous mixture of solute fully dissolved in solvent. A suspension is a two-phase system of insoluble solid particles dispersed in a liquid (must be shaken; may settle). An emulsion is a two-phase system of two immiscible liquids, one dispersed as droplets in the other (oil-in-water or water-in-oil), stabilised by an emulsifying agent.

What is an enteric coating and why is it used? Give the implication for crushing tablets.

An enteric (gastro-resistant) coating resists dissolution in the acidic stomach but dissolves in the more alkaline small intestine. It is used to protect acid-labile drugs, prevent gastric irritation, or target intestinal release (e.g. enteric-coated aspirin, omeprazole MR). Crushing destroys the coating, exposing the drug to acid and losing protection — such tablets should not be crushed.

Give the purposes of modified-release (MR/SR) formulations and a caution when switching brands.

Modified-release formulations slow drug release to reduce dosing frequency, smooth peak-to-trough fluctuations, improve adherence, and reduce side effects from high peaks. Caution: MR products of the same drug (e.g. diltiazem, nifedipine, lithium) are NOT interchangeable between brands because release profiles differ — prescribe/dispense by brand.

List the main routes of administration with one advantage of the parenteral route.

Routes include: oral, sublingual/buccal, rectal, topical, transdermal, inhalation, nasal, ophthalmic, otic, and parenteral (IV, IM, SC, intradermal, intrathecal). A key advantage of parenteral (especially IV) administration is rapid onset, 100% bioavailability, bypass of first-pass metabolism, and use when the patient cannot take oral drugs or the drug is poorly absorbed orally.

Compare onset of action and bioavailability across IV, IM, SC, oral, and sublingual routes.

IV: immediate onset, $F = 100\%$. IM/SC: fairly rapid (SC slower than IM), high bioavailability, depot effect possible. Sublingual: rapid (bypasses first pass, good for GTN). Oral: slowest/most variable onset, bioavailability often reduced by first-pass metabolism and incomplete absorption. Speed (fastest→slowest) roughly: IV > inhalation/sublingual > IM > SC > oral > rectal/topical.

What is the function of an excipient, and name common excipient categories in tablets.

Excipients are pharmacologically inactive ingredients added to formulate a stable, usable, accurately dosed product. Tablet categories include: diluents/fillers (e.g. lactose, microcrystalline cellulose), binders (e.g. PVP/povidone), disintegrants (e.g. starch, croscarmellose), lubricants (e.g. magnesium stearate), glidants (e.g. colloidal silica), coatings, preservatives, colourants and flavourings.

How do excipients and formulation influence bioavailability? Give an example.

Excipients affect disintegration, dissolution and absorption, and can change bioavailability and stability. Disintegrants speed tablet break-up; surfactants/solubilisers and salt/polymorph choice affect dissolution of poorly soluble drugs. Classic example: a change of excipient (lactose to calcium sulfate) in phenytoin capsules in Australia altered bioavailability and caused toxicity, showing excipients are not always inert.

Define dissolution rate's role in bioavailability and state the Noyes–Whitney concept.

For poorly soluble drugs, dissolution is the rate-limiting step for absorption. The Noyes–Whitney equation describes dissolution rate: $$\frac{dC}{dt} = \frac{DA(C_s - C)}{h}$$ where $D$ = diffusion coefficient, $A$ = surface area, $C_s$ = saturation solubility, $C$ = bulk concentration, $h$ = diffusion-layer thickness. Increasing surface area (smaller particle size, micronisation) increases dissolution and bioavailability.

What does the Biopharmaceutics Classification System (BCS) classify drugs by, and name the four classes?

The BCS classifies drugs by aqueous solubility and intestinal permeability. Class I: high solubility, high permeability (well absorbed). Class II: low solubility, high permeability (dissolution-limited). Class III: high solubility, low permeability (permeability-limited). Class IV: low solubility, low permeability (poorly absorbed). It predicts in-vivo absorption and guides biowaiver decisions.

What is bioequivalence and what pharmacokinetic parameters are compared to establish it?

Two products are bioequivalent if they deliver the same active drug at the same rate and extent to the systemic circulation, with no clinically significant difference. Compared parameters are $C_{max}$ (peak concentration), $T_{max}$ (time to peak), and AUC (extent of absorption). Regulatory acceptance is typically the 90% confidence interval of the ratio lying within $80$–$125\%$.

List the main routes of drug degradation affecting stability, and the formulation/storage measures used to prevent them.

Degradation routes: hydrolysis (water — use dry/solid forms, moisture-proof packaging), oxidation (oxygen/light — add antioxidants e.g. ascorbic acid, use nitrogen flushing and amber containers), photolysis (light — amber/opaque packaging), and microbial growth (add preservatives, sterility). Storage controls: appropriate temperature, protection from light/moisture, and observance of expiry dating. Shelf life is often defined as the time for potency to fall to 90% of label (the $t_{90}$).