Membership of the Royal College of Physicians (MRCP UK) Acute Medicine, Clinical Pharmacology and Professional Practice Syllabus

Define zero-order and first-order kinetics in pharmacokinetics.

First-order: a constant fraction of drug eliminated per unit time (rate proportional to concentration). Zero-order: a constant amount eliminated per unit time (saturated enzymes), e.g. ethanol, phenytoin, salicylates at high dose.

What is the volume of distribution ($V_d$) and how is it calculated?

$V_d$ is the theoretical volume into which a drug distributes to give the observed plasma concentration: $V_d = \dfrac{\text{total amount of drug in body}}{\text{plasma concentration}}$. High $V_d$ means extensive tissue distribution (lipophilic drugs).

How are clearance, volume of distribution, and elimination half-life related?

$t_{1/2} = \dfrac{0.693 \times V_d}{CL}$, where $CL$ is clearance. Half-life increases with larger $V_d$ and decreases with higher clearance.

What is bioavailability and what factors reduce it for oral drugs?

Bioavailability ($F$) is the fraction of administered drug reaching systemic circulation unchanged; IV $F=1$. Reduced by incomplete absorption and first-pass metabolism (gut wall and hepatic). $F = \dfrac{\text{AUC}_{oral}}{\text{AUC}_{IV}}$.

How many half-lives are needed to reach steady state, and what is the role of a loading dose?

Steady state is reached after approximately $4$–$5$ half-lives. A loading dose rapidly achieves the target concentration without waiting: $\text{loading dose} = C_{target} \times V_d / F$. Maintenance dose replaces eliminated drug.

Define $E_{max}$, potency, and efficacy in pharmacodynamics.

$E_{max}$ = maximal effect a drug can produce (reflects efficacy). Potency = amount needed for a given effect, measured by $EC_{50}$ (concentration giving half-maximal effect); a left-shifted curve is more potent. Efficacy = maximal achievable response.

Differentiate a competitive antagonist from a non-competitive (irreversible) antagonist on a dose-response curve.

Competitive antagonist: shifts agonist curve rightward (increased $EC_{50}$), surmountable, $E_{max}$ unchanged. Non-competitive/irreversible: reduces $E_{max}$ (insurmountable), curve flattened.

What is the difference between a Type A and Type B adverse drug reaction?

Type A (Augmented): dose-dependent, predictable, related to pharmacology, common, low mortality (e.g. bleeding on warfarin). Type B (Bizarre): idiosyncratic, unpredictable, not dose-related, often immunological, higher mortality (e.g. anaphylaxis).

Give the full classification of adverse drug reactions (A to F / DoTS extension).

A = Augmented (dose-related), B = Bizarre (idiosyncratic), C = Chronic (cumulative/dose & time), D = Delayed (e.g. teratogenesis, carcinogenesis), E = End-of-use (withdrawal), F = Failure of therapy. DoTS = Dose, Time, Susceptibility.

Which cytochrome P450 enzyme inducers and inhibitors are most clinically important?

Inducers (reduce drug levels): rifampicin, carbamazepine, phenytoin, barbiturates, St John's wort, chronic alcohol, smoking ('CRAP-GPS'). Inhibitors (raise drug levels): macrolides, azoles, protease inhibitors, grapefruit juice, ciprofloxacin, omeprazole, sodium valproate, isoniazid, cimetidine ('AODEVICES').

How should drug prescribing be adjusted in significant renal impairment?

Reduce dose and/or extend dosing interval for renally-cleared drugs; estimate using eGFR/creatinine clearance (Cockcroft-Gault). Avoid nephrotoxins (NSAIDs, aminoglycosides, contrast). Adjust loading dose minimally but reduce maintenance dose; monitor levels.

Which drugs require particular caution in hepatic impairment and why?

Hepatically metabolised drugs accumulate (reduced first-pass and clearance): opioids, benzodiazepines (precipitate encephalopathy), warfarin (reduced clotting factor synthesis enhances effect), statins, paracetamol (in chronic/severe disease), and avoid hepatotoxins. Reduced protein binding increases free drug.

What is the Cockcroft-Gault formula for creatinine clearance?

$CrCl = \dfrac{(140 - \text{age}) \times \text{weight (kg)} \times F}{\text{serum creatinine}\,(\mu\text{mol/L})}$, where $F = 1.23$ for men and $1.04$ for women. Used for drug dosing (e.g. DOACs).

What is therapeutic drug monitoring (TDM) and which drugs commonly require it?

TDM measures plasma drug levels to optimise dosing for drugs with a narrow therapeutic index. Common: digoxin, lithium, phenytoin, theophylline, aminoglycosides (gentamicin/vancomycin), ciclosporin/tacrolimus, methotrexate.

When should a trough (pre-dose) level be taken for lithium and digoxin monitoring?

Lithium: $12$ hours post-dose (target $0.4$–$1.0\,\text{mmol/L}$). Digoxin: at least $6$ hours post-dose to allow distribution (therapeutic $1.0$–$2.0\,\text{ng/mL}$); levels checked mainly when toxicity suspected.

How does protein binding affect interpretation of phenytoin levels in hypoalbuminaemia?

Phenytoin is highly protein-bound; in hypoalbuminaemia total measured level underestimates free (active) drug. Use a corrected level (Sheiner-Tozer): $C_{corrected} = \dfrac{C_{measured}}{(0.2 \times \text{albumin}) + 0.1}$, or measure free phenytoin.

Which drugs are absolutely contraindicated (teratogenic) in pregnancy?

Sodium valproate (neural tube defects, neurodevelopmental harm), warfarin (embryopathy), ACE inhibitors/ARBs (renal/oligohydramnios), retinoids, methotrexate, tetracyclines, lithium (Ebstein's anomaly), and live vaccines. Avoid NSAIDs in 3rd trimester.

What are the key principles of prescribing in the elderly (START/STOPP)?

Reduced renal/hepatic clearance, increased fat (longer half-life of lipophilic drugs), increased CNS sensitivity. Use STOPP (potentially inappropriate medications to stop) and START (under-prescribed beneficial drugs to start) criteria; 'start low, go slow.'

Define frailty and name a commonly used clinical measure.

Frailty is a state of increased vulnerability to stressors due to cumulative decline across multiple physiological systems, reducing homeostatic reserve. Measured by the Clinical Frailty Scale (CFS, 1–9), Fried phenotype, or Frailty Index.

What are the five components of the Fried frailty phenotype?

Unintentional weight loss, self-reported exhaustion, weakness (grip strength), slow walking speed, and low physical activity. $\geq 3$ = frail; $1$–$2$ = pre-frail.

What domains are assessed in a Comprehensive Geriatric Assessment (CGA)?

Medical (comorbidities, medications, nutrition), Functional (ADLs, mobility, falls), Psychological (cognition, mood), and Social/environmental (support, finances, housing). Multidisciplinary, with a coordinated care plan.

How is syncope distinguished from a seizure clinically?

Syncope: rapid recovery, pallor, brief myoclonic jerks possible, situational/postural trigger, no prolonged confusion. Seizure: aura, tongue-biting (lateral), prolonged tonic-clonic activity, post-ictal confusion, incontinence less specific. Tongue-biting and post-ictal confusion favour seizure.

What are the three main categories of syncope?

Reflex (neurally mediated): vasovagal, situational, carotid sinus. Orthostatic hypotension: drug-induced, volume depletion, autonomic failure. Cardiac: arrhythmia (brady/tachy) or structural (aortic stenosis, HOCM, PE). Cardiac syncope carries highest mortality.

How is orthostatic (postural) hypotension defined?

A sustained fall in systolic BP of $\geq 20\,\text{mmHg}$ or diastolic of $\geq 10\,\text{mmHg}$ within 3 minutes of standing (or head-up tilt).

What is the diagnostic feature distinguishing delirium from dementia?

Delirium: acute onset, fluctuating course, impaired attention/consciousness, often reversible with identifiable cause. Dementia: chronic, progressive, stable conscious level, attention relatively preserved early. Delirium can be superimposed on dementia.

What are the two motoric subtypes of delirium and which is more often missed?

Hyperactive (agitation, hallucinations, restlessness) and hypoactive (drowsiness, withdrawal, reduced activity). Hypoactive (and mixed) delirium is more common and more frequently missed, with worse prognosis.

Name common bedside cognitive assessment tools and what they measure.

AMT (Abbreviated Mental Test, /10), MMSE (/30), MoCA (Montreal Cognitive Assessment, /30, more sensitive to mild impairment), and 4AT (rapid delirium screen). The CAM (Confusion Assessment Method) diagnoses delirium.

What are the CAM (Confusion Assessment Method) criteria for diagnosing delirium?

Requires: (1) acute onset and fluctuating course AND (2) inattention, PLUS either (3) disorganised thinking OR (4) altered level of consciousness. Features 1 and 2 are mandatory.

Define polypharmacy and the principles of deprescribing.

Polypharmacy = concurrent use of multiple medications (often $\geq 5$); problematic polypharmacy is when harm outweighs benefit. Deprescribing: review indication, assess risk/benefit, prioritise stopping high-risk/low-benefit drugs, taper where needed, and monitor.

What is the Mental Capacity Act (2005) two-stage test for capacity?

Stage 1: Is there an impairment/disturbance of the mind or brain? Stage 2 (functional test): Can the person Understand, Retain, Weigh up the information, and Communicate their decision? Failing any one of these four = lacks capacity for that decision.

What are the five statutory principles of the Mental Capacity Act 2005?

(1) Presume capacity. (2) Support the person to make their own decision. (3) Unwise decisions don't equal lack of capacity. (4) Act in the person's best interests if they lack capacity. (5) Choose the least restrictive option.

What are the key requirements for valid consent?

Consent must be voluntary (free from coercion), informed (material risks, benefits, alternatives per Montgomery), and given by a person with capacity. Montgomery (2015) established a patient-centred standard of disclosure of material risks.

Under what circumstances can patient confidentiality be lawfully breached?

With patient consent; when required by law/statute (e.g. notifiable diseases); by court order; or in the public interest (risk of serious harm to the patient or others, e.g. unfit drivers to DVLA, safeguarding). Disclose the minimum necessary.

What does the SPIKES protocol for breaking bad news stand for?

S = Setting up, P = Perception (assess patient's understanding), I = Invitation (how much they want to know), K = Knowledge (give information), E = Emotions (respond with empathy), S = Strategy & Summary (plan and next steps).

What are the key principles of shared decision-making?

Collaborative process: clinician shares evidence-based options/risks/benefits; patient shares values and preferences; decision made jointly. 'No decision about me, without me.' Uses decision aids and checks understanding (teach-back).

What does a DNACPR decision cover and not cover?

DNACPR (Do Not Attempt CPR) applies ONLY to withholding CPR in cardiac/respiratory arrest. It does NOT affect any other treatment. It is a clinical decision; patients/families should be informed and consulted but consent is not legally required (per Tracey ruling).

What are the components of the duty of candour?

When a notifiable safety incident causes harm: inform the patient as soon as practicable, provide a truthful account and apology, explain what is known, offer support, and follow up in writing. It is both a professional and statutory (CQC) duty.

What is clinical governance and its key pillars?

A framework through which organisations are accountable for continuously improving care quality. Pillars include: clinical effectiveness/audit, risk management, education/training, patient/public involvement, information/IT, and staffing. Underpinned by a culture of safety and learning.

What is a clinical audit cycle?

Define standards/criteria → measure current practice → compare against standard → implement change → re-audit ('close the loop'). It improves care by comparing practice against evidence-based standards, distinct from research which creates new knowledge.

Rank the levels of evidence in the evidence hierarchy from highest to lowest.

1: Systematic reviews/meta-analyses of RCTs. 2: Individual RCTs. 3: Cohort studies. 4: Case-control studies. 5: Case series/cross-sectional. 6: Case reports. 7: Expert opinion. Higher levels have lower risk of bias.

Differentiate cohort, case-control, and cross-sectional study designs.

Cohort: prospective, follows exposed vs unexposed for outcomes; gives incidence and relative risk; good for rare exposures. Case-control: retrospective, compares cases vs controls for past exposure; gives odds ratio; good for rare diseases. Cross-sectional: snapshot at one time; gives prevalence.

Define sensitivity and specificity.

Sensitivity $= \dfrac{TP}{TP + FN}$ = proportion of true positives correctly identified (rules OUT disease when negative — SnNout). Specificity $= \dfrac{TN}{TN + FP}$ = proportion of true negatives correctly identified (rules IN disease when positive — SpPin).

Define positive and negative predictive value and how prevalence affects them.

PPV $= \dfrac{TP}{TP + FP}$ = probability disease is present given a positive test. NPV $= \dfrac{TN}{TN + FN}$ = probability disease is absent given a negative test. Both depend on prevalence: PPV rises and NPV falls as prevalence increases.

What are likelihood ratios and what values are clinically useful?

$LR^{+} = \dfrac{\text{sensitivity}}{1 - \text{specificity}}$, $LR^{-} = \dfrac{1 - \text{sensitivity}}{\text{specificity}}$. $LR^{+} > 10$ or $LR^{-} < 0.1$ strongly changes probability; LRs are prevalence-independent and used with pre-test odds to get post-test odds.

Define relative risk (RR) and odds ratio (OR).

$RR = \dfrac{\text{risk in exposed}}{\text{risk in unexposed}}$ (used in cohort/RCT). $OR = \dfrac{\text{odds in exposed}}{\text{odds in unexposed}}$ (used in case-control). OR approximates RR when the outcome is rare.

How are absolute risk reduction (ARR) and number needed to treat (NNT) calculated?

$ARR = \text{CER} - \text{EER}$ (control vs experimental event rates). $NNT = \dfrac{1}{ARR}$, rounded up. NNT = number of patients treated to prevent one additional adverse outcome; lower NNT = more effective.

What is relative risk reduction (RRR) and why can it mislead?

$RRR = \dfrac{\text{ARR}}{\text{CER}} = 1 - RR$. It can exaggerate benefit because it ignores baseline risk — a large RRR may correspond to a tiny absolute benefit (high NNT) when baseline risk is low.

What does a p-value and a 95% confidence interval tell you?

P-value: probability of observing the result (or more extreme) if the null hypothesis were true; <$0.05$ conventionally 'significant.' 95% CI: range within which the true value lies with 95% confidence; if it crosses the null (1 for ratios, 0 for differences), the result is non-significant.

What is the difference between a Type I and Type II statistical error?

Type I error ($\alpha$): false positive — rejecting a true null hypothesis (detecting an effect that isn't there). Type II error ($\beta$): false negative — failing to reject a false null hypothesis (missing a real effect). Power $= 1 - \beta$.

What is statistical power and what determines it?

Power $= 1 - \beta$ = probability of detecting an effect when one truly exists (conventionally $\geq 80\%$). Increased by larger sample size, larger effect size, lower variance, and a higher (less strict) $\alpha$.

What is intention-to-treat (ITT) analysis and why is it preferred?

ITT analyses participants in the groups to which they were randomised, regardless of compliance, crossover, or dropout. It preserves randomisation, avoids attrition bias, and reflects real-world effectiveness; per-protocol analysis can overestimate efficacy.

What is a forest plot in a meta-analysis and what does $I^{2}$ represent?

A forest plot displays individual study effect sizes with confidence intervals and a pooled (diamond) estimate. $I^{2}$ quantifies heterogeneity (proportion of variation due to between-study differences rather than chance): >$50\%$ suggests substantial heterogeneity.

What is publication bias and how is it detected in a systematic review?

Publication bias occurs when studies with positive/significant results are more likely to be published, skewing pooled estimates. Detected by funnel plot asymmetry (or Egger's test); asymmetry suggests missing small negative studies.

What are the components of critically appraising a paper (validity, results, applicability)?

Validity: was the design appropriate, randomisation/blinding adequate, follow-up complete, groups comparable? Results: what is the effect size and precision (CI)? Applicability: are patients similar to mine, do benefits outweigh harms/costs, is it feasible? Tools: CASP checklists.

What is the difference between intention-to-treat and the levels of blinding in an RCT?

Single-blind: participant unaware of allocation. Double-blind: participant and investigator/assessor unaware. Triple-blind: also the data analysts. Blinding reduces performance and detection bias; allocation concealment (separate concept) prevents selection bias at randomisation.

State Wilson and Jungner's key principles for a screening programme.

The condition should be an important health problem with a recognisable latent stage and understood natural history; there should be an acceptable, sensitive/specific test; an effective accepted treatment; agreed policy on whom to treat; and the cost should be economically balanced. Screening should be a continuing process.

What is lead-time bias in screening?

Lead-time bias is the apparent increase in survival time that results merely from earlier diagnosis through screening, without the natural course or time of death being altered — survival appears longer because the clock starts earlier.

What is length-time bias in screening?

Length-time bias is the overrepresentation of slow-growing, less aggressive disease in screen-detected cases (because indolent disease has a longer detectable preclinical phase), making screening appear to improve outcomes more than it truly does.

Distinguish selection bias, recall bias, and confounding.

Selection bias: systematic differences in who is included/retained. Recall bias: differential accuracy of recalled exposure (common in case-control). Confounding: a third variable associated with both exposure and outcome distorting the association (e.g. smoking confounding alcohol-cancer link).

How can confounding be addressed in study design and analysis?

Design: randomisation, restriction, matching. Analysis: stratification, multivariable regression, standardisation, and propensity scoring. Randomisation is most powerful as it balances both known and unknown confounders.

What are the grades of pressure ulcers (EPUAP/NPUAP categories)?

Grade 1: non-blanchable erythema, intact skin. Grade 2: partial-thickness loss (blister/abrasion, into dermis). Grade 3: full-thickness loss into subcutaneous fat. Grade 4: full-thickness loss exposing muscle/bone/tendon. Plus unstageable and deep tissue injury.

What are the main types of urinary incontinence and their mechanisms?

Stress (leak on raised intra-abdominal pressure, sphincter weakness), Urge (overactive detrusor), Mixed (both), Overflow (chronic retention/obstruction), and Functional (cognitive/mobility barrier). Management is guided by type after assessment.

What tool assesses pressure ulcer risk and what are key prevention measures?

The Waterlow score (or Braden scale) assesses risk. Prevention: regular repositioning (e.g. every 2 hours), pressure-redistributing mattresses/cushions, skin inspection, optimising nutrition and hydration, and keeping skin dry.

What is a multifactorial falls assessment and which interventions reduce falls?

Assess gait/balance, vision, cognition, postural BP, medications, footwear, continence, environmental hazards, and bone health. Interventions: strength/balance exercise, medication review (reduce sedatives/antihypertensives), vision correction, home hazard modification, and vitamin D where deficient.