Prescribing in Special Populations

Pregnancy

Core pharmacological principles

Prescribing in pregnancy requires balancing untreated maternal disease against fetal, placental and neonatal drug toxicity. The key exam principle is that “avoidance of all drugs” is not safe prescribing: uncontrolled epilepsy, hypertension, diabetes, asthma, infection or thromboembolism may carry greater fetal risk than rational pharmacotherapy. Decisions should use gestational age, prior reproductive history, drug dose, route, duration, maternal renal/hepatic function, and reliable sources such as BNF in Pregnancy, UKTIS, NICE and MHRA safety updates. Historic FDA pregnancy categories A–X are obsolete; contemporary assessment is narrative, indication-specific and risk–benefit based.

Gestational period	Approximate timing	Prescribing significance
Pre-implantation	0–2 weeks post-conception	“All-or-none” effect: embryonic loss or survival without structural malformation; avoid unnecessary exposure but teratogenesis is less likely.
Organogenesis	3–8 weeks post-conception, i.e. 5–10 weeks’ gestation	Highest risk of major structural malformation; classic period for folate antagonists, retinoids, valproate, warfarin embryopathy.
Fetal growth and functional maturation	9 weeks post-conception to term	Growth restriction, neurodevelopmental toxicity, renal impairment, ductus arteriosus effects, neonatal withdrawal or adaptation syndromes.
Peripartum/neonatal	Late third trimester to delivery	Drug accumulation and withdrawal: opioids, benzodiazepines, SSRIs; bleeding risk with anticoagulants/antiplatelets; neonatal hypoglycaemia with beta-blockers.

Maternal pharmacokinetics and placental transfer

Pregnancy substantially alters drug disposition. Plasma volume rises by approximately 40–50%, cardiac output by 30–50%, and glomerular filtration rate by 40–60% by early second trimester. Serum albumin falls, increasing free fraction of highly protein-bound drugs, although total measured concentrations may fall. Gastric emptying may be delayed in labour, and CYP activity changes: CYP3A4, CYP2D6 and CYP2C9 generally increase, whereas CYP1A2 decreases. Clinically important examples include increased clearance of lamotrigine, often requiring level-guided dose escalation during pregnancy and reduction postpartum to avoid toxicity.

Placental passage is favoured by low molecular weight (<500 Da), lipid solubility, non-ionisation and low protein binding. Heparins do not cross the placenta due to large molecular size and charge; warfarin crosses readily. Fetal exposure may also be affected by placental transporters such as P-glycoprotein and breast cancer resistance protein, and by fetal capacity for metabolism, which is limited particularly in early gestation.

High-yield teratogens and contraindicated drugs

Drug/class	Key fetal/neonatal risk	Exam prescribing point
Valproate	Neural tube defects approximately 1–2%; major congenital malformations around 10%; neurodevelopmental impairment in 30–40%.	MHRA: contraindicated in pregnancy unless no suitable alternative and pregnancy prevention programme applies; avoid in women of childbearing potential where possible.
Retinoids e.g. isotretinoin, acitretin	Craniofacial, cardiac, thymic and CNS malformations; high miscarriage risk.	Absolute contraindication; strict pregnancy prevention. Acitretin requires prolonged contraception after cessation.
Methotrexate	Antifolate embryopathy, miscarriage, growth restriction.	Contraindicated; stop before conception where possible and give folic acid rescue if inadvertent exposure considered.
Warfarin	Nasal hypoplasia/stippled epiphyses especially 6–12 weeks; fetal intracranial bleeding.	Use LMWH for most indications; specialist exception may apply for selected mechanical valves.
ACE inhibitors/ARBs/aliskiren	Second/third trimester fetal renal dysgenesis, oligohydramnios, pulmonary hypoplasia, skull hypoplasia, neonatal renal failure.	Stop promptly when pregnancy confirmed; switch to labetalol, nifedipine or methyldopa.
NSAIDs	After 20 weeks: fetal renal dysfunction/oligohydramnios; after 30 weeks: premature ductus arteriosus constriction and pulmonary hypertension.	Avoid routine use; if unavoidable before 20 weeks use lowest dose shortest duration.

Safer prescribing choices and dose principles

Paracetamol remains first-line analgesia at standard adult dosing, typically 500 mg–1 g every 4–6 hours, maximum 4 g/day, provided hepatic risk is considered. For nausea and vomiting, doxylamine–pyridoxine, cyclizine, promethazine, prochlorperazine or metoclopramide are commonly used; metoclopramide should generally be limited to short courses because of extrapyramidal risk. Ondansetron is effective but is usually reserved after first-line agents, with counselling regarding debated small first-trimester orofacial/cardiac signals.

Indication	Preferred options in pregnancy	Typical numerical prescribing point
Pre-eclampsia prevention	Low-dose aspirin for high-risk women, or more than one moderate risk factor.	NICE: 75–150 mg once daily from 12 weeks until birth; ASPRE used 150 mg nocte and reduced preterm pre-eclampsia in high-risk screened women.
Hypertension	Labetalol first-line; nifedipine or methyldopa alternatives.	Treat sustained BP ≥140/90 mmHg in chronic hypertension per NICE; target approximately 135/85 mmHg.
Folate supplementation	Folic acid for neural tube defect prevention.	400 micrograms daily pre-conception to 12 weeks; 5 mg daily if previous NTD, antiepileptic use, diabetes, BMI ≥30 kg/m² or malabsorption.
Venous thromboembolism	LMWH preferred; avoid DOACs.	Therapeutic enoxaparin commonly 1 mg/kg twice daily, using booking or early pregnancy weight; specialist anti-Xa monitoring for extremes or renal impairment.
Infection	Penicillins and cephalosporins generally safe; nitrofurantoin acceptable except near term if risk of haemolysis.	Avoid tetracyclines after first trimester; avoid trimethoprim in first trimester where possible unless folate covered and benefits outweigh risks.

Anticoagulants, antiepileptics and psychotropics

LMWH is the anticoagulant of choice because it does not cross the placenta and has lower osteoporosis and HIT risk than unfractionated heparin. It should be withheld when labour begins and before neuraxial anaesthesia: commonly at least 12 hours after prophylactic LMWH and 24 hours after therapeutic LMWH, subject to local obstetric anaesthetic policy. DOACs are avoided owing to insufficient safety data and potential placental transfer.

For epilepsy, monotherapy at the lowest effective dose is preferred, but seizure control is paramount. Lamotrigine and levetiracetam are generally lower-risk options; monitor lamotrigine levels because clearance may rise markedly, with postpartum reversal within days to weeks. Enzyme-inducing antiepileptics may reduce hormonal contraceptive efficacy and alter vitamin K-dependent clotting factors, although routine antenatal maternal vitamin K is not universally required.

SSRIs may be continued when maternal relapse risk is significant. Late exposure may cause transient neonatal adaptation syndrome; persistent pulmonary hypertension of the newborn is a rare association, with absolute risk still low. Paroxetine has a less favourable cardiac signal than sertraline. Lithium requires specialist supervision: teratogenic risk is smaller than historically taught but includes cardiac malformation signal; renal clearance changes necessitate serum monitoring, hydration vigilance and peripartum dose planning.

Elderly Patients

Physiological basis for altered prescribing

Prescribing in older adults is not simply “adult dosing with caution”; ageing produces predictable pharmacokinetic and pharmacodynamic changes, amplified by frailty, multimorbidity and polypharmacy. Chronological age is less informative than biological reserve: frailty indices, recurrent falls, delirium history, sarcopenia, malnutrition and functional dependence often predict drug harm better than age alone. In UK practice, structured medication review is recommended for patients taking multiple medicines, particularly ≥10 regular drugs, those with frailty, care-home residence, renal impairment or recent admission.

Domain	Age-related change	Prescribing consequence
Absorption	Higher gastric pH, slower gastric emptying; usually modest effect	Reduced absorption of drugs requiring acidity, e.g. ketoconazole; delayed onset rather than reduced total exposure
Distribution	↓ total body water and lean mass; ↑ body fat; ↓ albumin in illness/malnutrition	Higher peak levels of hydrophilic drugs, e.g. gentamicin, digoxin; prolonged half-life of lipophilic drugs, e.g. diazepam; increased free fraction of highly protein-bound drugs, e.g. warfarin, phenytoin
Metabolism	↓ hepatic mass and blood flow; phase I oxidation reduced more than phase II conjugation	Avoid long-acting benzodiazepines; prefer lorazepam/oxazepam/temazepam if unavoidable, but still use minimal dose and duration
Excretion	GFR declines approximately 0.75–1 mL/min/year after age 40, but serum creatinine may appear “normal” due to sarcopenia	Dose-adjust renally cleared drugs: DOACs, LMWH, aminoglycosides, lithium, metformin, gabapentin, digoxin
Pharmacodynamics	↑ CNS sensitivity; impaired baroreflexes; altered haemostatic reserve	More delirium, falls, postural hypotension and bleeding at equivalent plasma concentrations

Renal function estimation and dose adjustment

For drug dosing, renal function should be estimated using the method specified in the product licence. In older adults with low muscle mass, eGFR indexed to 1.73 m² can overestimate true clearance; Cockcroft–Gault creatinine clearance remains central for many anticoagulants and cytotoxics. Cockcroft–Gault: CrCl = [(140 − age) × weight(kg) × 1.23 if male or 1.04 if female] / serum creatinine(µmol/L). Use actual body weight unless extremes of body size suggest adjusted weight. A “normal” creatinine of 80 µmol/L in an 85-year-old 50 kg woman gives CrCl about 45 mL/min, not normal renal function.

• Digoxin: usual maintenance in older adults is 62.5–125 micrograms once daily; target serum concentration for heart failure is commonly 0.5–0.9 ng/mL. Toxicity is promoted by renal impairment, hypokalaemia, amiodarone and verapamil.
• Nitrofurantoin: avoid if eGFR <45 mL/min/1.73 m²; a short 3–7 day course may be used cautiously if eGFR 30–44 for lower UTI when benefits outweigh risks.
• Metformin: review if eGFR <45; avoid/initiate no new treatment if eGFR <30 mL/min/1.73 m²; withhold during acute illness, hypoxia, sepsis or iodinated contrast risk.
• Apixaban in AF: reduce from 5 mg twice daily to 2.5 mg twice daily if at least two of: age ≥80 years, weight ≤60 kg, serum creatinine ≥133 µmol/L.

Polypharmacy, deprescribing and high-risk medicines

Polypharmacy is not inherently inappropriate; the exam distinction is between appropriate polypharmacy and medicines where harms exceed realistic benefit. STOPP/START criteria and the American Geriatrics Society Beers Criteria are commonly examined frameworks. STOPP highlights potentially inappropriate medicines, including long-term benzodiazepines, anticholinergics in cognitive impairment, NSAIDs in uncontrolled hypertension/heart failure/CKD, duplicate drug classes and prolonged proton pump inhibitors at full dose without indication. START identifies omissions such as anticoagulation for atrial fibrillation when CHA₂DS₂-VASc warrants it, statin therapy where life expectancy and vascular risk justify treatment, or bone protection in chronic glucocorticoid use.

Drug/group	Mechanism of excess harm in older adults	Practical prescribing point
Benzodiazepines and Z-drugs	Enhanced GABAergic CNS sensitivity; long half-life accumulation; impaired balance	Avoid for chronic insomnia; if severe acute indication, use lowest dose for days not weeks, e.g. lorazepam 0.5 mg
Anticholinergics, e.g. oxybutynin, amitriptyline, chlorphenamine	Central muscarinic blockade causing delirium/cognitive decline; urinary retention, constipation, glaucoma exacerbation	Assess anticholinergic burden; prefer mirabegron or non-drug bladder strategies where suitable
NSAIDs	Afferent arteriolar constriction; GI mucosal injury; sodium retention	Avoid chronic use in CKD, heart failure or anticoagulation; if essential, shortest course plus gastroprotection where indicated
Opioids	Reduced clearance and CNS sensitivity; constipation and falls	Start low, titrate slowly; prescribe stimulant laxative; avoid codeine variability and tramadol delirium/hyponatraemia risk
Alpha-blockers and vasodilators	Impaired baroreflex compensation	Check lying/standing BP; significant postural hypotension is a systolic fall ≥20 mmHg or diastolic fall ≥10 mmHg within 3 minutes

Evidence, targets and individualisation

Guideline targets should be interpreted through frailty, falls risk, cognition and life expectancy. Intensive glycaemic control provides delayed microvascular benefit but immediate hypoglycaemia harm; in frail older adults HbA1c targets are often relaxed, commonly around 58–75 mmol/mol (7.5–9.0%), whereas fit older adults may justify tighter targets. The HYVET trial in patients ≥80 years showed benefit from treating sustained systolic hypertension ≥160 mmHg using indapamide SR 1.5 mg with optional perindopril, targeting <150/80 mmHg, reducing stroke and all-cause mortality; however, orthostatic symptoms and frailty still mandate individualisation. Anticoagulation should not be withheld solely because of age: in AF, stroke risk rises steeply with age, and DOACs generally reduce intracranial haemorrhage versus warfarin, but renal function, weight, drug interactions and adherence must be checked.

Operational prescribing approach

1. Define the indication, expected time-to-benefit and patient-centred goal; stop drugs without current indication.
2. Calculate renal function appropriately and review hepatic disease, albumin, weight, swallowing ability and adherence aids.
3. Use “start low, go slow”, but do not undertreat time-critical disease; titrate to response and adverse effects.
4. Check interactions, especially CYP3A4/P-glycoprotein inhibitors with DOACs, macrolides with statins, and ACE inhibitor/ARB plus diuretic plus NSAID “triple whammy”.
5. Plan monitoring at prescription: U&E/creatinine after ACE inhibitor, ARB or spironolactone initiation or dose increase within 1–2 weeks; lithium levels 12 hours post-dose; INR after warfarin changes; falls, cognition and bowel function after CNS-active or opioid therapy.

Obesity

Classification and prescribing risk stratification

Obesity alters pharmacokinetics, pharmacodynamics, technical drug delivery, and the reliability of renal function estimates. It should not be treated as a simple linear increase in body mass. WHO BMI categories define overweight as 25.0–29.9 kg/m², class I obesity 30.0–34.9, class II 35.0–39.9, and class III ≥40 kg/m². In South Asian, Chinese, Middle Eastern and Black African populations, cardiometabolic risk occurs at lower BMI; many guidelines use overweight ≥23 kg/m² and obesity ≥27.5 kg/m². Waist circumference refines risk: Europid thresholds are ≥94 cm in men and ≥80 cm in women for increased risk, and ≥102/88 cm for high risk.

The Edmonton Obesity Staging System is more clinically useful than BMI alone: stage 0 has no obesity-related risk factors; stage 1 subclinical risk factors or mild symptoms; stage 2 established obesity-related disease such as type 2 diabetes, hypertension, obstructive sleep apnoea or osteoarthritis; stage 3 end-organ damage; and stage 4 severe disability. For prescribing, stages 2–4 should prompt systematic review of drug efficacy, toxicity, drug–disease interactions, and opportunities for weight-modifying therapy.

Pharmacokinetic principles

In obesity, absolute fat mass and lean mass both increase, but not proportionately. Cardiac output, renal plasma flow and glomerular filtration may be increased early, whereas advanced obesity may coexist with chronic kidney disease, heart failure or non-alcoholic steatohepatitis. Volume of distribution is increased most for highly lipophilic drugs, but hydrophilic drugs distribute mainly into extracellular water and lean mass. Therefore dosing by total body weight may overdose aminoglycosides, neuromuscular blockers and some anticoagulants, whereas using ideal body weight may underdose antimicrobials with large therapeutic targets.

Weight scalar	Calculation	Typical use
Total body weight	Measured actual weight	Many loading doses for drugs with increased Vd; treatment-dose LMWH; some beta-lactams
Ideal body weight	Devine: male 50 kg + 2.3 kg/inch over 5 ft; female 45.5 kg + 2.3 kg/inch over 5 ft	Baseline size descriptor; some anaesthetic and renal calculations
Adjusted body weight	IBW + correction factor × (TBW − IBW); commonly 0.4	Aminoglycosides; Cockcroft–Gault when TBW grossly overestimates CrCl
Lean body weight	Formula-derived fat-free mass	Opioids, sedatives and drugs where pharmacodynamic sensitivity is important

Renal dosing is a recurrent examination trap. Laboratory eGFR is indexed to 1.73 m²; for drug dosing it may need de-indexing: absolute GFR = eGFR × patient BSA/1.73. Cockcroft–Gault using total body weight often overestimates creatinine clearance in severe obesity; using ideal body weight may underestimate it. Adjusted body weight is commonly used, but direct measurement or specialist advice is appropriate for narrow-therapeutic-index drugs. Serum creatinine may appear “normal” despite clinically relevant renal impairment, particularly in sarcopenic obesity.

Common prescribing applications

Drug/class	Obesity-specific prescribing point
Aminoglycosides	Use adjusted body weight, typically gentamicin 5–7 mg/kg for extended-interval dosing, then adjust by levels. Toxicity correlates with trough exposure; do not simply dose by total body weight.
Vancomycin	Loading dose 20–25 mg/kg using actual body weight, often capped at 3 g; maintenance should target AUC24/MIC 400–600 rather than trough alone where feasible.
Beta-lactams	Hydrophilic with time-dependent killing; obesity may increase Vd and clearance. Consider upper-end licensed doses and prolonged/continuous infusions for severe infection, sepsis or high MIC organisms.
LMWH	Treatment enoxaparin is commonly 1 mg/kg twice daily using actual body weight; consider anti-Xa monitoring in extreme weight, renal impairment or pregnancy. Prophylactic fixed doses may be inadequate; many protocols increase dose when BMI ≥40 kg/m2.
DOACs	ISTH 2021 guidance supports standard-dose apixaban or rivaroxaban in BMI >40 kg/m2 or weight >120 kg for VTE; evidence is weaker for dabigatran and edoxaban. Avoid empiric dose escalation.
Warfarin	Higher maintenance doses are often required, but dosing remains INR-guided; loading should not be excessive because delayed over-anticoagulation still occurs.
Paracetamol and opioids	Maximum paracetamol dose remains 4 g/day in adults, lower with hepatic risk. Opioids should be titrated to effect; obstructive sleep apnoea and obesity hypoventilation increase respiratory-depression risk.

Anti-obesity pharmacotherapy and post-bariatric prescribing

Drug treatment is an adjunct to structured lifestyle intervention, not cosmetic therapy. NICE generally considers pharmacotherapy at BMI ≥30 kg/m², or ≥27.5 kg/m² in high-risk ethnic groups, when weight-related comorbidity is present; specialist thresholds for newer incretin therapies may be stricter. Orlistat 120 mg three times daily with meals inhibits gastric and pancreatic lipases and reduces dietary fat absorption by approximately 30%; adverse effects are steatorrhoea, urgency, fat-soluble vitamin deficiency, and reduced absorption of ciclosporin, levothyroxine and some antiepileptics.

GLP-1 receptor agonism reduces appetite, slows gastric emptying and improves glycaemia. Semaglutide 2.4 mg once weekly produced mean weight loss of 14.9% versus 2.4% with placebo at 68 weeks in STEP 1. Liraglutide 3 mg daily produced approximately 8.0% versus 2.6% weight loss at 56 weeks in SCALE. Tirzepatide, a dual GIP/GLP-1 agonist, produced mean reductions of 15.0%, 19.5% and 20.9% with 5, 10 and 15 mg weekly versus 3.1% with placebo at 72 weeks in SURMOUNT-1. Key adverse effects are nausea, vomiting, diarrhoea, gallbladder disease, dehydration-related acute kidney injury, and rare pancreatitis; avoid in pregnancy and use caution with severe gastrointestinal disease.

After Roux-en-Y gastric bypass or sleeve gastrectomy, altered gastric pH, reduced surface area and shortened transit can impair absorption. Avoid modified-release, enteric-coated and large tablets where possible; prefer immediate-release or liquid preparations initially. NSAIDs increase marginal ulceration risk after bypass. Monitor drugs with narrow therapeutic indices, including levothyroxine, antiepileptics, immunosuppressants and anticoagulants.