Clinical pharmacology and prescribing: High-risk drugs, therapeutic drug monitoring, IV fluids and antimicrobial prescribing

• High-risk drugs: High-risk Medicines | Warfarin | DOACs and Heparins | Insulin | Opioid Prescribing | Potassium and Electrolyte Replacement
• Therapeutic drug monitoring: Principles of Drug Monitoring | Gentamicin and Vancomycin | Digoxin | Lithium | Phenytoin, Theophylline and Immunosuppressants | Blood Monitoring for Common Drugs
• Fluids, oxygen and antimicrobials: Prescribing IV Fluids | Choosing an IV Fluid | Prescribing Oxygen | Antimicrobial Prescribing and Stewardship
• Revision: High-risk Drugs at a Glance | Spot the Diagnosis | Exam-style Scenarios | Key Points | Guidelines and Further Reading

🩺 High-risk drugs, therapeutic drug monitoring, IV fluids and antimicrobial prescribing -page 5 of the Clinical Pharmacology and Prescribing chapter. A small number of medicines cause most serious medication harm -anticoagulants, insulin, opioids, IV potassium, IV fluids, antibiotics and narrow therapeutic index drugs. These are the drugs junior doctors prescribe every day, and they feature heavily in the PSA. Treatment of individual diseases is in the specialty chapters.
Your four questions for every high-risk drug: Is the dose right for this patient's weight, kidney function and indication? What level or test do I need, and when? What are the warning signs of toxicity? How would I reverse or treat it if something went wrong?

High-risk Medicines

• High-risk medicines -drugs with a high risk of causing significant harm when used in error or without proper monitoring.
• Common examples -"A PINCH":
  • A -Anti-infectives (aminoglycosides, vancomycin, antifungals), anticoagulants, antiepileptics.
  • P -Potassium and other electrolytes (IV), psychotropics (lithium, clozapine).
  • I -Insulin.
  • N -Narcotics (opioids) and sedatives.
  • C -Chemotherapy (including oral methotrexate).
  • H -Heparin and other anticoagulants.
• Also -IV fluids, digoxin, amiodarone, immunosuppressants, neuromuscular blockers, concentrated injections (midazolam, morphine), oral methotrexate, valproate (pregnancy).
• Safety measures -double-checking, standardised concentrations (pre-mixed bags), dedicated charts (insulin, anticoagulants), electronic decision support, pharmacist review, patient alert cards, monitoring protocols, avoiding abbreviations.

Warfarin

• Mechanism -vitamin K antagonist -reduces clotting factors II, VII, IX and X (and proteins C and S -a brief prothrombotic phase at the start).
• Indications and INR targets:
  • INR 2.5 (range 2–3) -AF, DVT and PE, most indications.
  • INR 3.5 -recurrent VTE while on warfarin at target INR 2.5.
  • Mechanical heart valves -target depends on valve type and position (e.g. 3.0 or 3.5 -per cardiology).
  • Warfarin is preferred over DOACs for mechanical valves, antiphospholipid syndrome, moderate–severe mitral stenosis, and some with severe kidney impairment.
• Starting -loading regimens (local protocol, e.g. Fennerty or lower doses in older people); for VTE, give LMWH alongside for at least 5 days and until INR has been 2 or more for 24 hours.
• Monitoring -INR frequently at the start, then up to every 12 weeks when stable; yellow anticoagulant book and alert card.
• Interactions -many:
  • Raise INR -antibiotics (clarithromycin, erythromycin, metronidazole, ciprofloxacin, co-trimoxazole), azole antifungals, amiodarone, alcohol binges, cranberry juice, SSRIs (bleeding), paracetamol (regular high doses), illness (diarrhoea, fever, liver congestion).
  • Lower INR -enzyme inducers (rifampicin, carbamazepine, phenytoin, St John's wort), vitamin K-rich foods (green vegetables) and supplements.
  • NSAIDs and antiplatelets -increase bleeding without changing INR.
• Managing a high INR (BNF):

  Situation	Action
  Major bleeding (any INR)	Stop warfarin; IV vitamin K (phytomenadione) 5 mg; prothrombin complex concentrate (or FFP if PCC unavailable)
  INR over 8, minor bleeding	Stop warfarin; IV vitamin K 1–3 mg; repeat if INR still high after 24 hours; restart when INR under 5
  INR over 8, no bleeding	Stop warfarin; oral vitamin K 1–5 mg; repeat if still high after 24 hours; restart when INR under 5
  INR 5–8, minor bleeding	Stop warfarin; IV vitamin K 1–3 mg; restart when INR under 5
  INR 5–8, no bleeding	Withhold 1–2 doses and reduce the maintenance dose

• Look for the cause of a high INR (interaction, illness, dose error); head injury on warfarin -low threshold for CT and reversal.
• Teratogenic -switch to LMWH before 6 weeks of pregnancy.

DOACs and Heparins

• DOACs (direct oral anticoagulants):
  • Factor Xa inhibitors -apixaban (twice daily), rivaroxaban (once daily with food for AF), edoxaban (once daily); direct thrombin inhibitor -dabigatran (twice daily, mostly renally cleared).
  • Advantages -fixed doses, no INR monitoring, fewer interactions, less intracranial bleeding than warfarin.
  • Dose by indication, age, weight and creatinine clearance (Cockcroft–Gault) -check the BNF for each drug; check U&E and FBC at least annually (more often if CrCl under 60 or frail).
  • Avoid in mechanical valves, antiphospholipid syndrome (especially triple positive), severe kidney impairment (thresholds vary), pregnancy and breastfeeding, and with strong enzyme inducers or inhibitors.
  • Reversal -idarucizumab for dabigatran; andexanet alfa (restricted use) or PCC for factor Xa inhibitors per local policy; supportive care; short half-lives help.
• Low molecular weight heparin (enoxaparin, dalteparin, tinzaparin):
  • Prophylaxis (fixed dose; adjust for weight extremes) and treatment (weight-based).
  • Renally cleared -reduce treatment dose if CrCl under 30 (or use UFH); anti-Xa monitoring in pregnancy, extremes of weight or kidney failure.
  • Preferred in pregnancy and cancer-associated VTE (or a DOAC in many cancers).
• Unfractionated heparin (UFH) -IV infusion with APTT monitoring (APTT ratio target per protocol); short half-life and reversible with protamine sulfate -useful in severe CKD, high bleeding risk, around procedures, and thrombolysis protocols.
• Heparin-induced thrombocytopenia (HIT):
  • Antibodies against heparin–PF4 complexes -platelets fall by over 50% 5–10 days after starting heparin (sooner if recent exposure) -paradoxically causes thrombosis (venous and arterial).
  • Assess with the 4Ts score; send HIT antibodies.
  • Stop all heparin (including flushes) and start a non-heparin anticoagulant (argatroban, fondaparinux, danaparoid, or a DOAC per specialist); don't give platelets; avoid warfarin until platelets recover.
• Other heparin effects -hyperkalaemia (aldosterone suppression), osteoporosis (long-term UFH).

Insulin

• Types:

  Type	Examples	Use
  Rapid-acting analogue	Insulin aspart (NovoRapid, Fiasp), lispro (Humalog)	With meals (bolus); correction doses; insulin pumps
  Short-acting soluble	Actrapid, Humulin S	IV infusions (VRIII, DKA), meals
  Intermediate	Isophane (Humulin I, Insulatard)	Once or twice daily basal; type 2 diabetes; steroid-induced hyperglycaemia
  Long-acting analogue	Glargine (Lantus, Toujeo -U300), detemir (Levemir), degludec (Tresiba)	Basal insulin once (or twice) daily
  Mixed (biphasic)	Humalog Mix 25, NovoMix 30, Humulin M3	Twice daily with breakfast and evening meal

• Safe prescribing:
  • Prescribe by brand name and device (pen or vial; strength -U100 standard; high-strength U200, U300, U500 exist -risk of error).
  • Write "units" in full; use only insulin syringes or pens (never IV syringes for SC insulin).
  • Record the time of administration relative to meals.
  • Never omit basal insulin in type 1 diabetes (DKA within hours) -even if not eating.
  • Let patients self-administer in hospital where possible.
• Variable-rate IV insulin infusion (VRIII) -for people with diabetes who are nil by mouth (missing more than one meal), unwell with persistent hyperglycaemia, or in some surgery -continue long-acting basal insulin; run with a glucose-containing substrate fluid (e.g. 0.45% saline with 5% glucose and potassium); hourly glucose; stop 30–60 minutes after the first subcutaneous rapid-acting dose with a meal.
• Hypoglycaemia (glucose under 4 mmol/L) in adults (JBDS):
  • Conscious and able to swallow -15–20 g fast-acting carbohydrate (e.g. glucose tablets, 150–200 mL fruit juice); recheck after 10–15 minutes; repeat up to 3 times; then a long-acting carbohydrate snack.
  • Drowsy or unable to swallow safely -IV glucose (e.g. 150–160 mL of 10% glucose or 75–80 mL of 20% over about 15 minutes) or IM glucagon 1 mg (less effective in liver disease, alcohol, starvation or sulphonylurea overdose).
  • Don't omit the next insulin dose after treating a hypo (especially basal) -review the dose.
  • Sulphonylurea hypoglycaemia can be prolonged -admit and monitor (may need a glucose infusion).
• Insulin errors are common -wrong insulin (Humalog vs Humulin), wrong dose ("U" read as 0), omission, timing, and failure to adjust when not eating.

Opioid Prescribing

• WHO analgesic ladder -non-opioid (paracetamol ± NSAID) → weak opioid (codeine, low-dose tramadol) → strong opioid (morphine, oxycodone) ± adjuvants; useful mainly for cancer pain.
• Starting strong opioids (NICE CG140 -palliative care):
  • Regular oral morphine -20–30 mg a day in total (immediate-release 4-hourly or modified-release twice daily, e.g. MR morphine 10–15 mg twice daily), with immediate-release morphine 5 mg as needed for breakthrough pain.
  • Lower starting doses in older people, frailty, kidney or liver impairment.
  • Breakthrough dose -about one-sixth to one-tenth of the total 24-hour dose.
  • Titrate daily according to breakthrough use.
  • Always prescribe a laxative (stimulant ± softener) and an antiemetic as needed (nausea usually settles in days).
• Approximate equivalences (check local guidance; reduce by 25–50% when switching between opioids because of incomplete cross-tolerance):

  From	To (approximate)
  Oral morphine 10 mg	SC morphine 5 mg
  Oral morphine 10 mg	Oral oxycodone 5–7.5 mg (ratio 1.5–2:1)
  Oral morphine 10 mg	SC diamorphine about 3.3 mg
  Oral codeine 60 mg	Oral morphine about 6 mg (codeine is about one-tenth as potent)
  Oral morphine about 60 mg/24 hours	Fentanyl 12 micrograms/hour patch (roughly -check conversion charts)

• Toxicity -drowsiness, confusion, hallucinations, myoclonus (metabolite accumulation in CKD), pinpoint pupils, respiratory depression -reduce dose or switch opioid; naloxone for life-threatening respiratory depression (in palliative patients, small titrated doses -e.g. 20–100 micrograms -to avoid reversing analgesia and causing pain crisis).
• Patches (fentanyl, buprenorphine) -for stable pain in opioid-tolerant patients; slow onset (12–24 hours) and offset; heat increases absorption; dispose of safely.
• Chronic non-cancer pain -opioids have limited long-term benefit and cause dependence; avoid high doses (over 120 mg oral morphine equivalent a day adds risk without benefit) (Faculty of Pain Medicine -Opioids Aware).
• Controlled drug rules apply (see page 2).

Potassium and Electrolyte Replacement

• Hypokalaemia (potassium under 3.5 mmol/L):
  • Mild (3.0–3.4) -oral potassium (e.g. Sando-K 2 tablets two or three times daily -24 mmol per 2 tablets) or increased dietary intake; treat the cause (diuretics, diarrhoea, vomiting); consider a potassium-sparing diuretic.
  • Moderate to severe (under 3.0), symptoms, arrhythmias or unable to take orally -IV potassium.
• IV potassium rules:
  • Use pre-mixed bags (e.g. 20 mmol or 40 mmol KCl in 1 L sodium chloride 0.9% or glucose) -never add concentrated KCl on the ward, never give as a bolus.
  • Maximum rate peripherally -usually 10 mmol/hour (up to 20 mmol/hour with cardiac monitoring per local policy; higher rates only centrally in critical care).
  • Maximum concentration peripherally -usually 40 mmol/L (higher concentrations irritate veins).
  • Monitor potassium regularly; check and correct magnesium (hypokalaemia won't correct if magnesium is low).
• Hypomagnesaemia -PPIs, diuretics, alcohol, diarrhoea; oral magnesium (diarrhoea) or IV magnesium sulfate (e.g. 20 mmol over several hours; 2 g over 10–15 minutes for torsades or severe asthma).
• Hypophosphataemia -refeeding, alcohol, DKA treatment -oral (Phosphate Sandoz) or IV phosphate.
• Hyperkalaemia -calcium gluconate 10% (30 mL -cardiac protection if ECG changes), insulin with glucose (10 units soluble insulin in 25 g glucose), salbutamol nebulisers, stop causative drugs; potassium binders (sodium zirconium cyclosilicate, patiromer) -see the Renal Emergencies chapter.

Principles of Drug Monitoring

• Therapeutic drug monitoring (TDM) -measuring drug levels to guide dosing when there's a narrow therapeutic index, variable pharmacokinetics, a level–effect relationship, suspected toxicity, poor adherence, interactions or organ impairment.
• Timing matters:
  • Trough levels (just before the next dose) -vancomycin, ciclosporin, tacrolimus, multiple-daily gentamicin.
  • Peak levels -some aminoglycoside regimens (e.g. endocarditis).
  • Fixed time after a dose -lithium (12 hours), digoxin (at least 6 hours), once-daily gentamicin (6–14 hours, nomogram).
  • Steady state -after 4–5 half-lives (unless checking for toxicity).
• Interpret levels with the patient -symptoms, kidney function, electrolytes, albumin (phenytoin), timing of the sample, recent dose changes.
• Monitoring the effect instead of the level -INR (warfarin), APTT (UFH), BP, glucose, TFTs (levothyroxine), heart rate (beta-blockers, rate control).

Gentamicin and Vancomycin

• Gentamicin (aminoglycoside):
  • Uses -serious gram-negative infections, sepsis of urinary or abdominal origin, endocarditis (synergy with beta-lactams).
  • Toxicity -nephrotoxicity (usually reversible) and ototoxicity (vestibular and cochlear -often permanent); neuromuscular blockade (avoid in myasthenia gravis).
  • Once-daily dosing -e.g. 5–7 mg/kg (local protocol; maximum dose caps), based on actual or adjusted body weight in obesity; interval based on creatinine clearance and level 6–14 hours after the dose plotted on a nomogram (e.g. Hartford).
  • Avoid or use with great care -CKD, older people, with other nephrotoxins (vancomycin, NSAIDs, contrast) and loop diuretics (ototoxicity); limit duration (often 3–5 days); MT-RNR1 variant -deafness after a single dose (genetic testing in some settings).
  • Monitor creatinine daily and ask about hearing and balance.
• Vancomycin (glycopeptide):
  • Uses -MRSA and other gram-positive infections, penicillin allergy; oral vancomycin for C. difficile (not absorbed -no levels needed).
  • Loading dose by weight (e.g. 25–30 mg/kg, max per protocol), then maintenance by kidney function; levels (trough) before the 4th dose (or AUC-guided dosing); or continuous infusion in some units.
  • Toxicity -nephrotoxicity (worse with piperacillin–tazobactam, aminoglycosides), ototoxicity (rare); vancomycin infusion reaction ("red man syndrome") -flushing and itching with fast infusion -slow the rate (not an allergy).
• Teicoplanin -related glycopeptide; loading doses; fewer infusion reactions.

Digoxin

• Mechanism -inhibits Na⁺/K⁺ ATPase (positive inotrope) and increases vagal tone (slows AV conduction).
• Uses -rate control in AF (especially sedentary patients or with heart failure), heart failure with reduced EF (symptom control).
• Dosing -loading dose for rapid effect; maintenance 62.5–250 micrograms daily, lower in kidney impairment and older people.
• Toxicity -risk factors:
  • Hypokalaemia (diuretics) -the most important; also hypomagnesaemia, hypercalcaemia, hypothyroidism.
  • Kidney impairment, dehydration, older age.
  • Interactions -amiodarone (halve digoxin dose), verapamil, diltiazem, clarithromycin, spironolactone.
• Features of toxicity -nausea, vomiting, anorexia, diarrhoea, confusion, visual disturbance (blurring, yellow-green vision), arrhythmias (bradycardia, heart block, ventricular ectopics, bidirectional VT, atrial tachycardia with block).
• ECG -"reverse tick" (scooped ST depression) -a digoxin effect, not necessarily toxicity.
• Management -stop digoxin, correct potassium and magnesium, monitor ECG; atropine for bradycardia; digoxin-specific antibody fragments (DigiFab) for life-threatening arrhythmias, severe toxicity or high potassium (see page 6).

Lithium

• Uses -bipolar disorder (mania prevention and treatment), treatment-resistant depression.
• Prescribe by brand (formulations differ -Priadel, Camcolit); liquid and tablet doses differ.
• Monitoring (NICE CG185):
  • Before starting -U&E (eGFR), TFTs, calcium, ECG (cardiac risk), weight, pregnancy plans.
  • Levels -12 hours after the last dose; weekly after starting or each dose change until stable; then every 3 months for the first year, then every 6 months (3-monthly in older people, interacting drugs, CKD, poor control).
  • U&E, TFTs and calcium every 6 months; weight.
• Long-term side effects -hypothyroidism, nephrogenic diabetes insipidus (thirst, polyuria), CKD, hyperparathyroidism (high calcium), weight gain, fine tremor, acne, psoriasis worsening, teratogenicity (Ebstein's anomaly -small risk).
• Toxicity (level over 1.5 mmol/L; but can occur at lower levels) -coarse tremor, diarrhoea and vomiting, ataxia, dysarthria, confusion, nystagmus, hyperreflexia, myoclonus, seizures, coma, arrhythmias.
• Triggers of toxicity -dehydration (vomiting, diarrhoea, heat, low salt diet), AKI, and drugs that reduce lithium clearance -NSAIDs, ACE inhibitors, ARBs, thiazides (and loop diuretics less so).
• Patient education -lithium card and record book, maintain fluid intake, avoid OTC NSAIDs, seek help if vomiting or diarrhoea; sick day advice.
• Management of toxicity -stop lithium, IV fluids, monitor levels; haemodialysis for severe toxicity (see page 6).

Phenytoin, Theophylline and Immunosuppressants

• Phenytoin:
  • Zero-order kinetics at therapeutic levels -small dose changes cause large level changes.
  • Highly protein-bound -in low albumin (or kidney failure), free drug rises; correct the measured level or measure free phenytoin.
  • Toxicity -nystagmus, ataxia, slurred speech, drowsiness, confusion.
  • Long-term effects -gum hypertrophy, hirsutism, coarse facies, osteomalacia, folate deficiency, peripheral neuropathy, cerebellar atrophy; teratogenic; enzyme inducer.
  • IV phenytoin (status epilepticus) -loading dose 20 mg/kg; cardiac monitoring (hypotension, arrhythmias, bradycardia); give slowly; "purple glove" with extravasation.
• Theophylline and aminophylline -asthma and COPD; narrow therapeutic index; levels affected by smoking (inducer -lowers levels; stopping smoking raises them), heart failure, liver disease and interactions (clarithromycin, ciprofloxacin raise levels); toxicity -vomiting, tachycardia, arrhythmias, hypokalaemia, seizures; don't give an IV loading dose to patients already taking oral theophylline.
• Ciclosporin and tacrolimus (calcineurin inhibitors) -transplant and autoimmune disease; trough level monitoring; toxicity -nephrotoxicity, hypertension, hyperkalaemia, tremor, diabetes (tacrolimus), gum hypertrophy and hirsutism (ciclosporin); many CYP3A4 interactions (clarithromycin and azoles raise levels; rifampicin and St John's wort lower them -rejection risk); prescribe by brand.
• Clozapine -mandatory FBC monitoring (agranulocytosis) -weekly for 18 weeks, then fortnightly to 1 year, then monthly; levels if toxicity suspected or smoking status changes; constipation can be fatal; myocarditis early.
• Methotrexate (high dose, oncology) -levels guide folinic acid rescue.

Blood Monitoring for Common Drugs

Prescribing IV Fluids

• IV fluids are drugs -errors (too much, too little, wrong type) cause harm: fluid overload, pulmonary oedema, hyponatraemia (especially children and older people), hyperchloraemic acidosis, AKI.
• NICE CG174 -the "5 Rs": Resuscitation, Routine maintenance, Replacement, Redistribution, Reassessment.
• Assess before prescribing -history (intake, losses), observations (HR, BP, capillary refill, JVP, NEWS2), fluid balance chart, weight, U&E, oedema and chest signs; can the patient drink or take enteral fluids instead?
• Resuscitation (hypovolaemia):
  • 500 mL bolus of crystalloid (sodium 130–154 mmol/L -e.g. 0.9% sodium chloride or Hartmann's) over under 15 minutes.
  • Reassess after each bolus; up to about 2,000 mL, then seek senior help.
  • Smaller boluses (250 mL) in heart failure or frailty; blood for haemorrhage; avoid starches.
• Routine maintenance (adults, for 24 hours):
  • Water -25–30 mL/kg/day (consider 20–25 mL/kg/day in older or frail people, heart failure, kidney impairment, malnutrition).
  • Sodium, potassium and chloride -about 1 mmol/kg/day each.
  • Glucose -50–100 g/day (to limit starvation ketosis -not nutrition).
  • Example -70 kg adult: about 2–2.1 L/day with about 70 mmol each of sodium and potassium -e.g. 0.18% sodium chloride with 4% glucose with potassium, or a combination of fluids per local guidance.
  • Review daily; stop IV fluids as soon as oral intake is adequate; prescribe for no more than 24 hours at a time.
• Replacement and redistribution -add ongoing losses (vomiting, diarrhoea, high-output stoma, drains, fever, polyuria) and consider fluid shifts (sepsis, pancreatitis, oedema, ascites).
• Children -isotonic fluids (e.g. 0.9% sodium chloride with 5% glucose) for maintenance -hypotonic fluids cause dangerous hyponatraemia (NICE NG29); use the Holliday–Segar formula (100/50/20 mL/kg/day).

Choosing an IV Fluid