Pharmacokinetics in Organ Failure — Written Clinical Reasoning

SAQ 1 — Integrated Medication Review in Organ Failure (20 marks, 30 minutes)

Prompt: Construct a problem list for this patient, perform a systematic medication review applying renal and hepatic dosing principles and the Beers/STOPP-START framework, and outline an integrated management plan with justification for each decision. [1]

Model Answer

Problem list (4 marks): [1]

1. Acute kidney injury (KDIGO stage 2) on chronic CKD stage 3b — precipitated by the 'triple whammy' (perindopril + frusemide + indomethacin) continued during a dehydrating illness, with metformin retained and accumulating.
2. Hyperkalaemia, K 5.9 — secondary to AKI and ACE inhibitor; medical urgency if ECG changes develop.
3. Polypharmacy with multiple potentially inappropriate medications — indomethacin (NSAID in CKD), amitriptyline (anticholinergic in a falls-prone older patient), full-dose allopurinol in CKD (300 mg with eGFR 32), metformin retained in AKI, gliclazide (hypoglycaemia risk in renal impairment), and the anticholinergic/sedative burden contributing to the fall.
4. A fall with confusion — likely multifactorial: dehydration, anticholinergic amitriptyline, possible hypoglycaemia from gliclazide (glucose 3.6), possible sepsis (urinalysis normal, but infection must be excluded).
5. Atrial fibrillation on anticoagulation — apixaban 5 mg BD; dose-reduction criteria to review (age below 80, but weight 55 kg below 60 and creatinine now 210 above 133 — two of three criteria now met). [1]

Medication review, drug by drug (8 marks): [1]

1. Indomethacin (NSAID) — STOP. This is the third arm of the triple whammy. NSAIDs inhibit renal prostaglandins, constricting the afferent arteriole; combined with ACEi (efferent dilation) and diuretic (volume depletion), GFR collapses during dehydration. Also raises bleeding risk on apixaban and worsens hypertension. STOP criteria flag: NSAID with CKD. Replace with paracetamol for gout pain; colchicine 0.5 mg BD (dose-reduced in CKD) for the acute flare if needed.
2. Perindopril (ACEi) — HOLD during AKI. ACE inhibitors dilate the efferent arteriole and contribute to functional AKI, and they cause hyperkalaemia (K 5.9). Hold now; resume only when renal function returns to baseline and potassium is normal. Reconsider the need: she has AF and hypertension; a beta-blocker (bisoprolol continued) and rate control may suffice, and an ACEi is not mandatory in AF alone.
3. Frusemide (diuretic) — HOLD once volume reassessed. She is dehydrated, so hold the loop diuretic. Resume only if she becomes volume overloaded (e.g., heart failure). This is the second arm of the triple whammy.
4. Metformin — HOLD. Metformin is renally cleared and retained in AKI; the eGFR today is effectively below 30 and the risk of metformin-associated lactic acidosis is high. The sick-day rule mandates holding metformin during dehydration. Restart only when eGFR returns above 30 and the patient is rehydrated and eating.
5. Allopurinol 300 mg — REDUCE to 100 mg daily. Full-dose allopurinol in CKD (eGFR 32) is the single biggest risk factor for allopurinol hypersensitivity syndrome (DRESS). She is already established on the drug, but the dose should be reduced to 100 mg daily and titrated slowly to a target urate, with a maximum of 200 mg/day below eGFR 30. Screen HLA-B*5801 if she were newly starting (high-risk population).
6. Amitriptyline — STOP. This is a Beers-listed drug in older adults: strong anticholinergic effect causing confusion, dry mouth, constipation, urinary retention, orthostatic hypotension and falls. It has directly contributed to her fall and confusion. If depression persists, switch to sertraline (SSRI, lower anticholinergic burden); use non-pharmacological strategies for sleep.
7. Gliclazide — REDUCE/HOLD temporarily. Sulfonylureas carry hypoglycaemia risk in renal impairment; her glucose is already 3.6. Hold temporarily during the acute illness; on recovery consider switching to a DPP-4 inhibitor or SGLT2i (renal/cardioprotective, though hold SGLT2i during acute illness). Glibenclamide/glyburide is the specifically Beers-flagged long-acting sulfonylurea to AVOID.
8. Apixaban — REASSESS dose. The dose-reduction criteria are: two of three of age above 80 (no), weight below 60 kg (yes, 55 kg), creatinine above 133 micromol/L (yes, now 210). Two criteria are now met, so reduce to apixaban 2.5 mg BD. When renal function recovers, recheck: if creatinine falls below 133 and she meets only one criterion, she returns to 5 mg BD. Anticoagulation should continue — her CHA2DS2-VASc is high (age, hypertension, diabetes, vascular disease). In severe AKI with bleeding risk, hold briefly and consider heparin.
9. Bisoprolol — CONTINUE (rate control for AF, no acute contraindication).
10. Multivitamin — CONTINUE (low risk). [1]

START (prescribing omissions) review: ensure she is on a statin (vascular disease — currently not prescribed; start atorvastatin 20 mg, moderate intensity), bone protection (osteoporosis with a recent fall — ensure bisphosphonate and calcium/vitamin D; consider zoledronate), and that her vaccinations (influenza, pneumococcal, COVID) are up to date. [1]

Management plan (8 marks): [1]

1. Resuscitate and treat the hyperkalaemia (2 marks): ABCDE, intravenous access, continuous cardiac monitoring. Treat K 5.9 with calcium resonium orally (if no ECG changes) or insulin/dextrose if ECG changes develop; the AKI itself will improve with fluid. Give isotonic saline cautiously (she has AF and is at risk of overload) — 500 mL boluses with reassessment.
2. Stop the offending drugs (2 marks): cease indomethacin and amitriptyline; hold perindopril, frusemide, metformin and gliclazide temporarily; reduce allopurinol to 100 mg; reduce apixaban to 2.5 mg BD.
3. Investigate the precipitant (2 marks): blood cultures, CXR, urinalysis (already normal), ECG; septic screen. Treat any infection found. Exclude hypoglycaemia (glucose 3.6 — give a carbohydrate source).
4. Deprescribe and plan for discharge (2 marks): a written medication list; arrange GP follow-up within one week and a pharmacy home medicines review; counsel the patient (and carer) on the sick-day rule in plain language — temporarily stop the 'water pill, blood-pressure pill, diabetes pill and painkiller' during vomiting, diarrhoea or fever and restart when eating and drinking normally for 24 hours; review in clinic to decide on resuming perindopril and metformin once eGFR returns to baseline. [1]

SAQ 2 — Therapeutic Drug Monitoring Interpretation (10 marks, 15 minutes)

Prompt: A 64-year-old ICU patient with severe hypoalbuminaemia (albumin 18 g/L) and AKI (creatinine 200) on a phenytoin infusion for seizure prophylaxis has a measured total phenytoin of 12 mg/L (therapeutic range 10-20) but is nystagmic and ataxic. Interpret the level, explain the pharmacokinetic principle, state the corrected level using the Sheiner-Tozer equation, and describe the correct next step. [1]

Model Answer

Pharmacokinetic principle (3 marks): Phenytoin is approximately 90% protein-bound to albumin; only the free (unbound) 10% is pharmacologically active and crosses the blood-brain barrier. In hypoalbuminaemia (albumin 18 g/L) and uraemia (renal failure, where uraemic compounds displace phenytoin from albumin), the free fraction rises. The TOTAL phenytoin level falls (less bound drug measured) while the FREE (active) level stays the same or rises — so a patient can be neurologically toxic on a total level that sits within the nominal therapeutic range. Phenytoin also follows saturable (Michaelis-Menten) kinetics, so small dose increments cause disproportionate level rises. [1]

Sheiner-Tozer correction (3 marks): Corrected phenytoin = measured total / [(0.2 x albumin in g/dL) + 0.1]. Albumin 18 g/L = 1.8 g/dL. Denominator = (0.2 x 1.8) + 0.1 = 0.36 + 0.1 = 0.46. Corrected level = 12 / 0.46 = approximately 26 mg/L — clearly toxic (above the upper limit of 20 mg/L). This explains the nystagmus and ataxia. [1]

Correct next step (4 marks): Reduce the phenytoin dose and recheck. Ideally, send a free phenytoin level (target 1-2 mg/L) rather than relying on corrections, particularly in renal failure where uraemic displacement makes the equation less accurate. Hold or reduce the infusion, monitor for seizure activity, and re-dose using the corrected/free level. Recognise that phenytoin follows saturable kinetics, so the dose reduction should be substantial and the level rechecked before further titration. Review concurrent drugs that raise phenytoin (CYP2C9/2C19 inhibitors such as amiodarone, fluconazole, isoniazid) and those that lower it (enzyme inducers such as rifampicin, carbamazepine). [1]

The broader principle: in any critically ill patient with hypoalbuminaemia or renal failure, never interpret a total phenytoin level without correcting for albumin or sending a free level. The same logic applies to valproate and other highly protein-bound anti-epileptics. [1]