Pharmacokinetics in Organ Failure — Clinical Case

DCE Long Case

Patient brief (provided to trainee)

Patient: Mrs Margaret Whitlam, 78 years old, retired schoolteacher. [1]

Presenting complaint: Found on the floor at home by her daughter this morning, confused and unable to get up. She has a laceration to her forehead but is orienting slowly. She reports three days of diarrhoea and reduced oral intake. [1]

Past history: Type 2 diabetes for 18 years; chronic kidney disease stage 3b (baseline eGFR 32, creatinine 150); ischaemic heart disease with a non-STEMI three years ago; atrial fibrillation (rate-controlled); hypertension; gout; osteoporosis (wrist fracture two years ago); depression. [1]

Current medications: Metformin 1 g BD, gliclazide 80 mg BD, apixaban 5 mg BD, bisoprolol 5 mg, perindopril 10 mg, frusemide 40 mg, indomethacin 50 mg BD, allopurinol 300 mg, amitriptyline 50 mg nocte, multivitamin. [1]

Examination findings (trainee elicits):

• GCS 14 (E4 V4 M6), confused to time; afebrile, BP 104/64 lying, HR 88 irregular
• Dry mucous membranes, reduced skin turgor; JVP not visible
• Cardiovascular: irregularly irregular, no murmurs; chest clear
• Abdomen: soft, non-tender; no bladder distension
• A 4 cm laceration to the forehead, no focal neurology; no evidence of fracture
• Weight 55 kg [1]

Investigations: Na 138, K 5.9, Cl 104, bicarbonate 18, urea 14, creatinine 210 (baseline 150), glucose 3.6, albumin 30 g/L, eGFR reported as 22. ECG: atrial fibrillation, no acute ischaemic changes, no peaked T waves. Urinalysis: normal. CXR: clear. [1]

Candidate's opening statement (SASPOP)

"Mrs Whitlam is a 78-year-old retired schoolteacher who presents after a fall at home with confusion, on a background of type 2 diabetes, chronic kidney disease stage 3b, ischaemic heart disease with atrial fibrillation, hypertension, gout, osteoporosis and depression. She takes metformin, gliclazide, apixaban, bisoprolol, perindopril, frusemide, indomethacin, allopurinol and amitriptyline." [1]

"Her main problems are:

1. Acute kidney injury, KDIGO stage 2, on chronic CKD stage 3b — precipitated by the triple whammy of perindopril, frusemide and indomethacin, continued through a dehydrating illness.
2. Hyperkalaemia, potassium 5.9, secondary to the AKI and the ACE inhibitor.
3. Polypharmacy with several potentially inappropriate medications — indomethacin, amitriptyline, full-dose allopurinol in CKD, metformin retained in acute renal impairment, and the hypoglycaemic risk from gliclazide.
4. A fall with confusion — multifactorial: dehydration, the anticholinergic amitriptyline, possible hypoglycaemia from gliclazide (glucose 3.6), and possible sepsis to exclude.
5. Atrial fibrillation on anticoagulation — apixaban dose-reduction criteria are now met." [1]

Structured problem list (prioritised)

1. AKI (stage 2) on CKD 3b — triple whammy + dehydration; immediate priority.
2. Hyperkalaemia (K 5.9) — monitor for ECG changes; treat if rising.
3. Polypharmacy — multiple PIMs by Beers and STOPP criteria; structured review required.
4. Fall with confusion — multifactorial; exclude intracranial injury and sepsis; review sedative/anticholinergic burden and hypoglycaemic agents.
5. AF on anticoagulation — apixaban dose reassessment; CHA2DS2-VASc high, continue anticoagulation.
6. Chronic disease optimisation — diabetes, gout, osteoporosis, depression (on recovery). [1]

Integrated management plan

Immediate (resuscitation and the hyperkalaemia):

• ABCDE, intravenous access, continuous cardiac monitoring.
• Treat hypoglycaemia: glucose 3.6 — give a carbohydrate source.
• Cautious intravenous isotonic saline (500 mL boluses with reassessment — she has AF and is at risk of overload; watch for pulmonary oedema).
• Hyperkalaemia K 5.9 with no ECG changes: oral calcium resonium; if ECG changes develop, insulin-dextrose and a beta-agonist. Recheck potassium in 2-4 hours. The AKI will improve with fluid once the offending drugs are stopped. [1]

Stop the offending drugs (the triple whammy and the renally-accumulating drugs):

• STOP indomethacin — the third arm of the triple whammy; raises bleeding risk on apixaban and worsens AKI and hypertension.
• HOLD perindopril — efferent arteriolar dilation; contributes to AKI and hyperkalaemia. Resume only when eGFR returns to baseline and potassium normal.
• HOLD frusemide — she is dehydrated; resume only if volume overloaded.
• HOLD metformin — risk of metformin-associated lactic acidosis in AKI; restart only when eGFR above 30 and rehydrated.
• HOLD gliclazide temporarily — hypoglycaemia risk in renal impairment; consider a DPP-4 inhibitor or a short-acting insulin regimen if needed while in hospital.
• STOP amitriptyline — Beers-listed; anticholinergic, contributing to fall and confusion.
• REDUCE allopurinol to 100 mg daily — full dose in CKD is the biggest DRESS risk factor; cap at 200 mg/day below eGFR 30.
• REDUCE apixaban to 2.5 mg BD — two of three dose-reduction criteria now met (weight 55 kg; creatinine 210). Reassess on recovery; revert to 5 mg BD if creatinine falls below 133 and only one criterion met.
• CONTINUE bisoprolol (rate control), apixaban at reduced dose (stroke prevention). [1]

Investigate the precipitant and the fall:

• Septic screen: blood cultures, CXR (clear), urinalysis (normal), consider stool cultures given diarrhoea; lactate.
• CT head: she has fallen, is on anticoagulation, and has a laceration and confusion — exclude intracranial haemorrhage.
• Review medications for causes of the fall: amitriptyline (anticholinergic, orthostatic hypotension), hypoglycaemia, dehydration. [1]

Deprescribing and START review (for discharge):

• Replace amitriptyline with sertraline if depression persists; non-pharmacological strategies for sleep.
• Replace indomethacin with paracetamol (up to 2 g/day if liver function is normal; she has no cirrhosis); colchicine 0.5 mg BD (dose-reduced in CKD) for an acute gout flare if needed.
• START a statin — atorvastatin 20 mg (vascular disease and diabetes; currently not prescribed).
• Ensure bone protection — bisphosphonate (consider annual zoledronate for adherence) and calcium/vitamin D for osteoporosis with a recent fall.
• Confirm influenza, pneumococcal and COVID vaccinations are current.
• Consider an SGLT2 inhibitor for renal and cardiovascular protection once she is rehydrated and renal function stable (hold during acute illness — sick-day rule).
• Resume perindopril and metformin only when eGFR returns toward baseline (perindopril for renoprotection if hypertension persists; metformin once eGFR above 30). [1]

Communication and shared decision-making:

• Explain the medication changes to the patient and her daughter in plain language: why the anti-inflammatory, the antidepressant and the water and blood-pressure tablets have been stopped or changed, and what is being used instead.
• Teach the sick-day rule with teach-back: "When you have vomiting, diarrhoea or fever and cannot drink normally, stop the water tablet, the blood-pressure tablet, the diabetes tablet and any painkiller, and restart when you are eating and drinking normally for 24 hours. Contact your GP if you are not improving."
• Provide a written, reconciled medication list at discharge.
• Arrange GP follow-up within one week and a pharmacy home medicines review. [1]

Discussion questions

Examiner: "What is the mechanism of the 'triple whammy'?" [1]

"Glomerular filtration depends on the pressure gradient across the glomerulus, maintained by afferent arteriolar tone — supported by prostaglandins, which the NSAID inhibits — and efferent arteriolar tone — supported by angiotensin II, which the ACE inhibitor inhibits. The diuretic reduces intravascular volume. During a dehydrating illness, the combination removes all three compensatory mechanisms and GFR collapses. The triple combination of ACE inhibitor or ARB, diuretic and NSAID should be avoided in older patients and in CKD; if AKI develops, all three must be stopped." [1]

Examiner: "How do you dose allopurinol in CKD and why?" [1]

"Allopurinol and its active metabolite oxypurinol are renally cleared. Full-dose allopurinol in CKD is the single biggest risk factor for allopurinol hypersensitivity syndrome — DRESS — which carries high mortality. The rule is to start at 100 mg daily, or 50 mg at very low eGFR, and titrate slowly to a target urate, with a recommended maximum of 200 mg per day when eGFR is below 30. In high-risk populations — Han Chinese, Korean, Thai — I would screen for HLA-B5801 before starting, as the allele confers very high DRESS risk."* [1]

Examiner: "How would you estimate her renal function, given her low body weight?" [1]

"Her eGFR is reported as 22, but I would not rely on a single eGFR value in an acute AKI — it reflects past function and lags. I would state that her renal function is changing and dose for her current creatinine and urine output, assuming low clearance and reassessing daily. Her low body weight and reduced muscle mass also mean her serum creatinine understates the severity of her renal impairment; the Cockcroft-Gault equation with her actual body weight would give a creatinine clearance of around 20 mL per minute, which is consistent. If I needed an accurate figure I would measure a 24-hour creatinine clearance or use a cystatin C-based eGFR." [1]

Examiner: "Which of her drugs would you re-dose for renal function, and how?" [1]

"Metformin — hold in AKI, restart only when eGFR above 30. Allopurinol — reduce to 100 mg daily, maximum 200 mg. Apixaban — reduce to 2.5 mg BD while two dose-reduction criteria are met, reassess on recovery. Gliclazide — hold or reduce during the acute illness for hypoglycaemia risk; on recovery consider switching to a DPP-4 inhibitor or SGLT2i. Bisoprolol is about 50 per cent renally cleared but at this low dose can continue. Frusemide and perindopril are held during the illness and resumed on recovery." [1]

Examiner: "What is the single most important piece of counselling at discharge?" [1]

"The sick-day rule. I would teach it with teach-back: 'When you have vomiting, diarrhoea or fever and cannot keep fluids down, temporarily stop the water tablet, the blood-pressure tablet, the diabetes tablet, and any painkiller, and restart when you are eating and drinking normally for 24 to 48 hours.' Those four drug classes — diuretics, ACE inhibitors or ARBs, metformin, and NSAIDs — are the ones that cause acute kidney injury, hyperkalaemia, lactic acidosis and hypoglycaemia respectively during dehydration. I would give her a written list, arrange GP follow-up, and a pharmacy home medicines review." [1]

Key learning points

• The triple whammy (ACEi/ARB + diuretic + NSAID) is the most testable nephrotoxicity. Recognise it, stop all three, and avoid the combination in older and CKD patients.
• Dose renally-cleared drugs off Cockcroft-Gault or a corrected estimate, not an uncorrected eGFR in low muscle mass.
• Apixaban dose reduction: two of three of age above 80, weight below 60 kg, creatinine above 133.
• Allopurinol in CKD: start 100 mg, cap 200 mg below eGFR 30; screen HLA-B*5801 in high-risk populations.
• Amitriptyline and other anticholinergics are Beers-listed in older adults and contribute to falls and delirium — deprescribe.
• START criteria catch omissions: statin in vascular disease, ACEi in heart failure, anticoagulation in AF, bone protection in osteoporosis and glucocorticoid therapy.
• The sick-day rule prevents iatrogenic AKI, hyperkalaemia, lactic acidosis and hypoglycaemia during intercurrent illness — teach it with teach-back. [1]