Pharmacokinetics in Organ Failure — Viva

Long Case Viva Defence

Candidate's opening statement (model answer)

"Mrs Whitlam is a 78-year-old retired schoolteacher admitted after a fall at home with a laceration and confusion. She has type 2 diabetes for 18 years, chronic kidney disease stage 3b with a baseline eGFR of 32, ischaemic heart disease with atrial fibrillation, hypertension, gout, osteoporosis and depression. She takes metformin 1 g twice daily, gliclazide 80 mg twice daily, apixaban 5 mg twice daily, bisoprolol 5 mg, perindopril 10 mg, frusemide 40 mg, indomethacin 50 mg twice daily, allopurinol 300 mg, and amitriptyline 50 mg at night." [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, all of which she 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, and metformin retained in acute renal impairment.
4. A fall with confusion — likely multifactorial: dehydration, the anticholinergic amitriptyline, possible hypoglycaemia from gliclazide, and possible sepsis.
5. Atrial fibrillation on anticoagulation — apixaban dose-reduction criteria are now met and must be addressed." [1]

"My immediate priorities are to resuscitate and treat the hyperkalaemia, stop the offending drugs, re-dose her medications for her current renal function, investigate the precipitant, and perform a structured deprescribing plan for discharge." [1]

Examiner probing questions and model answers

Examiner: "Which drugs would you stop immediately, and why?" [1]

"I would stop indomethacin and amitriptyline, and hold perindopril, frusemide, metformin and gliclazide temporarily. Indomethacin is the third arm of the triple whammy — it inhibits renal prostaglandins, constricting the afferent arteriole, and combined with the ACE inhibitor and the diuretic it has collapsed her glomerular filtration during dehydration. Amitriptyline is a Beers-listed drug in older adults — its anticholinergic effect has contributed to her confusion and her fall. Perindopril and frusemide are the other two arms of the triple whammy and the perindopril is causing hyperkalaemia. Metformin must be held in acute renal failure because of the risk of metformin-associated lactic acidosis. Gliclazide carries a hypoglycaemia risk in renal impairment and her glucose is already low at 3.6." [1]

Examiner: "How would you adjust her allopurinol?" [1]

"I would reduce it from 300 mg to 100 mg daily. Full-dose allopurinol in chronic kidney disease is the single biggest risk factor for allopurinol hypersensitivity syndrome, or DRESS — drug reaction with eosinophilia and systemic symptoms — which carries a high mortality. The standard recommendation is to start at 100 mg daily and titrate slowly to a target urate, with a maximum of 200 mg per day when eGFR is below 30. She is already on the drug so she is presumably tolerant of it, but the dose is excessive for her renal function and should be reduced. I would check an HLA-B5801 only if she were newly starting, as that allele confers very high DRESS risk in Han Chinese, Korean and Thai populations."* [1]

Examiner: "What about her apixaban — does the dose need to change?" [1]

"Yes. The apixaban dose-reduction criteria for atrial fibrillation require at least two of three of: age above 80, weight below 60 kg, and creatinine above 133 micromol/L. She weighs 55 kg and her creatinine is now 210, so two criteria are met — I would reduce her to apixaban 2.5 mg twice daily. When her renal function recovers, I would recheck: if the creatinine falls below 133 she would revert to one criterion and return to 5 mg twice daily. I would continue anticoagulation because her CHA2DS2-VASc score is high — age, female sex, hypertension, diabetes and vascular disease — and the stroke risk clearly outweighs the bleeding risk." [1]

Examiner: "How would you counsel her at discharge about the 'sick-day rule'?" [1]

"I would explain it in plain language: 'When you have vomiting, diarrhoea or fever and cannot keep fluids down, temporarily stop four of your tablets — the water tablet, the blood-pressure tablet, the diabetes tablet, and any painkiller — and restart them when you have been eating and drinking normally for 24 to 48 hours. Those are the drugs that can cause harm to your kidneys when you are dehydrated.' I would give her a written list of her sick-day pills, arrange GP follow-up within a week, and refer her for a pharmacy home medicines review. I would check her understanding with teach-back — ask her to repeat the rule back to me." [1]

Examiner: "Which of her drugs are renally cleared and which are hepatically cleared?" [1]

"The renally-cleared drugs are metformin, gliclazide is hepatic actually, allopurinol, apixaban is partly renal, and the gabapentinoids would be if she were on them. Let me be precise: metformin is renally cleared unchanged and accumulates in renal failure; allopurinol and its active metabolite oxypurinol are renally cleared; apixaban is about 27 per cent renally cleared with hepatic metabolism contributing the rest; bisoprolol is about 50 per cent renal and 50 per cent hepatic. Amitriptyline, perindopril becomes the active metabolite perindoprilat which is renal, frusemide is largely renal, indomethacin is hepatically metabolised. The key drugs I need to dose-adjust for her kidneys are metformin, allopurinol, and apixaban, and to hold frusemide and perindopril during the illness." [1]

Examiner: "What START criteria are relevant — what is she missing?" [1]

"She should be on a statin given her vascular disease and diabetes — she is not currently. I would start atorvastatin 20 mg at moderate intensity. She has osteoporosis and a recent fall, so I would ensure she is on bone protection — a bisphosphonate and calcium and vitamin D, considering an annual zoledronate infusion for adherence. I would confirm her influenza, pneumococcal and COVID vaccinations are up to date. And I would ensure her diabetes includes consideration of an SGLT2 inhibitor for renal and cardiovascular protection once she is rehydrated and her renal function stable — though I would hold it during acute illness as part of the sick-day rule." [1]

Short Case Viva — Therapeutic Drug Monitoring

Examiner: "A septic 64-year-old man on the ICU has a measured vancomycin trough of 22 mg/L on day 3 of therapy with concurrent piperacillin-tazobactam. His renal function has declined. How do you interpret this and what monitoring strategy should be in place?" [1]

"That trough of 22 mg/L is at the upper end of the traditional target for serious MRSA infection — 15 to 20 mg/L — and his renal function has declined, which is concerning for vancomycin-associated nephrotoxicity, particularly because he is on concurrent piperacillin-tazobactam, which independently increases the risk. The 2020 ASHP/IDSA consensus guideline moved vancomycin monitoring away from trough-only and toward AUC-guided dosing, targeting an AUC over MIC of 400 to 600 milligram-hours per litre, which achieves efficacy while reducing nephrotoxicity. I would switch to AUC-guided monitoring using Bayesian software and two levels, reduce the dose or extend the interval, review the need for piperacillin-tazobactam and consider switching to cefepime or another agent if appropriate, monitor his renal function closely, and investigate the source of the sepsis." [1]

Examiner: "If he were on gentamicin instead, how would you dose and monitor him?" [1]

"For most gram-negative infections I would use extended-interval, once-daily dosing at 5 to 7 mg per kilogram, exploiting the concentration-dependent killing and the post-antibiotic effect, and monitor with a random level drawn 6 to 14 hours post-dose interpreted on the Hartford nomogram to guide the next interval. This approach is as effective as divided dosing and marginally less nephrotoxic. However, extended-interval dosing is avoided in certain situations: enterococcal endocarditis, where synergy with a beta-lactam requires traditional divided low-dose gentamicin 1 to 1.7 mg per kg eight-hourly with peak and trough monitoring; pregnancy; burns; dialysis; and severe renal impairment. In this septic patient with declining renal function I would be cautious — I might use traditional divided dosing with peak and trough levels, and I would monitor renal function and review the duration, keeping it as short as possible." [1]

Examiner: "What is the most commonly tested pharmacology error in phenytoin monitoring?" [1]

"Interpreting the total phenytoin level without correcting for albumin in a hypoalbuminaemic or uraemic patient. Phenytoin is 90 per cent protein-bound to albumin; only the free 10 per cent is active. In hypoalbuminaemia or renal failure the free fraction rises, so the total level falls while the active free level rises — a patient can be toxic on a 'therapeutic' total level. The Sheiner-Tozer equation corrects the total level: corrected phenytoin equals measured total divided by open-bracket 0.2 times albumin in grams per decilitre plus 0.1 close-bracket. In practice, when albumin is very low or in renal failure, I send a free phenytoin level, targeting 1 to 2 mg per litre, because the equation becomes less accurate with uraemic displacement. The same principle applies to valproate." [1]

Key examiner-shaped takeaways

• Lead with the discriminating question: "How is this drug cleared?" — renal or hepatic. Water-soluble drugs accumulate in renal failure; lipid-soluble drugs do not.
• Estimate renal function honestly: Cockcroft-Gault for dosing, CKD-EPI 2021 for staging; neither is reliable in unstable AKI, low muscle mass, pregnancy or dialysis.
• Apply TDM where the index is narrow: vancomycin (AUC-guided), gentamicin (Hartford nomogram or divided dosing in endocarditis), phenytoin (free level in hypoalbuminaemia), digoxin (low target, beware hypokalaemia), lithium (beware thiazide, ACEi, NSAID, dehydration).
• Hepatic dosing: Child-Pugh to grade; high-extraction drugs (morphine, propranolol) most affected; avoid sedatives, NSAIDs and over-diuresis in cirrhosis.
• Polypharmacy in the elderly: Beers Criteria for PIMs, STOPP/START for omissions; the sick-day rule for the four key drug classes; deprescribe one drug at a time with monitoring. [1]