How should isoniazid be dosed in renal insufficiency to prevent neuropathy?/nThe question emerged f

Fråga: How should isoniazid be dosed in renal insufficiency to prevent neuropathy?

The question emerged from a question to our laboratory when to sample for therapeutic drug monitoring about a patient in peritoneal dialysis with peripheral neuropathy possibly related to isoniazid. That question was answered on a theoretical basis before in-depth studies of the literature. Two hours post-dose (to monitor the peak) and a trough value (to measure accumulation) were proposed.

Sammanfattning: There is no support in the literature to recommend a different dosing regimen to patients in dialysis. However, pyridoxine supplementation (10 mg/day) is strongly recommended. It is also important to insure adequate dialysis.

Svar: Isoniazid exerts its bactericidal action through inhibition of nicotinamide adenosine dinucleotide (NADH)-dependent fatty acid prolongation in tubercle bacilli. It is mainly eliminated by acetylation. The elimination half-life varies from 35-110 minutes in rapid acetylators to 110->400 minutes in slow acetylators. The metabolites lack antituberculous activity. In a Caucasian population, 50-60% are slow acetylators, in Asian populations only about 20% are slow acetylators (1). Acetylation fenotype does not influence the effect on tuberculosis (2).

Peripheral neuropathy was seen in 3.5-17% of patients dosed 3-5 mg/kg/day and in more than 40% of patients receiving 24 mg/kg/day. It mainly occurs in slow acetylators and can be prevented by supplementation of pyridoxine 6-10 mg/day (1,2). It is thought to be caused by an increased excretion of pyridoxine by conjugation with isoniazid metabolites to pyridoxal hydrazone (1). However, pyridoxine itself can cause neuropathy in high doses for long periods of time (several hundred milligrams for more than two or three weeks) (1), which can be a problem in differential diagnosis, when pyridoxine is given in higher than supplemental doses (3).

The fact that peripheral neuropathy mainly occurs in slow acetylators, suggest that it is either isoniazid in itself or monoacetylhydrazine that is responsible for this side-effect. The latter substance is associated with hepatotoxicity (1). Renal function is not a major determinant of isoniazid clearance and normal dosages (5-10 mg/kg/day, usually 300 mg/day) are recommended even to patients in renal replacement therapy (1,2).

Peripheral neuropathy is common in patients with end-stage renal disease. The treatment includes adequate dialysis and supplementation of B-vitamins, iron and zinc (4). There may be an additive or synergistic effect between renal disease and neurotoxins.

Current guidelines recommend B- and C-vitamin supplementation containing 4-10 mg pyridoxine/day to patients with severe renal failure (5). Dollery C Sir, editor. Therapeutic drugs. 2nd ed. Edinburgh: Churchill Livingstone; 1999 Davidson PT, Le HQ. Drug treatment of tuberculosis - 1992. Drugs 1992;43:651-73. Nisar M, Watkin SW, Bucknall RC, Agnew RA. Exacerbation of isoniazid induced peripheral neuropathy by pyridoxine. Thorax, 1990;45(5):419-20 (abstract). UpToDate online, Waltham, MA, USA. www.utdol.com (2005-11-02). Riktlinjer för omhändertagande av patienter med njursvikt. Svensk njurmedicinsk förening (2000). ISBN 91-973672-1-4.