Use of suboptimal doses of drugs in serious disease, sacrificing efficacy for avoidance of serious adverse effects, has been documented. It particularly affects drugs of low therapeutic index (see Index), i.e. where the effective and toxic dose ranges are close, or even overlap, e.g. heparin, anticancer drugs, aminoglycoside antimicrobials. In these cases dose adjustment to obtain maximum benefit with minimum risk requires both knowledge and attentiveness.

The clinical importance of missed dose(s)

Even the most conscientious of patients will miss a dose or doses occasionally. Patients should therefore be told whether this matters and what they should do about it, if anything.

• loss of efficacy (acute disease)

• resurgence (chronic disease)

• rebound or withdrawal syndrome.

Loss of efficacy relates to the pharmacokinetic properties of the drugs. With some short ty drugs there is a simple issue of a transient drop in plasma concentration below a defined therapeutic level. But with others there may be complex issues such as recovery of negative feedback homoeostatic mechanisms, e.g. adrenocortical steroids. Therapeutic effect may not decline in parallel with plasma concentration. With some drugs a single missed dose may be important, e.g. oral contraceptives, with others (long t'/2) several doses may be omitted before there is any serious decline in efficacy, e.g. thyroxine (levothyroxine).

54 A doctor wrote a prescription for isosorbide trinitrate 20 mg 6-hourly but because of the illegibility of the handwriting the pharmacist dispensed felodipine in the same dose (maximum daily dose 10 mg). The patient died and a court ordered the doctor and pharmacist to pay compensation of $450 000 to the family. Charatan F 1999 British Medical Journal 319:1456.

These pharmacokinetic considerations are complex and important, and are, or should be, taken into account by drug manufacturers in devising dosage schedules and informative Data Sheets. Manufacturers should aim at one or two doses per day (not more), and this is generally best achieved with drugs having relatively long biological effect t)/, or where the biological effect \}/2 is short, by using sustained-release formulations.

Discontinuation syndrome (recurrence of disease, rebound, or withdrawal syndrome) may occur due to a variety of mechanisms (see Index).

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