Nucleoside Reverse Transcriptase Inhibitors

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Zidovudine (Retrovir)

The human immunodeficiency virus replicates by converting its single-standed RNA into double-stranded DNA which is incorporated into host DNA; this crucial conversion, the reverse of the normal cellular transcription of nucleic acids, is accomplished by the enzyme reverse transcriptase. Zidovudine, as the triphosphate, was the first anti-HIV drug to be introduced and has a high affinity for reverse transcriptase. It is integrated by it into the viral DNA chain, causing premature chain termination. The drug must be present continuously to prevent viral alteration of the host DNA, which is permanent once it occurs.

Pharmacokinetics. Zidovudine is well absorbed from the gastrointestinal tract (it is available as capsules and syrup) and is rapidly cleared from the plasma (t1/^ 1 h); concentrations in CSF are approximately half those in plasma. It is also available i.v. for patients temporarily unable to take oral medications. The drug is mainly metabolically inactivated, but 20% is excreted unchanged by the kidney.

Uses. Zidovudine is indicated for serious manifestations of HIV infection in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex, i.e. those with opportunistic infection, constitutional or neurological symptoms, or with low CD4 counts; treatment reduces the frequency of opportunistic infections and prolongs survival when used in effective combinations. It is also indicated alone for pregnant women and their offspring for prevention of maternal-fetal HIV transmission.

Adverse reactions early in treatment may include anorexia, nausea, vomiting, headache, dizziness, malaise and myalgia, but tolerance develops to these and usually the dose need not be altered. More serious Eire anaemia and neutropenia which develop more commonly when the dose is high, and with advanced disease. A toxic myopathy (not easily distinguishable from HIV-associated myopathy) may develop with long-term use. Rarely, a syndrome of hepatic necrosis with lactic acidosis may occur with zidovudine (and with other reverse transcriptase inhibitors).

Didanosine (DDI) has a much longer intracellular duration than zidovudine and thus prolonged antiretroviral activity. Didanosine is rapidly but incompletely absorbed from the gastrointestinal tract and is widely distributed in body water; 30-65% is recovered unchanged in the urine which it enters both by glomerular filtration and tubular secretion (t'/21 h). Didanosine may cause pancreatitis with an incidence of 7% at a dose of 500 mg/d; a reduced dose may be tolerated after symptoms have resolved. Other adverse effects include peripheral neuropathy, hyperuricaemia and diarrhoea, any of which may give reason to reduce the dose or discontinue the drug. It reduces gastric acidity, which impairs absorption of a number of drugs frequently used in patients with AIDS including dapsone, ketoconazole, quinolones and indinavir.

Zalcitabine (DDC) (t\ 1 h) is similar. Adverse effects include peripheral neuropathy, hepatitis and pancreatitis which are reason to discontinue the drug. Oral ulceration, gastrointestinal symptoms and bone marrow suppression have also been reported.

Lamivudine (3TC) is a reverse transcriptase inhibitor with a relatively long intracellular half-life (14 h; plasma t'/2 6 h). In combination with zidovudine, lamivudine appears to reduce viral load effectively and to be well tolerated, although bone marrow suppression may be produced. Rarely, pancreatitis may occur. Lamivudine has also been used for treatment of chronic hepatitis B infection, but resistant strains of virus have been reported.

Abacavir (t'/2 2 h) may be the most potent reverse transcriptase inhibitor. It is usually well-tolerated, but adverse effects may include hypersensitivity reactions especially during the first 6 weeks of therapy.

Stavudine (t'/2 1 h). Hepatic toxicity and pancreatitis have been reported, and a dose-related peripheral neuropathy may occur.

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