Nucleoside-analogues

A nucleoside consists of a sugar or saccharide (ribose or deoxyribose) and a base (pyrimidine or purine). Nucleoside compounds have to be metabolised to triphosphate compounds before they become active, in contrast to non-nucleoside compounds, which are directly active. As nucleoside analogues have to be phosphorylated in the cell before becoming active, antagonism between molecules that use the same phosphorylation pathways should be taken into account. Hence AZT and d4T as well as ddC and 3TC are not combined with each other. Furthermore, combinations of drugs with a similar toxicity profile, such as ddC + ddI or ddC + d4T should be avoided.

Various drugs in this class can disturb the gamma-DNA polymerase in the mitochondria, resulting in mitochondrial dysfunction. This is characterised by myopathy, cardiomyopathy, neuropathy, liver steatosis and/or lactate acidosis. [Humans have 5 different DNA polymerases: alpha (replication lagging strand nuclear DNA), beta (repair nuclear DNA), gamma (replication mitochondrial DNA), delta (replication leading strand nuclear DNA), epsilon (repair nuclear DNA). Do not confuse these with the prokaryotic DNA polymerases I, II and III].

The intracellular half-life of the nucleoside-analogue triphosphates shows considerable variation:

• Zidovudine (Retrovir®). Zidovudine became available in 1987. Azidothymidine or zidovudine (Retrovir®, AZT) is a substance resembling thymidine, one of the constituents of DNA. After incorporation into a growing RNA-DNA heteroduplex, AZT prevents further synthesis of the chain. Hence virus replication in a newly infected cell is impaired and further infection of healthy cells is prevented since no progeny virus are produced. AZT is a very expensive drug. Its principal side-effect is bone marrow toxicity, though this is not very frequent (2% severe anaemia after 18 months’ therapy). Macrocytosis is quite frequent. Reversible myopathy sometimes occurs. A blue discolouration of finger- and toenails and mucosae can occur. There are no major drug interactions, though other myelotoxic drugs such as pyrimethamine or ganciclovir are best avoided. Use of Retrovir® should be avoided if the patient suffers from severe anaemia, leukopaenia or persistent muscle pain. It must not be combined with Zerit®. The favourable effect of azidothymidine monotherapy is short-lived and resistant mutants quickly appear. It definitely has a role in the reduction of perinatal transmission. Aztec® is an AZT extended release formulation. Zidovudine is also combined with other antiviral substances in one tablet, e.g. Combivir® (AZT + lamivudine) and Trizivir (AZT + 3TC + abacavir).

• Lamivudine (Epivir®). Lamivudine or 3TC is administered to an adult as two 150 mg doses per day. It can be taken with or between meals. Lamivudine undergoes renal excretion and the dose should be modified in cases of kidney failure (creatinine clearance <50>

• Emtricitabine (Emtriva®, Coviracil®; syn FTC) is the phosphorylated form of 3TC (lamivudine, Epivir®). It can be given once per day.

• Stavudine (Zerit®). This exists as capsules of 30 and 40 mg and as a solution of 1 mg/ml. The dose is 30 mg BD for adults under 60 kg and 40 mg BD for people weighing more than 60 kg. Combination with zidovudine is not advised. The principal side-effect is peripheral neuropathy, often occurring at a late stage and frequently irreversible. The slow-release formulation (Zerit EC® 100 mg) should be given only once per day and causes less intestinal discomfort. Like all reverse transcriptase inhibitors, Zerit® also inhibits DNA polymerase γ, the enzyme that catalyses replication of mitochondrial DNA. The ratio of mitochondrial DNA to nuclear DNA decreases during treatment. A number of side-effects of the drug can be interpreted as “mitochondriopathy”. Due to the impaired function of these energy-producing cell organelles there is an increased risk of hyperlactataemia and even lactate acidosis. Myopathy and neuropathy can also occur.

• Zalcitabine (Hivid®). This is given in a dose of 0.75 mg three times per day, and does not need to be given with meals. It is not a very potent drug. The principal side-effect is a peripheral sensomotor neuropathy. It should not be combined with Epivir®.

• Didanosine (Videx®). Didanosine (ddI or dideoxyinosine) became available in the West in 1992. This substance exists in the form of 100 mg tablets and as 10 mg/ml solution. The usual daily dose in an adult weighing more than 60 kg is 400 mg, in one or two doses. In view of the diminished intestinal absorption in the presence of food, ddI must be taken at least 30 minutes before or 2 hours after a meal. The substance is rapidly metabolised at an acidic pH. It is thus best not dissolved in drinks containing carbon dioxide. Patient compliance improves by taking one enterically coated ddI-capsule per day. The principal side-effects are pancreatitis as well as gastro-intestinal, liver and neurological abnormalities. Lactate acidosis is rare. Pancreatitis is a contra-indication. The formulation Videx EC permits the drug to be administered once per day (400 mg enteric coated tablet for an adult person weighing more than 60 kg). The absence of a buffer in Videx EC tablets makes it possible for it to be combined with indinavir, ketoconazole and ciprofloxacin.

• Abacavir (Ziagen®). The drug is chemically related to 2’-deoxyguanosine. Like all NRTIs (Nucleoside Reverse Transcriptase Inhibitors), abacavir is a prodrug that must be phosphorylated intracellularly in order to be activated. It is, however, not a substrate for enzymes that phosphorylate other NRTIs. Hypersensitivity reactions sometimes occur (4%). These can sometimes proceed mildly, such as cutaneous rash or a flu-like illness with cough, or very severely. Such reactions are absolute contra-indications for restarting the medication. They nearly always occur within the first 6 weeks after initiating treatment. The drug is rapidly absorbed (both from tablets and from syrup). This is not affected by food. The product has a high bioavailability, i.e. 83%. Penetration into the cerebrospinal fluid is good (30-44%). Elimination from the body is not dependent on the P450 isoenzyme complex (reduced risk of drug interactions). There is a definite synergism between abacavir (Ziagen®) and amprenavir (Agenerase®).

• Trizivir®. The combination zidovudine, lamivudine and abacavir (Trizivir®) has been available on the market since 2002. The patient should take one tablet twice per day. This scheme is expected to substantially improve compliance. It is probably less effective with high viral loads and when the CD4-cell count is less than 200.

Category: Medical Subject Notes , Medicine Notes