Zidovudine-uses, dosage and adverse effects

Zidovudine (ZDV)

Brands-Retrovir,Zidovir

Zidovudine (ZDV), also known as azidothymidine (AZT), is an antiretroviral medication used to prevent and treat HIV/AIDS.ZDV is of the nucleoside analog reverse-transcriptase inhibitor (NRTI) class.It works by inhibiting the enzyme reverse transcriptase that HIV uses to make DNA and therefore decreases replication of the virus.

Antiretroviral drugs do not cure HIV (human immunodeficiency virus) infection; they only temporarily suppress viral replication and improve symptoms. Patients receiving these drugs

require careful monitoring by appropriately trained health professionals in an adequately resourced setting. Rigorous promotion of measures to prevent new infections remains

essential and its need is not diminished by the availability of antiretroviral drugs. Effective therapy requires the simultaneous use of 3 or 4 drugs; alternative regimens are necessary

to meet specific requirements at start-up, to substitute for first-line regimens in cases of intolerance, or to replace failing regimens. The use of a 3- or 4-drug combination as specified in the WHO treatment guidelines is recommended. The use of fixed-dose preparations for these combinations is also recommended if the pharmaceutical quality is assured and interchangeability with the single products is demonstrated as specified by the relevant drug regulatory authority.

Indications

• Prevent and treatment of HIV infection in combination with at least 2 other antiretroviral drugs
• Monotherapy for prevention of maternal-fetal HIV transmission.
• To delay progress of AIDS.
• Prevent transmission of virus to fetus.
• Treatment of opportunistic infections with AIDS.

Availability

Tablets 30,40,100 and 300 mg;Capsules 100 and 300 mg;Syrup 50mg/ml.

Dose

• HIV infection

Adult-600 mg daily in divided doses in combination with other antiretroviral drugs.

Child-6 weeks to 12 years;160 mg/m2 every 8 hours,max dose 200 mg every 8 hour.

• Prevention of maternal -foetal HIV transmission.

Adult-100 mg 5 times daily or 200 mg thrice daily or 300 mg twice daily ,start treatment after 14th week of gestation until the start of labour.

• Prevention of HIV transmission in neonates.

Child-Neonates;2 mg/kg every 6 hours for first 6 weeks of life,starting with 12 hour after birth.

Contraindications

• Abnormally low neutrophil counts or haemoglobin
• Neonates either with hyperbilirubinemia requiring treatment other than phototherapy or with raised transaminase.
• Life threatening allergic reactions.

Precautions

• Haematological toxicity
• vitamin B12 deficiency
• reduce dose or interrupt treatment if anaemia or myelosuppression
• renal impairment
• hepatic impairment 
• risk of lactic acidosis
• elderly
• lactation 
• pregnancy
• myopathy
• use with interferon and ribavirin based regimens in HIV/HCV 
• coinfected patient 
•  immune reconstitution syndrome.

Adverse effects

• Anaemia (may require transfusion)
• neutropenia and leukopenia(all more frequent with high dose and advanced disease)
• nausea and vomiting
• abdominal pain
• dyspepsia
• diarrhoea
• flatulence
• taste disturbances
• pancreatitis
• liver disorders including fatty change and raised bilirubin and liver enzymes 
• chest pain 
• dyspnoea
• cough
• headache
• fever
• paraesthesia
• neuropathy
• convulsions
• dizziness
• somnolence
• insomnia
• anxiety
• depression 
• malaise
• anorexia
• asthenia
• myopathy
• myalgia
• pancytopenia
• thrombocytopenia,
• gynaecomastia
• urinary frequency
• rash
• pruritus
• pigmentation of nail,skin and mucosa.

Interactions

• Probenecid suppresses metabolism and excretion. 
• Rifabutin and rifampicin decreased plasma concentration.
• Clarithromycin decreased absorption.
• Paracetamol and fluconazole decreased metabolism.
• Lamivudine enhanced blood concentration.

Pharmacology

Mechanism of Action:
Zidovudine is a thymidine analogue that inhibits HIV replication.It is converted to the active monophosphate form by thymidine kinase and ultimately to zidovudine triphosphate by intracellular enzymes. This form exerts its activity at viral DNA polymerase (reverse transcriptase) by competing with other cellular deoxynucleosides and by acting as a chain terminator of DNA synthesis and finally suppressed virus replication.

Pharmacokinetics

Absorption

Rapid and nearly complete absorption from the gastrointestinal tract following oral administration; however, because of first-pass metabolism, systemic bioavailability of zidovudine capsules and solution is approximately 65% (range, 52 to 75%). Bioavailability in neonates up to 14 days of age is approximately 89%, and it decreases to approximately 61% and 65% in neonates over 14 days of age and children 3 months to 12 years, respectively. Administration with a high-fat meal may decrease the rate and extent of absorption.Zidovudine may be taken irrespective of food and undergoes rapid first-pass hepatic metabolism.Patients initiating zidovudine treatment often complain of fatigue, malaise, myalgia, nausea, anorexia, headache, and insomnia, which generally resolve within the first few weeks of therapy.

Distribution:Distributed in most of the tissues and body fluids and penetrates CNS well.

Half-Life: 1 hr

Volume of distribution: 1-2.2 L/kg

Protein binding: 25-38%

Metabolism: Metabolized in liver by glucuronidation. 

Excretion: Excreted through Urine.

Patient Instructions: HIV Drugs ;Underdosage, noncompliance, or partial compliance with drug regimens for these drugs might result in development of a resistant strains of HIV that will not be susceptible to treatment. Do not stop taking this medication unless told to do so by your healthcare provider. This drug should be used in combination with other anti-HIV medications. It is possible for a person taking this medication to transmit the virus to another person. Opportunistic infections and other complications associated with HIV infection can continue to develop while you take this medication. Non nucleoside reverse transcriptase inhibitors have a potential for serious interactions with a large number of commonly prescribed drug products. Always check with your health care provider before starting any new medication.
In case of missed Doses. Missing doses can result in the development of resistance that can lead to treatment failure. If you forget a dose, take it as soon as you remember. If it is almost time for your next scheduled dose (within 4 hours), skip the missed dose. Do not double your dose.

Parameters to Monitor. Hemoglobin, hematocrit, MCV, and WBC for hematologic toxicity. Monitor clinical signs, symptoms, and laboratory markers for progression of HIV disease to help decide regimen changes in antiretroviral therapy.Baseline CD4 and HIV-1 RNA polymerase chain reaction viral load tests are useful to measure clinical benefit of therapy. Repeat tests after 1 month and q 3–4 months thereafter have been suggested to monitor benefit of antiretroviral therapy.

Storage-Store protected from light and moisture.

Drug schedule -Zidovudine scheduled under H.Warning: "To be sold by retail on the prescription of a Registered Medical Practitioner only." on the label prominently.

Pregnancy category -C
Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.