Anti-viral Drugs.

Introduction The viral agents kill viruses by inhibiting their ability to replicate, but there are currently only about a dozen such agents that can destroy only a few of the known viruses. Cytomegalovirus (CMV) Herpes simplex virus (HSV) Human immunodeficiency virus (HIV) Influenza A

Continue One reason why only a few viruses can now be killed with the agents currently available is that often by the time the signs and symptoms of a viral illness appear, the virus has finished replicating.

Continue Because it is only during viral replication that antiviral agents can work, it is then too late for them to be effective. Another reason why there are so few agents is that because viruses live inside the body cells and use them to replicate, any drug that kills a virus could also kill healthy cells. So, for antiviral agent to be effective and safe, it must kill only the virus and not unduly harm the body cells, and there are few agents that have met these criteria.

Continue For a virus to replicate, it must first attach to and enter the healthy cell, where it makes use of the cells energy to generate both DNA and RNA synthesizing pathways as well as it is own protein synthesizing pathways to make more viruses.

Continue Antiviral agents inhibit this process in various ways Some antiviral drugs are able to enter the same cells that the viruses enter and then once inside interfere with viral nucleic acid synthesis. Other antiviral drugs work by keeping a virus from binding to cells. If a virus cannot then get in to the cells, it cannot replicate and it dies. Other antiviral agents stimulate the body’s immune system to kill the virus.

Continue Those patients who become a host for virus are frequently immunocompromised. These patients are prone to frequent and often severe viral infections, which may recur when antiviral drug therapy is stopped. Most of antiviral drug agents are a synthetic purine nucleoside analogue which means that they are chemically made purine nucleoside (adenine, guanine).

Mechanism of Action The different antiviral agents vary in the way in which they kill the viruses. To replicate, the virus First attaches to and diffuses in to the cell Then once in the cell it has it is genetic makeup copied After this the nucleus of the infected cell utilizes it is DNA and RNA to make new viruses The overall effect of these agents is the inhibition of viral replication.

Therapeutic effects Amantadine used for the treatment and prophylaxis of influenza A. Acyclovir was used primarily in treatment of herpes simplex virus infections of the newborn. Ganciclovir, Foscarnet used in the treatment of cytomegalovirus such as GI infection and pneumonitis. Didanosine, Zidovudine approved for the treatment of HIV infections in the setting of AIDS.

Side effects Headache Nausea Vomiting Diarrhea Weight loss Dizziness Bone marrow suppression Burning when topically applied Ataxia Hallucinations Hypercalcemia Rash

Acyclovir Acyclovir (Zovirax) is a synthetic analogue of guanine that is mainly used to suppress the replication of HSV 1,2 as well as the varicella- zoster virus, commonly known as chickenpox and shingles. It comes orally 200mg capsules Available 800mg tablets Available 200mg/5ml suspension Available 500mg and 1g injection It is a prescription drug Classified pregnancy category C Adult dosage 200mg q4h 5 times/day for 10 days in the treatment of HSV-2 800mg q4h 5 times /day for 7-10 days in the treatment of shingles

Amantadine Amantadine (Symmetrel) has a narrow antiviral spectrum in that it is only active against influenza A viruses. Used both prophylactically as well as therapeutically. It has been shown to be very effective, if not lifesaving, when used prophylactically in, for instance, elderly, chronically ill, or immunocompromised patients in whom influenza A infection can be particularly devastating. Amantadine is classified pregnancy as category C. Contraindicated in patients with a known hypersensitivity to it, lactating women, and children less than 12 months of age. Amantadine is only available orally as a 50mg/5ml solution and 100 mg filled capsule. Adult dosage, 100mg bid or 200mg once a day.

Zidovudine (d4T) Zidovudine (AZT, ZDV, and Retrovir) is a synthetic analogue of thymidine that has had an enormous impact on the treatment and quality of life of patients infected with HIV who have AIDS. To date the only antiviral agent used to treat HIV infections that has been shown to prolong survival has been Zidovudine. Besides it is antiviral activity, Zidovudine also has activity bactericidal activity against some gram negative bacteria. Zidovudine is major dose limiting adverse effect is bone marrow suppression, and this is often the reason why a patient with an HIV infection has to be switched to another HIV agent such as zalcitabine or didanosine. Zidovudine is classified as a pregnancy category C agent and is contraindicated in patients with a known hypersensitivity to it. Available both oral and parenterally formulations. Parenterally it comes as a 10mg/ml injection for IV infusion Orally it comes as 100mg capsules and a 50mg/5ml solution Adult dosage mg/day, divided dose

Lamivudine (3TC) This deoxycytidine analogue is phosphorylated intracellularly and inhibits HIV reverse transcriptase as well as hepatitis B virus (HBV) DNA polymerase. Most human DNA polymerases are not affected and systemic toxicity of Lamivudine is low. Point mutation in HIV reverse transcriptase and HBV-DNA polymerase gives rise to rapid Lamivudine resistance. Dose for chronic hepatitis B 100mg once a day. Dose for HIV infection 150mg BID. Lamivudine is generally well tolerated. Side effects are headache, fatigue, nausea, anorexia, abdominal pain. Hematological toxicity does not occur.

Nevirapine (NVP) and Efavirenz (EFV) These are nucleoside unrelated compounds which directly inhibit HIV reverse transcriptase without the need for intracellular phosphorylation. Viral resistance to these drugs develops by point mutation and cross resistance is common. Nevirapine is well absorbed orally and is extensively metabolized in the liver. Both NVP and EFV modestly induce CYP 3A4, 2D6 enzymes and enhance their own metabolism as well as that of the other drugs. Nevirapine dose is 200mg/day, may be increased later 200mg BID. The common side effects are rash, nausea, headache and potentially hepatotoxic. Efavirenz dose is 600mg OD on empty stomach. Side effects of Efavirenz are headache, rashes, dizziness and insomnia.

Preferred and alternative anti-HIV regimens Preferred regimen 2 NRTI + NNRTI (PI) Zidovudine + Lamivudine + Efavirenz 2 NRTI + PI Zidovudine + Lamivudine + Lopinavir

Continue Alternative regiments 2 NRTI + NNRTI (PI) Zidovudine + Lamivudine + Nevirapine Lamivudine + Stavudine + Efavirenz Lamivudine + Stavudine + Nevirapine Lamivudine + Abacavir + Efavirenz Lamivudine + Abacavir + Nevirapine

Continue 2 NRTI + PI Lamivudine + Zidovudine + Indinavir Lamivudine + Stavudine + Ritonavir Lamivudine + Abacavir + Lopinavir Lamivudine + Abacavir + Nelfinavir 3 NRTI Zidovudine + Lamivudine + Abacavir

Note NRTI: nucleoside reverse transcriptase inhibitors NNRTI: non-nucleoside reverse transcriptase inhibitors PI: protease inhibitors