Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSOR

DEPT. OF PHARMACOLOGYSSIMS & RC.

ANTIVIRAL DRUGS ( RETROVIRAL)

Anti-viral drugs

Viruses have no cell wall and made up of nucleic acid components

Viruses contain envelope – antigenic in nature Viruses are obligate intracellular parasite They do not have a metabolic machinery of their

own – uses host enzymes

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Anti-viral drugsKey characteristics

Able to enter the cells infected with virusInterfere with viral nucleic acid synthesis and/or regulationSome drugs interfere with ability of virus to bind to cellsSome drugs stimulate the body’s immune systemBest responses to antiviral drugs are in patients with

competent immune systemsA healthy immune system works synergistically with the drug

to eliminate or suppress viral activity

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Classification

Neucleoside reverse transcriptase inhibitors(NRTIs)

ZIDOVUDINE, STAVUDINE, LAMIVUDINE, ABACAVIR, ZALCITABLINE, EMTRICITABINE, DIDANOSINE

Non-Nucleoside reverse transcriptase inhibitors

(NtRTIs)EFAVIRENZ, NEVIRAPINE,

DELAVIRDINE, ETRAVIRINE

NEUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS(NtRTIs)-TENOFOVIR

PROTEASE INHIBITORS SAQUINAVIR, INDINAVIR, NELFINAVIR, AMPRENAVIR,

FOSAMPRENAVIR, RITONAVIR, LOPINAVIR, ATAZANAVIR, TIPRANAVIR, DARUNAVIR

ENTRY/FUSION INHIBITORS-ENFUVIRTIDECCR5 INHIBITORS-MARAVIROC

Classification

Classification

INTEGRASE INHIBITORS RALTEGRAVIRNEWER ANTIRETRO VIRAL DRUGSELVITEGRAVIR, BEVIRIMAT,

ELVUCITABINE,VICRIVIROC

Mechanism

When HIV infects a cell, reverse transcriptase copies the viral single stranded RNA genome into a double-stranded viral DNA.

The viral DNA is then integrated into the host chromosomal DNA, which then allows host cellular processes, such as transcription and translation to reproduce the virus.

RTIs block reverse transcriptase's enzymatic function and prevent completion of synthesis of the double-stranded viral DNA, thus preventing HIV from multiplying

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ZDV: Toxicity

Nausea Bone Marrow Suppression

Anemia Neutropenia

Headache

Myalgia Myopathy Insomnia Pigmentation of nail beds Lactic acidosis, fatty liver

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Lamivudine (3TC)

Dosing: 150mg BID or 300mg QDFood Interactions: noneToxicity: very rareComponent of all first-line regimens Also active against Hepatitis BMain disadvantage: rapid development of resistance

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Emtricitabine (FTC)

Dosing: 1 x 200mg capsule QD Food Interactions: no food

interactions Toxicity

Mild abdominal discomfort Occasional nausea

Emtricitabine is the fluorinated version of lamivudine

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Abacavir (ABC)

Dosing: 1 x 300mg tablet BIDFood Interactions: no food interactionsGenerally well toleratedToxicity

Hypersensitivity reaction Occurs within first 6 weeks of therapy

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Tenofovir Disoproxil Fumarate (TDF)

Dosing: 1 x 300mg tablet QDFood Interactions: NoneVery well tolerated, side effects are minimalToxicity Renal insufficiency (rare)

Must dose adjust with renal failureAlso has activity against Hepatitis B

Dosed 300mg QDActive against Lamivudine resistant HBV strainsHBV resistance 1% at 1 yearIf TDF is stopped, may have HBV hepatitis flare

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Didanosine (ddl) (2)

If taken with TDF must reduce ddI dose: > 60 kg < 60 kg 250 mg/d 200 mg/d

Without dose adjustment – blunted CD4 response

Toxicity Peripheral Neuropathy GI intolerance Pancreatitis (7%2%) Lactic acidosis, fatty liver

Protease inhibitors (PIs)

PIs prevent viral replication by inhibiting the activity of proteases

Protease inhibitors were the second class of antiretro viral drugs developed.

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Ritonavir (RTV)

Substantial GI intolerance prevents use at full, original dose

Now used to boost other PIs Doses < 400 mg/day – no anti-HIV

activity Nomenclature: /r (LPV/r, SQV/r) Requires refrigeration Hard to make

Saquinavir

Saquinavir was the first protease inhibitor HIV protease is vital for both viral

replication within the cell and release of mature viral particles from an infected cell. Saquinavir inhibits both HIV-1 and HIV-2 proteases.

Protease inhibitors (PIs)

Amprenavir , Indinavir Nelfinavir,Ritonavir Saquinavir

Inhibit the protease retroviral enzyme, preventing viral replication

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PI Class Side Effects

Metabolic Disorders Hepatotoxicity Hyperglycemia, insulin resistance Lipid abnormalities Fat redistribution

Bone Disorders

GI Intolerance Drug Interactions

CYP450 3A4 Inhibition: RTV, LPV > IDV = NFV = APV >SQV

Integrase inhibitor

Integrase inhibitors are a class of antiretoviral designed to block the action of integraace, a viral enzyme that inserts the viral genome into the DNA of the host cell.

Raltegravir targets integrase, an HIV enzyme that integrates the viral genetic material into human chromosomes, a critical step in the pathogenesis of HIV. The drug is metabolized away via glucuronidation

Fusion inhibitor-Enfuvirtide

Inhibit viral fusion, preventing viral replication

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Entry inhibitor

Entry inhibitors, also known as fusion inhibitors This class of drugs interferes with the binding, fusion

and entry of an HIV virion to a human cell. By blocking this step in HIV’s replication cycle, such agents slow the progression from HIV infection to AIDS

Maraviroc Maraviroc is an entry inhibitor. Specifically, maraviroc

is a CCR5 receptor antagonist, and binds to the chemokine receptor CCR5 and blocks the HIV gp120 (V3 loop) from associating with the receptor. HIV is then unable to bind and enter human macrophages.

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Drug interaction with PIs or NNRTIs

Statins (simvistatin & lovastatin)Azole antifungalsAnticonvulsantsAnti-TB (Rifampicin)Warfarin

Midazolam, trizolamAlternative medicine ClarithromycinOral contraceptivesAmitriptyline