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
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