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anti- retroviral drugs.pptx

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anti- retroviral drugs.pptx

  1. 1. Anti-Retroviral Drugs Dr. Monika Sharma
  2. 2. • Human Immunodeficiency Virus (HIV)- RNA virus • HIV is also known as the human T- lymphocyte virus (HTLV). • Types of HIV: • HIV type I. This is common in the USA and western Europe. • HIV type II. This is more common in West African countries. • HTLV III or LAV (lymphadenopathy-associated virus). • The viral genes are: • Gag forms group-specific proteins, antigens, and these proteins are named p24 and p18. • Env forms envelope proteins that are necessary for the interaction and presentation of target cells. These are gp120 and gp41. • Pol forms polymerase, reverse transcriptase enzymes, and other enzymes like protease and integrase. •
  3. 3. Property HIV I HIV II Envelope protein GP 41 and GP 120 GP 36 and GP 105 Core protein p 24 and p 18 p 34 and p 68 Spread Parenteral and sexual Sexual transmission The course of the disease Faster than HIV-1 to develop AIDS Slow to develop AIDS ELIZA test Available Not available (Western Blot can be used) Prevalence Worldwide pandemic Endemic in West Africa and spread to India
  4. 4. • The mechanism of injury: • HIV has a receptor present on the CD4+ cells, Helper cells, and macrophages. • Virus gp 120 attaches to CD4+ molecules on cells that are present on the lymphocytes. • It is then internalized in the cell with the help of the reverse transcriptase enzyme. • It changes RNA to DNA and integrates with the target cell DNA with the help of viral integrase. • These are known as provirus. • This will enter into the DNA of the host. • Now, this may become latent. • When the virus is assembled and leaves the cells, it does so by budding out, incorporating the host cell membrane into its coat.
  5. 5. Antiretroviral drugs • The clinical efficacy of anti-retrovirus drugs is monitored primarily by plasma HIV-RNA assays and CD4 lymphocyte count carried out at regular intervals. • The two established targets for anti-HIV attack are –  HIV reverse transcriptase: Which transcripts HIV-RNA into proviral DNA. HIV protease: Which cleaves the large virus directed polyprotein into functional viral proteins. Other targets: Chemokine coreceptor (CCR5) on host cells, HIV- integrase ( Viral enzyme which integrates the proviral DNA into host DNA)
  6. 6. DRUGS Zidovudine(AZT) TYPES Thymidine analogue MOA Zidovudine phosphorylated in the host cell - zidovudine triphosphate selectively inhibits viral reverse transcriptase in preference to cellular DNA polymerase. RESISTANCE when AZT was used alone, >50% patients became nonresponsive to AZT within 1–2 years therapy due to growth of resistant mutants. PK Oral absorption of AZT is rapid, but bioavailability is ~65%. – Cleared by hepatic glucuronidation (t½ 1 hr) – Excreted in urine – Plasma protein binding is 30% and CSF level is ~50% of that – in plasma. – It crosses placenta and is found in milk. USES HIV treatment: Zidovudine is used in HIV infected patients only in combination with at least 2 other ARV drugs. Highly Active Antiretroviral Therapy (HAART) is used to prevent the likelihood of HIV resistance. – HIV prevention: AZT, along with two other ARV drugs is the standard choice for post-exposure prophylaxis of HIV, as well as for mother to offspring transmission. ADR Anaemia and neutropenia are the most important and dose-related adverse effects – Nausea, anorexia, abdominal pain, headache, insomnia and myalgia. – Myopathy, pigmentation of nails, lactic acidosis, hepatomegaly, convulsions and encephalopathy are infrequent.
  7. 7. Didanosine Purine nucleoside analogue • Inhibits HIV reverse transcriptase • Terminates proviral DNA Stavudine Thymidine analogue • Acts in the same way as AZT • ADR- Peripheral Neuropathy • Serious or life-threatening lactic acidosis (build-up of acid in the blood) Lamivudine Deoxycytidine analogue Active against HIV-1 , HIV-2 & Hepatitis B Virus. • Inhibits HIV reverse transcriptase • Inhibits HBV-DNA polymerase ADR- Nausea, headache, Fatigue, Insomnia. Pancreatitis in children. Abacavir Guanosine analogue • Reduce plasma HIV-RNA count • Rapid rise in CD4 cell count. ADR- Hypersensitivity reactions. Intake of alcohol- increase the plasma level of Abacavir(partly metabolised by alcohol dehydrogenase) Emtricitabine Cytosine nucleoside analogue St. related to Lamivudine. Hyperpigmentation of skin.
  8. 8. DRUGS Tenofovir available as two prodrug ester forms- Tenofovir Disoproxil Fumarate (TFV-DF) & Tenofovir Alafenamide (TFV-AF). • Anti-HIV drugs , It is also active against HBV. • Tenofovir is first line 3 drug regimen as an alternative when either zidovudine or nevirapine/efavirenz cannot be used due to toxicity/ contraindication TYPES Tenofovir is a nucleotide reverse-transcriptase inhibitor (NtRTI). It inhibits HBV-DNA polymerase and HIV-reverse transcriptase MOA Tenofovir preventing the formation of the 5′ to 3′ phosphodiester linkage essential for DNA chain elongation thereby causes premature termination of DNA transcription, preventing viral replication. PK 25% oral bioavialabilty , increased 40% after meal. Plasma half life 17 hrs. USES Tenofovir is nonselective and inhibit viruses belonging to different classes and cover both DNA and RNA viruses – Active against hepatitis B virus (HBV) [DNA virus] – Active against retroviruses (anti-HIV drugs) ADR Well tolerated Increased plasma level of didianosine
  9. 9. Protease inhibitors • “An agent that can keep a protease from splitting a protein into peptidase. • Protease inhibitors (PIs) are a class of antiviral drugs that are widely used to treat HIV/AIDS and hepatitis caused by hepatitis C virus. • Protease inhibitors prevent viral replication by selectively binding to viral proteases (e.g. HIV-1 protease) and blocking proteolytic cleavage of protein precursors that are necessary for the production of infectious viral particles. • Drugs used as protease inhibitors in HIV . 1. Squinavir. 2. Nelfinavir 3. Amprenavir 4. Lopinavir 5. Fosamprenavir. 6. Indinavir Combination therapy • Lopinavir + Ritonavir
  10. 10. Protease inhibitors-
  11. 11. Saquinavir (SQV) Hard capsule or tablets(poor bioavailability), soft gel capsule( good bioavailability but not use due to lipodystrophy) Metabolized by CYP3A4, , excreted in bile and faeces, t1/2- 8hrs. SQV-H + Low dose of Ritonavir- (boosted therapy) Indinavir(IDV) Oral ab. Rapid, ab. Reduce with high calorie food, taken empty stomach, sufficient fluid- avoid crystalluria, Adr- Hyperbilirubinaemia, Lipodystrohy, Dermatological side effects. Ritonavir(RTV) Ab. Rapid mild increase with food , Potent inhibitor of CYP3A4 (Increase its own metabolism). Not use with Nelfinavir- both potent enzyme inhibitor. Nelfinavir(NFV) Ab. Slow increase with fatty food. metabolized by CYP2C19. Lopinavir(LPV) Ab. rapid increase with fatty food. Atazanavir(ATV) Most commonly used PI in second line treatment as per NACO followed by LPV & SQV. Fosmprenavir (FPV) Prodrug, withdrawn from market-serious toxicity like lactic acidosis, seizures and depression-due to propylene glycol. LPV+RTV 4:1- LPV-400mg BD, RTV-100 mg BD.
  12. 12. • ADR – • The most prominent adverse effects of PIs are • Gastrointestinal intolerance, asthenia, headache, dizziness, limb and facial tingling, numbness and rashes. • Lipodystrophy (abdominal obesity, buffalo hump with wasting of limbs and face), • Dyslipidaemia (raised triglycerides and cholesterol) • Insulin resistance.
  13. 13. Fusion Inhibitor- Enfuvirtide • Enfuvirtide is a synthetic peptide acts by binding to HIV-1 envelope transmembrane glycoprotein (gp41) which is involved in fusion of viral and cellular membranes. • – It is not active against HIV-2. • – No cross resistance with other classes of ARV drugs occurs. • – The injections are painful and cause local nodules/cysts.
  14. 14. CCR5 receptor inhibitor-Maraviroc • The globular glycoprotein gp120 of the HIV envelope anchors to the CD4 site of host cell by binding to a cell membrane receptor, which mostly is the CCR5 chemokine receptor (most HIV are CCR5-tropic) • ADR-hepatotoxicity
  15. 15. Integrase inhibitors- Raltegravir (RTG) Raltegravir is an orally active drug that blocks this step by inhibiting the integrase enzyme. It is active against both HIV-1 and HIV-2. Elvitegravir (ETG) Same as Raltegravir. Dolutegravir (DTG) Higher resistance resisting activity, single tablet regimen
  16. 16. Drug treatment To prevent viral replication Multiple drug used to prevent viral replication and mutants Prevent depletion of CD4 cell count Maintain immunity To treat AIDS related opportunistic infection
  17. 17. HAART(Highly active anti-retroviral therapy) • Combination therapy of ARV. • HAART decreases the patient's total burden of HIV, maintains function of the immune system, and prevents opportunistic infections that often lead to death.

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