anti-HIV Drugs

Anti-HIV Drugs :

Anti-HIV Drugs Prepared & Presented by Dr. Siva Reddy Challa, M.Pharm,Ph.D Professor & HOD, Dept. of Pharmacology KVSR Siddhartha College of Pharmaceutical Sciences, Siddhartha Nagar, Vijayawada-520010 Andhra Pradesh, INDIA Email: sivareddypharma@gmail.co m

Drugs for HIV/AIDS:

2 Drugs for HIV/AIDS Multi - drug regimen used for the treatment of HIV infection is referred as HAART “Highly active anti-retroviral Therapy”

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4 1. Binding 2. Reverse transcriptase 3. Integrase 4. Transcription 5. Translation 6. Assembly and maturation

Drugs for HIV/AIDS:

5 Drugs for HIV/AIDS Anti-retroviral drugs Reverse transcriptase inhibitors (RTI) Nucleoside analogs ( N R T I ) Non-nucleoside analogs ( N N RT I ) Nucleotide analogs – Tenofovir Protease inhibitors

Drugs for HIV/AIDS:

6 Drugs for HIV/AIDS Integrase Inhibitor : Zintevir Fusion inhibitor : Enfuvirtide

Drugs for HIV/AIDS:

7 Drugs for HIV/AIDS Currently the recommendation for HIV / AIDS patient is either Two Nucleoside reverse transcriptase inhibitors + One Protease Inhibitor or Two Nucleoside reverse transcriptase inhibitors + Non-nucleoside RT Inhibitor

Nucleoside reverse transcriptase inhibitors (NRTIs):

8 Nucleoside reverse transcriptase inhibitors (NRTIs) Nucleoside analogs

Nucleoside analogs:

9 Nucleoside analogs Nucleoside reverse transcriptase inhibitors (NRTIs): Zidovudine (AZT) – commonly used Didanosine ( ddI ) Lamivudine (3TC)- safest Stavudine (d4T) Zalcitabine ( ddc ) Abacavir – used in resistant cases

Nucleoside analogs:

10 Nucleoside analogs Nucleoside reverse transcriptase inhibitors (NRTIs): Activated intracellularly by phosphorylation by cellular kinases The triphosphate form acts by competitive inhibition of HIV-1 reverse transcriptase. Incorporation into HIV DNA results in chain termination.

Zidovudine (AZT):

11 Zidovudine (AZT) It is a thymidine analog ( Azidothymidine , AZT ). It gets phosphorylated to zidovudine triphosphate , which selectively inhibits viral reverse transcriptase (RNA dependent DNA polymerase)

Zidovudine:

12 Zidovudine It is effective against retrovirus only It gets incorporated into the viral DNA and terminates chain elongation It decrease the rate of clinical progression of disease and prolong survival in HIV infected patients.

Zidovudine:

13 Zidovudine In pregnancy : - oral dose of zidovudine is started from 2 nd trimester of gestation. - It is given intravenous during labor . Zidovudine syrup is given to the neonate from the birth through 6 weeks. It decreases the vertical transmission from mother to new born by 2/3 rds from 25% to 8%.

Zidovudine:

14 Zidovudine Post exposure prophylaxis: It is recommended for post exposure prophylaxis – (needle stick injury with HIV positive patients – transmission is 0.1%) Given from time of exposure to 6 weeks.

Zidovudine:

15 Zidovudine Pharmacokinetics : Oral absorption is good Bioavailability is 65% CSF conc. is ~ 50% of plasma Excreted by hepatic glucuronidation It crosses placenta and found in milk

Zidovudine: Adverse effects:

16 Zidovudine: Adverse effects Myelosuppression - anemia and neutropenia are the most common adverse effects Myopathy , convulsions and encephalopathy

Zidovudine:

17 Zidovudine Zidovudine : Interactions Acetaminophen increases AZT toxicity Azole anti-fungal agents inhibit AZT metabolism. Myelosuppression: with Ampho B, Ganciclovir Zidovudine and stavudine should not be combined in a treatment regimen – Antagonistic effect

Didanosine : (ddI):

18 Didanosine : ( ddI ) It is a synthetic analog of deoxyadenosine Food decreases absorption Major clinical toxicity is pancreatitis painful neuropathy

Stavudine : ( d4T ):

19 Stavudine : ( d4T ) It is a thymidine analog It has oral bioavailability ~ 90% Penetrates the BBB Major dose limiting effects are peripheral neuropathy

Lamivudine : (3 T C):

20 Lamivudine : (3 T C) It is a cytosine analog Oral bioavailability ~ 80% Majority of lamivudine is excreted unchanged in urine Can be administered with AZT but not with Zalcitabine ( ddC ) Side effects are – headache and insomnia

Emtricitabine :

21 Emtricitabine It is a fluorinated lamivudine ( analog) Orally well absorbed Plasma half life ~ 40 hrs - Once a day dose. Hyper pigmentation of palm and soles Lactic acidosis and hepatitis.

Zalcitabine : ( ddC ):

22 Zalcitabine : ( ddC ) It is a cytosine analog – has antiviral activity against zidovudine sensitive and resistance strains. High oral bioavailability ~ 80% Dose limiting toxicity is Pancreatitis peripheral neuropathy

Abacavir :

23 Abacavir It is a guanosine analog Used when other treatments fail or not tolerated. Well absorbed orally - 86% Hypersensitivity

Nucleotide Reverse Transcriptase Inhibitors :

24 Nucleotide Reverse Transcriptase Inhibitors Tenofovir

Tenofovir:

25 Tenofovir AZT resistant strains are also susceptible Oral administered and excreted in urine. Nausea and vomiting are the disadvantages. Also for Hepatitis B virus

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26 Zidovudine AZT Didanosine ( ddI ) STAV ( d4T ) LAMI ( 3TC ) ZALCI ( ddC ) Analog Thymidin Adenosin Thymidi Cytidin Cytidine Notes Avoid BM suppressive drugs Avoid neuropathy drugs Avoid neuropathy drugs Active against HBV also. Avoid neuropathy drugs and antacids. Adverse effects Anemia Neutropenia, myopath Pancreatiti Neuropathy SensoryNeuropathy Headache Pancreati Neuropathy

Non-nucleoside reverse transcriptase inhibitors : ( N N R T I ):

27 Non-nucleoside reverse transcriptase inhibitors : ( N N R T I ) Nevirapine, Efavirenz, Delaviridine

Non-nucleoside reverse transcriptase inhibitors : N N R T I:

28 Non-nucleoside reverse transcriptase inhibitors : N N R T I Nevirapine, Efavirenz, Delaviridine They bind to the RT enzyme and causes its inactivation non-competitively These agents do not require intracellular phosphorylation for their anti-viral activity

Non-nucleoside reverse transcriptase inhibitors : N N R T I:

29 Non-nucleoside reverse transcriptase inhibitors : N N R T I They have excellent oral bioavailability They have good penetration into CNS They are metabolized by cytochrome P – 450 They lack effect on the blood forming elements – no activity in BM

Nevirapine:

30 Nevirapine It is used in combination in HAART. Wide tissue distribution – CNS and fetus It is also effective in reducing vertical transmission during pregnancy.

Nevirapine:

31 Nevirapine Non-nucleoside reverse transcriptase inhibitors : N N R T I : Nevirapine : adverse effects : Hepatotoxicity Stevens – Johnson syndrome It is an i nducer of Cyto P 450

Efavirenz:

32 Efavirenz Non-nucleoside reverse transcriptase inhibitors : N N R T I : It significantly increase CD4 count Once a day dose – half life 40 hrs. Inducer of cyto P450 Adverse effects Rashes Neurologic: lack of concentration, delirium, hellucinations

Delaviridine:

33 Delaviridine Well absorbed orally Fecal and urine elimination It inhibits cyto P 450

Protease Inhibitors:

34 Protease Inhibitors

Protease Inhibitors ::

35 Protease Inhibitors : Protease is a viral enzyme that cleaves viral polyprotein into number of essential enzymes – RT, Integrase Protease inhibitors act by blocking the HIV protease enzyme

Protease Inhibitors ::

36 Protease Inhibitors : They interfere with the post – translational processing of HIV precursor proteins These protease inhibitors result in HIV copies that are immature and non-infectious.

Protease Inhibitors ::

37 Protease Inhibitors : Protease Inhibitors : They have poor oral bioavailability They Inhibit cyto P450. Combination therapy with NRTI produces additive effects and decrease the development of resistance.

Protease Inhibitors ::

38 Protease Inhibitors : Protease Inhibitors : Saquinavir, Ritonavir, Indinavir , Nelfinavir, Amprenavir, Atazanavir are the main HIV protease inhibitors. Adverse effects: Paresthesia hyperglycemia hypertriglyceridemia – buffalo hump.

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39 Absorption Excretion Comments Saquinavir Poor oral absorption. Feces excretion With ritonavir Indinavir Good oral absorption Feces excretion Hepatitis, renal stones, jaundice Ritonavir Good absorption Feces excretion Liver toxicity, increase plasma conc. of other PI Nelfinavir Good absorption Feces excretion diarrhea

HIV integrase inhibitor:

40 HIV integrase inhibitor Zintevir It is an inhibitor of HIV INTEGRASE enzyme, an enzyme required for integration of viral DNA into cellular DNA

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41 Integrase, an enzyme produced by the virus, is necessary for HIV to establish infection within a cell and make more copies. By blocking integration, an integrase inhibitor would prevent HIV from infecting "new" cells, but does not have any effect on cells with established infection.

Fusion inhibitor:

42 Fusion inhibitor Enfuvirtide

Fusion inhibitor:

43 Fusion inhibitor Viral Binding : Enfuvirtide, or T-20 (Fuzeon) It acts by blocking gp41 on the HIV particle and prevents binding to the human cell.

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