Anti viral Drugs Review from lipincott - Nucleoside Reverse Transcriptase Inhibitor NRTI, Non-Nucleotide Reverse Transcriptase Inhibitor NNRTI for HIV Infection , HIV Protease Inhibitors ,Entery Inhibitors ,Integrase inhibitor ( part 2/2)

 Nucleoside Reverse Transcriptase Inhibitor NRTI

Zidovudine approved in 1987

used to Suppress Replication of HIV & Restore no.of CD4+ cells in AIDS patients

HAART=”Highly Active Antiretroviral Therapy” include NRTI, NNRTI, Protease Inhibitor, Entry Inhbitor, Integrase Inhbitor

e.g 2NRTIs + 1Prot.Inhibitor OR 1NNRTI+1Integrase inhibitor

MOA: 

👉NRTI are RiboNucleoside analogue…lack 3-OH...Enter the cell convert into TriPhosphate…incorporate into Viral DNA by Reverse transcriptase….

b/c 3-OH not present, 3,5-Phosphodiester bond not fromed in Nucleoside Triphosphate...Terminate Elongation of DNA

1. HIV enters into cell→Maraviroc (Entery Inhibitor) block entery of HIV

2. Enfuvirtide (Entery In.) block FUSION of HIV & Host memb Viral RNA→═Viral DNA by Reverse Transcriptase, NRTI & NNRTI ϴ this enzyme

═Viral DNA integrate with ═Host DNA Integrase Inhibitor ϴ this process

≈Integrated Viral DNA convert into Viral RNA & Precursor Polyprotein,

Precursor Protein→Viral protein →Mature Virion, Protease Inhibitor ϴ this process 

S.E OF NRTI= Neuropathy, Pancreatitis, Lipoatrophy b/c suppress Mitochondrial DNA polymerase….Lactic acidosis, Hepatomegaly

Resistance= mutation at Viral codon 184

3 . Zidovudine (AZT, ZDV) = AZT for children & Pregnancy HIV infection 

4. Stavudine (d4T) = Thymidine analogue…ϴβ & γDNA polymerase

5. Didanosine (ddl) =Second drug approved for HIV-1 infection…2, 3-OH absent….

6. Tenofovir (TDF) =first Nucleotide analogue for HIV 

7. Emtricitabine (FTC) =Flouro derivative of Lamivudine…For HIV & HBV…39hr half life… 

S.E; Hyperpigmentation, Fatty liver, lactic acidosis 

8. Zalcitabine= removed from market 

9. Abacavir=Guanosine analogue…Sensitized individual Never Rechallenged…HLA genetic test for Hypersensitivity 

Non-Nucleotide Reverse Transcriptase Inhibitor NNRTI for HIV Infection 

Highly selective, Lack Host cell effect, lack Cross- resistance 

1ST Generation NNRTI 

1. Nevirapine= not used in Men <4000 CD4+ cells/mm3…not used in women <250 CD4+ cell/mm3….no need of Intracellular Activation of Phosphorylation…↑Vd, cross B.B.B… 

Enzyme Inducer…

S.E; Steven Jhonson Syndrome, Epidermal Necrolysis (TEN), Hepatotoxicity, ↑LFTS

2. Efavirenz=↑CD4+ cells,↓viral load…99%P.B, 40hr t1/2….Take an Empty stomach… 

Enzyme inducer…

S.E; Vivid dream, loss of conc….Avoid in pregnancy

2nd Generation NNRTI 

1. Ertavirine= HIV with K103N susceptible…taken with fatty meal…40hr t1/2

HIV Protease Inhibitors 

Introduced in 1995…affinity for HIV-1, HIV-2> human protease Renin, Cathepsin D/E … 

Substrate for P-glycoprotein…bind to α1-acid Glycoprotein…CYP3A4 substrate

S.E; 

“Buffalo hump” loss of fat from extremeties,accumulate in abdomen & base of neck

1. Ritonavir=”Booster” for other Protease I….S.E; Paresthesia

2.Saquinavir=always with Ritonavir..↑LFTs

3. Indinavir=Shortest t1/2 1.8hr…Acid require for digestion…S.E;stone formation

4. Nelfinavir= only protease not require Boosted dose of Ritonavir

5. Fosamprenavir= Prodrug…B.D used

6. Tipranavir= Black Box warning for “Fatal Hepatitis” & “Intracranial Hemorrhage” useful in “Salvage” reigemen for multidrug resistance

Entery Inhibitors

1. Enfuvirtide=Fusion inhibitor…36-Amino Acid change Viral Glycoprotein gp41…

Reconstituted before administration

2  Maraviroc=Block CCR5-Cotransporter facilitate HIV entery

Integrase inhibitor

1. Raltegravir=Block Integration of viral DNA with Host DNA…Metabolize by UGT1A1 glucuonidation….↑Creatine kinase, Rhabdomylysis, Sucidal ideation.