ANTI HIV DRUGS

Types of HIV Virus Anti-HIV drugs, classification, mechanism of action, pharmacological action, pharmacokinetics, adverse drug reactions, drug interactions, contraindications and therapeutic uses

1. ANTI HIV DRUGS
Integrase enzyme
Integrase inhibitor
CD4/T-cell’s instructions
HIV instructions
Presented by,
Dr. B.Revathi,
M.pharm, pharmacology, Ph.D

2. INTRODUCTION:
Acquiredimmunodeficiencysyndrome(AIDS)was
firstcharacterizedin1980s,byHumanImmuno
deficiencyvirus,asinglestrandedRNA,”Retro
virus”(retro:reverse;reversetranscription).
HIVVIRUSassociatedwithAIDSareoftwo
types:
1)HIV1
2)HIV2
HIV1isresponsibleforhumanAIDS.
HIV2isalsosimilartoHIV1virus,italsocauses
immunosuppression,butlessvirulentandis
confirmedtoWesternAfrica

3. What the HIV virus does and its replication:
HIVinfectioncollapsesthecellmediatedimmunitydueto
continueddeclineinCD4
+
Tlymphocytecell.Asaresult
manyapportunisticinfectionsandmalignanciesappear
AIDS–relatedcomplexleadtodeath.
REPLICATION:
Stepsinvolvedare:
1.Binding
2.Entry
3.Uncoating
4Reversetranscriptase
5.DNAcopyentershostnucleus
6.Transcriptionofprovirus
7.Transilationbyhostribosomes
8.Proteaseaction
9.Assemblyandbudding
10.Newvirons

4. TARGETS:
Maximally and durably inhibit the replication of
virus
And increasing the production of CD4
+
cells,to
preserve immunologic functions

5. CLASSIFICATION
1.Nucleoside and nucleotidereverse transcriptase
inhibitors(NRTIs)
eg.Zidovudine,Didanosine,Stavudine,
Lamivudin,Abacavir,Zalicitabine,Tenofovir.
2.Nonnucleoside reverse transcriptase
inhibitors(NNRTIs)
eg.Nevirapine,Delavirdine,Efavirenz
3.HIV / Retroviral Protease inhibitors(PIs)
eg.Indinavir,Nelfinavir,Ritonavir,
Saquinavir,Lopinavir
4.Fusion /entry inhibitors
eg.Enfuvirtide

6. NRTIs
MOA: Phosphorylated by host kinases enzymes
5’-triphosphateequivalent
host cellular triphosphate substrate for
proviral DNA synthesis by viral reverse transcriptase
CHAIN TERMINATION
RESISTANCE
•Due to rapid mutation,thevirus consequently move the
target
•Loss of efficacy of drugs,dueto decrease in activation of
drugs, increase in virus loading

7. ADRS:
Leukopenia,anemia
Toxicity is due to partial inhibition of cellular DNA
polymerase
DRUG INTERACTION:
Parcetamol increases the zidovidine toxicity
USES:
ApprovedforuseinAIDSforchildrenandadults
andpreventprenatalinfectioninpregnantmothers
.DOSE:100mg 5 times a day for 4 weeks
EffectiveintreatingtheHIVIandHIVII
Toxicity:
InhibitionofcellularaswellasmitochondrialDNA
polymerasealongwithvariouscellularkinases

8. PHARMCOKINETICS OF NRTIs
Drug Oral
bioavailability(
%)
Distribution;pr
otein binding
(%)
Metabolism
Zidovudine 60-65** All tissues, CSF,
35-38% PB
hepatic ,High
First Pass
Stavudine 85-90 Good;CSF
,negligible PB
Minor
Lamuvudine 85-90 CSF
20%;35%PB
Minor
Abacavir 83 CSF
33%PB50%
Liver, Alcohol
Dehydrogenase
Zalcitabine >80** CSF20%
<4% PB
Minor
** indicates food decreases bioavailability

9. NTRTIs
MOA: Tenofavir disoproxil fumarate(prodrug)
hydrolysed
by liver
Tenofavir
Tenofovir diphosphate

10. NNRTIs
Non competitive inhibitors of HIV I reverse
transcriptase.
MOA:
Binds to HIV reverse transcriptase
catalytic site adjacent to the active site
induce a conformational change in enzyme
Inhibition of cDNA
ADVANTAGE:
Lack of effect on the host blood forming elements
Lack of cross-resistance with NRTIs

11. USES:
All NNRTIs are active against HIV I reverse
transcriptase only
Used along with NRTIS and protease for
synergistic effects
ADRs:
skin rashes including Stevens-Johnson Syndrome,
increase levels of liver enzyme
Drug interaction :
Induction and inhibition of cytochrome P450
enyzmes

12. PHARMACOKINETICS OF NNRTIs
Drug Oral
Bioavailability
(%)
Distribution;
Protein
binding(%)
Metabolism
Nevirapine 90-95 Wide, CSF45%
PB 60%
Hepatic
CYP3A4
Efavirenz 50* CSF 1.0%
PB 99%
Hepatic
CYP3A4
CYP2B6
Delavirdine 85 CSF 0.4%
PB 98%
Hepatic
CYP3A4
CYP2D6
* Faaty meal increases bioavailability

13. PROTEASE INHIBITORS
MOA: Aspartic protease enzyme encoded by HIV
Involved in the production of structural
proteins and enzymes for new virons
Inhibition of new virus
USES:Active against HIV I and HIV II infections
ADRS:Lipodystrophy,limbs and facial tingling and numbness,
rashes,asthenia(loss of strength)
DRUGINTERACTIONS:
Competitive inhibitors of drugs metabolised by CYP3A4
family,so increase in plasma concentration may result with
concurrent use of such drugs

14. PHARMAKOKINETICS OF PROTEASE INHIBITORS
Drug Oral
Bioavalbility
(%)
Distribution;
Protein
binding(%)
Metabolism
Saquinavir 4* 97% PB CYP3A4,First
pass
metabolism
Ritonavir 75* 98% PB CYP3A4
Indinavir 65* CSF 76%
PB 60%
CYP3A4
Lopinavir Variable** 98-99% PB CYP3A4
*Food increases absorption
* *Ritonavir as well as food increases absorption

15. FUSION/ENTRY INHIBITORS
MOA: Enfuvirtide,recently introduced HIV derived synthetic
peptide
Acts by binding to HIV -1 envelope glycoprotein(gp41)
preventing fusion of viral and cellular membranes
Entry of virus is blocked
ADVANTAGES: No cross resistance
Used in patients failed with earlier regimens

16. CONTRAINDICATIONS
Nevirapine should not be initiated in women with
CD
4+ T-cell counts of greater than 250 cells/mm
3
or in men with CD
4+ T-cell counts greater than
400 cells/mm
3
.
NRTI’s contraindicated in anaemia, neutropenia
and renal impairment.
NNRTI’s contraindicated in hepatic diseases.
PI’s are contraindicated in diabetes and with
benzodiazepines.

17. PREFERREDREGIMENS
2 NRTI + NNRTI ( PI sparing )
1.Zidovudine + lamivudine + efavirenz
2 NRT + PI
1.Zidovudine + lamivudine + lopinavir / r
ALTERNATIVE REGIMENS
2 NRTI + NNRTI ( PI sparing )
1.Zidovudine + lamivudine + nevirapine
2.Lamivudine + stavudine + efavirenz
3.Lamivudine + stavudine + nevirapine
2 NRTI + PI
1.Lamivudine + zidovudine + indinavir
2.Lamivudine + stavudine + ritonavir
3 NRTI
1. Zidovudine + lamivudine + abacavir

18. REFERENCE
RANG N DALE’S PHARMACOLOGY, Page no:681 -686
ESSENTIAL OF MEDICAL PHARMACOLOGY by K.D
TRIPATHI ,Page no:767-775
LIPPINCOTT’S PHARMACOLOGY,Page no:448 -451
PRINCIPLES OF PHARMACOLOGY by HL.SHARMA and
KK.SHARMA ,page no:810-815
WWW.