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:
 Acquired immuno deficiency syndrome(AIDS) was
first characterized in 1980s,by Human Immuno
deficiency virus,a single stranded RNA, ”Retro
virus”(retro:reverse ;reverse transcription).
 HIV VIRUS associated with AIDS are of two
types:
1)HIV 1
2)HIV 2
 HIV 1 is responsible for human AIDS.
 HIV 2 is also similar to HIV 1 virus ,it also causes
immuno suppression ,but less virulent and is
confirmed to Western Africa

3. What the HIV virus does and its replication:
 HIV infection collapses the cell mediated immunity due to
continued decline in CD4+ T lymphocyte cell. As a result
many apportunistic infections and malignancies appear
AIDS –related complex lead to death.
 REPLICATION:
Steps involved are:
1.Binding
2.Entry
3.Uncoating
4Reverse transcriptase
5.DNA copy enters host nucleus
6. Transcription of provirus
7.Transilation by host ribosomes
8.Protease action
9.Assembly and budding
10.New virons

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 nucleotide reverse 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,the virus consequently move the
target
• Loss of efficacy of drugs,due to 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:
 Approved for use in AIDS for children and adults
and prevent prenatal infection in pregnant mothers
 .DOSE:100mg 5 times a day for 4 weeks
 Effective in treating theHIV I and HIV II
Toxicity:
Inhibition of cellular as well as mitochondrial DNA
polymerase along with various cellular kinases

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** CSF 20%
<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, CSF 45%
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)
DRUG INTERACTIONS:
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
CD4 + T-cell counts of greater than 250 cells/mm3
or in men with CD4 + T-cell counts greater than
400 cells/mm3.
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. PREFERRED REGIMENS
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.