Pharmacology PPT

1. ANTIVIRAL - II
ANTI HIV DRUGS
Dr. Chintan Doshi

2. Introduction
Retrovirus
Human immunodeficiency virus
(HIV)
AIDS
HumanT-cell lymphotrophic virus
T-cell Lymphoma
(RNA virus)

3. • HIV virus : Single stranded RNA retrovirus
• Other virus : RNA transcripted from DNA
• Retrovirus : DNA transcripted from RNA by the enzyme Reverse
transcriptase
• AIDS
• 2 types for viruses : HIV 1 (worldwide)
HIV 2 (western Africa & India)
• HIV infection : cell mediated immunity collapses – CD4+ T-cell decline
• So, massive opportunistic infection and malignancies - death

4. Basic components of HIV virus

5. Genes of HIV virus
• gag- codes for core proteins (RT, integrase and protease enzymes)
• pol – Same as gag
• env- codes for envelope proteins (gp120 and gp41)
Co-receptors
• CCR5 & CXCR

6. Replicative cycle of HIV

7. Classification
Existing Antiretroviral Drug
Classes
• Nucleoside reverse transcriptase
inhibitors (NRTIs)
• Non-nucleoside reverse
transcriptase enzyme inhibitors
(NNRTIs)
• Nucleotide ReverseTranscriptase
Inhibitors (NtRTIs)
• Protease inhibitors (PIs)
New Antiretroviral Drug Classes
• Entry inhibitors
• Chemokine receptor inhibitors
• CCR5 antibodies
• Fusion inhibitors
• Integrase inhibitors

8. Nucleoside Reverse Transcriptase
Inhibitors (NRTIs)
Mechanism of Action :
• All drugs require intra-cytoplasmic activation via phosphorylation by cellular
enzymes to tri-phosphate form
• Inhibit reverse transcriptase
• Incorporate into viral DNA and cause chain termination
Resistance :
• Mutation in reverse transcriptase - Monotherapy

9. • NRTIs backbone of an HIV treatment
• Preferred as First line drugs because of
 Favourable pharmacokinetic profile, especially long intracellular half life
 High oral bioavailability and administration without regard to food
 Availability as fixed dose combinations (FDC) with convenient once or
twice daily dosage schedule and
 Low risk for drug-drug interactions

10. • Thymidine analogue
• Oral absorption is rapid ; bioavilability 65%
• Metabolize by hepatic glucuronidation
• t1/2 : 1 hour
• Excreted unchanged in urine
Zidovudine (AZT)

11. Adverse effects :
• Anaemia & Neutropenia (MC)
• Nausea , anorexia, abdominal pain, headache, insomnia , myalgia
• Myopathy , Pigmentation of nails
• Convulsion,hepatomegaly, encephalopathy – infrequent
• Reason: inhibition of cellular mitochondrial DNA polymerase γ
Use :
• Palliative treatment of HIV-1 and HIV-2 with other 2 ARV drugs
• As Post exposure prophylaxis
• For mother to offspring transmission

12. • Thymidine analogue
Adverse effects :
• Peripheral neuropathy (Main)
• Lactic acidosis more frequent
• Pancreatitis & joint pain
Interaction :
• Neuropathic drugs (Didanosine, Zalcitabine & Isoniazid) –avoided
 One of the optional component of first line regimen used by NACO
Stavudine (d4T)

13. • Cytosine analogue
• Oral bioavailability is very high – 85-90%
• t1/2 : 5-7 hrs
• Well tolerated & lower toxicity – high priority in use
• Dose adjustment is needed in patient with renal insufficiency
• Lamivudine + Zalcitabine – inactivate each other
Dose : 150 mg BD orally
S/E:headache, fatigue, rashes nausea, anorexia,
abdominal pain
Lamivudine (3TC)

14. • Adenosine analogue
Adverse effects:
• Peripheral neuropathy ,Rarely pancreatitis
Use
• Declined due to higher toxicity than other NRTIs
Didanosine (ddl)

15. Non-nucleoside reverse transcriptase enzyme
inhibitors (NNRTIs)
Mechanism of Action :
• Do not require activation through phosphorylation
• Bind directly to the catalytic site of viral reverse transcriptase
• Cause enzyme inactivation and
• Inhibition of viral DNA synthesis
Resistance :
• Mutation in reverse transcriptase
• Cross resistance – in between NNRTIs
 No activity against HIV-2

16. • Nucleoside unrelated compound
• Well absorbed orally (95%)
• Metabolised mainly CYP3A4 ; lesser by CYP2B6
• t1/2 : 30 hrs
Adverse effects :
• Rashes (MC-including S J Syndrome)
• vomiting, headache, fever
• Hepatotoxicity
Nevirapine (NVP)

17. Use :
• HIV infected Adults and Children as multidrug therapy
• Prevention of mother to newborn transmission

18. • 50% bioavailability
• Metabolised mainly by CYP2B6; lesser by CYP3A4
Adverse effects :
• Headache, insomnia, dizziness, rashes
• Neuropsychiatric symptoms
Dose : 600 mg OD on empty stomach
Efavirenz (EFV)

19. • Use in HIV-1 infection in adults
• Use decline : 3 times daily dosing schedule
• Side effects : Skin rash, pruritus, elevate hepatic enzyme
• Teratogenic in rats
• Avoided in pregnancy
Delavirdine
New NNRTIs

20. • US-FDA approved in May-2011
• Shown in vitro activity against HIV resistant strains
• Evaluated as an alternative to efavirenz
• High genetic barrier to drug resistance
• Effective against HIV strains resistant to conventional NNRTIs
• Lack of antagonism with other ARV drugs
• Fewer adverse reactions
Rilpivirine

21. Nucleotide Reverse Transcriptase Inhibitors
(NtRTIs)
• Analogue of adenosine-5’-monophosphate
• Available as tenofovir disoproxil fumarate – prodrug
• Hydrolysed in liver → tenofovir → tenofovir diphosphate
• Action is same as NRTIs (except triphosphate form)
• Bioavilability 25% ; ↑ed after meal 40%
• t1/2 : 17 hrs
Tenofovir

22. Adverse effects :
• Nausea, flatulence, abdominal discomfort, loose motions
• Headache
• Renal toxicity is quite rare,
Combination
Tenofovir
+
Rilpivirine
+
Emtricitabine
Approved in
2011

23. Protease Inhibitors (PIs)
Mechanism of Action :
• Competitively inhibit the viral protease enzyme
• Prevent cleavage of gag-pol poly proteins;
Necessary for virion production
• Result in production of immature , non-infectious virions
• Effect on late step of viral cycle- effective in both newly as well as
chronically infected cells
• This isoform of protease is not present in the host – better option

24. Limitations
 Insulin resistance
 Dyslipidemia
 Hypertriglyceridemia
 High risk of coronary artery disease
 Clinically significant interactions:
 Antifungals, Antimycobacterials
 Hormonal contraceptives, HMG-coenzyme reductase inhibitors

25. • Current recommendation – use of PI in combination with either two NRTIs
or one NRTIs + one NNRTIs
• Avoided as 1st line regimen
• Most guideline reserve them for failure cases
• Problem : large tablet load
• “Boosted PI regimen”
• Combine with low & subtherapeutic dose of Ritonavir (100 mg)
• Ritonavir reduce first pass metabolism – increase bioavailability
Slowing systemic metabolism – decrease clearance

26. • PIs inhibit as well as induce specific CYP isoenzymes
• So, drug interactions are common
• Lopinavir is marketed only in combination with Ritonavir
• Nelfinavir is not to be combine with Ritonavir – mainly metabolise by
CYP2C19 ; not inhibited

27. • Oral bioavailability 65% ; food decrease it
• Characteristic S/E : Nephrolithiasis
Urolithiasis
Renal insufficiency
• Other : Hyperbilirubinaemia
Alopecia
Paronychia
Anaemia
Dose : 800 mg BD with 100 mg Ritonavir
Water intake is
recommended
Indinavir

28. • Most commonly used PI
• Relatively low toxicity profile
• Food increase bioavalability
• Only PI – cannot be boosted with Ritonavir (Not metabolise by CYP3A4)
• But, clinical efficacy somewhat lower than other
Nelfinavir

29. • Not well tolerated
• Food increase bioavalability
• Potent CYP3A4 enzyme inhibitor
• Always used as pharmacokinetic booster with other PIs
Side effects :
• Peripheral paraesthesias
• Elevated triglyceride and hepatic transamianses
Dose : 100 mg to boost other PIs
Ritonavir

30. • Only PI fixed dose combination
• Available as a 4:1 ratio
• Lopinavir (400mg BD) : Ritonavir (100 mg BD) with food
• If coadministered with Efavirenz or Nevirapine – Dose increase
Lopinavir + Ritonavir

31. New Antiretroviral
Drug Classes

32. Chemokine Receptor Inhibitors
(1) CCR5 receptor inhibitors
• FDA approved in August 2007
• Approved for use in treatment-experienced patients
• Investigations in treatment-naïve patients have demonstrated it to be
similar to efavirenz
• Hepatotoxicity, muscular/joint pain
Maraviroc

33. Fusion Inhibitors
• Approved by US FDA for treatment-experienced patients who failed other
antiretroviral therapy
• Synthetic peptide ; structurally similar to a section of gp41
• Blocks the conformational changes in gp41 and hence blocks an entry of
virus in the host cell
• Targets both CCR5 and CXCR4
Enfuvirtide

34. • Assessed as a part of multi-drug antiretroviral regimen
• Greater decline in viral RNA load when combined with darunavir/ritonavir,
tipranavir, tenofovir and zidovudine
• Hence, it is important as add on therapy
Side effects : local reaction due to subcutaneous administration
Bacterial pneumonia
• Reserve drug for patients when all treatment fails
• Resistance develops within a few weeks due to mutation of gp41

35. Integrase Inhibitors
Mechanism of action :
• Inhibit the viral enzyme integrase
• Preventing the insertion of HIV genetic material into chromosomes of the
host cells
• Halting the viral replication process

36. • Significant antiviral activity against HIV resistant to protease inhibitors,
NRTIs and NNRTIs
• Approved in October 2007
• As effective as efavirenz in reducing viral RNA count at 48 and 96 weeks
Raltegravir

37. • Integrase inhibitor; Superior to Raltegravir
• FDA approved in August 2013
• Absorption increase by food
• Metabolised by UDP-glucuronyltransferase
• Distribute in CSF, male & female genital tract tissue
Main S/E : Hypersensitivity reaction
Lipodystrophy
• Recommend for adults & children >12 yrs ; weighing at least 40 kgs
Dolutegravir

38. HIV Vaccine
• None of the vaccines tested so far has been successful
• Main problems : diversity of the virus, an ability of the virus to elude the
immune system and lack of animal models
• STEP study :
• Tested the efficacy of recombinant Ad5 HIV-1 vaccine (viral vector carrying
HIV-1 gag, pol and env antigens)
• But lack of efficacy and an increased HIV-1 acquisition in some subjects lead
to premature termination of the trial