pharmacology of antiretroviral drugs introduction and information

1. Dhananjay D.
Student,
Department of Microbiology
N. A. C. & Sc. College, A. Nagar.
dhananajyashokdesai@gmail.com

3. Step 1: Fusion
Step 2: Transcription
reverse
transcriptase
Step 3:
Integration
Step 4: Cleavage
Step 5: Packaging
and Budding
HIV

5. The first available agents:
 Nucleoside analog class → inhibition of the viral
reverse transcriptase
Non nucleoside reverse transcriptase inhibitors.
The protease inhibitors.
The combination of at least two antiretroviral agents
(cocktail therapy) → enhancing potency and delaying
resistance

6. pathway:
Viral
RNA
double helix
DNA
Incorporated
into host
genome
reverse
transcriptase
HIV integrase
transcription
translation
Polyproteins
Final
structural
proteins
HIV protease
Drugs
NRTIs
NNRTIs
PIs

7. Derivatives of Pyrimidine: AZT, ddC, d4T,
3TC
Derivatives of Purine: ddI, ABC

8. Inhibition of HIV-1 reverse transcriptase;
Incorporated into the growing viral DNA chain →
cause termination
Drugs requires intracytoplasmic activation---
phosphorylation → triphosphate form
Most have activity against HIV-2 as well as HIV-1.

9. Azidothymidine -AZT
Deoxythymidine analog
anti-HIV-1 and HIV-2
Well absorbed from the gut and distributed to most
body tissues and fluids, including the cerebrospinal
fluid.
Eliminated primarily by renal excretion following
glucuronidation in the liver.

10. Decrease the rate of clinical disease progression and
prolong survival.
Treatment HIV-associated dementia and
thrombocytopenia.
Reduce the rate of vertical (mother-to-newborn)
transmission of HIV.
Adverse effect: myelosuppression → anemia or
neutropenia; gastrointestinal intolerance, headache,
insomnia

11. Cytosine analog
Anti-HIV-1
Zalcitabine + Zidovudine + one protease inhibitor
Long intracellular half-life of 10hs.
Dose-dependent peripheral neuropathy.
Contraindication to use with other drugs that may
cause neuropathy.

12. Thymidine analog (d4T), not used with AZT because
AZT may reduce the phosphorylation of d4T.
Anti-HIV-1 and HIV-2.
High oral bioavailability (86%) that is not food-
dependent.
Plasma protein binding is negligible, mean
cerebrospinal fluid concentrations are 55% of those of
plasma.
Excretion is by active tubular secretion and
glomerular filtration.

13. Adverse effects:
 Dose-limiting toxicity is a dose-related peripheral
sensory neuropathy.
 Pancreatitis, arthralgia's, elevation in serum
aminotransferases.

14. Synthetic analog of deoxyadenosine
Plasma protein binding is low (<5%), cerebrospinal
fluid concentrations are 20% of serum concentrations.
Eliminated by glomerular filtration and tubular
secretion.
Should be taken on an empty stomach.
Anti-HIV activity of ddI is potentiated by
hydroxyurea due to a depletion of intracellular pools
of dATP, so two agents is administered in
combination.

15. Adverse effects:
Dose-dependent pancreatitis
Painful peripheral distal neuropathy
Diarrhea
Hepatitis
Esophageal ulceration.
Cardiomyopathy
Central nervous system toxicity (headache, irritability,
insomnia)

16. Including delavirdine, nevirapine, efavirenz.
Bind directly to a site on the viral reverse transcriptase
that is near to but distinct from the binding site of the
NRTIs.
Neither compete with nucleoside triphosphates nor
require phosphorylation to be active.
The binding to the enzyme’s active site results in
blockade of RNA- and DNA-dependent DNA
polymerase activities.

17. Specific activity against HIV-1.
Cross-resistance among this class of agents.
The rapid emergence of resistance prohibits mono
therapy with any of the NNRTIs.
No cross-resistance between the NNRTIs and the
NRTIs or the protease inhibitors.
Oral bioavailability is high.
Metabolized by the CYP3A P450 isoform, excreted in
the urine.
Adverse effects: skin rash

18. Including ritonavir, nelfinavir, saquinavir, indinavir
and amprenavir.
Gag and Gag-Pol
gene
Polyproteins,
Immature budding particles
translate
Final structural proteins,
Mature virioncore
protease

19. Combination therapy with other agents is
recommended to avoid emergence of resistance,
because of specific genotypic alterations.
Adverse effect:
Syndrome of altered body fat distribution (buffalo
hump and truncal obesity, with facial and peripheral
atrophy)
Insulin resistance
Hyperlipidemia.

20. Including:
Nucleoside antiviral agents
Nonnucleoside antiviral agents
Immune enhancement agent
Mechanism of action:
Compete the receptors, e.g.: Heparin,
Polysaccharide
Block viral adsorption to and penetration into host
cells and uncoating of viral nucleic acid, e.g.:
amantadine
Block viral biosynthesis, e.g.: idoxuridine
Enhance the host immune activity, e.g.: interferon

21.  Including Purine-nucleoside and Pyrimidine-
nucleoside.
 Drugs requires intracytoplasmic activation---
phosphorylation → triphosphate form →
competitive inhibition of viral DNA polymerase.
 Incorporated into the growing viral DNA chain →
cause termination

22. An acyclic guanosine derivative
Pharmacological effects:
Against HSV-1 and HSV-2 and against varicella-
zoster virus, Epstein-Barr virus and cytomegalovirus.

23. Mechanism:
Three phosphorylation steps for activation.
First converted to the monophosphate derivative
by the virus-specified thymidine kinase;
（selective activation）
Then to the di- and triphosphate compounds by
host’s cellular enzymes.
Acyclovir triphosphate inhibits viral DNA synthesis
by two mechanisms:
Competitive inhibition of deoxyGTP for the viral
DNA polymerase, with binding to the DNA
template as an irreversible complex;
Incorporation into the viral DNA → chain
termination

24. Resistance
HSV or VZV alteration in either the viral thymidine
kinase or the DNA polymerase → resistance
Cross-resistance to valacyclovir, famciclovir, and
ganciclovir.
Agents such as foscarnet, cidofovir, and
trifluridinedo not require activation by viral
thymidine kinase and thus have preserved activity
against the most prevalent acyclovir-resistant strains.

25. Pharmacokinetics
Available in oral, intravenous, and topical
formulations.
Oral bioavailability is 15-20%.
Plasma protein binding is low, diffuses into most
tissues and body fluids.
Cleared primarily by glomerular filtration and
tubular secretion.

26. Clinical uses
• Treatment of HSV infection —— first selection
• Topical acyclovir is much less effective than oral
therapy for primary HSV infection. It is of no
benefit in treating recurrences.
• VZV is less susceptible to acyclovir than HSV, high
doses are required.
Adverse reactions
• Nausea, diarrhea, headache
• Intravenous infusion → renal insufficiency or
neurologic toxicity

27. The L-valyl ester of acyclovir
It is rapidly converted to acyclovir after oral
administration, achieving serum levels three to five
times greater than those achieved with oral acyclovir.

28. Adenosine analog
Against HSV, VZV, CMV, HBV and some RNA
viruses.
Phosporylated intracellular by host enzymes to form
ara-ATP, incorporated into both viral and cellular
DNA. → excessive toxicity
Rapidly metabolized to hypoxanthine arabinoside.
Instability and toxicity limited its clinical utility.

29. Topical application for acute keratoconjunctivitis,
superficial keratitis, and recurrent epithelial keratitis
due to HSV-1 and HSV-2.
Intravenous for treatment of HSV encephalitis,
neonatal herpes, and VZV infection in
immunocompromised patients

30. Competitive inhibition of thymidylic acid synthase →
block DNA synthesis.
No effect on RNA virus.
Only topical application because of its greater side
effects in systemic application.
Treatment of ocular or dermal infections due to herpes
virus or cowpox virus, especially acute epithelial
keratitis due to herpes virus

31. Cytosine analog
Against HIV-1, synergistic with a variety of antiretroviral
nucleoside analogs, including zidovudine and stavudine.
Treatment of chronic hepatitis B infection.
Oral bioavailability exceeds 80% and is not food-
dependent.
The majority of lamivudine is eliminated unchanged in the
urine.

32. Including:
Rimantadine and Amantadine
Foscarnet

33. Rimantadine is Amantadine’s α–methyl derivative.
Cyclic amines.
Inhibit uncoating of the viral RNA of influenza A within
infected host cells.
Prevention of influenza A virus infection. Reduce the
duration of symptoms of influenza when administered
within 48h of onset.
Adverse effects: gastrointestinal intolerance, central
nervous system complaints (nervous, difficulty in
concentrating, lightheadedness)

34. An inorganic pyrophosphate compound.
Inhibit viral DNA polymerase, RNA polymerase, and
HIV reverse transcriptase directly, without activation
by phosphorylation.
Against HSV, VZV, CMV, EBV, HHV-6, HHV-8, and
HIV.

35. Poor oral bioavailability. Only intravenous
administration.
CMV retinitis and acyclovir-resistant HSV infection.

36. Interferon
 a group of endogenous proteins that exert complex
antiviral, immunoregulatory, and ant proliferative
activities through cellular metabolic processes
involving synthesis of both RNA and protein.
Although not specifically antiviral, they appear to
function by causing elaboration of effectors proteins
in infected cells, resulting in inhibition of viral
penetration and uncoating, mRNA synthesis and
translating, or virion assembly and release.

38.  Classified on the basis of the cell types from which
they were derived:
 Interferon α（type Ⅰ）：leukocyte
 Interferon β（type Ⅰ）：fibroblast
 Interferon γ（type Ⅱ）：immune cell

39.  Three known enzymes are induced by interferon:
 A protein kinase that leads to phosphorylation of
elongation factor 2, resulting in inhibition of
peptide chain initiation;
 Oligoisoadenylate synthase , which leads to
activation of a ribonuclease (RNA) and
degradation of viral mRNA;
 A phosphodiesterase that can degrade the
terminal nucleotides of tRNA, inhibiting peptide
elongation.

40. Treatment of chronic hepatitis C, AIDS-associated
Kaposi’s sarcoma, hairy cell leukemia, and chronic
myelogenous leukemia , malignant melanoma ,
condylomata acuminata , relapsing multiple sclerosis .
Toxicities: neutropenia, anemia, thrombocytopenia,
elevated aminotransferase levels, flu-like symptoms
(including fever, chills, headache, myalgias, fatigue)

42. NOW TOPIC IS OPEN FOR
DISCUSSION