pharmacology of antiretrovirals
TRANSCRIPT
Dhananjay D.
Student,
Department of Microbiology
N. A. C. & Sc. College, A. Nagar.
Step 1: Fusion
Step 2: Transcription
reverse
transcriptase
Step 3:
Integration
Step 4: Cleavage
Step 5: Packaging
and Budding
HIV
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
pathway:
Viral
RNA
double helix
DNA
Incorporated
into host
genome
reverse
transcriptaseHIV integrase
transcription
translation
Polyproteins
Final
structural
proteins
HIV protease
Drugs
NRTIsNNRTIs
PIs
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.
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.
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
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.
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.
Adverse effects:
Dose-limiting toxicity is a dose-related peripheralsensory neuropathy.
Pancreatitis, arthralgia's, elevation in serumaminotransferases.
Synthetic analog of deoxyadenosine
Plasma protein binding is low (<5%), cerebrospinalfluid concentrations are 20% of serum concentrations.
Eliminated by glomerular filtration and tubularsecretion.
Should be taken on an empty stomach.
Anti-HIV activity of ddI is potentiated byhydroxyurea due to a depletion of intracellular poolsof dATP, so two agents is administered incombination.
Adverse effects:
Dose-dependent pancreatitis
Painful peripheral distal neuropathy
Diarrhea
Hepatitis
Esophageal ulceration.
Cardiomyopathy
Central nervous system toxicity (headache, irritability,insomnia)
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.
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
Including ritonavir, nelfinavir, saquinavir, indinavir
and amprenavir.
Gag and Gag-Pol
gene
Polyproteins,
Immature budding particles
translate
Final structural proteins,
Mature virioncore
protease
Combination therapy with other agents isrecommended to avoid emergence of resistance,because of specific genotypic alterations.
Adverse effect:
Syndrome of altered body fat distribution (buffalohump and truncal obesity, with facial and peripheralatrophy)
Insulin resistance
Hyperlipidemia.
Including:Nucleoside antiviral agentsNonnucleoside antiviral agentsImmune enhancement agent
Mechanism of action:Compete the receptors, e.g.: Heparin,
PolysaccharideBlock viral adsorption to and penetration into host
cells and uncoating of viral nucleic acid, e.g.:amantadineBlock viral biosynthesis, e.g.: idoxuridineEnhance the host immune activity, e.g.: interferon
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
An acyclic guanosine derivative
Pharmacological effects:
Against HSV-1 and HSV-2 and against varicella-
zoster virus, Epstein-Barr virus and cytomegalovirus.
Mechanism:
Three phosphorylation steps for activation.
First converted to the monophosphate derivativeby the virus-specified thymidine kinase;(selective activation)
Then to the di- and triphosphate compounds byhost’s cellular enzymes.
Acyclovir triphosphate inhibits viral DNA synthesisby two mechanisms:
Competitive inhibition of deoxyGTP for the viralDNA polymerase, with binding to the DNAtemplate as an irreversible complex;
Incorporation into the viral DNA → chaintermination
Resistance
HSV or VZV alteration in either the viral thymidinekinase or the DNA polymerase → resistance
Cross-resistance to valacyclovir, famciclovir, andganciclovir.
Agents such as foscarnet, cidofovir, andtrifluridinedo not require activation by viralthymidine kinase and thus have preserved activityagainst the most prevalent acyclovir-resistant strains.
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.
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
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.
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.
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
Competitive inhibition of thymidylic acid synthase →block DNA synthesis.
No effect on RNA virus.
Only topical application because of its greater sideeffects in systemic application.
Treatment of ocular or dermal infections due to herpesvirus or cowpox virus, especially acute epithelialkeratitis due to herpes virus
Cytosine analog
Against HIV-1, synergistic with a variety of antiretroviralnucleoside 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 theurine.
Rimantadine is Amantadine’s α–methyl derivative.
Cyclic amines.
Inhibit uncoating of the viral RNA of influenza A withininfected host cells.
Prevention of influenza A virus infection. Reduce theduration of symptoms of influenza when administeredwithin 48h of onset.
Adverse effects: gastrointestinal intolerance, centralnervous system complaints (nervous, difficulty inconcentrating, lightheadedness)
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.
Poor oral bioavailability. Only intravenous
administration.
CMV retinitis and acyclovir-resistant HSV infection.
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.
Classified on the basis of the cell types from which
they were derived:
Interferon α(typeⅠ):leukocyte
Interferon β(typeⅠ):fibroblast
Interferon γ(typeⅡ):immune cell
Three known enzymes are induced by interferon:
A protein kinase that leads to phosphorylation ofelongation factor 2, resulting in inhibition ofpeptide chain initiation;
Oligoisoadenylate synthase , which leads toactivation of a ribonuclease (RNA) anddegradation of viral mRNA;
A phosphodiesterase that can degrade theterminal nucleotides of tRNA, inhibiting peptideelongation.
Treatment of chronic hepatitis C, AIDS-associatedKaposi’s sarcoma, hairy cell leukemia, and chronicmyelogenous leukemia , malignant melanoma ,condylomata acuminata , relapsing multiple sclerosis .
Toxicities: neutropenia, anemia, thrombocytopenia,elevated aminotransferase levels, flu-like symptoms(including fever, chills, headache, myalgias, fatigue)