Pharmacology of antiretrovirals

Dhananjay D.

Student,

Department of Microbiology

N. A. C. & Sc. College, A. Nagar.

[email protected]

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

Derivatives of Pyrimidine: AZT, ddC, d4T,

3TC

Derivatives of Purine: ddI, ABC

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.

Including:

Rimantadine and Amantadine

Foscarnet

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)

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