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ANTIVIRAL DRUGS I-II Dr. Mohammed Samir Hussein BCs of Pharmaceutical Science MD of Clinical Pharmacology
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VIRUSES Viruses are primitive entities, not quite proper living things. Consisting of a genome (RNA or DNA ), a few enzymes (biocatalysts) stored in a capsule made of protein, and sometimes covered with a lipid (fat) layer. Viruses cannot reproduce on their own, and so they propagate by hijacking cells to do the job for them, they use the metabolic process of the host cell.
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VIRUSES
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ANTIVIRALS FOR Herpes simplex viruses (HSV) AND Varicella zoster virus (VZV) Converted in vivo into triphosphate form (thymidine kinase and cellular kinase) which interferes with viral DNA polymerase and inhibits viral DNA replication. It is incorporated into DNA and leads chain termination (termination of replication). 1- Acyclovir Mechanism of Action
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ANTIVIRALS FOR HSV AND VZV Herpes simplex infection. Herpes genitals infection. Neonatal herpetic dissemination. Prophylactically before bone marrow transplants. After heart transplants to prevent dissemination of herpes from existing lesion. 1- Acyclovir CLINICAL USES Topical Applications: Local discomfort, Oral therapy: Nausea, vomiting, diarrhea, headache I/V therapy : Thrombophlebitis, rash, nephrotoxicity ADVERSE EFFECTS
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ANTIVIRALS FOR HSV AND VZV Genital herpes Orolabial herpes Orolabials & Genital herpes in immunodeficient H. Zoster infection 2- Valacyclovir & Famciclovir CLINICAL USES (ORALLY) Ester of acyclovir, rapidly converted to acyclovir after oral administration, resulting in 3 to 4 times greater serum levels than oral acyclovir. 3- Foscarnet for acyclovir-resistant HSV & VZV 4- Docosanol for Orolabials Herpes 5- Penciclovir for recurrent herpes labialis 6- Trifluridine for herpes keratitis (eye herpes) & Acyclovir resistant HSV infection
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ANTIVIRALS FOR Cytomegalovirus (CMV) Similar to Acyclovir Gancyclovir MECHANISM OF ACTION Cytomegalovirus Varicella zoster virus Epstein-Barr virus (human herpesvirus 4) CLINICAL USES Myelosuppression (bone marrow suppression) if given I/V Nausea, diarrhea, fever, rash, headache, insomnia, p. neuropathy retinal detachment, CNS toxicity Resistance may develop ADVERSE EFFECTS
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ANTI HEPATITIS AGENTS Produce cellular enzymes that subsequently block viral reproduction by inhibiting the viral penetration, translation transcription, protein processing, maturation and release. Increase major histocompatibility complex antigens. Enhance phagocytic activity of macrophages, and increase survival of T cells. Interferon MECHANISM OF ACTION
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Herpes zoster infection in patients with lymphoma Neoplastic disease Viremia with hepatitis B virus & hepatitis C virus Interferon CLINICAL USES Flu like syndrome: during first week of therapy and resolved after continuous use Transient hepatic enzyme elevations Neurotoxicity Myelosuppression Alopecia Weight loss ,fatigue , myalgia Retinopathy, pneumonitis, and possibly cardiotoxicity ADVERSE EFFECTS ANTI HEPATITIS AGENTS
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Hepatic decompensation. Autoimmune disease. Cardiac arrhythmia. Caution is advised. Psychiatric disease, epilepsy, thyroid disease, ischemic cardiac disease, severe renal insufficiency,& cytopenia. Drug -Drug interaction :Increase levels of theophylline, and methadone. Interferon CONTRAINDICATIONS ANTI HEPATITIS AGENTS
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TREATMENT OF HEPATITIS B VIRUS Current therapies suppress HBV replication rather than eradication Following nucleoside reverse transcriptase inhibitors NRTIs are very potent Emtricitabine Lamivudine Tenofovir MOA: It inhibit HBV DNA polymerase & reverse transcriptase & cause chain termination. USES: Chronic therapy in hepatitis patient may be limited due to lamivudine resistant HBV , resistant associated with hepatitis & liver disease. SAFTEY: It has excellent safety profile and some of its rare adverse effects are headache, nausea, and dizziness. Lamivudine
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TREATMENT OF HEPATITIS C VIRUS Primary goal is viral eradication. Efficacy end point is achievement of sustained viral response (SVR) i.e. absence of detectable viremia for 6 months after completion of therapy. MOA: It may interfere with the formation of viral messenger RNA and may inhibit viral RNA polymerase It may act by interfering with guanidine monophosphate formation and subsequent nucleic acid synthesis. USES: Herpes simplex infection, Influenza A and B, and Hepatitis C. Ribavirin
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TREATMENT OF HEPATITIS C VIRUS ADVERSE EFFECTS: Depression, fatigue, irritability, insomnia Cough, Nausea Pruritis Rash CONTRAINDICATIONS: End stage renal failure, ischemic heart disease, & pregnancy Ribavirin
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ANTI INFLUENZA AGENTS Amantadine – Rimantadine – Zanamivir - Oseltamivir Cyclic amines that block the M2 proton ion channel of the virus particle and inhibit uncoating of the viral RNA within infected host cells, thus preventing its replication They are active against influenza A only. Rimantadine is four to ten times more active than amantadine It inhibits the penetration of cells or the uncoating of certain Myxoviruses e.g. Influenza A, rubella and some tumor viruses. Amantadine and Rimantadine MECHANISM OF ACTION:-
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ANTI INFLUENZA AGENTS For prophylaxis during influenza A virus Parkinson’s disease ( potentiates the dopaminergic function) CLINICAL USES CNS: Restlessness, depression, irritability, insomnia, agitation, excitement, hallucinations, confusion, headache. Note: These effects occur as the drug causes release of stored catecholamine. CVS: Congestive heart disease, postural hypotension, peripheral edema. GIT: Dry mouth, anorexia, nausea, constipation. Renal Urinary retention. ADVERSE EFFECTS Amantadine and Rimantadine
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ANTI INFLUENZA AGENTS Interfere with release of progeny influenza virus from infected to new host cells, thus slowing the spread of infection within the respiratory tract. Zanamivir and Oseltamivir MECHANISM OF ACTION:- Activity against both influenza A and influenza B viruses. Zanamivir is delivered directly to the respiratory tract via inhalation. Oseltamivir is an orally administered prodrug that is activated by hepatic esterases. CLINICAL USES
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ANTI INFLUENZA AGENTS Side effects include cough, bronchospasm (occasionally severe), reversible decrease in pulmonary function, and transient nasal and throat discomfort. ADVERSE EFFECTS Zanamivir and Oseltamivir
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ANTIVIRAL DRUGS USED IN AIDS PATIENTS human immunodeficiency viruses (HIV) life cycle
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ANTIVIRAL DRUGS USED IN AIDS PATIENTS Goals of HIV therapy
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ANTIVIRAL DRUGS USED IN AIDS PATIENTS Selection of combination of regimes
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ANTIVIRAL DRUGS USED IN AIDS PATIENTS Classification of Anti-Retrovial drugs (Anti-HIV drugs)
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NRTIs Mechanism of action: Once they enter cells, they are phosphorylated by a variety of cellular enzymes to the corresponding triphosphate analog, which is preferentially incorporated into the viral DNA by virus reverse transcriptase → viral DNA is incomplete
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NRTIs Renally excreted Require dose adjustment in renal disease (Except Abacavir) Due to inhibition of the mitochondrial DNA polymerase in certain tissues, Zalcitabine, Didanosine, and Stavudine, have a greater affinity for the mitochondrial DNA polymerase, leading to such toxicities as peripheral neuropathy, pancreatitis, and lipoatrophy. All the NRTIs have been associated with a potentially fatal liver toxicity characterized by lactic acidosis and hepatomegaly with steatosis. . Pharmacokinetics: Adverse Effects:
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NRTIs The first agent available for treatment of HIV infection is the pyrimidine Zidovudine. AZT is approved for use in children and adults and to prevent prenatal infection in Pregnancy. It is also recommended for prophylaxis in individuals exposed to HIV infection. Well absorbed orally and its penetration across the blood-brain barrier is excellent. Glucuronylated by the liver and then excreted in the urine. AZT is toxic to bone marrow. Headaches are also common. Zidovudine
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NRTIs The second drug approved to treat HIV-1 infection was Didanosine. Like AZT, the resulting ddATP is incorporated into the DNA chain, causing termination of chain elongation. Pancreatitis, which may be fatal is a major toxicity . Dose-limiting toxicity is peripheral Neuropathy. Didanosine Derivative of lamivudine, inhibits HIV & HBV reverse transcriptase does not affect cytochrome P450 isozymes, no drug interactions . Emtricitabine causes hyperpigmentation of the soles and palms, and it has been associated with lactic acidosis, fatty liver, and hepatomegaly. Withdrawal of emtricitabine in HBV-infected patients may result in worsening of the hepatitis. Emtricitabine
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NNRTIs Mechanism of action: Highly selective, noncompetitive inhibitors of HIV-1 reverse transcriptase Bind to HIV reverse transcriptase at a site adjacent to the active site, inducing a conformational change that results in enzyme inhibition Major advantage is their lack of effect on the host blood-forming elements and their lack of cross-resistance with NRTIs
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Used in combination with other antiretroviral drugs for the treatment of HIV-1 infections in adults and children lipophilic nature of nevirapine accounts for its entrance into the fetus and for its wide tissue distribution, including the CNS Nevirapine Results in increases in CD4+ cell counts and a decrease in viral load. Potent inducer of cytochrome P450 Most adverse effects are tolerable and are associated with the CNS, including dizziness, headache, vivid dreams, and loss of concentration Rash is the other most common side effect Efavirenz NNRTIs
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PROTEASE INHIBITORS Mechanism of action: Inhibitors of HIV protease have significantly altered the course of this devastating viral disease All the drugs in this group are reversible inhibitors of the HIV protease Exhibit at least a thousand-fold greater affinity for HIV-1 and HIV-2 enzymes than they have for comparable human proteases
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PROTEASE INHIBITORS Pharmacokinetics: Poor oral bioavailability. All are substrates for the CYP3A4 isozyme of cytochrome P450. Distribution into some tissues may be affected by the fact that the protease inhibitors are substrates for the P-glycoprotein multidrug efflux pump. The presence of this pump in endothelial cells of capillaries in the brain may limit protease inhibitor access to the CNS. The HIV protease inhibitors are all substantially bound to plasma proteins, specifically acid glycoprotein. This may be clinically important because the concentration of acid glycoprotein increases in response to trauma and surgery.
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PROTEASE INHIBITORS Adverse Effects: Protease inhibitors commonly cause paresthesias, nausea, vomiting, and diarrhea. Can cause diabetes, hypertriglyceridemia and hypercholesterolemia. Chronic administration results in fat redistribution, including loss of fat from the extremities and its accumulation in the abdomen and the base of the neck. Drug Interactions: Drug interactions are a common problem for all protease inhibitors. Because they are not only substrates but also potent inhibitors of CYP isozymes. Examples of potentially dangerous interactions from drugs that are contraindicated with protease inhibitors include rhabdomyolysis from simvastatin or lovastatin, excessive sedation from midazolam.
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PROTEASE INHIBITORS Is used as a enhancer or booster of other protease inhibitors. Ritonavir is a potent inhibitor of CYP3A, and at low doses increases the bioavailability of the second protease inhibitor. Retonavir Acidic gastric conditions are necessary for absorption. Indinavir causes nephrolithiasis and hyperbilirubinemia. Adequate hydration is important to reduce the incidence of kidney stone formation, and patients should drink at least 1.5 L of water per day. Fat redistribution is particularly troublesome with this drug. Indinavir A prodrug that is metabolized to amprenavir following oral absorption. Fosamprenavir boosted with ritonavir is one of the preferred protease inhibitors. Fosamprenavir
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PROTEASE INHIBITORS All PI agents, with the possible exception of amprenavir, carry the risk of: hyperlipidemia, fat maldistribution, hyperglycemia, and insulin resistance as a potential adverse event. Common Adverse Effects of PIs
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First of new class of antiretroviral drugs known as entry inhibitors. Enfuvirtide is a fusion inhibitor. Common adverse effects are pain, erythema, induration, and nodules. Enfuvirtide - Maraviroc ENTRY INHIBITORS/FUSION INHIBITOR Enfuvirtide
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First of new class of antiretroviral drugs known as integrase inhibitors. Inhibits the final step in integration of strand transfer of the viral DNA into our own host cell DNA. Well-tolerated with nausea, headache and diarrhea as the most common side effects. INTEGRASE INHIBITORS Raltegravir
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THANK YOU FOR YOUR ATTENTION