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Viruses are obligate intracellular parasites. They lack a cell wall and a cell membrane Do not carry out metabolic processes and uses the host’s metabolic machinery for reproduction, therefore antiviral drugs are capable of injury to the host. Symptoms of viral illness appear late in the course of the disease when most of the virus particles have replicated. At this stage, administration of antiviral drugs have limited effectiveness though some are used as prophylaxis Viral Structure Contains DNA or RNA Virus attaches to surface of host cell Host cell’s proteolytic enzymes break down envelope. Virus takes control of host cell’s molecular synthesizing capability to begin making new viral enzymes and proteins. Making new viruses New viruses are released either by exocytosis or lysis of host cell. Drugs for respiratory virus infections Drugs for hepatic viral infections Drugs for herpes and CMV infections Drugs for HIV infections For influenza A and B Respiratory syncytial virus Antiviral drugs are used against influenza A for those allergic to the vaccine, or when the outbreak is due to a variant of the virus not covered by the vaccine or when the outbreak occurs among unvaccinated individuals at risk who are in closed settings oseltamivir, zanamavir are sialic acid analogs MOA : inhibits neuraminidase, thereby inhibiting the release of new virions and their spread from cell to cell Spectrum : Influenza A & B—prior to exposure-good Route : Oral(oseltamivir), inhalation/intranasal(zanamivr) Excretion : renal SE : GI disturbance(not zanamivir), ataxia, dizziness CI : preg, lactating, zanamavir --asthmatics Due to mutations of the neuraminidase Amantadine, rimantadine—adamantine derivatives Used in the treatment of influenza A infections MOA: Block viral membrane matrix protein, M2 preventing viral uncoating. Both absorbed well orally Amantadine crosses bbb. Can cause insomnia, dizziness, hallucinations and seizures. Rimantadine does not efficiently cross the BBB, so fewer CNS effects Resistance: change in an amino acid in the M2 protein Other uses: Amantadine is used in the treatment of Parkinson disease. CI: pregnant, lactating patients, cerebral atherosclerosis, renal impairment, epilepsy MECH : synthetic Guanosine analog converted to its triphosphate derivate →inhibition of viral RNA polymerase and mRNA capping. ROUTE – ORAL / IV, AEROSOL EXCRETION : RENAL SE: ANEMIA CI : Preg USES : CHILD RSV INFECTIONS, can also be used for Hepatitis C, Influenza A & B, Lassa fever HEPATITIS VIRUSES THUS FAR IDENTIFIED A,B,C,D and E. HEP B & C ARE MOST COMMON—chronic hepatitis, cirrhosis and hepatocellular ca. Chronic hep B is treated with interferon alfa plus lamivudine Chronic hep C responds to interferon alfa plus ribavarin. MECH : induces host cell enzymes that INHIBIT VIRAL RNA TRANSLATION→ degradation of viral mRNA and tRNA ALPHA INTERFERON (α-INTERFERON) IS USED FOR HEPATITIS B AND C PAPILLOMA VIRUS KAPOSI’S SARCOMA HAIRY CELL LEUKEMIA SE : BONE MARROW, neurotoxicity, HYPERSENSITIVITY, flu-like symptoms (fever, chills, myalgias, arthralgias) INTERFERON β: Treatment of multiple sclerosis INTERFERON γ: Treatment of chronic granulomatous disease Lamivudine— a cytosine analog Converted to its triphosphate derivative inhibitor of HBV & HIV-reverse transcriptase Competitively inhibits HBV Dna polymerase Well absorbed orally T1/2 ---9 hrs Adefovir Nucleotide analog phosphorylated to its diphosphate derivative and then incorporated into viral DNA—termination of DNA synthesis ACYCLOVIR, a guanosine analog MECH : phosphorylated by bacteria thymidine kinase then host cell kinase to its triphosphate derivative which competes with deoxyguanosine triphosphate as a substrate for VIRAL DNA POLYMERASE → incorporation into the viral DNA causing premature chain termination SPECTUM:HSV 1, HSV 2, V-Z , EBV SPECIFIC – HSV USES : DOC – HS ENCEPHALITIS COMMON : GENITAL HERPES RESISTANT : CMV Oral, I.V., topical,, crosses BBB Exe: Renal SE: Headache, vomiting, diarrhea and also renal dysfunction. GANCICLOVIR, an analog of acyclovir (IV) MOA: Converted to triphosphate derivative by another route cos CMV lacks thymidine kinase SPECTRUM : CMV USE : CMV RETINITIS SE: NEUTROPENIA CI: Pregnancy FAMCICLOVIR (oral) , penciclovir (topically) famciclovir : ACUTE HERPES ZOSTER Pencicovir:HSV-1, HSV-2 and VZV MOA: triple phosphorylation →incorporation into viral DNA causing premature chain termination →inhibition of viral DNA polymerase CIDOFOVIR, analog of cytosine MOA: triple phosphorylation not dependent on viral thymidine kinase → inhibition of viral DNA synthesis CMV – Retinitis in HIV/AIDS patients I.V route SE: Nephrotoxic, Neutropenia, Metabolic acidosis VIDARABINE (IV, TOPICAL) IMMUNO COMPROMISED PATIENTS WITH HS KERATITIS, ENCEPHALITIS, VZV TRIFLURIDINE, IDOXURIDINE TOPICAL – HS KERATO CONJUCTIVITIS FOSCARNET(IV) – not purine or pyrimidine analog MOA: INHIBIT VIRAL RNA & DNA POLYMERASES→termination of chain elongation FOR CMV retinitis in immunocompromised host Acyclovir RESISTANT HSV and VZV infections. SE : NEPHROTOXICITY,ANEMIA, ELECTROLYTE IMBALANCE( hypokalemia, hypocalcemia, hypomagnesemia, hypo and hyper phosphatemia) Life Cycle of HIV 1. attachment: Virus binds to surface molecule (CD4) of T helper cells and macrophages. Coreceptors: Required for HIV infection. CXCR4 and CCR5 mutants are resistant to infection. 2. fusion: Viral envelope fuses with host cell membrane, 3. Penetration and uncoating: penetrates host cell releasing contents into the cell. Life Cycle of HIV 4. Reverse Transcription: Viral RNA is converted into DNA by unique enzyme reverse transcriptase. Reverse transcriptase RNA ---------------------> DNA Reverse transcriptase is the target of several HIV drugs: AZT, ddI, and ddC. Life Cycle of HIV 5. Integration: Viral DNA is inserted into host cell chromosome by unique enzyme integrase. Integrated viral DNA may remain latent for years and is called a provirus. 6. Replication: Viral DNA is transcribed and RNA is translated, making viral proteins. Viral genome is replicated. 7. Release: New virus RNA and precursor polyprotein bud through the cell membrane. 8. Assembly & maturation: virion protease is activated and cleaves the precursor polyprotein into component protein(attachment protein & fusion protein) which then assemble into the mature virion.New viruses are made. Transmission of AIDS (Worldwide) 1. Sexual contact with infected individual: All forms of sexual intercourse (homosexual and heterosexual). 75% of transmission. 2. Sharing of unsterilized needles by intravenous drug users and unsafe medical practices: 5-10% of transmission. 3. Transfusions and Blood Products: Hemophiliac population was decimated in 1980s. Risk is low today. 3-5% of transmission. 4. Mother to Infant (Perinatal): 25% of children become infected in utero, during delivery, or by breast-feeding (with AZT only 3%). 5-10% of transmission. AIDS Associated Disease Categories 1. Gastrointestinal: Cause most of illness and death of late AIDS. Symptoms: Diarrhea Wasting (extreme weight loss) Abdominal pain Infections of the mouth and esophagus. Pathogens: Candida albicans, cytomegalovirus, Microsporidia, and Cryptosporidia. AIDS Associated Disease Categories 2. Respiratory: 70% of AIDS patients develop serious respiratory problems. Partial list of respiratory problems associated with AIDS: Bronchitis Pneumonia Tuberculosis Lung cancer Sinusitis Pneumonitis AIDS Associated Disease Categories 3. Neurological: Opportunistic diseases and tumors of central nervous system. Symptoms may include: Headaches, peripheral nerve problems, and AIDS dementia complex (Memory loss, motor problems, difficulty concentration, and paralysis). AIDS Associated Disease Categories 4. Skin Disorders: 90% of AIDS patients develop skin or mucous membrane disorders. Kaposi’s sarcoma 1/3 male AIDS patients develop KS Most common type of cancer in AIDS patients Herpes zoster (shingles) Herpes simplex Thrush Invasive cervical carcinoma 5. Eye Infections: 50-75% patients develop eye conditions. CMV retinitis Conjunctivitis Dry eye syndrome Uses combination of drugs to suppress replication of HIV and restore a degree of immunocompetency to the host The multidrug regimen is commonly referred to as “highly active antiretroviral therapy” or HAART There are three classes of antiretroviral drugs, each of which targets one of two viral processes (reverse transcriptase, protease) Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Protease inhibitors (PIs) Current recommendation: 2NRTIs plus either a PI or a NNRTI. Reason for multidrug therapy: maximize the inhibition of viral replication and minimize drug toxicities Drugs Against HIV Reverse Transcriptase Inhibitors: Competitive enzyme inhibitors. Example: AZT, ddI, ddC. Protease Inhibitors: Inhibit the viral proteases. Prevent viral maturation. Problem with individual drug treatments: Resistance. Are nucleosides or nucleotides containing ribose which all lack a 3′-hydroxyl group. Once they enter cells, they are converted to corresponding triphosphate analog by mammalian thymidine kinase which is incorporated into the viral DNA by virus reverse transcriptase and DNA chain elongation is terminated. ZIDOVUDINE / AZT ( Thymidine analog) Approved for use in children and adults and to prevent prenatal infection in pregnancy. It is also used as prophylaxis in individuals exposed to HIV infection ORAL ABSORPTION Pharmacokinetics: AZT is glucuronylated by the liver Excretion: kidney in urine SE : BONE MARROW toxicity, HEADACHE , SEIZURES Toxicity is potentiated if glucuronylation is decreased by co-administration of drugs probenecid, indomethacine, cimetidine, lorazepam DIDANOSINE ( Adenosine) : RESISTANT HIV SE : PANCREATITIS, PERIPHERAL NEUROPATHY ZALCITABINE ( Cytosine): - SE-PERIPHERAL NEUROPATHY OTHER DRUGS: STAVUDINE (Thymidine), LAMIVUDINE (Cytosine) also used for Hep - B - NEVIRAPINE DELAVIRDINE EFAVIRENZ MOA: are selective noncompetitive inhibitors of HIV-1 reverse transcriptase - They do not require activation to triphosphate derivatives by cellular enzymes - Advantage: their lack of effect on host blood forming cells Used for treatment HIV-1 infections in adults and children Effective in reducing vertical transmission during pregnancy and may be used as a substitute for AZT for this purpose Oral route Renal exe. SE: Rash, fever, Stevens – Johnson Syndrome and Toxic epidermal necrolysis, elevated serum transaminases, Fatal heptotoxicity. DELAVIRDINE Oral route Bile and renal exe. SE: nausea, rash, dizziness EFAVIRENZ Good increase in CD4+ count, decreases viral load SE: Mostly CNS effects, vivid dreams SAQUINAVIR RITONAVIR INDINAVIR: NELFINAVIR AMPRENAVIR MOA: inhibit viral protease preventing the formation of new mature virions SE; Important are lipodystrophy & hyperglycemia, hypertriacylglycerolemia, fat redistribution including loss of fat from the extremities and its accum in the abdomen and the base of the neck “buffalo hump”(indanavir) & breast enlargement, nephrolithiasis & hyperbilirubinemia (indanavir) CI : with many drugs Antiarrhythmic’s Antihistamines Ergot derivatives Antimycobacterial drugs Benzodiazepines GI drugs such as cisapride VIRAL FUSION INHIBITOR ENFUVIRTIDE new class of anti retroviral drug in order to gain entry into the host cell it must fuse its membrane with that of host cell. This is accomplished by changes in the conformation of viral transmembrane glycoprotein gp41. Enfuvirtide binds to gp41 preventing the conformational change. Given subcutaneously.