Viruses

Viruses

1. ANTIVIRAL DRUGS

   • Key characteristics
     • ability to enter the cells infected with virus
     • interfere with viral nucleic acid synthesis/regulation
     • interfere with ability of virus to bind to cells
     • stimulate body’s immune system
   • Classification
     • type of infection they target
       • HIV infection
         • HIV life cycle
         • HAART
           • highly active antiretroviral therapy
             • multidrug regimen to suppress replication of HIV and restore the number of CD4+ cells and immunocompetence to the host
         • Classification of antiretroviral drugs
           • Entry/ fusion inhibitors
             • Enfuvirtide
               • Enfuvirtide binds to gp 41, prevents its conformational change, and inhibits fusion of HIV-1 to CD4+ cells
               • Fu - Fusion
             • Maraviroc
               • blocks CCR5 co-receptor on T-cell surface to prevent viral entry
                 • against HIV that uses the CCR5 co-receptor exclusively
               • metabolized in the liver by CYP450 enzymes.
           • Reverse transcriptase inhibitors
             • Nucleoside reverse transcriptase inhibitors (NRTI’s)
               • Zidovudine
                 • pyrimidine analog, 3'-azido- 3'-deoxythymidine (AZT).
                 • used in children and adults
                   • to prevent prenatal infection in pregnancy.
                 • orally
                   • Penetration across BBB is excellent
                   • with food total amount absorbed is not affected
                 • toxicity
                   • myelosuppression
                   • Headaches
               • abacavir
                 • guanosine analog
                 • well absorbed orally
                   • metabolized by non-CYP450-dependent reactions (alcohol dehydrogenase and glucuronyl transferase)
                     • renal excretion
                 • AE
                   • fatigue
                   • GI distrubtion
                   • fever
                   • fatal skin rash
               • Lamivudine
                 • Cytidine analogue
                 • Inhibits both HIV and Hepatitis B virus
               • Stavudine
               • analogs of native ribosides (nucleosides or nucleotides), which all lack a 3′-hydroxyl group.
                 • Once they enter cells, they are phosphorylated by cellular enzymes to the corresponding triphosphate analog, which is preferentially incorporated into the viral DNA by reverse transcriptase (RT).
                   • Affinities of the drugs host cell DNA polymerases are low, although mitochondrial DNA polymerase γ appears to be susceptible at therapeutic concentrations. (cause myelosuppression)
               • AE
                 • Lactic acidosis
                 • Hepatosteatosis
                 • lipodystrophy
               • resistance
                 • mutation at viral codon 184 (common)
                 • cross-resistance and antagonism occur between agents of the same analog class
                   • zidovudine plus stavudine- both are thymidine analogs
               • Drug interactions
                 • Due to the renal excretion of the NRTls, there are not many drug interactions encountered with these agents
             • Nonnucleoside reverse transcriptase inhibitors (NNRTI’s)
               • First generation
                 • Nevirapine
                   • well absorbed orally
                     • Due to its lipophilicity, it passes into the fetus and mother's milk and CNS
                       • pregnancy category B
                   • severe hepatotoxicity
                 • Efavirenz
                   • potent inducer of CYP450 enzymes and, therefore, may reduce the concentrations of drugs that are substrates of the CYP450
                   • AE
                     • Effects on CNS: dizziness, headache
                     • Rash
                     • should be avoided in pregnancy
               • Second generation
                 • Etavirine
                   • adv on 1st generation: do not have CNS adverse effects that occur with efavirenz.
                   • potent inducer of CYP450
                   • oral administration
                     • well distributed
                       • bioavailability is enhanced when taken with a high-fat meal
                       • extensively metabolized to inactive products
                   • HIV treatment-experienced, multidrug-resistant adult patients who have evidence of ongoing viral replication
                   • AE
                     • Rash
               • They do not require activation by cellular enzymes
               • Inhibit reverse transcriptase at a site different from the one NRTIs bind to. They cause conformational change that results in enzyme inhibition.
                 • Additive or synergistic if used in combination with NRTIs and / or protease inhibitors
               • major advantage is lacking the effect on blood cells and no cross-resistance with NRTls
           • Integrase inhibitors
             • Raltegravir
               • It inhibits the final step in integration of strand transfer of the viral DNA into the own host cell DNA
               • NO drug interactions with CYP450 inducers, inhibitors, or substrates
               • AE
                 • elevated CK with muscle pain
                 • rhabdomyolysis
                 • possible depression with suicidal ideation
           • protease inhibitors
             • most effective drugs available
             • All inhibit cytochrome P450 – dosage is a challenge
             • Resistance problem
               • mutations of the protease gene.
             • Never used alone – always with 2 other drugs (NNRTI or NRTI)
             • Saquinavir
             • Indinavir
             • Nelfinavir
             • Ritonavir
               • is no longer used as a single protease inhibitor but, instead, is used as a pharmacokinetic enhancer or "booster" of other protease inhibitors
                 • potent inhibitor of CYP3A
                 • administration (at low doses) increases the bioavailability of the second protease inhibitor, often allowing for longer dosing intervals
                 • helps to prevent the development of resistance
             • reversible inhibition of the HIV aspartyl protease, which is the viral enzyme responsible for cleavage of the viral polyprotein into a number of essential enzymes and several structural proteins
               • This prevents viral maturation and results in the production of noninfectious virions.
             • poor oral bioavailability.
               • extensively metabolized by the CYP3A4 isozyme of CYP450
                 • substrates for the P-gp multidrug efflux pump (affects their CNS distribution)
             • AE
               • Paresthesias
               • Diarrhea
               • Nausea and vomiting
               • fat redistribution
                 • Hypertriglyceridemia
                 • Hyperglycemia
                 • Hypercholesterolemia
         • HIV Prophylaxis
           • Needle stick injury
             • Tenofovir (NRTI)–emtricitabine (NRTI)-raltegravir (integrase inhibitor) initiated within 1 to 2 hours of exposure for not least than 4 weeks.
           • pregnanc
             • The preferred NRTI backbone combinations
               • Tenofovir /emtricitabine
               • Tenofovir /emtricitabine
           • infants
             • born to HIV infected mothers should also receive zidovudine (± several doses of nevirapine) prophylaxis for 4 to 6 weeks after birth
       • respiratory viral infections
       • herpes virus and cytomegalovirus infections
       • hepatic viral infections

2. Type of genome

   • DNA
     • SS
       • Parovirus
     • DS
     • envelopped
     • naked
       • papillo
       • adeno
       • polyoma
   • RNA
     • SS
     • DS
       • reovirus
     • naked
       • picorna
       • calici
     • envelopped
     • positive sense
       • retrovirus
       • togavi rus
       • flavivirus
       • coronavirus
       • (hepevi rus
       • calicivirus
       • picornavirus
     • negative sense

3. HIV

   • HIV- 1
     • M-tropic
       • CCR5
     • T-tropic
       • CXCR5
   • HIV-2
   • mode of transmission
     • body fluids
       • blood
       • semin and vaginal fluid
       • saliva
     • unprotected sex
     • injecting drugs
     • mother to child
     • blood transfusions
     • working in health care
   • life cycle

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