Pharmacology - Viral, Fungal, Derm Flashcards Preview

DD & BL Unit III / Final Exam > Pharmacology - Viral, Fungal, Derm > Flashcards

Flashcards in Pharmacology - Viral, Fungal, Derm Deck (65)
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Oseltamivir & Zanamivir - Mechanism & Resistance

Mechanism: Inhibits neuraminidase from cleaving N-acetyl neuraminic acid (sialic acid) from the host cell membrane; this inhibits the ability of newly synthesized virions to bud from the cell, resulting in reduced infectivity

Resistance: Relatively rare (1-4%) from mutations in viral hemagglutinin or neuraminidase


Oseltamivir & Zanamivir - Pharmacokinetics

Oseltamivir - oral administration as a pro-drug; renally eliminated

Zanamivir - administered via inhalation (poor oral bioavailability); renally eliminated


Uses of Oseltamivir & Zanamivir in influenza

Started within 28 hours of influenza symptom onset, can decrease severity and duration of symptoms (by 1-2 days); effective against influenza A and B in adults and children

80-90% effective as prophylaxis in flu contacts


Oseltamivir & Zanamivir - Adverse Reactions

Oseltamivir - minor; occasional nausea and vomiting

Zanamivir - bronchospasm in patients with ashtma or COPD


Amantadine & Rimantadine - Mechanism & Resistance

Mechanism: Inhibitors of viral uncoating; blocks virally-encoded H+ channel (M2 protein), preventing changes in intracellular pH necessary for uncoating; this prevents release of virion RNA genome for replication in the cytosol

Resistance: Occurs to both amandatine and rimantadine in response to mutations in transmembrane domains of M2 proton channel; most 2012 seasonal A influenza strains were resistant


Amantadine & Rimantadine - Pharmacokinetics

Amantadine - oral absorption with accumulation in lungs; renal excretion

Rimantadine - oral absorption with accumulation in lungs; hepatic elimination


Uses of Amantadine & Rimantadine in influenza

For prophylaxis and treatment of influenza A only; best used 1-2 days prior and 6-7 days during infection to reduce incidence and severity of symptoms


Amantadine & Rimantadine - Adverse Reactions

Amantadine - insomnia, concentration difficulty, lightheadedness, dizziness, headache

Rimantadine - better tolerated due to poor CNS penetration

Both excreted in breastmilk; not recommended during pregnancy or breast feeding


Inhibitors of Viral Genome Replication - Basic Mechanism

Nucleoside analogs that specifically target DNA polymerase or viral reverse transcriptase

Action of purine or pyrimidine analogs requires passage of the lipid soluble analog across the cell membrane; it is converted to the active triphosphate form by intracellular kinases

Highest degree of selective toxicity with analogs that are activated by viral kinases rather than host kinases


Inhibitors of Viral Genome Replication - Viral DNA Polymerase



Acyclovir - Mechanism & Resistance

Mechanism: Acyclovir monophosphate traverses the infected cell membrane; once inside the cell, viral host thymidine kinase phosphorylates Acyclovir to its triphosphate form with 200x greater affinity than the host thymidine kinase; Acyclovir-TP competes with cellular dGTP for viral DNA polymerase, which incorporates the nucleside analog into its replicating viral DNA strand, terminating DNA replication

Resistance: Occurs as a result of altered viral thymidine kinase substrate specificity (loss of kinase activity) or reduced expression of viral thymidine kinase


Acyclovir - Pharmacokinetics

Poor oral absorption (15-30%); also available topical and IV

Renal elimination; neonatal clearance only 1/3 of adults

Requires dosing 3-5x/day


Valacyclovir - Pharmacokinetics & Uses

Valyl ester prodrug of acyclovir; given orally, achieves plasma levels 3-5 times higher than acyclovir

Daily dosing

Used in HSV-1, HSV-2, VZV


Penciclovir - Pharmacokinetics & Uses

Poor oral absorption; topical administration only

Used in HSV-1, HSV-2


Famciclovir - Pharmacokinetics & Uses

Penciclovir prodrug with increased oral bioavailability

Used in HSV-1, HSV-2, VZV


Uses of acyclovir in HSV

Oral - shortens symptom duration of primary and recurrent genital herpes and reduces mean duration of pain; also effective in secondary prevention

IV - treatment of choice for herpes simplex encephalitis, neonattal HSV, and serious HSV or VZV in immunocompromised patients


Uses of acyclovir in VZV

Oral - decreases number of lesions and duration of both varicella and zoster; suppression with oral acyclovir reduces VZV reactivation in immunocompromised patients


Acyclovir - Adverse Reactions

Minor toxicities - headache, nausea, vomiting, reversible renal dysfunction

IV acyclovir associated with encephalopathy


Docosanol - Mechanism

Inhibitor of viral penetration; long chain saturated alcohol that prevents fusion between cellular and viral envelope membranes, blocking viral entry into cell


Uses of docosanol

Topical treatment (5x daily to lips or face) begun within 12 hours of symptoms reduces healing time by ~ 1 day; administration at later stages does not elicit therapeutic response


Ganciclovir - Mechanism & Resistance

Mechanism: Ganciclovir is taken up by the infected cell; within the cell, phosphorylation occurs by viral protein kinases which convert Ganciclovir-MP to its TP form

Ganciclovir-TP competes with cellular dGTP for viral DNA polymerase, which incorporates the nucleotide analog into replicating viral DNA strands, stopping further viral DNA chain elongation

Resistance: Mutations in protein kinase decrease ganciclovir phosphorylation and activation

Mutations in viral DNA polymerase, altering its activity


Ganciclovir - Pharmacokinetics

Administration: IV, interocular, oral (poor bioavailability)

Renal excretion

Valganciclovir prodrug is rapidly de-esterified and converted to ganciclovir by GI and hepatic esterases


Uses of Ganciclovir

Treatment and chronic suppression of CMV-related disease (retinitis, colitis, etc.) in immuno-compromised patients

Opthalmic gel treats HSV keratitis


Ganciclovir - Adverse Reactions

Less selective toxicity than acyclovir because the host kinase can also perform first phosphorylation step to MP form

Myelosuppression with neutropenia and thrombocytopenia is the major side effect (20-40%), reversed by drug cessation

GI disturbances, nausea

Rarely CNS toxicity and abnormal liver function


Foscarnet - Mechanism & Resistance

Mechanism: Inorganic pyrophosphage analog; noncompetitively binds to the pyrophosphate binding site of RNA and DNA polymerases; inhibits cleavage of pyrophosphate from deoxy-TPs, resulting in a block of viral genome replication

Resistance: Alterations in DNA polymerase


Foscarnet - Pharmacokinetics

Poor oral bioavailability; IV administration

Renal elimination


Foscarnet - Uses

Effective against CMV retinitis, esp. in immunocompromised patients

Also effective against ganciclovir-resistant CMV infections and acyclovir resistant HSV and VZV infections


Foscarnet - Adverse Reactions

Nephrotoxicity and hypocalcemia

CNS abnormalities - headache, tremor, seizures, hallucinations

Rash, fever, nausea


Amphotericin B - Mechanism

Binds to ergosterol in fungal cell membrane, creating pores that result in leakage of cellular contents and subsequent cell death; fungicidal

Less selective toxicity because also binds to cholesterol in mammalian cells


Amphotericin B - Spectrum & Uses

Broad spectrum, including opportunistic (Candida, Aspergillus) and systemic (Histoplasma, Cryptococci, Blastomyces, Coccidioides)

Drug of choice for life-threatening, systemic fungal infections commonly seen in immunosuppressed patients