Pharmacology - Viral, Fungal, Derm Flashcards
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
Valacyclovir
Penciclovir
Famciclovir
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
Amphotericin B - Pharmacokinetics & Adverse Reactions
IV administration with slow renal excretion; half life 15 days
VERY TOXIC
Nephrotoxicity (nearly 100%)
Infusion-related toxicity - fever, chills, vomiting, hypotension
Anemia (75%)
Nystatin
Similar to Amphotericin B but toxicity limits use to topical treatment of Candidal infections of skin, mucous membranes and GI tract
Capsofungin - Mechanism
Echinocandins class
Inhibits synthesis of B (1,3)-D-glucan, an essential component of fungal cell walls
High selective toxicity due to absence of these enzymes in mammalian cells
Capsofungin - Pharmacokinetics & Adverse Reactions
Administered by IV infusion; hepatic excretion (possible DDIs with CYP inducers/inhibitors)
Adverse Reactions: Histamine-mediated symptoms (rash, facial swelling, pruritis)
Capsofungin - Spectrum & Uses
Treatment of invasive aspergillosis and candidiasis in patients who fail other treatment
Triazoles - 3 drugs
Fluconazole
Itraconazole
Terconazole
Triazoles - Mechanism
Highly selective inhibition of fungal cytochrome P450, reducing fungal sterol synthesis; fungistatic
Greater selectivity for fungal vs. mammalian cytochrome enzymes than seen with imidazoles (ketoconazole), resulting in less hepatic toxicity
Fluconazole - Pharmacokinetics & Uses
Absorbed orally with long half life allowing once daily dosing
Distributed to CSF for treatment of fungal meningitis
Eliminated renally
Used in treatment of vaginal candidiasis in patients who fail topical treatment; treatment for oropharyngeal and esophageal candidiasis
Itraconazole - Pharmacokinetics & Uses
Good oral absorption with long half life allowing once daily dosing
Hepatic elimination
Used in treatment of aspergillosis, hisoplasmosis, and sporotrichosis; also used in dermatophytoses and onychomycosis
Triazoles - Adverse Effects
GI distress, headaches, allergic rash, elevation of liver enzymes (more severe in HIV patients)
Itraconazole & fluconazole inhibit CYP450
Imidazoles - 3 drugs
Ketoconazole
Clotrimazole
Miconazole
Imidazole - Mechanism
Inhibits P450-dependent enzyme 14a-demethylase, resulting in decreased levels of ergosterol
Disruption in synthesis of cell membrane sterols leads to alterations in membrane permeability - can be fungistatic or fungicidal depending on concentration
Imidazoles - Pharmacokinetics
Only ketoconazole used systemically (oral and IV)
Poorly absorbed but better at low pH
Enters CNS poorly but crosses placenta
Eliminated by hepatic metabolism
Excreted in breast milk
Imidazoles - Clinical uses
Miconazole and Clotrimazole - topically for oral and vaginal candidiasis
Ketoconazole - chronic mucocutaneous candidiasis and other systemic infections
Imidazoles - Adverse Reactions
Systemic ketoconazole is highly toxic:
Anorexia, nausea, vomiting
Hepatotoxicity - mild jaundice
Inhibition of testosterone synthesis and adrenal steroidogenesis
Ketoconazole is a strong inhibitor of CYP3A4
Terbinafine
Interferes with ergosterol synthesis by inhibiting squalene oxidase; fungicidal
Once daily oral for toe / finger nail infections
Topical for athletes foot
ARs include GI upset, rash, headache, taste disturbances
Flucytosine
Converted in fungal cell into 5-fluorouracil (via cytosine deaminase); 5-FU interfers with DNA synthesis leading to cell death; high selective toxicity as mammals lack cytosine deaminase enzyme; resistance occurs in fungi that lack cytosine deaminase
Good oral absorption; distributed to CNS; renal elimination
Used for serious infections of cryptococcis, candidiasis, and chromboblastomycosis
ARs include nausea, vomiting, skin rash
Bone marrow suppression, abnormal liver function with prolonged high doses
Griseofulvin
Binds to microtubules, inhibiting fungal mitosis; fungistatic
Oral absorption with affinity for diseased skin; excreted in feces
Treatment of severe, superficial dermatophytosis involving skin, hair, and finger/toe nails; rarely used due to long course of therapy
ARs include hypersensitivity reactions, headache, GI distress, mental confusion
Treatment of superficial fungal infections
Topical azole-antifungal agents:
Ketoconazole
Miconazole
Clotrimazole
Treatment of cutaneous-mucocutaneous fungal infections
i.e. Tinea corporis (ringworm), tinea pedis
Topical anti-fungal agents (Clotrimazole, Miconazole, Terbinafine)
Hair infections - Oral Griseofulvin
Nail infections - Systemic Itraconazole, Terbinafine
Treatment of Candida
Topical: Nystatin, Clotrimazole, Terconazole
Fluconazole via systemic (oral) route can be given for patients who fail topical therapy
Treatment of systemic fungal infections
i.e. Blastomycosis, Coccidiodomycosis, Cryptococcosis, Histoplasmosis
Longterm therapy with systemic amphotericin B infusions generally required
Treatment of opportunistic fungal infections
i.e. Candida, Aspergillus, Pneumocystis infections in immunocompromised patients
Disseminated candidiasis - fluconazole
Aspergillosis - Amphotericin B, Capsofungin
Ointment
Water in oil emulsion
Strong potency, hydrating, low irritation risk
Best for use on non-intertreginous sites
Cream
Oil in water emulsion
Moderate potency, moderate hydration, low irritation risk
Can be used on virtually all body sites
Lotion
Powder in oil or water
Lower potency, variable drying, moderate irritation risk
Best for use on scalp and intertrigenous areas
Gel
Semisolid emulsion in alcohol base
Strong potency but potentially drying and iritating
Best for use on oral mucosa and scalp
Foam
Pressured collection of gaseous bubbles in a matrix of liquid film
Rapid evaporation of volatile components leaves behind supersaturated active ingredient
Allows maximal delivery of active ingredient to the skin
Best for application on hair-bearing areas
Finger Tip Unit (FTU)
The amount of ointment dispensed from a 5mm diameter nozzle that is applied to the distal third of the index finger, from the crease under the DIP to the fingertip
1 gram of cream covers ~ 10cm x 10cm of skin and 1 gram of ointment spreads 10% farther than the same amount of cream
Hydrocortisone 2.5%
Low potency (class 7) cream or ointment
Effective for mild eczeme in children & adults, and for inflammatory dermatoses involving the face or intergrigenous areas
Triamcinolone Acetonide 0.1%
Class 4 - moderate potency; formulated as cream or ointment
Effective against eczema, allergic contact dermatitis, arthropod bites, drug reactions
Not recommended for long term use on face or intertriginous areas
Clobetasol Propionate 0.05%
Class 1 - high potency; formulated as cream or ointment
Best used for severe, acute eruptions requiring rapid treatment; should be avoided on the face or intertriginous areas
Long term use requires monitoring for adverse effects including skin atrophy and systemic gluccocorticoid effects (adrenal suppression, Cushing’s Syndrome, growth retardation in children)
What enzyme do Imidazoles inhibit?
14-a-demethylase, required for ergosterol synthesis
What enzyme does Terbinafine inhibit?
Squalene epoxidase, required for erogsterol synthesis
What enzyme to Triazoles inhibit?
Fungal cytochrome P450, required for ergosterol synthesis
