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

Pharmacology - Viral, Fungal, Derm Flashcards

(65 cards)

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1
Q

Oseltamivir & Zanamivir - Mechanism & Resistance

A

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

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2
Q

Oseltamivir & Zanamivir - Pharmacokinetics

A

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

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

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3
Q

Uses of Oseltamivir & Zanamivir in influenza

A

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

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4
Q

Oseltamivir & Zanamivir - Adverse Reactions

A

Oseltamivir - minor; occasional nausea and vomiting

Zanamivir - bronchospasm in patients with ashtma or COPD

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5
Q

Amantadine & Rimantadine - Mechanism & Resistance

A

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

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6
Q

Amantadine & Rimantadine - Pharmacokinetics

A

Amantadine - oral absorption with accumulation in lungs; renal excretion

Rimantadine - oral absorption with accumulation in lungs; hepatic elimination

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7
Q

Uses of Amantadine & Rimantadine in influenza

A

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

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8
Q

Amantadine & Rimantadine - Adverse Reactions

A

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

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9
Q

Inhibitors of Viral Genome Replication - Basic Mechanism

A

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

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10
Q

Inhibitors of Viral Genome Replication - Viral DNA Polymerase

A

Acyclovir
Valacyclovir
Penciclovir
Famciclovir

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11
Q

Acyclovir - Mechanism & Resistance

A

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

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12
Q

Acyclovir - Pharmacokinetics

A

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

Renal elimination; neonatal clearance only 1/3 of adults

Requires dosing 3-5x/day

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13
Q

Valacyclovir - Pharmacokinetics & Uses

A

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

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14
Q

Penciclovir - Pharmacokinetics & Uses

A

Poor oral absorption; topical administration only

Used in HSV-1, HSV-2

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15
Q

Famciclovir - Pharmacokinetics & Uses

A

Penciclovir prodrug with increased oral bioavailability

Used in HSV-1, HSV-2, VZV

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16
Q

Uses of acyclovir in HSV

A

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

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17
Q

Uses of acyclovir in VZV

A

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

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18
Q

Acyclovir - Adverse Reactions

A

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

IV acyclovir associated with encephalopathy

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19
Q

Docosanol - Mechanism

A

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

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20
Q

Uses of docosanol

A

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

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21
Q

Ganciclovir - Mechanism & Resistance

A

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

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22
Q

Ganciclovir - Pharmacokinetics

A

Administration: IV, interocular, oral (poor bioavailability)

Renal excretion

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

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23
Q

Uses of Ganciclovir

A

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

Opthalmic gel treats HSV keratitis

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24
Q

Ganciclovir - Adverse Reactions

A

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

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25
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
26
Foscarnet - Pharmacokinetics
Poor oral bioavailability; IV administration Renal elimination
27
Foscarnet - Uses
Effective against CMV retinitis, esp. in immunocompromised patients Also effective against ganciclovir-resistant CMV infections and acyclovir resistant HSV and VZV infections
28
Foscarnet - Adverse Reactions
Nephrotoxicity and hypocalcemia CNS abnormalities - headache, tremor, seizures, hallucinations Rash, fever, nausea
29
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
30
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
31
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%)
32
Nystatin
Similar to Amphotericin B but toxicity limits use to topical treatment of Candidal infections of skin, mucous membranes and GI tract
33
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
34
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)
35
Capsofungin - Spectrum & Uses
Treatment of invasive aspergillosis and candidiasis in patients who fail other treatment
36
Triazoles - 3 drugs
Fluconazole Itraconazole Terconazole
37
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
38
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
39
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
40
Triazoles - Adverse Effects
GI distress, headaches, allergic rash, elevation of liver enzymes (more severe in HIV patients) Itraconazole & fluconazole inhibit CYP450
41
Imidazoles - 3 drugs
Ketoconazole Clotrimazole Miconazole
42
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
43
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
44
Imidazoles - Clinical uses
Miconazole and Clotrimazole - topically for oral and vaginal candidiasis Ketoconazole - chronic mucocutaneous candidiasis and other systemic infections
45
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
46
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
47
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
48
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
49
Treatment of superficial fungal infections
Topical azole-antifungal agents: Ketoconazole Miconazole Clotrimazole
50
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
51
Treatment of Candida
Topical: Nystatin, Clotrimazole, Terconazole Fluconazole via systemic (oral) route can be given for patients who fail topical therapy
52
Treatment of systemic fungal infections
i.e. Blastomycosis, Coccidiodomycosis, Cryptococcosis, Histoplasmosis Longterm therapy with systemic amphotericin B infusions generally required
53
Treatment of opportunistic fungal infections
i.e. Candida, Aspergillus, Pneumocystis infections in immunocompromised patients Disseminated candidiasis - fluconazole Aspergillosis - Amphotericin B, Capsofungin
54
Ointment
Water in oil emulsion Strong potency, hydrating, low irritation risk Best for use on non-intertreginous sites
55
Cream
Oil in water emulsion Moderate potency, moderate hydration, low irritation risk Can be used on virtually all body sites
56
Lotion
Powder in oil or water Lower potency, variable drying, moderate irritation risk Best for use on scalp and intertrigenous areas
57
Gel
Semisolid emulsion in alcohol base Strong potency but potentially drying and iritating Best for use on oral mucosa and scalp
58
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
59
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
60
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
61
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
62
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)
63
What enzyme do Imidazoles inhibit?
14-a-demethylase, required for ergosterol synthesis
64
What enzyme does Terbinafine inhibit?
Squalene epoxidase, required for erogsterol synthesis
65
What enzyme to Triazoles inhibit?
Fungal cytochrome P450, required for ergosterol synthesis

DD & BL Unit III / Final Exam (7 decks)

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