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

Pharmacology - Viral, Fungal, Derm Flashcards

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
Q

Foscarnet - Mechanism & Resistance

A

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

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26
Q

Foscarnet - Pharmacokinetics

A

Poor oral bioavailability; IV administration

Renal elimination

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27
Q

Foscarnet - Uses

A

Effective against CMV retinitis, esp. in immunocompromised patients

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

28
Q

Foscarnet - Adverse Reactions

A

Nephrotoxicity and hypocalcemia

CNS abnormalities - headache, tremor, seizures, hallucinations

Rash, fever, nausea

29
Q

Amphotericin B - Mechanism

A

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
Q

Amphotericin B - Spectrum & Uses

A

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
Q

Amphotericin B - Pharmacokinetics & Adverse Reactions

A

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
Q

Nystatin

A

Similar to Amphotericin B but toxicity limits use to topical treatment of Candidal infections of skin, mucous membranes and GI tract

33
Q

Capsofungin - Mechanism

A

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
Q

Capsofungin - Pharmacokinetics & Adverse Reactions

A

Administered by IV infusion; hepatic excretion (possible DDIs with CYP inducers/inhibitors)

Adverse Reactions: Histamine-mediated symptoms (rash, facial swelling, pruritis)

35
Q

Capsofungin - Spectrum & Uses

A

Treatment of invasive aspergillosis and candidiasis in patients who fail other treatment

36
Q

Triazoles - 3 drugs

A

Fluconazole
Itraconazole
Terconazole

37
Q

Triazoles - Mechanism

A

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
Q

Fluconazole - Pharmacokinetics & Uses

A

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
Q

Itraconazole - Pharmacokinetics & Uses

A

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
Q

Triazoles - Adverse Effects

A

GI distress, headaches, allergic rash, elevation of liver enzymes (more severe in HIV patients)

Itraconazole & fluconazole inhibit CYP450

41
Q

Imidazoles - 3 drugs

A

Ketoconazole
Clotrimazole
Miconazole

42
Q

Imidazole - Mechanism

A

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
Q

Imidazoles - Pharmacokinetics

A

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
Q

Imidazoles - Clinical uses

A

Miconazole and Clotrimazole - topically for oral and vaginal candidiasis

Ketoconazole - chronic mucocutaneous candidiasis and other systemic infections

45
Q

Imidazoles - Adverse Reactions

A

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
Q

Terbinafine

A

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
Q

Flucytosine

A

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
Q

Griseofulvin

A

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
Q

Treatment of superficial fungal infections

A

Topical azole-antifungal agents:

Ketoconazole
Miconazole
Clotrimazole

50
Q

Treatment of cutaneous-mucocutaneous fungal infections

A

i.e. Tinea corporis (ringworm), tinea pedis

Topical anti-fungal agents (Clotrimazole, Miconazole, Terbinafine)

Hair infections - Oral Griseofulvin

Nail infections - Systemic Itraconazole, Terbinafine

51
Q

Treatment of Candida

A

Topical: Nystatin, Clotrimazole, Terconazole

Fluconazole via systemic (oral) route can be given for patients who fail topical therapy

52
Q

Treatment of systemic fungal infections

A

i.e. Blastomycosis, Coccidiodomycosis, Cryptococcosis, Histoplasmosis

Longterm therapy with systemic amphotericin B infusions generally required

53
Q

Treatment of opportunistic fungal infections

A

i.e. Candida, Aspergillus, Pneumocystis infections in immunocompromised patients

Disseminated candidiasis - fluconazole
Aspergillosis - Amphotericin B, Capsofungin

54
Q

Ointment

A

Water in oil emulsion

Strong potency, hydrating, low irritation risk

Best for use on non-intertreginous sites

55
Q

Cream

A

Oil in water emulsion

Moderate potency, moderate hydration, low irritation risk

Can be used on virtually all body sites

56
Q

Lotion

A

Powder in oil or water

Lower potency, variable drying, moderate irritation risk

Best for use on scalp and intertrigenous areas

57
Q

Gel

A

Semisolid emulsion in alcohol base

Strong potency but potentially drying and iritating

Best for use on oral mucosa and scalp

58
Q

Foam

A

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
Q

Finger Tip Unit (FTU)

A

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
Q

Hydrocortisone 2.5%

A

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
Q

Triamcinolone Acetonide 0.1%

A

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
Q

Clobetasol Propionate 0.05%

A

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
Q

What enzyme do Imidazoles inhibit?

A

14-a-demethylase, required for ergosterol synthesis

64
Q

What enzyme does Terbinafine inhibit?

A

Squalene epoxidase, required for erogsterol synthesis

65
Q

What enzyme to Triazoles inhibit?

A

Fungal cytochrome P450, required for ergosterol synthesis

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

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