Pharm Lecture 18: Anti-fungal and non-hiv antiviral agents (In progress)

Important facts of Griseofulvin: Note: "Grizzly!!!" Think gross fingernail picture (slide 17)

1.Disruption of fungal mitosis 2.Incorporated into newly formed keratin 3.Fungistatic 4.Clinical Uses: -Dermatophyte infection (Skin/hair/nails) 5. *LONG treatment duration

10. More than 90% of this drug is excreted in the urine in intact form. Because its urinary solubility is low, patients should be well hydrated to prevent nephrotoxicity. Which drug is described? (A) Acyclovir (B) Efavirenz (C) Indinavir (D) Trifluridine (E) Zidovudine

A. Acyclovir is eliminated in the urine by glomerular filtration and by active tubular secretion, which is inhibited by probenecid. Nephrotoxic effects, including hematuria and crystalluria, are enhanced in patients who are dehydrated or who have preexisting renal dysfunction. Adequate hydration is equally important in the case of indinavir because it causes nephrolithiasis. However, more than 80% of a dose of indinavir is eliminated via hepatic metabolism. Trifluridine is used topically to treat herpes keratoconjunctivitis. The answer is A.

Which of the following drugs is Fungistatic and disrupts microtubules? A. Griseofulvin B. Flucytosine C. Terbinafine D. Fluconazole

A. Griseofulvin

Which drug is clinically used for Candidiasis and has "No side effects or drug interactions" ? A. Nystatin B. Amphotericin B C. Itraconazole D. Efinaconazole

A. Nystatin

Which medication has a BBW(black box warning) stating "Not for use for non-invasive infections and to monitor closely to prevent overdose?"

Amphotericin B

Which drug is least likely to be effective in the treatment of esophageal candidiasis if it is used by the oral route? (A) Clotrimazole (B) Griseofulvin (C) Ketoconazole (D) Itraconazole (E) Nystatin

B. Griseofulvin has no activity against C albicans and is not effective in the treatment of systemic or superficial infections caused by such organisms. "Swish and swallow" formulations of clotrimazole and nystatin have been used commonly. Most of the azoles are effective in esophageal candidiasis. The answer is B.

What drug is indicated for ALL life threatening myotic infections? A. Nystatin B. Amphotericin B C. Itraconazole D. Efinaconazole

B. Amphotericin B

Which Azole Antifungal drug is the first choice for Aspergillosis? A. Itraconazole B. Voriconazole C. Clotrimazole D. Fluconazole

B. Voriconazole

Black box warning for Azole Antifungal drugs:

Black Box Warnings Use only when no other therapies are available or tolerated and benefits outweigh the risks Hepatotoxicity: Possibly life threatening QT prolongation

Which statement about the mechanisms of action of antiviral drugs is accurate? (A) Acyclovir has no requirement for activation by phosphorylation (B) Ganciclovir inhibits viral DNA polymerase but does not cause chain termination (C) Increased activity of host cell ribonucleases that degrade viral mRNA is one of the actions of interferon-α (D) The initial step in activation of foscarnet in HSV-infected cells is its phosphorylation by thymidine kinase (E) The reverse transcriptase of HIV is 30-50 times more sensitive to inhibition by fosamprenavir than host cell DNA polymerases

C. Acyclovir is activated by host cell kinases. Like acyclovir, ganciclovir inhibits viral DNA polymerase and causes chain termination. However, foscarnet inhibits viral DNA polymerase without requiring bioactivation. Fosamprenavir is the prodrug of amprenavir, an inhibitor of HIV protease; it has no significant effect on reverse transcriptase. The answer is C.

Serious cardiac effects have occurred when this drug was taken by patients using the antihistamines astemizole or terfenadine (A) Amphotericin B (B) Griseofulvin (C) Ketoconazole (D) Terbinafine (E) Voriconazole

C. Ketoconazole was the first oral azole introduced into clinical use, but it has a greater propensity to inhibit human cytochrome P450 enzymes than other azoles and is no longer widely used in the United States. Cardiotoxicity may occur when ketoconazole is used by patients taking astemizole or terfenadine as a result of the ability of ketoconazole to inhibit their metabolism via hepatic cytochromes P450. The answer is C.

Which of the following antifungal agents is available over the counter and treats Tinea infections by disrupting ergosterol synthesis? A. Itraconazole B. Clotrimazole C. Terbinafine D. Fluconazole

C. Terbinafine

6. The dose of indinavir in this patient may need to be increased above normal. This is because (A) Fluconazole slows gastric emptying (B) Ganciclovir increases the renal clearance of indinavir (C) Gastric absorption is inhibited by fluconazole (D) Rifabutin increases hepatic drug metabolism (E) Sulfamethoxazole increases indinavir plasma protein binding

D. Drug interactions can be severe in the immunocompromised patient because many of the drugs administered can influence the pharmacokinetic properties of other drugs. Rifabutin, like rifampin, acts as an inducer of several isoforms of hepatic cytochrome P450. This action can result in an increased clearance of other drugs, including indinavir. The answer is D.

Regarding the clinical use of liposomal formulations of amphotericin B, which statement is accurate? (A) Amphotericin B affinity for these lipids is greater than affinity for ergosterol (B) Less expensive to use than conventional amphotericin B (C) More effective in fungal infections because they increase tissue uptake of amphotericin B (D) They decrease the nephrotoxicity of amphotericin B (E) They have a wider spectrum of antifungal activity than conventional formulations of amphotericin B

D. Liposomal formulations of amphotericin B result in decreased accumulation of the drug in tissues, including the kidney. As a result, nephrotoxicity is decreased. With some lipid formulations, infusion-related toxicity may also be reduced. Lipid formulations do not have a wider antifungal spectrum; their daily cost ranges from 10 to 40 times more than the conventional formulation of amphotericin B. The answer is D.

Which statement about fluconazole is accurate? (A) Does not penetrate the blood-brain barrier (B) Drug of choice in treatment of aspergillosis (C) Induces hepatic drug-metabolizing enzymes (D) Has the least effect of all azoles on drug metabolism (E) Oral bioavailability is less than that of ketoconazole

D. The azoles with activity against Aspergillus are itraconazole and voriconazole. Fluconazole is the best absorbed member of the azole group by the oral route and the only one that readily penetrates into cerebrospinal fluid. Although fluconazole may inhibit the metabolism of some drugs, it has the least effect of all azoles on hepatic microsomal drug-metabolizing enzymes. The answer is D.

Interactions between this drug and cell membrane components can result in the formation of pores lined by hydrophilic groups present in the drug molecule. (A) Caspofungin (B) Flucytosine (C) Griseofulvin (D) Nystatin (E) Terbinafine

D. The polyene antifungal drugs amphotericin B and nystatin are amphipathic molecules that can interact with ergosterol in fungal cell membranes to form artificial pores. In these structures, the lipophilic groups on the drug molecule are arranged on the outside of the pore, and the hydrophilic regions are located on the inside. The fungicidal action of the polyenes derives from this interaction, which results in leakage of intracellular constituents. The answer is D.

Which Azole Antifungal drug is the FIRST choice for cryptococcal meningitis A. Itraconazole B. Voriconazole C. Clotrimazole D. Fluconazole

D. Fluconazole (most commonly used agent for the treatment of fungal ifnections)

7. May or may not be an important question?? A 27-year-old nursing mother is diagnosed as suffering from genital herpes. She has a history of this viral infection. Previously, she responded to a drug used topically. Apart from her current problem, she is in good health. Which drug to be used orally is most likely to be prescribed at this time? (A) Amantadine (B) Foscarnet (C) Ritonavir (D) Trifluridine (E) Valacyclovir

E. Three of the drugs listed (foscarnet, trifluridine, valacyclovir) are active against strains of herpes simplex virus. Foscarnet is not used in genital infections (HSV-2) because clinical efficacy has not been established, it has poor oral bioavailability and the drug causes many toxic effects. Trifluridine is used topically but only for herpes keratoconjunctivitis (HSV-1). Valacyclovir is converted to acyclovir by first-pass metabolism in the intestine and liver. The answer is E.

Which drugs are are only available in parenteral form and act to disrupt the ell wall and inhibit beta-glucan synthesis?

Echinocandins

Which antifungal agent is used (off-label) for the treatment of Cushing's Syndrome?

Ketoconazole

Amphotericin B and Nystatin are considered what?

Polyenes

Whats is the leading cause of fatal acute respiratory infection in infants and young children?

Respiratory Syncytial Virus (RSV)

Azole Antifungal drugs inhibit what?

They inhibit human CYP450

When you see 5-FU: what should come to mind?

When you see 5-FU: Think "CANCER DRUG"