AntiMycobacterial, Anti Fungals, Antiviral

Question 1

Drugs to tx TB

Answer 1

Rifampin, Isoniazid, Pyrazinamide, Ethambutol (RIPE for treatment)

Question 2

Drug to treat M.Avium intracelluare

Drug for M. Avium prophylaxsis

Answer 2

Azithromycin or clarithromycin + ethambutol. Can add rifabutin or ciprofloxacin.

Prophy: Azithromycin, rifabutin

Question 3

What tx do we prescribe for pts with Mycobacterium Leprae

Answer 3

Long-term treatment with dapsone and rifampin for tuberculoid form.

Add clofazimine for lepromatous form.

Question 4

What is teh Mechanism of Rifampin?

Answer 4

Inhibit DNA-dependent RNA polymerase.

Question 5

What are the 4 R’s of Rifampin?

Answer 5

Rifampin’s 4 R’s:
RNA polymerase inhibitor
Ramps up microsomal cytochrome P-450

• *R**ed/orange body fluids
• *R**apid resistance if used alone

Rifampin ramps up cytochrome P-450, but rifabutin does not.

Question 6

Uses for Rifampin:

Answer 6

1. Mycobacterium tuberculosis
2. delay resistance to dapsone when used for leprosy.
3. Used f or meningococcal prophylaxis and chemoprophylaxis in contacts of children with Haemophilus influenzae type B.

Question 7

What is the toxicity profile of Rifampin?

Answer 7

Minor hepatotoxicity and drug interactions (? INDUCES cytochrome P-450); orange body fluids (nonhazardous side effect).

Rifabutin favored over rifampin in patients with HIV infection due to less cytochrome P-450 stimulation.

Question 8

?DECREASES synthesis of mycolic acids.

Bacterial catalase- peroxidase (encoded by KatG) needed to convert to active metabolite.

Answer 8

Isoniazid

Question 9

Mycobacterium tuberculosis:only agent used as solo prophylaxis against TB.

What is it’s mechanism of action?

Answer 9

Isoniazid?

DECREASE synthesis of mycolic acids. Bacterial catalase- peroxidase (encoded by KatG) needed to convert INH to active metabolite.

Question 10

What are the associated toxicities with Isoniazid?

What can we do to prevent them?

Answer 10

Neurotoxicity, hepatotoxicity. : INH Injures Neurons and Hepatocytes.

Pyridoxine (vitamin B6) can prevent neurotoxicity.

Question 11

What is the mechanism of Pyrazinamide?

What toxicity is it associated with?

Answer 11

Mechanism uncertain. Pyrazinamide is a prodrug that is converted to the active compound pyrazinoic acid.

Sides: Hyperuricemia, hepatotoxicity

Question 12

?Decrease carbohydrate polymerization of mycobacterium cell wall by blocking arabinosyltransferase.

Answer 12

Ethambutol

Question 13

Mech of Ethambutol

What side effect do we worry about?

Answer 13

Optic neuropathy (red-green color blindness). Pronounce “eyethambutol.”

Decreases carbohydrate polymerization of mycobacteruim cell wall by blocking arabinoltransferase

Question 14

Binds ergosterol (unique to fungi); forms membrane pores that allow leakage of electrolytes.

Answer 14

Amphotericin B

Amphotericin “tears” holes in the fungal membrane by forming pores.

Question 15

What are the clinical uses for Ampho B?

What toxicities are associated with it?

Answer 15

Serious, systemic mycoses. Cryptococcus (amphotericin B with/without flucytosine for cryptococcal meningitis), Blastomyces, Coccidioides, Histoplasma, Candida,
Mucor. Intrathecally for fungal meningitis. Supplement K+ and Mg2+ because of altered renal tubule permeability.

Fever/chills (“shake and bake”), hypotension, nephrotoxicity, arrhythmias, anemia, IV phlebitis (“amphoterrible”). Hydration ?to Decrease nephrotoxicity. Liposomal amphotericin ? Decrease toxicity.

Question 16

Mechanism and use of Nystatin?

Answer 16

Same as amphotericin B: Binds ergosterol (unique to fungi); f_orms membrane pores_ that allow leakage of electrolytes.

Topical use only as too toxic for systemic use.
“Swish and swallow” for oral candidiasis (thrush); topical for diaper rash or vaginal candidiasis.

Question 17

Mechanism of Flucotyosine

Uses

Toxicity

Answer 17

inhibits DNA and RNA biosynthesis by conversion to 5-fluorouracil by cytosine deaminase.

Systemic fungal infections (especially meningitis caused by Cryptococcus) in combination with amphotericin B.

Toxicity: MBone marrow suppression.

Question 18

inhibits DNA and RNA biosynthesis by conversion to 5-fluorouracil by cytosine deaminase.

Answer 18

Flucytosine

Question 19

Inhibit fungal sterol (ergosterol) synthesis by i_nhibiting the cytochrome P-450 e_nzyme that converts lanosterol to ergosterol.

What drugs?

What toxicities associated?

Answer 19

Azoles: Clotrimazole, fluconazole, itraconazole, ketoconazole, miconazole, voriconazole

Toxicity: Testosterone synthesis inhibition (gynecomastia, especially with ketoconazole), liver dysfunction (inhibits cytochrome P-450).

Question 20

What is the Mechanism of Terbinafine

When do you use it?

Answer 20

Inhibits the fungal enzyme squalene epoxidase.
Use: Dermatophytoses (especially onychomycosis—fungal infection of finger or toe nails). GI upset, headaches, hepatotoxicity, taste disturbance.

Question 21

General outline of antifungals

Answer 21

Question 22

Interferes with microtubule function; disrupts mitosis. Deposits in keratin-containing tissues (e.g., nails).

What are it’s uses?

Answer 22

Griseofulvin

Oral treatment of superficial infections; inhibits growth of dermatophytes (tinea, ringworm).

Question 23

Used orally to treat superficial infections and inhibits dermatophytes

Teratogenic, carcinogenic, confusion, headaches, INCREASE ?cytochrome P-450 and warfarin metabolism.

Answer 23

Griseofulvin

Question 24

What drugs are recommended for malaria?

Answer 24

Pyrimethamine (toxoplasmosis), suramin and melarsoprol (Trypanosoma brucei), nifurtimox (T. cruzi), sodium stibogluconate (leishmaniasis).

Question 25

When do we use Chloroquinre?

What’s it’s mechanism of action?

Answer 25

_Blocks detoxification of hem_e into hemozoin. Heme accumulates and is toxic to plasmodia.

Treatment of plasmodial species other than P. falciparum (frequency of resistance in P. falciparum is too high). Resistance due to membrane pump that decreae ?intracellular concentration of drug. Treat P. falciparum with artemether/lumefantrine or _atovaquone/proguani_l.

For life-threatening malaria, use quinidine in U.S. (quinine elsewhere) or artesunate.

Question 26

What drugs are used to treat helminths?

Answer 26

Mebendazole, pyrantel pamoate, ivermectin, diethylcarbamazine, praziquantel.

Question 27

Inhibit influenza neuraminidase–> Decrease ??release of progeny virus.

What drug and what’s the use?

Answer 27

Oseltamivir, zanamivir

Treatment and prevention of both influenza A and B.

Question 28

What is the mechanism and use of Oseltamivir, Zanamivir

Answer 28

Inhibit influenza neuraminida–> DECREASE se??release of progeny virus.

CLINICAL USE Treatment and prevention of both influenza A and B.

Question 29

What is the mechanism of Acyclovir, Famciclovir, Valacyclovir

Answer 29

Guanosine analogs. Monophosphorylated by HSV/VZV thymidine kinase and not phosphorylated in uninfected cells?few adverse effects. Triphosphate formed by cellular enzymes. Preferentially inhibit viral DNA polymerase by chain termination.

Question 30

Used for HSV and VZV (not great for EBV and not at all for CMV)

Answer 30

Acyclovir, Famciclovir, Valcycovir

Question 31

Used for HSV- induced mucocutaneous and genital lesions as well as for encephalitis. Prophylaxis in immunocompromised patients. No effect on latent forms of HSV and VZV.

Answer 31

Acyclovir, famciclovir, valacyclovir

Question 32

Guanosine analogs. Monophosphorylated by HSV/VZV thymidine kinase and not phosphorylated in uninfected cells?few adverse effects. Triphosphate formed by cellular enzymes. Preferentially inhibit viral DNA polymerase by chain termination.

Drug? and toxicity?

Answer 32

Acyclovir, Famciclovir, Valacyclovir

Obstructive crystalline nephropathy and acute renal failure if not adequately hydrated.

Question 33

Use and mechanism of Ganciclovir?

Answer 33

CMV, especially in immunocompromised patients. Valganciclovir, a prodrug of ganciclovir, has better oral bioavailability.

5′-monophosphate formed by a CMV viral kinase. Guanosine analog. Triphosphate formed by cellular kinases. Preferentially i_nhibits viral DNA polymerase._ Preferentially inhibit viral DNA polymerase by chain termination.

Question 34

Drug used to treat CMV

What is the toxicity profile

Answer 34

Ganciclovir

L_eukopenia, neutropenia, thrombocytopenia,_ renal toxicity. More toxic to host enzymes than acyclovir

Question 35

What do we use Foscarnet?

What’s the mechanism?

Answer 35

CMV retinitis in immunocompromised patients when ganciclovir fails; acyclovir-resistant HSV.

Viral DNA/RNA polymerase inhibitor and HIV reverse transcriptase inhibitor. Binds to pyrophosphate-binding site of enzyme. Does n_ot require activation by viral kinase._

Question 36

Viral DNA/RNA polymerase inhibitor and HIV reverse transcriptase inhibitor. Binds to pyrophosphate-binding site of enzyme. Does not require activation by viral kinase.

Use and Toxicity?

Answer 36

Foscarnet

Use: CMV retinitis;

Nephrotoxicity, electrolyte abnormalities (hypo- or hypercalcemia, hypo- or hyperphosphatemia, hypokalemia, hypomagnesemia) can lead to seizures.

Question 37

Preferentially inhibits viral DNA polymerase. Does n_ot require phosphorylation_ by viral kinase.

Answer 37

Cidofovir

Question 38

Used for CMV retinitis in immunocompromised patients; acyclovir-resistant HSV. Long half-life.

Causes Nephrotoxicity

Answer 38

Cidofovir

Preferentially inhibits viral DNA polymerase. Does _not require phosphoryla_tion by viral kinase.