Tuberculosis Drugs, Antivirals, Antiretrovirals, Antifungal and Anti-Parasitics Felix Hernandez, M.D.

Antituberculosis Drugs

    Isoniazid   MOA: inhibits mycolic acid synthesis in the wall Side Effects: peripheral neuropathies (prevent with treatment with pyridoxine), hepatitis, hepatotoxicity Rifampin   MOA: blocks the beta subunit of bacterial RNA polymerase thus stopping bacterial RNA synthesis Side Effects: urine and sweat turn red, induces P450, hepatitis Pyrazinamide    MOA: nicotinamide analog with unknown mechanism Side Effects: hepatitis, hyperuricemia with gouty arthritis.

Is never used alone because of rapid resistance Ethambutol  MOA: inhibits mycolic acid synthesis in bacterial cell wall  Side Effects: reversible retrobulbar neuritis, loss of central vision

Antiviral Drugs (DNA and RNA)

  Acyclovir    MOA: inhibits DNA polymerase and incorporates itself into viral DNA Clinical Use: herpes simplex 1 and 2 and Varicella zoster Side Effects: skin irritation and burning, crystalline nephropathy with rapid infusion Ganciclovir  MOA: same as Acyclovir   Clinical Uses: CMV retinitis and severe systemic CMV infections in immunocompromised patients Side Effects: granulocytopenia, anemia, thrombocytopenia, renal dysfunction

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Antiviral Drugs (DNA and RNA)

Foscarnet   MOA: analog of pyrophosphate and competes with it in viral DNA polymerase and reverse transcriptase therefore inhibiting DNA synthesis Clinical Uses: CMV retinitis in immunocompromised patients and acyclovir resistant HSV  Side Effects: renal toxicity, seizures, hypocalcaemia, anemia   Is deposited in bone and teeth.

Hydrate patient to protect the kidneys Amantadine    MOA: prevents virus from entering susceptible cells Clinical Uses: treatment/prophylaxis of Influenza A in the elderly Side Effects: depression, CNS toxicity, CHF, orthostatic hypotension, urinary retention  Rimantadine is used for prophylaxis in children

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Antiviral Drugs (DNA and RNA) Ribavirin

    MOA: unknown Clinical Uses: RSV in children Side Effects: decreased pulmonary function, teratogenic in animals Is given via aerosol but is absorbed systemically

Oseltamivir

   MOA: analog of adenosine monophosphate Clinical Uses: chronic hepatitis B Side Effects: HA, asthenia (weakness and loss of strength)

Antiretroviral Therapy

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Zidovudine, Didanosine, Lamivudine

   MOA: nucleoside HIV reverse transcriptase inhibitor Clinical Uses: HIV in combination therapy  Zidovudine is used in the prevention of maternal fetal transmission  Mom takes it prenatally then infant takes it for 6 weeks Side Effects: peripheral neuropathy, pancreatitis, myelosuppression with Zidovudine

Antiretroviral Therapy

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Ritonavir, Indinavir

   MOA: protease inhibitor (cleaves gag-pol) that results in immature virus formation Clinical Uses: HIV in combination therapy Side Effects: weakness, anorexia, parasthesias, indinavir has an increased risk of kidney stones

Antiretroviral Therapy

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Nevirapine, Efavirenz

    MOA: non-nucleoside inhibitor of HIV reverse transcriptase Clinical Uses: HIV  never as monotherapy due to rapid resistance Side Effects: severe skin rash Nevirapine crosses the placenta

Pneumocystis carinii Agents

   Trimethoprim-Sulfamethoxazole (Bactrim)   MOA: inhibits folate synthesis pathway Clinical Uses: Oral is DOC for PCP prophylaxis in immunocompromised patients. IV is DOC for PCP infection Pentamidine (Pentam)  MOA: unknown   Clinical Uses: nebulized form used as an alternative for prophylaxis, IV is alternative for treatment Side Effects: Bronchospasm Atovaquone (Mepron)  MOA: unknown  Clinical Uses: treatment for TMP-SMZ resistant strains

Antifungal Drugs

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Polyenes

 Amphotericin B   MOA: disrupts the plasma membrane of fungal cells Clinical Uses: DOC for systemic fungal infections, fungal meningitis and fungal UTI  Side Effects: is toxic at therapeutic doses, nephrotoxicity, hypokalemia, thrombophlebitis, anemia  Nystatin  MOA: same   Clinical Uses: DOC for intestinal Candida or thrush Side Effects: few adverse effects

Antifungal Drugs

 Imidazoles  Ketoconazole    MOA: impairs synthesis of ergosterol which is a principle component of the fungal plasma membrane Clinical Uses: DOC for thrush and chronic mucocutaneous candidiasis Side Effects: fetal hepatic necrosis, gynecomastia and breast pain (due to inhibition of testosterone synthesis)  Fluconazole (Diflucan)  MOA: inhibits fungal P450 and damages the plasma membrane by inhibiting sterol demethylation which is an integral step in plasma membrane synthesis   Clinical Uses: systemic histoplasmosis, candidal vaginitis and esophagitis Side Effects: rash, diarrhea  Has no effects on testosterone synthesis

Antifungal Drugs

   Itraconazole   MOA: same as fluconazole Clinical Uses: aspergillosis, histoplasmosis, local tinea or candidal infections   Side Effects: edema, hepatitis No testosterone effects Clotrimazole (Lotrimin)  MOA: mechanism unknown  Clinical Uses: DOC for candida and dermatophyte infections of the skin and vaginal candidiasis Miconazole (Monistat)    MOA: unknown Clinical Uses: vaginal candidiasis Side Effects: phlebitis, pruritis, rash

Antifungal Drugs

   Flucytosine   MOA: converted to 5-fluoro-uracil by the fungus and is incorporated into the RNA where thymidilate synthetase is inhibited Side Effects: leukopenia, increased LFT, bone marrow suppression Griseofulvin    MOA: interferes with the synthesis of nucleic acids Clinical Uses: dermatophytes of hair, skin and nail. May require up to 6mo treatment Side Effects: decreased memory and judgment, leukopenia, photosensitivity, possible teratogen (CI in prego) Terbinafine (Lamisil)    MOA: inhibits squalene epoxidase a critical enzyme in ergosterol synthesis Clinical Uses: toe nail infection due to Trichophyton Side Effects: neutropenia, skin reactions and ophthalmic toxicity

Antiparasitic Drugs

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Metronidazole (Flagyl)

   MOA: binds DNA and inhibits synthesis in bacteria. In parasites it’s unknown Clinical Uses: E. histolytica, Trichomonas, Giardia Side Effects: seizures, ataxia, Disulfiram-like reaction

Lindane

   MOA: induces seizures in ectoparasites Clinical Uses: Scabies and lice Side Effects: seizures, CNS disturbance and risk of arrhythmias

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Antiparasitic Drugs

Antihelminthic Drugs    Mebendazole    MOA: disrupts microtubules in worms Clinical Uses: DOC for pinworm and is also effective against roundworms  Pinworms is highly contagious and the entire family should be treated Side Effects: GI pain Praziquantel    MOA: increases cell membrane permeability causing a loss of calcium which results in paralysis of the worm and release from host tissue Clinical Uses: Schistosomiasis (single dose) Side Effects: minimal, flu-like symptoms Ivermectin    MOA: Glutamate-gated channel antagonist that causes worm paralysis Clinical Uses: strongyloides and Onchocerca Side Effects: pruritis

Antimalarial Drugs

  Chloroquine or Hydroxychloroquine   MOA: Mechanism unclear and has wide resistance (UK) Clinical Uses: prophylaxis and acute attacks  Side Effects: irreversible retinal damage, hemolysis in G6PD-deficient patients Quinine   MOA: not clear Clinical Uses: treat chloroquine resistant P. falciparum  Side Effects: Cinchonism ( flushed and sweaty skin, ringing of the ears ( tinnitus ), blurred vision, impaired hearing, confusion, reversible high-frequency hearing loss), Most toxic antimalarial and should only be used when all other fail, cardiac arrhythmias

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Antimalarial Drugs

Mefloquine    MOA: structural analog of quinine Clinical Uses: multidrug resistant malaria Side Effects: well tolerated, benign sinus bradycardia Pyrimethamine    MOA: inhibits folate synthesis by inhibiting dihydrofolate reductase Clinical Uses: Malaria prophylaxis and used in combination for acute attacks Side Effects: Few and are very mild Primaquine  MOA: unclear but likely to involve crosslinking of glutathione   Clinical Uses: chloroquine resistant Vivax malarias Side Effects: hemolysis in patients with G6PD deficiency