Tuberculosis Drugs, Antivirals, Antiretrovirals, Antifungal and Anti-Parasitics

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

2. 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

3. 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

4. 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

5. 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)

6. Antiretroviral Therapy • 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

7. Antiretroviral Therapy • 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

8. Antiretroviral Therapy • 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

9. 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

10. Antifungal Drugs • 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

11. 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

12. 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

13. 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

14. Antiparasitic Drugs • 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

15. 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

16. 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

17. 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