ANTI-FUNGAL DRUGS

AGENTS A. Subcutaneous and Systemic Anti-fungal Agents – Amphotericin B – Caspofungin – Flucytosine – Imidazoles: Ketoconazole, Itraconazole, Fluconazole, Miconazole, Voriconazole – Nystatin – Terbinafine, Amorolfine B. Topical Anti-fungal Agents – Amphotericin B, Butenafine, Butoconazole, Griseofulvin, Ciclopirox, Clioquinol, Clotrimazole, Econazole, Gentian violet, Ketoconazole, Miconazole, Naftifine, Nystatin, Oxiconazole, Sulconazole, Terbinafine, Terconazole, Tolnaftate Antifungal Antibiotics – Amphotericin B – Nystatin – Griseofulvin MECHANISM OF ACTION OF SOME ANTIFUNGAL DRUGS

MOA: Binds to sterols (ergosterol) in the cell membranes, forming pores or channels which increase membrane permeability, making the cell more susceptible to destruction. • MOR: Decreased ergosterol content of the fungal membrane. • Active in growing and resting cells; not highly selective and will interfere with membrane function of mammalian host cell. Pharmacokinetic profile: – Given by slow IV injection, topical, intrathecal (meningitis) or oral. – Highly CHON-bound; excreted very slowly through the urine. ADR: Infusion reactions: Fever, shaking chills, hypotension, anorexia, NAV, headache, dyspnea, tachypnea. • Others: Renal toxicity (potentiated by sodium depletion), electrolyte impairment (hypokalemia, hypomagnesemia, hypocalcemia), normocytic normochromic anemia, impaired hepatic function, local thrombophlebitis; intrathecal à neurotoxicity; topical à skin rash. Therapeutic Uses: Acute, severe, systemic fungal infections (primary drug – DOC). Local dermatophytic and mucocutaneous infections (topical). Fungal infections of the GIT (oral). NYSTATIN • Isolated from Streptomyces; first antimycotic antibiotic. • Polyene antibiotic with broad spectrum of activity. • MOA: Binds to sterols in fungal cell membranes, thereby increasing membrane permeability and making the cell more susceptible to destruction. Pharmacokinetic profile: – Given by oral or topical route. • ADR: Local burning and itching (topical).

AMPHOTERICIN B • A polyene antibiotic derived from Streptomyces nodosus. • Broad spectrum of activity (C. albicans, H. capsulatum, C. neoformans, C. immitis, aspergillus) both fungistatic and fungicidal activity.

GI upset (NAV, diarrhea), renal toxicity. • Therapeutic Uses: Prevention and topical treatment of superficial candidal infections of the skin and mucous membranes (gums, GIT, rectum, vagina).

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GRISEOFULVIN • Fungistatic in activity. • MOA: Inhibits fungal cell mitosis by being accumulated in the newly-synthesized keratin-containing tissue, thus producing multinucleated defective cells that bind to the microtubules, thereby disrupting mitotic spindle. • Pharmacokinetic profile: – Orally administered; t1/2: 24 hours. – Distributes to growing nails and skin, binding to keratin and making the cells resistant to fungal infection. – Biotransformed in the liver to 6methyl-griseofulvin; urinary excr. • ADR: Headache, lethargy, fatigue, blurred vision, insomnia, GI upset, hepatotoxicity. Drug Interactions: – With anticoagulants à reduced effectiveness of anticoagulants because of enhanced metabolism. – With barbiturates à enhanced metabolism of griseofulvin. – With alcohol à tachycardia and flushing; potentiation of intoxicating effects of alcohol. – With oral contraceptives à amenorrhea, increased breakthrough bleeding. Therapeutic Use: For tinea infections of the skin, hair, nails including athlete’s foot and ringworm caused by Microsporum, Epidermophyton, and Trichophyton (oral). FLUCYTOSINE

Fluorinated pyrimidine derivative for candidiasis, cryptococcosis, and chromomycosis. Fungistatic, synergistic effect with Amphotericin B. MOA: Converted to 5-FU in sensitive fungi à biotransformed to 5-fluorodeoxyuridylic acid that inhibits thymidylate synthetase, thus depriving the organism of thymidilic acid (essential DNA component) à disrupts DNA synthesis. MOR: Decreased level of the enzymes in the conversion of flucytosine to 5-FU.

Pharmacokinetic profile: – Administered by oral route; t1/2: 3-6 hours. Excretion: Urine. • ADR: NAV, diarrhea, rash, anemia, leukopenia, thrombocytopenia; increased liver enzymes, BUN, & creatinine.

SYSTEMIC IMIDAZOLE Ketoconazole • Broad antifungal activity; fungistatic activity. • MOA: Selectively increases fungal cell membrane permeability by blocking the demethylation of lanosterol to ergosterol. (effective only in growing cells) • MOR: Mutation in the C14 ademethylase gene à decreased azole binding; fungi’s ability to pump the azole out of the cell. • Orally given; readily absorbed under acidic pH. • ADR: NAV, diarrhea, rash, itching, dizziness, constipation, fever, chills, and headache; gynecomastia and impotence; hepatocellular toxicity. Therapeutic Uses: Rx of systemic and vaginal candidiasis, mucocandidiasis, oral thrush, histoplamosis, chromomycosis. coccidioidomycosis, dermatophytosis.

Other Azoles • Fluconazole – Administered PO or IV. – May produce teratogenic effects. – DOC for Cryptococcus neoformans. • Itraconazole – DOC for blastomycosis, aspergillosis, sporotrichosis, histoplasmosis, and paracoccidioidomycosis. – Orally administered. – With teratogenic capability. • Voriconazole – Administered orally and effective for invasive aspergillosis and serious infections caused by Scedosporium apiospermum and fusarium species. – ADR: Transient visual disturbance. Caspofungin • First of the echinocandins class of antifungal drugs. • MOA: Interferes with the synthesis of the fungal cell wall by inhibiting the synthesis of b-D-glucan à cell lysis and death. • ADR: Fever, rash, nausea, phlebitis, flushing. SYSTEMIC & TOPICAL IMIDAZOLE: Miconazole • Administered both parenterally and topically. • Therapeutic Uses: For Rx of candidal and dermatophytic infections of the skin and for vaginal candidiasis (topical). For severe systemic fungal infections unresponsive or not tolerant to

TOPICAL IMIDAZOLE Clotrimazole • Broad antifungal activity. • Therapeutic Uses: Vulvovaginal candidiasis (topical) Oropharyngeal candidiasis (topical oral) • ADR: Erythema, blistering, edema, pruritus, urticaria. TOPICAL IMIDAZOLES Econazole and Butoconazole ECONAZOLE – Derivative of miconazole. – Used for the treatment of tinea pedis, tinea cruris, tinea corporis, tinea versicolor, and cutaneous candidiasis. – ADR: Burning, itching, rash. – BUTOCONAZOLE – Azole cream for vaginal use and is effective against vaginal infections caused by Candida albicans and Candida tropicalis. – May cause vulvovaginal burning and itching. OTHER TOPICAL ANTIMYCOTIC AGENTS – Undecylenic acid, haloprogin. • TERBINAFINE, NAFTIFINE, AMOROLFINE

Amphotericin B (IV) • ADR: Local burning, itching, and rash (topical). NAV, anemia, anaphylactoid reactions, CNS toxicity, hyponatremia, phlebitis (IV).

TERBINAFINE • Fungicidal agent that acts by selectively inhibiting squalene epoxidase that is involved in the synthesis of ergosterol from squalene in the fungal cell wall à accumulation of squalene à toxicity to organism. • Given orally or topically for fungal infections of the nails. • ADR: GI disturbances, rashes, pruritus, headache, dizziness, joint and muscle pains, hepatitis. Related drug: Naftifine AMOROLFINE • A morpholine derivative that interferes with fungal sterol synthesis.

Given orally for fungal infections of the nails.

BUTENAFINE • A synthetic benzylamine. • MOA – Alters fungal membrane permeability and growth inhibition. – Interferes with sterol biosynthesis by allowing squalene to accumulate within the cell. • Therapeutic Uses – Dermatophytoses, including tinea corporis, tinea cruris, and tinea pedis (1% cream). CICLOPIROX • MOA: – Intracellular depletion of amino acids and ions necessary for normal cellular function. – Therapeutic Uses: – Tinea pedis, tinea cruris, tinea corporis, tinea versicolor, cutaneous candidiasis (topical). • Clioquinol – Available in 3% ointment for tinea pedis and cruris. – May cause local irritation, rash, and sensitivity reactions. Oxiconazole – Available in 1% cream or lotion for tinea cruris, corporis, mannum, and pedis and tinea versicolor.

Phase 1: Adsorption, penetration, and uncoating as the virus enters the host cell and sheds its protective coating. Phase 2: Synthesis of viral components. Phase 3: Assembly and release of the virus which can destroy or permanently change the cell.

INHIBITORS OF VIRAL CELL MULTIPLICATION • Phase 1 and phase 3 inhibitor: Amantadine. • Phase 2 inhibitors: Acyclovir, Ganciclovir, Vidarabine, Trifluoridine, Idoxuridine, Ribavirin, Zidovudine. Drugs for Respiratory Virus Infections – Amantadine, Oseltamivir, Ribavirin, Rimantadine, Zanamirvir Drugs for Hepatic Viral Infections – Adefovir, Entecavir, Interferon, Lamivudine Drugs for Herpes and Cytomegalovirus Infections – Acyclovir, Cidofovir, Famciclovir, Fomivirsen, Foscarnet, Ganciclovir, Penciclovir, Valacyclovir, Valgancyclovir, Vidarabine Drugs for HIV Infections – Abacavir, Amprenavir, Atazanavir, Delavirdine, Didanosine, Emtricitabine, Enfuvirtide, Efavirenz, Indinavir, Lamivudine, Lopinavir, Nelfinavir, Nevirapine, Ritonavir, Saquinavir, Stavudine, Tenofovir, Zalcitabine, Zidovudine Treatment of Respiratory Virus Infections  Neuraminidase Inhibitors: Oseltamivir, Zanamivir – Sialic acid analogues – MOA: Inhibits the neuraminidase enzyme à preventing the release of new virions and their spread from cell to cell. – MOR: Mutation of the neuraminidase. – Oseltamivir: Orally active prodrug à active metabolite in

Sulconazole – Imidazole derivative available in 1% cream or solution and used for tinea corporis, cruris, pedis, versicolor and impetigo. Terconazole – Imidazole derivative available in vaginal cream and suppository and used for vulvovaginal candidiasis.

ANTIVIRAL DRUGS
• STAGES OF VIRUS MULTIPLICATION

liver; ADR: GI discomfort and nausea. Zanamavir: Inhalation or intranasal administration; avoided in severe reactive asthma or COPD. Effective for influenza A and B infections.

 Inhibitors of Viral Uncoating: Amantadine, Rimantadine, Ribavirin AMANTADINE & RIMANTADINE • Adamantadine derivatives. • Synthetic tricyclic amine with a narrow spectrum of activity. • Therapeutic Uses: Treatment or prophylaxis of influenza A virus and for Parkinson’s disease. • MOA: >Inhibits the adsorption of viral particles to host cells, resulting in delayed penetration of the virus into the cell and/or inhibition of uncoating. > Inhibits virus assembly. • MOR: Change in one amino acid of the M2 matrix protein. • Given orally; t1/2: 12-36 hours; peak effects in 2-4 hours. • ADR: Dizziness, insomnia, and slurred speech; confusion, ataxia, sleep disorders, tumors, hallucinations; anorexia, NAV, orthostatic hypotension; edema. RIBAVIRIN • A synthetic nucleoside analog. • MOA: Interferes with guanidine monophosphate, thereby reducing nucleic acid synthesis. • Therapeutic Uses: RSV infections, herpes simplex infections, influenza A and B infections. • ADR:Rash, headache, fatigue. TREATMENT OF HEPATIC VIRAL INFECTIONS • Hepatitis B: Rx with interferon-a and lamivudine • Hepatitis C: Rx with interferon-a and ribavirin

INTERFERON – Immunomodulator. – Inducible proteins synthesized by mammalian cells and now produced by recombinant DNA technology. – MOA: Induces, in the ribosomes of the host cells, the production of enzymes that inhibit translation of viral mRNA into viral CHON à stops reproduction of viruses. – Given IV; t1/2 of 2-4 hours. – Therapeutic Uses: Hepatitis B infection and AIDS-related Kaposi sarcoma (a interferon)Hepatitis C infection (a2b interferon) – ADR: Fever, lassitude, headache, myalgia, bone marrow depression, rashes, alopecia. Other Drugs for Hepatic Viral Infections • Lamivudine – Cytosine analog that inhibits both hepatitis B virus (HBV) DNA polymerase and human immunodeficiency (HIV) reverse transcriptase. – Oral administration with t1/2 of 9 hours. • Adefovir – Nucleotide analog that is phosphorylated into adefovir diphosphate and incorporated into the viral DNA à terminates further synthesis à prevents viral replication. • Entecavir – Guanosine analog that is converted into entecavir triphosphate which competes for viral reverse transcriptase. ACYCLOVIR • Acycloguanosine, 9-2-OHethoxymethylguanine. • A nucleoside analog of the pyrimidine, guanosine. • MOA: Its triphosphate (acyclo GTP) competitively inhibits viral DNA

polymerase and is also incorporated into viral DNA where it functions as a chain terminator, thus preventing the further elongation of the DNA molecule and therefore viral replication. • MOR: Changes in the viral genes coding for DNA polymerase. • Given orally, topically, and intravenously; t1/2 of 2.5 - 3.5 hrs. • Related drugs: Valaciclovir (prodrug of aciclovir) Famciclovir (met. to penciclovir active) • Therapeutic Uses: > Rx of mucocutaneous herpes and genital and disseminated adult herpes simplex. > Mgt. of initial herpes genitalis and in nonlife-threatening cutaneous simplex virus infections in immunocompromised px. >Rx or suppression of recurrent episodes of genital herpes infection and in varicella zoster. • ADR: Mild pain, transient burning and stinging, pruritus, and rash (ointment); NAV, headache, diarrhea, dizziness, anorexia, fatigue, edema, skin rash, leg pain, adenopathy, sore throat (oral); phlebitis, transient elevation of serum creatinine, rash (IV). GANCICLOVIR • A synthetic purine nucleoside analog. • Therapeutic Use: Cytomegalovirus infections (IV) and for maintenance therapy in AIDS patients (oral). • MOA: Activated to its triphosphate form which competes with guanosine triphosphate for incorporation into the viral DNA. • Given intravenously and orally with t1/2 of 4 hours. • ADR: Bone marrow depression, carcinogenicity. • Drug Interactions: – With Probenecid à increased ganciclovir level à toxicity.

With Imipenem-Cilastatin à generalized seizures. – With Zidovudine and cytotoxic drugs à neutropenia. VIDARABINE • Adenine arabinoside. • MOA: Its triphosphate inhibits viral DNA polymerase, thus reducing DNA synthesis. • Administered topically or intravenously (slow infusion). • T1/2: 4 hours. • Undergoes deamination to arabinosylhypoxanthine. • Therapeutic Uses:  Herpes simplex keratitis (ophthalmic).  Herpes simplex encephalitis,  other severe systemic herpes infections, and varicella zoster (IV). • ADR: NAV, anorexia, diarrhea; decreased Hgb and Hct, increased SGOT, tremors, dizziness, hallucinations. TRIFLURIDINE • Trifluorothymidine; a halogenated thymidine derivative used as ophthalmic solution for herpes simplex-induced keratoconjunctivits. • MOA: Converted to its triphosphate which inhibits DNA polymerase. • ADR: Local burning or stinging. – IDOXURIDINE • Halogenated derivative of deoxyuridine. • MOA: Inhibits the replication of of DNA viruses by its incorporation into the virus. • Given topically. • Used for the treatment of herpes simplex keratitis. • ADR: Inflammatory edema of the eyelids, photophobia, lacrimal duct occlusion, and contact dermatitis. FOSCARNET • Trisodium phosphonoformate hexahydrate or PFA • A synthetic non-nucleoside analog of pyrophosphate; given IV.

MOA: Inhibits viral DNA polymerase by binding directly to the pyrophosphate binding site. • ADR: Nephrotoxicity; hyper/hypocalcemia, seizures. ZIDOVUDINE • Azidothymidine or AZT. • Therapeutic Indication: Rx of AIDS patients with P. carinii pneumonia or advanced AIDS-related complex. • Given orally or by IV; t1/2: 1 hour. • MOA: Interferes with HIV replication by being converted to triphosphate and inhibiting the DNA polymerase. • MOR: Rapid mutation of the virus; decreased activation of the drug to its triphosphate; increased virus load due to reduction in immune mechanisms. • ADR: Insomnia, myalgia, nausea, severe headache, anemia, and neutropenia. • DIDANOSINE • Dideoxyinosine, ddI. • A synthetic purine analog. • MOA: Phosphorylated to triphosphate which acts as a chain terminator and inhibitor of the viral reverse transcriptase. • Given orally with plasma t1/2 of 30 mins. and intracellular t1/2 of 12 hours. • Used to treat AIDS. • ADR: Pain and sensory loss in the feet; dose-related pancreatitis. ZALCITABINE • Dideoxycytidine, ddC. • A synthetic nucleoside analog. • MOA: Inhibits the reverse transcriptase enzyme. • Given orally with a plasma t1/2 of 20 mins. and intracellular t1/2 of 3 hours. • Used in the Rx of AIDS in combination with Zidovudine. • ADR: Dose-related neuropathy, GI disturbances, headache, mouth ulcers, edema of the lower limbs, general malaise, pancreatitis.

NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS Abacavir, Adefovir, Lamivudine, Stavudine, Zalcitabine, Didanosine, Zidovudine. • Competitive inhibitors of reverse transcriptase à chain termination when incorporated into the viral DNA chain. NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS Delavirdine, Efavirenz, Nevirapine • Competitive inhibitors of reverse transcriptase à chain termination when incorporated into the viral DNA chain. PROTEASE INHIBITORS Amprenavir, Indinavir, Nelfinavir, Ritonavir, Saquinavir. • Competitively inhibit the viral protease enzyme, preventing the enzyme from cleaving the polyprotein necessary for the production of the infectious virions. Viral Fusion Inhibitor • Enfuvirtide – Antiretroviral drug. – A 36 AA peptide that binds to gp41, preventing the conformational change of the viral transmembrane that is necessary for the fusion of the HIV membrane with that of the host cell – Subcutaneous administration. NATIONAL GUIDELINES FOR ANTI-HIV TREATMENT • When to begin treatment – Treat any symptomatic patient. – Offer treatment to asymptomatic patients with CD4 <500 or HIVRNA >20,000 or recommend observing patients with CD4 350500 and RNA <20,000. – Observe or treat asymptomatic patients with CD4 >500 and HIVRNA <20,000. • Preferred Regimen – Choose from one of the protease inhibitors and one of the

nucleoside reverse transcriptase inhibitor combinations (NRTI) (zidovudine + lamivudine, zidovudine + didanosine, zidovudine + zalcitabine, stavudine + lamivudine) Alternative Regimen – Choose 2 NRTI combinations + 1 non-nucleoside RTI, either nevirapine or delavirdine. Monitoring – Monitor HIV-RNA level; if HIV-RNA does not fall more than 10-fold by week 8, change drug regimen and use 2-3 new agents. – Consider changing if CD4 is falling or if there is clinical deterioration.

• PRIMAQUINE. • >Drugs that affect both exo- and erythrocytic forms • Anti-folate drugs or dihydorfolate reductase inhibitors. • CHLOROGUANIDE, PYRIMETHAMINE, TRIMETHOPRIM. GAMETOCIDES • Prevent infection in mosquitoes by destroying the gametocytes in the blood. • PRIMAQUINE, CHLOROQUINE. SPORONTICIDES • Render the gametocytes non-infective in the mosquito. • PYRIMETHAMINE, PROGUANIL. • BLOOD SCHIZONTICIDES • 4-AMINOQUINOLINES: Chloroquine, Amodiaquine. • QUINOLINE METHANOLS: Quinine, Mefloquine. • PHENANTHRENE METHANOL: Halofantrine. CHLOROQUINE (Aralen) • MECHANISMS OF ACTION – Blocks the enzymatic synthesis of DNA and RNA in humans and protozoal cells à forms a complex with DNA à prevents DNA from acting as template for the replication and transcription to RNA. – Forms a complex with ferriprotoporphyrin à damage to cell membrane à lysis of the parasite and RBC. • MECHANISM OF RESISTANCE – Impaired mechanism of drug transport across the parasite cell wall à concentration of drug in resistant schizonts never reaches a level sufficient to arrest nucleic acid synthesis. • PHARMACOKINETICS – Formulation: Phosphate, hydrochloride. – PPB: 50-65%.

ANTI-PROTOZOAL DRUGS
ANTI-MALARIAL DRUGS DRUG CLASSIFICATION >Blood schizonticides • Drugs for suppressive or clinical cure. • Affect the erythrocytic stage of life cycle. • Suppress the symptoms of actual attack by destroying the schizonts and merozoites in the erythrocytes. • CHLOROQUINE, AMODIAQUINE, MEFLOQUINE, QUININE, HALOFANTRINE. >Tissue schizonticides • Effects radical cure by acting on the malarial hepatic stage. • Destroys gametocytes, thus reducing the spread of infection.

High concentrations in the erythrocytes, liver, spleen, kidneys, lungs, leukocytes. – Penetrates the CNS and crosses the placenta. – T1/2: 3-5 days. PHARMACOLOGIC EFFECTS – Antimalarial effect. – Quinidine-like effect on the heart à depresses the cardiac function. – Distinct anti-inflammatory capability especially in rheumatoid arthritis and chronic discoid LE. – CHLOROQUINE (Aralen) THERAPEUTIC USES – Acute malarial attacks. • Terminates fever in 24-48 hours. • Terminates parasitemia in 48-72 hours. – Chemophophylaxis vs all forms of malaria except P. falciparum resistant to 4-aminoquinolines. – Amoebiasis, autoimmune disorders as DMARD. ADR – Mild: GI complaints (nausea, epigastric distress), skin rash, headache. – High dosage: Alopecia, graying of the hair, skin eruptions and desquamations, keratopathy, retinopathy. – Overdosage: Visual disturbances, hyperexcitability, convulsions, AV block, death. –

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QUININE • Alkaloid from the cinchona bark. • MECHANISM OF ACTION – Complexes with double-stranded DNA to prevent strand separation, transcription, and CHON synthesis. • PHARMACOLOGIC EFFECTS – Peripheral vosodilation. – Quinidine-like depression of myocardial excitability and conduction velocity.

Direct relaxant effect on the smooth muscles à severe or lethal hypotension. – Distinct curare-like action. – Contraction of the pregnant uterus. – Hypoglycemia. PHARMACOKINETICS – Administration: PO, IV, IM (7day course). – PPB: 70-80%. – T1/2: 7-12 hours. – Highest concentrations in the liver, lungs, kidneys, spleen. – Metabolism in the liver; excretion through the urine. THERAPEUTIC USES – Parenteral treatment of severe falciparum malaria. – Oral Rx of falciparum malaria resistant to Chloroquine. – Prophylaxis for Chloroquineresistant falciparum strains. – Relief of nighttime leg cramps. – Severe babesiosis with Clindamycin. Adverse Reactions GI: Irritation à NAV, epigastric pain. Cinchonism: At a drug plasma level of 7-10 mg/ml. – GI distress, tinnitus, vertigo, headache, blurred vision. Hematologic effects – Hemolysis, leukopenia, agranulocytosis, thrombocytopenia purpura, Henoch-Schonlein purpura, hypoprothrombinemia. Hypoglycemia, thrombophlebitis, moderate-severe hypotension, seizures, ventricular fibrillation, death. Severe toxicity – Fever, skin eruptions, GI symptoms, deafness, visual abnormalities, CNS effects (syncope, confusion), quinidinelike effects. Blackwater fever – Characterized byexcessive intravascular hemolysis followed –

by hemoglobinuria, dark urine, azotemia, renal failure. • DRUG INTERACTIONS (QUININE) – + aluminum-containing antacids à delayed absorption of Quinine. – + Digoxin à decreased renal clearance of Digoxin à increased serum concentration of Digoxin. – + Warfarin and other anticoagulants à enhanced action of these anticoagulants. – + Cimetidine à slowed elimination of Quinine. •

MEFLOQUINE  Synthetic 4-quinoline methanol derivative chemically related to quinine. • MECHANISM OF ACTION – Inhibition of heme polymerase (enzyme that polymerizes toxic free heme to hemozoin) à parasite becomes harmless. • PHARMACOKINETICS – Administered by oral route; highly protein-bound, concentrated in the RBC and extensively distributed to the tissues; t1/2 of > 6 days. • PHARMACOLOGIC EFFECT – Quinidine-like effects on the heart à BP reduction and depression of cardiac function. • THERAPEUTIC USES – Prophylaxis and treatment of Chloroquine-resistant strains of P. falciparum. • ADVERSE REACTIONS – Prophylactic dose: • GI disturbances, headache, dizziness, syncope, extrasystoles. • Transient leukocytosis, thrombobocytopenia, aminotransferase elevations. • Transient neuropsychiatric events as convulsions, depression, and psychosis. – Treatment dose:

GI disturbances, fatigue, neuropsychiatric symptoms, pruritus, skin rash, myalgia. CONTRAINDICATIONS – History of epilepsy, psychiatric illness, arrhythmias, cardiac conduction defects, or sensitivity to quinidine or related drugs. – Concurrent use with quinine, quinidine, or halofantrine. – Pregnancy. – Persons whose work requires fine coordination and spatial discrimination. – With anti-convulsant drugs à breakthrough seizures. •

HALOFANTRINE • Active against strains of P. falciparum resistant to chloroquine, pyrimethamine, or quinine and the erythrocytic form of P. vivax. • PHARMACOKINETICS – Administered PO with peak plasma concentration 4-6 hours after ingestion. – Main metabolite: N-debutylhalofantrine; excretion: feces. – T1/2: 4-5 days. • ADR – Abdominal pain, GI disturbances, headache, cough, transient rise in hepatic enzymes, pruritus, syncope, dysrhythmias, hemolytic anemia, convulsions. PRIMAQUINE  An 8-aminoquinoline drug. • MECHANISM OF ACTION – Forms quinoline-quinone metabolites which interfere with electron transport causing oxidative damage to mitochondrial enzyme system in the parasite à swelling and vacuolation of the mitochodria à lysis of the parasite. • PHARMACOKINETICS – Administered PO.

Concentrated in the liver, lungs, brain, heart, and skeletal muscles. – Rapidly biotransformed (liver) to carboxyprimaquine. – T1/2: 3-5 hours. THERAPEUTIC USES – Terminal prophylaxis of vivax and ovale malaria. – Radical cure of acute vivax and ovale malaria. – Gametocidal action. – Pneumocystis carinii pneumonia. – ADVERSE REACTIONS – Abdominal discomfort, nausea, headache, changes in visual accommodation. – Leukopenia, agranulocytosis, leukocytosis, pruritus, arrhythmias. – Primaquine sensitivity • Intravascular hemolysis accompanied by the formation of methemoglobin in G6PDdeficient patients. –

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Prophylaxis against malaria and in Chloroquine-resistant falciparum malaria (Chloroguanide.) Treatment of Chloroquine-resistant P. falciparum malaria (with sulfone or sulfonamide). ADVERSE REACTIONS Anorexia (Chloroguanide). Folic acid deficiency manifested as bone marrow depression and megaloblastosis (Pyrimethamine).

ANTIFOLATE DRUGS OR FOLATE METABOLISM INHIBITORS OR DIHYDROFOLATE REDUCTASE INHIBITORS • DRUGS: Chloroguanide/Proguanil, Pyrimethamine, Trimethoprim • MECHANISM OF ACTION – Inhibits plasmodial dihydrofolate reductase (DHFR) à reduction of dihydrofolic acid to tetrachydrofolic acid (folinic acid) is inhibited. PHARMACOKINETICS • Chloroguanide – Slowly absorbed from the GIT; activated by conversion to the triazine compound; t1/2 of 16 hours. • Pyrimethamine/Trimethoprim – Rapidly absorbed in the GIT; tissue concentration is high; t1/2 of 4 days. • THERAPEUTIC USES

ALTERNATIVE ANTIMALARIAL DRUG: QINGHAOSU • Also known as Artemisinin. • Sesquiterpene lactone endoperoxide. • Extract from a Chinese herbal medicine (Artemisia amma). • Other derivatives: Artesunate, artemether, artether. • PHARMACOKINETICS – Administered PO, IV, IM, rectal insertion. – Converted into dihydroqinghaosu or dihydroartemisinin. – T1/2: Artemisinin - 4 hours; artesunate - 45 minutes; artemether - 4-11 hours. • CLINICAL USES – Effective blood schizonticide against all malarial forms and Chloroquine-resistain falciparum malaria; cerebral falciparum malaria. • ADVERSE REACTIONS – Abdominal pain, diarrhea; depression of reticulocyte ct; transient heart block. ALTERNATIVE ANTIMALARIAL DRUGS • QUINACRINE – A blood schizonticide that suppresses all types of human malaria; effects radical cure of P. malariae and non-resistant strains of falciparum malaria. – ADR: yellowish discoloration of the skin, psychotic rxns – Also used in the treatment of giardiasis.

DOXYCYCLINE – A tetracycline used vs multidrug resistant P. falciparum. DRUG

CONDITION

THERAPEUTIC OPTIONS FOR THE TREATMENT AND PREVENTION OF MALARIA

All Plasmodium Chloroquine species except Chloroquineresistant P. falciparum Chloroquineresistant P. falciparum Quinine + Pyrimethaminesulfadoxine or Doxycycline or Clindamycin Alternate drug: Mefloquine Primaquine

Prevention of relapses: P. vivax and P. ovale only Prevention of malaria

In Chloroquine-sensitive geographic areas: Chloroquine In chloroquine-resistant geographic areas: Mefloquine Chloroquine or Mefloquine

In pregnancy –

Also for blood stages of the other Plasmodium species. – With quinine for acute malaria. – ADR: GI symptoms, candidal vaginitis, photosensitivity. DAPSONE – 4,4-diaminodiphenylsulfone (DDS) used in the prophylaxis of malaria usually combined with Pyrimethamine.

POTENTIAL NEW ANTIMALARIAL DRUGS • PYRONARIDINE – Synthetic schizonticidal agent derived from mepacrine; developed in China. – ATOVAQUONE – Hydroxynapthoquinone for P. carinii penumonia.

AMOEBIASIS: E. histolytica • DRUG CLASSIFICATION – Mixed amoebicidal drug • Effective against both luminal and systemic forms. • METRONIDAZOLE. – Luminal amoebicides • Act on the parasite in the lumen of the bowel. • Dichloroacetamides: DILOXANIDE FUROATE, TECLOZAN, ETOFAMIDE. • Halogenated hydrogquinolines: IODOQUINOL, CLIOQUINOL. • Antibiotics: TETRACYCLINE, PAROMOMYCIN. – Systemic amoebicides • Effective against amoebae in the intestine and liver. • EMETINE, DEHYDROEMETINE, CHLOROQUINE. NITROIMIDAZOLES: >Metronidazole (Flagyl, Anerobia) >Tinidazole (Fasigyn) • MECHANISM OF ACTION – Undergoes reductive bioactivation of its nitro group by ferredoxin to form reactive cytotoxic products. • PHARMACOKINETICS – Administered PO, IV, rectal insertion. – Peak plasma concentration 1-3 hours after administration. – T1/2: Metronidazole - 7 hours; Tinidazole - 12-14 hours. • Drug of choice in severe intestinal wall disease and in hepatic abscess and other extra-intestinal amoebic disease. • CLINICAL USES: Mild-severe intestinal disease, liver abscess, amoeboma, extraintestinal infections.

TOXICITY: Bitter metallic taste, GI irritation, headache, discoloration of the urine, leukopenia, dizziness, ataxia. DRUG INTERACTION: Disulfiram-like rxn with ethanol and potentiation of coumarin anticoagulant effect.

ADVERSE REACTIONS – Mild: Diarrhea, NAV, gastritis, CLINICAL SYNDROME Asymptoma tic cyst carriers Diarrhea / dysentery Extraintesti nal Amoebic liver abscess – DRUG

DILOXANIDE FUROATE • Drug of choice in the treatment of asymptomatic passers of cysts and in the treatment of intestinal amoebiasis. • Direct amoebicidal action, affecting the amoeba before encystment. • Administered PO; converted in the gut to diloxanide-free base which is active. • ADR: Flatulence, dryness of the mouth, nausea, pruritus, urticaria. • CI in pregnant women and children under 2 years old. EMETINES: Emetine, Dehydroemetine  Alkaloid obtained from Brazil root. • MECHANISM OF ACTION – Inhibits protein synthesis by blocking ribosomal movement along the messenger RNA. • Used as back-up drugs for the treatment of severe intestinal or hepatic amoebiasis in hospitalized patients. • Given parenterally (IM); widely distributed; excreted slowly by the kidneys. • TOXICITY: Pain, tenderness, GI distress, muscle weakness, CV dysfunction (arrhythmias and CHF with dyspnea and hypotension. • CLINICAL USES: Amoebic dysentery, amoebic liver abscess, amoebomas, and extra-intestinal amoebiasis. HALOGENATED HYDROQUINOLINES: Iodoquinol, Clioquinol • Orally active luminal amoebicides used as alternative drugs for mild to severe intestinal infections. • CLINICAL USES – Intestinal amoebiasis, T. vaginalis vaginitis, other intestinal parasites as B. coli, G. lamblia.

Iodoquinol or Paromomycin or Diloxanide furoate Metronidazole + Iodoquinol or Paromomycin or Diloxanide furoate Chloroquine + Metronidazole or Emetine

headache, malaise. Large doses and prolonged use: SMON (subacute myelooptic neuropathy.

OTHER DRUGS • CHLOROQUINE – Active against amoebas in the liver especially when given with Emetine. – Used in combination with Metronidazole and Diloxanide furoate to treat and prevent amoebic liver abscesss. – PAROMOMYCIN (Humagel) – Aminoglycoside antibiotic used as a 2nd-line amoebicide (luminal type). – Reduces the population of the intestinal flora. – ADR: GI distress, diarrhea, headache, rashes, arthralgia. – For mild intestinal disease à combine with Doxycycline.

Therapeutic options for amoebiasis

disturbances, such as severe vomiting and abdominal pain; hemolytic anemia in G-6-PD deficiency. Pentamidine isethionate – Administered IM or by aerosol; no metabolized but excreted very slowly into the urine; t1/2 of 5 days. – Used to prevent and treat the organism’s hematologic stage. Nifurtimox – Used for Chagas’ disease. – Undergoes reduction into intrecellular oxygen radicals (superoxide and hydrogen peroxide radicals) à toxic to organism. – Administered orally. – ADR (elderly): Hypersensitivity reaction and GI problems; peripheral neuropathy. Suramin – – – Used for African trypanosomiasis. MOA: Inhibits many enzymes involved in energy metabolism. Given IV.

Treatment for trypanosomiasis • African sleeping sickness – Caused by Trypanosoma brucei gambiense and Trypanosoma brucei rhodiense. – Live and grow in the blood à invade CNS à inflammation of the brain and spinal cord à lethargy and continuous sleep. • American sleeping sickness – Chagas’ disease. – Caused by Trypanosoma cruzi. – Occurs in South America. Melarsoprol – A derivative of mersalyl oxide that is used for the treatment of late stage of the infection with CNS involvement. – MOA: Reacts with sulfhydryl groups of various substances, including the enzymes à toxic compounds. – MOR: Decreased permeability of the drug. – Administered by IV; short t 1/2; rapidly oxidized into nontoxic pentavalent arsenic compound. – DOC in the Rx of T. brucei rhodiense and for meningoencephalitis caused by T. brucei gambiense. – ADR: Encephalopathy; hypersensitivity reactions; GI

Treatment for other protozoal infections  LEISHMANIASIS o Sodium stibogluconate  TOXOPLASMOSIS o Pyrimethamine o Sulfadiazine + Pyrimethamine  GIARDIASIS – Metronidazole

BACILLARY POPULATION (IN LUNG FIELDS)
• population A – bacilli lining the cavity wall – rapid growth and multiplication due to abundant supply of O2 – reside in neutral or slightly alkaline [pH] environment

– •

source of infectiousness, communicability, and resistant mutants population B (Persisters) – bacilli in caseous nodules and inner linings of cavitary lesions – slow or intermittent metabolism [persisters] – environment contains little O2 and pH is slightly acidic – source of relapse à difficult to eradicate population C (Intracellular Bacilli) – bacilli inside macrophages [intracellular population] – slow metabolizers [persisters] – environment is poorly oxygenated and frankly acidic – source of relapse

Given for the next 4 months – Maintenance – – • INH RFP Same dose as mentioned above

Total number of Rx= 6 months

CONTRAINDICATIONS TO SCC • • • • History of liver disease (SGPT, SGOT, alcoholics) History of chronic and acute renal disease History of gout or predisposition to gout (PZA) Patients taking steroids for more than 6 months – Immunosuppression

VITAL FACTORS IN THE CHEMOTHERAPY OF TB
S**M
active Streptomycin (Oldest, 1944)

Pop. A
Most active
We akly active

Se cond m active ost

• • • •

Correct dosage Regularity of administration Adequate duration Proper drug combination

Mos active t

INH
Le active than RFP ss

Pop. B Pop. C
Most active

RFP
2nd m active ost

PRIMARY HEALTH CARE [PHILIPPINES] • For 2 months daily Rx -intensive – Rifampicin 450mg – INH 300mg – Pyrazinamide 1000mg to 15000mg For 4 months -maintenance – Rifampicin 450mg – INH 300mg

2

PZA

ETHAMBUTOL • • • • Bacteriostatic to populations A and C Inhibits the growth of mutants resistant to INH and RFP Not hepatotoxic but causes optic neuritis, give to adults only, not in children. Hepatotoxic: – Isoniazid – Pyrazinamide ß Causes gout – Rifampicin

Pyrazinamide 500mg/ tab (aka Para amino salicylic acid) • Above 50 kilos – 3tabs (1,500 mg) • 50 kilos and below – 2tabs (1,000 mg) • Rifater, Pyrina – RNZ (Rifampicin, INH, PZA) – For 2 months • Rifinah – RN (Rifampicin, and INH) – For 4 months REASONS FOR RX FAILURE 1. Non-observance of vital factors of Rx by either physician or px 2. Very extensive disease 3. Uncontrolled DM and alcoholism 4. Primary resistance to drugs 5. Inherent of cellular immunity in the px

SHORT COURSE THERAPY OR SHORT COURSE CHEMOTHERAPY [AUGUST 19, 1986] Given for the first 2 months - Intesnsive – – – INH [Isoniazid] 300 mg PO daily PZA [Pyrazinamide] 500 mg PO daily RFP [Rifampicin] 450 mg PO AC OD

ADVERSE DRUG REACTIONS [ADR] – 1ST MONTH • • • • • • • • • • • – Loss of appetite and tiredness without reason - INH Unexplained nausea and vomiting, collapse - INH Rash and persistent itchiness - INH Yellowish discolorations of skin and eyeballs Rifamp Flu-like syndrome- fever, chills, pain When R is given intermittently in high dose - Rifamp Tingling and burning sensation of hands and feet Swelling and generalized edema Shortness of breath - INH Petechiae and ecchymoses – Rifampicin Advice- stop medication for few days and do desensitization Dose- 1/10, ¼, ½ à average dose • 4 drugs given initially [2 months] – Big bacillary population especially cavitary lesion – Previous use of anti-TB drugs – High primary resistance to H ? – Close contact with resistant source case

MDT FOR LEPROSY [WHO]
Disease Other Name Paucibacillary Tuberculoid, Indeterminate type Multibacillary Lepromatous, mid borderline (Serious, fingerless)

Rx

DRUG DOSE ADJUSTMENT • • • INH – 5-10mg/kg, up to 400mg/ day Rifampicin – 10mg/kg, up to 600mg/day Pyrazinamide – 25-35 mg/kg, not to exceed 2grams daily • irrespective of serum uric and level for as long as px is asymptomatic • Ethambutol – 25mg/ kg/ day for 1st 2 months – 15mg/ kg for next 4 months • Streptomycin – 15-20mg/ kg up to 1 gram daily by IM INH PROPHYLACTIC USE – Infants and children up to 6 years who converts to [+] PPD [without previous BCG] – PPD [–] medical personnel and students who are in close contact with active cases in wards – Recent tuberculin converters in close contact with open cases of TB – Px on corticosteroid, anti-metabolite therapy with previous TB history • dose- 10mg/kg/ day - 300-400mg daily
Rx duration Surveillance after Rx completion

Rifampicin 600mg once -Same a month, Dapsone 100 mg 1-2 mg/kg/d -Same -Clofazimine (Lamprene) 300mg once a month AND 50 mg/d 6 months Annual exams for at least 2 years 2 years or until skin smears are negative Annual exams for at 14 least 5 years

SIDE NOTES • • • • • • Give Vitamin B complex (Pyridoxine) to prevent INH (Isoniazid H) toxicity DOT – Direct Observance Therapy Streptomycin – Only anti TB drug administered IM Increased dose in INH causes convulsions 2 months is INTENSIVE, 4 months is MAINTENANCE Myrin P – Combination of the following drugs, 2 months: (INTENSIVE) – R = Rifampicin – I = Isoniazid – P = Pyrazinamide – E = Ethambutol Myrin (4 months), only R I E Rifampicin has PAE against leprosy, it is leprocidal PHILCAT – Philippine Coalition Against tuberculosis

• • •

Rx regimen Best recommended Rx regimen for pulmonary TB [MDRTB ?] – – • RHZE or RHZS daily [2 months] RH [4 months] daily I. 2 HRZE (2 RIPE) / 4HR (4 RI) New pulmonary smear (+) cases New seriously ill pulmonary smear negative cases with parenchymal involvement III. New seriously ill extrapulmonary TB cases I. II. 2 HRZES (2 RIPES) / 1 HREZ (1 RIPE) / 5 HRE (5 RIE)

Chemoprophylaxis of adult patient [13-35 years] – INH + Ethambutol daily for 6 months; – Or INH + Rifampicin daily for 4 months

II.

I. II. III. III.

Failure cases Relapse cases X-ray smear (+)

2 HRZ (2 RIP) / 4 HR (4 RI) New cases, smear (--) but with minimal pulmonary TB on x-ray confirmed by medical officer II. New extrapulmonary TB (Not serious) I.

• • • •

H = Isoniazid H R = Rifampicin Z = Pyrazinamide E = Ethambutol

• • • • •

INH & rifampicin- hepatotoxic Streptomycin & ethambutol- parenteral route Rifampicin- nephrotoxic Pyrazinamide- increase uric acid- gout Ethambutol- cause optic neuritis in chidren

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