Antiparasitic Drugs 2012

Antiparasitic Drugs

Malaria, one of the most widespread disease, is caused by a Plasmodium parasite. Its name is derived from mala aria (bad air), and it has been called ague, intermittent fever, marsh fever, and The Fever. The name is based on the early knowledge that malaria was associated with swamp and badly drained areas. The disease was spread by mosquito. Proof that the Anopheles mosquito is the carrier of the causative protozoa was obtained by Dr. Ronald Ross, who was recognized in 1902 with the Nobel Prize in Medicine.

Malaria Malaria is caused by plasmodium whose sporozoites was inoculated to initiate human infection by anopheline mosquito. Four species of plasmodium cause human malaria: Plasmodium falciparum responsible for nearly all serious complicationsand deaths. P vivax benign malaria P malariae P ovale seldom

Parasite Life CycleI.

Asexual stage in human:Primary exoerythrocytic stage: sporozoites invade liver cells schizonts incubation period Asexual erythrocytic stage: merozoites invade erythrocytes, trophozoites schizonts, rupture host erythrocytes repeated cycles cause clinical illness Secondary exoerythrocytic stage: In P vivax and P ovale infections, a dormant hepatic stage, hypnozoite relapses

II.

Sexual stage in anopheline mosquito:Sexual stage gametocytes also develop in erythrocytes before being taken up by mosquitoes, where they develop into infective sporozoites.

Malaria transmission life cycle: Sporozoites tissue schizonts (in liver) merozoites infect RBC (blood schizonts) rupture of RBC (clinical attack) new crops of merozoites Sexual form: some merozoites differentiate into male & female gametocytes ingested by a mosquito where they form Sporozoites human

P. malariae & p. falciparum have one cycle of liver invasion and end by the 4th week i.e. no relapse occurs. P.ovale & p. vivax have dormant stages (hypnozoites) in the liver. These hypnozoites may rupture months or years later causing relapse of the attacks.

Treatment of malariaP. vivax, P. ovale & P. malariae:

ChloroquineNB: It is also allowed in pregnancy. P. Falciparum (most cases are chloroquine-resistant):

Quinine 600 mg salt/8h till patient become better and blood is free of parasites (usually in 3-5 days). Followed by a single dose of fansidar (3 tablets). In pregnancy 7-day course of quinine alone should be given.

Alternative therapy Mefloquine 20 mg base/kg up to a maximum of 1.5 g in two divided doses 8 hours apart. Mefloquine is contraindicated in pregnancy. Cerebral malaria: Quinine 10 mg/kg i.v infusion over 4 h. could be repeated at intervals of 8-12 h. until patient can take drug orally. Or Halofantrine: orally only Or Qinghaosu (Artemisinin): oral & i.v

Antimalarial Agents Quinoline group quinine, quinidine, CQ, MQ, PQ, amodiaquine, halofantrine

Anti-folate pyrimethamine, proguanil, chloroproguanil, trimethoprim

Artemisinin analog artemisinin, artisunate, artemether, arteether, dihyroartemisinin

Some antibiotics like tetracycline, Clindamycin, macrolides (azithromycin), atovaquone

Classification of Antimalarial DrugsAntimalarial DrugsChemoprophylaxis Radical Cure Acute Attack Prevent Transmission

Drugs for Acute Attack Known also as blood schizoniticidal agents Used for clinical cure (suppressive) Act on Erythrocytic form of plasmidium Can affect a cure for P. falciparum and P. malariae (no exoerythrocytic stage) Agents: Quinine, quinidine, chloroquine, mefloquine, halofantrine, sulphones, pyrimethamine, atovaquone, doxycycline, Qinghaosu derivatives

Agents Used for Prophylaxis Prevents malaria attack by blocking the link between Pre-erythrocytic and Erythrocytic stages Agents: Chloroquine Mefloquine Doxycycline Atovaquone/Proguanil Dapsone

Agents for Radical Cure Also known as tissue schizonticidal agents Cause a radical cure (eradication) of dormant stage in the liver of P vivax, P ovale Agents: PRIMAQUINE

Drug Used to Prevent Transmission These agents destroy gametocytes and prevent transmission by the mosquito, thus preventing spread of disease Not used alone for this action, usually combined with other agents Agents: Primaquine Pyrimethamine Proguanil

Chemoprophylaxis of malariaChloroquine-sensitive area: Chloroquine 150 mg base ( 2 tab/week) Chloroquine-resistant area: Chloroquine ( 2 tab/week) plus proguanil 100 mg (one or two tab/ day) or Mefloquine 250 mg (one tab./ week)

Control symptoms

Chloroquine

A synthetic 4-aminoquinoline formulated as the phosphate salt for oral use. Pharmacokinetics Rapidly and almost completely absorbed from the gastrointestinal tract. Very large apparent volume of distribution of 100-1000 L/kg. Necessitate the use of a loading dose to rapidly achieve effective serum concentrations. Slowly released from tissues and metabolized. Principally excreted in the urine.

Chloroquine (4- aminoquinoline derivative) Mechanism of action: Inhibits synthesis of DNA and RNA in the plasmodium. Increases pH of the vacules in the parasite, so prevent its utilization of erythrocyte hemoglobin. Uses: Acute attack 600 mg base (4 tab.) then 300 mg after 6 h. then 150 mg bid for two more days. Add 100 mg proguanil/ day (2 tab.) in chloroquine-resistant area.

Mechanism of action:

The organism digest HB of the host releases heme which is toxic to theorganism polymerizes heme to hemozoin (non toxic to the parasite).Chloroquine inhibits heme polymerization to hemozoin oxidative damage lysis of parasite and RBC.

Pharmacological Effects1. Antimalarial action: highly effective blood schizonticide. Moderately effective against gametocytes of P vivax, P ovale, and P malariae but not against those of P falciparum. not active against liver stage parasites. Mechanism: plasmodium aggregates chloroquine. chloroquine incorporated into DNA chain of plasmodium inhibit proliferation. chloroquine prevents the polymerization of the hemoglobin breakdown product, heme, into hemozoin and thus eliciting parasite toxicity due to the buildup of free heme. pH plasmodium protease activity Resistance: very common among strains of P falciparum and uncommon but increasing for P vivax. The mechanism of resisitance to chloroquine is resistant strains excretes drug more rapidly. 2. Killing Amibic trophozoites : chloroquine reaches high liver concentrations. 3. Immunosuppression action:

Clinical Uses1. Treatment: non falciparum and sensitive falciparum malaria. Primaquine must be added for the radical cure of P vivax and P ovale, because chloroquine does not eliminate dormant liver forms of these species. 2. Chemoprophylaxis: for without resistant falciparum malaria in malarious regions. 3. Amebic liver abscess: not effective in the treatment of intestinal or other extrahepatic amebiasis.

Adverse Effects and Cautions Usually very well tolerated, even with prolonged use. Pruritus is common. Nausea, vomiting, abdominal pain, headache, anorexia, malaise, blurring of vision, and urticaria are uncommon. Dosing after meals may reduce some adverse effects. Rare reactions include hemolysis in G6PD-deficient persons, impaired hearing, confusion, psychosis, seizures, hypotension, ECG changes. teratogenesis

Control symptoms

Quinine

Quinine and quinidine remain first-line therapies for falciparum malariaespecially severe disease. Quinine is an alkaloid derived from the bark of the cinchona tree, a traditional remedy for intermittent fevers from South America. Quinine is the levorotatory stereoisomer of quinidine. Rapidly absorbed after oral administration. Metabolized in the liver and excreted in the urine.

MOA: acts primarily as a blood schizonticide. May be by intercalation of the quinoline moiety into the DNA of the parasite, thereby reducing the effectiveness of DNA Also by pH elevation in intracellular organelles of the parasites

Pharmacological Effects Highly effective blood schizonticide against the four species of human malaria paresites. Gametocidal against P vivax and P ovale but not P falciparum. Not active against liver stage parasites. Depressing cardiac contractility and conduction, lengthening refractory period, exciting uterine smooth muscle, depressing central nervous system, little antipyretic-analgesic effect.

Clinical Uses: mainly for chloroquine-resistant falciparum malaria, especially for cerebral malaria. Parenteral treatment of severe falciparum malaria Oral treatment of falciparum malaria Malarial chemoprophylaxis Babesiosis

Adverse Effects and Cautions1. Cinchonism: tinnitus, headache, nausea, dizziness, flushing, visual disturbances 2. Cardiovascular effects: severe hypotension and arrhythmia can follow too-rapid intravenous infusion. 3. Idiosyncrasy: hemolysis with G6PD deficiency. 4. Others: hypoglycemia through stimulation of insulin release, stimulate uterine contractions

Control symptoms

Mefloquine

A synthetic 4-quinoline methanol that is chemically related to quinine. Pharmacokinetics Only be given orally because severe local irritation occurs with parenteral use. Well absorbed. Highly protein-bound, extensively distributed in tissues, and eliminated slowly. t1/2 is 20 days.

Pharmacological Effects: Strong blood schizonticidal activity against P falciparum and P vivax, but not active against hepatic stages or gametocytes.

MOA: causes destruction of asexual blood forms of malaria Clinical Uses Chemoprophylaxis: Treatment: mainly for chloroquine-resistant falciparum malaria.

Adverse Effects and Cautions Nausea, vomiting, diarrhea, abdominal pain dose-dependent Neuropsychiatric toxicities: dizziness, headache, behavioral disturbances, psychosis, seizures.

Control symptoms

Malaridine

Developed by China. blood schizonticidal activity. Treatment for all types malaria, including chloroquine-resistant falciparum malaria. Mechanism: destroy parasite compound membrane and food vacuoles.

Control symptoms

Artemisinin

Extracted from yellow flower mugwort. Kill trophozoites of erythrocytes. quick and effective. maybe kill earlier period trophozoites. Through blood-brain barrie, treatment for cerebral malaria. recurrence rate is high. Resistence. Interaction with others antimalarial drugs:

Control symptoms

It is a blood schizonticide against all types of malaria including chloroquine-resistant p. falciparum. Artemether and Artesunate Dihydroartemisinin

Control relapse and transmission

Primaquine

Synthetic 8-aminoquinoline. Pharmacological Effects Against hepatic stages of malaria parasites. The only available agent active against the dormant hypnozoite stages of P vivax and P ovale. Also gametocidal against the four human malaria species.

MOA: Unknown ? disrupts mitochondria and binds to DNA

Clinical Uses Therapy (Radical Cure) of Acute Vivax and Ovale Malaria: chloroquine + primaquine Terminal Prophylaxis of Vivax and Ovale Malaria: prevent a relapse Chemoprophylaxis of Malaria: protection against falciparum and vivax malaria. But potential toxicities of long-term use limited its routinely administration. Gametocidal Action: A single dose of primaquine (45 mg base) can be used as a control measure to render P falciparum gametocytes noninfective to mosquitoes. This therapy is of no clinical benefit to the patient but will disrupt transmission Pneumocystis carinii infection: clindamycin+primaquine mild to moderate pneumocystosis

Adverse Effects and Cautions Nausea, epigastric pain, abdominal cramps, headache. Hemolysis or methemoglobinemia, especially in persons with G6PD deficiency or other hereditary metabolic defects.

Etiological factor prophylaxis

Pyrimethamine

Pharmacokinetics Slowly but adequately absorbed from the gastrointestinal tract. Slowly eliminated and excreted from urine.

Pharmacological Effects Kill schizonts of primary exoerythrocytic stage. Act slowly against premature schizonts of erythrocytic stage. No action against gametocytes, but can inhibit development of plasmodium in mosquito. Inhibit plasmodial dihydrofolate reductase inhibiting breeding of plasmodium.

Adverse Effects and Cautions Gastrointestinal symptoms, skin rashes. Interfering folic acid metabolism in human megalocyte anemia, granulocytopenia. Acute intoxication Teratogenesis

Etiological factor prophylaxis

Sulfonamides and Sulfone Competing dihydropteroatesye synthase with PABA inhibiting to form dihydrofolic acid inhibiting production of purines and synthesis of nucleic acids. Only inhibiting plasmodial of exoerythrocytic stage Not used as single agents for the treatment. Combination with other agents.

Halofantrine: Old agent reemerging for treatment of MDRM MOA: Similar to mefloquine, destruction of asexual blood forms, possible inhibition of proton pump Effective against erythrocytic stages of all human malaria species, not hepatic stages or gametoytes

Used only by oral route in P. falciparum cerebral malaria. No parenteral preparation. Not used for prophylaxis. Not used during pregnancy unless benefit outweighs the risk.

Proguanil MOA: similar to pyrimehamine (antifolate) Proguanil is a prodrug; needs to be metabolized to cycloguanil to be active Need to be given daily in prophylaxis; unlike pyrimethamine which is given weekly

Fansidar: It is a combination of sulfadoxin and pyrimethamine. It is used in chloroquine-resistant p. falciparum. Not used for prophylaxis as it causes agranulocytosis & StevensJohnson syndrome. A.E: Sulfonamide: rashes, kidney damage, hemolysis & GIT upset. Pyrimethamine: folic acid deficiency, agranulocytosis & StevensJohnson syndrome. Disadvantages: slow blood schizonticide activity, drug resistance & numerous & serious adverse effects. C/I: pregnancy & nursing women, G-6-PD, renal impairment & children under 2 months of age.

Atovaquone: Unknown mechanism of action. Used alone for treatment of pneumocytosis and toxoplasmosis in patients with AIDS. Atovaquone + proguanil (malarone) for treatment & prophylaxis of chloroquine-resistant P. falciparum. A/E: fever, rashes, cough, nausea, vomiting, diarrhea, headache & insomnia.

Rational Use of Antimalarial Drugs1.

Choice of Antimalarial Drugs:Control symptoms: chloroquine Cerebral malaria: chloroquine phosphate, quinine bimuriate, artemisinin injection Chloroquine-resistant falciparum malaria: quinine, mefloquine, artemisinin Dormant hypnozoite stages : pyrimethamine + primaquine Prophylaxis: pyrimethamine, chloroquine

2.

Combination therapy: chloroquine + primaquine: symptom stages pyrimethamine + primaquine: dormant hypnozoite stages Combination of drugs with different mechanisms: therapeutic effect, resistance

Anti-amebiasis Drugs Amebiasis is infection with Entamoeba histolytic. Amebiasis is transmitted through gastrointestinal tract. Ameba has two stages of development: cyst and trophozoite.Cysts small intestine little trophozoites (ileocecum)

cysts (colon) asymptomatic intestinal infection, source of infection big trophozoites (tissues of intestine) intestinal amebiasis

Treatment of amebiasis:Infection with E.histolytica produced by ingestion of cysts (non invasive form). - In the intestine trophozoites (active invasive form) invade submucosa of the host cells resulting in: A-Luminal amebiasis: cysts are passed into faeces (carriers or cyst passers).

Treatment is directed at eradicating cysts luminal amebicides diloxanide, iodoquinol, paromomycin &tetracycline.

-

B- Tissue invading amebiasis: dysentery (acute intestinal

amebiasis), amebic granuloma (ameboa in the intestinal wall,) hepatic abscess & extra-intestinal disease. A systemic tissue amebicides against trophozoites should be used e.g.nitroimidazole (metronidazole or tinidazole), dihydroemetine, and chloroquine. N.B.: treatment with tissue amebicide should be followed by

a course of luminal amebicide to eradicate the source ofinfection

Metronidazole A nitroimidazole.The nitro group of metronidazole is chemically reduced in anaerobic bacteria and sensitive protozoans. Reactive reduction products appear to be responsible for antimicrobial activity. Pharmacokinetics Oral metronidazole is readily absorbed and permeates all tissues by simple diffusion. Protein binding is low (