Antiprotozoal Drugs

2. Antiprotozoal Drugs

3. MALARIA

4. 1. Malaria Malaria is the most important of the transmissible parasitic diseases. Over 90 million cases occur each year. DRUG-RESISTANT MALARIA Plasmodium falciparum is now resistant to chloroquine in many parts of the world. Areas of high risk for resistant parasites include Sub-Saharan Africa, Latin America, Oceania, and some parts of South-East Asia.

6. The incubation period of malaria is 10–35 days. Female anopheles mosquitoes require a blood meal for egg production and in the process of feeding they inject salivary fluid containing sporozoites into humans. Hepatic cycle Sporozoites enter liver cells where they develop into schizonts which form large numbers of merozoites which, usually after 5–16 days, are released into the circulation. persisting hepatic forms (hypnozoites)

7. Erythrocyte cycle Merozoites enter red cells where they develop into schizonts which form more merozoites which are released when the cells burst giving rise to the features of the clinical attack. The merozoites reenter red cells and the cycle is repeated.

8. Life cycle • of malaria • parasites • Pl. falciparum • Pl. malariae • Pl. ovale • Pl. vivax

9. ▪ A patient with cerebral malaria ▪ Morphological changes in erythrocytes Light micrograph of a cerebral capillary blocked with malarial parasitized erythrocytes

10. MALARIA • Plasmodium species that infect humans: ►P falciparum (only 1 cycle of liver cell invasion) ► P malariae (only 1 cycle of liver cell invasion) ► P ovale ► P vivax

11. DRUGS FOR MALARIA • Primary tissue schizonticides (primaquine) ► Kill schizonts in the liver • Blood schizonticides (chloroquine, quinine) ► Kill parasitic forms only in the erythrocyte • Sporonticides (proguanil, pyrimethamine) ► Prevent sporogony and multiplication in the mosquito

12. CHLOROQUINE ▪ Rapidly absorbed (orally) ▪ Antacids →↓ absorption of the drug ▪ Excreted largely unchanged in the urine

13. CHLOROQUINE • Mechanism of action: ▪ Accumulates in the food vacuole of plasmodia ▪ Prevents polymerization heme to Hemozoin (Heme → hemoglobin breakdown product) ▪ Intracellular accumulation of heme is toxic to the parasite

14. CHLOROQUINE • Resistance: ▪ Chloroquine → ↓ Intracellular accumulation (via↑activity of membrane "pumps“) ▪ P falciparum→ ↓ Intra-vacuolar accumulation of chloroquine via a transporter encoded by the pfcrt gene (P falciparum chloroquine-resistance transporter)

15. CHLOROQUINEClinical use • Drug of choice for: ► Acute attacks of non-falciparum & sensitive falciparum malaria (Pregnancy) • Chemoprophylaxis (except in regions where P falciparum is resistant) • Autoimmune disorders (rheumatoid arthritis) ►Chloroquine & hydroxy-chloroquine

16. CHLOROQUINEToxicity • At low doses: ► Gastrointestinal irritation ► Skin rash ► Headaches

17. CHLOROQUINEToxicity • High doses: ▪ Severe skin lesions ▪ Peripheral neuropathies ▪ Myocardial depression ▪ Retinal damage (irreversible) • Corneal deposits of chloroquine ▪ Auditory impairment ▪ Toxic psychosis ▪ Precipitate porphyria attacks

19. Quinine as cinchona bark was introduced into Europe from South America in 1633. It was used for all fevers, amongst them malaria. Further advance in the chemotherapy of malaria was delayed until 1880, when Charles Louis Alphonse Laveran, Prof. of Military Medicine in Paris (Nobel prize winner 1907) finally identified the parasites in the blood.

20. QUININE Pharmacokinetics: ► Quinine is rapidly absorbed (orally) ► Metabolized before renal excretion ► In severe infections (I.V. administration)

21. QUININE • Mechanism of action: • ► Complexes with double-stranded to plasmodial DNA → prevent strand separation → block of DNA replication and transcription to RNA, prevent protein synthesis. • Solely a blood schizonticide

22. QUININEClinical use ▪ P falciparum infections resistant to chloroquine in patients who can tolerate oral treatment (main use) , Pregnancy ▪ Quinine + Doxycycline or Clindamycin → shorten the duration of therapy & limit toxicity

23. Quinidine ▪ Dextrorotatory stereoisomer of quinine ▪ I.V. for treatment of severe falciparum malaria (in United States) ▪ The drugs should not be used routinely for prophylaxis (To delay emergence of resistance)

24. QUININEToxicity • Cinchonism: (commonly) ▪ Gastrointestinal distress ▪ Headache ▪ Vertigo ▪ Blurred vision ▪ Tinnitus

25. QUININEToxicity ▪Hematotoxic effects: ►Hemolysis (in G6PD-deficient patients) ►Black-water fever (intravascular hemolysis) (rare and fatal in quinine-sensitized persons)

26. QUININEToxicity ▪Severe overdose: ►Disturbances in cardiac conduction (resemble quinidine toxicity) ▪Contraindication: ► visual or auditory problems

27. Wild Quinine

29. Quinine

30. Quinine

31. Quinine Dyhydrochloride Quinine 324 mg Quinine 200 mg

32. MEFLOQUINEClinical uses ▪Prophylaxis: ► In all geographical areas with chloroquine resistance (Pregnancy) ▪Alternative drug to quinine: ► In acute attacks from P falciparum ▪Resistance: ► Emerged in regions of South-east Asia

33. MEFLOQUINEToxicity ▪Adverse effects: (Common) ► Gastrointestinal distress ► Skin rash ► Headache ► Dizziness

34. MEFLOQUINEToxicity ▪Adverse effects: (high doses) ► Cardiac conduction defects ► Psychiatric disorders ► Neurologic symptoms ► Seizures

35. MEFLOQUINE ▪Contraindication: patient with a history of epilepsy psychiatric disorders cardiac conduction defects arrhythmia

38. PRIMAQUINEMechanism of action • Primaquine forms quinoline-quinone metabolites → electron-transferring → cellular oxidants • Tissue schizonticide • Limits malaria transmission (by acting as a gametocide)

39. PRIMAQUINEClinical use • Eradicates liver stages of P vivax and P ovale • Used in conjunction with a blood schizonticide • Not active alone in acute attacks of vivax and ovale malaria • A 14-day course of primaquine is standard after treatment with chloroquine

40. PRIMAQUINEToxicity • Gastrointestinal distress • Pruritus • Headaches • Methemoglobinemia • Hemolysis (in G6PD-deficient patients)

41. PRIMAQUINEContraindication ▪In pregnancy (the fetus is relatively G6PD-deficient and thus at risk of hemolysis) ▪ In G6PD-deficient patients ▪ In patients with history of Methemoglobinemia

43. Primaquine

44. ANTI FOLATE DRUGS • Antifolate group: (half life> 100 h) ▪ Pyrimethamine ▪ Proguanil (chloroguanide) [half-life (12-16 h)] ▪ Sulfadoxine ▪ Dapsone

45. ANTI FOLATE DRUGS • Mechanisms of action: ▪ Sulfonamides → Anti-metabolites of PABA ▪ Inhibiting dihydropteroate synthase → Block folic acid synthesis in certain protozoans ▪ Proguanil → Bioactivated to cycloguanil ▪ Pyrimethamine & Cycloguanil → Selective inhibitors of protozoan dihydrofolate reductases ▪ Pyrimethamine +Sulfadoxine → Synergistic anti-malarial effects (sequential blockade of 2 steps in folic acid synthesis)

47. ANTI FOLATE DRUGSClinical use • Blood schizonticides (mainly against P falciparum) • Pyrimethamine + Sulfadoxine →Fansidar ▪ Treatment of chloroquine-resistant forms of species ▪ Onset of activity is slow • Proguanil + Atovaquone →Malarone ▪ Chemoprophylaxis of chloroquine-resistant malaria (First-line choice ) ▪ Used against mefloquine-resistant falciparum strains

48. Fansidar Adverse Effects • Most patients tolerate pyrimethamine and proguanil well. • GI symptoms, skin rashes, and itching are rare. • Mouth ulcers and alopecia ( proguanil) • Fansidar is no longer recommended for chemoprophylaxis because of uncommon but severe cutaneous reactions, including erythema multiforme • Stevens-Johnson syndrome life-threatening skin condition

49. Stevens–Johnson syndrome

50. Atovaquone as a component of Malarone (atovaquane+ proguanil ) is recommended for treatment and prevention of malaria. absorption is increased by fatty food an alternative therapy (mefloquine and doxycycline)