Species of plasmodium. Clinical features and complications. Life-cycle of plasmodium.

1. Antimalarial Drugs • Species of plasmodium. • Clinical features and complications. • Life-cycle of plasmodium. • Classification of antimalarial drugs. • Individual drugs. Pharma Team

2. Malaria • Each year, it causes disease in approximately 650 million people and kills between one and three million. Species of Malaria • Plasmodium falciparum. • P.vivaxP.vivax & P.ovale. • P.ovale is mainly confined to Africa.

3. Endemic areas of Malaria N.B. in Saudi, P. falciparum is chloroquine resistant

4. In KSA

5. Clinical Features • Acute falicparum malaria is potentially fatal. • Symptoms of malaria.

6. Complications:-. • Hemolytic anemia, hepatospleenomegaly, capillary obstruction, death • Chronic repeated CNS infection: • Clinical manifestationsof cerebral malaria are numerous, but there are three primary symptoms generally common to both adults and children: 1)impaired consciousness with non-specific fever, 2)generalized convulsions and neurological sequelae; and 3) coma that persists for 24-72 hours, initially rousable and then unrousable.

7. Oocyst Sporozoites Mosquito Salivary Gland Zygote Hypnozoites (for P. vivax and P. ovale) Gametocytes Erythrocytic Cycle Malaria Life Cycle Life Cycle Sporogony Sporozoites Exo- erythrocytic (hepatic) cycle Merozoites Merozoites Schizogony

8. Eradication of dormant

9. Classification of Antimalarials • Tissue schizontocides:-. • Proguanil (chlorguanide) • Pyrimethamine

10. Blood schizontocides:-. • 2 types • Chloroquine, Mefloquine, Halofantrine, & Quinine. • Proguanil, Pyrimethamine, & sulfadoxine.

11. Gametocides:-destroy the sexual forms of the parasite. • Primaquine, Chloroquine, & Quinie. • Primaquine the only drug that kills P. falciparum gametocytes • Hypnozoitocides: • primaqunie • kills dormant hypnozoites of P.vivax & P.ovale in the liver.

12. Sprontocides:-interrupt development of sporogonic phase in mosquitos . • Proguanil, pyremethamine primaquine

15. Uses • 1- Prophylactic:-to prevent clinical attack • Suppressive prophylaxis:-use of blood schizontocides to prevent acute attack • Causal prophylaxis:-use of tissue schizontocides to prevent the parasite from establishing in the liver

16. 2-Curative:-suppressive treatment of the acute attack usually with blood schizontocides. • 3-Prevention of transmission:- eradication of infection in mosquitos using gametocytocides or sporontocides. • 4-Prevention of relapse:- • Primaquine

18. P falciparum and P malariae causes one cycle of liver invasion so, if u eliminates the parasited in the RBC the disease will be cured. • P vivax and P ovale there is a dormant parasites in the liver  relapses. So u need to kill parasited in RBC and liver.

19. 4-Aminoquinolines • Chloroquine and amodiaquine • potent blood schizontocide. • Used nonfalciparum and sensitive falciparum malaria

20. Mechanism of action

21. MOA In the previous figure : The parasite digests the human hemoglobin in order to get amino acid, but the problem here is that the heme part of Hb is toxic to the parasite. To overcome this obstacle, the parasite has developed an enzyme responsible for polymerization of heme. To form insoluble crystals called hemozoin which are collected in vacuoles. Chloroquine enters parasite cell by simple diffusion. Chloroquine then becomes protonated as the digestive vacuole is known to be acidic (pH 4.7), chloroquine then cannot leave by diffusion. Chloroquine inhibits polymerization of heme accumulation of heme. Chloroquine binds to heme (or FP) to form what is known as the FP-Chloroquine complex, this complex is highly toxic to the cell and disrupts membrane function. Action of the toxic compound results in cell lysis and ultimately parasite cell autodigestion.

22. Resistance results from enhanced efflux of the parasite vesicleexpression of the human multi drug resistance transpoter P-glycoprotein.

23. Rapidly & completely absorbed from the GIT, has high volume of distribution(100-1000 L/kg). • The drug is distributed into 2 compartments: The drug highly concentrated in tissues, thus low concentration in plasma • Concentrated into parasitised RBCs. • Administered as 1g loading dose, 6 hours later 0.5g as maintenance dose for 2-3 days

24. Released slowly from tissues & metabolized in the liver, excreted in the urine 70% unchanged. Elimination is slow. • Initial t½ =2-3days (for the first compartment, plasma, highly perfused tissues e.g. liver and spleen) & terminal t ½=1-2months ( 2nd compartment, in moderately perfused tissues e.g. muscle and bone). • ADR:- Nausea, vomiting, dizziness, blurring of vision, headache, urticaria • Large doses retinopathy. (most serious , occurs with long time administration) • Bolus injection hypotension & dysrrhythmias • Safe for pregnant women. • Used in acute attack

25. Contraindications: • Psoriasis or prophyria • Visual field abnormalities or myopathy • Ca and Mg containing antacid interfere with absorption • Used with caution in liver disease or neurologic or hematologic disorders. • Other uses: • It is a disease modifying antirheumatoid drug. (6-9 month) • SLE • In amebic liver abscess

26. Quinine • Blood schizontocide effective against the erythrocytic form of all species of malaria. • Acts by parasite’s heme polymerase. • Depresses the myocardium, why? Because it has structural similarity with quinidine, an antiarrhythmic agent, as it is its d- isomer.

27. Clinical uses: • Blood schizonticide against all species. • Gametocidal against P vivax and P ovale PK: • Given orally in a7-day course or by slow IV for severe P. falciparum infection, • bitter taste →poor compliance, • metabolized in the liver, short t½=10h. ADRS: • Mild oxytoxic ( sever contraction) effects pregnant uterus, can cause abortion • slight neuromuscular blocking action, • weak antipyretic action.

28. NV, concentrations >30-60mol/l cinchonism [nausea, dizziness, headache, tinnitus, blurring of vision]. • Higher doses can cause hypotension, cardiac arrhythmias, delirium, coma. • Hypoglycaemia by influencing insulin’s secretion, blood dyscrasias, hypersensitivity reactions • Blackwater fever, a fatal condition in which acute hemolytic anemia is associated with renal failure. Blackwater fever because of methanol group

29. CONTRAINDICATIONS: • Prolonged QT Interval • Glucose-6-Phosphate Dehydrogenase Deficiency • Myasthenia Gravis • Hypersensitivity • Optic Neuritis, auditory problems • Dose should be reduced in renal insufficiency

30. Drug Interactions:- • Antacids: Antacids containing aluminum and/or magnesium may delay or decrease absorption of quinine. • Erythromycin, Cimetidine (CYP3A4 inhibitors)  ↑ concentration of quinine • Mefloquine • Quinine can raise plasma levels of warfarin and digoxin.

31. Hydroxynaphthoquinone • Atovaquone: • parasite’s electron transport chain by mimicking the natural substrate ubiquinone • Has synergistic effect with proguanil.

32. Resistance to atovaquone is rapid , results from a single point mutation in the gene for cytochrome b. Thus, it should be used in combination with Proguanil • Low bioavailability, slow, erratic absorption, yet ↑ by fatty food, • highly protein- bound, • t½ =2-3d, eliminated unchanged in feces. • ADR:- fever, rash, Nausea, vomiting, & Diarrhoea, Insomnia • Pregnant & breast feeding women should not use atovaquone.

33. Mefloquine • Strong blood schizontocide active against P.vivax & P.falciparum, but does not affect hepatic forms of the parasite. • Same MOA • Inhibits haem polymerase. • Resistance has occurred in southeast Asia.

34. Given orally ,well absorbed, slow onset of action, • high protein bound, extensive distribution • t½= 30 day  enterohepatic recycling or tissue storage. • ADR:-GIT disturbances, leukocytosis, thrombocytopenia. • Most common side effects are: transient CNS toxicity, confusion, Gidiness=dizziness, vertigo, dysphoria, insomnia. (contraindicated in CNS disease) • May provoke neuropsychiatric disorder. • Contra-indicated in pregnant women.

35. Halofantrine • Blood schizontocide, active against strains resistant to chloroquine, pyrimethamine, quinine. • Only in hospitalized pateint, to monitor their ECG • Cross-resistance in falicparum infection occurred . • Absorbed orally slowly , t½=11-12day • Absorption  with meals, elimination in feces.

36. ADR:-abdominal pain, headache, transient in hepatic enzymes, cough, pruritus, lengthening of QT interval. • May cause hemolytic anemia & convulsions. • Reserved for infection caused by resistant organisms. Contraindications: • with mefloquine. • Patients with cardiac conduction defects. • In pregnancy → embriotoxic in animals

37. Antifolates • Type 1 antifolates sulphonamides & sulphones , compete with PABA. • Type 2 ,pyrimethamine & proguanil inhibition of dihydrofolate reductase.

38. Have slow action against the erythrocytic forms of the parasite. • Pyrimethamine is used in combination with either dapsone or sulfadoxine. • High resistance

39. Sulfonamides & sulfones are active against the erythrocytic forms of P.falciparum. • Pyrimethamine -sulfodoxine is used for chloroquine –resistant malaria. • Pyrimethamine & proguanil are slowly orally absorbed. • t½ of pyrimethamine =4d, proguanil=16h. • Proguanil is metabolized to an active metabolite ,cycloguanil which is excreted in urine.

40. ADR:- large doses of pyrimethamine -dapsone combination causes haemolytic anaemia, agranulocytosis. • In high doses pyrimethamine mammalian dihydrofolate reductase megaloblastic anaemia. • Resistance → a single mutation in the genes encoding parasite dihydrofolate reductase. Dapsone

41. Primaquine • The only drug which is active against liver hypnozoites. • MOA: produces radical cure for parasites which have dormant stage in the liver [P.ovale & P.vivax]. • Has gametocidal action against all species. most effective for preventing transmission of the disease. • Combined with chloroquine, mechanism unknown, resistance rare.

42. Given orally, rapidly metabolized to etaquine & tafenoquine which are more active and more oxidizing & slowly metabolized, t½=3-6h • For radical cure of acute vivax and oval malaria”:- chloroquine is given to eradicate erythrocytic forms and then primaquine(30mg daily for 14 days) to eradicate liver hypnozoites

43. ADR:- GIT disturbances, in large doses  methemoglobinemia with cyanosis • Causes hemolysis in G-6-P –dehdrogenase deficiency, metabolites have greater hemolytic activity • Contraindications: • History of methemoglobinemia • Pregnancy

44. Artemisinin • Derived from the Chinese herb qinghaosu (Artemisia) • Artemisinin is poorly soluble in water & a fast acting blood schizontocide. • Effective in treating severe acute attacks, including chloroquine –resistant & cerebral malaria. Artemesia annua

45. Artesunate[a water- soluble derivative], artemether & artether [synthetic analogues] have higher activity & are better absorbed. • It damages the parasite membrane by carbon- centered free radicals. • Used orally, Rapidly absorbed, widely distributed,

46. Converted in the liver to the active metabolite dihydroartemisinin. • t½ of artemisinin 4h,artesunate=45min, artemether 4-11h. • No known resistance • ADR:- transient heart block, neutrophil count, brief episodes of fever. • Neurotoxic in animal, • No reported resistance

47. Antibiotics • Doxycycline : active against ertythrocytic schizonts of all species is used as a suppressive prophylactic in areas where mefloquine resistance is common. • Clindamycin has proved effective in the treatment of uncomplicated falicparum malaria, may be used in combination with quinine.

48. Prophylaxis • Use of prophylactic drugs is seldom practical for full-time residents of malaria-endemic areas (This is due to the cost of purchasing the drugs + their side effects ), and their use is usually restricted to short-term visitors and travelers to malarial regions. • People temporarily visiting malaria-endemic areas usually begin taking the drugs one to two weeks before arriving and must continue taking them for 4 weeks after leaving.

49. Include mefloquine ,doxycycline, and the combination of atovaquone and proguanil (only needs be started 2 days prior and continued for 7 days afterwards).

50. Resistance • About 90% of malaria deaths occur in sub Saharan Africa. • The key factor contributing tomalarial morbidity & mortality is resistance of P.falciparum to chloroquine, sulfodoxin-pyrimethamin [SP] & amodiaquine. • Artemisinin compounds produce a very rapid therapeutic response ,active against multi-drug resistant P.falciparum, well tolerated by the patient,gametocyte carriage, no resistance is detected. • Artemisinins cure falciparum malaria in 7d, if combined with another drug in 3d.