PARASITIC DISEASES. PPT. A LECTURE DELIVERED TO UNDERGRADUATE STUDENTS

A LECTURE ON PARASITIC DISEASES DELIVERED TO UNDERGRADUATE MEDICAL STUDENTS IN THE UNIVERSITY OFTHE GAMBIA.

1. PARASITIC DISEASES Prof. KABIRU ABUBAKAR

2. Parasitic Diseases Parasites normally inflict some degree of injury to the host The extent of which depends on such factors: Parasite load Nutritional status and Immunologic competence of the host The primary reasons for death due to malaria are: Failure to take chemoprophylaxis Inappropriate chemoprophylaxis Delay in seeking medical care and misdiagnosis

3. Malaria Malaria represents the most devastating disease in terms of human suffering and economics It affects the largest # of people Between 300 & 500 million new cases reported yearly globally With 2million deaths worldwide

4. Epidemiology The exact distribution of the various species is not well documented. Plasmodium vivax is more prevalent in India, Pakistan, Bangladesh, Sri Lanka. P. falciparum is predominant in Africa, Haiti, Dominican Republic, South America. P.ovale occur in Africa as well P.malariae is considered worldwide

5. Etiology Malaria is transmitted by the bite of an infected anopheles mosquito that introduces sporozoites ( tissue parasite) into the blood stream The sexual stage occurs in the mosquito whereas the asexual stage occurs in humans The sporozoites invade the parenchymal hepatocytes, multiplies in stages become hepatic vegetative forms or schizonts Schizonts rupture to release daughter cells or merozoites that then infect erytherocytes

6. Etiology P.facliparum and P.malariae remain in the primary exoerythrocytic stage in the liver for about 4weeks before invading the erythrocytes Whereas P.vivax and P.ovale can exist in the liver in the latent exoerythrocytes for longer

7. Etiology

8. Life cycle of the malarial parasite Sporogeny (sexual) Schizogony (asexual) Man : Intermediate host Mosquito : Definitive host True causal prophylactics Causal prophylactics Supressives Gametocidal Sporonticide

9. Pathology The erythrocytic phase causes extensive hemolysis, which results in:Anemia and splenomegaly The most complications usually are associated with P. falciparum infections Infants and kids, and non-immune women are at high risk for P. falciparum malaria

10. Complications of Malaria Complications associated with falciparum malaria are a result of: High parasitemia , ability of parasite to sequester in capillaries and post capillary vessels of organs such as brain, and kidney These are associated with vascular diseases and severe metabolic effects

11. Clinical Presentations Initial presentation Nonspecific fever, chills, rigor, diaphoresis, malaise, vomiting, and orthostatic hypotension, and electrolyte abnormalities Erythrocytic phase Headache, anorexia, malaise, fatigue, myalgia, abdominal pain, diarrhea, chest pain, dry skin, delirium, lactic acidosis, hypoglycemia, anemia, splenomegaly, renal failure, pulmonary edema

12. Diagnosis The primary goal in management of malaria is the rapid diagnosis of the plasmodia spp by blood smears (repeated every 12hrs for 3 days) So as to initiate timely antimalarial therapy to eradicate it within 48 to 72hrs Thereby avoiding complications such as hypoglycemia, pulmonary edema, renal failure

13. Therapeutic classification Causal prophylaxis: (Primary tissue schizonticides ) Destroy parasite in liver cells and prevent invasion of erythrocytes Primaquine , proguanil, Pyrimethamine, Sulphadoxine/pyrimethamine Supressives Prophylaxis: Suppress the erythrocytic phase and thus attack of malarial fever can be used as prophylactics Chloroquine, proguanil , mefloquine , doxycycline

14. Therapeutic classification Clinical cure: erythrocytic schizonticides used to terminate an episode of malarial fever there are two types; Fast acting, high efficacy Slow acting, low efficacy drugs

15. Therapeutic classification Fast acting high efficacy Chloroquine, quinine, mefloquine , atovaquone , artemisinin Slow acting low efficacy drugs Proguanil , pyrimethamine , sulfonamides, tetracyclines

16. Fast Acting Agents Fast acting drugs can be used singly to treat attacks of malarial fever faster acting drugs are preferred in falciparum malaria where delay in treatment may result in death even if the parasites are cleared from blood Recrudescence can occur in falciparum malaria if blood is not totally cleared of parasite by drug Slow efficacy drugs are used only in combination for clinical cure

17. Chemical Classification Diaminopyrimidines Pyrimethamine Sulfonamides Sulfadoxine , dapsone Tetracyclines : tetracycline, doxycycline Naphthoquinone: Atovaquone Sesquiterpene lactones: Artesunate , artemether , arteether Amino alcohols : halofantrine , lumefantrine

18. Chloroquine & Hydroxychloroquine C hloroquine It was discovered that the compound had been synthesized by Germans as early as 1934 under name of resochin at B ayer laboratories in Germany but had been rejected due to toxicity in avian models Hydroxychloroquine N-ethyl substituent of chloroquine is hydroxylated same as chloroquine P referred over chloroquine in treatment of rheumatoid arthritis and lupus erythematosus because in the high doses required it may cause less ocular toxicity

19. Pharmacological actions Antimalarial activity: High against erythrocytic forms of vivax , ovale , malariae & sensitive strains of falciparum Gametocytes of vivax No activity against tissue schizonts Resistance develops due to efflux mechanism Other parasitic infections: Giardiasis, taeniasis , extra-intestinal amoebiasis Other actions: Depressant action on myocardium, direct relaxant effect on vascular smooth muscles, anti inflammatory , antihistaminic , local anaesthetic effect.

20. Adverse Effects Nausea , vomiting, anorexia, skin rashes, angioneurotic edema, photosensitivity, pigmentation, exfoliative dermatititis Long term therapy may cause bleaching of hair. Rarely thrombocytopenia, agranulocytosis, pancytopenia

21. Adverse Effects Occular toxicity: High dose prolonged therapy Temporary loss of accommodation Lenticular opacities, subcapsular cataract Retinopathy: constriction of arteries, edema, blue black pigmentation , constricted field of vision. CNS: Insomnia, transient depression seizures, rarely neuromyopathy & ototoxicity CVS: ST & T wave abnormalities, abrupt fall in BP & cardiac arrest in children reported

22. Chloroquine Dosing Chloroquine is well absorbed after oral administration. It is extensively tissue bound and sequestrated by tissues particularly liver, spleen, kidney It has got large apparent volume of distribution So it is given in loading dose to rapidly achieve the effective plasma conc.

23. Other Indications of Chloroquine Hepatic amoebiasis : Giardiasis Clonorchis sinensis Rheumatoid arthritis Discoid Lupus Erythematosus Control manifestation of lepra reaction Infectious mononucleosis

24. Quinine 1820 Pelletier & caventou isolated quinine from cinchona bark. MOA: Oxidative damage to the membranes , digestive proteases & other critical biomolecules of malarial parasite quinine also inhibits RNA & DNA synthesis Similar to chloroquine MOA

25. Pharmacologic Actions Antimalarial action: Erythrocytic forms of all malarial parasites including resistant falciparum strains . Gametocidal for vivax & malariae Local irritant effect: Local pain sterile abcess . 3. Cardiovascular: depresses myocardium, ↓ excitability, ↓ conductivity, ↑ refractory period, profound hypotension IV. 4. Miscellaneous actions: Mild analgesic, antipyretic activity , stimulation of uterine smooth muscle, curaremimitic effect

26. Adverse Effects Cinchonism :( after a large single or higher therapeutic dose) characterized by: Tinnitus, nausea & vomiting, Headache, mental confusion, vertigo, difficulty in hearing & visual disturbances. Diarrhoea , flushing & marked perspiration. At higher doses , exagerated symptoms with delirium , fever, tachypnoea , respiratory depression and cyanosis

27. Adverse Effects Idiosyncrasy : similar to cinchonism but occurs in therapeutic doses Cardiovascular toxicity : cardiac arrest, hypotension ,fatal arrhytmias Black water Fever: characterized by Hypoglycemia; Triad of hemolysis, hemoglobinemia , hemoglobinuria with fever Rare type of hypersensitivity to quinine therapy having immunological basis. Presence of incompletely supressed falciparum malaria.

28. Quinine Uses Malaria : uncomplicated resistant falciparum malaria Cerebral malarial Nocturnal muscle cramps : 200 – 300 mg before sleeping Spermicidal in vaginal creams Myotonia congenita : hereditory myopathy characterized by tonic spasm of skeletal muscles Myotonia congenita : 300 to 600 mg BD/ TDS

29. Adverse Effects Gastrointestinal: epigastric distress, abdominal cramps , Haemopoetic : mild anemia, methaemoglobinemia , cyanosis, hemolytic anemia in G6PD deficiency Avoided during pregnancy, G6PD deficient

30. Pyrimethamine Diaminopyrimidine more potent than proguanil & effective against erythrocytic forms of all species. Tasteless so suitable for children Dose: Once Weekly for Prophylaxis Adverse events: megaloblastic anemia, thrombocytopenia, agranulocytosis

31. Sulfadoxine-pyrimethamine Sequential blockade Sulfadoxine 500 mg + Pyrimethamine 25 mg, 3 tablets once for acute attack Use: Single dose treatment of uncomplicated chloroquine resistant falciparum malaria Patients intolerant to chloroquine First choice treatment for toxoplasmosis

32. Artemisinin Artemisinin is the active principle of the plant A rtemisia annua Most potent and rapid acting blood schizonticides Short duration of action high recrudescence rate Poorly soluble in water & oil Adult and children: 25mg/kg on day 1, followed by 12.5mg/kg on days 2 and 3 in combo with mefloquine 15mg/kg

33. Artemisinin Derivatives Artesunate Artemether Arteether Artemisinin is not very soluble either in water or oil This and its short elimination half life led to the search for the derivatives that had improved pharmacological properties as well as better antimalarial activity Converted to dihydroartemisinin , which is a potent antimalarial compound Available for oral and rectal use in several countries in Asia.

34. Artemisinin Derivatives These compounds have presence of endoperoxide bridge Endoperoxide bridge interacts with heme in parasite Heme iron cleaves this endoperoxide bridge There is generation of highly reactive free radicals which damage parasite membrane by covalently binding to membrane proteins

35. Artemisinin Derivatives Intraparasitic ferrous protoporphyrin IV catalyses breakdown of endoperoxide bridge Chloroquine antagonizes the antimalarial activity MEANING? Iron chelators antagonize antiparasitic effect of artemisinin MEANING?

36. Antimalarial action Artemisinin Artemisinin Conventional Treatment

37. Artemisinin Derivatives These compunds are mainly schizonticides and are effective against plasmodium vivax A s well as chloroquine resistant and sensitive strains of plasmodium falciparum they are useful in cerebral malaria and MDR MALARIA

38. Artesunate Water soluble ester of dihydroartemisinin Dose: can be given oral, IM,IV, rectal Oral 100 mg BD on day 1 50 mg BD day 2 to day 5 Parenteral (IM, IV and RECTAL) 120 mg on day 1 (2.4 mg/kg BD ) 60 mg OD ( 2.4 mg/kg) for 7 days Artesunate Duration of action 3 to 4 hrs

39. Artemether Methyl ether of dihydroartemisinin Dose: Oral & IM 80 mg BD on day 1 (3.2 mg/kg) 80 mg OD (1.6 mg/kg) for 7 days Duration of action: 4 to 11 hours

40. Arteether Ethyl ether of dihydroartemisinin Therapeutically equivalent to quinine in cerebral malaria A longer t 1/2 & more lipophilic than artemether favouring accumulation in brain Dose:3.2 mg/kg on day1 followed by 1.6 mg/kg daily for next 4 days

41. Artemether & Artesunate Artemether & Artesunate are prodrugs converted to dihydroartemisinin responsible for antimalarial activity

42. Adverse Effects Leucopenia Hypersensitivity: Drug fever, itching GIT: nausea, vomiting, abdominal pain (common) ECG changes: ST-T changes, QT prolongation Abnormal bleeding, dark urine Reticulocytopenia

43. Artemisinin based combination therapy (ACT) Artemisinin compunds are shorter acting drugs Monotherapy needs to be extended beyond disappearance of parasite to prevent recrudescence This can be prevented by combining 3-5 day regimen of artemisin compounds with one long acting drug like mefloquine 15 mg/kg single dose Indicated by WHO in acute uncomplicated resistant falciparum malaria

44. ACT Regimens in use Artesunate – Sulfadoxine , pyrimethamine : Adopted as first line in some Asian countries eg India ARTESUNATE 100 mg BD for 3 days with S-P, 3 tablets Artesunate - Mefloquine : By combining artesunate further spread of mefloquine resistance can be prevented Artesunate 100 mg BD for 3 days, + mefloquine 750 mg on second day & 500 mg on third day

45. Treatment In adults including pregnant women, the chemoprophylaxis for all species of Plasmodium is chloroquine phosphate 300mg once weekly Beginning 1 week prior to departure and continued for 4 weeks after leaving the endemic area The pediatric dose is 5mg/kg Primaquine phosphate 15mg daily for 14 days is indicated in areas infected with P.vivax , P.ovale The pediatric dose of primaquine is 0.3mg/kg per day for 14 days

46. Treatment In areas where chloroquine-resistance P.falciparum strains exist, travelers should receive mefloquine ( Lariam ) 250mg once weekly Therapy initiated 1 week prior to travel and continue for full period of exposure To ensure a positive diagnosis, blood smears should be obtained q12-24hrs for 3 consecutive days Presence of parasites in the blood after 3 to 5 days after initiation of therapy suggests drug resistance

47. Treatment Doxycycline serves as an alternative regimen for prophylaxis in chloroquine-resistant areas Used doxycycline 100mg daily starting 1 week before departure, during the exposure period and continue for 4 weeks upon return Doxycycline is contraindicated in: Children younger than 8 years In pregnant women During breast feeding Another alternative regimen is atovaquone and proguanil ( Malarone ); 1 tablet daily beginning 1 to 2 days before traveling and continue for duration of stay and 1 week after leaving the area

48. Treatment In an uncomplicated malaria attack, the recommended regimen is chloroquine 600mg initially Followed by 300mg 6 hours later, and then 300mg for 2 days In severe illness or when oral therapy is not tolerated, or when parenteral quinine is not