Antimalarial drugs and Regimens for malaria.pptx

medicine

1. Antimalarial drugs 1

2. Malaria Endemic in most tropical countries.

3. COMPETENCY: The student should be able to (PH 1.47) Describe the mechanism of action, types, doses,side effects, indications and Contraindications of the drugs used in malaria. SPECIFIC LEARNING OBJECTIVES At the end of the class, the student should able to: Explain the life cycle of plasmodium spp. Classify the drugs for malaria based on chemical structure and clinical use with examples. Describe the mechanism, spectrum, resistance, pharmacokinetics, clinical uses, adverse effects & interactions of 4 & 8 of Aminoquinolines. Describe the mechanism, spectrum, resistance, pharmacokinetics, clinical uses, adverse effects & interactions of Artemisinin and derivatives. Describe the drug regimens used for treatment and prophylaxis of chloroquine sensitive and chloroquine resistant malaria. Outline the Artemisinin based combination therapy for malaria.

4. Introduction The oldest diseases known to mankind that has profound impact on our history. Malaria is a vector-borne infectious disease caused by single-celled protozoan parasites of the genus Plasmodium. Malaria is transmitted from person to person by the bite of female mosquitoes. 4

5. INDIA: NMEP started in 1958, malaria complete disappearance but came back in 1970 and still now prevails a major disease. Changed to NAMP then finally named it to NVBDCP. 2016 – 1.06 million cases in INDIA. 50% Falciparum malaria 242 – Recorded deaths. WHO : 2017 estimated 216 million cases, 0.445million deaths, mostly among Africa(90%) & 7% South East Asia. Incidence & Prevalence of malaria 5

6. Causes of malaria Plasmodium falciparum : Falciparum malaria or Malignant Tertian malaria Plasmodium vivax : Benign Tertian, Tertian Malaria Plasmodium malariae : Quartan malaria Plasmodium ovale : Ovale tertian Malaria   The plasmodium transmitted to human by the bite of an infected female anopheles mosquito. 6

7. Transfusion of infected blood, congenitally, and by sharing needles, but mainly by the bites of  female Anopheles mosquitoes Man develops disease after 10 to 14 days of being bitten by an infective mosquito Life cycle of malarian parasite : Hepatic cycle/pre or exo Erythrocytic cycle Erythrocytic cycle 3)Sexual forms Transmission of malaria 7

8. Symptoms of malaria 8 P. falciparum: Most dangerous invading erythrocytes of any age, producing endotoxin-like products, cause heavy parasitemia, hypoglycemia, and shock with multiorgan failure. Delay in treatment may lead to death. If treated early, the infection usually responds within 48 hours. Coma / cerebral malaria, convulsions, Renal Impairment, Noncardiogenic pulmonary edema Liver Dysfunction , Hypoglycemia, Metabolic acidosis/acidemia Hematological abnormality like hemoglobinuria, Hypovolemic shock

9. Symptoms cont … 9 P. vivax has low mortality rate - untreated adults relapses caused by the reactivation of latent tissue forms. P. ovale affects periodicity and relapses similar to those of P. vivax, but it is milder. P. malariae causes a generally indolent infection that is common in localized areas of the tropics. Clinical attacks may occur years or decades after infection.

10. 10 1. Prevent the clinical attack of malaria (Prophylactic) 2. Treat the clinical attack of malaria (Clinical cure) 3. Completely eradicate the parasite from the patient’s body (Radical cure) 4. Reduce the human reservoir of infection – cut down transmission to mosquito (gametocidal) Aim of treatment

11. The life cycle of malarial parasite in man Antimalarials that act on erythrocytic schizogony are called erythrocytic (blood) schizontocides Those that act on preerythrocytic as well as exoerythrocytic ( P. vivax ) stages in liver are called tissue schizontocides Those which kill gametocytes in blood are called gametocides .

12. Pre – Erythrocytic cycle (Intra hepatic) Exo – Erythrocytic cycle Erythrocytic cycle Gametocidal Causal prophylactics Suppressive prophylatics Clinical cure Radical cure SPOROZOITES MEROZOITES SPOROZOITES TROPHZOITES SCHZONTS MEROZOITES SPOROZOITES

13. Pre – Erythrocytic cycle (Intra hepatic) Exo – Erythrocytic cycle Erythrocytic cycle Gametocidal Causal prophylactics Suppressive prophylatics Clinical cure Radical cure Primaquine, Proguanil Chloroquine, Mefloquine, Doxycycline, Proguanil Artemisinin Chloroquine Amodiaquine Quinine Mefloquine Halofantrine Lumefantrine Atovaquone Proguanil, Pyrimethamine Sulfonamides, Tetracyclines Primaquine Tafenaquine Primaquine SPOROZOITES MEROZOITES SPOROZOITES TROPHZOITES SCHZONT MEROZOITES

14. Classification of anti malarial drugs 15 1. 4- Aminoquinolines – Chloroquine, Amodiaquine, Piperaquine 2. Quinoline- methanol – Mefloquine 3. Chinchona alkaloid - Quinine, Quinidine 4. Biguanides - Proguanil 5. Diaminopyrimidine - Pyrimethamine 6. 8-Aminoquinoline – Primaquine, Bulaquine , Tafenoquine

15. 16 Classification cont.. 7. Sulfonamide & sulfone - Sulfadoxine , Sulfamethopyrazine , Dapsone 8. Antibiotics - Doxycycline, Clindamycin 9. Sesquiterpene Lactones - Artesunate, Artemether, Arteether , Arterolane, Dihydroartemisinin 10. Amino alcohols - Halofantrine, Lumefantrine 11. Naphthoquinone - Atovaquone 12. Napthyridine - Pyronaridine

16. Concentrating in parasite food vacuoles Prevent the polymerization of Hb breakdown product, heme, into hemozoin Elicits parasite toxicity Mechanism of Action CHLOROQUINE Spectrum of activity: Rapid acting Erythrocytic schizonticide against all species of malaria

17. Mechanism of action: alkaline, Malarial Parasites utilize hemoglobin as food, broken down into heme (toxic) heam polymerase polymerization hemozoin food vacuoles of the parasite Lysis of parasite and heme ( Increases pH & accumulation of toxic heme , produces oxidative damage to the membranes, leading to lysis of both the Malarial Parasites & RBCs )

18. 19 Resistance to chloroquine PFCRT gene seen in chloroquine resistant P.Falciparum it pumps out the drug protecting heme ↓ ability of parasite to accumulate drug is the cause NVBDCP : first line treatment against P.vivax & it slowly developing resistance too within 1-2wks of treatment P.vivax resistance to Chloroquine : Quinine with Doxycycline/Clindamycin or ACT followed by Primaquine for radical cure is treatment of choice

19. Pharmacokinetics of chloroquine 20 Absorbed orally, rapid absorption from IM, SC. Concentrated in various tissues like liver, spleen, kidney, lungs & melanin. Distribution in brain & spinal cord with large apparent volume of distribution -13000 liters in adult, loading dose – to attain therapeutic concentration in plasma & steady state concentration t1/2 : 3- 10 days, 60% plasma protein bound Metabolism- two active forms

20. PK Cont…. 21 Desethylchloroquine & Bisdesethyl chloroquine by CYP-450 in liver 50% eliminated by systemic and remaining eliminated renally On parentral administration entry is rapid & removal is slow causes toxicity To prevent it slow IV & S.C/I.M is given in small divided doses Preparation – Chloroquine phosphate (250mg = 150mg base) – 150mg, 500mg,100mg/10ml syp .

21. Therapeutic uses Of Chloroquine 22 1.Malaria prophylaxis : 300mg once a week for prevention person visiting endemic area should receive one week before and four week after. Dose of Chloroquine Uncomplicated vivax / ovale / malaria: 600mg(10mg/kg)- 300mg(5mg/kg) after 8hrs,continue for next 2 days total 25mg/kg over 3 days + primaquine 15mg(0.25mg/kg)daily for 14 days Chloroquine sensitive falciparum Dose as above + primaquine 45mg(0.75mg/kg) single dose(gametocidal)

22. 23 Other uses of Chloroquine: Extra intestinal amoebiasis/hepatic amaoebiasis : 500mg TDS for 2 Days/ 200mg BD for 2-3 wks Photogenic reactions Infectious mononucleosis Rheumatoid arthritis:250mg 6-12 mths once a week Lepra reaction –TYPE 2 DLE :250-500mg daily 1-4wks followed by maintenance

23. Adverse effects of Chloroquine 24 Common: Nausea, vomiting, anorexia, itching, epigastric pain, difficult in accommodation, headache are frequent & unpleasant Toxic effects after prolonged use : Skin eruptions, headache, blurring of vision, diplopia, confusion & convulsions. EKG changes : abnormal T waves, Wide QRS interval reversible Discoloration of nail beds, hairs & mucous membrane Haemolysis & blood dyscrasis

24. Adverse effects of chloroquine cont … 25 Retinopathy with reduced visual acuity - accumulation of drug in melanin rich tissues (Bulls eye maculopathy) –reversible Ototoxicity irreversible Myopathy, cardiomyopathy, peripheral neuropathy, suicidal tendency occurs Periodic neurological and retinal check up should be done

25. Adverse effects of chloroquine cont … 26 >5g Cardiovascular – hypotension due to vasodilatation, suppressed myocardiac function, cardiac arrhythmias & cardiac arrest CNS – mental confusion, convulsion & coma

26. Interactions & precautions of chloroquine 27 with Mefloquine convulsion will occur Digoxin level increases used along With gold & phenylbutazone dermatitis will occur Drug should be avoided in patients with ocular ,hepatic disease ,hemorrhage, hematological disease, peptic ulcer & neurological disease Epilepsy attacks will be precipitated in epileptic patients & Myasthenia gravis will worsen Haemolysis occurs in G6PD deficient patients Aggrevates exfoliative dermatitis & psoriasis

27. Amodiaquine 28 ↓ cost & safety in chloroquine resistance P.falciparum in certain areas Faster action & better tolerance than chloroquine Prophylactically not used because of hepatotoxicity & agranulocytosis in certain areas can be used in clinical attacks Dosage : 25-35mg/kg for 3 days (10mg/kg is given immediately following 5mg/kg after 6hrs then 5mg/kg for next 2 days ) Mechanism, resistance, uses & ADR are similar to chloroquine

28. Chloroquine Congener with similar mechanism High efficacy, erythrocytic schizonticide with prolonged action & onset is slow Activity: Chloroquine sensitive & Chloroquine resistant P. falciparum malaria piperaquine 29

29. Mefloquine : Tested during world war II, introduced in 1963 Its 4-quinoline methanol related chemically to quinine used in chloroquine resistant P.falciparum malaria Faster acting erythrocytic schizonticide slower than Chloroquine or quinine. Effective against Chloroquine sensitive organism also Its suppressive prophylactic for multi resistant falciparum & other types of malariae 30

30. Therapeutic uses Acute attack of Malaria Chemoprophylaxis of Malaria 1 ) Extraintestinal amoebiasis 2) Rheumatoid arthritis 3) Discoid lupus erythematosus – very effective less valuable in systemic LE. 4) Lepra reactions 5) Photogenic reactions 6) Infectious mononucleosis : affords symptomatic relief.

31. Chief alkaloid of cinchona bark (known as ‘cardinal Bark'). Less effective and more toxic than chloroquine . Skeletal muscle action – contractile power decreased Local irritant & anesthetic action Myometrium stimulant, Cardiac depressant action Enhance Insulin release – Hypoglycemia QUININE Blood schizonticide Gametocytocidal activity against P.Vivax and P.Malariae . Pre erythrocytic & exoerythrocytic stage – No effect Gametocytes

32. Dr.G.C Sahu/ROHFW/GoI/A'Bad 60 …..And Fight The Bite......... Before it is too late.........

33. THE END T H A N K S......