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Anti-malarial Drugs Life Cycle and Mechanisms of Action
- 1. Prof. Shaikh Abusufiyan Assistant Professor, AIKTC-School of Pharmacy, New Panvel-410206 Pharma Learning Forever Anti-protozoal/ Anti-malarial Drugs
- 2. At the end of this e-learning session you are able to… A. Discuss Neurohumoral Transmission. B. Explain role of GABA, Glutamate, Glycine, Serotonin and Dopamine in neurohumoral transmission.
- 3. The main protozoa that produce disease in humans are those causing - malaria - amoebiasis - leishmaniasis - trypanosomiasis - and trichomoniasis
- 4. Malaria
- 5. - Malaria is mosquito-borne and is one of the major killer diseases of the world. - Malaria causes up to 2.7 million deaths per year among young children in Africa, especially in remote rural areas with limited or no access to medical care.
- 6. The symptoms of malaria: - fever - shivering - pain in the joints - headache - repeated vomiting - generalised convulsions and coma. - Symptoms become apparent --> 7-9 days after being bitten by an infected mosquito.
- 7. Life cycle of malaria parasites • The life cycle consists of - a sexual cycle --> which takes place in the female anopheline mosquito - And an asexual cycle --> which occurs in humans 1. Pre-erythrocytic stage – Liver (10-14 days) Sporozoites Merozoites 2. Erythrocytic stage Merozoites trophozoites (motile parasites)
- 8. 2. Erythrocytic stage..... - During maturation within the red cell, the parasite undergoes mitotic replication i.e Remodels the host cell Insert parasite proteins and phospholipids into the red cell membrane. The host's haemoglobin is digested and transported to the parasite's food vacuole Where it provides a source of amino acid.
- 9. Free haem hemozoin polymerisation toxic to the plasmodium harmless • Some antimalarial drugs act by inhibiting the haem polymerase
- 10. Following mitotic replication of nucleus in RBCs - The parasite in the red cell is called a schizont and its rapid growth and division, schizogony results in the production of further merozoites (which are released when the red cell ruptures) These merozoites then bind to and enter fresh red cells and the erythrocytic cycle starts all over again.
- 11. 3. Exoerythrocytic cycle In certain forms of malaria, some sporozoites on entering the liver cells form hypnozoites, or 'sleeping' forms of the parasite which can be reactivated to continue an exoerythrocytic cycle of multiplication. - The dormancy can last for months or years.
- 12. Q&A Q.1 Enlist 2 stages of asexual cycle of malarial parasite. Q2. Which form of heam is used by malarial parasite and how? Q.3 What is schizogony? Copyright @shaikhabusufiyan2021
- 13. • Malaria parasites can multiply in the body at a phenomenal rate a single parasite of Plasmodium vivax being capable of giving rise to 250 million merozoites in 14 days. • For an antimalarial drug - destruction of 94% of the parasites every 48 hours will only maintain equilibrium and will not reduce their number
- 14. Sexual cycle in mosquito: - Some merozoites, on entering red cells differentiate into male and female forms of the parasite, called gametocytes. - Thy can only complete their cycle when taken up by the mosquito, when it sucks the blood of an infected host.
- 15. - The cycle in the mosquito involves fertilisation of the female gametocyte by the male gametocyte the formation of a zygote which develops into an oocyst (sporocyst).
- 16. - A further stage of division and multiplication takes place leading to rupture and release of sporozoites which then migrate to the mosquito's salivary glands and enter another human host with the mosquito's bite.
- 17. - The periodic episodes of fever that characterise malaria result from the synchronised rupture of red cells with release of merozoites and cell debris. - The rise in temperature – due to rise in the concentration of TNF-α in the plasma. - Relapses of malaria are likely to occur with those forms of malaria that have an exoerythrocytic cycle.
- 18. ACTIVITY II: Self study
- 19. The chief species of human malaria parasites are as follows: - P. Falciparum - P. Vivax - P. Ovale - P. malariae
- 20. 1.P. Falciparum- erythrocytic cycle of 48 hours in humans - produces malignant tertian malaria - 'tertian' - the fever was believed to recur every third day - 'malignant' because it is the most severe form of malaria and can be fatal
- 21. 2. P. vivax - produces benign tertian malaria -'benign' - it is less severe than falciparum malaria and rarely fatal. - Exoerythrocytic forms may persist for years and cause relapses.
- 22. 3. P. Ovale - It has a 48-hour cycle and an exoerythrocytic stage 4. P. malariae has a 72-hour cycle, causes quartan malaria and has no exoerythrocytic cycle.
- 23. Q&A Q1. Enlist different form of malarial parasite. Q1. Name most severe form of malarial parasite? Q2 In which form of malaria there is possibility of relapse? Copyright @shaikhabusufiyan2021
- 24. Antimalarial therapy based on parasite life cycle 1. Drugs used to treat the acute attack of malaria - act on the parasites in the blood - It Can cure infections with parasites (e.g. P. falciparum) that have no exoerythrocytic stage.
- 25. 2. Drugs used for chemoprophylaxis (causal prophylactics) act on merozoites emerging from liver cells. - Used to prevent malarial attacks when in a malarious area
- 26. MoA: - Block the link between exoerythrocytic stage and the erythrocytic stage. - Eg. Chloroquine, mefloquine, proguanil, pyrimethamine, dapsone and doxycycline - used often in combinations.
- 27. 3. Drugs used for radical cure are active against parasites in the liver. e.g. 8-aminoquinolines (e.g. primaquine and tafenoquine) 4. Drug used to prevent transmission - act on gametocytes and prevent transmission by the mosquito. e.g. primaquine, proguanil and pyrimethamine
- 28. 4-AMINOQUINOLINES - The main 4-aminoquinoline used clinically is Chloroquine. - Amodiaquine has very similar action to Chloroquine. withdrawn several years ago as it causes agranulocytosis - But now been re-introduced in several areas of the world where Chloroquine resistance is endemic.
- 29. - Chloroquine is a very potent blood schizonticide drug - Effective against the erythrocytic forms of all 4 plasmodial species (sensitive to the drug) -But it does not have any effect on sporozoites, hypnozoites or gametocytes.
- 30. - At high concentrations, Chloroquine inhibits - protein - RNA - and DNA synthesis.
- 31. - Chloroquine acts mainly on haem disposal by preventing digestion of haemoglobin by the parasite reduces the supply of amino acids
- 32. • It also inhibits haem polymerase Free haem hemozoin polymerisation toxic to the plasmodium harmless
- 33. Resistance - P. falciparum is now resistant to chloroquine. - Resistance appears to result from enhanced efflux of the drug from parasitic vesicles - As a result of increased expression of the human multidrug resistance transporter P- glycoprotein.
- 34. Pharmacological actions: - Chloroquine is a disease-modifying anti-rheumatoid drug has some quinidine-like actions on the heart.
- 35. Pharmacokinetics • Route: Chloroquine is given orally, is completely absorbed • In severe falciparum malaria it may be given by - frequent intramuscular or subcutaneous injection of small doses or - by slow continuous intravenous infusion. Distribution: is extensively distributed throughout the tissues and is concentrated in parasitised red cells.
- 36. • Metabolism: metabolised in the liver. • Excretion: It is excreted in the urine, 70% as unchanged drug and 30% as metabolites. • Elimination is slow, the major phase having a half- life of 50 hours, and a residue persists for weeks or months.
- 37. Unwanted effects - It has few adverse effects when given for chemoprophylaxis. - With the larger doses unwanted effects can occasionally occur, including - nausea and vomiting - dizziness and blurring of vision - headache - and urticarial symptoms - retinopathies.
- 38. Q&A Q1. How drugs used for chemoprophylaxis work? Q1. Name chemical class of Chloroquine? Q2 Give MoA of Chloroquine? Copyright @shaikhabusufiyan2021
- 39. QUINOLINE-METHANOLS • The two most widely used quinoline- methanol are quinine and mefloquine Quinine - Quinine is an alkaloid derived from cinchona bark. - It is a blood schizonticide drug - Effective against the --> erythrocytic forms of all 4 species of plasmodium, site A) - But it has no effect on --> exoerythrocytic forms or on the gametocytes of P. falciparum.
- 40. - Its mechanism of action is like chloroquine i.e inhibition of the parasite's haem polymerase. - but it is not so extensively concentrated in the plamodium as chloroquine other mechanisms could also be involved. - With the emergence and spread of chloroquine resistance, quinine is now the main chemotherapeutic agent for P. falciparum.
- 41. Pharmacological actions: - depressant action on --> the heart - a mild oxytocic effect on --> the uterus in pregnancy - a slight blocking action on --> the neuromuscular junction - and a weak --> antipyretic effect.
- 42. Pharmacokinetic aspects - Quinine is usually --> given orally in a 7-day course - It can also be given --> by slow intravenous infusion for severe P. falciparum infections and in patients who are vomiting. - A loading dose --> may be required - But bolus intravenous administration --> is contraindicated because of the risk of cardiac dysrhythmias.
- 43. - It is well absorbed from the gastrointestinal tract - And it is metabolised in the --> liver - The metabolites is excreted --> in the urine (within about 24 hours). - The half life --> 10 hours.
- 44. Unwanted effects - It is given orally, but as it is bitter --> compliance is poor. - It is irritant to the gastric mucosa --> can cause nausea and vomiting.
- 45. - If the concentration in the plasma exceeds 30-60 μmol/l, 'cinchonism' is likely to occur - nausea - dizziness - tinnitus - headache - and blurring of vision.
- 46. Unwanted effects: Excessive plasma levels of quinine can result in: - hypotension - cardiac dysrhythmias - and severe central nervous system (CNS) disturbances such as delirium and coma.
- 47. Unwanted effects: Other rarer unwanted reactions that have been reported are - hypoglycaemia - blood dyscrasias (especially thrombocytopenia) - And hypersensitivity reactions.
- 48. Q&A Q1. What is category of quinine? Q1. How quinine produces resistance? Q2 What is Cinchonism? Copyright @shaikhabusufiyan2021
- 49. ACTIVITY II: Self study
- 50. - Quinine can stimulate insulin release. - Patients with marked falciparum parasitaemia can have low blood sugar - And also because of glucose consumption by the parasite. - This can cause diagnostic confusion between coma caused by cerebral malaria and hypoglycaemic coma--> which responds to glucose.
- 51. - Blackwater fever, a severe and often fatal condition - In which acute haemolytic anaemia is associated with renal failure - It is a rare result of treating malaria with quinine or of erratic and inappropriate use of quinine for a 'fever'.
- 52. Resistance - Like Chloroquine, resistance is conferred by increased expression of P-glycoprotein, which effectively pumps the drug out of the parasite.
- 53. 8-AMINOQUINOLINES - The only 8-aminoquinoline licensed for current use is primaquine. - Etaquine and tafenoquine are currently undergoing clinical evaluation. The mechanism of action of these compounds is not known.
- 54. - The antimalarial action of these drugs is exerted against the liver hypnozoites. - They can effect a radical cure of those forms of malaria in which the parasites have a dormant stage in the liver- • P. vivax and P. ovale. - Primaquine does not affect sporozoites and has little if any action against the erythrocytic stage of the parasite.
- 55. - It has a gametocidal action and is the most effective antimalarial drug for preventing transmission of the disease in all four species of plasmodium. - It is almost invariably used in combination with another drug, usually Chloroquine.
- 56. Pharmacokinetic aspects - Primaquine is given orally and is well absorbed. - The half-life is 3-6 hours. - Tafenoquine is broken down much more slowly and, therefore, has the advantage that it can be given on a weekly basis.
- 57. - Dose-related gastrointestinal symptoms can occur - And large doses may cause met-haemoglobinaemia with cyanosis. - It cause haemolysis in individuals with an X-chromosome- linked genetic metabolic condition- (a deficiency of glucose 6- phosphate dehydrogenase in the red cells).
- 58. • Deficiency of glucose 6-phosphate dehydrogenase the red cells are not able to regenerate NADPH - the metabolic functions of the red cells are impaired haemolysis of RBCs. • Primaquine metabolites have greater haemolytic activity than the parent compound.
- 59. - The deficiency of the enzyme occurs in up to 15% of Black males and is also fairly common in some other ethnic groups. Precaution: -glucose 6-phosphate dehydrogenase activity should be estimated before giving primaquine.
- 60. Q&A Q1. Name drugs which act on hypnozoites? Q1. How 8-aminoquinoline causes Hemolysis of RBCs? Copyright @shaikhabusufiyan2021
- 61. Reference: • H.P Rang. M M Dale, J.M Ritter, R.J Flower, G Henderson. Pharmacology, Seventh Edition. Elsevier Churchill Livengston Publication. Page no:655-664