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Antimalarial drugs
This document discusses various anti-malarial drugs. It begins by describing the life cycles of malarial parasites and the different species that cause malaria. It then covers the classes of anti-malarial drugs, including 4-aminoquinolines like chloroquine, quinoline-methanols like mefloquine, and artemisinin derivatives. The mechanisms of action, pharmacokinetics, uses, and adverse effects of several important anti-malarial drugs like chloroquine, quinine, mefloquine, primaquine, and artemisinins are discussed in detail. Resistance to chloroquine and the combinations of sulfonamides and py
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Antimalarial drugs
- 1. Anti-malarial drugs Dr. LokendraSharma, Professor, Pharmacology S.M.S. Medical college, Jaipur
- 2. Introduction Malaria • Caused byPlasmodium protozoa – 4 different species • P. falciparum • P. vivax • P. malariae • P. ovale • Cause: the bite of an infected adult female anopheline mosquito • Also transmitted by infected individuals via blood transfusion, congenitally, or infected needles by drug abusers
- 3. Malarial Parasite (Plasmodium) Twointerdependent life cycles • Sexual cycle: occurs in the mosquito • Asexual cycle: occurs in the human • Knowledge of the life cycles is essential in understanding antimalarial drug treatment • Drugs are effective only during the asexual cycle
- 4. Types of Malaria Plasmodiumfalciparum -Most dangerous species -Causes an acute, rapidly fulminating disease i.e. characterized by persistent high fever, orthostatic hypotension, and massive erythrocytosis -capillary obstruction and death if treatment is delayed Plasmodium vivax Causes a milder form of the disease Plasmodium malariae Common to many tropical regions Plasmodium ovale Rarely encountered
- 6. Plasmodium Life Cycle Asexualcycle: two phases • Exoerythrocytic phase • Occurs “outside” the erythrocyte • Also known as the tissue phase • Erythrocytic phase • Occurs “inside” the erythrocyte • Also known as the blood phase Erythrocytes = RBCs
- 8. Antimalarial Drugs • Attackthe parasite during the asexual phase, when it is vulnerable • Erythrocytic phase drugs: chloroquine, hydroxychloroquine, quinine, mefloquine • Primaquine: kills parasite in both phases • May be used together for synergistic or additive killing power
- 9. Antimalarial Drugs Classes Drugs 4-AminoquinolinesChloroquine (CQ) ,Amodiaquine (AQ), Piperaquine Quinoline-methanol Mefloquine Cinchona alkaloid Quinine, Quinidine Biguanide Proguanil (Chloroguanide) Diaminopyrimidine Pyrimethamine 8-Aminoquinoline Primaquine ,Tafenoquine Sulfonamides and sulfone Sulfadoxine , Sulfamethopyrazine, Dapsone Antibiotics Tetracycline, Doxycycline, Clindamycin Sesquiterpine lactones Artesunate, Artemether, Arteether, Arterolane Amino alcohols Halofantrine ,Lumefantrine Naphthyridine Pyronaridine Naphthoquinone Atovaquone
- 10.
- 13. Drugs used inmalaria Tissue schizontocides- drugs eliminating developing or dormant liver forms Blood schizontocides- drugs acting on erythrocytic parasites Gametocides- drugs that kill sexual stages and prevent transmission to mosquitoes
- 14. Antimalarial Therapy Antimalarial therapyis given in following ways: 1. Causal prophylaxis: Destroy parasite in liver cells and prevent invasion of erythrocytes Drug : Primaquine, proguanil 2. Suppressive Prophylaxis: Suppress the erythrocytic phase and thus attack of malarial fever can be used as prophylactics Drug : Chloroquine, proguanil, mefloquine, doxycycline
- 15. Antimalarial Therapy 3.Clinical cure:erythrocytic schizonticides used to terminate an episode of malarial fever Fast acting high efficacy Chloroquine, quinine, mefloquine, atovaquone, artemisinin Slow acting low efficacy drugs Proguanil, pyrimethamine, sulfonamides, tetracyclines 4.Radical curatives: Eradicate all forms of P.vivax & P.ovale from the body Supressive drugs + hypnozoitocidal drugs For vivax: primaquine 15 mg daily for 14 days
- 16. Antimalarial Therapy 5. Gametocidal:Destroy gametocytes and prevent transmission Drugs :Primaquine, artemisinin – against all plasmodia Chloroquine, quinine – P Vivax Proguanil ,pyrimethamine – prevent development of sporozoites
- 17. Chloroquine Synthesized byGermans in 1934 ( resochin) d & l isomers, d isomer is less toxic Cl at position 7 confers maximal antimalarial efficacy Rapidly acting erythrocytic schizontocide against all species of plasmodia
- 18. Chloroquine Mechanism ofaction
- 19. Chloroquine Pharmacological Actions 1.Antimalarial activity: High against erythrocytic forms of P. vivax, P. ovale, P. malariae & sensitive strains of P. falciparum Gametocytes of P. vivax, P. malariae, P. ovale No activity against tissue schizonts 2. Other parasitic infections: Giardiasis, taeniasis, hepatic amoebiasis 3.Other actions: Anti-inflammatory, local irritant, , local anaesthetic , weak smooth muscle relaxant , antihistaminic, antiarrhythmatic
- 20. Chloroquine Pharmacokinetics Wellabsorbed, peak plasma concentration in 2-5 hrs , 60 % protein bound Concentrated in liver , spleen, kidney, lungs , leucocytes Selective accumulation in retina: occular toxicity T1/2 = 3-10 days increases from few days to weeks 13
- 22. Contraindications of Chloroquine Psoriasis ,porphyria Retinal and visual field abnormalities or myopathy Calcium , magnesium containing antacids
- 23.
- 24. Adverse Effects *Q*Chloroquine isconcentrated in melanin containing tissues like retina and skin. Short –term use “ as in malaria” 1) Mild headache and visual disturbances 2) Gastro-intestinal upsets; Nausea, Vomiting 3) Pruritis, urticaria “allergy”
- 25. Prolonged therapy “asin Rheumatoid arthritis” 1. Retinopathy, characterized by loss of central acuity, macular pigmentation and retinal artery constriction 2. Lichenoid skin eruption, bleaching of hair. 3. Weight loss 4. Hemolytic anemia in patients with G6PD deficiency Bolus injection ------ hypotension and dysrrhythmias
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- 27. Chloroquine Uses Malaria Extraintestinal amoebiasis Rheumatoid arthritis Discoid lupus erythematousus Lepra reaction Photogenic reaction
- 28. CQ Resistance: • Themechanism of resistance involves a reduced accumulation of the drug. • Possible explanations include an energy-dependent efflux of preaccumulated drug via parasite protein named PfCRT, • the mutated form of which is able to reduce chloroquine accumulation in the digestive vacuole of the pathogen • or an increase in vacuolar pH such that the proton gradient responsible for drug concentration is reduced.
- 29. Quinine • l-isomer ofalkaloid obtained from cinchona bark • Quinidine (antiarrhythmic) - d-isomer **An effective erythrocytic schizontocide as suppressive and used to prevent or terminate attacks of vivax, ovale, malariae, sensitive falciparum. • Moderately effective against hepatic form (pre- exoerythrocyte and gametocytes)
- 30. Mechanism of action?? **Weak base, and acts by inhibiting polymerization of heme to hemozoin. •Free heme or heme-quinine complex damages parasite’s membrane and kills it.
- 31. Adverse effects ?? Cinchonism: •Higher dose symptoms include nausea, vomiting, tinnitus, vertigo, headache, mental confusion, difficulty in hearing and visual defects, diarrhea, flushing Rapid i.v. injection: • Hypotension and cardiac arrhythmias • Hypoglycemia
- 33. Uses Malarial attacks •Uncomplicated resistantfalciparum •Complicated and severe malaria including cerebral malaria •Adjunctive therapy with doxycycline, tetracycline and clindamycin needed.
- 34. Mefloquine (Mq) • Fastacting erythrocytic (blood) schizontocide but slower than CQ or quinine • Effective against CQ-sensitive as well as resistant Plasmodia • Efficacious suppressive prophylactic for multi-resistant P. falciparum
- 35. Mechanism of action •Like CQ, it accumulates in infected RBCs, binds to heme and this complex damages the parasite’s membrane. • Recently it was suggested that the site of action of MQ is in the parasitic cytosol rather than in the acidic vacuole.
- 36. Adverse effects • Bittertaste • At high doses: • Nausea, vomiting, diarrhea, abdominal pain, bradycardia • Ataxia, hallucinations, depression • Safe in pregnancy Contraindications • In patients with anxiety, depression, psychosis, and in cardiac conduction defects
- 37. Primaquine • Poor erythrocyticschizontocide • Marked effect on primary and secondary hepatic phases of malarial parasite • Highly active against gametocytes and hypnozoites
- 38.
- 39.
- 40. Adverse effects ?? •Abdominal pain, gastrointestinal upset, weakness or uneasiness chest • Leucopenia (high dose) • *Q*Hemolysis • *Q*Methaemoglobinaemia • Tachypnoea • Cyanosis
- 41. Contraindications • Pregnancy --fetus - glucose-6-phosphate dehydrogenase (G-6-PD) deficient Clinical uses • *Q*Radical cure of relapsing malaria (P.ovale and P.vivax) • *Q*Single 45 mg dose given with curative dose of chloroquine to kill gametes (P. falciparum)
- 42. Proguanil (Chloroguanide) • Slowacting erythrocytic schizontocide • Cyclized in body to a triazine derivative (cycloguanil) *Q*Inhibits plasmodial dihydrofolate reductase (DHFRase) • Resistance developed due to mutational changes in the plasmodial DHFRase enzyme
- 43. Adverse effects •Mild abdominalupset, vomiting •Stomatitis •*Q* Haematuria, rashes and transient loss of hair •Safe during pregnancy
- 44. Pyrimethamine • Slow actingerythrocytic schizontocide. *Q*Direct inhibitor of plasmodial dihydrofolate reductase (DHFRase) • High doses inhibits Toxoplasma gondii • Resistance develops by mutation in DHFRase enzyme
- 45. Adverse effects • Nauseaand rashes • Folate deficiency - rare *Q*Megaloblastic anaemia and granulocytopenia with higher dose • Combined with a sulfonamide (S/P) or dapsone for treatment of falciparum malaria
- 46. Sulfonamide-pyrimethamine (S/P) • Sulphadoxinecompetes with para–amino benzoic acid – inhibits the formation of dihydrofolic acid. • Pyrimethamine inhibits DHFRase enzyme as a result of which conversion of dihydrofolic acid to tetrahydrofolic acid is blocked. • Treatment and prophylaxis of falciparum malaria resistant to chloroquine
- 47. Adverse effects?? • MildGIT upset • Megaloblastic anemia, bone marrow depletion • Rashes, urticaria, serum sickness, drug fever *Q*Exfoliative dermatitis, Stevens Johnson syndrome • Nephrotoxicity
- 49. Artemisinin and ItsDerivatives: Active principle of plant Artemisia annua It includes: 1. Artesunate 2. Artemether 3. Arteether 4. Arterolane Artemisia annua
- 50.
- 51. 1. Artesunate • Sodiumsalt - water soluble and is administered by oral, i.m. or i.v. route • Rapidly converted to active metabolite dihydroartemisinin (DHA) • Q*After repeated dosing, causes autoinduction of its own metabolism by CYP2B6 and CYP3A4
- 52. 2. Artemether • Lipidsoluble and is administered orally or i.m. • Absorption - slower taking 2-6 hrs • Substantial first pass metabolism and is converted to DHA
- 53. 3. α/β Arteether •Availablefor i.m. administration only to adults for complicated malaria •Q*Longer elimination (t1/2=23hrs), so recommended in a three day schedule
- 54. Artemisinin Adverse effects • *Firstdegree A-V block • *Q-T prolongation • Transient leucopenia (rare) • Bleeding, dark urine • Headache, tinnitus, dizziness • Abdominal pain, itching, nausea, vomiting
- 55. Artemisinin Based CombinationTherapy (ACT) •*One of artemisinin compound in combination with another effective erythrocytic schizontocide. •Kills >95% of the plasmodia
- 56. Advantages of ACT •Rapid clinical and parasitological cure • Q* High cure rates(>95%) and low recrudescence rate • Absence of parasite resistance • Good tolerability profile • Dosing schedule is simpler
- 57. 1. Artesunate-sulfadoxine +pyrimethamine(AS-S/P) • First line drug for uncomplicated falciparum malaria • Fewer side effects than AS/MQ 2. Artesunate/mefloquine(AS/MQ) • Highly effective and well tolerated in uncomplicated falciparum malaria
- 58. 3.Artemether-lumefantrine(AS/LF) • Clinical efficacy:95-99% • Q*Must be administered with fatty food or milk to allow absorption and ensure adequate blood level of AS/LF • Quickly reduces parasite biomass, resolve symptoms, prevent recrudescence, check gametocyte population
- 59. AS/LF Adverse drugreaction Headache, dizziness, abdominal pain, arthralgia, myalgia, pruritus and rashes Drug interaction Not to be given with drugs metabolized by CYP2D6 ( e.g. metoprolol) as lumefantrine inhibits isoenzyme CYP2D6 Contraindication First trimester of pregnancy , lactation
- 60. 4. Dihydroartemisinin(DHA)-piperaquine • Q*Used in dose ratio of 8:1 for multidrug resistant Plasmodium falciparum • Good safety profile and even tolerated by children (>98% response rate) Adverse drug reaction • Dizziness, rashes • Vomiting and GI symptoms
- 61. 5. Artesunate-amodiaquine(AS/AQ) • Q*Firstline therapy of uncomplicated falciparum malaria • To be taken twice daily for three day treatment 6. Arterolane-piperaquine Q *Acts rapidly at all stages of asexual schizogony of malarial parasite including multidrug resistant P. falciparum 7. Artesunate-pyronaridine - Under clinical trial
- 63. Tetracycline and Doxycycline •*Q*Used against chloroquine resistant malaria • Kills erythrocytic stage of the malarial parasite • For acute attack only • Doxycycline - for prophylaxis and acute attack • Q *Should not be given to children and pregnant women
- 64. Clindamycin • Q*Active againstthe erythrocytic stage of the malaria parasite • Liver stage and gametocytes are not affected Q*Drug used adjunct to quinine to treat malaria caused by chloroquine resistant Plasmodium falciparum • Q*Can be used in children and pregnant women
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- 76.
- 77. Why Chloroquine concentrationis 1000 times more in food vacuole of parasite? 1. Its protonation and ion trapping occures in the vacuole (because it is acidophilic and food vacuoles have low PH) 2. Its active uptake by a parasite transporter. 3. Its binding to a specific receptor in the food vacuole.
- 78. What is themechanism of Chloroquine Resistance? • Resistance occure due to increased expression of the human multidrug resistance transporter(PfCRT) and • it leads to efflux of preaccumulated drug and second mechanism is that there is increase in vacuolar pH such that the proton gradient responsible for drug concentration is reduced.
- 79. What is themechanism of Antimalarial drug induced hemolytic anaemia? Primaquine produces hemolytic anaemia in G6PD deficiency It oxidizes the glutathione=>no enough NADPH=> therefore thee is reduced form of glutathion and RBCs lysis by oxidants.
- 80. Mechanism of bulleye ? The possible mechanism is that the drugs bind to melanin in the retinal pigment epithelium (RPE) and affect photoreceptor metabolism.
- 81. Antimalarial Drug havingslight neuromuscular blocking property and Oxytoxic property? Quinine is the drug having neuromuscular blocking property. Therefore useful in some muscular disorders, especially nocturnal leg cramps and myotonia congenita, and also stimulates uterus contraction to deliver the fetus .
- 82. Mechanisms of nonmalarial uses of choloroquine? Due to its anti inflammatory action, it can be used in rheumatoid arthritis and SLE. It also decreases the formation of peptide-MHC protein complexes required To stimulate CD4+ T cells and result in down-regulation of the immune response against autoantigenic peptides. In Amebiasis act by directely on the trophozoites of E. histolytica.
- 83. What happens whencholoroquine gets accumulated in melanin containing tissues like skin & retina? It is accumulated in pigment epithelium and choroid in much higher concn than in other eye tissues. It leads to Retinopathy, characterized by loss of central visual acuity,Lichenoid Accumulation in skin leads to Pruritus,urticaria, eruption,bleaching of hair.
- 84. Chloroquine is safein pregnancy, but yet not given.Why? Because its resistance is very common if the pregnant lady has P.falciparum infection, she will die from the infection due to resistance parasite not from the drug. So we must give another drug that is both safe and can attack all parasites whether sensitive or resistance.
- 85. Why relapse donot occure in case of P. falciparum &P.malariae? In both the species Exo-erythrocytic stage is absent and therefore do not form hypnozooites.Therefore no relapse
- 86. Why does onlyfemale anopheles mosquito cause malaria? Because female need blood from vertebral host to nourish eggs.
- 87. Role of Leucovorinin folate-deficient megaloblastic anemia produced by pyrimethamine? It is a DHFRase inhibitors which inhibit formation of folic acid in the body. Hence Leucovorin(folinic acid ) , reduced form of folic acid is gven in a dose of 5-10 mg daily prophylactically to all patients receiving pyrimethamine.
- 88. Urinary excretion ofquinine (or chloroquine) can be enhanced by? Quinine, chloroquine, Quinidine are basic drugs and there excertion can be enhanced by acidifying the urine by Ammonium chloride
- 89. Urinary excretion ofquinine (or chloroquine) can be enhanced by? Quinine, chloroquine, Quinidine are basic drugs and theri excertion can be enhanced by acidifying the urine by Ammonium chloride
- 90.
Editor's Notes
- #26 Progressive visual loss is halted by stopping the drug, but not reversible.
- #29 The mechanism of resistance involves a reduced accumulation of the drug. Possible explanations include an energy-dependent efflux of preaccumulated drug via parasite protein named PfCRT, the mutated form of which is able to reduce chloroquine accumulation in the digestive vacuole of the pathogen or an increase in vacuolar pH such that the proton gradient responsible for drug concentration is reduced.
- #35 Fast acting erythrocytic (blood) schizontocide but slower than CQ or quinine Effective against CQ-sensitive as well as resistant Plasmodia Efficacious suppressive prophylactic for multi-resistant P. falciparum
- #36 Like CQ, it accumulates in infected RBCs, binds to heme and this complex damages the parasite’s membrane. Recently it was suggested that the site of action of MQ is in the parasitic cytosol rather than in the acidic vacuole.
- #46 Can be treated with folinic acid
- #56 Consideration must be made about t1/2 of companion drug to maintain its effective concentration in the blood for at least 3-4 asexual cycles of the parasite.