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Antimalarial Drugs Malaria • • o o i. ii. iii. iv. Malaria is an acute infectious disease Causative agent : Plasmodium species Protozoan parasite 4 species infecting humans P. falciparum P. vivax P. malariae P. ovale • Transmitted by female Anopheles mosquito • Is characterized by high fever with rigor, anaemia, profuse sweating Types of malaria Plasmodium falciparum Plasmodium vivax •most dangerous •Causes a milder species form of the disease •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 malariae Plasmodium ovale •Common to many tropical regions •rarely encountered Life cycle of Malaria 1. Hepatic (Pre erythrocytic) stages -parasites localize in liver -patient is asymptomatic 2. Erythrocytic stages -parasite invade RBCs -patient develops fever cycle 3. Development of sexual forms -occurs in Anopheles mosquitos Life cycle of Malaria Antimalarial Drugs CLASSES DRUGS 1. 4-Aminoquinolines Chloroquine (CQ) Amodiaquine (AQ) Piperaquine 2. Quinoline-methanol Mefloquine 3. Cinchona alkaloid Quinine, Quinidine 4. Biguanide Proguanil (Chloroguanide) 5. Diaminopyrimidine Pyrimethamine 6. 8-Aminoquinoline Primaquine Tafenoquine Antimalarial Drugs CLASSES DRUGS 7. Sulfonamides and sulfone Sulfadoxine Sulfamethopyrazine Dapsone 8. Antibiotics Tetracycline Doxycycline Clindamycin 9. Sesquiterpine lactones Artesunate Artemether Arteether Arterolane 10. Amino alcholos Halofantrine Lumefantrine 11. Naphthyridine Pyronaridine 12. Naphthoquinone Atovaquone Drugs used in malaria • 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 Forms of Antimalarial Drugs • Clinically malarial infections can be controlled by the drugs used in following ways: 1. Causal prophylaxis 2. Suppressive prophylaxis 3. Clinical cure 4. Radical cure 5. Gametocidal 1. Causal prophylaxis • Drugs prevent the maturation of or destroy the sporozoites within the infected hepatic cell- thus prevent erythrocytic invasion • Primaquine – for all species of malaria but not used due to its toxic potential • Proguanil- primarily for P. falciparum and not effective against P. vivax (weak activity), rapid development of resistance 2. Suppressive prophylaxis • Schizontocides inhibit erythrocyte phase and prevent the rupture of the infected erythrocytes, lead to freedom from rigors and pyrexia • Includes quinine, chloroquine, proguanil, pyrimethamine, artemicinin and tetracycline 3. Clinical cure • Erythrocytic schizontocides are used to terminate episodes of malarial fever • o o o Fast acting high efficacy drugs: Chloroquine, quinine, mefloquine, halofantrine, artemicinin Used singly to treat malaria fever Faster acting, preferably used in falciparum malaria where delayed treatment may lead to death even if parasites are clear from blood • Slow acting low efficacy drugs: o Proguanil, pyrimethamine, sulfonamides, tetracyclines o Used only in combination 4. Radical cure • Drug attack exoerythrocytic stage (hypnozoites) given with clinical curative for the total eradication of the parasite from the patient’s body • Radical cure of the P. falciparum malaria can be achieved by suppressives only • For radical cure of P.vivax infection, primaquine and proguanil are effective 5. Gametocial • Removal of male and female gametes of Plasmodia formed in the patient’s blood • It has no benefit for treated patient • Primaquine and artemisinins are highly effective against gametocytes of all species Antimalarial drugs CHLOROQUINE (CQ) • Rapidly acting erythrocytic schizontocide against all species of Plasmodia • Drug of choice for treating acute attacks caused by sensitive strains of P. vivax or P. falciparum • Controls most clinical attack in 1-2days with disappearance of parasite from peripheral blood in 1-3days • No effect on exo- erythrocytic phase • Neither prevent primary infection nor relapse in P. vivax and P.ovale • Drug of choice for use in pregnancy, prophylaxis Chloroquine Mechanism of action Chloroquine Mechanism of action i. The parasite digests the host cell’s hemoglobin to obtain essential amino acids ii. The process releases large amounts of heme, which is toxic to the parasite iii. To protect itself the parasite ordinarily polymerizes the heme to nontoxic hemozoin, which is sequestered in the parasite’s food vacuole iv. Cholroquine prevents the polymerization to hemozoin v. The accumulation of heme results in lysis of both the parasite and the red blood cell Chloroquine Pharmacokinetics • Rapidly and completely absorbed from GI tract • Substantial amount is deposited in erythrocytes, liver, spleen, kidney, lung, melanin containing tissues and leukocytes • Slow release from these sites helps in maintaining the therapeutic plasma levels – when used for prophylaxis, it is administered just once a week • Also crosses the blood- brain barrier and traverses the placenta • Excreted predominantly in the urine Chloroquine Adverse effects • CNS- mild headache, confusion, psychosis, convulsion, impaired hearing • Eye (with high dose)- loss of vision due to retinal damage, reversible corneal damage • GIT- Nausea, vomiting, anorexia, epigastric pain, diarrhea( can be minimized by taking with meal) • Skin- uncontrolled itching, urticaria, exfoliative dermatitis • Parenteral administration- Hypotension, cardiac arrhythmias, cardiac depression Chloroquine Uses • Extraintestinal amoebiasis • Rheumatoid arthritis • Discoid lupus erythematosus • Lepra reaction • Photogenic reactions • Infectious mononucleosis Chloroquine Contraindications • Patient with psoriasis, porphyria • In dermatitis, liver damage, alcoholism, neurological, retinal and hematological diseases MEFLOQUINE (MQ) • 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 Mefloquine Mechanism of action • Like CQ, it accumulates in infected RBCs, binds to heme and this complex damages the parasite’s membrane • However recent evidence suggests that the site of action of MQ is in the parasitic cytosol rather than in the acidic vacuole Mefloquine Pharmacokinetics • Prolonged absorption after oral ingestion • It is highly plasma protein bound and concentrated in the liver, lung and intestines • Extensive metabolism occurs in liver and is primarily secreted in bile • It has a long half life (17days) due to its concentration in various tissues and its continuous circulation through the enterohepatic and enterogastric systems • Its major excretory route is feces Mefloquine Adverse effects • • o o • • MQ is bitter in taste At high doses: Nausea, vomiting, diarrhea, abdominal pain, bradycardia Ataxia, hallucinations, depression MQ is safe in pregnancy Rare events of toxicity are seen Contraindications • In patients with anxiety, depression, psychosis, and in cardiac conduction defects Mefloquine Drug interactions • Cardiac arrests are possible if MQ is taken concurrently with quinine or quinidine Uses • Effective for multidrug resistant P. falciparum • However its use is restricted due to its toxicity, cost and long half life QUININE • Quinine is a l-isomer of alkaloid obtained from cinchona bark and quinidine (antiarrhythmic) is its 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 (preexoerythrocyte and gametocytes) Quinine Mechanism of action • Like CQ it is a weak base, and acts by inhibiting polymerization of heme to hemozoin • Free heme or heme-quinine complex damages parasite’s membrane and kills it Pharmacokinetics • Well absorbed from GI tract, even in patients with diarrhea • Metabolized in liver and excreted in urine Quinine Adverse effects • Cinchonism: o Higher dose symptoms include nausea, vomiting, tinnitus, vertigo, headache, mental confusion, difficulty in hearing and visual defects, diarrhea, flushing • Rapid i.v. injection: o Hypotension and cardiac arrhythmias • Can cause profused hypoglycemia Adverse effects • Pregnancy: o Causes abortion in early pregnancy by stimulating myometrium and premature labor by stimulating uterus o Hypoglycaemia Clinical uses • Malarial attacks o Uncomplicated resistant falciparum o Complicated and severe malaria including cerebral malaria • Is not highly active, adjunctive therapy with doxycycline, tetracycline and clindamycin is needed PROGUANIL (CHLOROGUANIDE) • Slow acting erythrocytic schizontocide • Cyclized in body to a triazine derivative(cycloguanil) • Cycloguanil inhibits plasmodial dihydrofolate reductase (DHFRase) • Resistance developed due to mutational changes in the plasmodial DHFRase enzyme Proguanil • Slow but adequate absorption from the gut • Partly metabolized and excreted in urine • Half life 16-20 hour ; noncumulative Adverse effects • Mild abdominal upset, vomiting • Occasional stomatitis • Haematuria, rashes and transient loss of hair • Note : Safe during pregnancy PYRIMETHAMINE • Slow acting erythrocytic schizontocide • Direct inhibitor of plasmodial dihydrofolate reductase (DHFRase) • Conversion of dihydrofolic acid to tetrafolic acid is inhibited • High doses inhibits Toxoplasma gondii • Resistance develops by mutation in DHFRase enzyme Pyrimethamine Adverse effects • Occasional nausea and rashes • Folate deficiency rare • Megaloblastic anaemia and granulocytopenia with higher dose • Can be treated with folinic acid • Combined with a sulfonamide (S/P) or dapsone for treatment of falciparum malaria SULFONAMIDE-PYRIMETHAMINE(S/P) • Sulphadoxine is a sulfonamide thus competes with para– amino benzoic acid – inhibits the formation of dihydropteric acid • Pyrimethamine inhibits DHFRase enzyme as a result of which conversion of dihydrofolic acid to tetrahydrofolic acid is blocked – thus inhibits DNA synthesis • Effective blood schizontocide against Plasmodium falciparum • Treatment and prophylaxis of falciparum malaria resistant to chloroquine Sulfonamide-Pyrimethamine(S/P) Adverse effects • Mild GIT upset • Megaloblastic anemia, bone marrow depletion • Rashes, urticaria, serum sickness, drug fever • Exfoliative dermatitis, Stevens Johnson syndrome • Nephrotoxicity PRIMAQUINE • Poor erythrocytic schizontocide • Has marked effect on primary and secondary hepatic phases of malarial parasite • Highly active against gametocytes and hypnozoites Mechanism of action • Intermediate act as oxidant that are responsible for the schizontocial action Primaquine Pharmacokinetics • Readily absorbed after oral absorption • Oxidized in liver with a plasma half life of 3-6 hours • Excreted in urine within 24 hour • Not a cumulative drug Primaquine Adverse effects • Abdominal pain, gastrointestinal upset, weakness or uneasiness chest • Leucopenia (high dose) • Hemolysis • Methaemoglobinaemia • Tachypnoea • Cyanosis Primaquine Contraindications • Should not be given during pregnancy because fetus is glucose-6-phosphate dehydrogenase ( G-6-PD) deficient Clinical uses • radical cure of relapsing malaria (P.ovale and P.vivax) • single 45mg dose given with curative dose of chloroquine to kill gametes (P. falciparum) TETRACYCLINE AND DOXYCYCLINE ( Antibiotics) • Used against chloroquine resistant malaria • Kills erythrocytic stage of the malarial parasite • Tetracycline is used for acute attack only • Doxycycline is used for prophylaxis and acute attack • For treating acute attack they are used in combination with quinine • Should not be given to children and pregnant women CLINDAMYCIN ( Antibiotics) • Active against the erythrocytic stage of the malaria parasite • Liver stage and gametocytes are not affected • Drug used adjunct to quinine to treat malaria caused by chloroquine resistant Plasmodium falciparum • Can be used in children and pregnant women ARTEMISININ AND ITS DERIVATIVES: • Active principle of plant Artemisia annua • Sesquiterpene lactone endoperoxide • 1. 2. 3. 4. It includes: Artesunate Artemether Arteether Arterolane Mechanism of action 1. ARTESUNATE • Its sodium salt is water soluble and is administered by oral, i.m. or i.v. route • Rapidly converted to active metabolite dihydroartemisinin (DHA) • After repeated dosing, artesunate causes autoinduction of its own metabolism by CYP2B6 and CYP3A4 2. ARTEMETHER • Lipid soluble and is administered orally or i.m. • Absorption after oral or i.m. dosing is slower taking 2-6 hrs • Undergoes substantial first pass metabolism and is converted to DHA • Extensive metabolism by CYP3A4 yields a variable half life of 3-4 hrs 3. α/β ARTEETHER • Available for i.m. administration only to adults for complicated malaria • Due to its longer elimination (t1/2=23hrs), it is recommended in a three day schedule ARTEMISININ Adverse effects • First degree A-V block • Q-T prolongation • Transient reticulopenia and leucopenia (rare) • Bleeding, dark urine • Headache, tinnitus, dizziness • Abdominal pain, itching, nausea, vomiting Artemisinin Drug interaction • Concurrent administration of artemisinins with drugs prolonging Q-T like astemizole, antiarrhythmics, tricyclic antidepressants and phenothiazines may increase the risk of cardiac conduction ARTEMISININ BASED COMBINATION THERAPY (ACT) • One of artemisinin compound in combination with another effective erythrocytic schizontocide is used. • 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. • Kills >95% of the plasmodia Advantages of ACT • Rapid clinical and parasitological cure • High cure rates(>95%) and low recrudescence rate • Absence of parasite resistance • Good tolerability profile • Dosing schedule is simpler 1. Artesunate-sulfadoxine + pyrimethamine(AS-S/P) • First line drug for uncomplicated falciparum malaria • Not effective against multidrug-resitant strains which are non responsive to S/P • Fewer side effects than AS/MQ 2. Artesunate/mefloquine(AS/MQ) • Highly effective and well tolerated in uncomplicated falciparum malaria 3.Artemether-lumefantrine(AS/LF) • Clinical efficacy: 95-99% • 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 AS/LF Adverse drug reaction • 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 • during first trimester of pregnancy and lactation period 4. Dihydroartemisinin(DHA)piperaquine • 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 5. Artesunate-amodiaquine(AS/AQ) • First line therapy of uncomplicated falciparum malaria • To be taken twice daily for three day treatment • Other recently developed ACT are: 6. Arterolane-piperaquine • Acts rapidly at all stages of asexual schizogony of malarial parasite including multidrug resistant P. falciparum 7. Artesunate-pyronaridine • Under clinical trial CEREBRAL MALARIA • Most severe neurological complication of infection with Plasmodium falciparum • Aggregation of infected and non infected red cells and plugging in capillary endothelium of brain due to secreted proteins on red cell surface by late stage schizonts • Enhanced by the pro-inflammatory status of the host and virulence characteristics of the infecting parasite variant • Manifested by confusion, coma and death due to anoxia, ischaemia and haemorrhage Drugs used in Cerebral malaria • Quinine by slow intravenous infusion • Artemisinin derivatives that produce a very rapid therapeutic response and are effective against multi-drug resistant P. falciparum are preferred • Some of the drugs used as a combination therapy for cerebral malaria are: o Arteether with quinine o Artemether with quinine REFERENCES 1. Tripathi KD, Essentials of MEDICAL PHARMACOLOGY, Jaypee Brothers Medical Publishers (P) Ltd, 7th edition, 2013. 2. Finkel Richard et all, Pharmacology, Lippincott’s Illustrated Reviews, 4th edition. 3. The treatment of complicated and severe malaria, BRITISH MEDICAL BULLETIN.