Antimalarial drugs

Pharmacology of Antimalarial Drugs: Slide contents include definition, classification, objectives and pharmacology of different antimalarial drugs

1. ANTIMALARIAL DRUGS Anusha Shaji , B.Pharm , M.Pharm Assistant Professor Department of Pharmacology Nirmala College of Pharmacy, Muvattupuzha , Ernakulam

2.   Antimalarial drugs These are drugs used for prophylaxis, treatment and prevention of relapses of malaria. malaria is an acute infectious disease caused by four species of the protozoal genus Plasmodium Plasmodium species which infect humans Plasmodium vivax ( tertian) Plasmodium ovale (tertian ) Plasmodium falciparum (tertian ): Most dangerous species Plasmodium malariae ( quartan ) The parasite is transmitted to human through the bite of a female Anopheles mosquito

3. Symptoms of Malaria

4. Classification of Antimalarial Drugs

5. Objectives and use of Antimalarial Drugs The aims of using drugs in relation to malarial infection are; To prevent clinical attack of malaria (prophylactic) To treat clinical attack of malaria (clinical curative) To completely eradicate the parasite from the patient’s body (radical curative) To cutdown human to mosquito transmission ( gametocidal )

6. Life Cycle of the malarial parasite, Plasmodium falciparum

7. Drugs used in malaria Tissue schizonticides - drugs eliminating developing or dormant liver forms Blood schizonticides - drugs acting on erythrocytic parasites Gametocides - drugs that kill sexual stages and prevent transmission to mosquitoes

8. Forms of Antimalarial Drugs Clinically malarial infections can be controlled by the drugs used in following ways: Causal prophylaxis Suppressive prophylaxis Clinical cure Radical cure Gametocidal 1.Causal prophylaxis Drugs prevent the maturation of or destroy the sporozoites within the infected hepatic cell- thus prevent erythrocytic invasion

9. 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

10. Fast acting high efficacy drugs: Chloroquine , quinine, mefloquine , halofantrine , artemisinin Used singly to treat malaria fever o 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: Proguanil , pyrimethamine , sulfonamides, tetracyclines - 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

11. 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

12. 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

13. Chloroquine - Mechanism of action The parasite digests the host cell’s hemoglobin to obtain essential amino acids ↓ The process releases large amounts of heme , which is toxic to the parasite ↓ To protect itself the parasite ordinarily polymerizes the heme to nontoxic hemozoin , which is sequestered in the parasite’s food vacuole Cholroquine prevents the polymerization to hemozoin ↓ The accumulation of heme results in lysis of both the parasite and the red blood cell

14. Mechanism of Chloroquine

15. 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 Uses Extraintestinal amoebiasis • Rheumatoid arthritis • Discoid lupus erythematosus • Lepra reaction • Photogenic reactions • Infectious mononucleosis

16. 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

17. 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 Mechanism of action Like CQ, it accumulates in infected RBCs, binds to heme and this complex damages the parasite’s membrane

18. However recent evidence suggests that the site of action of MQ is in the parasitic cytosol rather than in the acidic vacuole 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

19. Adverse effects MQ is bitter in taste At high doses: Nausea, vomiting, diarrhea, abdominal pain, bradycardia o 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 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

20. 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 (pre- exoerythrocyte and gametocytes) Mechanism of action Like CQ it is a weak base, and acts by inhibiting polymerization of heme to hemozoin

21. 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 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 Can cause profused hypoglycemia

22. Pregnancy Causes abortion in early pregnancy by stimulating myometrium and premature labor by stimulating uterus Hypoglycaemia Clinical uses Malarial attacks Uncomplicated resistant falciparum Complicated and severe malaria including cerebral malaria Is not highly active, adjunctive therapy with doxycycline , tetracycline and clindamycin is needed

23. 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 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

24. 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 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

25. 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 Adverse effects •Mild GIT upset • Megaloblastic anemia, bone marrow depletion • Rashes, urticaria , serum sickness, drug fever • Exfoliative dermatitis, Stevens Johnson syndrome • Nephrotoxicity

26. 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 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

27. Adverse effects Abdominal pain, gastrointestinal upset, weakness or uneasiness chest Leucopenia (high dose) Hemolysis Methaemoglobinaemia Tachypnoea Cyanosis 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 )

28. ARTEMISININ ARTEMISININ DERIVATIVES Artesunate Artemether Arteether

29. ARTEMISININ- BASED COMBINATION THERAPY Artesunate - sulfadoxine + pyrimethamine (AS-S/P) Artesunate - mefloquine (AS/MQ) Artesunate - amodiaquine (AS/AQ) Artemether-lumefantrine Dihydroartemisinin (DHA)- piperaquine Arterolane - piperaquine Artesunate - pyronaridine

30. ATOVAQUONE Synthetic naphthaquinone Rapidly acting erythrocytic schizontocide as well as active against pre erythrocytic stage of P. falciparum and other plasmodia. Pneumocystis jiroveci and Toxoplasma gondii are also susceptible to atovaquone . It collapses plasmodial mitochondrial membranes and interferes with ATP production Proguanil potentiates its antimalarial action Side effects Diarrhoea , vomiting, headache, rashes, fever