.Antimalarials drugs _1652888760000.pptx

A brief introduction and modes of action for different antimalarials

1. Antimalarials S 19

2. Malaria

3. Drugs used in acute attack Rapidly acting 1) Artemisinin, its derivatives 2) Quinine, mefloquine 3) Halofantrine 4) Amodiaquine, chloroquine Slow acting 5) S/P (+other antifolates) 6) Antibacterials – tetracyclines Tissue Schizonticides Primaquine (radical cure) Drugs used for chemoprophylaxis (prevent clinical attack) Mefloquine Chloroquine Proguanil Doxycyline Dapsone ± (pyrimethamine) S/P Gametocytocidal agents Primaquine (all species) Quinine, chloroquine, (not on P. falciparum)

4. Malaria 1. ARTEMISININ and its derivatives ♦ Artemisinin – water insoluble, ltd to oral use ♦ Artesunate – water soluble, oral, IV, IM, rectal ♦ Artemether – lipid soluble - oral, IM, rectal ♦ Arteether, Artelinic acid Uses : ♦ Increasingly the DOC for P. falciparum ♦ Quinine resistant P. falciparum Mxn : Fast acting blood schizonticide on all species ♦ The endoperoxide ring is cleaved w/in parasite to release free radicals that damage the parasite Abs ; rapid Elimination : metabolized to active drug - dihydroartemisinin ♦ Short t 1/2 - (leads to high recrudescence rate, best co-adm with other drugs i.e. Artemisinin-based combination Therapy - ACT ) e.g. lumefantrine, fansidar, doxycycline S/E (fairly well tolerated) ♦ GIT disturbance (nausea, vomiting, diarrhea) ♦ High doses, so far only in animals ♦ Avoid in pregnancy

5. 2. QUININE, QUINIDINE Mxn : - Actual mxn not clear - rapid blood schizonticide against all 4 sp ♦ NOT active against liver stages ♦ Other P’cological effects i) curare-like effect (use on leg cramps) ii) oxytoxic effect – esp with advanced pregnancy iii) local irritant action – site of adm iv) mild analgesic and antipyretic effect Adm : oral, parenteral Abs : rapid, impaired by Al 3+ containing antacids Distribution : wide, protein- bound, (give a loading dose to achieve peak levels soonest) Elimination : Quinidine shorter t 1/2 Metabolized, renal excretion

6. S/E 1. Cinchonism –Tinnitus, impaired hearing, visual disturbance, dizziness, headache, nausea, flushed skin Serious S/E 2. Audio-visual disturbance 3. GIT irritation – abdominal pain, vomiting, diarrhea 4. Hypersensitivity rxns – e.g. urticaria, bronchocospasm, angioedima, (some hematological, below) 5. Hematological abnormalities – ● Thrombophlebitis at site of infusion 6. Hypoglycemia (stimulates insulin release, most felt by pregnant patients) 7. GIT irritation –pain, vomiting, diarrhea 8. Uterine contractions in pregnancy (esp 3rd trimester) – still DOC for severe falciparum but observe patient 9. Hypotension – with rapid infusion 10. ECG changes

7. 2. Quinine: Precautions/ avoid: ♦ If severe cinchonism occurs (discontinue therapy) ♦ Auditory or visual problems ♦ Cardiac abnormalities ♦ Patients who have recently received mefloquine ♦ Hypersensitivity rxns - hemolysis D/I ♦ Mefloquine (increases its toxicity) – do not co-administer ♦ Warfarin and Digoxin – quinine raises their plasma conc. Uses: 1. Severe falciparum malaria (DOC, parenteral) often combined w/ another drug (fansidar, doxycycline) to shorten duration of Rx and limit toxicity. 2. Babesiosis (Babesia microti) DOC in combination w/ clindamycin

8. 3. MEFLOQUINE Mxn : unclear Blood schizonticide (NOT gametocytes or liver stages) Resistance : not common in E. Africa ● Associated w/ resistance to quinine and halofantrine but not CQ Adm : oral only (severe local irritation with parenteral use) Abs : good, slow Distribution : extensively in tissues Elimination : t 1/2 - long ● Some metabolism, Biliary excretion mainly S/E ● GIT irritation ● Sleep disorders ● Neuropsychiatric disturbance, discontinue if serious ● Hepatic damage (mild) ● Cardiac (conduction) defects – arrhythmias, bradycardia

9. 3. MEFLOQUINE C/I – presence or Hx of 1. Cardiac conduction defects, use of cardiotoxic drugs 2. Epilepsy 3. Neuropsychiatric disorders 4. Hypersensitivity (to related drugs) 5. Quinine, quinidine or halofantrine (do not co-adm) 6. 1 st trimester of pregnancy (NB can use in pregnancy 2 nd , 3 rd trimester – as last option) Uses : 1.Chemoprophylaxis (all 4 sp) (CQ preferred in areas where it is still sensitive) 2. Rx of falciparum malarial infection – not DOC, not recommended

10. 4. HALOFANTRINE Mxn : not clear Rapid blood schizonticide against all 4 sp (NOT gametes or hepatic stages) Resistance : cross resistance w/ mefloquine Adm : oral Abs : variable, enhanced with meals (esp fatty foods) - but take on empty stomach to avoid high plasma conc. ass. w/ toxicities S/E ♦ GIT irritation ♦ Headache, cough ♦ Pruritus, rash ♦ Mild hepatic damage (elevated liver enzymes) ♦ Cardiac conduction defects – arrhythmias, death dose – related , worsened by prior mefloquine therapy ♦ Embryotoxic in animals C/I ♦ Persons w/ cardiac conduction defects ♦ Persons recently on mefloquine ♦ Use of other drugs that prolong Q-T interval ♦ Pregnancy & lactation Uses : Rx of falciparum malaria (NOT for chemoprophylaxis)

11. 5. CHLOROQUINE (CQ) Synthetic, 4-aminoquinoline Mxn : prevents polymerization of heme to hemozoin, heme accumulates and is toxic to parasite ♦ Rapid b lood schizonticide (v. effective on sensitive strains) ♦ Moderately effective on gametes of all except P. falciparum ♦ Not effective against hepatic forms Other p’cological effects anti-inflammatory, Anti-amoebic Quinidine –like effect Adm : oral, parenteral Abs : rapid, almost complete, Ca 2+ , Mg 2+ antacids and Kaolin interfere w/ abs. Distribution : wide, sequestration in tissues - loading dose, Elimination : metabolized, renal excretion

12. 5. CHLOROQUINE S/E : fairly well tolerated (in small malarial doses) reduced by taking after food ♦ Pruritus (esp in Africans), urticaria ♦ GIT irritation, anorexia ♦ Malaise ♦ Blurred vision ♦ Large or rapid parenteral adm – hypotension (severe), respiratory and cardiac arrest ( always infuse slowly) Rare S/E ♦ Hemolysis (w/ G6PDH deficiency), agranulocytosis ♦ CNS disturbance – ♦ Impaired hearing ♦ Allergic rxn – ♦ Cardiac conduction defects S/E -Long –term and high doses ♦ The most important toxicities are on the eyes, avoid in Patients with underlying retinopathies do baseline ophthalmologic examination and a follow-up examination every 12 months ♦ Irreversible ototoxicity, myopathy, peripheral neuropathy, CNS disturbance

13. 5. CHLOROQUINE C/I • Psoriasis, porphyria – it precipitates these diseases • Visual& muscle disorders • Caution in persons w/ Liver, hematological or neurologic disorders Uses : 1a. Rx of Acute P. vivax, ovale, malariae infection (+ primaquine for radical cure) 1b. Rx of sensitive forms ONLY of acute falciparum malaria – • Advantages: Rapid clearance of parasitemia, cheap, convenient regimen, few S/E 2.Suppressive Chemophrophylaxis – ONLY in areas w/out resistance, (+ primaquine for radical cure) 3. Hepatic amebiasis (where Metronidazole has failed or is C/I) + a lumicide 4. Anti-inflammatory – rheumatoid arthritis, SLE etc – last options 5. Infection w/ Clonorchis sinensis, Fasciola hepatica, Paragonimus spp, giardia spp

14. 6. AMODIAQUINE ( Similar to CQ in many ways) Adm: oral S/E • Agranulocytosis, hepatotoxic Uses: • Sensitive strains of malaria • (don’t use for prophylaxis due to S/E) 7. ATAVAQUONE + proguanil = malarone - Still under study Atavaquone Adm : oral Abs : erratic – improved by fatty food Distribution : sig. protein binding Elimination : biliary excretion S/E GIT effects- nausea, vomiting diarrhea Fever, Headache, insomnia Rash Uses Uncomplicated malaria and prophylaxis – combined w/ proguanil Alternative in P. jirovecii infection (not as efficacious as Co-trimox) Toxoplasmosis

15. 8. PRIMAQUINE Mxn : Molecular mxn not clear Active against all hepatic stages (the only drug against hypnozoites) but too toxic for causal prophylaxis ♦ Gametocytocidal to all 4 sp (prevents transmission - to mosquitoes) ♦ (schizonticidal power is too weak to be significant) Adm : oral (NEVER give parenteral – severe hypotension) Abs : adequate S/E ♦ GIT distress -improved if taken w/ food ♦ Hemolysis and methemoglobinemia esp in G6PDH deficiency Serious ♦ Hematological abnormalities – leucopenia, agranulocytosis, ♦ Cardiac arrhythmias C/I ♦ Those at risk of granulocytopenia, methemoglobinemia, mylosuppression ♦ In pregnancy (just in case fetus is G6PDH deficient) Uses : 1. Radical cure of P.vivax & ovale infections (add a blood schizonticide too) 2. Terminal prophylaxis (after end of travel) to eradicate any liver forms 3. May be used for causal prophylaxis of malaria (any sp)- given before travel to endemic area (then it need not be continued for long after return from endemic area 4. Alternative for mild Pnuemocystis jirovecii infection (along w/ clindamycin)

16. 9. Pyrimethamine ( Sulphonamide-pyrimethamine (SP) Mxn : plasmodial dihyrofolate reductase inhibitor Acts slowly against erythrocytic stage of all 4 sp. Adm : oral Elimination : Extensive metabolism, t 1/2 allows once a week dosing S/E (few) ♦ GIT irritation ♦ Rashes, itching ♦ Teratogenic in animals (but fansidar still used in pregnancy) NB. Always supplement folic acid if antifolates are used in pregnancy) Uses : 1. Acute attacks and suppression of Malaria (in combination) (sensitive strains) 2. Toxoplasmosis (1st line - combined w/ sulfadiazine or clindamycin and folic acid tabs) congenital, acute infection, immunocompromized FANSIDAR = SULPHADOXINE (500 mg) + PYRIMETHAMINE (25 mg) METAKELFIN = SULFALENE (500 mg) + PYRIMETHAMINE (25 mg) MALOPRIM = DAPSONE (100mg) + PYRIMETHAMINE (12.5mg) NB. Sulfonamides and sulfones (inhibitors of dihydropteroate synthetase) – weak blood schizonticide, must not be used alone but combined

17. 10. PROGUANIL (a biguanide) Mxn : A dihydrofolate reductase inhibitor ♦ A prodrug – must be metabolized to cycloguanil ♦ Active against pre-eerythrocytic intrahepatic forms of P. falciparum but not hypnozoites ♦ Its activity as a blood schizonticide is too slow ♦ not gametocidal Adm : oral Abs ; adequate Elimination : t 1/2 – once daily dosing S/E ♦ GIT irritation ♦ Skin rash ♦ Mouth ulcers ♦ Alopecia ♦ Headache, vertigo Uses : 1. Prophylaxis of malaria – (alternative to mefloquine) in combination w/ choloroquine (sensitive strain areas), (not acute attack) NB it is safe in pregnancy

18. 11. Antibacterial antimalarials – schizonticides Tetracycline, Doxycycline, Clindamycin ♦ Are SLOW – never use alone for Rx (e.g . used w/ quinine – to shorten course) Uses : 1. Rx of falciparum malaria in conjuction w/ other drugs e.g. quinine 2. Chemoprophylaxis of malaria (Doxy) 3. Clindamycin – along w/ quinine (e.g. where tet is not indicated - children)