Antimalarial agents by Dr. Iribhogbe .pptx

Antimalaria Agents by Dr Iribhogbe O.I. MBBS, MPH, PhD, Cert. Clin. Pharm Highlights Introduction Classification Pharmacology of Selected Agents Treatment of Malaria in Pregnancy AntimalarialDrug Resistance Antimalaria Drug Combination Therapy  Introdu...

Antimalaria Agents by Dr Iribhogbe O.I. MBBS, MPH, PhD, Cert. Clin. Pharm Highlights Introduction Classification Pharmacology of Selected Agents Treatment of Malaria in Pregnancy AntimalarialDrug Resistance Antimalaria Drug Combination Therapy  Introduction Malaria is a protozoan disease that is caused primarily by Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae Plasmodium ovale, and more recently Plasmodium knowelsi P. falciparum is responsible for severe malaria morbidity and mortality in sub- Parasite Life Cycle  CONTD There are 3 main stages in the life cycle: Pre-erythrocytic stage: sporozoites are released into the blood following the bite of female anopheles mosquito Undergoes development in the liver to form schizonts which are released into the blood as merozoites Exo-erythrocytic: Schizonts of P. vivax and Ovale remain as hypnozoites which are the dormant forms of the parasite  ErythrocyticStage: merozoites invade RBCs, develops into schizonts and get ruptured and released into the blood as merozoites  Classification Classified based on: A. Stage of the life cycle they inhibit/clinical use B. Chemical group/mechanism of action A: Primary tissue schizonticides: target the pre-erythrocytic stage and kills tissue schizonts Examples: Proguanil, pyrimethamine, primaquine Used for causal prophylaxis of malaria  CONTD Erythrocytic schizonticides: kills blood schizonts Used for Px of acute malaria episodes as well as for suppressive prophylaxis of malaria Subdivided into: Fast-acting drugs: e.g. chloroquine, halofantrine, mepacrine, atovaquone, quinine, mefloquine, and artemisinin derivatives Slow-acting drugs: proguanil, pyrimethamine, sulphonamides and tetracyclines  CONTD  Exo-erythrocytic Schizonticides: kills the exo- erythrocytic form (hypnozoites). Prevents malaria relapse e.g. primaquine and pyrimethamine  Gametocytocidal drugs: destroy or kill the gametocytes in the blood and prevent their development into oocytes  Thus, prevents transmission of malaria   E.g. chloroquine, mepacrine, quinine which specifically kills the gametocytes of P. vivax and P. malariae   CONTD Sporonticides: prevents the development of oocytes in the mosquito and ablates the transmission of the parasite to the host  E.g. primaquine and chloroguanide Effective treatment of malaria should include the use of blood schizonticides and gametocytocidal agents Tissue schizonticides is required in the case of P.  B Aryl amino alcohols:  Examples are quinine, quinidine, mefloquine 4-amino quinolines:  Examples are chloroquine and amodiaquine 8-amino quinolines:  Example primaquine  CONTD  Folate synthesis inhibitors: grouped into type I and type II agents  Type I agents: are competitive inhibitors of dihydropteroate synthetase  Examples are the sulfones such as dapsone and the sulfonamides such as sulfadoxine, sulfametopyrazine, sulfamethoxazole  Type II drugs: are inhibitors of dihydrofolate reductase  Examples include biguanides such as proguanil and chloroproguanil, and the diaminopyrimidines such as pyrimethamine and trimethoprim  CONTD Antimicrobials: E.g.tetracycline, doxycycline, clindamycin, vancomycin, azithromycin, and the fluoroquinolones such as ciprofloxacin and pefloxacin Peroxides: e.g. artemisinin derivatives such artemether, arteether, artesunate, dihydroartemisinin, artemotil, and artenilic acid  Naphthoquinones: These are parasite redox chain inhibitors e.g. atovaquone  Phenanthrene Methanol: e.g. halofantrine and lumefantrine  Pharmacology of Selected Agents Quinine: Chemistry: it is an aryl amino alcohol cinchona alkaloid MOAs: accumulates within the food vacuole of the parasite and prevents the conversion of toxic heam to the malaria pigment hemozoin Forms H-bond(Hydrogen bond)complexes with parasite DNA and prevents strand separation and transcription leading to the inhibition of protein synthesis Clinical uses: Px of severe P. falciparum malaria Post-exposure Px of individual from high endemic areas  CONTD ADR: Cinchonism characterized by tinnitus, rashes, vertigo, nausea, vomiting and abdominal pain Impairment of the 8th cranial nerve, confusion, delirium and coma Hypoglycemia and respiratory depression, cardiac arrhythmias  CONTD CQ (Chloroquine): Chemistry: it is a 4-aminoquinoline MOAs: accumulates within the food vacuole of the parasite and prevents the conversion of toxic heam to the malaria pigment hemozoin Clinicaluses: previously used for the px of uncomplicated malaria Recommended as a prophylactic drug against P. vivax and in regions with CQ-sensitive P. falc. Malaria Other uses include px of amoebiasis, RA, and used experimentally for prevention and px of COVID-19  CONTD Adverse effects: CNS: blurring of vision, confusion, depression, personality changes, hearing impairment, muscle weakness GIT: nausea, vomiting, abdominal cramp Skin: photosensitivity reactions, easy bruising and bleeding, palor of the lips, skin and oral mucosa Darkening of the skin, hair loss, hair color changes Drug fever, weakness, hepatotoxicity   CONTD AQ: Chemistry:it is a 4-aminoquinoline MOAs: Not fully elucidated. Proposed to inhibit heme polymerase activity involved in biocrystalization of heme to hemozoin Clinicaluses: used in artemisinin-based combination (AS+ AQ) and non-artemisinin based combination (AQ+SP) in px of acute uncomplicated malaria Adverseeffects: CNS: Headache, drowsiness  CONTD Eye:Visual disturbances such as blurring of vision CVS: cardiovascular collapse, bradycardia, hypotension, ventricular fibrillation GIT:nausea, vomiting, abdominal pain, drug- induced hepatitis Hematologicalabnormalities such as aplastic anemia, agranulocytosis pruritus  Artemisinin Derivatives Source: derived from Artemisia annua The derivatives are; AS(Artesunate),AM(Artemether),AE(Arteether),DH(Dihydroart emisinin) Chemistry: peroxides MOAs: converted to the active metabolite dihydroartemisinin which inhibits ca ATPase in the SR(Sarcoplasmic reticulum)of the parasites Freeradicals are generated from the destruction of the peroxide bridge linkage which destroys the parasite  CONTD Clinical uses: It is used in combination therapy in the px of acute uncomplicated falciparum malaria Also used in the px of severe malaria i.e. Iv artesunate Adverse effects: Abdominal discomfort, nausea, vomiting, headache, abnormal bleeding, allergic rxn, drug fever, neurotoxicity, ST and QT changes  Treatment of Malaria in P.Pregnancy falciparum malaria poses a great threat to the outcome of pregnancy  Itis responsible for pregnancy complications such as IUFD(Intrauterine fetal death), still birth, fetal anemia and contributes to the prevalence of neonatal morbidity and mortality Therefore the aim of px of MiP(Malaria in Pregnancy) is to counter the threat of P. falciparum malaria and improve pregnancy outcome  CONTD The recommended WHO px schedule is to use: Oral quinine + clindamycin for 7 days for uncomplicated malaria in first trimester of pregnancy Artemisinin combination therapy(ACTs) such as AS+AQ(Amodiaquine), AS+Q(Quinine), Art+Lum can be used as alternative regimen Inthe second trimester of pregnancy Q+SP(Sulfadoxine- Pyrimethamine) or the ACTs can be use in the px of uncomplicated malaria  CONTD Alternativeregimen include the use of AS+Clindamycin or Q+Clindamycin orally for 7 days For severe malaria: Iv artesunate given at a dose of 2.4mg/kg at 0hour, 12hours, and 24hours then daily thereafter  Switchto tab artesunate at a dose 2mg/kg + tab Q at a dose of 600mg tds or to ACTs when pt can tolerate orally Alternatively,atovaquone+proguanil or a seven-day course of quinine+clindamycin can be used in the absence of artesunate tablets or ACTs  Intermittent Preventive Treatment of MiP (IPTp) Due to the substantial of malaria in pregnancy to the mother and child, WHO recommends the use of IPTp This px strategy is aimed at preventing malaria episodes in pregnancy Theregimen includes the use of SP in all areas with moderate to high malaria transmission in Africa  CONTD SP is given to all pregnant women at each scheduled Antenatal care (ANC) visit except during the first trimester of pregnancy  Thistranslates to giving the drug at least twice during pregnancy Once in the second trimester and at least 1 month after the first treatment  Antimalarial Drug Resistance The emergence of Antimalarial Drug Resistance(AmDR) threatens malaria control and elimination efforts AmDR it is the ability of a parasite to survive and multiply despite the administration and absorption of drugs  That are given in doses equal to or higher than the dose usually recommended for clinical use but within the tolerance of the patient  CONTD Treatment failure is defined as inability to clear parasitemia and recover from an acute clinical episode of malaria when a suitable treatment has been administered  Hence treatment failure can be a result of AmDR Factors that Determine AmDR/Px Failure: Non-compliance to medication Poor drug quality Use of monotherapy  CONTD Interactions with other pharmaceuticals which may cause alteration in the pharmacokinetics or pharmacodynamic property of the drug Poor absorption Misdiagnosis and Incorrect dosing  Mechanisms of AmDR Initiatedprimarily through a spontaneous mutation that confers an evolutionary benefit to the parasite The spontaneous mutation may be a single point mutation or multiple mutations  Which can be fatal to the parasite or can create a selective drug pressure that results in The elimination of susceptible strains and the selection of resistant strains that will survive the drug pressure  The selected resistant parasite can be transmitted and become firmly established in the parasite population for a long time  CONTD The mutations might confer the ability to extrude drugs from the parasite food vacuole e.g. in CQ resistance  The genes involved in mutation associated with CQ resistance are: Pf MDR1­– Plasmodium falciparum multidrug resistance protein 1 Pf Crt-k76T– Plasmodium falciparum chloroquine-resistant gene  Threonine replaces lysine at residue 76  Control of AmDR This can be achieved through these strategies: Prevention of antimalarial drug resistance Monitoringof antimalarial drug efficacy and when necessary drug resistance Ensure the development of a continuous pipeline of new antimalarial drugs through research  Prevention of AmDR This can be achieved through: Use of combination therapies Halting the use of oral monotherapies Improving access to good quality combination drugs Improving compliance to recommended treatment regimen by   CONTD Encouraging universal parasitological confirmation of malaria before treatment Eliminating poor quality and counterfeit drugs from the market Reducing the transmission rate of malaria. This helps to lower the malaria burden and reduce the use of antimalaria drugs Thiscan be achieved through: Vector control method such as in-door and out-door spraying with insecticide  CONTD Clearing of swamps and shrubs around the environment Use of personal protective methods such as use of mosquito repellents and Insecticide treated nets(ITNs) Decrease the reservoir of infection via appropriate therapeutic practice and  Antimalaria Combination ItTherapy is the use of two or more combinations of antimalarials to eradicate parasitemia and prevent the emergence of drug resistance Thebasic principle of treatment is to use two or more blood schizonticidal drugs with independent or different modes of action and with unrelated biochemical targets in the parasite  CONTD The combination regimen is grouped as: A. Artemisinin-based combination therapy (ACT) B. Non-artemisinin-based combination therapy A. ACT: the regimen used are available as fixed-dose combination or non-fixed dose combination regimen E.g. FD: AS+AQ, Art+Lume, DH+Piperaquine NFD: AS+Q, AS+SP, AS+AQ B. These includes SP+Q, SP+AQ, SP+MfQ(Mefloquine), Q+Clindamycin, Atovaquone+Proguanil e.t.c.  SUMMARY/CONCLUSION The presentation has examined the classification of antimalarials, their MOAs and their clinical uses The emergence of antimalarial drug resistance has posed a major challenge in the prevention and control of malaria Strategies to curtail these challenges were examined and there is a need to comply with the National antimalaria treatment guideline in the management of complicated and uncomplicated malaria ASSIGNMENT READUP NATIONAL ANTI- MALARIAL DRUG GUIDELINES THANK YOU CLASS