Antimalarial agents Pawitra Pulbutr M.Sc. In Pharm (Pharmacology)

วัตถุประสงค์เชิงพฤติกรรม มีความเข้าใจและอธิบายถึงกลไกการออก ฤทธิ์, เภสัชจลนศาสตร์, อาการไม่พึง ประสงค์ และข้อห้ามใช้ของยาต้านมาลาเรีย แต่ละชนิด มีความเข้าใจและอธิบายถึงการใช้ ประโยชน์ทางคลินิกของยาต้านมาลาเรีย

Malaria Tropical disease Tropical disease Protozoa genus Plasmodium Protozoa genus Plasmodium P. falciparum P. falciparum P. vivax P. vivax P. ovale P. ovale P. malariae P. malariae Anopheles mosquito=Sexual cycle Anopheles mosquito=Sexual cycle Human=Asexual cycle Human=Asexual cycle

The life cycle of malaria

Classification of antimalarial drugs 1. Drugs used to treat acute attack blood schizontocide … blood schizontocide 2. Drugs which effect radical cure tissue schizontocide ….tissue schizontocide 3. Drugs used for chemoprophylaxis blood schizontocide ….blood schizontocide 4. Drugs used to prevent transmission gametocytocide ….gametocytocide

Drugs used to treat acute attack Blood schizontocide Blood schizontocide Drugs for suppressive or clinical cure Cure for P. falciparum & P. malariae Every antimalarial drugs Primaquine Every antimalarial drugs except … Primaquine

Drugs used to treat acute attack 1. Quinoline methanol Quinine, Mefloquine Amino-quinoline Chloroquine 3. Phenanthrene Halofantrine 4. Sulfonamides, Sulfones 5. Dihydrofolate reductase inhibitors Pyrimethamine, Proguanil 6. Tetracyclines Tetracycline, Doxycycline 7. Quinghaosu derivatives Artemisinin, Artesunate, Artemether = slow acting blood schizontocide

Drugs which effect radical cure Tissue schizontocide(Act at liver) Tissue schizontocide (Act at liver) Radical cure for P. vivax & P. ovale Prevent relapse Primaquine only Primaquine only

Drugs used for chemoprophylaxis True causal prophylaxis should kill sporozoite No true causal prophylaxis available Blood schizontocide Suppress clinical symptom Prevent RBC lysis Use in travelers No chemoprophylactic regimen give 100% prevention Best protection is prevention of mosquito bites

Drugs used to prevent transmission Prevent disease transmission Kill gametocyte (Gametocytocide) Kill gametocyte (Gametocytocide) Some antimalarial drugs Primaquine Proguanil Pyrimethamine Quinine Chloroquine Not often use clinically

Mechanism of action of antimalarial agents w Inhibit Hemoglobin digestion w Inhibit Heme polymerase enzyme Accumulation of toxic hemeAccumulation of toxic heme w Inhibit DNA/ RNA synthesis w Inhibit protein synthesis w Inhibit folate synthesis / folate action w Free radical formation… membrane destruction

Drugs for the prevention of malaria in travelers (CDC) Chloroquine sensitive P.F. Chloroquineweekly Chloroquine resistant P.F. Mefloquineweekly Doxycyclinedaily Malarone®daily P.V. & P.O. Primaquine... Terminal prophylaxis Take 1 week (1-2 day) before enter & continue for 4 weeks after leave

Not true causal prophylaxis.... Not 100 % effective PREVENTION OF MOSQUITOES BITE IS THE BEST

Drugs for the prevention of malaria in travelers (CDC) Chloroquine sensitive P.F. Chloroquineweekly Contraindicate in psoriasis Contraindicate in allergy

Drugs for the prevention of malaria in travelers (CDC) Chloroquine resistant P.F. Mefloquineweekly Contraindicate in allergy Avoid in epilepsy, severe psychiatric, cardiac arrhythmia

Chloroquine resistant P.F. Doxycyclinedaily Contraindicate in children < 8 yrs Contraindicate in pregnancy Contraindicate in lactating women Start 1-2 day before enter Continue for 4 weeks after leaving Drugs for the prevention of malaria in travelers (CDC)

Chloroquine resistant P.F. Malarone® daily Contraindicate in wt. < 11 kg Contraindicate in pregnancy & feeding mother Contraindicate in renal impairment Start 1-2 day before enter Start 1-2 day before enter Continue for 1 week after leaving Continue for 1 week after leaving

P.V. & P.O. Primaquine... Terminal prophylaxis take for 14 days after leave Contraindicate in G 6 PD def. Drugs for the prevention of malaria in travelers (CDC)

Treatment of Malaria Table 3 CDC, USA

Clinical diagnosis/ Plasmodium species Region infection acquired Recommended drugs and adult doses Recommended drug and pediatric dose Pediatric dose should never exceed adult dose Uncomplicated malaria P.falciparum or species not identified If species not identified is subsequently diagnosed as P.vivax or P.ovale retreatment with primaquine Chloroquine sensitive Chloroquine phosphate (Arelen®) 600 mg base (=1,000 mg salt) po immediately, followed by 300 mg base (=500 mg salt) po at 6, 24, 48 hrs Total dose: 1,500 mg base (=2,500 mg salt) Chloroquine phosphate (Arelen®) 10 mg base/ kg po immediately, followed by 5 mg base/ kg po at 6, 24, 48 hrs Total dose: 25 mg base/ kg Chloroquine resistant or unknown A. Quinine sulfate plus one of the following: Doxycycline, Tetracycline, or Clindamycin Quinine sulfate: 542 mg base (=650 mg salt) po tid x 3 to 7 days Doxycycline: 100 mg po bid x 7 days Tetracycline: 250 mg po qid x 7 days Clindamycin: 20 mg base/ kg/day po divided tid x 7 days A. Quinine sulfate plus one of the following: Doxycycline, Tetracycline, or Clindamycin Quinine sulfate: 8.3 mg base/ kg (=10 mg salt/kg) po tid x 3 to 7 days Doxycycline: 4 mg/ kg/ day po divided bid x 7 days Tetracycline: 25 mg/ kg/ day po divided qid x 7 days Clindamycin: 20 mg base/ kg/ day po divided tid x 7 days

B. Atovaquone-proguanil (Malarone®) Adult tab = 250 mg atovaquone/ 100 mg proguanil 4 adult tabs po qd x 3 days B. Atovaquone-proguanil (Malarone®) Adult tab = 250 mg atovaquone/ 100 mg proguanil Peds tab = 62.5 mg atovaquone / 25 mg proguanil 5-8 kg: 2 peds tabs po qd x 3 d 9-10 kg: 3 peds tabs po qd x 3 d kg: 1 adult tab po qd x 3 d kg: 2 adult tab po qd x 3 d kg: 3 adult tab po qd x 3 d > 40 kg: 4 adult tab po qd x 3 d C. Mefloquine (Lariam®) 648 mg base (=750 mg salt) po as initial dose, followed by 456 mg base (=500 mg salt) po given 6-12 hrs after initial dose Total dose = 1,250 mg salt C. Mefloquine (Lariam®) 13.7 mg base/ kg (=15 mg salt/ kg) po as initial dose, followed by 9.1 mg base/ kg (=10 mg salt/kg) po given 6-12 hrs after initial dose Total dose = 25 mg salt/ kg

Uncomplicated P. malariae All regionsChloroquine phosphate: Treatment as above Uncomplicated P. vivax or P.ovale All regionsChloroquine phosphate plus Primaquine phosphate Chloroquine phosphate: treatment as above Primaquine phosphate: 30 mg base po qd x 14 days Chloroquine phosphate plus Primaquine phosphate Chloroquine phosphate: treatment as above Primaquine phosphate: 0.6 mg base/ kg po qd x 14 days Chloroquine resistant (Papua New Guinea & Indonesia) A. Quinine sulfate plus either Doxycycline or Tetracycline plus Primaquine phosphate Quinine sulfate: Treatment as above Doxycycline: Treatment as above Primaquine phosphate: Treatment as above A. Quinine sulfate plus either Doxycycline or Tetracycline plus Primaquine phosphate Quinine sulfate: Treatment as above Doxycycline: Treatment as above Primaquine phosphate: Treatment as above B. Mefloquine plus Primaquine phosphate Mefloquine: Treatment as above Primaquine phosphate: Treatment as above B. Mefloquine plus Primaquine phosphate Mefloquine: Treatment as above Primaquine phosphate: Treatment as above

Uncomplicated malaria alternatives for pregnant women Chloroquine sensitive Chloroquine phosphate: Treatment as above Not applicable Chloroquine resistant P.falciparum Quinine sulfate plus Clindamycin Quinine sulfate: Treatment as above Clindamycin: Treatment as above Not applicable Chloroquine resistant P.vivax Quinine sulfate Quinine sulfate: 650 mg salt pot id x 7 days Not applicable

Severe malaria P. falciparum All regionsQuinine base 16.7 mg/kg loading dose [quinine dihydrochloride (salt) 20 mg/kg], by IV infusion over 4 hrs, then 8.3 mg base/ kg [quinine dihydrochloride (salt) 10 mg/ kg] diluted in 10 ml/ kg isotonic fluid by IV infusion over 4 hrs, repeated 8 hourly for up to 72 hrs or until can swallow, then quinine tablets to complete 3-7 days of treatment OR Quinidine (base) 15 mg/ kg loading dose [quinidine gluconate (salt) 24 mg/ kg] in a volume of 250 ml of normal saline infused over 4 hrs followed by a maintenance dose, beginning 8 hrs after the beginning of the loading dose, of quinidine (base) 7.5 mg/ kg [quinidine gluconate (salt) 12 mg/ kg infused over 4 hrs, every 8 hrs for up to 72 hrs or until the patient can swallow, then quinine tablets to complete 3-7 days of treatment Plus (either concurrently with quinine/ quinidine or immediately after) Doxycycline: Treatment as above Tetracycline: Treatment as above Clindamycin: Treatment as above AlternativeArtesunate 2.4 mg/ kg IV or IM, then 1.2 mg/kg every 12 hrs for one day, then every day OR Artemether 3.2 mg/kg IM, then 1.6 mg/ kg/ day IM