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AntimalariAntimalarial agentsal agents
Pawitra PulbutrPawitra Pulbutr
M.Sc. In Pharm M.Sc. In Pharm (Pharmacology)(Pharmacology)
วั�ตถุ�ประสงค์�เชิ�งพฤต�กรรมวั�ตถุ�ประสงค์�เชิ�งพฤต�กรรม• ม�ค์วัามเข้�าใจและอธิ�บายถุ งกลไกการออกฤทธิ�#,
เภส�ชิจลนศาสตร�, อาการไม'พ งประสงค์� และข้�อ ห้�ามใชิ�ข้องยาต�านมาลาเร�ยแต'ละชิน�ด
• ม�ค์วัามเข้�าใจและอธิ�บายถุ งการใชิ�ประโยชิน�ทางค์ล�น�กข้องยาต�านมาลาเร�ย
MalariaMalaria• Tropical diseaseTropical disease
• Protozoa genus PlasmodiumProtozoa genus Plasmodium
• P. falciparumP. falciparum
• P. vivaxP. vivax
• P. ovaleP. ovale
• P. malariaeP. malariae
• Anopheles mosquitoAnopheles mosquito == Sexual Sexual cyclecycle
• HumanHuman == Asexual cycleAsexual cycle
The life cycle of malaria The life cycle of malaria
Classification of Classification of antimalarial drugsantimalarial drugs
1. Drugs used to treat acute attack
…bbbbb bbbbbbbbbbbbbbbbbb bbbbbbbbbbbbb 2. Drugs which effect radical cure
…. bbbbbb bbbbbbbbbbbbbbbbbbb bbbbbbbbbbbbb 3. Drugs used for chemoprophylaxi
b…. blood schizontocide blood schizontocide
4. Drugs used to prevent transmission
…. bbbbbbbbbbbbbbbbbbbbbbbbbbbb
Drugs used to treat acute Drugs used to treat acute attackattack
• Blood schizontocide Blood schizontocide
• Drugs for suppressive or clinical cure
• Cure for P. falciparum & P. malariae
• Every antimalarial drugs Every antimalarial drugs except… PrimaquinePrimaquine
Drugs used to treat acute attackDrugs used to treat acute attack
1. Quinoline methanol
• Quinine , Mefloquine
2. 4- 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
4-5-6 = slow acting blood 4-5-6 = slow acting blood schizontocideschizontocide
Drugs which effect radical cureDrugs which effect radical cure
• Tissue schizontocideTissue schizontocide (Act at (Act at liver)liver)
• Radical cure for P. vivax & P. ovale
• Prevent relapse
• Primaquine onlyPrimaquine only
Drugs used for chemoprophylaxisDrugs used for chemoprophylaxis
• True causal prophylaxis should kill sporozoite
• No true causal prophylaxis available
• Blood schizontocideBlood schizontocide
• Suppress clinical symptom
• Prevent RBC lysis
• Use in travelers
• No chemoprophylactic regimen give 100% No chemoprophylactic regimen give 100% preventionprevention
Best Best protection is protection is prevention of prevention of
mosquito bitesmosquito bites
Drugs used to prevent transmissionDrugs used to prevent transmission
• Prevent disease transmission
• Kill gametocyte Kill gametocyte (Gametocytocide)(Gametocytocide)
• Some antimalarial drugs
• Primaquine
• Proguanil
• Pyrimethamine
• Quinine
• Chloroquine
• Not often use clinicallyNot often use clinically
Mechanism of action of Mechanism of action of antimalarial agentsantimalarial agents
Inhibit Hemoglobin digestionInhibit Hemoglobin digestion Inhibit Heme polymerase Inhibit Heme polymerase
enzymeenzyme• Accumulation of toxic hemeAccumulation of toxic heme
Inhibit DNA/ RNA synthesisInhibit DNA/ RNA synthesis Inhibit protein synthesisInhibit protein synthesis Inhibit folate synthesis / folate Inhibit folate synthesis / folate
actionaction Free radical formation… Free radical formation…
membrane destructionmembrane destruction
Drugs for the prevention of malaria in travelers (CDC)
Chloroquine sensitive P.F.
• Chloroquine weekly
Chloroquine resistant P.F.
• Mefloquine weekly
• Doxycycline daily
• 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 Not true causal prophylaxis.... prophylaxis....
Not 100 % effective Not 100 % effective
PREVENTION OF PREVENTION OF MOSQUITOES BITEMOSQUITOES BITE
IS THE BESTIS THE BEST
Drugs for the prevention of Drugs for the prevention of malaria in travelers (CDC)malaria in travelers (CDC)
Chloroquine sensitive P.F.
• Chloroquine weekly
• Contraindicate in psoriasis
• Contraindicate in allergy
Drugs for the prevention of Drugs for the prevention of malaria in travelers (CDC)malaria in travelers (CDC)
Chloroquine resistant P.F.
• Mefloquine weekly
• Contraindicate in allergy
• Avoid in epilepsy, severe psychiatric, cardiac arrhythmia
Chloroquine resistant P.F.
• Doxycycline daily
• 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 Drugs for the prevention of malaria in travelers (CDC)malaria in travelers (CDC)
Drugs for the prevention of Drugs for the prevention of malaria in travelers (CDC)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 enterStart 1-2 day before enter
• Continue for 1 week after leavingContinue 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 Drugs for the prevention of malaria in travelers (CDC)malaria in travelers (CDC)
Treatment of Treatment of MalariaMalaria
Table 3Table 3
CDC, USACDC, 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 identifiedIf 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 by300 mg base (=500 mg salt) po at 6, 24, 48 hrsTotal 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 hrsTotal dose: 25 mg base/ kg
Chloroquine
resistant or
unknown
A. Quinine sulfate plus one of the following: Doxycycline, Tetracycline, or ClindamycinQuinine sulfate: 542 mg base (=650 mg salt) po tid x 3 to 7 daysDoxycycline: 100 mg po bid x 7 daysTetracycline: 250 mg po qid x 7 daysClindamycin: 20 mg base/ kg/day po divided tid x 7 days
A. Quinine sulfate plus one of the following: Doxycycline, Tetracycline, or ClindamycinQuinine sulfate: 8.3 mg base/ kg (=10 mg salt/kg) po tid x 3 to 7 daysDoxycycline: 4 mg/ kg/ day po divided bid x 7 daysTetracycline: 25 mg/ kg/ day po divided qid x 7 daysClindamycin: 20 mg base/ kg/ day po divided tid x 7 days
B. Atovaquone-proguanil (Malarone®)Adult tab = 250 mg atovaquone/ 100 mg proguanil4 adult tabs po qd x 3 days
B. Atovaquone-proguanil (Malarone®)Adult tab = 250 mg atovaquone/ 100 mg proguanilPeds tab = 62.5 mg atovaquone / 25 mg proguanil5-8 kg: 2 peds tabs po qd x 3 d9-10 kg: 3 peds tabs po qd x 3 d11-20 kg: 1 adult tab po qd x 3 d21-30 kg: 2 adult tab po qd x 3 d31-40 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 doseTotal 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 doseTotal dose = 25 mg salt/ kg
Uncomplicated P. malariae
All regions
Chloroquine phosphate: Treatment as above
Chloroquine phosphate: Treatment as above
Uncomplicated P. vivax or P.ovale
All regions
Chloroquine phosphate plus Primaquine phosphateChloroquine phosphate: treatment as abovePrimaquine phosphate: 30 mg base po qd x 14 days
Chloroquine phosphate plus Primaquine phosphateChloroquine phosphate: treatment as abovePrimaquine 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 phosphateQuinine sulfate: Treatment as aboveDoxycycline: Treatment as abovePrimaquine phosphate: Treatment as above
A. Quinine sulfate plus either Doxycycline or Tetracycline plus Primaquine phosphateQuinine sulfate: Treatment as aboveDoxycycline: Treatment as abovePrimaquine phosphate: Treatment as above
B. Mefloquine plus B. Mefloquine plus Primaquine phosphatePrimaquine phosphateMefloquine: Treatment as abovePrimaquine phosphate: Treatment as above
B. Mefloquine plus B. Mefloquine plus Primaquine phosphatePrimaquine phosphateMefloquine: Treatment as abovePrimaquine phosphate: Treatment as above
Uncomplicated malaria alternatives for pregnant women
Chloroquine
sensitive
Chloroquine phosphate: Treatment as above
Not applicable
Chloroquine
resistant P.falcipar
um
Quinine sulfate plus ClindamycinQuinine sulfate: Treatment as aboveClindamycin: Treatment as above
Not applicable
Chloroquine
resistant P.vivax
Quinine sulfateQuinine sulfate: 650 mg salt pot id x 7 days
Not applicable
Severe malaria P. falciparum
All regions
Quinine 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 treatmentORQuinidine (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 treatmentPlus (either concurrently with quinine/ quinidine or immediately after)Doxycycline: Treatment as aboveTetracycline: Treatment as aboveClindamycin: Treatment as above
Alternative
Artesunate 2.4 mg/ kg IV or IM, then 1.2 mg/kg every 12 hrs for one day, then every dayORArtemether 3.2 mg/kg IM, then 1.6 mg/ kg/ day IM