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

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



• Mefloquine weekly

• Contraindicate in allergy

• Avoid in epilepsy, severe psychiatric, cardiac arrhythmia


• 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




• 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.


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


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


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

Documents

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