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ANTIMALARIA

Oleh : Faizal Hermanto, S.Si., M.Si., Apt.

Out line Presentation


Pendahuluan Konsep pengobatan antiparasit Siklus hidup Plasmodium Morfologi Plasmodium Jenis malaria Diagnosa Prinsip Terapi Antimalaria

PENDAHULUAN

Konsep Pengobatan Antiparasit

Manusia

Parasit

Obat

Pendahuluan
Etiologi Malaria Mala = buruk Aria = udara

Malaria adalah penyakit infeksi dengan demam berkala yang disebabkan oleh parasit Plasmodium dan ditularkan oleh nyamuk anofeles betina

Statistik Malaria
Setengah dari populasi dunia berada pada risiko malaria Setiap tahun terjadi sekitar 250 juta kasus malaria Setiap tahun terjadi hampir satu juta kematian.

World Health Organization, Geneva, 2009

Plasmodium
Termasuk kedalam protozoa Plasmodium dapat menginfeksi : - Hewan pengerat/rhodent (P. berghei, P. Yollie) - Primata (P. Knowlesi) - Manusia (P. vivax, P. ovale, P. malariae, P. falciparum)

Siklus Hidup Plasmodium

Gambar : siklus hidup pasmodium sp

Morfologi Plasmodium

Plasmodium falciparum

Plasmodium malariae

Plasmodium vivax

Plasmodium ovale

Stadium Eritrositer P. falciparum

Cincin

Tropozoit

Schizont

Jenis Malaria

Jenis malaria dan gejalanya


Malaria tropika disebabkan oleh Plasmodium falciparum. Gejala yang timbul berupa berkurangnya kesadaran dan demam yang tidak menentu, yang kadangkala berlangsung terus menerus dengan suhu rektal di atas 48 C. Jenis malaria ini paling ganas dan berbahaya coz jumlah merozoit banyak, rosseting & sitoadheren.

Jenis malaria dan gejalanya


Malaria tersiana disebabkan oleh plasmodium vivax atau ovale. Ciri-cirinya demam berkala tiga hari sekali dengan puncak 48 jam. Malaria tersiana tidak bersifat mematikan, meskipun tanpa pengobatan tetapi sering kali terjadi kambuh.

Malaria kwartana yang disebabkan oleh Plasmodium malariae mengakibatkan demam berkala empat hari sekali, dengan puncak demam setiap 72 jam.

Kekambuhan
Recrudescense kekambuhan yang terjadi dalam masa 8 minggu setelah berakhirnya serangan primer. Recurrence kekambuhan yang terjadi dalam masa minggu setelah berakhirnya serangan primer. Relapse kekambuhan yang terjadi dalam masa 5 tahun. 24

Diagnosa

Diagnosa
Mikroskopik Isotopic Parasit laktat dehidrogenase (pLDH) Histidin Rich Protein-2 (HRP-2)

Mikroskopik
Pemeriksaan dengan menggunaan apusan darah tipis dan tebal dengan pewarnaan Giemsa. Pemeriksaan persentase parasitemia dilakukan dengan mikroskop cahaya dengan perbesaran 1000 x dan dilakukan per 1000 eritrosit. (%) Parasitemia = Jmlh eritrosit yg terifeksi X 100% 1000 eritrosit

Prinsip Terapi

Prinsip terapi penyakit Malaria


1. Resistensi Klorokuin?

2. Harus tau penyebab : P. falciparum, P. vivax, P. ovale dan P. malariae diagnosis harus benar 3. Infeksi campuran : PF + PV

4. Kepatuhan: muntah harus ulangi obat/dosis sama


5. Cek berkala pengobatan tuntas kekambuhan: - muncul cepat (btk eritrosit, semua spesies), - lambat (hipnozoit: P. vivax dan P. ovale) 6. Kebiasaan pend. kesehatan, kontrol vektor
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Prinsip terapi penyakit Malaria


7. Untuk malaria otak/parah: Quinin/Quinidin iv s/ bisa oral monitor fungsi jantung selama iv Q a QD 8. Masuk daerah endemik profilaksis kausal - Khemoprofilaksis klinis dan - Khemoprofilaksis Kausal (profilaksis) 9. Untuk cegah kambuh: Primakuin (s/14 hari) setelah travel 10. Kondisi patologi: - wanita hamil, - insufisiensi ginjal, hati, dll
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KLASIFIKASI ANTIMALARIA
Skhizontosida jaringan: eliminasi perkembangan dan bentuk dormant di hati S. J. primer (preventing RBC infection, p. causal)
- S. J. sekunder (p. terminal, cegah kambuh) -

Skhizontosida darah (untuk p. klinik & supresif) - Kerja cepat : Q, CQ, MQ, AQ, QHS
- Kerja lambat: Antifolat, antibiotik Gametosida kill sexual stages and prevent transmission to mosquitoes

Sporontosida: cegah transmisi malaria

Radical cure eliminate both hepatic and erythrocytic stages.

Drug?

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Major antimalarial drugs


Drugs
Chloroquine Amodiaquine Quinine Quinidine Mefloquine

Class
4-aminoQuinoline

Use
Treatment & chemoprofilaxis of infection with sensitive parasites Treatment of infection with some chloroquine-resistant P. falciparum strains Oral treatment of infections with chloroquine-resistant P. falciparum

Primaquine
Doxycycline

Quinoline Intravenous therapy of severe infection with methanol P. falciparum Chemoprophylaxis & treatment of infection with P. falciparum 8-aminoRadical cure and terminal prophylaxis of infection quinoline with P. vivax and P. ovale

Tetracycline

Treatment (with quinine) of infection with P. falciparum; Chemoprophylaxis

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Drugs
SulfadoxinePyrimethamine (Fansidar)

Class
Folat antagonist combination Folat antagonist methanol

Use
Treatment of infectios with some chloroquine-resistant P. falciparum

Proguanil

Chemoprophylaxis with chloroquine Treatment of infections with some chloroquine-resistant P. falciparum Treatment of P. falciparum malaria in fixed combination with artemether (Coartem) Treatment of infection with multidrugresistant P. falciparum Treatment & chemoprofilaxis of P. falciparum infection
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Halofantrine Phenantren
Lumefantrine Amyl alcohol

Artemisinin Sesquiterpen

lactone endoperoxides

Atovaquone Quinone-Folat - proguanil antagonist


(Malarone)

combination

Drugs for the prevention of malaria in travelers


Drug Use
Area without resistant P. falciparum
Area with chloroquine resistant P. falciparum

Adult dosage
500 mg weekly
250 mg weekly

Chloroquine
Mefloquine Doxycycline Malarone

Area with multidrug-resistant 100 mg daily P. falciparum Area without resistant P. falciparum Terminal prophylaxis of P. vivax and P. ovale 1 tablet (250 mg Atovaquone/100 mg proguanil) daily 15 mg base daily for 14 days after travel
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Primaquine

TREATMENT OF MALARIA
Clinical setting Drug therapy Alternative drugs

CQ-sensitive PF and PM infections

CQ-phosphate, 1 g then 500 mg in 6 h, followed by 500 mg daily for 2 days Or CQ-phosphate, 1 g at 0 and 24 h, then 500 mg at 48 h CQ (as above), then (if G6PD normal) primaquine 26,3 mg daily for 14 d

PV and PO infections

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TREATMENT OF MALARIA
Clinical setting
Uncomplicated infections with CQ-resistant PF

Drug therapy
Q sulfate 650 mg 3x daily for 3-7 d

Alternative drugs
MQ 15 mg/kg once or 750 mg, then 500 mg in 6-8 h

Or plus of the following: Malarone 4 tab (total of 1 g atovaquone, 400mg proguanil) daily for 3 d Doxycycline 100 mg Or 2x daily for 7 d Artesunate or artemether Or single daily doses of 4 Clindamycin 600 mg mg/kg on day 0, 2mg/kg on day 2 and 3, 1mg/kg on 2x daily for 7 d days 4-7 Or Or Fansidar, 3 tab. once Halofantrine 500 mg every 6 h for 3 doses; repeat in 1 week 30

TREATMENT OF MALARIA
Clinical setting
Severe or complicated infections with PF

Drug therapy
QD gluconate 10 mg/kg IV over 1-2 h, then 0.02 mg/kg IV/min Or 15mg/kg IV over 4 h, then 75 mg/kg IV over 4 h every 8 h
(cardiac monitoring should be in place during IV; change to oral if patient can tolerate it)

Alternative drugs
Artesunate 2.4 mg/kg IV or IM, then 1.2 mg/kg very 12 h for 1 d, then everyday Or Artemether 3.2 mg/kg IM, then 1.6 mg/kg/d IM

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Chloroquine
Drug of choice:
treatment & prophylaxis malaria since 1940s Blood schizonticide (Rapid acting) Moderate effect against gametocytes of Pv, Po, and Pm (but not for PF) Not active against liver stages malaria parasites (except for E. histolytica)

Mechanism of action :
- concentrating in parasite food vacuoles, - preventing polymerization of the Hb breakdown product, heme, into hemozoin.

Resistance :
mutations in a putative transporter can be reversed by Verapamil.

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Adverse effects CQ:


- long-term used of h doses: irreversible ototoxicity, retinopathy, myopathy and peripheral neuropathy - parenteral adm. is best avoided cardiac and respiratory arrest.

CI:
psoriasis or porphyria, abnormalitas visual field/retinal, myopathy - Considered safe in pregnancy and for young children.

Interaction:
- antacids-Mg, -Ca intefere with CQ abs.

Pharmacokinetics:

4-aminoquinoline derivative Phosphate salt-oral use; hydrochloride-parenteral use Rapid, complete GI absorption; very large apparent volume of distribution (13,000 L = significant tissue binding) Crosses the placenta Renal excretion (half-life 3-5 days; real excretion enhanced by urinary acidification
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Dosing considerations:
Large volume of distribution requires a loading dose if schizonticidal CQ plasma levels are rapidly needed for management of acute attack Parenteral administration should proceed by slow infusion or by a series of small intramuscular doses to avoid life-threatening CQ tox.

Antimalarial activity:
Highly effective; most widely used 4-aminoquinoline for chemoprophylaxis Used to treat attacks of Pv, Po, Pm, and sensitive strains of PF malaria Somewhat effective against gametocytes of Pv, Po and Pm but not against those of Pf Not active against preerythrocytic plasmodium Does not provide radical cures of Pv or Po {does not eliminate persistent liver parasitic stages}

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Adverse Effects CQ

Generally well tolerated during chronic administration (prophylaxis/treatment);


Uncommon Side-effects include: Gastrointestinal symptoms, headache, pruritus (particularly in black individuals), anorexia, blurred vision, Possible long-term effects (> 100 g accumulated) Opthalmological/neuromuscular effects Recommendations: periodic evaluations relative to baseline levels Retinal/visual fields changes or muscular weakness: discontinue medication Cardiovascular ECG changes-T-wave alterations; QRS Intramuscular injections (large dose, 10 mg/kg) & severe hypotension, respiratory & cardiac arrest complex widening intravenous infusion:

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Contraindications/cautions: CI in patients with: CQ psoriasis-may cause acute attacks

CQ should not be used in combination with other agents which may cause dermatitis porphyria-chloroquine (Aralen) may cause acute attacks retinal/visual fields abnormalities {consider risk-benefit in prescribing decision}
Cautious Use in patients with: hepatic damage, alcoholism, neurologic or hematologic

disorders

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Contraindications/cautions:
Drug-drug pharmacokinetic effects:

antacids + antidiarrheal drugs (kaolin, magnesium trisilicate, calcium carbonate) decision should not be taken within about four hours before or after CQ (Aralen).
During pregnancy: no reports of teratogenic effects

considering risk vs. benefit: CQ benefits appear to outweigh possible fetal risks Oral CQ: safe for children

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Clinical Uses:
Acute malarial attacks by Pv, Po, Pm and Pf (not CQ-resistant) Termination

by CQ of fever 24-48 hours parasitemia 48-72 hours

Indications for parenteral CQ: vomiting precludes oral route peripheral asexual parasitemia > 5% presents of cerebral malaria
Cure for Pv and Po malaria requires primaquine

concurrent administration to eliminate persistent stages.


Alternative to CQ: - hydroxycholoroquine
Chemoprophylaxis:

liver

CQ-preferred agent for prophylaxis against all forms of malaria {except where Pf exhibits resistance to 4-aminoquinolines

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Clinical Uses:
Amebiasis: CQ + emetine (generic): alternative for amebic hepatic abscess Autoimmune Disease: Long-term CQ (or hydroxycholoroquine): reported useful for management of autoimmune disorders

CQ-Resistance:
unknown mechanism probably similar to resistance described for multidrug-resistant cancer cells (membrane P- glycoprotein pump) in vitro resistance reversible by verapamil and desipramine

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MEFLOQUINE (LARIAM)
Overview:
Synthetic, 4-quinoline methanol derivative (related to quinine) Oral Route of Administration only (local irritation upon injection) Highly plasma protein-bound Hepatic clearance; very slow elimination; half-life = 13-33 days

Antimalarial Properties:
Blood schizonticidal activity against: Pf & Pv Inactive against Pf gametocytes or hepatic stages of Mechanism of action: unknown

Pv

Resistance has been reported

- Quinidine-like cardiac effects

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Clinical Uses (MQ): Prophylaxis of CQ-resistant P. falciparum strains


effective against most CQ & pyrimethamine-sulfadoxine resistant Pf Curative protocol: 4 weeks after leaving an endemic region; used this way-prophylaxis provided against Pv and probably against Po and Pm Curative protocol for Pv & Po necessitates the addition of primaquine (against hepatic stages) in

MQ should be only used in malarious regions where CQ not effective.


Treatment of CQ-resistant P. falciparum Oral treatment of mild-moderate MQ-susceptible Pf infection Less rapid onset of action compared to Q or quinidine-suggesting that these drugs should not be used in treating severe illness.

is

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Adverse Reactions (MQ)


Minor/transient adverse reaction, including gastrointestinal disturbances, syncope, extra-systoles. Transient thrombocytopenia, leukocytosis, and aminotransferase elevation Transient neurological reactions {convulsions, depression, psychoses} Symptoms are more likely to occur at doses > 1000 mg -frequency = as high as 1% CI MQ Contraindicated in patients with a history of: epilepsy

psychiatric disturbance cardiac conduction anomalies quinidine (and related compound) sensitivities
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CI of MQ
Not appropriate for use in children under 15 kg or under two years of {poorly tolerated/unsubstantiated efficacy in this group} Probably should not be used during first trimester of Women of child-bearing age: use precautions against three months following last dosage of MQ. Neuropsychiatric disturbance development during MQ for cessation of MQ MQ may induce seizures in patients taking anticonvulsant (e.g. valproic acid & divalproex sodium). pregnancy pregnancy for at least treatment: indication medications age

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PRIMAQUINE
Overview:
synthetic, 8-aminoquinoline derivative well absorbed orally completely metabolized & excreted in the urine major metabolite (carboxyprimaquine) accumulates with daily dosing primaquine and/or one of its metabolites: responsible for clinical activity

Antimalarial Properties
Activity profile Active against late hepatic stages {hypnozoites & schizonts of Po,Pv} provides radical cure in these cases Highly active against primary exoerythrocytic Pf stages Prophylaxis (with CQ): protective against Po & Pv Highly gametocidal against Pv, Po, Pm & Pf
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Mechanism of action PQ antimalarial activity may be secondary to quinoline-quinone oxidants Adverse Effects: Few major side effects some gastrointestinal disturbances, headache More serious side effects include (rare): leukopenia/agranulocytosis Normal Doses:

limited hemolysis (noted by urinary darkening/ reddening) significant hemolysis, methemoglobinemia (cyanosis evident) in patients with variance of glucose-6 phosphate dehydrogenase or certain other erythrocyte pentose phosphate pathway abnormalities.

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Clinical Uses of PQ
Terminal Pv & Po Malaria Prophylaxis PQ + a blood schizonticide (typically CQ) may allow a radical cure {terminal prophylaxis} due to effects on persistent hepatic stages Radical cure of acute Pv & Po Malaria: PQ + CQ: used to treat these infections (2 week primaquine duration typical) Gametocidal Action: Single PQ dose causes Pf gametocides to become noninfective Pneumocystis carinii Pneumonia:
Clinical Features

"The symptoms of P. carinii pneumonia (PCP) include dyspnea, non-productive cough, and fever. Chest radiography demonstrates bilateral infiltrates. Extrapulmonary lesions occur in a minority (<3%) of patients, involving most frequently the lymph nodes, spleen, liver and bone marrow. Typically, in untreated PCP increasing pulmonary involvement leads to death"-CDC
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Other pharmacological effects of PQ myeloid suppression (high doses) may affect erythrocytes (standard doses but in genetically susceptible individuals)
Resistance Primaquine relative resistance in some Pv strains CI/cautions: Primaquine should not be used in patients:

Currently taking quinidine Having connective tissue abnormalities who have history of methemoglobinemia or granulocytopenia who are pregnant (definitely not during first trimester)
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SULFONAMIDES & SULFONES


Overview: - Blood schizonticidal activity against Pf (some strains) Mechanism:
Dihydrofolic acid synthesis inhibition Weak effects against blood schizonts of Pv Inactive against immunocytes or liver stages of Pf or Pv. Synergistic blockade of folic acid synthesis following combination of sulfones or sulfonamide with an antifols pyrimethamine-sulfadoxine (Fansidar) or pyrimethamine-dapsone Major disadvantage: sulfonamides and sulfones exhibit slow onset blood schizonticidal activity as well as significant adverse effects.
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For management of CQ-resistant P. falciparum

Sulfonamides & Sulfones


Pyrimethamine-sulfadoxine (Fansidar)
Pharmacokinetics: Fansidar-well absorbed Renal route of excretion

Antimalarial Activity/Resistance:
Effective against falciparum malaria (some strains) For serious cases, quinine is given concurrently since Fansidar activity develops slowly Ineffective against vivax malaria

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QUININE
Overview:
Quinine-alkaloid from the bark of the cinchona tree Pharmacokinetics
- rapid absorption; wide tissue distribution - elimination halftime: normal individuals: 7-12 h ; 8-21 h in malaria infected patients - hepatic metabolism (80%) - urine excretion - Effective concentration range: ineffective < 2 ug/mL > 7 ug/mL-associated with "cinchonism" narrow therapeutic range: frequent side effects with falciparum malaria management with Q.

associate

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QUININE
Antimalarial activity
rapid onset; highly effective blood schizonticide against the four

malarial parasites: Pv, Po, Pf, and Pm. Gametocidal for Pv & Po; not very effective as a gametocidal agent for Pf gametocytes No effect on sporozoites or liver stages of any parasite.

Pharmacological effects
Oral use: gastric irritation

Myocardial effects similar to Q, but quinine's effect less intense Skeletal muscle: curare-like effect; lengthened skeletal muscle membrane refractory. May be used to reduce contracture of myotonia congenita. Slight oxytoxic effect (especially third trimester time frame) With therapeutic doses: occasional hypoglycemia {secondary to pancreatic B-cell insulin release}-especially prominent in patients who are pregnant or with severe infections.
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QUININE
Clinical Uses Parenteral treatment: severe falciparum malaria
slow, intravenous administration alternative: dilute intramuscular injection acceptable

Oral treatment of falciparum malaria (CQ-resistant)


management (with other drugs) for acute Pf-CQ resistant malarial

attacks Q alone will not eliminate the infection {will reduce parasitemia, however} Q-less effective than CQ; Q not used to manage acute attacks of Po, Pm or CQ-sensitive Pf malaria

Pv,

Prophylaxis: Q generally not used, Exceptions: P. falciparum CQ resistance and mefloquine; doxycycline - unavailable
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QUININE
Other Uses nighttime leg cramps Q + clindamycin: for management in cases of severe babesiosis (Babesia microti) http://www.dpd.cdc.gov/DPDx/HTML/Babesiosis.htm

Resistance: resistance for monotherapy increasing; therapeutic failure due to resistance of Q + second-drug has not been confirmed.

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QUININE
Adverse Effects
Gastrointestinal Effects: nausea, epigastric pain, vomiting Cinchonism: occurs if plasma levels > 7-10 ug/mL symptoms:-if symptoms do not abate, discontinue Q and obtain blood level. slight visual disturbances, - mild tinnitus, - dizziness Headache, - nausea Hematologic effects: Rare: (0.05%): hemolysis; they also occur in patients with glucose-6phosphate dehydrogenase deficiency Rare: leukopenia, thrombocytopenic purpura, hypoprothrombinemia, agranulocytosis, Schonlein-Henoch purpura Hypoglycemia: may occur at therapeutic doses; glucose administration may result and further insulin release and hypoglycemia exacerbation.
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QUININE
Other Toxicities:
IV quinine-rare thrombophlebitis rapid IV infusion: hypotension, seizures, ventricular fibrillation, death congenital malformation if large-doesquinine in failed abortion severe toxicity: rare {may include -- fever, deafness, visual abnormalities, CNS effects including syncope & confusion, quinidine-like effects}

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QUINIDINE GLUCONATE Overview


Dextrorotatory diasteriomer of quinine Quinidine gluconate - typically used for management of cardiac arrhythmias
Also used for parenteral treatment of severe malaria, when parenteral quinine form is unavailable {note: in the United States, parenteral form of quinine, quinine hydrochloride is unavailable}

IV quinidine gluconate: adverse effects, cautions, and CI


rare: thrombophlebitis potentially cardiotoxic-consider risk vs. benefit ratio if administration to a patient with cardiac conduction hepatic or renal abnormalities generally contraindications/caution or quinidine gluconate similar to that for quinine
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