ANTI – MALARIALS HEPATIC CYCLE Radical cure: Primaquine Causal Prophylaxis: Prevent Initial Hepatic Cycle. Primaquine, Proguanil (Weak), Doxycycline

ERYTHROCYTE CYCLE -Treatment of acute attacks. -Prevention of attacks–suppressive prophylaxis SEXUAL FORMS: Gametocytocides: Quinine, Mefloquine, Chloroquine, Artesunate, Artemether & Primaquine.

ANTI-MALARIALS 1)Chloroquine, Amodiaquine, Piperaquine 2)Quinine, Quinidine 3)Mefloquine 4)Primaquine 5)Sulfadoxine-pyrimethamine(fansidar)

6.Atovaquone- Proguanil 7.Doxycycline 8.Halofantrine 9.Lumefantrine 10.Artemisinins (Artesunate, Artemether, Dihydroartemisinin)

Betwee340AD Anti-fever properties of qinghao first described by Ge Hong in China

Between 1620 and 1630 AD Spanish Jesuit missionaries in Peru learn the healing power of a tree bark

1632 Jesuit Barnabé de Cobo takes Cinchona bark to Europe

1633 Properties of the bark in the treatment of malaria first written by Father Antanio de la Calancha

1640 Juan de Lugo first employed the tincture of the cinchona bark for treating malaria in Countess of Chinchon

1658 The first prescription of cinchona in England by Robert Brady

1670s Robert Talbor develops an infusion of cinchona powder in white wine and uses it as a 'secret remedy'

1712 Fransesco Torti writes a book on the therapeutic properties of the bark

1742 Linnaeus, a Swedish botonist, classifies the Peruvian bark and names the tree cinchona

1820 French chemists Joseph Pelletier and Jean Biename Caventou isolate quinine

1844/1910 Sporadic resistance to quinine reported

1934 Resochin (chloroquine) synthesised at Bayer, Germany by Hans Andersag

1944 Proguanil or Paludrine (chlorguanide hydrochloride) developed by Curd, Davey and Rose

1945, 1950 Camoquin (amodiaquin) and Primaquine (Elderfield) developed

1952 Pyrimethamine developed

1971 The active ingredient of qinghao isolated by Chinese scientists

Mefloquine jointly developed by the U.S. Army Medical Research and Development Command, World Health Organization and Hoffman-La Roche

1992 and 1998 Atovaquone becomes available in 1992; a combination of proguanil and atovaquone, called Malarone, becomes available in Australia in 1998

UNCOMPLICATED MALARIA 1.Chloroquine Each tab (150mg base) Day 1: 4 tab Day 2: 4 tab Day 3: 2 tab

2. PRIMAQUINE P. FALCIPARUM [45mg (6 tab) base] 15 & above 6 tab P. VIVAX [15mg (6 tab) base] 15 & above 14days6 tab

3. ARTESUNATE+SULPHADOXINE / SULPHALENE- PYRIMETHAMINE (ACT) COMBINATION 15 yearsAS444 and aboveSP3NilNil 50mg artesunate + 500mg suohadoxine / sulphalene and 25mg pyrimethamine Artemisnin group of drugs is not recommended in pregnancy.

SEVERE & COMPLICATED MALARIA 1)QUININE – 10mg / kg IV in 5D over 4h. 8hrly oral 650 mg tid X 7d 2)ARTEMISININE inj A) Artesunate- 2.4mg / kg IM / IV stat-day1 B) Artether – 1.6 mg / kg IM od X 6 D C) Artether – 150 mg day IM X 3d D) Artemisinine – 10mg / kg at 0x4h. 7mg / kg at 24,36,48 &60h Mefloquine – pf resistant to chloroquine

UNCOMPLICATED, RESISTANT TO CHLORO QUINE 1) Quinine 650mg tid x 3-7 d plus Doxycycline 100mg bd x 7d or Clindamycin 600mg bd x7d

Alternatives: MALARONE 4 tab od x 3days ↓ (1g atovaquone + 400mg proguanil) or Mefloquine 15mg/kg once (750mg) then 500mg in 6 - 8h or Artemether 20mg, Lumefanfrine 120mg – 4 tab bd x 3 days.

WHO falciparum malaria 1) Artemether – lumefanfrine 2) Artesunate – amodiaquine 3) artesunate – mefloquine 4) Artesunate – Sulfadoxine – pyrimethamine 5) Amodiaquine – sulfadoxine - pyrimethamine

Chloroquine Large V D t 1/2 MOA: Concentrates In Parasite Food Vacoule ↓ Prevents Biocrystallization of Heme to Hemazoin ↓ Increase free Heme →Parasite Toxicity

Chloroquine Resistance Uses ADR

AMODIAQUINE + ARTESUNATE + SULFADOXINE – PYRIMETHAMINE PIPERAQUINE + DIHYDROARTEMISININ

QUININE -Loading dose -Plasma levels more In Patients with Malaria -t½ More In Malaria (18h Vs 11h)

MOA – Unknown RESISTANCE Parenteral treatment of severe falciparum malaria Oral treatment Babesiosis + clindamycin

ADVERSE DRUG REACTION: -Cinchonism -Hypersensitivity -Hematologic -Stimulate uterine contractions -Severe hypotension -ECG –  QTc -Blackwater fever

DRUG INTERACTION Do not give with mefloquine Increased warfarin, digoxin levels Antacids Treatment of nocturnal cramps Cocktail purpura

MEFLOQUINE: for chloroquine resistant pf -only orally -Long t½ - 20days – weekly dose for chemoprophylaxis MOA unknown Uses: Prophylaxis Treatment: NOT for severe/complicated malaria ARTESUNATE + MEFLOQUINE ---South East Asia

Mefloquine ADR: GI Headache, dizziness Seizures, psychosis 50% Leukocytosis, thrombocytopenia Deranged LFT Arrhythmias, bradycardia,

MEFLOQUINE: Contraindications: Epilepsy, psychiatry, arrhythmias NOT WITH: Quinine, Halofantrine.

ARTEMISININ DRUGS Immediate onset and rapid reduction of parasitaemia with complete clearance in most cases within 48 hours Clinical recovery of the patient, e.g. defervescence is faster than with other antimalarials Efficacy is high even in areas with multidrug resistant strains.

ARTEMISININ Artemisinin is not very soluble either in water or oil. Converted to dihydroartemisinin, which is a potent antimalarial compound Available for oral and rectal use in several countries in Asia.

DERIVATIVES OF ARTEMISININ USED IN TREATMENT OF MALARIA Artemether Arteether Artesunate

ARTEMETHER Methyl ether of dihydroartemisinin Superior to intravenous quinine with respect to survival and parasite clearance Available as tablets, capsules and as IM injectable form In India, available as 40mg capsules and 80mg/ml ampoule

ARTEMETHER CAPSULES - MONOTHERAPY

ARTEMETHER CAPSULES + MEFLOQUINE TABLETS

ARTEMETHER INJECTION

ARTEETHER Ethyl ether of dihydroartemisinin Therapeutically equivalent to quinine in cerebral malaria Available as  arteether and  /  arteether  arteether developed by WHO and The Special Programme for Research and Training in Tropical Diseases (TDR)  /  arteether developed by CDRI

ARTEETHER A longer t 1/2 beta and more lipophilic properties than artemether favouring accumulation in brain tissue and thus the treatment of cerebral malaria were regarded as advantages over the other compounds. Available as 150mg per 2ml ampoule

RAPITHER - AB INJECTION (IM Only)

ARTESUNATE Water soluble hemisuccinate derivative Used for oral, rectal, intravenous and intramuscular administration. Available as tablets and as powder with separate vial containing 5% sodium bicarbonate In India, available as 50mg tablets and 60mg/ml injection In China also available as 100mg suppository and in Switzerland available as 200mg rectocap

ARTESUNATE TABLETS - MONOTHERAPY

ARTESUNATE TABS + MEFLOQUINE TABS

ARTESUNATE INJECTION

MECHANISM OF ACTION iron-mediated cleavage of the peroxide bridge and generation of an organic free radical. Haem bound iron (but also free iron) may serve as a catalyst. The artemisinin radical binds subsequently to membrane proteins, and alkylation reactions eventually cause destruction of the parasite.

ANTIMALARIAL EFFICACY Rapidly acting blood schizontocidal antimalarials against chloroquine sensitive and chloroquine resistant falciparum as well as vivax malaria quickly arrest the ring or the trophozoite development and also prevent pathological sequelae Fever subsides and parasites are cleared rapidly Defervescence occurs within 2-3 days after drug administration Ninety percent clearance of asexual erythrocytic parasitaemia is usually observed within 4 hours

ARTEMISININ DERIVATIVES – EFFECTS ON ROSETTING AND CYTOADHERANCE erythrocytes containing mature forms of P. falciparum ahdere to microvascular endothelium cytoadherance. disappears from circulation→ sequestration. Erythrocytes containing mature parasites also adhere to uninfected parasites, leading to the formation of “rosettes”.

Cytoadherance and rosetting → microcirculatory obstruction in falciparum malaria, All artemisinin drugs prevent the development of ring stage parasites to the more mature pathogenic stages that rosette and cytoadhere to capillaries

PHARMACOKINETICS Absorption of orally administered artemisinin or its derivatives seems to be rapid but incomplete Substantial hydrolysis of artesunate (probable complete) and artemether into dihydroartemisinin probably occurs even before absorption Elimination is mainly by hepatic metabolism Arteether has much slower elimination

Artesunate, artemether, arteether and probably also artemisinin itself are transformed into dihydro- artemisinin, which is subsequently converted into inactive metabolites

INDICATIONS As a safe and effective alternative to quinine in the treatment of severe malaria Treatment of uncomplicated malaria - limited to patients infected with multidrug resistant malaria

ADR The artemisinins are extremely well tolerated and virtually without adverse effects Toxicological studies in animals have shown that the toxicity of artemisinin, artemether and artesunate is much less than that of chloroquine. Significant adverse effects or signs of toxicity of the artemisinins have not been reported in human patients treated with therapeutic dosages

ADR Common adverse effects - Headache, nausea, abdominal pain, vomiting, occasional diarrhoea, symptoms that are associated with with malaria and which resolve with appropriate treatment. Animal studies have demonstrated limited symptomatic and pathological evidence of neurotoxicity following the parenteral administration of high doses of either artemether or arteether

There is no clinical evidence of serious neurotoxicity from the use of any artemisinin drug in man in prospective studies of over patients.

PRIMAQUINE: Radical care. 3 major metabolites – less antimalarial activity - more hemolysis MOA: UNKNOWN Uses: - Radical care of vivax & ovale - Terminal prophylaxis of vivax & ovale - Terminal Chemoprophylaxis of malaria - Patient jiroveci + Clindamycin

ADR: Nausea, epigastric pain, abdominal, cramps, headache, - Hematological, G6 PD. - Cardiac arrhythmias - Masked hypotension parenterally - Not in pregnancy

ATOVAQUONE: + Proguanil – Treatment & prevention of malaria. - Mild to moderate patient jiroveci Absorption increased by fatty food M.O.A: Disrupts mitochondrial electron transport Both Treatment & chemoprophylaxis ADR: General I headache, rash Increase LFT. ? Pregnancy Decrease Concentration with teracycline & Rifampin

INHIBITORS OF FOLATE SYNTHESIS: Pyrimethamine 25mg & Sulfadoxine 500 mg Proguanil → Cycloguanil M.O.A: Sequential blockade Uses: Prophylaxis: Chloroquine 500mg/wk & Proguanil 200mg/d Fansidar Maloprim → Pyrimethamine & Dapsone No longer used

INTERMITTENT PREVENTIVE THERAPY High risk patient Africa – pregnant women & children Treatment of Chloroquine–resistant pf Not used! Toxoplasmosis: Pyrimethamine + sulfadoxine Pneumocytosis. ADR.

HALOFANTRINE & LUMEFANTRINE: Increase absorption with food, - only for treatment – not for chemoprophylaxis - Cardiac toxicity - GI, Increased LFT. - Increase QT & PR - C/I pregnancy - Lumefantrine & artemether.

ANTIBIOTICS: Tetracycline, Doxycycline, Clindamycin, Azithromycin