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Vishnupriya M.D NMCH

The oldest diseases known to mankind that has profound impact on our history.

Malaria is a vector-borne infectious disease caused by single-celled protozoan parasites of the genus Plasmodium.

Malaria is transmitted from person to person by the bite of female mosquitoes.

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INDIA: NMEP started in 1958 caused malaria complete disappearance but

came back in 1970 and still now prevails a major disease changed to NAMP then finally named it to NVBDCP

WHO : 2012 estimated 627 000 deaths (with an range of 473 000 to

789 000), mostly among African children.

Mortality rates ↓ 45% globally since 2000, by 49% in the African Region.

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Plasmodium falciparum : Falciparum malaria or Malignant Tertian malaria

Plasmodium vivax : Benign Tertian, Tertian Malaria

Plasmodium malariae: Quartan malaria

Plasmodium ovale: Ovale tertian Malaria

 Plasmodium knowlesi  a species that causes malaria among monkeys.

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Transfusion of infected blood, congenitally, and by sharing needles, but mainly by the bites of  female Anopheles mosquitoes

Man develops disease after 10 to 14 days of being bitten by an infective mosquito

Life cycle of malarian parasite:1) Hepatic cycle/pre or exo Erythrocytic cycle

2) Erythrocytic cycle

3)Sexual forms

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P. falciparum: Most dangerous invading erythrocytes of any age, producing endotoxin-like products, cause heavy parasitemia, hypoglycemia, and shock with multiorgan failure.

Delay in treatment may lead to death. If treated early, the infection usually responds within 48 hours.

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P. vivax has low mortality rate - untreated adults relapses caused by the reactivation of latent tissue forms.

(3) P. ovale affects periodicity and relapses similar to those of P.

vivax, but it is milder.

(4) P. malariae causes a generally indolent infection that is common in localized areas of the tropics. Clinical attacks may occur years or decades after infection.

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Clinical Diagnosis Malaria Blood Smear Fluorescent microscopy Antigen Detection Serology Polymerase Chain Reaction

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Coma / cerebral malaria, convulsions

Renal Impairment

Noncardiogenic pulmonary edema

Liver Dysfunction

Hypoglycemia

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Metabolic acidosis/acidemia

Hematological abnormality like hemoglobinuria,

Normocytic anemia, bleeding, DIC

Other complications : jaundice, extreme weakness, hyperparasitemia, impaired consciousness

Hypotension/shock

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1.prevent & treat clinical attack of malaria (prophylactic)

2.completely eradicate the parasite from pt’s body (clinical cure)

3.reduce the human reservoir of infection – cut down transmission to mosquito (gametocidal)

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4- Aminoquinolines – Chloroquine, Amodiaquine, Piperaquine

Quinoline- methanol – Mefloquine

Chinchona alkaloid - Quinine, Quinidine

Biguanide - Proguanil

Diaminopyrimidine- Pyrimethamine

8-Aminoquinoline – Primaquine,Tafenoquine

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Sulfonamides & sulfone- Sulfadoxine, Sulfamethopyrazine, Dapsone

Antibiotics- Tetracycline,Doxycycline,Clindamycine

Sesquiterpine - Artesunate

Lactones- Artemether, Arteether,Arterolane

Amino alcohols - Halofantrine,Lumefantrine

Napthyridine - Pyronaridine

Napthoquinone - Atovaquone

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Classification cont..

Discovered in 1934 by Hans Andersag and coworker Produced in U.S , introduced into clinical practice in 1947 for the

prophylactic treatment of malaria Spectrum of activity• Rapid acting Erythrocytic schizonticide against all species of

malaria

MOA :• Accumulates in acidic vacuole of parasite it increases ph & inhibits

heme polymerisation.

• By formation CQ -heme complex it damages plasmodial membrane complex inhibits formation of hemozoin

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Resistance to chloroquine

PFCRT gene seen in chloroquine resistant p.falciparum it pumps out the drug protecting heme

↓ ability of parasite to accumulate drug is the cause

NVBDCP : first line treatment against P.vivax & it slowly developing resistance too within 1-2wks of treatment

P.vivax resistance to Chloroquine : Quinine with Doxycycline/Clindamycin or ACT followed by Primaquine for radical cure is treatment of choice

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Absorbed orally, rapid absorption from IM, SC.

•Concentrated in various tissues like liver, spleen, kidney, lungs & melanin.

•Distribution in brain & spinal cord with large apparent volume of distribution -13000 liters in adult,

• loading dose – to attain therapeutic concentration in plasma & steady state concentration

•t1/2 : 214 h, 60% plasma protein bound

•Metabolism- two active forms 18

• Desethylchloroquine & Bisdesethyl chloroquine by CYP-450 in liver

• 50% eliminated by systemic and remaining eliminated renally

• On parentral administration entry is rapid & removal is slow causes toxicity

• To prevent it slow IV & S.C/I.M is given in small divided doses

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1.Malaria prophylaxis : 300mg once a week for prevention person visiting endemic area should receive one week before and four week after

Dose of ChloroquineDose of ChloroquineUncomplicated vivax /ovale/ malaria:600mg(10mg/kg)- 300mg(5mg/kg) after 8hrs,continue for next 2 days total 25mg/kg over 3 days + primaquine 15mg(0.25mg/kg)daily for 14 days

Chloroquine sensitive falciparumDose as above + primaquine 45mg(0.75mg/kg) single dose(gametocidal)

Therapeutic uses OF Chloroquine

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Other uses of Chloroquine:

Extra intestinal amoebiasis/hepatic amaoebiasis : 500mg TDS for 2 Days/ 200mg BD for 2-3 wks

Giardiasis: Metronidazole is preferred

Clonorchis sinensis :250mg daily for 6wks

Rheumatoid arthritis:250mg 6-12 mths once a week

Lepra reaction –TYPE 2

SLE :250-500mg daily 1-4wks followed by maintenance

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Common:Nausea, vomiting, anorexia, itching, epigastric pain, difficult in accommodation, headache are frequent & unpleasant

Toxic effects after prolonged use :•Skin eruptions, headache, blurring of vision, diplopia, confusion & convulsions.

•EKG changes : abnormal T waves, Wide QRS interval reversible

•Discoloration of nail beds, hairs & mucous membrane

•Haemolysis & blood dyscrasis

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Retinopathy with reduced visual acuity - accumulation of drug in melanin rich tissues (Bulls eye maculopathy) –reversible

Ototoxicity irreversible

Myopathy, cardiomyopathy, peripheral neuropathy, suicidal tendency occurs

Periodic neurological and retinal check up should be done

Adverse effects of chloroquine cont…

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>5gCardiovascular – hypotension due to vasodilatation, suppressed myocardiac function, cardiac arrhythmias & cardiac arrest

CNS – mental confusion, convulsion & coma

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with Mefloquine convulsion will occur

Digoxin level increases used along

With gold & phenylbutazone dermatitis will occur

Drug should be avoided in patients with ocular ,hepatic disease ,hemorrhage, hematological disease, peptic ulcer & neurological disease

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Epilepsy attacks will be precipitated in epileptic patients

Myasthenia gravis will worsen

Haemolysis occurs in G6PD deficient patients

Aggrevates exfoliative dermatitis & psoriasis

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↓ cost & safety in chloroquine resistance P.falciparum in certain areas

Faster action & better tolerance than chloroquine

Prophylactically not used because of hepatotoxicity & agranulocytosis in certain areas can be used in clinical attacks

Dosage : 25-35mg/kg for 3 days (10mg/kg is given immediately following

5mg/kg after 6hrs then 5mg/kg for next 2 days)

Mechanism, resistance, uses & ADR are similar to chloroquine27

Chloroquine Congener with similar mechanism

High efficacy, erythrocytic schizonticide with prolonged action & onset is slow

Activity:Chloroquine sensitive & Chloroquine resistant P. falciparum

malaria

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Mefloquine :Tested during world war II, introduced in 1963

Its 4-quinoline methanol related chemically to quinine used in chloroquine resistant P.falciparum malaria

Faster acting erythrocytic schizonticide slower than Chloroquine or quinine.

Effective against Chloroquine sensitive organism also

Its suppressive prophylactic for multi resistant falciparum & other types of malariae

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Relapses - vivax , due to long t1/2 chances of resistant strains are high

Cross resistance is seen with Quinine & Halofantrine

MOA of Mefloquine : Similar to morphological changes in the intraerythrocytic

parasite of Chloroquine & Quinine

Act in cytosol of the parasite

Mechanism is unclear it can also inhibit heme polymerization forming toxic complex with heme & damages membrane

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Enhanced translation of Pfmdr1 gene

Pharmacokinetics of Mefloquine :

Well absorbed orally, enhanced in presence of food

High plasma protein bound 98% & concentrated in many organs

Metabolism in liver, 10 secreted in bile, undergoes enterohepatic circulation, t1/2: 2-3wks

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1.Prophylaxis : Reserved for prevalent Chloroquine resistant P.falciparum areas

Dose: 5mg/kg or 250mg/wk for adults 1-2wks before travel.

2.Treatment of malaria : Reserve drug for multi drug resistance mainly Chloroquine resistant

vivax or falciparum

3.Current recommendation : With Artesunate as ACT For uncomplicated falciparum malaria

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25mg/kg - 1.25gm single or 2 doses of 750 & 500mg 12hr apart

Children weight < 45kg : First dose 15mg/kg → 10mg/kg after 12h after meals with plenty of water since its irritant

Adverse drug reactions :

Common : Dizziness, nausea, vomiting, diarrhoea ,abdominal pain, sinus bradycardia & QT prolongation

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Dose related effects :

Neuropsychiatric reactions present Rare-hematological , hepatic & cutaneous toxicity Safe during pregnancy but should be avoided in first trimester

Drug Interactions :

Halofantrine or Quinidine/Quinine or Chloroquine with this drug causes QT lengthening & cardiac arrest reported.

Avoided : Epileptic patients, Neuropsychiatric disorders

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QuinineIsolated from bark of chinchona tree in 1820,due to military importance many drugs were developed

Its levorotatory alkaloid

Spectrum Activity of Quinine :

Erythrocytic schizonticide for all species

Concentrated in food vacuole , less effective more toxic than Chloroquine

Kills vivax & malariae gametes & also effective against Chloroquine resistant & falciparum resistant strains

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Terminates acute attack but does not completely eliminate the parasite totally Doxycycline or Clindamycin are used

Its local irritant , anesthetic ,weak analgesic & antipyretic

MOA of Quinine It forms heme – quinine complex , Inhibits polymerization of heme to hemozoin Damages parasite membrane & kills it

Resistance: Similar to Mefloquine Have emerged in some parts of India

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Rapidly absorbed orally, peaks -5hr

70% bound to alpha1 acid glycoprotein ↑ during malarial infection

Metabolized in liver by CYP3A4

Excreted in urine, crosses placental barrier

t1/2 9-18 hr, vol of distribution 100 L in adults

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Uses of Quinine

1. Uncomplicated Chloroquine resistant malaria :

Its used orally alternative to S/P-ACT

NVBDCP : 7 day quinine 600mg 8hrly+ Doxycycline 100mg daily/clindamycin 600mg 12hrly is second line treatment in chloroquine resistance to falciparum & vivax malaria

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Uses of quinine cont…

Complicated & severe malaria-cerebral malaria:

Dose : (7 days course)

Loading dose : 20mg/kg i.v over 4hrs diluted in 5% dextrose to prevent hypoglycemia

Maintenance Dose: 10mg/kg over 4hr in adults or 2hr in children every 8hr

Then switch over to oral 10mg/kg 8hrly

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Parental Artemisinin are fast ,more effective, better tolerated and now preferred over Quinine for severe malaria

2. Nocturnal muscle cramps & myotonia congenita – Single tablet 300mg bed time

Adverse effects of Quinine

Higher doses : Affects hearing & vision Cardio depressant , anti arrhythmic & hypotensive actions similar to Quinidine

On rapid i.v it causes hypoglycemia

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Toxicity : 8-10g taken in single dose may be fatal

Cinchonism :reversible Ringing in ears, nausea, vomiting, headache, mental confusion,

vertigo, difficulty in hearing & visual disturbance, diarrhoea ,flushing & marked perspiration

Poisoning higher doses: QT prolongation during i.v

some develop idiosyncratic/hypersensitive reactions

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Occasionally:

Haemolysis in pregnant women – falciparum malaria causing hemoglobin urea & kidney damage

Caution : pregnant women only life threatening infection it can be used

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Slow acting erythrocytic schizontocide

Inhibits preerythrocytic stage of P.fal. gametocytes prevents its development

It gets converted to active form cycloguanil, which inhibits plasmodial DHFRase

MOA :

Inhibits DHFRase-thymidylate synthetase

Depletes folinic acid & DNA synthesis inhibition43

partial cross resistance with pyrimethamine,

resistance develops due to mutation of DHFRase –thymidylate

Pharmacokinetics Slow absorption Except erythrocytes no accumulation in tissue Peak plasma concentration : 5hr, t1/2:16-20h, Noncumulative, well tolerated Racial variations seen Excreted : urine

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Prophylaxis : ( P.falciparum & vivax )

Dose: > 200mg daily in adults & children 4weeks after leaving endemic area Currently its either prophylaxis nor for clinical attack

Causal prophylaxis:400mg proguanil + Atovaquine 1g for 3 days in multidrug resistance suppressive prophylactic : With chloroquine in moderately CQ resistant P.falciparum areas.

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Mild abdominal symptoms, Occasional stomatitis, haematuria, rashes & transient loss of hair

Pyrimethamine It direct inhibitor of DHFRase

Its slow acting blood schizonticide & More potent than Proguanil

Used with Sulfonamide or Dapsone to prevent resistance ,it may be due to mutation in DHFRase .

resistance with falciparum is common than vivax

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Pharmacokinetics: Slow & good absorption

Attains good concentration in organs

Metabolized & excreted in urine

t1/2: 4 days,prophylactically stays in blood – 2wks

Uses: Suppressive treatment chloroquine resistant falciparum

Toxoplasmosis -high doses given

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Adverse drug reactions of pyrimethamine:

Nausea, rashes ,megaloblastic anemia & granulocytopenia with higher doses.

Sulfonamide – pyrimethamineSupra additive synergism - sequential blockFaster acting against chloroquine resistant p.falciparumHas long half lifeIn India - with artesunate for all falciparum cases

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Fixed dose Combinations :

Pyrimethamine 25mg + sulfadoxine 500mg

Pyrimethamine 25mg + sulphamethopyrazine 500mg

Pyrimethamine 25mg +dapsone 100mg :given in 2nd & 3rd trimester of pregnancy with folic acid

In resistance quinine given with these combination

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ADR :Exfoliative dermatitis, stevens johnson syndrome

Precautions Avoided in pregnancy due to antifolate & teratogenic effects, avoid in children

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Primaquine

8 – Aminoquinoline

Radical cure : given with chloroquineonly agent active against dormant hepatic forms of vivax & ovaleGametocidal action against all four species of plasmodium

Mechanism of action Primaquine:Not clear, its converted & produces active oxygen interfere with plasmodial mitochondrial function

Resistance induced among p.vivax

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Pharmacokinetics of primaquine:Well absorbed oral,wide distributionHalf life 3-8h,peak :1-2hrsGenerates 3 active metabolite ,excreted in urine

Uses of primaquine1.Radical curea)P.vivax & ovale :Given in acute attack or throughout incubation period

prevents relapse

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Prophylactically: before & after leaving the endemic area to eradicate hepatic forms

Effective vector control is possible or used in areas of low transmission

b) Falciparum malaria:

45mg with chloroquine or ACT used like gametocidal & cut down transmission or where effective control is needed

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Primaquine cont..

2. AIDS: 15mg/day with clindamycin 600mg TDS alternatively used

Adverse drug reaction of PrimaquineTherapeutic doses: Haemolysis & methaemoglobinaemia commonly seen in G6PD

deficiency

Causes nausea, headache, epigastric pain &abdominal cramps on empty stomach

Rarely : leucopenia, leucocytosis & agranulocytosis

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Precaution - PrimaquineG6-PD deficiency checked & blood counts repeated if >30mg of Primaquine given

AVOIDIn patient with haemolysis ,Rheumatoid arthritis & SLE

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Tafenoquine Newer 8-aminoquinolone single dose for vivax hypnozoites Some activity was seen against asexual erythrocytic stage of

P.vivax,P.falciparum & chloroquine resistant state

Tafenoquine pharmacokinetics: With long half life 16-19 days, acts lasting upto a week

Causes haemolysis in G6PD deficient patient, anaemia, haemolysis & methaemoglobinaemia reported

Its undergoing phase-3 trial in India with 3 day chloroquine to prevent relapse in vivax ,likely to be single dose radical cure

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Tetracyclines & Doxycyclins

Erythrocytic schizonts are inhibited by all malarial parasite

Tetracycline used in combination with quinine in treatment of chloroquine resistant as well vivax malaria

Avoid in children & pregnant women

Dose: 250mg QID or Doxycycline 100mg OD equally effective

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Doxycycline cont..

Doxycycline used in places where high resistance present

200mg Doxycycline combined with artesunate to treat mefloquine/chloroquine/s-p resistant malaria

100mg/day of Doxycycline used 2nd line prophylactic for short travels to chloroquine resistant P.falciparum

Adverse effects: Photosensitivity & suprainfection

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Clindamycin:

Slow erythrocytic schizontocide, bacteriostatic

With Quinine used in treatment of resistant P.Falciparum

Its used where tetracyclines can not be used in pregnancy & children less than 8 years old

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Derived from plant Artemisia annua – (Chinese traditional medicines)

Its sesquiterpine lactone endoperoxide, poorly soluble in oil & water-used orally/rectally

Other compounds : Dihydroartemisinin (oral)

Artemether(oral or i.m) & artesunate(oral/rectal/i.v/i.m)

Arteether –(i.m) produced in India in 1990

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Arterolone - (oral) synthetic compound are developed

Spectrum Actions: Rapidly acting erythrocytic schizonticides clears parasite in

<48hrs

Safe & 10-100 times potent compared to other antimalarials Active against P.falciparum resistant to all other anti malarial

drugs as well sensitive strains

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They are lethal to early gamete stage by reducing number of gametes

MOA: Endoperoxide moiety produces carbon centered radicals by

intramolecular rearrangement which modify & damages malarial proteins

High reacted free radicals inhibit plasmodial sarcoplasmic endoplasmic calcium ATPase –(pf ATP6)

Resistance ↓s response & combination of drug with different mechanism & longer acting drugs given with these drugs in 3 days course will solve the problem

Artemisinin comp cont…

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Artemisinin comp cont…

Pharmacokinetics

ORAL absorption of Artesunate -rapid peak of <60min, causes auto induction by CYP2B6 & CYP3A4

Artemether absorption is delayed 2-4h, to increase absorption taken with food,CYP3A4 metabolism extends ½ life to 3-10h

Both these drugs get converted to dihydroartemisinin presystemically

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Artemisinin comp cont…

Half life is 1-2h

Artemisinin and dihydroartemisinin extensively metabolised little amount excreted in urine

Arteether long half life 24h can be used alone in 3days with very low recrudescence

Dose:12mg of total oral dose for both children & adults in which 4mg/kg given on first day followed by 2mg/kg for 4 days(5 daystreatment)

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Artemisinin comp cont…

Parenteral:Artesunate-120mg i.v/i.m on first day followed by 60gm for next 4 days by same routeArtemether: 2mg/kg for 5 daysArteether: for complicated malaria in adults i.m 150mg daily is preferred since it has long t1/2 24h its used in 3 day course but WHO recommends 5 day Course

UsesFor uncomplicated falciparum malaria,Chloroquine resistant & sensitive strains:FDC of ACT used

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in vivax where Chloroquine is resistant & Quinine + Clindamycin cannot be used Artemisinin (ACT) is used

Single dose Primaquine used to kill circulating gametes after ACT therapy

Severe complicated malaria:

Parentral artemisinin high effective &lower mortality

Quinine is used alternative when artemisinin cannot be used

During pregnancy quinine i.v given during 1st trimester of pregnancy since safety of artemisinin compounds not yet proved

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Adverse effects:Mild :nausea, vomiting, abdominal pain, itching &drug fever

Headache, tinnitus, dizziness, bleeding, dark urine, S-T segment changes, Q-T prolongation, first degree A-V block, transient reticulopenia & leucopenia are rare

Halofantrine (phenanthrene methanol)Not preferred due to erratic bioavailability & cardiotoxicity & extensive cross resistance with MEFLOQUINE

It was used in multidrug resistant strain of both falciparum & vivax,it’s a blood schizonticide

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Lumefantrine Belongs to the arylaminoalcohol

has a similar mechanism of action it alters protein & nucleic acid synthesis.

racemic fluorine derivative developed in China. It is only available in an oral preparation coformulated with artemether.

This ACT is highly effective against multidrug resistant P. falciparum.

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Lumefantrine cont…

orally active, long acting, highly effective blood schizonticidePharmacokinetics Its lipophilic ,absorption starts after 2hrs peaks 6-8h 99%plasma protein bound Metabolized by CYP3A4 ½ Life 4-6 days Taken with fatty diet to achieves adequate blood levelsDose: 480mg BD - 3days,adult & chidren >35kg 4tab given with

artemether 80mg BD Children 26-35 kg-3tab,16-25kg-2tab,5-15kg-1tab

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Lumefantrine cont…Uses:In combination with artemether 20mg+lumefantrine 120mg in one tab used as FDC Both drugs prevent resistanceDecreases gametocyte number & prevents recrudescenceIt achieves 99% cure rates

Adverse effectsMinor effects: Gastrointestinal disturbances, headache, dizziness rashes & pruritis Little Q-T prolongation seenAvoided in pregnant & lactating women

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Pyronaridine

Newer drug from Mepacrine developed in chinaMechanism similar to chloroquineHigh effective erythrocytic schizonticide,effective against chloroquine sensitive & resistant vivax & falciparum malaria Slow onset & long duration of action, concentrated in RBCWater soluble, t1/2 : 7daysOrally & parenterally used , well tolerated At high dose used analgesic/anti pyretic

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Its used FDC with Artesunate in multi drug resistant falciparum & vivax

Clinical trial proves >95% success rate in India This ACT not approved for use in India

Adverse effects:Abdominal pain, vomiting, headache, dizziness , loss of appetite,

palpitation

Dose:Artesunate 100-200mg(2-4mg/kg)+pyronaridine 300-600mg(6-

12mg/kg)/day-3days

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Atovaquone: Hydroxy naphthoquinone antiparasitic drug active against all

Plasmodium species.

Rapid acting erythrocytic schizontocide & inhibits pre-erythrocytic stage of falciparum.

Also active against pneumocystis jiroveci & Toxoplasma gondii combined with proguanil Where its resistant, reduces relapse &

which is synergistic.

Collapses mitochondrial membrane interferes with cytochrome electron transport.

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Dosage 250 mg of atovaquone and 100 mg of proguanil hydrochloride for adults. QID with food

Tablets containing 62.5 mg of atovaquone and 25 mg of proguanil hydrochloride for paediatric use.

Given 3 days for uncomplicated chloroquine resistant falciparum & vivax used in some countries but not in India

Uses: Mild –mod malaria chloroquine & multi drug resistant

Can be used prophylactically by non immune travellers visiting endemic areas,

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In oppurtunistic infections, pneumonia, Toxoplasmosis & Babesiosis

Pharmacokineticspoorly absorbed following oral administration can be improved by taking the drug with fatty foods.

99% bound to plasma proteins and has plasma half-life of around 66–70 h due to enterohepatic recycling. It is excreted in the faeces as unchanged drug

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Adverse effectsSkin rashes, headache, fever, insomnia, nausea, diarrhoea, vomiting, raised liver enzymes, hyponatraemia Rarely: haematological disturbances.Drug interactions↓ plasma concentrations with Tetracycline and Acyclovir, antidiarrhoeal drugs, Benzodiazepines, cephalosporins, laxatives, Opioids and Paracetamol.

Atovaquone ↓ the metabolism of zidovudine and cotrimoxazole.

it displace other highly protein-bound drugs from plasma-protein binding sites.

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Antimalarial drugs alone – Resistance & fail to prevent malaria

WHO :Acute uncomplicated resistant P.F malaria should be treated only by combining one of the artemisinin compounds with another effective erythrocyte schizontocide.

Advantages of ACT over other antimalarials:

Rapid clinical & parasitological cure. High cure rates, low relapse rate. No resistance. Good tolerability.

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ACT regimens for uncomplicated falciparum malaria. 1.Artesunate – mefloquine (AS/MQ)

Artesunate 100 mg BD (4 mg / kg / day) 3 days + Mefloquine 750 mg (15 mg / kg) on 2 nd day and 500 mg (10 mg / kg) on 3 rd day (total 25 mg / kg).

2.Artimether – lumefantrine (1:6)

Artemether (80 mg BD) + lumefantrine (480 mg BD) 3 DAYS

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Adult and child >35 kg :4 tab BD; child 25 – 35 kg : 3 Tabs bid; 15 – 25 kg :2 tab BD; 5 – 15 kg 1 tab BD, All for 3 days

3.Artesunate – sulfadoxine + pyrimethamine

Artesunate 100 mg BD (4 mg / kg / day ) 3 days + sulfadoxine 1500 mg (25 mg / kg) and pyrimethamine 75 mg (1.25 mg / kg) single dose

Act reg cont…….

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4.Arterolane – Piperaquine.Arterolane (as maleate)150mg+ Piperaquine750mg daily -3daysOne capsule OD for 3 days

5. Dihydroartemisinin- Piperaquine(DHA/PPQ 1:8)DHA120mg(2mg/kg)+piperaquine960mg(16mg/kg)daily for 3 days

6. Artesunate – Amodiaquine (AS/AQ)Artesunate 200mg(4mg/kg)+Amodiaquine(10mg/kg)per day-3 days

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ACT regimen cont…

Artesunate 25mg/50mg/100mg+Amodiaquine 67.5mg/135mg/270mg FDC approved in India

7.Artesunate -Pyronaridine(1:3) Artesunate 100-200mg (2-4mg/kg) + pyronaridine 300-600mg(6-

12mg/kg)per day- 3 days.

TREATMENT OF UNCOMPLICATED MALARIA a) Vivax (ovale,malariae) :1. Chloroquine 600mg (10mg/kg base) followed by

300mg(5mg/kg)after 8hrs for next 2 days(total 25mg/kg over 3 days) + Primaquine 15mg(0.25mg/kg)daily -14days

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ACT regimen cont…

In occasional case of chloroquine resistance: Quinine 600mg(10mg/kg)8hrly – 7days + Doxycycline 100mg daily

-7 days or + Clindamycin 600mg 12hrly -7days +Primaquine (as above) (or)ACT based combination + primaquine (as above)

B) Chloroquine - sensitive falciparum malaria

Chloroquine(as above) + primaquine 45mg(0.75mg/kg)single dose (gametocidal)

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1. Artesunate 100mg BD (4mg/kg/day) – 3 days + Sulfadoxine 1500mg(25mg/kg)+ Pyrimethamine 75mg (1.25mg/kg) single dose

Or

2. Artesunate 100mg BD(4mg/kg/day)- 3 days + Mefloquine 750mg(15mg/kg) on 2nd day & 500mg(10mg/kg) on 3rd day

or

3. Artemether 80mg+ lumefantrine 480mg BD – 3 days(Child 25-35kg BW ¾ Dose;15-25 kg BW ½ dose;5-15 kg BW ¼ dose

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(or)4.Arterolane (as maleate) 150mg + Piperaquine 750mg OD – 3 daysOr

5. Quinine 600mg(10mg/kg)8hrly – 7 days + Doxycycline 100mg daily -7 days

OrClindamycin 600mg 12hrly -7 days

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Artesunate 2.4 mg/kg IV or i.m as a first dose followed by 2.4mg/kg after 12 & 24h then OD -7days switch over to 3 day Oral ACT in between whenever patient can take & tolerate oral medication

(or)

2)Artemether 3.2 mg/kg IM on first day followed by 1.6 mg/kg daily for seven days switchover to 3 days oral ACT inbetween whenever patient can take & tolerate oral medication

(Or)

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Arteether 3.2mg/kg i.M on the first day followed by 1.6mg/kg daily for next 4 days switchover to 3 days oral act in between whenever patient can take & tolerate oral medication

Or

Quinine di hcl 20mg/kg loading dose diluted in 10ml/kg 5%dextrose/dextrose –saline infused i.V -4hrs,followed 10mg/kg(maintenance dose)i.V. Infusion over 4hrs(in adults)or 2h(in children)every 8hrs until patient can swallow switchover to oral quinine 10mg/kg 8hrly to complete 7 day course

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Drugs Used in pregnancy:

Proguanil with folic acid 5mg/day Chloroquine in usual doses Quinine in low dose –chloroquine resistant malaria high dose- induce labour Pyrimethamine + Dapsone -2nd & 3rd trimester with

folinic acid

Chloroquine, quinine & proguanil safe but pyrimethamine with folinic acid can be used

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NEWER DRUGS

4(1H)-quinolone-3-diarylethers :

selective potent inhibitors of the parasite's mitochondrial cytochrome bc1 complex. highly active against the human malaria parasites Plasmodium falciparum and Plasmodium vivax. They target both the liver and blood stages of the parasite as well as gametocytes, the zygote, the ookinete, and the oocyst.

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preclinical candidate, ELQ-300 has good oral bioavailability at efficacious doses in mice

Metabolically stable

highly active in blocking transmission in rodent models of malaria.

Given its predicted low dose in patients and its predicted long half-life, ELQ-300 has potential as a new drug for the treatment, prevention, and, ultimately, eradication of human malaria.

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A Phase III trial began in May 2009 and has completed enrolment in 2011

are expected to become available to WHO in 2014-2015.

evaluated as an addition to, not a replacement for, existing preventive, diagnostic and treatment measures.

The need for long-lasting insecticidal nets, rapid diagnostic tests and artemisinin-based combination therapies will continue 

90

References :

- Pharmacological basis of Therapeutics – Goodman & Gilman

12th Edition

- Principles of pharmacology – HL Sharma & KK sharma 2nd

edition

- Text book of pharmacology – K. D. Tripathi.7th Edition

- Pharmacology & Therapeutics - R.S.Satoskar -

Twentieth second Edition.

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www.ncbi.nlm.nih.gov/pubmed www. ranbaxy.Com www.who.int/malaria/areas/vaccine/en.

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