Antimalarials

• Introduction:

– Most devastating parasitic infection

– 1-3 million deaths world wide each year

– India 8 lac deaths

• Etiology: Plasmodium

• Transmission : Female anopheles

• Clinical features: a) Cold stage: onset with fatigue, headache, chills,

nausea, followed by rigors. Skin feels cold lasts for 1 hr

b) Hot stage: feels, burning hot , casts off his clothes , skin is hot & dry to touch, lasts for 2 to 6 hrs

c) Sweating stage: fever comes down with profuse sweating & temperature drops rapidly to normal. Skin is cool & moist. Pt feels relieved lasts for 2 to 4 hrs

Life cycle of malarial parasite

Sporogeny (sexual)

Schizogony (asexual)

Man : Intermediate hostMosquito : Definitive host

True causal prophylactics

Causal prophylactics

Supressives

Gametocidal

Sporonticide

• Classification of antimalarial drugs

– Based on stage of life cycle they affect

– Based on chemical structure

• Based on stage of parasite they affect: – True causal prophylactics:

– Causal prophylactics: Primaquine, Pyrimethamine,proguanil

– Supressives: quinine, 4-aminoquinolines, mefloquine,artemisinin

– Radical curatives: primaquine,pyrimethamine

– Gametocidal: • Supressives (Chloroquine, quinine, artesunate )

– Pl Vivax ,

• Primaquine – against all,

• Proguanil ,pyrimethamine – prevent development of sporozoites

• Based on chemical structure:– Cinchona alkaloids: quinine,quinidine

– 4 aminoquinolines: chloroquine, hydroxychloroquine, amodiaquine, pyronaridine

– 8 aminoquinolines: primaquine, tafenoquine, bulaquine

– quinoline methanol: mefloquine, halofantrine, lumefantrine

– Antifolates:• Diaminopyrimidine: pyrimethamine

• Biguanides: proguanil

• Sulfonamides: sulfadoxine

– Antibiotics: tetracycline, doxycycline, clindamycin

– Hydronaphthoquinone: Atovaquone

– Qinghaosu compounds: Artesunate, artemether, arteether

• Chloroquine:

– Germans 1934 resochin

– closely resembles 8 amino quinolines

– d & l isomers, d isomer is less toxic

– Cl at position 7 confers maximal antimalarialefficacy

• Mechanism of action

Hemoglobin Globin utilized by malarial parasite

Heme (highly toxic for malaria parasite)

Chloroquine

Quinine,

mefloquine (-) (+)Heme polymerase

Hemozoin (Not toxic to plasmodium)

• Pharmacological actions:

1. Antimalarial activity:

• Highly against erythrocytic forms of vivax, ovale, malariae & sensitive strains of falciparum

• Gametocytes of vivax , ovale, malariae

• No activity against tissue schizonts

• Resistance develops due to efflux mechanism

2. Other parasitic infections:

• Giardiasis, taeniasis, extrainstestinal amoebiasis

3. Other actions:

• Depressant action on myocardium, direct relaxant effect on vascular smooth muscles, antiinflammatory, antihistaminic , local anaesthetic

• Pharmacokinetics:– Well absorbed, tmax 2-3 hrs , 55 % protein bound

– Conc in liver , spleen, kidney, lungs , leucocytes

– T1/2 = 3- 5 hrs increases from few days to weeks

• Adverse drug reaction: – Intolerance:

• skin rashes, angioneurotic edema, photosensitivity, pigmentation, exfoliative dermatititis

• Long term therapy may cause bleaching of hair

• Rarely thrombocytopenia, agranulocytosis, pancytopenia

• Occular toxicity: High dose prolonged therapy– Temporary loss of accommodation

– Lenticular opacities, subcapsular cataract

– Retinopathy: constriction of arteries, edema, blue black pigmentation , constricted field of vision. These changes are reversible on stopping therapy

• CNS:– Insomnia, transient depression seizures,

rarely neuromyopathy & ototoxicity

• CVS:– ST & T wave abnormalities, abrupt fall in BP &

cardiac arrest in children reported

• Dosage:

• Therapeutic uses:

1. Hepatic amoebiasis:

2. Giardiasis

3. Clonorchis sinensis

4. Rheumatoid arthritis

5. DLE

6. Control manifestation of lepra reaction

• Hydroxy chloroquine:

– Less toxic, properties &uses similar

• Amodiaquine:

– As effective as chloroquine in single dose

– Pharmacological actions similar

– Chloroquine resistant strains may be effective

– Adverse events: GIT, headache , photosensitivity, rarely agranulocytosis

– Not recommended for prophylaxis

• Pyronaridine: China , effective in resistant cases

• Quinine: – 1820 Pelletier & caventou isolated quinine from

cinchona bark.

– Pharmacological actions:

1. Antimalarial action: primarily on erythrocyticforms of all malarial parasites especially resistant falciparum strains . gametocidal for vivax & malariae

2. Local irritant effect: depresses variety of enzymatic processes, reduces ciliary activity , inhibits phagacytosis & growth of protoplasm so called general protoplasmic poison. Local pain sterile abcess.

3. Cardiovascular: depresses myocardium, ↓ excitability, ↓ conductivity, ↑ refractory period, profound hypotension IV.

4. Miscellaneous actions: mild analgesic, antipyretic activity , stimulation of uterine smooth muscle, curaremimitic effect on skeletal muscles

• Pharmacokinetics:

• administered orally is completely absorbed

• Tmax = 1-3 hrs , crosses placental barrier

• Metabolized in liver degradation products excreted in urine t ½ = 10 hrs

• Adverse drug reactions: • Cinchonism: – Mild: Nausea, headache visual impairment – Tinnitus, nausea & vomiting – Headache mental confusion, vertigo, difficulty in

hearing & visual disturbances – Diarrhoea , flushing & marked perspiration – Still higher doses , exagerated symptoms with

delirium , fever, tachypnoea, respiratory depression , cyanosis.

• Idiosyncrasy : similar to cinchonism but occurs in therapeutic doses

• Cardiovascular toxicity: cardiac arrest, hypotension ,fatal arrhytmias

• Black water fever: – Triad of hemolysis, hemoglobinemia, hemoglobinuria

with fever

– Rare type of hypersensitivity to quinine therapy having immunological basis. Presence of incompletely supressed falciparum malaria.

• Hypoglycemia:

• Uses: – Malaria:

• uncomplicated resistant falciparum malaria

• Cerebral malarial

– Myotonia congenita: heriditory myopathy characterized by tonic spasm of skeletal muscle, benefitted by 300 to 600 mg BD/ TDS

– Nocturnal muscle cramps: 200 – 300 mg before sleeping

– Spermicidal in vaginal creams

– Varicose veins: along with urethane causes thrombosis & fibrosis of varicose vein mass

• Primaquine: – Mechanism of action:

– Interferes with oxygen transport system

Primaquine

Converted to electrophiles

Generates reactive oxygen species

• Antimalarial action: – Liver hypnozoites

– Weak action against erythrocytic stage ofvivax, so used with supressives in radical cure

– No action against erythrocytic stage offalciparum

– Has gametocidal action and is most effectiveantimalarial to prevent transmission diseaseagainst all 4 species

• Pharmacokinetics:– Readily absorbed, t1/2 = 3-6 hrs

– Oxidised in liver, excreted in urine

• Adverse effects: – Gastrointestinal: epigastric distress, abdominal

cramps , can be minimised by taking drug with or after food , or with antacids

– Hemopoetic: mild anemia, methemoglobinemia, cyanosis, hemolytic anemia in G6PD deficiency

– Avoided during pregnancy, G6PD deficient

• Uses:– Primary use is radical cure of relapsing malaria 15

mg daily for 14 days with dose of chloroquine

– India 5 day therapy

– Falciparum malaria 45 mg of single dose with chloroquine curative dose to kill gametes & cut down transmission of malaria.

• Tafenoquine:

– More active slowly metabolized analog of primaquine, has advantage that it can be given on weekly basis.

• Bulaquine:

– Congener of primaquine developed in india

– Comparable antirelapse activity when used for 5 days

– Partly metabolized to primaquine

– Better tolerated in G6PD deficiency

• Mefloquine;– Quinoline methanol derivative developed to deal

with chloroquine resistant malaria – Rapidly acting erythrocytic schizonticide , slower

than chloroquine & quinine – Effective against chloroquine sensitive & resistant

plasmodia

• Pharmacokinetics: – Good but slow oral absorption– High protein binding – Concentrated in liver, lung, intestine – extensive metabolism in liver, primarily secreted

in bile , under goes enterohepatic circulation– Long t1/2 = 2 – 3 weeks

• Adverse events: 1. GIT: bitter in taste, nausea, vomiting , abdominal

pain , diarrhoea

2. neuropsychiatric disturbances: disturbed sense of balance, anxiety, hallucinations, sleep disturbances, psychosis, errors in operating machinery, convulsions

3. CVS: Bradycardia, sinus arhythmia, & QT prolongation

4. Teratogenicity: avoided in first trimester

5. Miscellaneous: allergic skin reactions, hepatitis & blood dyscrasias

• Uses: – Effective drug for MDR falciparum

1. T/t of uncomplicated falciparum in MDR malaria 25 mg/kg (1.5 gm) in 2 divided doses taken on same day

2. Prophylaxis in MDR areas 5 mg/kg (250 mg) per week started 2- 3 weeks before to asses side effects

• Due to fear of development of drug resistance mefloquine should not be used as single drug for prophylaxis.

• Halofantrine: – Quinoline methanol – Used in chloroquine resistant malaria since

1980 – Erratic bioavailabilty, lethal cardiotoxicity &

cross resistance to mefloquine limited its use – Now a days used only when no other

alternative available – Adverse events; Nausea, vomiting, QT

prolongation , diarrhoea, itching , rashes – C/I: along with quinine, chloroquine,

antidepressants, antipsychotics.

Drugs affecting synthesis & utilisation of folate:

PABA + Dihydropterine+ Glutamic acid

Di hydrofolicacid

Tetra hydrofolicacid

Dihydrofolatereductase

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sulfonamides

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DHFRinhibitors

Sulfonamides: Sulfanilamide moeity structural analog of PABA, PABA essential for folate synthesis Sulfonamides compete with PABA for folate synthetaseWeak effect , potentiate action of DHFR inhibitors ,hence used in combination

Advantages of combination Supradditive , sequential block Combination faster acting

Dihydrofolate reductase inhibitors:

• Proguanil :

– Biguanide converted to cycloguanil active compound

– Act slowly on erythtocytic stage of vivax & falciparum

– Sporonticidal & also prevents development of gametes

Adverse effects: Stomatitis, mouth ulcers, larger doses depression of

myocardium , megaloblastic anemia

Not a drug for acute attack

Causal prophylaxis: 100 – 200 mg daily

• Pyrimethamine: – Diaminopyrimidine more potent than proguanil &

effective against erythrocytic forms of all species.

– Tasteless so suitable for children

Adverse events: megaloblastic anemia, thrombocytopenia, agranulocytosis.

– Generally combined with sulfadoxine 500 mg + pyrimethamine 25 mg, 3 tablets once for acute attack

– Not recommended for prophylaxis due to severe cutaneous reactions like exfoliative dermatitis & stevenson johnson syndrome.

ARTEMISININ DERIVATIVATIVES: • Mechanism of action:• Antimalarial action:

Shorter acting drugs, so recrudescence Prevented by combining with long acting drugs

• Dose: Artesunate, arteether, artemether• Adverse events:

– No serious adverse events– Most common GIT , Itching & fever – Abnormal bleeding, dark urine , ST-T changes,

QT prolongation– Transient reticulocytopenia & leucopenia

• Use:

Artemisinin based combination therapy:

• WHO: acute uncomplicated Pl Falciparum be treated only by combining one Artemisinin with other effective erythrocytic schizonticide?

• ACT Regimens in use:– Artesunate – Sulfadoxine, pyrimethamine:

• Adopted as first line in india under NMP

• ARTESUNATE 100 mg BD for 3 days with S-P, 3 tablets

– Artesunate Mefloquine:• By combining artesunate further spread of mefloquine

resistance can be prevented

• Artesunate 100 mg BD for 3 days, + mefloquine 750 mg on second day & 500 mg on third day

• Artemether & lumefantrine: – Lumefantrine is highly effective , long acting oral

erythrocytic schizonticide related to mefloquine

– Same mechanism of action

– Highly lipophilic onset delayed , peak 6 hrs

– Slower acting than chloroquine, 99 % bound , metabolized by CYP3A4, T1/2= 2-3 days

– Available as fixed dose combination

– Adverse events: headache, dizziness, sleep disturbances, abdominal pain, arthralgia, pruritis & rash

– 80 mg artemether BD WITH 480 mg lumefantrineBD for 3 days

• DHA – Piperaquine, Artesunate- pyronaridine

• Tetracyclines: – Slow but potent action on erythrocytic stage of

all MP & Pre-erythrocytic stage of falciparum – Always used in combination with quinine or S-

P for treatment of chloroquine resistant malaria

• Atovaquone: – Synthetic napthoquinone derivative, rapidly

acting erythrocytic schizonticide for plasmodium falciparum & other plasmodia

– Pnemocystis carinnii & toxoplasma gondii– Mechanism of action: – Combined with proguanil– 250 mg of atovaquone + 100 mg proguanil

Management of malaria:• Prophylaxis;

– Indication – Duration :– Drug regimens:

• Chloroquine sensitive malaria: 300 mg / week • Chloroquine resistant malaria: mefloquine, doxy,

malarone• Drugs not allowed for prophylaxis: quinine,

artemisinin, pyrimethamine, sulfadoxine, amodiaquine

– Other measures – Causal prophylaxis – Supressive prophylaxis

Treatment of acute attack • Diagnosis , thick & thin smear • Acute clinical attack of chloroquine

sensitive malaria: – Chloroquine /– Amodiaquine: 600 mg base followed by 200

mg base on day1 then 400 mg OD on day 2 & day3/

– Quinine– Patients who cannot take orally

• 2.5 mg/kg IM every 4 hrs or 3.5 mg/kg IM every 6 hrs

• 10 mg/kg IV over 4 hrs then 5 mg/kg over 2 hrs BD

– Role of primaquine– Precautions:

• Treatment of chloroquine resistant malaria acute attack

A. Pts who can take orally:– Pyrimethamine sulfadoxine 3 tabs , quinine for 2 days

or

– Quinine 3 days with doxy 7 days or

– Quinine 3 days with mefloquine

– (Atovaquone 250 mg + proguanil 100 mg) 4 tab 3 days

– Sodium artesunate 100 mg BD day1 , 50 mg BD for 4 days

• Pts who cannot take orally – Inj Quinine Hcl 20 mg/kg in 500 ml dextrose saline

over 4 hrs then – 10 mg/kg in dextrose saline over 2 hrs every 8 hrly

till pt able to swallow – Then quinine 600 mg TDS for 7 days &

tetracycline/ doxycycline– Or artemether / arteether injection

• When should resistance be suspected: – All pts with complication – Any pt who has already received chloroquine last 1

month – Hb continues to fall in absence of bleeding &

asexual forms persist along with symptoms after 48 hrs of treatment

• Severe / Complicated / cerebral malaria – CNS symptoms, convulsions, coma

– Hypoglycemia, metabolic acidosis, renal failure or other complications

– Quinine is drug of choice IV dose

– S-P , doxycycline added with oral therapy

– BP, blood sugar, ECG Monitored during quinine therapy.

– Supportive measures:• ICU administration

• Good nursing care,Tepid sponging, Na bicarbonate

• Hypoglycemia, anemia, BP , Increase ICT

– GC, urea, mannitol not used now a days

• Malaria in children:– Quinine parenteral high toxicity / oral well tolerated

– Chloroquine convulsions in infants & small children

– Primaquine avoided in neonates

– Mefloquine not used in children below 15 kg weight

• Acute malaria in pregnant women– Chloroqune, quinine, S-P in usual doses

– Mefloquine C/I in first trimester

– Primaquine/ tetracycline avoided

– Anemia: folic acid & iron

• Vaccines for malaria:– Pre-erythrocytic stage vaccines

• RTS VACCINE designed to prevent invasion of hepatocytes by sporozoites

– Erythrocytic stage vaccine: • Aim is to reduce or eliminate number of blood stage

parasites • Malarial surface protein 1 (MSP1) vaccine• Apical merozoite antigen 1 (AMA1) vaccine

– Transmission blocking vaccines:• Designed to prevent mosquitoes that feed on

vaccinated individuals from becoming infected & reduce transmission (indirect prevention)

– Multicomponent vaccines: combination vaccines • Combination vaccine of 3 blood stage antigens