Malaria & Anti-Malarial Drugs

Pharmacological action

1.     Antimalarial activity

·         High against erythrocytic forms of vivax, ovale, malarise and sensitive strains of falciparum.

·         Gametocytes of vivax

·         No activity against tissue schizonts.

·         Resistance develops due to efflux mechanism

2.     Other parasitic infections

·         Giardiasis, taeniasis, extraintestinal amoebiasis.

3.     Other action

·         Depressant action on myocardium

·         direct relaxant effect on vascular smooth muscle

·         anti-inflammatory

·         antihistaminic

·         local anesthesia

Pharmacokinetics

·         well absorbed orally

·         t_max 2-3 hours, 60% protein bound

·         Concentrated in liver, spleen, kidney, lungs, and leukocytes.

·         Selective accumulation in retina: ocular toxicity.

·         T ½ : 3-10 days increases from few days to weeks.

Adverse effects

·         Tolerance

o   Nausea, vomiting, anorexia (an abnormally low body weight / fear of gaining weight).

o   Skin rashes, angioneurotic edema (swelling may occur in the face, tongue, larynx, abdomen, or arms and legs.), dermatitis.

o   Photosensitivity, pigmentation, exfoliative (severe inflammation of the entire skin surface).

o   Long term therapy may cause bleaching of hair.

o   Rarely thrombocytopenia (low platelet level), agranulocytosis (low WBC counts), pancytopenia.

·        Ocular toxicity

o   Temporary loss of accommodation.

o   Lenticular opacities (produces swelling and opacity of the entire lens)

o   Sub capsular contract  (reduce vision in bright light / interfere with reading vision)

o   Blue black pigmentation

o   Constrictcted field of vision

·        CNS

o   Insomnia (poor sleeping habits)

o   Transient depression seizures

o   Rarely neuropathy and ototoxicity

·        CVS

o   ST and T wave abnormalities, decrease in BP and cardiac arrest in children reported.

Dosage

·         600 mg of base start

·         300 mg base after 8 hours

·         150 mg base BD for 2 days

·         200 mg oral tablet of chloroquine phosphate

Hydroxycloroquine

·         Less toxic

·         Properties and uses same as chloroquine.

Amodiaquine

·         As effective as chlroquine.

·         Similar pharmacological action.

·         Chloroquine resistant strains may be effective.

·         Adverse effect: headache, photosensitivity, agranulocytosis (rare).

·         Amodiaquine is not recommended for prophylaxis treatment.

Quinine

·         It is isolated form the bark of cinchona (1820 Pelletier and caventou).

·         Same mechanism of action to chloroquine.

Pharmacological action

1.      Antimalarial action

·         Erythrocytic, forms of all malarial parasites including resistant falciparum strain.

2.      Local irritant effect

·         Local pain sterile abcess.

3.      Cardiovascular

·         Depress myocardium: decrease excitability, decrease conductivity, increase refractory period.

4.      Miscellaneous action

·         Mild analgesic antipyretic activity, stimulation of uterine smooth muscle, curaremimitic effect.

Adverse drug reaction

·         Tinnitus, nausea, and vomiting.

·         Headache mental confusion, vertigo, difficulty in hearing and visual disturbances.

·         Diarrhea, flushing and marked perspiration.

·         High doses: delirium, fever, tachypnea, respiratory depression, cyanosis.

·         Idiosyncrasy: similar to cinchonism but occurs in therapeutic doses.

·         Cardiovascular toxicity: cardiac arrest, hypotension, fatal arrhythmias.

·         Black water fever (massive intravascular hemolysis).

·         Hypoglycemia.

Uses

·         Uncomplicated resistant falciparum malaria

PRIMAQUINE

·         Poor erythrocytic schizonticides

·         Has marked effect on primary and secondary hepatic phases of malarial parasite

·         Highly active against gametocytes and hypnozoites.

Mechanism of action

·         Intermediate act as oxidant that are responsible for the schizontocial action

Pharmacokinetics

·         Readily absorbed after oral absorption

·         Oxidized in liver with a plasma half-life of 3-6 hours

·         Excreted in urine within 24 hour

·         Not a cumulative drug.

Adverse effects

·         Abdominal pain, gastrointestinal upset, weakness or uneasiness chest

·         Leucopenia (high dose) (reduced number of white blood cells)

·         Hemolysis

·         Methaemoglobinaemia

·         Tachypnoea (abnormally rapid breathing).

·         Cyanosis (bluish discoloration – especially skin and mucous membrane, due to excessive concentration of deoxyhemoglobin in the blood caused by deoxygenation).

Contraindications

·         Should not be given during pregnancy because fetus is glucose-6-phosphate dehydrogenase ( G 6-PD) deficient

Clinical uses

·         Radical cure of relapsing malaria (P.ovale and P.vivax)

·         Single 45mg dose given with curative dose of chloroquine to kill gametes (P. falciparum)

MEFLOQUINE (MQ)

·         Fast acting erythrocytic (blood) schizontocide but slower than CQ or quinine.

·         Effective against CQ-sensitive as well as resistant Plasmodia.

·         Efficacious suppressive prophylactic for multi-resistant P. falciparum.

Mechanism of action

·         It accumulates in infected RBCs, binds to heme and this complex damages the parasite’s membrane.

·         Action at parasitic cytosol rather than in the acidic vacuole.

Pharmacokinetics

·         Prolonged absorption after oral ingestion

·         It is highly plasma protein bound and concentrated in the liver, lung and intestines

·         Extensive metabolism occurs in liver and is primarily secreted in bile

·         It has a long half-life (17days) due to its concentration in various tissues and its continuous circulation through the enterohepatic and enterogastric systems

·         Its major excretory route is feces.     

Adverse effects

·         MQ is bitter in taste

·         At high doses:

o   Nausea, vomiting, diarrhea, abdominal pain, bradycardia

o   Ataxia, hallucinations, depression

·         MQ is safe in pregnancy

·        Rare events of toxicity are seen.

Contraindications

·         In patients with anxiety, depression, psychosis, and in cardiac conduction defects

Drug interactions

·         Cardiac arrests are possible if MQ is taken concurrently with quinine or quinidine

Uses

·         Effective for multidrug resistant P. falciparum

·         However its use is restricted due to its toxicity, cost and long half life