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Anti Malarial Drugs

Anti Malarial Drugs Mechanism, Indications, Contraindications and Dose

PHARMACOLOGY

Alok Bains

5/14/20238 min read

Anti-malaria drugs;

Mechanism, Dose, Indication and Contraindications

Some commonly used anti-malarial drugs schozonticides

Chloroquine

It is highly effective against the asexual erythrocytic phase and sexual phase (gametocytes) of Plasmodium. The chloroquine-resistant strain of Plasmodium falciparum has been reported in India.

Pharmacokinetics: Chloroquine is rapidly and almost completely absorbed from GIT upon oral administration. It is also rapidly absorbed upon intramuscular injection. 50% of Chloroquine present in plasma binds with plasma protein. It is widely distributed throughout the body and a high concentration is found in the liver, spleen, kidney, CNS, leukocytes and skin cells containing melamine. Due to this, it has a very high apparent volume of distribution. It can cross BBB and placental barriers.

It is extensively metabolised by dealkylation in the liver by the enzyme mixed-function oxidase. Some of its metabolites are active metabolites that retain an antimalarial effect. These active metabolites have a longer half-life of about 15 days. Both unchanged drugs and metabolites are excreted in the urine. Acidic urine increases its rate of excretion.

Mechanism (Principles) of action: It is effective against the erythrocytic stage of malarial parasites. Chloroquine does not affect malaria parasites present in plasma outside RBC.

  1. Malarial parasites in digest haemoglobin to release water-soluble heme. Water-soluble heme is toxic to malarial cells. Malarial cells polymerise soluble heme to hemozoin, a pigment, using enzyme polymerase to protect them.

    Chloroquine enters erythrocyte cells and binds with enzyme polymerase to block the polymerisation of toxic water-soluble heme. This water-soluble heme kills malarial cells. Break down of haemoglobin by malarial cells also releases ferriprotoporphyrin IX (Hemin). Chloroquine also binds with ferriprotoporphyrin IX (Hemin). This complex damages the cell walls of malarial parasites and the cell wall of RBC. This causes rupturing of both RBC and malarial cells by lysis.

  2. Malerial parasite food vacuole is acidic. Chloroquine enters the food vacuolet. Chloroquine is an alkaloid, highly alkaline. Chloroquine develops alkalinity that blocks all activity of malarial parasites' cell organelles. Malarial cells cannot survive in alkaline media.

  3. Chloroquine inhibits malarial cells' nucleic acid biosynthesis which inhibits the elongation of DNA.

  4. Chloroquine inhibits calcium ion-dependent protein.

Indications (Pharmacological effects):

  1. Plasmodium clinical symptoms are quickly controlled by Chloroquine. Malarial fever peripheral blood smear becomes parasite negative within one or two days from the first dose of Chloroquine. Chloroquine does not affect malaria parasites present in plasma outside RBC.

  2. It acts as an anti-inflammatory agent in rheumatoid arthritis and discoid lupus erythematosus. 

  3. It is effective in extra intestinal amoebiasis treatment and Giardia lamblia treatment.

Contraindications: Chloroquine is a safe drug but it is not used with caution under the following conditions

  1. Hypersensitivity: Persons allergic to Chloroquine,

  2. Hepatic impairment: Chloroquine damages the liver cells. It will exaggerate liver problems. Chloroquine is metabolised in the liver. The liver impairment will increase the half-life of chloroquine which exaggerates other side effects of chloroquine.

  3. Kidney disease: Chloroquine accumulates in the kidney. Thus causing kidney damage. Thus it should be used with caution in kidney disease.

  4. GIT upset: Chloroquine cause nausea and vomiting. Thus it will exaggerate GIT upset.

  5. Blood disorder: Chloroquine causes RBC lysis. Thus it will exaggerate blood disorders problems.

  6. Neurologic disorder: Chloroquine cause psychiatric illness. Thus it will exaggerate neurological disorders such as epilepsy.

  7. Heart disease: Chloroquine changes heart rhythm Thus it is contraindicated in heart disease.

  8. Pregnancy and breastfeeding: Chloroquine can cross the placental barrier and excrete into breast milk. Thus it is harmful to the foetus and nursing infants.

  9. Psoriasis and Porphyria

Dose: 600 mg daily for 2 days followed by 300 mg daily for 2 to 3 weeks.

Quinine

It is a blood schizonticide obtained from cinchonine tree bark. Mefloquine is synthesised in the laboratory. It has structural similarities with quinine and has more antimicrobial effects and less toxic effects than quinine. It is only used as a therapeutic agent, not as a prophylactic agent or suppressive agent for malarial infection. It is less effective and more toxic than chloroquine.

Mechanism of action: Not known clearly. It inhibits the growth of Plasmodium. 

Pharmacokinetics: Quinine is rapidly and almost completely absorbed from GIT upon oral administration. It has a high affinity with plasma protein. It can cross the placental barrier and enter into foetus circulation while penetration into CNS is poor. It is metabolised in the liver. Both metabolites and 10% of unchanged drugs are excreted into the urine. Alkalisation of urine decreases its rate of excretion. Its half-life is 10 hours.

Indication:

  1. Uncomplicated chloroquine-resistant material infection is treated by quinine. Here, quinine is used to produce rapid killing of schizonts (Rapid scizonticide effect). Then quinine administration is discontinued and slow-acting schizonticide is administered to cure the disease.

  2. Treatment of leg muscle cramps caused by vascular spasms or nocturnal spasms.

  3. Myasthenia Gravis diagnosis.

  4. Vaginal cream to produce the spermicidal effect.

  5. Treatment of internal haemorrhoids and varicose vein

Contraindication: Quinine is a very toxic drug. A single large dose of quinine or prolonged therapeutic dose administration develops cinchona poisoning or cinchonism. Thus it should be used with great caution under the following conditions:

  1. Hypersensitivity,

  2. Cardiovascular diseases: It causes irregular heart rhythm. Thus it should be used with caution in CVS diseases,

  3. Blood disorders: Quinine causes raptures of RBC that develops anaemia. It should be used with caution in blood disordersnsuch as glucose-6phosphate dehydrogenase(G6PD) deficiency, thrombocytopenias, anaemia, etc.

  4. Myasthenia gravis: Quinine exacerbates symptoms of myasthenia gravis.

  5. Liver or kidney disease: Under this condition, there will be an increase in side effects of quinine.

  6. Pregnancy: It crosses the placental barrier thus harming the foetus.

Dose: 600 to 650 mg every eight hours for three to seven days.

Mefloquine

It is blood schizonticides. It has structural similarities with quinine but is more effective and less toxic than quinine and other antimalarial drugs. It is used as a suppressive agent as well as a therapeutic agent to treat multi-drug-resistant Plasmodium infection.

Mechanism of action: Exact mechanism of action is not clear.

It rapidly enters the erythrocytic stage of Plasmodium. Mafloquin forms a toxic complex with water-soluble heme (A free form of heme produced by Plasmodium after digestion of haemoglobin). This toxic soluble heme mefloquine complex damages the Plasmodium membrane. It also increases pH and causes swelling in the food vacuoles of plasmodium cells. This leads to the death of plasmodium cells inside RBC, which is the death of schizonts. Chloroquine-resistant plasmodium also takes up mefloquine in plasmodium cells. However, the accumulation of mefloquine inside resistant plasmodium is at a slower rate.

Pharmacokinetics: It is slowly absorbed from GIT. However, 80% of the drug is absorbed from GIT. The presence of food in GIT increases the absorption of mefloquine. It has a high affinity with plasma proteins and the highest concentration is found in the liver, lungs and intestine. Its metabolites and unchanged drugs enter into enterohepatic circulation and most metabolites are excreted in bile and passed out from the body through faeces. High affinity with plasma protein and its entry into enterohepatic circulation increases the half-life of mefloquine by about 17 days.

Indications: Mefloquine is an effective prophylactic and therapeutic agent as an antimalarial drug. Mefloquine is reserved for prophylactic or therapeutic use in malaria due to chloroquine-resistant or multidrug-resistant. Mefloquine is not administered through the parenteral route due to its high toxicity. It is always administered orally.

Mefloquine is not recommended in normal malaria due to its high toxicity, long duration of action, and high cost.

Contraindication:

  1. It is also not recommended in complicated malaria and cerebral malaria.

  2. Concurrent administration of mefloquine with quinine or quinidine, β blockers, calcium channel blockers, antidepressants, and cardiotonic digitalis may cause disturbance in ECG, exaggerated bradycardia and cardiac arrest.

  3. Mefloquine alone is safe in pregnancy, but it should be avoided during the first four months of pregnancy. During the rest period of pregnancy, it should be recommended if other drugs are ineffective.

  4. It is also not recommended in an epileptic patient due to its side effect that promotes seizure episodes.

Dose:

Prophylactic dose: 250 mg once in a week for 1 to 2 weeks entering the malaria endemic area.

Therapeutic dose: It varies depending upon severity of the illness.

Pyrimethamine

Pyrimethamine and trimethoprim are diamino pyrimidine derivatives. Pyrimethamine is preferred over trimethoprim in the treatment of malaria. Pyrimethamine acts as erythrocytic schizonticides in human blood and strong sporonticie in the mosquito gut.

Mechanism of action enzyme dihydrofolate reductase (DHFR) converts dihydrofolate to tetra dihydrofolate in human cells, bacterial cells and also protozoal cells. Tetra hydro folate is used by cells to synthesise amino acids, purine and pyramidin and nucleic acid (RNA and DNA).

Pyrimethamine inhibits the dihydrofolate reductase enzyme (DHFR) and blocks the conversion of dihydrofolate to tetrahydrofolate which ultimately blocks the synthesis of RNA and DNA in cells. The affinity of pyrimethamine to plasmodial (protozoal) dihydrofolate reductase is 5000 times more than bacterial DHFR and 1400 times more than human cell DHFR. Thus in a therapeutic dose, Pyrimethamine inhibits the synthesis of purine and pyrimidine in plasmodial cells without affecting the synthesis of purine and pyrimidine in human cells.

Pyrimethamine has more affinity to plasmodial DHFR than trimethoprim.

Pyrimethamine is effective against all plasmodial species. If it is used alone then plasmodium may develop resistance to Pyrimethamine. To avoid the development of resistance, Pyrimethamine is used in combination with sulphonamide. Pyrimethamine and sulphonamide combination produces a synergistic effect.
Pharmacokinetics: Pyrimethamine is slowly and completely absorbed from GIT. It concentrates in the kidney, liver, spleen and lungs. It is metabolised and excreted in the urine. It is also excreted in breast milk. The half-life of the drug is 4 days. After a single dose, it can protect humans from malaria for 14 days.

Indication: It is used in combination with sulfadoxine to treat acute malaria. This combination therapy produces a synergistic effect, avoids the development of resistance in plasmodium to Pyrimethamine and promotes the onset of action because Pyremethamine alone is a slow-acting drug. It is used alone as a suppressive agent. It is administered for at least 10 weeks to people coming from the endemic zone of malaria to produce a suppressive effect.

Dose: 25 mg once daily with food for 2 to 3 days.

Proguanil

Proguanil is prodrug. It is metabolised inside the body to Cycloguanil. Cycloguanine acts as an erythrocytic schizonticide. It is used as a therapeutic agent, Prophylactic agent and suppressive agent in malarial infection. It does not kill Plasmodium gametocytes inside a human host. But these gametocytes' sexual form becomes non-infectious and does not grow inside the mosquito gut.

Mechanism of action: It has more affinity to plasmodial DHFR than human DHFR. Same as Paramethamine.

Pharmacokinetics: It is slowly absorbed from GIT after oral administration. It is metabolised into active drugs. Both unchanged drugs and metabolites are excreted in the urine. The plasma half-life is about 20 hours. It concentrates on RBC. It is a safe drug and can be used as a prophylactic agent for a longer duration. In some individuals, it is not metabolised and is excreted unchanged in the urine. In these individuals Proguanil is ineffective.

Dose:

Prophylactic dose: 200 mg daily for two days before the start of travelling in the endemic area and continue for 7 days.

Therapeutic dose: 200 mg three times daily for three days along with other anti-malarial drugs.

Primaquine

Primaquine is an 8-aminoquinoline compound that is more potent, and less toxic than all 8-aminoquinoline compounds. It acts as tissue schizonticide in the treatment of acute malaria. It is very effective in the exoerythrocytic stage. (Plasmodium outside RBC. It easily eradicates plasmodium present outside RBC, It is also very active against the sexual form of plasmodium gametocytes. It destroys these gametocytes inside human blood and inhibits the spread of infection to mosquitoes.

Pharmacokinetics: It is well absorbed from GIT and oxidised in the liver Metabolites are excreted in the urine. Its half-life is about 3 to 6 hours. A small amount of unchanged drugs is also excreted in the urine. Some metabolites are toxic and produce a haemolytic effect and schizonticide effect while other metabolites are non-toxic and also have no therapeutic effect. These metabolites are excreted in the urine.

Mechanism of action: Primaquine inhibits nucleic acid synthesis in the plasmodium inside the liver. This stops the multiplication of plasmodium inside the liver.

Indications:

  1. Treatment and prevention of malaria.

  2. In the treatment of pneumonia,

  3. In the treatment of rheumatoid arthritis,

  4. Anti-inflammatory agent

Contraindications

  1. G6PD deficiency: Severe side effects of primaquine occur in G6PD deficiency. There will be intravascular hemolysis, anaemia and dark urine.

  2. Pregnancy and breast-feeding,

  3. Children below 6 months.

  4. Renal and hepatic diseases,

  5. Concurrent use of primaquine with other drugs such as anticoagulants,

Dose: 30 mg once daily for 14 days.