Antimalarial Drugs Species of plasmodium. Clinical features and complications. Life-cycle of plasmodium. Classification of antimalarial drugs. Individual drugs.

Malaria Each year, it causes disease in approximately 650 million people and kills between one and three million.

Species of Malaria Plasmodium falciparum. P.vivax P.vivax & P.ovale. P.ovale is mainly confined to Africa.

Clinical Features Acute falicparum malaria is potentially fatal. Symptoms of malaria. Chills are caused by rapid muscle contraction and relaxation, and are the body's way of generating heat when it feels that it is cold. Chills often predict the coming of a fever, or an increase in the body's core temperature.

Chronic repeated infection. Complications:-. Chronic repeated infection. Clinical manifestations of cerebral malaria are numerous, but there are three primary symptoms generally common to both adults and children: (1) impaired consciousness with non-specific fever; (2) generalized convulsions and neurological sequelae; and (3) coma that persists for 24-72 hours, initially rousable and then unrousable.

Quiz? One cycle of liver invasion and multiplication: A) P vivax B) P falciparum C) P. malariae D) P ovale

Classification of Antimalarials Tissue schizontocides:-.

Blood schizontocides:-.

Gametocides:-destroy the sexual forms of the parasite.

Hypnozoitocides:-kill the dormant hypnozoites of P. vivax & P Hypnozoitocides:-kill the dormant hypnozoites of P.vivax & P.ovale in the liver.

Sprontocides:-interupt development of sporogonic phase in mosquitoes .

Uses Prophylactic:-to prevent clinical attack Suppressive prophylaxis:-use of blood schizontocides to prevent acute attack Causal prophylaxis:-use of tissue schizontocides to prevent the parasite from establishing in the liver

Curative:-suppressive treatment of the acute attack usually with blood schizontocides. Prevention of transmission:- Erradication of infection in mosquitoes using gametocytocides or sprontocides.

4-Aminoquinolines Chloroquine and amodiaquine potent blood schizontocide. At the acid pH of the lysosome it is converted into protonated form, trapped in the parasite. Inhibits digestion of haemoglobin by the parasite AA supply necessary for parasite viability. It also haem polymerase.

During this process, the parasite produces the toxic and soluble molecule heme. The heme moiety consists of a porphyrin ring called Fe(II)-protoporphyrin IX (FP). To avoid destruction by this molecule, the parasite polymerizes heme to form hemozoin, a non-toxic molecule. Hemozoin collects in the digestive vacuole as insoluble crystals. Chloroquine enters the red blood cell, inhabiting parasite cell, and digestive vacuole by simple diffusion. Chloroquine then becomes protonated (to CQ2+) as the digestive vacuole is known to be acidic (pH 4.7), chloroquine then cannot leave by diffusion. Chloroquine caps hemozoin molecules to prevent further polymerization of heme, thus leading to heme build up. Chloroquine binds to heme (or FP) to form what is known as the FP-Chloroquine complex, this complex is highly toxic to the cell and disrupts membrane function. Action of the toxic FP-Chloroquine and FP results in cell lysis and ultimately parasite cell autodigestion. In essence, the parasite cell drowns in its own metabolic products.

Resistance results from enhanced efflux of the expression of the human multi drug resistance transpoter P-glycoprotein.

It is a disease modifying antirheumatoid drug. Rapidly & completely absorbed from the GIT, has high volume of distribution(100-1000l/kg). Concentrated into parasitised RBCs.

Released slowly from tissues & metabolized in the liver, excreted in the urine 70% unchanged. Elimination is slow. Initial t½ =2-3days & terminal t ½=1-2months. ADR:-Nausea, vomiting, dizziness, blurring of vision, headache,urticarial symptoms. Large doses retinopathy. Bolus injection hypotension & dysrrhythmias Safe for pregnant women.

Quiz? Plasmodial resistance to chloroquine is due to (A) Change in receptor structure (B) Increased expression of P-glycoprotein (C) Increase in the activity of DNA repair mechanisms (D) Induction of inactivating enzymes (E) Inhibition of dihydrofolate reductase

Quiz? Of the following which is not a clinical use of chloroquine are:- A) amebiasis B) malaria prophylaxis C) acute malarial attacks D) guardiasis E) rheumatoid arthritis

Quinine Blood schizontocide effective against the erythrocytic form of all species of malaria. Acts by parasite’s haem polymerase. Depresses the myocardium,

Mild oxytoxic effect on pregnant uterus, Slight neuromuscular blocking action, weak antipyretic action. Given orally in a7 day course or by slow IV for severe P. falciparum infection, Metabolized in the liver,t½=10h.

ADR:-bitter taste →poor compliance, NV, concentrations >30-60mol/l cinchonism [nausea, dizziness, headache, tinnitus, blurring of vision]. Higher doses can cause hypotension , cardiac arrhythmias, ,delirium, coma.

Hypoglycaemia, blood dyscrasias, hypersensitivity reactions Blackwater fever, a fatal condition in which acute haemolytic anaemia is associated with renal failure. Resistance →↑ expression of P-glycoprotein.

CONTRAINDICATIONS Prolonged QT Interval Glucose-6-Phosphate Dehydrogenase Deficiency Myasthenia Gravis Hypersensitivity Optic Neuritis, auditory problems Dose should be reduced in renal insufficiency

Drug Interactions:- Antacids: Antacids containing aluminum and/or magnesium may delay or decrease absorption of quinine. Erythromycin (CYP3A4 inhibitor): Cimetidine Mefloquine. Quinine can raise plasma levels of warfarin and digoxin.

Quiz? Which is false about quinine : A) rapid onset B) poorly effective blood schizonticide against P vivax C) gametocidal for P ovale D) causes cinchonism E) causes hypoglycemia

Hydroxynaphthoquinone Atovaquone parasite’s electron transport chain by mimicking the natural substrate ubiquinone Has synergestic effect with proguanil.

Pregnant & breast feeding women should not use atavaquone. Resistance to atavaquone is rapid , results from a single point mutation in the gene for cytochrome b. Low bioavailability, slow, erratic absorption, ↑by food, highly protein- bound, t½ =2-3d, eliminated unchanged in faeces. ADR:- fever, rash, NVD, insomnia

Mefloquine Blood schizontocide active against Pvivax & P.falciparum, but no effect on hepatic form of the parasite. Inhibits haem polymerase. Resistance has occurred in southeast Asia.

May provoke neuropsychiatric disorder. Given orally ,well absorbed, slow onset of action, t½=30d enterohepatic recycling or tissue storage. ADR:-GIT disturbances, transient CNS toxicity, confusion, Gidiness, dysphoria, insomnia. May provoke neuropsychiatric disorder. Contra-indicated in pregnant women. Gidiness=dizziness, vertigo

Quiz? Mefloquine : A) active against P falciparum gametocytes B) indicated to pregnant women C) active against hepatic stages of P vivax D) contraindicated in cardiac conduction anomalies

Halofantrine Blood schizontocide, active against strains resistant to chloroquine , pyrimethamine, quinine. Cross resistance in falicparum infection occurred . Absorbed orally slowly , t½=11-12d., Absorption by a fatty meal, elimination in faeces.

May cause haemolytic anaemia & convulsions. ADR:-abdominal pain, headache, transient in hepatic enzymes, cough, pruritus, lengthening of Q-T interval. May cause haemolytic anaemia & convulsions. Reserved for infection caused by resistant organisms. Contraindicated with mefloquine. Patients with cardiac conduction defects. In pregnancy → embriotoxic in animals Itching, an unpleasant cutaneous sensation that provokes the desire to rub or scratch the skin to obtain relief.

Antifolates Type 1 antifolates sulphonamides & sulphones , competes with PABA. Type 2 ,pyrimethamine & proguanil dihydrofolate reductase.

Have slow action against the erythrocytic forms of the parasite. Pyrimethamine is used in combination with either dapsone or sulfadoxine.

Sulfonamides & sulfones are active against the erythrocytic forms of P Sulfonamides & sulfones are active against the erythrocytic forms of P.falciparum. Pyrimethamine -sulfodoxine is used for chloroquine –resistant malaria. Pyrimethamine & proguanil are absorbed orally slowly. t½ of pyrimethamine =4d, proguanil=16h. Proguanil is metabolized to an active metabolite ,cycloguanil which is excreted in urine.

ADR:- large doses of pyrimethamine -dapsone combination causes haemolytic anaemia, agranulocytosis. In high doses pyrimethamine mammalian dihydrofolate reductase megaloblastic anaemia. Resistance → a single mutation in the genes encoding parasite dihydrofolate reductase.

Quiz? Antimalarials dihydrofolate reductase inhibitors:- A) chloroquine B) chloroguanide C) pyrimethamine D) trimethoprim E) primaquine

Quiz? Concerning sulfonamides & sulfones and antimalarial activity: - a) Blood schizonticidal activity against P falciparum b) useful in acute sever attack of P falciparum c)  Active against liver stages of P falciparum or P vivax d) rapid onset of action e)  minimal side effects

Primaquine Active against liver hypnozoites, produces radical cure for parasites which have dormant stage in the liver [P.ovale &P.vivax]. Has gametocytcide action , most effective for preventing transmission of the disease. Combined with chloroquine, mechanism unknown, resistance rare.

Given orally, rapidly metabolized to etaquine & tafenoquine which are more active & slowly metabolized, t½=3-6h For radical cure of acute vivax and oval malaria”:- chloroquine is given to eradicate erythrocytic forms and then primaquine(30mg daily for 14 days) to eradicate liver hypnozoites

ADR:- GIT disturbances, in large doses  methaemoglobinaemia with cyanosis Causes haemolysis in G-6-P –dehdrogenase deficiency, metabolites have greater haemolytic activity

Quiz? This is the antimalarial agent most commonly associated with causing an acute hemolytic reaction in patients with glucose-6-phosphate dehydrogenase deficiency. (A) Chloroquine (B) Clindamycin (C) Mefloqui (D) Primaquine (E) Quinine

Artemisinin Derived from the herb qing haosu [Artemisia]. Artemisinin is poorly soluble in water & fast acting blood schizontocide. Effective in treating acute attack , including chloroquine –resistant & cerebral malaria. When the parasite that causes malaria infects a red blood cell, it consumes hemoglobin and liberates free heme, an iron-porphyrin complex. The iron reduces the peroxide bond in artemisinin generating high-valent iron-oxo species, resulting in a cascade of reactions that produce reactive oxygen radicals which damage the parasite leading to its death.[3] Artemesia annua

Artesunate[a water- soluble derivative], artemether & artether[synthetic analogues] have higher activity & are better absorbed. It damages the parasite membrane by carbon- centered free radicals. Rapidly absorbed , widely distributed,

Converted in the liver to the active metabolite dihydroartemisinin. t½ of artemisinin 4h,artesunate=45min, artemether 4-11h. ADR:- transient heart block, neutrophil count, brief episodes of fever. Neurotoxic in animal , no reported resistance

Quiz? An antimalarial drug effective against multidrug resistant P. falciparum, which rapidly terminates an attack of malarial fever, but has a short duration of action, so that recrudescence is common:- (A) Chloroquine (B) Artemisinine (C) Mefloquine (D) Primaquine (E) Quinine

Antibiotics Doxycycline is used as a suppressive prophylactic in areas where mefloquine resistance is common. Clindamycin has proved effective in the treatment of uncomplicated falicparum malaria, may be used in combination with quinine.

Prophylaxis Use of prophylactic drugs is seldom practical for full-time residents of malaria-endemic areas, and their use is usually restricted to short-term visitors and travelers to malarial regions. People temporarily visiting malaria-endemic areas usually begin taking the drugs one to two weeks before arriving and must continue taking them for 4 weeks after leaving.

include mefloquine ,doxycycline and the combination of atovaquone and proguanil hydrochloride The prophylactic effect does not begin immediately upon starting taking the drugs, so people temporarily visiting malaria-endemic areas usually begin taking the drugs one to two weeks before arriving and must continue taking them for 4 weeks after leaving (with the exception of atovaquone proguanil that only needs be started 2 days prior and continued for 7 days afterwards). Use of prophylactic drugs is seldom practical for full-time residents of malaria-endemic areas, and their use is usually restricted to short-term visitors and travelers to malarial regions. This is due to the cost of purchasing the drugs, negative side effects from long-term use, and because some effective anti-malarial drugs are difficult to obtain outside of wealthy nations.

Case A 35-year-old medical entomologist comes to the hospital with chief complaints of fever, headache, and photophobia. This illness began about 6 days prior to admission, when he returned from a 2-month visit to the jungles of Central and South America. He took a drug for prophylaxis of malaria before starting the trip. On his return flight, about 6 days prior to admission, he described having fever and shaking chills. He saw his physician 2 days prior to admission; the physician made a diagnosis of influenza and prescribed tetracycline. <procedure, surgery> General term for abdominal surgery

Case On the day of admission, the patient had shaking chills followed by temperature elevation to 104°F (40°C). Physical examination revealed a well-developed man who appeared ill. There is some left upper quadrant tenderness but no organomegaly; blood pressure,126/90; pulse, 120; and respirations, 22. Laboratory findings were hemoglobin, 14.5 mg/dL (normal, 13.4–17.4 mg/dL); hematocrit, 45% (normal, 40–54%); Giemsa-stained blood smear (thick and thin) revealed Plasmodium vivax <procedure, surgery> General term for abdominal surgery

Q1 The drug she took for prophylaxis was probably (A) Chloroquine (B) Mefloquine (C) Primaquine (D) Proguanil (E) Pyrimethamine

Q2? Which of the following drugs should be used for oral treatment of the entomologist's acute attack of P vivax malaria? (A) Chloroquin (B) Mefloquine (C) Primaquin (D) Pyrimethamine-sulfadoxine (E) Quinine

Q3? Which of the following drugs should be given later in order to eradicate schizonts and latent hypnozoites in the patient's liver? Chloroquine (B) Mefloquine (C) Primaquine (D) Proguanil (E) Quinine

Resistance About 90% of malaria deaths occur in sub Saharan Africa. The key factor contributing tomalarial morbidity & mortality is resistance of P.falciparum to chloroquine, sulfodoxin-pyrimethamin [SP] & amodiaquine. Artemisinin compounds produce a very rapid therapeutic response ,active against multi-drug resistant P.falciparum, well tolerated by the patient,gametocyte carriage, no resistance is detected. Artemisinins cure falciparum malaria in 7d, if combined with another drug in 3d.

WHO Recommendations WHO recommends that all countries experiencing resistance to conventional monotherapies should use combination therapy, preferably containing artemisinins [ACTs -artemisinin-based combination therapies]. WHO recommends the following therapeutic options:- Artemether/lumefantrine Artesunate+amodiaquine Artesunate+SP Artesunate+ mefloquine [area with low to moderate transmission. Amodiaquine+SP

Quiz? Regarding drugs used for malaria, which one of the following statements is false? (A) Chloroquine is the drug of choice for acute attacks of non falciparum malaria (B) Cinchonism is associated with the use of quinine (C) Hemolysis has occurred with primaquine in patients deficient in G6P dehydrogenase (D) Mefloquine is used for prophylaxis in regions where chloroquine resistance occurs (E) Quinine is contraindicated in pregnancy

Case A57-year-old photographer developed fever, diarrhea, headache, vomiting, and dark urine about 10 days after returning to the United States from a month-long trip to East Africa. The patient has been taking chloroquine and proguanil chemoprophylaxis. On physical examination the patient is feverish, agitated, sweating, weak, and in mild distress, with a blood pressure 95/60 (normal, 120/80), a pulse of 120 (normal, 60–100), <procedure, surgery> General term for abdominal surgery

Case and temperature of 104°F (40°C) (normal, 98.6°F, 37°C). Laboratory findings are a hematocrit of 25% (normal for male, 40–54%); platelet count 29,000 (normal, 150,000–400,000/mm3); parasitemia 6% (P. falciparum); serum creatinine 3.5 mg/dL (Normal for male, 0.8–1.5 mg/dL); and plasma glucose 39 mg/dL (Normal fasting, 65–110 mg/dL). <procedure, surgery> General term for abdominal surgery

Q1 What is the best choice of drug therapy?