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Species of plasmodium.

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

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

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

Endemic
Endemic areas
areas of
of Malaria
Malaria

N.B. in Saudi, P. falciparum is
chloroquine resistant

Acute falicparum
malaria is potentially
fatal.
Symptoms of malaria.

capillary obstruction. Hemolytic anemia. . but there are three primary symptoms generally common to both adults and children: 1)impaired consciousness with nonspecific fever. death Chronic repeated CNS infection:  Clinical manifestations of cerebral malaria are numerous. 2) generalized convulsions and neurological sequelae. and 3) coma that persists for 24-72 hours. hepatospleenomegaly. initially rousable and then unrousable.Complications:-.

Malaria Malaria Life Life Cycle Cycle Life Life Cycle Cycle Sporogony Oocyst Sporozoite s Mosquito Zygote Salivary Gland Sporozoites Hypnozoites (for P. ovale) Gametocytes Exoerythrocytic (hepatic) cycle Merozoites Erythrocytic Cycle Schizogony Merozoites . vivax and P.

Eradication of dormant .

1. Proguanil (chlorguanide) 2.Tissue schizontocides:-.Pyrimethamine .

& sulfadoxine. . Pyrimethamine. 2. Mefloquine. Proguanil. 2 types 1. & Quinine. Chloroquine. Halofantrine.Blood schizontocides:-.

Primaquine the only drug that kills P.Gametocides:-destroy the sexual forms of the parasite.vivax & P. Primaquine. .ovale in the liver. falciparum gametocytes Hypnozoitocides: primaqunie kills dormant hypnozoites of P. & Quinie. Chloroquine.

Proguanil.Sprontocides:interrupt development of sporogonic phase in mosquitos . pyremethamine primaquine .

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1.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 . 2. 1.

3-Prevention of transmission:eradication of infection in mosquitos using gametocytocides or sporontocides.2-Curative:-suppressive treatment of the acute attack usually with blood schizontocides. 4-Prevention of relapse:Primaquine .

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. if u eliminates the parasited in the RBC the disease will be cured.•P falciparum and P malariae causes one cycle of liver invasion so. •P vivax and P ovale there is a dormant parasites in the liver  relapses. So u need to kill parasited in RBC and liver.

Used nonfalciparum and sensitive falciparum malaria .Chloroquine and amodiaquine potent blood schizontocide.

Mechanism of action .

MOA In the previous figure : The parasite digests the human hemoglobin in order to get amino acid. Chloroquine inhibits polymerization of heme accumulation of heme. Action of the toxic compound results in cell lysis and ultimately parasite cell autodigestion. but the problem here is that the heme part of Hb is toxic to the parasite. this complex is highly toxic to the cell and disrupts membrane function.7). the parasite has developed an enzyme responsible for polymerization of heme. To overcome this obstacle. Chloroquine binds to heme (or FP) to form what is known as the FP-Chloroquine complex. . Chloroquine then becomes protonated as the digestive vacuole is known to be acidic (pH 4. To form insoluble crystals called hemozoin which are collected in vacuoles. chloroquine then cannot leave by diffusion. Chloroquine enters parasite cell by simple diffusion.

.Resistance results from enhanced efflux of the parasite vesicleexpression of the human multi drug resistance transpoter Pglycoprotein.

6 hours later 0. The drug is distributed into 2 compartments: The drug highly concentrated in tissues.5g as maintenance dose for 2-3 days .Rapidly & completely absorbed from the GIT. thus low concentration in plasma Concentrated into parasitised RBCs. has high volume of distribution(100-1000 L/kg). Administered as 1g loading dose.

liver and spleen) & terminal t ½=1-2months ( 2nd compartment. muscle and bone). Initial t½ =2-3days (for the first compartment.Nausea. plasma. Used in acute attack . occurs with long time administration) Bolus injection hypotension & dysrrhythmias Safe for pregnant women. (most serious . highly perfused tissues e. Elimination is slow. blurring of vision.Released slowly from tissues & metabolized in the liver. urticaria Large doses retinopathy. dizziness. in moderately perfused tissues e.g. ADR:. headache.g. vomiting. excreted in the urine 70% unchanged.

(6-9 month) SLE In amebic liver abscess . Other uses: It is a disease modifying antirheumatoid drug.Contraindications: •Psoriasis or prophyria •Visual field abnormalities or myopathy •Ca and Mg containing antacid interfere with absorption •Used with caution in liver disease or neurologic or hematologic disorders.

Acts by parasite’s heme polymerase. as it is its d.Blood schizontocide effective against the erythrocytic form of all species of malaria. an antiarrhythmic agent. why? Because it has structural similarity with quinidine. . Depresses the myocardium.isomer.

can cause abortion slight neuromuscular blocking action.Clinical uses: •Blood schizonticide against all species. metabolized in the liver. . weak antipyretic action. bitter taste →poor compliance. falciparum infection. •Gametocidal against P vivax and P ovale PK: Given orally in a7-day course or by slow IV for severe P. short t½=10h. ADRS: Mild oxytoxic ( sever contraction) effects pregnant uterus.

Higher doses can cause hypotension. tinnitus. Hypoglycaemia by influencing insulin’s secretion.NV. hypersensitivity reactions Blackwater fever. Blackwater fever because of methanol group . headache. delirium. blood dyscrasias. cardiac arrhythmias. blurring of vision]. concentrations >30-60mol/l cinchonism [nausea. a fatal condition in which acute hemolytic anemia is associated with renal failure. dizziness. coma.

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

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

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

Thus. Insomnia Pregnant & breast feeding women should not use atovaquone.fever. highly protein. t½ =2-3d. erratic absorption. results from a single point mutation in the gene for cytochrome b. rash. .Resistance to atovaquone is rapid . vomiting. yet ↑ by fatty food. eliminated unchanged in feces. & Diarrhoea. Nausea.bound. ADR:. slow. it should be used in combination with Proguanil Low bioavailability.

Same MOA Inhibits haem polymerase. .Strong blood schizontocide active against P.falciparum.vivax & P. but does not affect hepatic forms of the parasite. Resistance has occurred in southeast Asia.

insomnia. extensive distribution t½= 30 day  enterohepatic recycling or tissue storage. ADR:-GIT disturbances. leukocytosis. Contra-indicated in pregnant women. . dysphoria. (contraindicated in CNS disease) May provoke neuropsychiatric disorder.Given orally . Gidiness=dizziness. thrombocytopenia. slow onset of action.well absorbed. vertigo. high protein bound. confusion. Most common side effects are: transient CNS toxicity.

.Blood schizontocide. elimination in feces. t½=11-12day Absorption  with meals. Absorbed orally slowly . active against strains resistant to chloroquine. pyrimethamine. quinine. to monitor their ECG Cross-resistance in falicparum infection occurred . Only in hospitalized pateint.

headache. transient in hepatic enzymes. In pregnancy → embriotoxic in animals . Patients with cardiac conduction defects. pruritus. lengthening of QT interval.ADR:-abdominal pain. Reserved for infection caused by resistant organisms. cough. May cause hemolytic anemia & convulsions. Contraindications: with mefloquine.

Type 1 antifolates sulphonamides & sulphones . Type 2 . .pyrimethamine & proguanil inhibition of dihydrofolate reductase. compete with PABA.

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

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

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

resistance rare. . Has gametocidal action against all species. Combined with chloroquine. mechanism unknown.The only drug which is active against liver hypnozoites.ovale & P. most effective for preventing transmission of the disease. MOA: produces radical cure for parasites which have dormant stage in the liver [P.vivax].

rapidly metabolized to etaquine & tafenoquine which are more active and more oxidizing & 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 .Given orally.

GIT disturbances. metabolites have greater hemolytic activity Contraindications: •History of methemoglobinemia •Pregnancy . in large doses  methemoglobinemia with cyanosis Causes hemolysis in G-6-P – dehdrogenase deficiency.ADR:.

Artemesia annua .Derived from the Chinese herb qinghaosu (Artemisia) Artemisinin is poorly soluble in water & a fast acting blood schizontocide. including chloroquine –resistant & cerebral malaria. Effective in treating severe acute attacks.

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

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

Clindamycin has proved effective in the treatment of uncomplicated falicparum malaria.Doxycycline : active against ertythrocytic schizonts of all species is used as a suppressive prophylactic in areas where mefloquine resistance is common. may be used in combination with quinine. .

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. and their use is usually restricted to short-term visitors and travelers to malarial regions. .Use of prophylactic drugs is seldom practical for full-time residents of malaria-endemic areas (This is due to the cost of purchasing the drugs + their side effects ).

and the combination of atovaquone and proguanil (only needs be started 2 days prior and continued for 7 days afterwards).doxycycline. .Include mefloquine .

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

5.1. preferably containing artemisinins [ACTs -artemisinin-based combination therapies]. 3. 2. 4. WHO recommends the following therapeutic options:Artemether/lumefantrine Artesunate+amodiaquine Artesunate+SP Artesunate+ mefloquine [area with low to moderate transmission. Amodiaquine+SP . WHO recommends that all countries experiencing resistance to conventional monotherapies should use combination therapy.