Chemotherapy of Malarial infections

·        Life cycle of malaria parasite.

·        Chemotherapy of acute attack.

·        Chemoprophylaxis.

Malarial Infection

1.    The incubation period of malaria is 10 – 35 days.

2.       Female anopheles mosquitos require a blood meal for egg production and in the process of feeding they inject salivary fluid containing sporozoites into humans.

3.       Since no drugs are effective against sporozoites, infection with the malaria parasite cannot be prevented.

Hepatic cycle

1.       Sporozoites enter liver cells where they develop into schizonts which form large numbers of merozoites which, usually after 15 – 16 days but sometimes after months or years, are released into the circulation.

2.       Plasmodium falciparum differs in that it has no persistent hepatic cycle.

3.       Drugs the eradicate hepatic schizonts (tissue schizontocides):

a.       Primaquine.

b.       Proguanil.

c.       Tetracycline.

4.    They are used for:

a.       Radical cure.

b.       Causal prophylaxis: preventing the initial hepatic cycle.

Erythrocyte cycle

1.       Merozoites enter red cells where they develop into schizonts.

2.       These schizonts form more merozoites which are released when the cells burst giving rise to the features of the clinical attack.

3.       Drugs that kill merozoites (blood schizontocides):

a.       Chloroquine.

b.       Quinine:

c.       Mefloquine.

d.       Halofantrine.

e.       Proguanil.

f.       Pyrimethamine.

g.       Tetracyclines.

4.    They are used for:

a.       Treatment of acute attacks of malaria.

b.       Suppressive prophylaxis: prevention of attacks by early destruction of the erythrocytic forms.

Sexual forms

1.       Some merozoites differentiate into male and female gametocytes in the erythrocytes and can develop only if they are ingested by a mosquito where they form sporozoites.

2.       Drugs that act on sexual forms:

a.       Quinine.

b.       Mefloquine.

c.       Chloroquine.

d.       Artesunate.

e.       Artemether.

f.       Primaquine.

Chemotherapy of acute attack of Malaria

1.       Principles of Therapy:

a.       Diagnosis should be confirmed before treatment by examination of blood smears.

b.       When the infecting organism is not known or infection is mixed, treatment should begin as for Plasmodium falciparum.

c.       Drugs used to treat Plasmodium falciparum must always be selected with regard to the prevalence of local patterns of drug resistance.

d.       Patients not at risk of reinfection should be re-examined several weeks later after treatment for signs of recrudescence.

2.       Falciparum malaria:

a.    A quinine salt 600mg x 8h by mouth for 7 days followed by pyrimethamine + sulfadoxine (Fansidar) 3 tablets as a single dose. (tetracycline is substituted for Fansidar in cases of resistance).

b.       Mefloquine 20mg/kg by mouth may be given as 2 divided doses 6-8h apart.

c.       Halofantrine 1.5g given as 3 doses of 500mg 6h apart on an empty stomach.

3.       Benign malaria:

a.       These are usually due to Plasmodium vivax or less commonly to Plasmodium ovale or Plasmodium malariae.

b.    The drug of choice is chloroquine which should be given by mouth.

c.    For Plasmodium vivax and Plasmodium ovale, eradication of the hepatic parasites is necessary to prevent relapse by giving primaquine.

Chemoprophylaxis of Malaria

1.       Chemoprophylaxis is part of a broader regiment; travellers should protect against bites by using mosquito nets and repellents.

2.       Drugs used for Chemoprophylaxis:

a.       Mefloquine.

b.       Chloroquine.

c.       Proguanil.

d.       Pyrimethamine + dapsone (Maloprim).

e.       Doxycycline.

3.       Effective chemoprophylaxis requires that there is a plasmodicidal concentration of drug in the blood when the first mosquito bites.

4.       Examples of standard regimens:

a.       Chloroquine 300mg once weekly (start one week before travel).

b.       Proguanil 200mg once weekly (start 2-3 days before travel).

c.       Mefloquine 250mg once weekly (start one week before travel).

5.    If the subjects are on antiepileptic or cardiovascular drugs, it is desirable to start prophylaxis 2 – 3 weems in advance to establish safety.

6.       Prophylaxis should continue for at least 4 weeks after leaving an endemic area to kill parasites that are acquired about the time of departure.

Summary of Drugs

Chloroquine

1.       Mechanism of action:

a.       Concentrated within parasitised red cells and form complexes with plasmodial DNA.

b.       Active against the blood forms and also the gametocytes.

c.       Ineffective against many strains of Plasmodium falciparum and also its immature gametocytes.

2.       Pharmacokinetics:

a.    Half-life: 50 days.

b.       Readily absorbed from GI tract.

c.       Concentrated in several tissues, e.g. erythrocytes, liver, spleen, heart, kidney, cornea and retina.

d.    A priming dose is required in order to achieve adequate free plasma concentration.

e.       Partly inactivated by metabolism and the remainder is excreted unchanged in the urine.

3.       Adverse effects:

a.       Corneal deposits: photophobia.

b.       Retinal toxicity: irreversible, visual field defects, scotomas, defective color vision and visual acuity.

c.       Pruritus.

d.       Headaches.

e.    GI disturbances.

f.       Precipitation of acute intermittent porphyria in susceptible individuals.

g.       Quinine-like action: cardiac dysrhythmias.

4.       Acute overdose:

a.       Rapidly fatal without treatment.

b.       Pulmonary edema is followed by convulsions, cardiac dysrhythmias. and coma.

c.       Treatment: diazepam + adrenaline.

Halofantrine

1.       Pharmacokinetics:

a.    Half-life: 1 – 4h.

b.       Absorption from GI tract is variable and incomplete.

c.       Metabolized to an active metabolite and no unchanged drug is recovered in the urine.

2.       Spectrum of activity:

a.       Erythrocytic forms of all four Plasmodium species.

b.       Schizont stage.

3.       Clinical use:

a.       Treatment of uncomplicated Plasmodium falciparum and Plasmodium vivax malaria.

b.       Should not be given for prophylaxis.

4.       Adverse effects:

a.    GI symptoms.

b.       Pruritus.

c.       Prolongs QT interval: cardiac dysrhythmias.

5.    The drug should not be taken with:

a.       Food.

b.       Other dysrhythmics: TCAs, antipsychotics.

c.       Patients with cardiac disease.

Mefloquine

1.       Pharmacokinetics:

a.    Half-life: 21 days

b.       Rapidly absorbed from GI tract.

c.       Action terminated by metabolism.

d.       Should not be given to patients with hepatic or renal impairment.

2.       Clinical use:

a.       Malaria chemoprophylaxis.

b.       Treat uncomplicated Plasmodium falciparum.

c.       Chloroquine-resistant Plasmodium vivax.

3.       Adverse effects:

a.       Nausea.

b.       Dizziness.

c.       Vertigo.

d.       Vomiting, diarrhoea and abdominal pain.

e.    Loss of appetite.

4.       Mefloquine should be avoided in patients taking beta-adrenoceptor and calcium channel blockers for it causes sinus bradycardia.

5.    Use of mefloquine is contraindicated in those whose activities require the find coordination of spatial performance.

Primaquine

1.       Pharmacokinetics:

a.    Half-life: 6h.

b.    Well absorbed from GI tract.

c.       Moderately concentrated in tissues.

d.       Rapidly metabolized.

2.    Acts at several stages in the development of the plasmodial parasite by interfering with its mitochondrial function.

3.    Used clinically to eliminate hepatic forms of Plasmodium vivax and ovale.

4.       Adverse effects:

a.       Anorexia.

b.       Nausea.

c.       Abdominal cramps.

d.       Methaemoglobinaemia.

d.       Hemolytic anaemia esp. in G6PD.

Proguanil

1.       Pharmacokinetics:

a.    Half-life: 17h.

b.    Well absorbed from gut.

c.       Excreted in urine as unchanged forms and metabolites.

d.       Stored little in tissues.

2.       Inhibits dihydrofolate reductase which converts folic to folinic acid, deficiency of which inhibits plasmodial cell division.

Pyrimethamine

1.       Pharmacokinetics:

a.    Half-life: 4 days.

b.    Well absorbed from gut.

c.       Extensively metabolized.

2.       Inhibits plasmodial dihydrofolate reductase.

3.       Seldom used alone.

4.       Pregnant women should receive supplementary folic acid when taking pyrimethamine.

5.       Adverse effects:

a.       Anorexia.

b.       Abdominal cramps.

c.       Ataxia.

d.       Tremor.

e.       Seizures.

f.       Megaloblastic anaemia.

6.       Fansidar:

a.    Acts synergistically with sulfadoxine (as Fansidar) to inhibit folic acid metabolism.

b.       Chiefly used with quinine to treat acute attacks of malaria caused by Plasmodium falciparum.

Quinine

1.       Pharmacokinetics:

a.    Half-life: 9 – 18.

b.    Well absorbed from gut.

c.       Almost completely metabolized in the liver.

2.       Binds to plasmodial DNA to prevent protein synthesis.

3.    Used to treat Plasmodium malaria in areas of multi-drug resistance.

4.       Adverse effects:

a.       Cinchonism: headache, tinnitus, vertigo, blurred vision.

b.       Pruritus, rashes and urticaria.

c.       Quinidine-like effects: hypotension and cardiac arrest.

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