Objectives and Use of Antimalarials

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Chapter: Essential pharmacology : Antimalarial Drugs

The aims of using drugs in relation to malarial infection are:


OBJECTIVES AND USE OF ANTIMALARIALS

 

The aims of using drugs in relation to malarial infection are:

 

·          To prevent and treat clinical attack of malaria.

·          To completely eradicate the parasite from the patient’s body.

·  To reduce the human reservoir of infection cut down transmission to mosquito.

 


 

 

These are achieved by attacking the parasite at its various stages of life cycle in the human host (see Fig. 59.1). Antimalarials that act on erythrocytic schizogony are called erythrocytic schizontocides, those that act on preerythrocytic as well as exoerythrocytic (P. vivax) stages in liver are called tissue schizontocides, while those which kill gametocytes in blood are called gametocides. Antimalarial drugs exhibit considerable stage selectivity of action (see Table 59.1). Antimalarial therapy is given in the following forms.

 


 

1. Causal Prophylaxis

 

The preerythrocytic phase (in liver), which is the cause of malarial infection and clinical attacks, is the target for this purpose.

 

Proguanil is a causal prophylactic, primarily for P. falciparum, but is not employed routinely because it has to be given daily and is not very effective against P. vivax.

 

Primaquine is a causal prophylactic for all species of malaria, but has not been used in mass programmes, because of its toxic potential. Trials in Kenya and Irian Jaya have successfully used primaquine 0.5 mg/kg daily against both P. falciparum and P. vivax in subjects with normal G6PD levels. The CDC (USA) recommends it only for subjects who cannot take any other prophylactic drug.

 

2. Suppressive Prophylaxis

 

The schizontocides which suppress the erythrocytic phase and thus attacks of malarial fever can be used as prophylactics. Though the exoerythrocytic phase in case of vivax and other relapsing malarias continues, clinical disease does not appear.

 

Chloroquine 300 mg (base*) or 5 mg/kg weekly. In travellers, start one week before with a loading dose of 10 mg/kg and continue till one month after return from endemic area. The last dose should be 25 mg/kg over 3 days along with primaquine 15 mg/day for 14 days. It should not be given for > 3 yr for fear of cumulative toxicity.

 

Proguanil 200 mg daily with chloroquine 300 mg weekly affords substantial protection against moderately chloroquine-resistant P. falciparum, but less than that afforded by mefloquine. This has been successfully used in Africa. In India NVBDCP recommends it for visitors to areas with chloroquine resistance.

 

Mefloquine 250 mg weekly till 4 weeks after return from endemic area has been used for areas where chloroquine-resistant P. falciparum is prevalent. In India use of mefloquine for prophylaxis is not allowed among residents, but may be used by travellers.

 

Doxycycline 100 mg daily starting day before travel and taken till 4 weeks after return from endemic area for chloroquine resistant P. falciparum, is an alternative regimen for individuals unable to take mefloquine. It is contraindicated in pregnant women and children < 8 yr.

 

Chemoprophylaxis of malaria should be limited to short-term use in special risk groups, such as — nonimmune travellers, nonimmune persons living in endemic areas for fixed periods (army units, labour forces) and pregnant women (falciparum malaria has serious consequences in the pregnant). Start prophylaxis after 1st trimester and continue till 1 month after delivery.

 

3. Clinical Cure

 

The erythrocytic schizontocides are used to terminate an episode of malarial fever. The available drugs can be divided into:

 

Fast-Acting High-Efficacy Drugs: Chloroquine, amodiaquine, quinine, mefloquine, halofantrine, lumefantrine, atovaquone, artemisinin; they can be used singly to treat attacks of malarial fever.

Slow-Acting Low-Efficacy Drugs: Proguanil, pyrimethamine, sulfonamides, tetracyclines; they are used only in combination for clinical cure.

 

The faster acting drugs are preferred, particularly in falciparum malaria where delay in treatment may result in death even if the parasites are cleared from blood by the drug. The exoerythrocytic phase of vivax and ovale persists which can cause relapses subsequently without reinfection. Thus, the above drugs are radical curatives for falciparum, but not for relapsing malaria. Recrudescences occur in falciparum infection if the blood is not totally cleared of the parasites by the drug.

 

The drugs and regimens used for uncomplicated falciparum and vivax malaria are detailed in the box. Only oral drugs are used for uncomplicated malaria.

 

Treatment Of Uncomplicated Malaria

 

Vivax malaria

 

1. Chloroquine 600 mg (10 mg/kg) followed by 300 mg (5 mg/kg) after 8 hours and then for next 2 days (total 25 mg/kg over 3 days) + Primaquine 15 mg (0.25 mg/kg) daily × 14 days

 

In occasional case of chloroquine resistance

2. Quinine 600 mg (10 mg/kg) 8 hourly × 7 days + Doxycycline 100 mg daily × 7 days + Primaquine (as above)

 

Chloroquine-sensitive Falciparum malaria

 

1.  Chloroquine       (as           above) + Primaquine 45 mg (0.75 mg/kg) single dose (as gametocidal)

 

In case of intolerance to chloroquine

2. Sulfadoxine 1500 mg (25 mg/kg) + Pyrimethamine 75 mg (1.25 mg/kg) single dose + Primaquine 0.75 mg/kg single dose

 

Chloroquine-Resistant Falciparum malaria

 

1.* Artesunate 100 mg BD (4 mg/kg/day) × 3 days + Sulfadoxine# 1500 mg (25 mg/kg) + Pyrimethamine 75 mg (1.25 mg/kg) single dose

 

or

 

2.  Artesunate 100 mg BD (4 mg/kg/day) × 3 days + Mefloquine# 750 mg (15 mg/kg) on 2nd day and 500 mg (10 mg/kg) on 3rd day.

 

or

 

Artemether 80 mg + Lumefantrine 480 mg twice daily × 3 days (child 25–35 kg BW ¾ dose; 15–25 kg BW ½ dose; 5–15 kg BW ¼ dose)

 

or

 

4.$ Quinine 600 mg (10 mg/kg) 8 hourly × 7 days + Doxycycline 100 mg daily × 7 days.

 

*First line ACT under NVBDCP

$Second line drug under NVBDCP

#Sulfadoxine-pyrimethamine (S/P) alone and mefloquine alone are also used, but should preferably be combined with artesunate.

 

Relapses of vivax/ovale malaria are treated in the same way as the primary attack because the parasite remains sensitive to the drug. Recrudescence in falciparum malaria indicates resistant infection: should be treated with an alternative drug as per local needs.

 

Severe And Complicated Falciparum malaria

 

This includes P. falciparum infection attended by any one or more of—hyperparasitaemia, hyperpyrexia, fluid and electrolyte imbalance, acidosis, hypoglycaemia, prostration, cardiovascular collapse, jaundice, severe anaemia, spontaneous bleeding, pulmonary edema, haemoglobinuria, black water fever, renal failure and cerebral malaria. Parenteral (i.m./i.v.) drugs have to be used; oral drugs may be substituted when the condition improves. Drugs and regimens employed are detailed below.

 

Treatment Of Severe And Complicated Falciparum Malaria*

 

Artesunate: 2.4 mg/kg i.v. or i.m., followed by 2.4 mg/kg after 12 and 24 hours, and then once daily for 7 days. Switchover to 3 day oral ACT inbetween whenever the patient can take and tolerate oral medication.

 

or

 

Artemether: 3.2 mg/kg i.m. on the 1st day, followed by 1.6 mg/kg daily for 7 days. Switchover to 3 day oral ACT inbetween whenever the patient is able to take oral medication.

 

or

 

Arteether: 3.2 mg/kg i.m. on the 1st day, followed by 1.6 mg/kg daily for the next 4 days. Switchover to 3 day oral ACT inbetween whenever the patient is able to take oral medication.

 

or

 

Quinine diHCl: 20 mg/kg (loading dose) diluted in 10 ml/kg 5% dextrose/dextrosesaline and infused i.v. over 4 hours, followed by 10 mg/kg (maintenance dose) i.v. infusion over 4 hours (in adults) or 2 hours (in children) every 8 hours, untill patient can swallow. Switchover to oral quinine 10 mg/kg 8 hourly to complete the 7 day course.

 

(Volume of fluid for i.v. infusion of quinine should be reduced in patients with volume overload/pulmonary edema).

(If possible, oral quinine should be substituted by 3 day oral ACT, or doxycycline 100 mg daily should be combined with it).

(Chloroquine HCl i.v. to be used only if none of the above is available and only in adults).

 

 

4. Radical Cure

 

Drugs which attack the exoerythrocytic stage (hypnozoites) given together with a clinical curative achieve total eradication of the parasite from the patient’s body. A radical curative is needed in relapsing malaria, while in falciparum malaria — adequate treatment of clinical attack leaves no parasite in the body (there is no secondary exoerythrocytic tissue phase).

 

Drug of choice for radical cure of vivax and ovale malaria is:

Primaquine 15 mg daily for 14 days. A shorter course of 5 days used earlier by NAMP in India has been found inadequate, and is no longer recommended. This treatment should be given concurrently with or immediately after chloroquine/other schizontocide only to individuals who test negative for G6PD deficiency.

 

There is no point in antirelapse treatment in highly endemic areas, because chances of reinfection would be high; a subsequent attack may be erroneously labelled as failure of radical cure. Antirelapse treatment of vivax malaria should be restricted to:

 

·        Areas with very low level of transmission (where only sporadic cases occur).

·          Patients treated during an epidemic along with effective vector control measures to cut down transmission.

 

5. Gametocidal

 

This refers to elimination of the male and female gametes of Plasmodia formed in the patient’s blood. Gametocidal action is of no benefit to the patient being treated, but will reduce the transmission to mosquito.

 

Primaquine and artemisinins are gametocidal to all species of Plasmodia, while chloroquine and quinine are active against vivax but not falciparum gametes. Gametes exposesd to proguanil or pyrimethamine fail to carry on the life cyle normally in the mosquito. Adequate control of clinical attacks will reduce formation of gametes.

 

A single 45 mg (0.75 mg/kg) dose of primaquine is employed immediately after clinical cure of falciparum malaria to kill the gametes and cut down transmission to mosquito. This is not necessary when an artemisinin is used for clinical cure.

 

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