MALARIA

MALARIA:  A TREATABLE AND PREVENTABLE DISEASE
Malaria is caused by the infection of the red blood cells by the protozoan parasite of the genus

PLASMODIUM. The four species of Plasmodium include P.falciparum, P.ovale, P.vivax, and P.malariae. The parasite is inoculated into the host human by a feeding female anopheles mosquito and transmitted from person to person by the bite of an infected female anopheles mosquito.

THE MALARIA SCOURGE:

• 350-500 million cases of malaria is reported every year worldwide.
• 40% of world’s population is at risk. Malaria affects 5 times as many people as HIV/AIDS, Tuberculosis, measles, leprosy, road traffic accident combined.
• 1 million deaths annually.
• 90% of this occurs in Africa. A person dies of malaria every 10 seconds.
• Pregnant women and children under five years are more at risk.
• In Nigeria
• Malaria is endemic
• Over 90% of the population is at risk.50% of the population will have at least one attack per year.
• 300,000 children dies of malaria every year. A child dies of malaria every 30 seconds.
• 48% prevalence among pregnant women. Malaria is responsible for 11% of maternal deaths.
• Malaria accounts for 30-50% of in-patient admissions in Nigeria.
• 50% of out-patients visits in areas of high malaria transmission like Nigeria.
• Nigeria losses $4-6 billion yearly to malaria.
• Malaria accounts for 10% of Africa’s disease burden and 40% of public health expenditures.
• The economic cost to Africa is about $12 billion yearly which is not inclusive of the emotional cost of pain and suffering.

RISK POPULATION:

• Pregnant women.
• Children under 5 years of age.
• HIV infected persons.
• Sickle cell patients.
• Immigrants from non endemic areas.

CLASSIFICATION OF MALARIA ILLNESS:

• UNCOMPLICATED MALARIA:

The patient presents with several non specific symptoms such as

• Headache
• Fatigue
• Abdominal discomfort
• Fever
• Shivering or Chills
• Muscle and joint pains
• Loss of appetite.
• SEVERE (CEREBRAL ) MALARIA:

The patient presents with several life threatening conditions such as

• Impaired consciousness
• Acute respiratory distress syndrome.
• Acute renal failure
• Circulatory collapse
• Hemoglobinuria(blood in the urine)
• High fever
• Jaundice
• Multiple convulsions.
• Prostration (inability to sit or stand).
• Hypoglycemia (fall in blood sugar levels that can be dangerous to health).
• Hyperparastemia(high density of parasite in the blood)

DIAGNOSIS:

Prompt and accurate diagnosis is very important. The diagnosis of malaria is based on clinical criteria (clinical diagnosis) supplemented by the detection of parasites in the blood (parasitological or confirmatory diagnosis).

• Clinical diagnosis:

The most important element in the clinical diagnosis of malaria, in both endemic and non-endemic areas, is to have a high index of suspicion.
Malaria is mostly diagnosed on the symptoms of fever or history of fever, headache, aches and pain elsewhere in the body, and occasionally abdominal pain and diarrhea may be present. In a young child there may be irritability, refusal to eat and vomiting. In some patients the spleen and liver are palpable.

• Parasitological diagnosis:

This involves the use of light microscopy and rapid diagnostic test (RDT) to examine the presence of the parasite in the thick and thin film of the peripheral blood. The greater the parasite density in the peripheral blood, the greater the likelihood that severe disease is present or will develop.
The light microscopy method has the advantage of low cost, high sensitivity and specificity when carried out by well trained personnel.

MANAGEMENT/TREATMENT APPROACH

This involves guidelines from the Federal Ministry of Health and World Health Organization (FMOH/WHO).

• Use of Insecticide Treated Nets (ITN).
• Use of IPT (intermittent preventive treatment for pregnant women. This involves the administration of Sulphadoxine-Pyrimethamine (SP).
• Use of ACT (antimalarials containing Artemisinin or its derivatives in combination with other antimalarials therapy) as first line drugs for malaria treatment due to multi drug resistance to Chloroquine and related therapy.

ISSUES IN MALARIA THERAPY

• Drug resistance to chloroquine and Sulphadoxine-Pyrimethamine.
• Self treatment
• Misdiagnosis
• Confusion of malaria fever with typhoid fever.

RATIONAL PHARMACOTHERAPY-Choosing the right antimalarial.
Utmost consideration should be on the following benefits

• Therapeutic efficacy of the therapy.
• Clinical safety in diverse age and risk group( children and pregnant women)
• Potential for use in all healthcare settings.
• Potential  for patient compliance
• Delay in parasite resistance
• Cost effectiveness
• Availability of product.

An Ideal antimalaria should therefore,

• Have a fast onset of action.
• Have high tissue penetrability
• Have potent schizonticidal action
• Have high safety profile

NEW ADVANCES IN MALARIA THERAPY

 ACT (Artemisinin Combination Therapy).
Artemisinin (Qinghaosu) is the active principal of the Chinese medicinal herb Artemisia annua .
Artemisinin and its derivatives (Artesunate, Arteether, and Artemether) produce rapid clearance of parasitemia and rapid resolution of symptoms. They reduce parasite number by a factor approximately 10,000 in each asexual cycle, which is more than any other antimalarials (others reduce by 100- 1,000 folds per cycle).They are effective against multi drug resistant P.falciparum malaria.
They are rapidly eliminated from the system hence minimal side effects.
The only significant adverse effect is hypersensitivity reactions which may manifest as urticaria.
These drugs also have the advantage from a public health perspective of reducing gametocyte carriage and thus the transmissibility of malaria. This contributes to malaria control in areas of low endemicity.

ARTEMISININ DERIVATIVES

• ARTEMETHER

This is an oil soluble methyl ether derivative of dihydroartemisinin. It is available for oral and parenteral use as oil based injection. Indicated for treating uncomplicated and severe malaria. 

• ARTEETHER

This is an oil soluble ethyl ether derivative of dihydroartemisinin. Available as oil based injection. Indicated in the treatment of uncomplicated and severe P.falciparum malaria.

• ARTESUNATE  (REKMAL INJECTION)

Artesunate is available for oral and parenteral use as water soluble injection (REKMAL INJECTION). It is used in the treatment of P.falciparum malaria in combination with another effective blood schizonticide to prevent recrudescence and delay the selection of resistant strains.
The use of Artesunate monotherapy should be limited to specific indications, such as in patients with history of adverse reaction to the combination drug. When monotherapy is used, a 7 days course of therapy is recommended and efforts should be made to ensure adherence.

REKMAL INJECTION (ARTESUNATE 60MG)
Artemisinin derivative containing Artesunate 60mg. it is a water soluble derivative. It is indicated in the treatment of severe and uncomplicated P.falciparum malaria.

• Clinical Effectiveness
•  More convenient to administer intra muscular(IM) &intra venous( IV) ‏
• Artesunate has more reliable pharmacokinetics characteristics, hence absorption is not limited in severe malaria, unlike fat soluble Artemether (7) ‏
• Tolerance
• No local pain or abscess, unlike quinine or oil soluble Artemisinin (8) ‏
• WHO recommends Artesunate or quinine during 1st trimester, but Artesunate as first line therapy during 2nd & 3rd trimester (5)

ARTESUNATE VS ARTEMETHER/ARTEETHER

• Neurotoxicity, IM Artemether is associated with more convulsion and prolonged coma than IM quinine (9).
• Due to the oil base of IM Arteether and Artemether there is pain at the site of injection, unlike Artesunate which is water based.

SUPERIORITY OVER QUININE

• Reduces parasitemia ten times faster than quinine (1,2) ‏
• Significant mortality reduction by 34.7% (3) ‏
• Better coma recovery time (4) ‏
• No change of dosage due to hepatic, renal failure or concomitant or previous medication with mefloquine, quinine or primaquine (5) ‏
• Cardiac monitoring is not mandatory during treatment with Artesunate (6) ‏

INDICATION
In the treatment of uncomplicated and severe P.falciparum malaria and Artesunate IV is also needed in high level of malaria parasites in the blood and inability to take oral medications.

CONTRAINDICATION
In patients that are hypersensitive to Artesunate or Artemisinin derivatives.

ADVERSE EFFECT
No reports of any serious adverse reaction.

DOSAGE
For severe malaria: I.M: 2.4mg/kg by the intramuscular route followed by 1.2mg/kg at 12 and 24hours then 1.2mg/kg daily for 6 days. If the patients can swallow, recommended oral antimalaria can be given.
I.V: 2.4mg/kg intravenous on the first day followed by 1.2mg/kg daily until the patient can take orally recommended antimalaria drugs. The speed for I.V. injection is 3-4ml per minute.

PARENTERAL ADMINISTRATION

• Step. 1: The powder for injection should be reconstituted with 1ml of 5% sodium bicarbonate and shaken vigorously till the solution becomes clear.
• Step 2: For I.V. use. Add 5 ml of normal saline.

            For I.M.use. Add 2 ml of normal saline

• Step 3: For I.V. use, the required amount of the drug is administered slowly over a period of 3 - 4 minutes.

With REKMAL injection. (ARTESUNATE 60mg)

• No danger of CNS neuropathic change/toxicity like oil-soluble Artemisinin derivatives.
• No pain at site of injection.
• Administered IM or IV enhanced compliance and convenience to prescriber and patient.
• Faster acting with reliable pharmacokinetic unlike Artemether and Arteether.
• Predictable and reliable absorption from IM depot and rapid hydrolysis to lipophilic DHA unlike oil-soluble derivatives which are erratically absorbed and with little conversion to DHA.
• In cerebral malaria, speed is key; hence REKMAL is the choice agent.
• REKMAL is safe and preferred in pregnancy.

IN SEVERE MALARIA, think EFFICACY, think SPEED, think SAFETY.
THINK REKMAL!!!!!!

PRESENTATION
A single dose vial pack contains 1ml ampoule of sodium bicarbonate injection and 5ml ampoule sodium chloride (normal saline) injection.

References:

• Clinical behaviour and socioeconomic factors related to sever malaria. A multicentre study in the Africa region. WHO – Regional office for Africa 2002.
• Manning L et al. Rectal administration of Artemisinin derivatives for the treatment of malaria. JAMA 2007; 297:2381-2390
• Lancet 2005; 366:717-725
• Win K et al. Comparisons of Parenteral Artemisinin derivatives plus oral mefloquine with intravenous quinine plus oral tetracycline for treating cerebral malaria. Bulletin World Health Organisation 1992; 70(6):777-82.
• Philip JR. Artesunate for the treatment of severe falciparum malaria. Clinical Therapeutics, vol 358: 1829-1836 April 24, 2008 Number 17.
• Am J Respir Crit Care Med 2003; 167:684-689.
• Hien TT, et al. Comparative pharmacokinetics of intramuscular Artesunate and Artemether in patients with severe falciparum malaria. Antimicrobial agents chemotherapy 2004; 48:4234-4239.
• Danis M, et al. Result obtained with IM Artemether vs. IV quinine in the treatment of severe malaria in a multi-centre study in Africa, Jpn J Trop Med Hyg 1996; 24(suppl 1): 93-6.
• Thomas G, et al. Fatal neurotoxicity of Arteether and Artemether. Am J Trop Med Hyg. 51(3), 1994, pp. 251-259.