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Friday, May 15, 2009

MALARIA – A REVIEW


MALARIA – A REVIEW
V. NishadHH, Teena Tom
National College of Pharmacy, Manassery, Calicut

Cite this: V. Nishad, Teena Tom "MALARIA – A REVIEW", B. Pharm Projects and Review Articles, Vol. 1, pp. 950-991, 2006. (http://farmacists.blogspot.in/)



INTRODUCTION
    Malaria is a potentially fatal tropical disease that is caused by a parasite known as Plasmodium. It is spread through the bite of an infected female mosquito.
    The infected person may have feverish attacks, influenza-like symptoms, tiredness, diarrhoea or a whole range of other symptoms. Malaria should always be suspected if these symptoms occur within the first year of return from an infected area; a test should be carried out to exclude the possibility of malaria as soon as possible3.
Epidemiology
    Malaria affects more than 2400 million people, over 40% of the world's population. Every year 300 million to 500 million people suffer from this disease . WHO forecasts a 16% growth in malaria cases annually22. About 1.5 million to 3 million people die of malaria every year (85% of these occur in Africa), accounting for about 4-5% of all fatalities in the world. One child dies of malaria somewhere in Africa every 20 sec., and there is one malarial death every 12 sec somewhere in the world. Malaria kills in 1 year what AIDS killed in 15 years6. Malaria ranks third among the major infectious diseases in causing deaths- after pneumococcal acute respiratory infections and tuberculosis. It is expected that by the turn of the century malaria would be the number one infectious killer disease in the world7.
Aetiology
    Malaria is an infectious disease caused by the parasite called Plasmodia. There are four identified species of this parasite causing human malaria, namely, Plasmodium vivax, P. falciparum, P. ovale and P. malariae. It is transmitted by the female anopheles mosquito. It is a disease that can be treated in just 48 hours, yet it can cause fatal complications if the diagnosis and treatment are delayed. It is re-emerging as the # 1 Infectious Killer and it is the Number 1 Priority Tropical Disease of the World Health Organization11.

 

 
PATHOPHYSIOLOGY
Pathophysiology of malaria can be explained with the help of life cycle of plasmodium1.

 

 
Life Cycle Of Plasmodium21

 

 

 

Tissue schizogony (Pre- erythrocytic schizogony):

    This phase starts with the inoculation of the parasite into the human blood by the bite of a female anopheles mosquito. Within half an hour, the sporozoites reach the liver and invade the liver cells.  The mechanism of targeting and invading the hepatocytes with this rapidity is not yet clear1.
    Within the liver cells, the trophozoites start their intracellular asexual division.  At the completion of this phase, thousands of extra erythrocytic merozoites are released from each liver cell. The time taken for the completion of the tissue phase is variable, depending on the infecting species; (8 - 25 days for P. falciparum, 8 - 27 days for P. vivax, 9 - 17 days for P. ovale, 15 - 30 days for P. malariae) and this interval is called as pre-patent period8.
    In case of P. vivax and P. ovale, some sporozoites may go into hibernation - the cryptobiotic phase- in which they are called as hypnozoites. They can lie dormant for months or years and on reactivation they cause clinical relapse.
Erythrocytic schizogony:

    The merozoites released from the liver cells attach onto the red blood cell membrane and by a process of invagination, enter the red cell. Within the red blood cell, the asexual division starts and the parasites develop through the stages of rings, trophozoites, early schizonts and mature schizonts; each mature schizont consisting of thousands of erythrocytic merozoites.  These merozoites are released by the lysis of the red blood cell and they immediately invade uninfected red cells. This repetitive cycle of invasion - multiplication - release - invasion continues.  The intra erythrocytic cycle takes about 48 hours in P. vivax, P. ovale and P. falciparum infections and 72 hours in case of P. malariae infection. It occurs synchronously and the merozoites are released at approximately the same time of the day. The contents of the infected cell that are released with the lysis of the RBC stimulate Tumor Necrosis Factor and other cytokines, which results in the characteristic clinical manifestations of the disease5.
    A small proportion of the merozoites in the red blood cells undergo transformation into gametocytes - male and female. Mature gametocytes appear in the peripheral blood after a variable period and enter the mosquito when it bites an infected individual. (Appear on the 5th day of primary attack in P. vivax and P. ovale, and thereafter become more numerous; appear at about 5 - 23 days after primary attack in P. malariae; appear after 8 - 11 days of the primary attack in P. falciparum, rising in number
until 3 weeks and falling thereafter, but may circulate for several
weeks)10.
Sporogony:

    The gametocytes continue their development in the mosquito. The male and female gametes fuse and form into a zygote. This transforms into an ookinete which penetrates the gut wall and becomes an oocyst. The oocyst divides asexually into numerous sporozoites which reach the salivary gland of the mosquito. On biting a man, these sporozoites are inoculated into human blood stream. The sporogony in the mosquito takes about 10 - 20 days and thereafter the mosquito remains infective for 1 - 2 months.
Differentiation of Malarial Parasites21
P. falciparum
P. vivax
P. malariae
P. ovale
RBC Size
Not enlarged 
Enlarged 
Not enlarged 
Enlarged 
RBC Shape
Round, sometimes crenated 
Round or oval, frequently bizarre 
Round 
Round or oval, often fimbriated 
RBC Colour
Normal, but may become darker; may have a purple rim
Normal to pale 
Normal 
Normal 
StiplingMaurer's spots, appear as large red spots, loops and clefts; up to 20 or fewer. 
Schuffner's dots, appear as small red dots, numerous. 
Ziemann's dots, few tiny dots, rarely detected 
Schuffner's dots (James's dots). Numerous small red dots.
Pigment
Black or dark brown; in asexual forms as one or two masses; in gametocytes as about 12 rods 
Seen as a haze of fine golden brown granules scattered through the cytoplasm 
Black or brown coarse granules; scattered 
Intermediate between P. vivax and P. malariae
Early trophozoite (ring)
Smallest, delicate; sometimes two chromatin dots; multiple rings commonly found
Relatively large; one chromatin dot, sometimes two; often two rings in one cell
Compact; one chromatin dot; single
Compact; one chromatin dot; single
Schizont
Medium size; compact; numerous chromatin masses; coarse pigments; rarely seen in peripheral blood
Large; amoeboid; numerous chromatin masses; fine pigments
Small; compact; few chromatin masses; coarse pigments
Medium size; compact; few chromatin masses; coarse pigments
Gametocyte
Crescent shaped, larger and slender; central chromatin
Spherical; compact
Similar to P. vivax, but smaller and less numerous
Like P. vivax, but smaller
  

PATHOLOGY OF MALARIA
    The most pronounced changes related to malaria involve the blood and the blood-forming system, the spleen and the liver. Secondary changes can occur in all the other major organs, depending on the type and severity of the infection. The pathological changes are more profound and severe in case of P. falciparum malaria5.
Changes in the blood

Red blood cells: Red blood cells are the principal sites of infection in malaria. All the clinical manifestations are primarily due to the involvement of red blood cells.
    The growing parasite consumes and degrades the intracellular proteins, mainly hemoglobin. The transport properties of the red cell membrane are altered, cryptic surface antigens are exposed and new parasite derived proteins are inserted. The red cell becomes more spherical and less deformable. In P. falciparum infection, membrane protuberances appear on the red cell surface in the second 24-hour of the asexual cycle. Accretions of electron-dense, histidine-rich parasite proteins are found under these 'knobs'. These knobs extrude a strain specific, adhesive variant protein of high molecular weight that mediates red cell attachment to receptors on venular and capillary endothelium, causing cytoadherence. P. falciparum infected red cells also adhere to uninfected red cells to form rosettes7.
Anemia is a fairly common problem encountered in malaria and it poses special problems in pregnancy and in children. It can be due to multiple causes. Repeated hemolysis of infected red cells is the most important cause for a reduction in hemoglobin levels. Anemia depends on the degree of parasitemia, duration of the acute illness and the number of febrile paroxysms. It may occur even after 3-5 febrile paroxysms. P. vivax predominantly invades young red cells and the number of parasites infected rarely exceeds 2%. P. malariae develops mostly in mature red cells and the parasitemia is rarely greater than 1%. P. falciparum affects red cells of all ages and the parasitemia can be as high as 20-30% or more. Massive destruction of red cells accounts for rapid development of anemia in P. falciparum malaria. Immune and non-immune hemolysis of non-infected red cells, increased splenic clearance of parasitized as well as non-parasitized red cells, reduction of red cell survival even after disappearance of parasitemia, dyserythropoeisis in the bone marrow, drug induced hemolysis etc. can also contribute to the anemia. Some of these mechanisms may perpetuate anemia even after completion of the treatment9.
Thrombocytopenia is also fairly common in malaria. It has been observed that the platelet count shows a moderate decline during the paroxysms of fever. Thrombocytopenia may be related to the sequestration of the platelets in the spleen. Severe thrombocytopenia however indicates severe infection and may herald bleeding syndromes.
Bone marrow

    Bone marrow may show evidence of dyserythropoeisis, iron sequestration and erythrophagocytosis in the acute phase of falciparum malaria. Maturation defects may be present in the marrow for 3 weeks after the clearance of parasitemia. Large, abnormal looking megakaryocytes have been found in the marrow and the circulating platelets may also be enlarged, suggesting dysthrombopoeisis4.

 

Spleen

    Spleen plays an important role in the immune response against malarial infection and splenectomy invariably activates a latent infection. Enlargement of the spleen is one of the early and constant signs of malarial infection. Spleen may become palpable as early as the first paroxysm7.
Liver

    Enlargement of the liver also occurs early in malaria. The liver is enlarged after the first paroxysms, it is usually firm and may be tender. It is oedematous, coloured brown, grey or even black as a result of deposition of malaria pigment. Hepatic sinusoids are dilated and contain hypertrophied Kupffer cells and parasitized red cells. Small areas of centrilobular necrosis may be seen in severe cases and these may be due to shock or disseminated intravascular coagulation. Prolonged infection may be associated with stromal induration and diffuse proliferation of fibrous connective tissue. However, changes of cirrhosis are not seen. In falciparum malaria, in addition to the involvement of the mesenchyma, the hepatocytes may also be involved, causing functional changes as well (malarial hepatitis)8.
Lungs

    Involvement of the lungs occurs in P. falciparum malaria and is secondary to the changes in the red blood cells and the microcirculation. Acute pulmonary oedema is an infrequent but nearly fatal complication of P. falciparum malaria, largely due to capillary endothelial lesions and perivascular oedema. Fluid overload and blood transfusion may also contribute to this problem. Pulmonary capillaries and venules are packed with inflammatory cells and parasitized red cells. The vascular endothelium is oedematous with narrowing of the lumen. Interstitial oedema and hyaline-membrane formation is also seen9.

 

 
Cardiovascular system

    Malaria is commonly associated with cardiovascular function abnormalities. The most frequent changes during a paroxysm include decrease in blood pressure, tachycardia, muffled heart sounds, transient systolic murmur at the apex and occasional cardiac dilation. Also there is peripheral vasodilation, leading to postural hypotension.
Gastro-intestinal tract

    Malaria is often accompanied by nausea and vomiting, mainly central in origin. In the acute phase, patient may have anorexia, abdominal distention, and pain in the epigastrium. Some times the abdominal colics may be so severe as to mimic acute abdomen or appendicitis. Some patients may have watery diarrhoea and the condition may mimic gastro-enteritis or cholera.
Kidneys

Malaria can cause varied problems in the kidneys. During the acute attack, albuminuria may be seen commonly. Acute diffuse malarial nephritis with hypertension, albuminuria and oedema may also be seen rarely.
Central nervous system

    Central nervous system manifestations in malaria could be due to pathological involvement of the brain, paroxysms of fever or due to the side effects of antimalarial drugs.
    The febrile paroxysms are usually accompanied by head aches, vomiting, delirium, anxiety and restlessness. These are as a rule transient and disappear with normalization of the temperature.
    Antimalarial drugs like chloroquine, quinine, mefloquine and halofantrine can cause various symptoms like dizziness, vertigo, tinnitus, restlessness, hallucinations, confusion, delirium or even frank psychosis, convulsions etc. Quinine can induce hypoglycemic coma. Artemisinin derivatives are known to cause brain stem dysfunction in animal studies. These factors should always be kept in mind while managing cases of malaria.

 
CLINICAL MANIFESTATION
Typical features:

The characteristic, text-book picture of malarial illness is not commonly seen. It includes three stages viz. Cold stage, Hot stage and Sweating stage. The febrile episode starts with shaking chills, usually at mid-day between 11 a.m. to 12 noon, and this lasts from 15 minutes to 1 hour (the cold stage), followed by high grade fever, even reaching above 1060 F, which lasts 2 to 6 hours (the hot stage). This is followed by profuse sweating and the fever gradually subsides over 2-4 hours. These typical features are seen after the infection gets established for about a week. The febrile paroxysms are usually accompanied by head aches, vomiting, delirium, anxiety and resetlessness. These are as a rule transient and disappear with normalization of the temperature13.
Atypical features16:

Atypical fever
Headache:
Body ache, back ache and joint pains
Dizziness, vertigo
Altered behaviour, acute psychosis
Altered sensorium
Convulsions, coma
Cough
Breathlessness
Chest pain
Acute abdomen

 


 

DIAGNOSIS
Microscopic examination of stained blood smears    
Microscopic examination of stained blood smears obtained before antimalarial drugs have been administered and preferably collected during pyrexia, is the standard procedure for the demonstration of the parasite. In the thick drop method (concentration method) 2 to 3 drops of blood are spread in a thick film about 1 cm in diameter and dehaemoglobinised in buffered distilled water. Both thin and thick films are stained by one of the Romanowsky stains – Leishman Giemsa Wright, Field, or J.S.B. stain; all of these are combinations of polychromatic methylene blue and eosin17.
    The thick smear is used to screen the presence of parasites and the thin smear is used for species identification. It is important to identify the species, because the treatment of different species can differ. because of the severity of disease possible drug resistance or persistence of exeerythrocytic forms identification of the parasite of the species level is critical. Ring shaped trophozoites can be seen within infected red blood cells. The ring forms have red chromatin and bluish cytoplasm. The gametocytes of P. falciparum are cresent shaped whereas those of other plasmodia are spherical.
QBC tube system:
Another method which is adopted by some centres is acridine orange staining in the quantitative buffy coat (QBC) tube system, which is provided with a simple fluorescence microscope system consisting of a battery powered and a special ultraviolet lens and a battery powered centrifuge. This method is reported to be more sensitive than the Giemsa staining for detection of malarial parasites.
Although the peripheral blood smear examination that provides the most comprehensive information on a single test format has been the "gold standard" for the diagnosis of malaria, the immunochromatographic tests for the detection of malaria antigens, developed in the past decade, have opened a new and exciting avenue in malaria diagnosis. However, their role in the management and control of malaria appears to be limited at present.

 

 

Immunochromatographic Tests for Malaria Antigens

    Immunochromatographic tests are based on the capture of the parasite antigens from the peripheral blood using either monoclonal or polyclonal antibodies against the parasite antigen targets. Currently, immunochromatographic tests can target the histidine-rich protein 2 of P. falciparum, a pan-malarial Plasmodium aldolase, and the parasite specific lactate dehydrogenase. These RDTs do not require a laboratory, electricity, or any special equipment.
Histidine-rich protein 2 of P. falciparum (PfHRP2) is a water soluble protein that is produced by the asexual stages and gametocytes of P. falciparum, expressed on the red cell membrane surface, and shown to remain in the blood for at least 28 days after the initiation of antimalarial therapy. Several RDTs targeting PfHRP2 have been developed.
Plasmodium aldolase is an enzyme of the parasite glycolytic pathway expressed by the blood stages of P. falciparum as well as the non-fa1ciparum malaria parasites. Monoclonal antibodies against Plasmodium aldolase are pan-specific in their reaction and have been used in a combined 'P.f/P.v' immunochromatographic test that targets the pan malarial antigen (PMA) along with PfHRP2.
Parasite lactate dehydrogenase (pLDH) is a soluble glycolytic enzyme produced by the asexual and sexual stages of the live parasites and it is present in and released from the parasite infected erythrocytes. It has been found in all 4 human malaria species, and different isomers of pLDH for each of the 4 species exist. With pLDH as the target, a quantitative immunocapture assay, a qualitative immunochromatographic dipstick assay using monoclonal antibodies, an immunodot assay, and a dipstick assay using polyclonal antibodies have been developed.

 

TREATMENT11
Treatment of malaria depends on the following factors:
  1. Type of infection.

  1. Severity of infection.
  2. Status of the host.
  3. Associated conditions/ diseases.
Type of infection: Treatment obviously depends on the type of infection. Patients with P. falciparum malaria should be evaluated thoroughly in view of potential seriousness of the disease and possibility of resistance to anti malarial drugs. 
P. vivax: Only Chloroquine 25 mg/kg + Primaquine for 14 days.
P. falciparum: Treat depending on severity & sensitivity. Primaquine as gametocytocidal is a must to prevent spread.
Mixed infections: Blood schizonticides as for P. falciparum and Primaquine as for P. vivax.
Severity of infection:
All patients with malaria should be carefully and thoroughly assessed for complications of malaria. Acute, life-threatening complications occur only in P. falciparum malaria. Malaria is probably the only disease of its kind that can be easily treated in just 3 days, yet if the diagnosis and proper treatment are delayed, it can kill the patient very quickly and easily. 
Associated conditions/ diseases:
Treatment of malaria may have to be modified due to certain associated conditions/ diseases. Therefore, all such should be carefully assessed before starting the patient on anti malarial treatment.
  1. Pregnancy: Treatment of malaria in pregnancy may prove to be difficult due to contra indication for use of certain antimalarials. Chloroquine can be used safely in all trimesters of pregnancy. Artemisinin is not shown to have any deleterious effects on the fetus in animal studies and therefore can be considered if the situation demands. Quinine can be used in pregnancy, but one should be watchful about hypoglycemia. Whereas mefloquine is contraindicated in the first trimester of pregnancy, pyrimethamine/ sulphadoxine is contraindicated in the first and last trimesters. Halofantrine, tetracycline and doxycycline are absolutely contra indicated in pregnancy. Primaquine is also contra indicated in pregnancy, and therefore pregnant women with P. vivax malaria should be started on 500 mg of chloroquine weekly as suppressive chemoprophylaxis against relapse of malaria6.
  2. Epilepsy: Malaria as well as anti malarials can trigger convulsions. Mefloquine is better avoided in these patients. See C.N.S. Disease and malaria
  3. Cardiac disease: Fever should be controlled with anti-pyretics and tepid sponging. Chloroquine, artemisinin, pyrimethamine/ sulphadoxine, tetracyclines and primaquine can be safely used in these patients.
  4. Hepatic insufficiency: None of the antimalarial drugs have any direct hepatotoxic effect.
  5. Renal failure: The initial dose of antimalarial drugs need not be reduced in patients with renal failure.
  6. Dermatitis: Concomitant use of chloroquine with gold salts and phenyl butazone should be avoided because all the three can cause dermatitis.
CLASSIFICATION OF ANTIMALARIAL DRUGS5
  1. 4 aminoquinolines    :    chloroquine, amodiaquine
  2. quinolinemethonol    :    mefloquine
  3. acridine    :    mepacrine
  4. cinchona alkaloids    :    quinine
  5. biguanides    :    progronil
  6. diaminopirimidines    :    pyrimethamine
  7. 8 aminoquinoline    :    primaquine
  8. sulfonamides and sulfone    :    sulfamethopyrazine
  9. tetracyclines    :    tetracycline, doxycycline
  10. artemisinin deviatives    :    artesunate, artemether, artether
  11. phynanthrene methanol    :    thalofantrine
  12. naphthoquinane    :    atovaquone
Antimalarial drugs category11
    Antimalarials can be categorized by the stage of the parasite that they affect and the clinical indication for their use. Some drugs have more than one type of activity.
DRUGS USED FOR CAUSAL PROPHYLAXIS
    These agents act on primary tissue forms of plasmodium within the liver. Which are distined within less than a month to initiate the erythrocytic stage of infection .invation of erythrocytes and further transmission are thereby prevented.proguanil is the prototype drug of this class.

 
DRUGS USED TO PREVENT RELAPSE
These compounds act on latent tissue forms of P. vivax and P .ovale remaining after the primary hepatic forms are then released in to the circulation. Such latent tissue forms eventually mature, invade the circulation , and produce malarial attack , ie , relapsing malaria , month or years after the initial infection. Drugs active against latin tissue forms are used for terminal prophyilaxis and for radical cure of relapsing malarial infection. Primaquine is the prototypical drug used to prevent relapse, the term reserved to specify recurring erythrositic infection stemming from laten tissue plasmodia.
Drugs (blood schizontocides) used for clinical and suppressive cure
    The rapidly acting blood schizontocides include classical antimalarial alkaloids such as chloroqine, quinine. Atvaquone and the artemisinin antimalarial endopeoxides also are rapidly acting agents. Slower acting less effective blood schizontocides are exemplified by the antimalarial antifolate and antibiotic compounds. These drugs most commonly are used in conjunction with their more rapidly acting counterparts.
Gametocytocides
    This agents are act against sexual erythrocytic forms of plasmodia, thereby preventing transmission of malaria to mosquitoes. Chloroquine and quinine have gametocytocidal activity against P. vivax, P. ovale and P. malaraie, whereas primaquine displace especially potent activity against gametocytes of P. falciparum. However, antimalarials are not used clinically just for their gametocytocidal action.
Sporontocides
    Such drugs ablate transmission of malaria by preventing or inhibiting formation of malarial oocysts and sporozoites in infected mosquitoes. Although chloroquine prevents normal plasmodium development within mosquitoes, neither this nor other antimalarial agents are used clinically for this purpose.

 
DOSE AND ADMINISTRATION OF ANTIMALARIAL DRUGS21
Drugs for treatment of uncomplicated malaria
    All cases of P. vivax malaria and uncomplicated cases of P. falciparum malaria are treated with oral drugs. Chloroquine is the ONLY drug used for P. vivax malaria, because resistance to chloroquine in P. vivax malaria is almost unknown (only sporadic reports). Most cases of P. falciparum malaria can also be treated with chloroquine alone, however, in areas with known resistance to chloroquine, it is safer to combine chloroquine with another oral antimalarial like pyrimethamine/ sulphadoxine. Primaquine should be used in both types of malaria for radical treatment11.
Dose of commonly used antimalarial drugs
Age in years
Dose of Chloroquine (as base)(Each 250 mg tablet contains 150 mg base and
each 5 ml of suspension contains 50 mg base)
Dose of Primaquine
Dose of Pyri/Sulpha
(Of 25+500 mg tablet)
1st dose*
2nd dose
3rd dose
4th dose
P. vivax/ mixed
(for 14 days)**
P. falciparum Single dose
0-1 
75 mg 
37.5 mg 
37.5 mg 
37.5 mg 
Nil 
Nil 
1/4 tablet 
1-5 
150 mg 
75 mg 
75 mg 
75 mg 
2.5 mg 
7.5 mg 
1/2 tablet 
5-9 
300 mg 
150 mg 
150 mg 
150 mg 
5 mg 
15 mg 
1 tablet 
9-14 
450 mg 
225 mg 
225 mg 
225 mg 
10 mg 
30 mg 
2 tablets 
>14
600 mg 
300 mg 
300 mg 
300 mg 
15 mg 
45 mg 
3 tablets 
Dose spacing for chloroquine
1st dose
2nd dose
3rd dose
4th dose
If the patient comes in the morning and treatment can be started by mid-day 
Stat. 
After 6 hours 
After 24 hours 
After 48 hours 
If the patient comes in the afternoon and treatment is started by evening
Stat 
After 12 hours 
After 24 hours 
After 36 hours 
If the patient is coming from a far off place and /or if the MP test report is available only next day 
Stat (as presumptive) 
2nd and 3rd doses together after 24 hours
After 48 hours 
Parenteral Chloroquine: Parenteral chloroquine may be needed in patients with complicated, yet drug sensitive, P. falciparum malaria and in case of persistent vomiting
Intravenous infusion
10 mg / kg (max.600mg) in isotonic fluid, over 8 hours; followed by 15 mg / kg (max.900mg) over 24 hours.
Intramuscular or subcutaneous injections
3.5 mg of base/ kg (max.200 mg) every 6 hours or
2.5 mg of base/ kg (max.150mg) every 4 hours.
(Intramuscular injection can cause fatal hypotension, especially in children)

 
Treatment of complicated/ chloroquine resistant P. falciparum malaria
    It is safer to treat cases of severe P. falciparum malaria as chloroquine resistant, unless one is very certain about the sensitivity. It is better to use two drugs, one rapid acting and one slower acting. Severe malaria should always be treated with parenteral antimalarials to ensure adequate treatment.
Quinine
In intensive care unit

 

7mg of salt/kg over 30 minutes., followed immediately by 10mg/kg diluted in 10ml/kg isotonic fluid over 4 hours; after 4 hour interval, 10mg/ kg over 4 hours, repeated every 8-12 hours until patient can swallow. OR 20mg of salt/kg diluted in 10 ml/kg isotonic fluid, infused over 4 hrs; then 10 mg of salt / kg over 4 hrs, every 8-12 hrs until patient can swallow.

 
Children
24 mg of salt/kg diluted in 10 ml/kg isotonic fluid, infused over 4 hrs; then 12mg of salt/kg over 4 hrs, every 8-12 hrs until patient can swallow.
20mg of salt/kg diluted to 60 mg/ml by deep i.m. injection, (divided into two sites); then 10mg of salt/kg every 8 hours.

 
COMBINATIONS OF ANTIMALARIAL DRUGS21
    Early and effective chemotherapy for malaria has a pivotal role in reducing morbidity and mortality especially since a vaccine is unlikely to emerge within the next decade. Multidrug resistance has been reported from most parts of the world and as a result, monotherapy or some of the available combination chemotherapies for malaria are either ineffective or less effective. New antimalarial regimens are, therefore, urgently needed and antimalarial combination chemotherapy is widely advocated. Antimalarial combinations can increase efficacy, shorten duration of treatment (and hence increase compliance), and decrease the risk of resistant parasites arising through mutation during therapy11.
    Combination therapy with antimalarial drugs is the simultaneous use of two or more blood schizontocidal drugs with independent modes of action and different biochemical targets in the parasite. The concept of combination therapy is based on the synergistic or additive potential of two or more drugs, to improve therapeutic efficacy and also delay the development of resistance to the individual components of the combination.
    Artemisinin based combinations are known to improve cure rates, reduce the development of resistance and they might decrease transmission of drug-resistant parasites. The total effect of artemisinin combinations (which can be simultaneous or sequential) is to reduce the chance of parasite recrudescence, reduce the within-patient selection pressure, and prevent transmission.
Combination 
Dose 
Artesunate + amodiaquine 
Artesunate 4 mg/kg and amodiaquine 10mg base/kg. Once a day 3 days 
Atovaquone + proguanil 
Atovaquone 20 mg/kg and proquanil 8 mg/kg once daily for 3 days
Chloroproguanil + dapsone 
Chloroproguanil 2 mg/kg and dapsone 2.5 mg/kg once daily for 3 days 
Sulphrdoxine + pyrimethamine 
Sulfadoxine 500 mg + pyrimethamine 25 mg 
Dapsane + pyrimethamine 
Dapsone 100mg + pyrimethamine 25 mg 

 
Complication of falciparum malaria21
1. Cerebral malaria: C.N.S. dysfunction in falciparum malaria could be multi
factorial.
Therefore, to differentiate from various causes of transient cerebral dysfunction, a strict definition of cerebral malaria has been developed.
For a
diagnosis of cerebral malaria, the following criteria should be met: (i.) Deep, unarousable coma: Motor response to noxious stimuli is non-localising or absent. (ii.) Exclusion of other encephalopathies: Coma should persist for more than 30 minutes after a generalized convulsion to exclude transient post-ictal coma. Hypoglycemia, meningoencephalitis, eclampsia, intoxications, head injuries, cerebrovascular accidents and metabolic disorders should be excluded as the cause of coma. (iii.) Confirmation of P. falciparum infection: Asexual forms of P. falciparum must be demonstrated in peripheral blood or bone marrow smear during life, or in a brain smear after death.
2. Severe anemiaHematocrit less than 15% (hemoglobin less than 3.1 mmol/l or 5g/dl). 
3. Metabolic (Lactic) AcidosisMetabolic acidosis is defined by an arterial blood pH of <7.35 with a plasma bicarbonate concentration of <22 mmol/L; hyperlactatemia is defined as a plasma lactate concentration of 2-5 mmol/L and lactic acidosis is characterized by a pH <7.25 and a plasma lactate >5 mmol/L.
4. JaundiceSerum bilirubin of more than 50m mol/l (3 mg/dl). 
5. Renal failureUrine output of less than 400 ml in 24 hours or <12ml/kg per 24 hours in children and a serum creatinine of more than 265 m mol/l (> 3.0 mg/dl), failing to improve after rehydration.
6. Pulmonary edema or ARDSBreathlessness, bilateral crackles, and other features of pulmonary oedema. 
7.
Hypoglycemia
Blood glucose concentration of less than 2.2 mmol/l (less than 40 mg/dl). 
8. Hypotension and shockSystolic blood pressure <50 mmHg in children 1-5 years or <80 mm Hg in adults; core-skin temperature difference >100C
9. Bleeding and clotting disturbancesSignificant bleeding and haemorrhage from the gums, nose, gastrointestinal tract, retinal haemorrhages and/or evidence of disseminated intravascular coagulation. 
10. HyperpyrexiaRectal temperature above 400C
11. Fluid, electrolyte or acid-base disturbancesRequiring intravenous fluid therapy; arterial pH <7.25 or plasma bicarbonate <15 mmol/L, venous lactate >6mmol/L
12. HaemoglobinuriaMacroscopic black, brown or red urine; not associated with effects of oxidant drugs or enzyme defects (like G6PD deficiency)
13.
Hyperparasitemia
Density of asexual forms of P. falciparum in the peripheral smear exceeding 5% of erythrocytes (more than 250,000 parasites per m l at normal red cell counts)
14.
Complicating or associated infections
Aspiration bronchopneumonia, septicemia, urinary tract infection etc. 
15. Vomiting of oral drugs Patients with persistent vomiting may have to be admitted for parenteral therapy.
16. Impaired consciousness Various levels of impairment may indicate severe infection although not falling into the definition of cerebral malaria. These patients are generally arousable. 
17. Extreme weaknessProstration, dehydration, needs support 
18. Convulsions More than two generalized seizures in 24 hours with regaining of consciousness. 
19. Other indicators of poor prognosis Leukocyte count >12,000/cumm; high C.S.F. lactate and low C.S.F. glucose; low antithrombin III levels; peripheral schizontemia
Complications of P. vivax, P. ovale and Quartan malaria21
Plasmodium vivax and P. ovale infections are generally benign and complications leading to significant morbidity and mortality are uncommon.
The clinical symptoms of fever, headache, nausea and vomiting may be incapacitating, particularly for those who are non-immune and suffering the infection for the first time.
Rupture of spleen: Malaria is an important cause for spontaneous rupture of spleen. It is more common in vivax malaria than falciparum malaria and tends to occur in up to 0.7% of the patients.
Rupture occurs in acute, rapid, hyperplastic enlargement of spleen. It is rare in chronic malaria, despite massive enlargement. Rapid enlargement results in increased capsular tension and increased parenchymal friability.  Marked splenomegaly can occur even in low-grade parasitemia (50/ml) and it may persist for weeks or months after effective and complete treatment.

 
Hepatic dysfunction: Hepatomegaly and non-specific hepatitis, with or without jaundice can occur in vivax malaria. Fever, jaundice, tender hepatomegaly, mild elevation in the levels of hepatic enzymes and bilirubin are observed. Liver biopsy in such cases has demonstrated brown malarial pigments in Kupffer's cells, small to moderate sized granulomatous lesions with mononuclear infiltration and hepatocyte necrosis.
Liver function returns to normal shortly after antimalarial treatment.
Thrombocytopenia: Decrease in platelet counts can occur in vivax malaria, however, it is usually mild and bleeding does not occur.
Severe anemia:
P. vivax can cause severe anemia, particularly when it is chronic and recurrent. Very rarely this can be life threatening or even fatal.
C.N.S. manifestations: Changes in behaviour and level of sensorium can occur in P. vivax malaria. Frank cerebral malaria does not occur and if present, it should prompt a search for other causes, most commonly an associated P. falciparum infection. Some of the C.N.S. manifestations could be caused by chloroquine also.
Quartan malarial nephropathy: In areas where P. malariae is prevalent, there is epidemiological evidence to link P. malariae infection to immune-complex mediated glomerulonephritis, leading to nephrotic syndrome. Because only a few of the infected develop nephrosis, it is possible that other factors are also involved in the pathogenesis of this entity. Histologically there is progressive focal and segmental glomerulosclerosis with fibrillary splitting or flaking of the capillary basement membrane, producing characteristic lacunae. Dense subendothelial deposits are seen on electron microscopy and immunofluorescence reveals deposits of compliments and immunoglobulins. In about 25% of patients P. malariae antigen may also be seen21.
Prevention and control
    It was recommended that malaria control should be based on an epidemiological approach and that it should be planned and co-ordinated within primary health care with active participation of the community.
    Prevention and control can be aimed at three targets (1) protection of the individual (mosquito netting, protective clothing, insect repellants) (2) Control of the Anopheline vector (insecticide sprays, drainage of stagnant water in swamps and ditches to reduce the breeding areas), (3) treatment of reservoirs of infection by using drugs. There are as yet no proven vaccines available for the prevention of malaria. The technology known as insecticide treated mosquito net (ITN) is highly practical which could succeed in saving millions of lives from malaria9.

 
CONCLUSION
Chloroquine, quinine, primaquine, proguanil etc are first line drugs used in the treatment of malaria. Less effective drugs like sulfadoxine and pyrimethamine are second line drugs. Use of combination therapy is desirable due to emergence of chloroquine resistant and multidrug resistant falciparum injection. Combination therapy helps to prevent or delay the emergence of resistance to first line drugs.

 
    Newer and highly potent drugs like artemisinin should be used only in cases of severe falciparum malaria or chloroquine or multiple drug resistant falcipurum intection to avoid the possibility of development of resistance.

 

 
BIBLIOGRAPHY

 
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Cite this: V. Nishad, Teena Tom "MALARIA – A REVIEW", B. Pharm Projects and Review Articles, Vol. 1, pp. 950-991, 2006. (http://farmacists.blogspot.in/)

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