Treatment of Malaria - 2

8/6/2019 Treatment of Malaria - 2

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TREATMENT OF MALARIA

Around 2 million laboratory confirmed cases of malaria are reported in thecountry annually. Out of the total malaria cases, 40-50% are P.falciparum. It isobserved that P.falciparum infection may lead to complications in 0.5% to 2% ofcases. Mortality may result in about 30% of such cases if timely treatment is notgiven. A single dose of chloroquine may save the life in P.falciparum cases byaverting complications.

National antimalaria drug policy essentially provides a framework for the

safe and effective treatment of uncomplicated and severe malaria as well asprevention of malaria in vulnerable groups, such as pregnant women and youngchildren. As a general principle, the policy aims at the greatest possiblereduction of malaria morbidity and mortality, while containing the development ofresistance. All health care providers in both the public and private health sectorsmust be aware of, understand the rationale for, and implement the national anti-malaria drug policy.

Since guaranteed access to early diagnosis and appropriate treatment offebrile illness constitutes the key to reduce malaria morbidity and mortality anychange which might influence the provision of prompt and effective treatment isof critical importance to malaria control efforts.

1. Disease management

Disease management remains a fundamental and indispensable element ofmalaria control. Its aims are:

(i) Prompt and adequate treatment of suspected/ confirmed cases


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( ) p q p

Age in Year hloroquine Phosphate

Mg. Base No. of Tablets(150 mg)

< 1 75

1-4 150 1

5-8 300 2

9-14 450 3

15 & above 600 4

High Risk area:

As per revised policy of NVBDCP presumptive treatment of all suspected malariacases, up to sub-centre level only, in high risk areas(as defined in the MAP 95),is as follows:

Chloroquine Base Day 1 10 mg/kg (600 mg adult)

Primaquine Day 1 0.75 mg/kg (45 mg adult)Chloroquine base Day 2 10 mg/ kg (600 mg adult)

Chloroquine base Day 3 5 mg/kg (300 mg adult)

Dosage as per age groups

Age inyears

Day 1 Day 2 Day 3

TabChloroquine(150 mg base)

Primaquine(7.5 mg)



< 1 0


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1-4 150 1 2.5 1

5-8 300 2 5.0 2

9-14 450 3 10.0 415 & above 600 4 15.0 6

Plasmodium falciparum

In Low Risk Areas where presumptive treatment with 600 mg chloroquine alone(adult dose) has been given and later blood smear is found positive for Pf, thecomplete radical treatment should be given with a single dose of tabletchloroquine 10 mg/kg bw combined with 0.75 mg/kg bw of primaquine.

High Risk Area

Plasmodium vivax

In high risk areas where presumptive treatment with 1500 mg chloroquine

base spread over three days and 45 mg primaquine (adult dose) has been given,chloroquine need not be administered again, but primaquine must be given for 5days.

Age in year Tablets Primaquine2.5 mg base

Daily dose for 5 days

Mg base No. of tablets


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sulfalene combination therapy (SP ACT) in confirmed chloroquine resistantcases. This must be followed with Primaquine (45 mg). The age-wise dosage is

as follows:

Age in year Artesunate (AS)Sulfadoxine+pyrimethamine(SP)

I day (no. oftablets)

II day (no. oftablets)

III day (no. oftablets)


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Atypical: In atypical cases, classical presentation as mentioned above may notmanifest. Hence, any fever case until unless proved otherwise, may be

considered as malaria in the endemic areas during transmission season.

In most of the cases the first symptoms are non-specific and similar to those of aminor viral illness with malaise, headache, fatigue, abdominal discomfort andmuscle aches followed by fever and chills. Repeated infections lead to anaemia,enlargement of spleen and chronic ill health with bouts of fever. Most patientswith uncomplicated acute infection have few abnormal physical findings otherthan mild anaemia and in some cases a palpable spleen. None of the clinical

features of malaria is pathognomonic. With appropriate treatment outcome inuncomplicated malaria is excellent.

The factors to be taken into account in treatment of uncomplicated malariacases are:

(i) drug effectiveness is determined mainly by efficacy, patient complianceand drug quality

(ii) drug side effects, tolerance, cost, affordability, availability andacceptability to the community and service providers

(iii) health care seeking pattern(iv) characteristic of health services

The management of uncomplicated malaria involves patients, carers, healthcare staff, drug vendors including pharmacists and drug suppliers. Themanagement of malaria disease includes:

recognition of signs and symptoms of the patient; diagnosis of malaria disease and/ or other febrile conditions;

referral to higher level of care, if necessary;

education of patient or family on :


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2.2. Management of severe and complicated malaria at the periphery

The priority requirement is the early recognition of signs and symptoms ofsevere malaria that should lead to emergency care in in-patient settings. Thesigns and symptoms that can be used are non-specific and may be due to severe

febrile disease, which may be severe malaria, another severe febrile disease orconcomitant malaria and severe bacterial infection.

Children: The signs and symptoms in children are a history of high fever, plus atleast one of the following :-

(i) prostration (inability to sit), altered consciousness lethargy or coma;(ii) breathing difficulties;

(iii) severe anaemia;(iv) convulsions;(v) inability to drink/ vomiting

The crucial concern is the timeliness of correct treatmentwith the correct drug. A mild facliparum malaria case can

progress to severe disease in a few hours, especially inchildren. Effective treatment for the disease must beavailable close to the home and must be complete.


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Jaundice Very common Common

Renal failure Common Less common

Pulmonary oedema, ARDS Less common RareDuration of illness Longer (5-7 days) Shorter (1-2 days)

Resolution of coma Longer (2-4 days) Shorter (1-2 days)

For settings where patients with severe malaria present regularly and it isnot possible to refer them rapidly to facilities, a basic package for initial treatmentcould be made available, supported by training and supervision.

The

contents of basic package for management of severe malaria at PHCs/ CHCs inmalaria endemic areas should include:

(i) a parenteral antimalarial

(i) a parenteral antibiotic(ii) an effective oral antimalarial(iii) a rectal anticonvulsant(iv) intravenous fluid

Severe malaria is the serious and life-threatening form of falciparummalaria, which needs urgent and intensive patient care. Therefore, earlyrecognition of the signs and symptoms of severe malaria helps in emergencycare and reduction of malaria related mortality. Unfortunately, the signs andsymptoms are non-specific and are present in most other severe febrile diseasescommonly seen in malarious areas. Some of the important diseases, havingi il t ti l i i iti h liti ti i

The training of medical and paramedical professionalsshould emphasize that, if at all possible, patients who haveimproved after initial treatment, but are ill, should be referred.


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Semiconscious or comatose patients of severe P.falciparum infection should betreated with Quinine. It is the drug of choice also for pregnant women and

infants.

a. Quinine I.V. 10mg/kg body wt. (600 mg.) 8 hourly, (total 24 hour intakeshould not exceed 1.8 gms in an adult) till the patient regainsconsciousness and is able to take drugs orally. Oral Quinine 600 mg TDSis to be continued for seven to ten days. When adequate facilities formanagement of complications arising out of Quinine toxicity are availablea loading dose of Quinine dihydrochloride 20 mg per kg body weight as

infusion is given, and it should be well diluted with 500 ml. Of 5 per centglucose. Infusion is given over a period of 5 hours (2 ml per minute). If noI.V. facility is available, deep intramuscular dose of 10 mg per kg body wt.is given 8 hourly. I.M. injections produce complications which, sometimesin the long run, are crippling if proper precautions are not taken.

b. Injection Arteether:

It is available in 2 ml ampoules containing 150 mg. The recommendedregime is 150 mg /day once daily by intramuscular route for three days foradults. The dosage for children is 3 mg/kg per day IM for three days.

c. Chloroquine injection:

Chloroquine is not well tolerated specially by infants or young children. In apatient of any age it may produce low blood pressure, sudden collapse withhigh mortality. Parenteral administration of Chloroquine is more hazardousthan parenteral administration of quinine. It should be used only when


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Glucose saline I.V., measure urine output, maintain slightly negative fluidbalance and avoid pulmonary complications

II. Acute renal failure with anuria or oliguria and black water fever

It must be managed with proper biochemical examination of blood,serum electrolytes and E.C.G. etc.

a. Dextran with glucose saline I.V. to correct dehydration If this failsto induce urine secretion and output remains less than 60 cc per

hour, giveb. Furosemide 20 mg or as required, upto 500 mg I.V. or I.M. as

considered appropriatec. Constantly keep watch on urinary outputd. If no improvement, dialysis. It should not be delayed and treating

physician may take quick decision. It may require haemodialysis orperitoneal dialysis.

e. Keep watch on serum creatinine, blood urea and serum potassiumlevels

f. Alkalinise the urine if there is haemoglobinuriag. Maintain diet control and restrict protein intake to 20 to 30 gms. per

day.

III. Hyperkalaemia : Cardiac arrythmia and cardiac arrest may occur whenserum potassium is 7 mol and above. Calcium charged resin (calzeocarb

225) 15 30 g orally 3-4 tmes a day, or 30 g in 100 ml of water rectally,may be given. When the potassium level is over 60 mol, 100 to 200 ml of84 % sodium bicarbonate may be infused over three hours. Therapy with20 units of insulin with 50 gm glucose may cause entry of extracellular


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VI. Gastro Intestinal complications :a. I.V. fluids

b. For vomiting: Chlorpromazine I.V. or I.M. as required.

VII. Bleeding (pulmonary oedema or gastro intestinal complications) :-

a. Parenteral vit. K, dosage to be regulated depending on patientscondition

b. Fresh whole blood transfusion

VIII. Jaundice and Liver damage

a. I.V. glucoseb. Restrict fatsc. Vitamin K and Vitamin B complex supplementd. Bed rest

X. Shock

a. I.V. Plasma expandersb. Corticosteroids: if condition indicates, use hydrocortisone up to 100 mg

8 hourlyc. Dopamine drip

XI. Anaemia (PCV< 20, Hb less than 7 gm)

- If associated with high parasitaemia

a. Whole fresh blood transfusion


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- I.V. Glucose 50% (up to 1 ml per kg body wt.)Followed by 5-10% I.V drip. Keep constant watch on blood sugar

levels.

XIV. Hyperparasitaemia (Parasitized RBCs 10 % and above)

- Exchange transfusion

Errors in management of severe falciparum malaria:

1) Misdiagnosis, particularly during epidemics of meningitis and encephalitis2) Missed microscopic confirmation3) Missed associated diseases /complications4) Missed hypoglycaemia5) Errors of fluid/electrolyte replacement6) Failure to control convulsions7) Mismanagement of respiratory complications

3. Chemoprophylaxis:

3.1 Antimalarial

In chloroquine sensitive areas chloroquine is to be given

In chloroquine resistant areas it is to be supplemented by proguanil

3.2 Regimen

Chemoprophylaxis is to be started a week before arriving at malariousarea for visitors.


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1) The clinical management of acute malaria 1990. WHO regional publications,South-East Asia Series No.9

2) Epidemiology and control of malaria in India 1996. R.S. Sharma, G.K.Sharma and G.P.S. Dhillon

3) The use of Antimalarial drugs 2000. Report of a informal consultation.WHO/CDS/RBM/2001.33


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Annexure I

Classification of the currently used anti-malarials

A. aminoquinolines, eg. Chloroquine, Hydroxychloroquine,Amodiaquine

B. 8- aminoquinolines, eg. Primaquine, Tafenoquine,Bulaquine

C. Arylamino alcohols, eg. Quinine

D. Methanols

i. 4 quinoline methanolii. 9- phenanthrene methanol

eg. Mefloquineeg. Halofantrine, Lumefantrine

E. Biguanides eg. Proguanil

F. Diaminopyrimidines eg. Pyrimethamine

G. Antimalarial endoperoxidasesi. First generation endoperoxidases

(Artemisinin derivatives)

ii. Second generationendoperoxidasesa. Trioxanesb. Tetroxanes

eg. Artesunate, Artemether, Arteether

H. Hydroxynaphthoquinone eg. Atovaquone

I. Benzonaphthyridine deriative eg. Pyronaridine

J. Antibiotics eg. Sulfonamides, Tetracycline,Doxycycline, Clindamycin,

Azithromycin


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Annexure IINAME MECH. OF ACTION Elimination

half lifeACTION ADVANTAGE DISADVANTAGE

Chloroquine

? Inhibits plasmodialheme polymerase

Toxic drug-hemecomplex form n

Dg. Intercalation of Pl.DNA

Intravacuolar pHalteration

10 days

Schizonticidal forall species

Gametocidal forPv. PO.PM.

No action onhypnozoites

Highly potentagainstsensitivestrains

Long half life

Effective atonce a weekdose asprophylacticagent

Rapiddevelopmentof resistance

Quinine (Same as Chloroquine) 11 hrs. Primary blood

schizonticide Little effect on

sporozoite

Gametocidal toPV and PM

Rapid

developmentof resistancenot yet seen

Higher toxicity

Artesunate /

Artemether /

Arteether

Activated by heme/molecular iron toproduce carboncentered free radicals

Membrane damage byfree radical

20 hrs.

Bloodschizonticide

Gametocidalaction recentlydescribed

Broaderwindowperiod ofeffectiveness

Little/ nocrossresistance

Resistancenot yetrecorded

Highrecrudescence rate whenused asmonotherapy(10-50%)

when used for


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NAME MECH. OF ACTION T ACTION ADVANTAGE DISADVANTAGE

Mefloquine Formation of toxic

subs. with heme Damages membrane

and other comp.

Causes swelling offood vacuole

20 days Strong

schnizonticidal actionagainst allspecies.

Gametocidal l againstPV, PM, PO

Sporonticidal act

Useful as

prophylacticagent for non-immune travellers

Single dosesufficient

Good alt. Toquinine in MDRPf.

Only oral prep.

available. So cannotbe used in sev. Pfmalaria

High chances of cross-resistance, might leadto quinine resistance aswell

Halofantrine Concentrates andcombines with ferri

protop orphyrin IX,leading to memb.Damage1

10-90hrs.

Schizonticidal to all

species No action

on latenttissue formof PV andgametocytes

Good alternativeto mefloquine/

quinine inchloroquine/ MDRPf.

Oral absorption erratic

High chances of cross

resistance withmefloquine

Cardiotoxicity

Atovaquone Inhibits parasitemitochondrial electrontransport chain(complex III )(

70 hrs. Bloodschizonticide (usedprimarily forMDR Pf.)_

Erratic absorption

High recrudescencerate when used alone

Pyronaridine Inhibits vacuolardegradation, leading totimpaired Hbdegradation

60 hrs. Schizonticide for PF,PV,MDR, PF

Good oralabsorption

Cross resistancenot yetdocumented

Well tolerated

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NAME MECH. OF ACTION T ACTION ADVANTAGE DISADVANTAGE

Sulfadoxine -

Pyrimethamine

Acts against the

parasite dihydrofolatereductase enzyme

Sulfadoxine

180 hrs.Pyrimethamine 95 hrs

Active against

blood schizonts ofP.falciparum.Less activeagainst otherspecies

Can be used

againstchloroquineresistantP.falciparum.

No crossresistance withthe 4aminoquinolines, mefloquine,quinine,artemisinin

derivatives

Risk of severe

skin reactions

Primaquine May get converted toelectrophiles that actas redox mediators

6 hrs. Destroys latehepatic stage andlatent forms of PVand PO

Gametocidal to allsp., mainly Pf.

No action onerythrocyte stageof Pf., thoughactive against the

hepatic stage

Useful for theterminalprophylaxis andradical cure ofPV and PO

Cannot beused inpatient withG-6PDdeficiency.

Proguanil Selective inhibition ofthe bi-functionaldihydrofolatereductase-thymidylatesynthetase of Pl.

16 hrs. Weakschizonticidalaction against allspecies.

Goodprophylacticagent for Pf ormixed infection,when used withchloroquine

Can not beused alone intreatment ofmalaria

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Treatment of Malaria - 2