Malaria

Malaria
Malaria is a protozoan disease transmitted by the

bite of infected Anopheles mosquitoes.

Most important of the parasitic diseases of humans,
with transmission in 103 countries affecting more
than 1 billion people and causing between 1 and 3
million deaths each year
Four species of the genus Plasmodium cause nearly
all malarial infections in humans : P. falciparum, P.
vivax, P. ovale, and P. malariae
Almost all deaths are caused by falciparum malaria.

Causative Agent
Malaria is caused by one of four species

of the protoctist plasmodium.

Female Anopheles

mosquitoes feed on
human blood to obtain the protein they
need to develop their eggs.

Epidemiologi

Malaria occurs throughout most of the tropical regions

of the world

Endemicity traditionally has been defined in terms of

parasitemia rates or palpable-spleen

The Life Cycle of Plasmodium

i.

Mosquitoes transmit Plasmodium when they feed on

an infected human host and absorb the parasites
gametes.

ii.

These fuse and develop in the mosquitos gut to

form infective stages, which move to the mosquitos
salivary glands.

iii.

When the mosquito feeds again the infective stages

pass out into the blood together with an
anticoagulant in saliva.

iv.

The parasites enter the red blood cells, where they

multiply.

Life cycle of malaria

Human infection begins when a female anopheline mosquito inoculates plasmodial

sporozoites from its salivary gland during a blood meal carried rapidly via the
bloodstream to the liver, where they invade hepatic parenchymal cells and begin a
period of asexual reproduction
By this amplification process (intrahepatic or preerythrocytic schizogony or merogony), a
single sporozoite eventually may produce 10,000 to more than 30,000 daughter
merozoites discharging motile merozoites into the bloodstream and symptomatic
stage of the infection begins.
In P. vivax and P. ovale infections, a proportion of the intrahepatic forms do not divide
immediately but remain dormant for months to years before reproduction begins. These
dormant forms, or hypnozoites, are the cause of the relapses that characterize infection
with these two species.
After entry into the bloodstream, merozoites rapidly invade erythrocytes and become
trophozoites. Attachment is mediated via a specific erythrocyte surface receptor. During
the early stage of intraerythrocytic development, the small "ring forms" of the four
parasitic species appear similar under light microscopy. As the trophozoites enlarge,
species-specific characteristics become evident, pigment becomes visible, and the
parasite assumes an irregular or ameboid shape. By the end of the 48-h intraerythrocytic
life cycle (72 h for P. malariae), the parasite has consumed nearly all the hemoglobin and
grown to occupy most of the red cell (merogony) red cell ruptures to release 6 to 30
daughter merozoites, each capable of invading a new red cell and repeating the cycle.

The disease in human beings is caused by the direct effects of

red cell invasion and destruction by the asexual parasite and
the host's reaction. After a series of asexual cycles (P.
falciparum) or immediately (P. vivax, P. ovale, P. malariae),
some of the parasites develop into morphologically distinct
long-lived sexual forms (gametocytes) that can transmit
malaria.
After being ingested in the blood meal of a biting female
anopheline mosquito, the male and female gametocytes form
a zygote in the insect's midgut. This zygote matures into an
ookinete, which penetrates and encysts in the mosquito's gut
wall. The resulting oocyst expands by asexual division until it
bursts to liberate myriad motile sporozoites, which then
migrate in the hemolymph to the salivary gland of the
mosquito to await inoculation into another human at the next
feeding.

Masuk
Masuk
sirkulasi
sirkulasi

Lamina
Lamina
basalis
basalis

-- 1
1 jam
jam

Ovale
Ovale ::
tachisporozoit
tachisporozoit &
&
bradisporozoit
bradisporozoit

2-10
2-10 hr
hr

PrePrepaten
paten

10-30
10-30 ribu
ribu parasit
parasit
anak
anak

 The vector, the

Pathogenesis

Anopheles species mosquito, passes

plasmodia, which is contained in its saliva, into its host while
obtaining a blood meal. Plasmodia enter circulating
erythrocytes (RBCs) and feed on the hemoglobin and other
proteins within the cells.
This protozoan brood replicates inside the cell. This
replication induces RBC cytolysis and causes the release of
toxic metabolic byproducts into the bloodstream symptoms
: chills, headache, myalgias, and malaise in a cyclic pattern.
The parasite also may cause jaundice and anemia.
P falciparum, may induce kidney failure, coma, and death.
P vivax and P ovale may produce a dormant form that
persists in the liver

Pathogenesis
Malaria-causing Plasmodium species metabolize hemoglobin and
other RBC proteins to create a toxic pigment termed hemozoin.
The parasites derive their energy solely from glucose, and they
metabolize it 70 times faster than the RBCs they inhabit, thereby
causing hypoglycemia and lactic acidosis.
The plasmodia also cause lysis of infected and uninfected RBCs,
suppression of hematopoiesis, and increased clearance of RBCs
by the spleen, which leads to anemia. Over time, malaria infection
also causes thrombocytopenia and hepatosplenomegaly.

The morbidity and mortality caused by P falciparum are increased greatly over that
caused by other Plasmodium species because of the increased parasitemia of P
falciparum and its ability to cytoadhere.
Infected RBC produces proteinaceous knobs that bind to endothelial cells. The
adherence of these infected RBCs causes them to clump together in the blood vessels
in many areas of the body, leading to much of the damage incurred by the parasite.

CLINICAL FEATURES
Clinical symptoms include the following: Cough, Fatigue,

Malaise, Shaking chills, Arthralgia, Myalgia, Paroxysm of

fever, shaking chills, and sweats
The classic paroxysm begins with a period of shivering
and chills, which lasts for approximately 1-2 hours, and is
followed by a high fever. Finally, the patient experiences
excessive diaphoresis, and the body temperature of the
patient drops to normal or below normal
Less common symptoms include the following:
Anorexia and lethargy
Nausea and vomiting
Diarrhea
Headache

Laboratory examination
Giemsa-stained thick and thin peripheral blood smears
These smears are the criterion standard for malaria

detection and should be sent to the laboratory

immediately, since malaria is a potentially lifethreatening infection.
When reading the smear, 200-300 oil-immersion
fields should be examined (more if the patient
recently has taken prophylactic medication, because
this temporarily may decrease parasitemia).
Rapid diagnosis test
PF test, ICT test, paracheck, OptiMAL

Manifestations of Severe Falciparum Malaria

Signs

Manifestations

Unarousablecoma/cerebral
malaria

Failuretolocalizeorrespondappropriatelytonoxiousstimuli;comapersistingfor
>30minaftergeneralizedconvulsion

Acidemia/acidosis

ArterialpH<7.25orplasmabicarbonatelevelof<15mmol/L;venouslactatelevelof
>15mmol/Lmanifestsaslaboreddeepbreathing,oftentermed"respiratory
distress"

Severenormochromic,
normocyticanemia

Hematocritof<15%orhemoglobinlevelof<50g/L(<5g/dL)withparasitemialevel
of>100,000/mL

Renalfailure

Urineoutput(24h)of<400mLinadultsor<12mL/kginchildren;noimprovement
withrehydration;serumcreatininelevelof>265mmol/L(>3.0mg/dL)

ARDS

Noncardiogenicpulmonaryedema,oftenaggravatedbyoverhydration

Hypoglycemia

Plasmaglucoselevelof<2.2mmol/L(<40mg/dL)

Hypotension/shock

Systolicbloodpressureof<50mmHginchildren1-5yearsor<80mmHginadults;
core/skintemperaturedifferenceof>10C

Bleeding/disseminated
intravascularcoagulation

Significantbleedingandhemorrhagefromthegums,nose,andgastrointestinal
tractand/orevidenceofdisseminatedintravascularcoagulation

Convulsions

Morethantwogeneralizedseizuresin24h

Hemoglobinuriaa

Macroscopicblack,brown,orredurine;notassociatedwitheffectsofoxidant
drugsandredbloodcellenzymedefects(suchasG6PDdeficiency)

Other

Impairedconsciousness

Obtundedbutarousable

Extremeweakness

Prostration

Hyperparasitemia

Parasitemialevelof>5%innonimmunepatients

Complication of malaria

Coma (cerebral malaria)

Defined as coma, altered mental status, or multiple seizures with P falciparum in the
blood. This complication is the most common cause of death in malaria patients. If
untreated, cerebral malaria is lethal. Even with treatment, 15% of children and 20%
of adults who develop cerebral malaria die. The symptoms of cerebral malaria are
similar to those of toxic encephalopathy.
Seizures
Renal failure
Up to 30% of nonimmune adults infected with P falciparum suffer acute renal failure.
Haemoglobinuria (blackwater fever)
Blackwater fever is the passage of dark, Madeira-colored urine. This is due to
haemolysis (destruction) of the blood cells
Profound hypoglycemia (low blood sugar)
Hypoglycemia often occurs in young children and pregnant women and often is
difficult to diagnose
Lactic acidosis
This occurs when the small blood vessels becomes clogged with P falciparum.
Haemolysis resulting in severe anemia and jaundice
Bleeding (coagulopathy)

Differential Diagnosis
Typhoid fever
Dengue Fever
URTI
Leptospirosis

MALARIA THERAPY

Properties of Antimalarial Drugs

Drug(s)

Pharmacokinetic
Properties

Antimalari
al Activity

Minor Toxicity

Major Toxicity

Quinine,
quinidine

Good oral and IM

absorption (quinine);
Cl and Vd reduced,
but plasma protein
binding (principally
to 1 acid
glycoprotein)
increased (90%) in
malaria; quinine t1/2:
16 h in malaria, 11 h
in healthy persons;
quinidine t1/2: 13 h in
malaria, 8 h in
healthy persons

Acts mainly
on
trophozoite
blood
stage; kills
gametocyte
s of P. vivax,
P. ovale,
and P.
malariae;
no action
on liver
stages

Common:
"Cinchonism": tinnitus,
high-tone hearing loss,
nausea, vomiting,
dysphoria, postural
hypotension; ECG QTc
interval prolongation
(quinine usually by <10%
but quinidine by up to
25%)
Rare:
Diarrhea, visual
disturbance, rashes
Note:
Very bitter taste

Common:
Hypoglycemia
Rare:
Hypotension, blindness,
deafness, cardiac
arrhythmias,
thrombocytopenia,
hemolysis, hemolyticuremic syndrome,
vasculitis, cholestatic
hepatitis,
neuromuscular
paralysis
Note:
Quinidine more
cardiotoxic

Chloroquine

Good oral absorption,

very rapid IM and SC
absorption; complex
pharmacokinetics;
enormous Cl and Vd
(unaffected by malaria);
blood concentration
profile determined by
distribution processes in
malaria; t1/2: 1-2 months

As for
quinine but
acts slightly
earlier in
asexual cycle

Common:
Nausea, dysphoria, pruritus in
dark-skinned patients,
postural hypotension
Rare:
Accommodation difficulties,
rash
Note:
Bitter taste, well tolerated

Acute:
Hypotensive shock
(parenteral), cardiac
arrhythmias,
neuropsychiatric reactions
Chronic:
Retinopathy (cumulative
dose, >100 g), skeletal and
cardiac myopathy

Properties of Antimalarial Drugs

Drug(s)

Pharmacokinetic
Properties

Antimalarial
Activity

Minor Toxicity

Major Toxicity

Mefloquine

Adequate oral
absorption; no
parenteral preparation;
t1/2: 14-20 days
(shorter in malaria)

As for
quinine

Nausea, giddiness,
dysphoria, fuzzy
thinking,
sleeplessness,
nightmares, sense of
dissociation

Neuropsychiatric reactions,
convulsions, encephalopathy

Tetracycline,
doxycyclinea

Excellent absorption;
t1/2: 8 h for
tetracycline, 18 h for
doxycycline

Weak
antimalarial
activity;
should not
be used
alone for
treatment

Gastrointestinal
intolerance, deposition
in growing bones and
teeth, photosensitivity,
moniliasis, benign
intracranial
hypertension

Renal failure in patients with

impaired renal function
(tetracycline)

Halofantrineb

Highly variable
absorption related to
fat intake; t1/2: 1-3
days (active desbutyl
metabolite t1/2: 3-7
days)

As for
quinine

Diarrhea

Cardiac conduction
disturbances; atrioventricular
block; ECG QTc interval
prolongation; potentially lethal
ventricular tachyarrhythmias

Artemisinin
and derivatives
(artemether,
artesunate)

Good oral absorption,

variable absorption of IM
artemether; artesunate and
artemether biotransformed
to active metabolite
dihydroartemisinin; all
drugs eliminated rapidly;
t1/2: <1 h

Broader stage
specificity and
more rapid
than other
drugs; no
action on liver
stages

Reduction in reticulocyte
count; fever; allergy

Neurotoxicity of oil-based IM
preparations reported in animals, but
no evidence in humans

Properties of Antimalarial Drugs

Drug(s)

Pharmacokinetic
Properties

Antimalarial Activity

Minor Toxicity

Major Toxicity

Pyrimethamine

Good oral absorption,

variable IM absorption;
t1/2: 4 days

For blood stages, acts

mainly on mature forms;
causal prophylactic

Well tolerated

Megaloblastic anemia,
pancytopenia,
pulmonary infiltration

Proguanil
(chloroguanide)

Good oral absorption;

biotransformed to active
metabolite cycloguanil;
t1/2: 16 h

Causal prophylactic; not

used alone for treatment

Well tolerated; mouth

ulcers and rare alopecia

Megaloblastic anemia
in renal failure

Primaquine

Complete oral absorption;

active compound not
known; t1/2: 7 h

Radical cure; eradicates

hepatic forms of P. vivax
and P. ovale;
ovale; kills
gametocytes of P.
falciparum

Nausea, vomiting,
diarrhea, abdominal pain,
hemolysis,
methemoglobinemia

Massive hemolysis in
subjects with severe
G6PD deficiency

Atovaquone

Highly variable absorption

related to fat intake; t1/2:
30-70 h

Acts mainly on
trophozoite blood stage

None identified

Lumefantrine

Highly variable absorption

related to fat intake; t1/2:
3-4 days

As for quinine

None identified

a Tetracycline and doxycycline should not be given to pregnant women or to hildren <8 years of age.
b Halofantrine should not be used by patients with long ECG QTc intervals or known conduction disturbances or by those taking
drugs that may affect ventricular repolarization, e.g., quinidine, quinine, mefloquine, chloroquine, neuroleptics, antiarrhythmics,
tricyclic antidepressants, terfenadine, or astemizole.
ABBREVIATIONS: Cl,
Cl, systemic clearance; Vd,
Vd, total apparent volume of distribution; IM, intramuscular; SC, subcutaneous; ECG,
electrocardiogram; G6PD, glucose-6-phosphate dehydrogenase.

RECOMMENDED DOSES OF ANTIMALARIAL DRUGS FOR THE

TREATMENT OF MALARIA IN ADULTS

Recommended Therapeutic Doses of Antimalarial Drugs

Drug

Uncomplicated Malaria (Oral)

Severe Malariaa
(Parenteral)

Chloroquine

10 mg of base/kg followed by 10 mg/kg at

24 h and 5 mg/kg at 48 h or by 5 mg/kg at
12, 24, and 36 h (total dose, 25 mg/kg);
for P. vivax or P. ovale, primaquine (0.25
mg of base/kg per day for 14 daysc)
added for radical cure

10 mg of base/kg by
constant-rate infusion over
8 h followed by 15 mg/kg
over 24 h or by 3.5 mg of
base/kg by IM or SC
injection every 6 h (total
dose, 25 mg/kg)b

Sulfadoxine/pyrimet 25/1.25 mg/kg, single oral dose (3 tablets

hamine
for adults)

Mefloquine

15 mg/kg followed 8-12 h later by second

dose of 10 mg/kg

Quinine

10 mg of salt/kg q8h for 7 days combined

with tetracyclined (4 mg/kg qid) or
doxycycline (3 mg/kg once daily) or
clindamycin (10 mg/kg bid) for 7 days

20 mg of salt/kg by IV
infusion over 4 he
followed by 10 mg/kg
infused over 2-8 h every 8
h

Quinidine gluconate

10 mg of base/kg by
constant-rate infusion over
1-2 h followed by 0.02
mg/kg per min, with ECG
monitoringf

Recommended Therapeutic Doses of Antimalarial Drugs

Drug

Uncomplicated Malaria (Oral)

Severe Malariaa
(Parenteral)

Artesunate

In combination with 25 mg of
mefloquine/kg, 12 mg/kg given in divided
doses over 3-5 days (e.g., 4 mg/kg for 3
days or 4 mg/kg followed by 2 mg/kg per
day for 4 days); if used alone, give for 7
days (usually 4 mg/kg initially followed
by 2 mg/kg daily)

2.4 mg/kg IV or IM stat

followed by 1.2 mg/kg at
12 and 24 h and then
daily

Artemether

Same regimen as for artesunate

3.2 mg/kg IM stat

followed by 1.6 mg/kg per
day

Atovaquoneproguanil

For adults >40 kg, each dose comprises

4 tablets (each containing atovaquone
250 mg and proguanil 100 mg) taken
once daily for 3 days with food

Artemetherlumefantrine

For adults 35 kg, each dose comprises

4 tablets (each containing artemether 20
mg and lumefantrine 120 mg) at 0, 8, 24,
and 48 h (semi-immunes) or at 0, 8, 24,
36, 48, and 60 h (nonimmunes) taken
after food

ALGORITME MALARIA CASE MANAGEMENT

Microscopic Exam
NoRapidTest&
NoMicrosc

RapidTest(Yes)&
NoMicroscopic
Vivax

Mixed/F+V

Falciparum

Rapid Test +

Rapid Test -

Microscopic Confirmation

Noevidence :
URTI
TYPHOID
UTI
DENGUE
Leptospirosis
Other Infection

STEP.I:CQ3+PQ14

MILD /
MODERATE

Step.I:CQ3+PQ1
Step.II:QN7+PQ14

Step.III:CQ1+PQ1/week

Step.II:QN7+PQ1

Parasite ++++/>5% or /
+complications ;
Cerebral
Icteric, Bil > 3mg%
Systolic <70 mmHg

Step.II:SP1+PQ1

Step.I:CQ3+PQ1

SEVERE

Breathless/ Resp > 35

Noevidence :
URTI
TYPHOID
UTI
DENGUE
Leptospirosis
Other Infection

Oliguria+Creat> 3 mg%

Step.III:QN7+PQ1
SEVERE
Malaria
Treatment

Step.I:CQ3+PQ1

Management of Severe Malaria

MANAGEMENT SEVERE MALARIA

RAPID DETECTION & Early Management
SUPPORTIVE TREATMENT
SPECIFIC TREATMENT
ANTI MALARIAL DRUGS

ORGAN FAILURE TREATMENT

ANCILLARY TREATMENT

GENERAL SUPPORTIVE MEASURES

Patients should be treated in an ICU
In endemic areas treatment should be

commenced as early as possible, sometimes

before positive parasitology
Patients should be weighed so that dose of anti
malarial can be calculated
IV fluids should be given to maintain fluid
balance and caloric requirements. A central line
and monitoring of central venous pressure may
be necessary, especially in elderly. All intake
should be recorded carefully

GENERAL SUPPORTIVE MEASURES

Urinary

catheterization should be used to monitor

output
Patients should be observed for vomiting. To
ensure patients safety, cot-sides may be required
Regular re-positioning of patient is necessary to
prevent development of pressure sores
Nasogastric tube should be avoided because of
the risk of aspiration

SUPPORTIVE MANAGEMENT C.M.

AIRWAY
FLUID REQUIREMENT : HYDRATION / OVERHYDRATION
CONVULSION : DIAZEPAM
MONITORING GCS & VITAL SIGN
LAB : FBC, GLUCOSE, PAR.COUNT, CREATININE,
UREUM, BLOOD GAS, URINE S.G, SODIUM,
POTASSIUM.
PREVENT : SHOCK, SEPTICAEMIA, ACIDOSIS, ARDS,
HYPOGLYCAEMIA, ASPIRATION, BEDSORES.
TREAT HYPERPYREXIA
VOLUME URINE & CATHETERIZATION
CM:cerebral Mal

SPECIFIC TREATMENT SEVERE

MALARIA ( Anti Malaria)
PARENTERAL
START IMMEDIATELY
DOSAGE, WEIGHT THE PATIENT
MONITORING RESPONSE
SWITCHED TO ORAL WHEN POSSIBLE
MONITORING SIDE EFFECTS

ANTI MALARIAL THERAPY FOR S.M

QUININE
QUINIDINE
CHLOROQUINE
ARTEMISININ :
ARTESUNATE : I.V/ I.M /

SUPPOSITORIES
ARTEMETHER : I.M
ARTEMISININ SUPP
SM:Severe Malaria

RECOMMENDED DOSES OF ANTI MALARIAL

DRUGS FOR TREATMENT OF SEVERE/CEREBRAL
MALARIA
DRUGS
Quinine

20 mg of dihydrochloride salt/kg by
iv infusion over 4 hr, then after
loading, followed by 10 mg/kg
over 4 hr every 8 hr. Patients
should not received quinine or
mefloquine within last 24 hr
Alternatively, 7 mg of salt/kg can
be infused over a period of 30
min, followed by 10 mg salt/kg
over a period of 4 hr, or
10 mg of salt/kg (500 mg for adult)
by i.v infusion over 8 hr
continously 3 x a day

SIDE
EFFECTS
Hypoglycemia,
chinchonism, tinnitus,
hearing impairment,
nausea, dysphoria,
vomiting, prolonged
QT interval,
dysrhythmias,
hypotension

RECOMMENDED DOSES OF ANTI MALARIAL

DRUGS FOR TREATMENT OF SEVERE/CEREBRAL
MALARIA
DRUG
S
Artemeter

3.2 mg/kg im initially, followed

by 1.6 mg/kg daily. Not to be
given iv (1 amp = 80 mg)
Artemisinin Suppositories, 10 mg/kg at 0 &
4 hr followed by 7 mg/kg at
24,36,48 & 60 hrs.
Chloroquine 10 mg base/kg infusion at
constant rate over 8 hrs
followed by 15 mg/kg over 24
hrs, or
3.5 mg base/kg 6 hourly or 2.5
mg base/kg 4 hourly by im or
sc injection. Total dose 25 mg
base /kg

SIDE
EFFECTS

Hypotensi
on

TREATMENT OF ORGAN FAILURE

ENCEPHALOPATHY/ CONVULSION
RENAL FAILURE
ACIDOSIS
HYPOGLYCAEMIA
HYPERBILIRUBINAEMIA
RESPIRATORY FAILURE
HYPOTENSION
SEPSIS
SEVERE ANAEMIA

Convulsions
I.v. diazepam

10 mg adult or rectal 0.5-

1.0 mg/kg
i.m paraldehyde o.1 mg/kg adult
Repeated conv- chlormethiazol infussion
0.8 %,
Phenytoin 5 mg/kg i.v. 20 minutes
Fosphenytoin 7.5 mg/kg i.v 20 mnutes

HYPOGLYCAEMIA ( Bl. Sugar < 40 mg% )

Coma, 20 -50 ml 50% dextrose i.v. 5 10

minutes ( routine is not recommended )

Infussion 10 % dextrose ( children 5%
dextrose) beware hyponatremia
Hypoglycaemia may developed Day 1 --- 7
Pushed 50% dextrose if necessary
Glucagon injection
Via nasogastric , beware gastric distension
In peritoneal dialysis, add glucose in dialysis fluid
Somatostatin analoque octreotide (Sandostatin)

TERIMA
KASIH