Malaria

• Globally, 96 countries and territories are

endemic for malaria with an estimated 3.2
billion people at risk
• The WHO estimated 214 million malaria cases
worldwide annually (uncertainty range 149-303
million) with 438,000 deaths (uncertainty range
236,000-635,000) in 2015
• Among the ten malaria endemic countries of
the WHO Southeast Asian region, Bangladesh
is considered as hypo-endemic for malaria
transmission where 90% of malaria is caused by
P. falciparum
• Malaria is a substantial public health problem in
Bangladesh
• Up to 400,000 clinical cases and more than 57,000
laboratory confirmed malaria cases with more
than 500 deaths per year have been reported
from Bangladesh
• During 2009 a total of 63.873 cases and 47 deaths
were reported
• 13 out of 64 districts in the country are seriously
affected by malaria, accounting for about 99% of
the country’s disease burden
• A total of 13-25 million people are at risk of
malaria inhabited in those districts
• In 2013 the prevalence rate of malaria was found
to be 0.7% in these districts
• About two-thirds (80%) of the laboratory
confirmed cases occur in the Chittagong Hill
Tracts (CHT) districts (Khagrachari, Rangamati
& Bandarban) including Chittagong and the
costal district Cox’s Bazar. Total population of
the three CHT districts is 1.6 million
• Four districts (Mymensingh, Netrakona, Sherpur
and Kurigram) with eight endemic upazilas have
low transmission of malaria and have shown
<5% malaria positive rates (RDT and
Microscopy) over last three years (2013-2015).
• There is significant progress in malaria control in
Bangladesh during the period from 2008 to 2013
showing a progressive decline in total cases and
deaths
• Bangladesh received two grants from the Global
Fund to Fight AIDS, Tuberculosis and Malaria
(GFATM), Round 6 (in 2007) to scale-up malaria
control interventions, and another in 2009
(Round 9) for further expansion of intervention
coverage. As a result, malaria prevalence has
decreased by 65%, severe malaria decreased by
79%, and malaria-associated mortality decreased
by 91% from 2008 to 2012
• The malaria situation continues to improve in
Bangladesh, according to the latest WHO report
(25 April, 2016). Bangladesh is among the six low-
endemic South Asian countries that reported a
decrease of more than 75% in the incidence of
confirmed malaria cases between 2000 and 2014
• The total deaths came down to 15 in 2013 as
against 154 in 2008 showing 90.2% reduction
• Reduction of malaria prevalence and an increase
level of awareness of malaria has a positive health
impact through active collaboration between
NMCP, Government of Bangladesh and NGO
partners in Bangladesh
 Anti malarial agents
• Malaria is an acute infectious disease caused by
four species of the protozoal genous
Plasmodium
• Plasmodium falciparum is the most dangerous
species, causing an acute, rapidly fulminating
disease (malignant tertian malaria) that is
characterized by persistent high fever,
orthostatic hypotension, & massive
erythrocytosis
• P. falciparum can lead to capillary obstruction
& death if treatment is not instituted promptly.
Organism reside in the RBC, adhesion with cell
• membrane, due to this adhesive property RBC
forms rouleux, blocks the microcapillary 
unconscious, death
• Plasmodium vivax causes milder form of the
disease (benign tertian malaria), liver, spleen
enlarged
• Plasmodium malariae is common to many
tropical regions, but Plasmodium ovale is
rarely encountered
Life cycle of the malarial parasite
• The anopheline mosquito is the definitive host
for plasmodium. It is infected by blood borne
gametocytes from man
• These gametocytes develop in the mosquito &
sporozoites are formed which pass into the
blood stream of man when bitten
• Hepatic cycle:
– Sporozoites enter liver cells where they
develop into schizonts which form large
number of merozoites which, usually after 4-
16 days but sometimes after months or years,
are released into the circulation
– Plasmodium falciparum differ in that it has
no persistent hepatic cycle
• Erythrocytic cycle:
– Merozoites enter the RBC where they
develop into schizont which forms more
merozoites which are released when the cell
bursts giving rise to the features of the
clinical attack.
– The merozoites re enter RBC & the cycle is
repeated
• Some merozoite mature into male & female
gametocyte which are released into the blood
where they can re infect the mosquito
 Sexual cycle
in mosquito
1. Sporozoite

Liver
Exoerythrocytic
5. Gametocyte cycle
2. Hypnozoite

Liver
4. Exoerythrocytic
Erythrocytic cycle
cycle 3. Merozoite
 Anti malarial drugs
Malaria Drugs
Acute attack Chloroquine, quinine,
mefloquine, halofantrine,
sulphones, pyrimethamine,
doxycycline
Chemoprophylaxis Chloroquine, mefloquine,
proguanil, maloprim,
pyrimethamine, doxycycline
Radical cure Primaquine
Prevent Primaquine, proguanil,
transmission pyrimethamine
• Classification of antimalarial drugs:
– Blood schizontocidal: blood schizont
responsible for acute attack.
• Chloroquine (symptomatic relief due to
killing of schizont)
– Gametocidal: to prevent transmission
• Pyrimethamine
• Proguanil
• Primaquine
• Chloroquine (P. vivax, P. malariae -
gametocidal)
– Chloroquine worldwide resistant to P.
falciparaum
– Drugs used in chemoprophylaxis:
• They block the primary exoerythrocytic
stage & act on merozoite emerging from
liver
–Chloroquine (chloroquine sensitive area)
–Proguanil, Mefloquine, Pyremethamine
– Recent blood schizontocidal drugs:
• Artemether (parenteral)
• Artisunate (oral)
– Quinine & artemether: same quality
– Artemether produces afebrile condition very
fast in falciparum malaria than quinine
 – Tissue schizontocides:
• Primaquine Proguanil
– Antibiotics:
• Tetracycline, Doxycycline,
– Mefloquine (drug of choice for
chemoprophylaxis against P. falciparum as
they are blood schizontocides)
• Among the antimalarial drugs chloroquine is
commonly used.
• Pyrimethamine, sulfones, & tetracyclines are
slower acting, less effective, & nearly always
used in combination with other antimalarial
drugs
• 1. Sporontocidal:
– Proguanil, Pyrimethamine & Atovaquone
• 2. Hypnozoitocidal (For preventing relapse/
antirelapse drugs/ Radical cure):
– Primaquine (most effective), Tafenoquine,
Pyrimethamine may also be used
• 3. Tissue Schizontocidal ( For causal
prophylaxis/ Chemoprophylaxis):
– Chloroquine, Mefloquine, Proguanil, Maloprim,
Pyrimethamine with or without Sulfonamide,
Doxycycline
– Primaquine is a causal prophylactic for all species,
but not used because of its toxic potentials
• 4. Blood Schizontocidal (For clinical or
suppressive cure):
– High efficacy drugs:
• Chloroquine, Mefloquine, Quinine,
Halofantrine & Artimisinin derivatives
– Low efficacy drugs:
• Proguanil, Pyrimethamine, Sulfonamide &
tetracycline
• 5. Gametocidal:
– Primaquine for P. falciparum & Chloroquine
& Quinine for P. vivax & malariae
• Objectives and uses of antimalarial drugs:
– The aim of using drugs in relation to
malarial infection are
• To prevent clinical attack of malaria
(Prophylactic)
• To treat clinical attack of malaria (Clinical
curative)
• To completely eradicate the parasite from
the patient’s body (Radical Curative)
• To cutdown human-to-mosquito
transmission (Gametocidal)
• Chemical classification of antimalarial drugs:
– 4 Aminoquinolines:
– Chloroquine, Amodiaquine, Piperaquine
– Quinoline methanol:
– Mefloquine
– Cinchona alkalloid
– Quinine, Quinidine
– Biguanide
– Proguanil
– Diamino pyrimidine
– Pyrimethamine
– 8 Aminoquinoline:
– Primaquine, tafenoquine
– Sulfonamides and Sulfone:
– Sulfapyrazine, Dapsone
– Antibiotics:
– Tetracycline, Doxycycline
– Sequiterpine lactones:
– Artesunate, Artemether, Arteether, Arterolane
– Amiono alcohols:
– Ahlofantrine, Lumefantrine
– Naphthyridine:
– Pyronaridine
– Naphthoquinone:
– Atovaquone
 Selection of drug
• The selection of antimalarial drug depends on
– Whether it is to be used for
chemoprophylaxis or for treatment
– The species of Plasmodium
– The area of infection where it is used
• It also depends on
– The adverse effects of the drug
– Age of the patient
– Pregnancy
– Lactating mother
– Hepatic or renal impairment
• Several drugs such as chloroquine, quinine are
used for the treatment of acute attack of malaria.
• All plasmodial acute infections except
chloroquine resistant P. falciparum are treated
with chloroquine
• Halofantrine is contraindicated in pregnancy or
in female who might become pregnant within the
next 3 months
• Primaquine is used for a radical cure (tissue
schizontocidal agents effect a radical cure by
acting on the parasites in the liver i.e. an attack
on persisting hepatic forms {hypnozoite i.e.
sleeping} once the parasite has been cleared from
the blood )
Clinical Setting Drug Therapy Alternative Drugs
Chloroquine- Chloroquine
sensitive P phosphate, 1 gm,
followed by 500 mg at
falciparum & P
6, 24, & 48 hours
malariae
Or-
infections
Chloroquine
phosphate, 1 g at 0 &
24 hours, then 0.5 g at
48 hours

P vivax & Chloroquine (as

P ovale above), then (if G6PD
infections normal) primaquine,
26.3 mg/d for 14
days
Cl. Setting Drug Therapy Alternative Drugs
Uncomplicat Quinine Malarone, 4 tablets (total of
sulfate, 650 mg 1 g atovaquone, 400 mg
ed infections 3 times daily proguanil) daily for 3 days
with for 3-7 days Or-
chloroquine Plus one of the Mefloquine, 15 mg/kg
following- once or 750 mg, then 500
resistant P mg in 6-8 hours
Doxycycline,
falciparum 100 mg twice Or-
daily for 7 days Artesunate or artemether,
Or- single daily doses of 4
Clindamycin, mg/kg on day 0, 2 mg/kg
600 mg twice on days 2 & 3, 1 mg/kg
daily for 7 days on days 4-7
Or- Or
Fansider, 3 tabs Coartem (coartemether 20
once mg, lumefantrine 120
mg), 4 tablets twice daily
for 3 days
Cl. Setting Drug Therapy Alternative Drugs
Severe or Quinine Artesunate, 2.4 mg/kg IV
complicated gluconate, 10 or IM, then 1.2 mg/kg
infections mg/kg IV over every 12 hours for 1 day,
1-2 hours, then then every day
with P
0.02 mg/kg Or-
falciparum
IV/minute Artemether, 3.2 mg/kg
Or- IM, then 1.6 mg/kg/d IM
15 mg/kg IV
over 4 hours,
then 7.5 mg/kg
IV over 4 hours
every 8 hrs
 Malaria Treatment Regimens
• Uncomplicated Malaria Confirmed:
– Tab. Co-artem (Artemether 20 mg +
Lumefantrine 120 mg Combination): The total
recommended treatment is a 6-dose regimen of
artemether-lumefantrine twice daily for 3
days. The second dose on the first day should
be given any time between 8 h & 12 h after the
first dose. Dosage on the second & third day is
twice a day (morning & evening)
»OR
• If for any reason co-artem can not be given
–Pregnancy in 1st trimester
–Children < 5 kg of body weight
– Tab. Quinine sulfate (300 mg). 600 mg 8 hourly
for 7 days
• Alternative regimen may be:
– Quinine for 7 days + Tetracycline 250 mg 6
hourly for 7 days or
Quinine for 7 days + Doxycycline 100 mg 12
hourly for 7 days
– Artesunate (50 mg) + mefloquine (500 mg)
– Dose in mg (no. of tablets)
Artesunate Mefloquine
– Day 1 Day 2 Day 3 Day 1 Day 2 Day
3
– 200 (4) 200 200 - 1000 (2) 500 (1)
• Uncomplicated Malaria Presumptive:
– The drug should be Chloroquine – 3 days
• Drug Day Weight in kg (>50kg)
• Chloroquine Day-1 4
Tab. 150 mg Day-2 4
base Day-3 2
But all efforts should be made for confirming
the diagnosis as soon as possible by Blood Slide
Examination (BSE) or Rapid Diagnostic Test
(RDT) - ICT for malaria. If BSE/RDT is positive
treatment should be started in the line of
uncomplicated malaria confirmed
• Coartem dose:
– 6kg up to 14 kg: 1 tablet
– Up to 25 kg: 2 tablets
– Up to 35 kg: 3 tablets
– >35 kg & above: 4 tablets
• 1st day:1st dose: “0” hour, 2nd dose: 8 hours after 1st
dose
• 2nd and 3rd day: 12 hourly
• Quinine: 10 mg/kg
• Chloroquine:
– 10 mg/kg day 1
– 7.5 mg/kg day 2
– 7.5 mg/kg day 3
• Treatment of Severe Malaria:
– IV Quinine drip/ IM Quinine followed by
oral Quinine for a total of 7 days
or
– IM Artemether / IV Artesunate followed by
oral Artesunate tablet
• Quinine:
– Loading dose: Quinine dihydrochloride
20 mg salt/kg of body weight (loading
dose) by infusion over 4 hours, in 5%
dextrose saline (5-10 ml/kg of body
weight depending on the patient’s
overall fluid balance).
 – Maintenance dose: Eight hours after the
start of the loading dose, maintenance
dose of quinine 10 mg salt/kg of body
weight in dextrose saline diluted as
above over 4 hours. This maintenance
dose should be repeated every 8 hours &
up to six doses (including loading dose).
Thereafter the quinine dose will be
reduced to 15 – 20 mg salt/kg body
weight, the dose should be repeated at
intervals of 8-12 hours, until the patient
can take oral medication
• If the patient is conscious & can swallow &
without complication:
– Oral quinine: Quinine sulphate 10 mg
salt/kg, 8 hourly to complete a 7 day course
of treatment
• Artesunate:
– 2.4 mg/kg (loading dose) IV, followed by 1.2
mg/kg at 12 hours, then 1.2 mg/kg daily for
6 days, if the patient is able to swallow, the
daily dose can be given orally
– Oral Artesunate:
• 1st day – 2 mg/kg/dose
• 2nd day – after 12 hours
• 3rd to 8th dose – daily (total duration of
treatment 7 days & total 8 doses)
• Artemether:
– 3.2 mg/kg (loading dose) IM followed by 1.6
mg/kg daily for 5 days
• Arteether:
– 150 mg deep IM once daily for 3 days for
adults
• Treatment of plasmodium Vivax case:
– Chloroquine (Davidson)
• 150 mg (base) 4 tablets stat 1st day
• 6 hours later – 2 tablets
• Then, 1 tablet twice daily for 3 days
+
– Prevention of relapse: radical cure  On the
4th day Primaquine15 mg/day orally for 14
days for adults (0.3 mg/kg daily for children)
• Multidrug resistant falciparum malaria:
– Combination of Atovaquine 250 mg +
Proguanil 100 mg (Malarone): 4 tablets once
daily for 3 days
• Management of Severe Malaria In Pregnancy:
– Woman living in endemic areas in which
Plasmodium falciaparum remains sensitive
to chloroquine should take chloroquine
prophylactically throughout pregnancy
– Proguanil may be taken for prophylaxis
provided it is accompanied by folic acid 5
mg/day
– Chloroquine may be used in full dose to treat
chloroquine-sensitive infections
– Quinine is the only widely available drug
that is acceptable as suitable for treating
chloroquine-resistant infections during
pregnancy
– Quinine in the doses advocated for the
treatment of life-threatening malaria, is safe
in pregnancy. Quinine is not an abortificient
in therapeutic doses & safe in all trimester in
pregnancy. It has been shown that the initial
IV infusion of quinine in woman who are >
30 weeks pregnant is not associated with
uterine stimulation or fetal distress. Its major
adverse effect if hypoglycemia.
– Mefloquine is teratogenic in animals & a
woman should avoid pregnancy while taking
it, & for 3 months after
– Pyrimethamine plus dapsone (Maloprim)
should not be given in the first trimester, but
may be given in the 2nd & 3rd trimester with a
folate supplement
– Artesunate & Artemether should not be used
in first trimester of pregnancy
Blood schizontocide: Chloroquine
• A very potent blood schizontocidal drug,
effective against all 4 plasmodial species
(if sensitive to the drug), but it does not
have any effect on sporozoite, hypnozoite
or gametocytes
• A synthetic, 4-aminoquinoline that has
been the mainstay of antimalarial therapy
• A chlorine atom attached to position 7 of
the quinoline ring confers the greatest
antimalarial activity in both avian &
human malarias
• Mechanism of action:
– It has a complex mechanism of action that is
not fully understood. It is uncharged at
neutral pH & can therefore, diffuse freely
into the parasite lysosome. At the acid pH of
the lysosome, it is converted to a protonated,
membrane impermeable form & is ‘trapped’
in side the parasite. At high concentration,
chloroquine inhibits protein, RNA & DNA
synthesis but these effects are unlikely to be
involved in its antimalarial activity.
– Chloroquine acts mainly on heme disposal
by preventing digestion of hemoglobin by
the parasite & thus reducing the supply of
amino acids necessary for parasite viability.
– Plasmodia derive nutrition by digesting
hemoglobin in their acidic vacuoles. During
the digestion process, large amounts of soluble
heme (ferriprotoporphyrin IX) are released,
which is toxic to the parasite. To protect itself,
the parasite ordinarily polymerizes the heme
to hemozoin (a pigment), which is sequestered
in the parasite’s food vacuole. Chloroquine
specifically binds to heme, preventing its
polymerization to hemozoin. The increased pH
& the accumulation of heme result in oxidative
damage to the membranes, leading to lysis of
both the parasite & the red blood cell
• Cause of Chloroquine resistance:
– Most important mechanism: An efflux pump
in the membrane of the acidic vacuoles thus
protects heme detoxifying mechanism of the
resistant parasite
– The pfmdr gene encoded P-glycoprotein is an
energy dependent ABC transporter which
confers resistance to many antimalrial like
quinine, mefloquine & halofantrine. This
transporter is also involved in certain cases of
P. falciparum resistance to Chloroquine
• Pharmacokinetics:
– Route of administration – oral, parenteral
– Absorption – well absorbed from the GIT
after oral administration
– Distribution – rapidly distributed to the
tissues. Volume of distribution 100 – 1000
L/kg (due to extensive accumulation in
organs – liver, spleen, lungs, heart, kidney,
pancreas, brain, eyes, erythrocyte & skin) &
is slowly released from tissues &
metabolized in the liver
– Excretion – mainly in the urine with a initial
t½ of 3-5 days but a much longer terminal
elimination t½ of 1-2 months
• Indications:
– Chemoprophylaxis & treatment of malaria
where there is no chloroquine resistance
– Hepatic amoebiasis (effective amoebicidal as
it reaches high concentration in the liver)
– Discoid & systemic lupus erythematosus
– Rheumatoid arthritis (anti inflammatory
action is due to – inhibition of lymphocyte
proliferation, decrease leukocyte chemotaxis,
decrease lysosome enzyme release & inhibit
phospholpase A2 which decrease
prostaglandin & thus decreased
inflammation)
– Severe polymorphous light eruption
• Contraindications:
– Psoriasis
– Patient with retinal or visual field
abnormality or myopathy
– History of liver disease or neurologic or
hematologic disorders
• Adverse effects:
– Corneal deposits of chloroquine may be
asymptomatic or may cause halos around
lights or photophobia (these reverse when
the drug stopped). Retinal toxicity is more
serious, & may be irreversible. In early stage
it takes the form of visual field defects; late
retinopathy classically gives the picture of
– macular pigmentation surrounded by a ring
of pigment (the ‘bull’s eye’ macula). The
functional defect can take the form of
scotomas, in the extreme case, in blindness
– Pruritus
– Nausea, vomiting, abdominal pain,
headache, anorexia, malaise, blurring of
vision & urticaria – uncommon
– Rare – hemolysis in G-6-PD deficient patient,
impaired hearing, confusion, psychosis,
seizure, agranulocytosis, exfoliative
dermatitis, alopecia, bleaching of hair,
– hypotension, & electroencephalographic
changes (QRS widening, T wave
abnormalities)
– Long term administration of high doses of
chloroquine for rheumatoid disease can
result in – irreversible ototoxicity,
retinopathy, myopathy & peripheral
neuropathy
– Larger I.M. injection or rapid I.V. infusion of
chloroquine hydrochloride can result in
severe hypotension & respiratory & cardiac
arrest
• Chloroquine is the drug of choice because –
– Rapidly causes remission of fever &
parasitemia within 24-48 hours after receiving
therapeutic dose
– Well tolerated & more reliably administered
than quinine
– No toxic synergism when given with
primaquine
– Duration of treatment shorter with choroquine
(3 days) than quinine (7 days)
– As a both suppressive & therapeutic agent
chloroquine is superior to quinine i.e. more
potent & less toxic than quinine
– Hypoglycemia less with chloroquine
– Quinine cause more GI upset
– Quinine narrow therapeutic index
 Blood schizontocide: Quinine
• Quinine & Quinidine remain first-line therapies
for falciparum malaria- specially severe disease
• Chemistry & pharmacokinetics:
– Quinine (levo rotatory alkaloid) is derived
from the bark of cinchona tree, a traditional
remedy for intermittent fevers from South
America
– Orally active. Rapidly & completely absorbed
from the GIT.
– Widely distributed in body tissues.
– Highly bound (90%) to plasma proteins.
– The pharmacokinetics of quinine varies
among populations. Individuals with malaria
– develop higher plasma levels of the drug
than healthy controls, but toxicity is not
increased, apparently because of increased
protein binding
– The half-life is longer in those with severe
malaria (18 hours) than in healthy controls (11
hours). Quinidine (d-isomer of Quinine) has a
shorter half-life (6 hours) than quinine, mostly
as a result of decreased protein binding.
– Primarily met. in the liver & excreted in the
urine
– Readily cross placental barrier
– CSF concentration is only 2-5 % of that in the
plasma
– Less effective & more toxic than Chloroquine
• Mechanism of action:
– Unknown.
– Quinine is a rapidly acting, highly effective
blood schizontocide against the four species
of human malarial parasites.
– The drug is gametocidal against P vivax & P
ovale but not P falciparum.
– It is not active against liver stage parasites.
– It’s mechanism of action is thought to be
associated with inhibition of parasite’s heme
polymerase, resulting in the death of the
erythrocytic form of the plasmodial parasite
• Pharmacological action:
– Antiplasmodial action: quinine binds with
plasmodial DNA & thus inhibit protein
synthesis. It also inhibit hemoglobin
metabolism by parasite
– Antimalarial action: blood schizontocide.
– Heart “quinidine like action”: a depressant
action on heart. Antidysrhythmic action.
– Skeletal muscle: a slight blocking action on the
neuromuscular junction used in mytonia &
muscle cramp because it prolongs the muscle
refractory period
– Pancreas: stimulate insulin secretion –
hypoglycemia
– Others:
• Weak antipyretic action.
• Mild oxytocic action on the gravid uterus
• Clinical use:
– Parenteral treatment of severe falciparum
malaria
– Malarial chemoprophylaxis: not generally
used owing to toxicity, although a daily dose
of 325 mg is effective
– Babesiosis: first-line therapy in combination
with clindamycin, in the treatment of
infection with Babesia microti or other
human babesial infection
– Myotonia congenita
– Nocturnal muscle cramp
• Contraindication:
– Hypersensitivity to quinine
– Evidence of hemolysis, cinchonism
– Optic neuritis
– Myasthenia
• Adverse effects:
– Hearing & vision are particularly disturbed.
• Tinnitus, vertigo, decreased auditory
acuity, blurred vision, disturbed color
perception, photophobia, diplopia, night
blindness, mydriasis
– Skin – hot & flushed. Sweating is prominent
– Nausea, vomiting, abdominal pain &
diarrhoea, hypoglycemia – more in children,
pregnant woman & the elderly patient
– Black water fever is a rare severe illness that
includes marked hemolysis &
hemoglobinuria due to hypersensitivity
reaction to the drug, though its pathogenesis
is uncertain
Points Chloroquine Quinine
Chemical nature 4-aminoquinoline Cinchona alkalloid
Effective against P falciparum P falciparum
sensitive strains, resistant strain, P
P malariae, P vivax, P ovale, P
ovale, P vivax malariae
Effect on No action Little action
sporozoite &
pre-erythrocytic
form of parasite
On relapse Does not prevent Prevent relapse of
relapse of vivax vivax malariae
malariae
Potency More potent Less potent
Toxicity Less More
Points Chloroquine Quinine

Duration of Shorter (3 days) Longer (7 days)

treatment
Patient Well tolerated, Not well tolerated
compliance reliable
t½ 50 hours 10 hours
Plasma protein 50-65% 90%
binding
Adverse effect Large dose causes Hypoglycemia,
– retinopathy, cinchonism
ototoxicity,
cardiovascular
toxicity
 Blood schizontocide: Mefloquine
• Mefloquine is effective therapy for many
chloroquine-resistant strains of P falciparum &
against other species
• One of the recommended chemoprophylactic
drugs for use in most malaria-endemic regions
with chloroquine-resistant strains
• It is a synthetic 4-quinoline methanol that is
chemically related to quinine
• It can only be given orally because severe local
irritation occurs with parenteral use
• Pharmacokinetics:
– Well absorbed
– Highly protein bound, extensively
distributed in tissues, & eliminated slowly,
allowing a single-dose treatment regimen
 – t½ 15-30 days, allowing weekly dosing for
chemoprophylaxis. Prolonged t½ probably
due to fact that it undergoes extensive
enterohepatic cycle & it has high tissue storage
– Mefloquine & acid metabolites of the drug are
slowly excreted, mainly in the feces
– The drug can be detected in the blood for
months after the completion of therapy
• Mechanism of action:
– Has strong blood schizontocidal activity
against P falciparum & P vivax, but it is not
active against hepatic stages or gametocytes.
The exact mechanism of action is unknown.
However, it causes secondary swelling of
lysosome & raises intracellular pH of
plasmodia. Also inhibit heme polymerase
• Advantage for chemoprophylaxis:
– It is active against multi-drug-resistant P
falciparum
– It has extended duration of action &
– It has relatively minor adverse effects
• Simultaneous administration of mefloquine &
chloroquine increase the chance of convulsion,
so this is not encouraged
• Clinical uses:
– Chemoprophylaxis: against most strains of P
falciparum & probably all other human
malarial species as well except for those with
 – no chloroquine resistance (where
chloroquine is preferred). Eradication of P
vivax & P ovale requires a course of
primaquine
– Treatment: most falciparum malaria
• Adverse effects:
– GI disturbance: nausea, vomiting, abdominal
pain, diarrhoea & loss of appetite
– Transient CNS toxicity: giddiness, confusion,
dysphoria & insomnia
– Cardiac conduction defect, arrhythmia &
bradycardia
– Rash
 – Leukocytosis, thrombocytopenia, &
aminotransferase elevations
– Rarely neuropsychiatric reactions:
depression, confusion, seizure, acute
psychosis & hallucination
• Disadvantage for treatment of acute malaria –
– Expensive, about 50% of the patient complain
of GI disturbances, transient CNS toxicity,
should not be used in patients undertaking
precision tasks, should not be used in
pregnant woman or in woman liable to
become pregnant within 3 months of
stopping the drug
• Contraindication & cautions:
– Contraindicated if there is history of
epilepsy, psychiatric disorders, arrhythmia,
cardiac conduction defects, or sensitivity to
related drugs
– It should not be co administered with
quinine, quinidine, or halofantrine, & caution
is required if quinine or quinidine is used to
treat malaria after mefloquine
chemoprophylaxis
– Now considered safe in young children
– Available data suggest that mefloquine use is
safe throughout pregnancy, although
experience in the first trimester is limited
 Tissue schizontocide: Primaquine
• Is the drug of choice for the eradication of
dormant liver forms of P vivax & P ovale
• It is a synthetic 8-aminoquinoline
• Well absorbed orally. t½ is 3-8 hours.Widely
distributed to the tissues, but a small amount is
bound there. It is rapidly metabolized &
excreted in the urine. Its three major
metabolites appears to have less antimalarial
activity but more potential for inducing
hemolysis than the parent compound
• Mechanism of action:
– Primaquine is active against hepatic forms of
all human malarial parasites. It is the only
available agent active against the dormant
hypnozoite stages of P vivax & P ovale.
– Primaquine is also gametocidal against the
four human malarial species.
– Primaquine acts against erythrocytic stage
parasites, but this activity is too weak to play
an important role.
– The mechanism of antimalarial action is
unknown. Metabolites of primaquine are
believed to act as oxidants that are
responsible for the schizontocidal action
• Clinical uses:
– Therapy (radical cure) of acute
vivax & ovale malaria
– Terminal prophylaxis of vivax &
ovale malaria
– Chemoprophylaxis of malaria
– Gametocidal action
– Pneumocystis jiroveci infection
• Adverse effects:
– Primaquine in recommended doses is
generally well tolerated. Infrequently causes
nausea, epigastric pain, abdominal cramps, &
headache (with higher dosages & in empty
stomach)
– Serious but rare adverse effects include
leukopenia, agranulocytosis, leukocytosis, &
cardiac arrhythmias
– Standard dose of primaquine may cause
hemolysis or methemoglobinemia
(manifested by cyanosis), especially in
persons with G6PD deficiency or other
hereditary metabolic defects
• Contraindication & cautions:
– Avoided in patients with history of
granulocytopenia or methemoglobinemia, in
those receiving potentially myelosuppressive
drugs (e.g. quinidine), & in those with
disorders that commonly include
myelosuppression
– Never given parenterally because it may
induce marked hypotension
– Avoided in patients with G6PD deficiency
– Avoided in pregnancy because the fetus is
relatively G6PD-deficient & thus at risk of
hemolysis
• Pyrimethamine
– Pyrimethamine is a 2,4-diaminopyrimidine
related to trimethoprim
– Effect a radical cure as a blood schizontocide
& strong sporontocide in the mosquito’s gut
when the mosquito ingests it with the blood
of human host
– Has an elimination half-life of about 3.5 days.
Therefore it can be given once a week
• Proguanil
– Is a biguanide derivative
– Has an elimination half-life of about 16
hours, therefore it must be administered
daily for chemoprophylaxis
– is a prodrug; only its metabolite, cycloguanil,
is active
• Both drugs are slowly but adequately absorbed
from the GIT
• Mechanism of action of folate antagonist:
– Selectively inhibit plasmodial dihydrofolate
reductase, a key enzyme in the pathway for
synthesis of folate
– Sulfonamides & sulfones inhibit another
enzyme in the folate pathwy,
dihydropteroate synthetase. Combinations of
inhibitors of these two enzymes provide
synergistic activity
• Clinical uses:
– Chemoprophylaxis; Treatment of
chloroquine resistant falciparum malaria;
Presumptive treatment of falciparum
malaria; Toxoplasmosis; pneumocystosis
• Adverse effects & caution:
– Well tolerated
– GI symptoms, skin rash & itching are rare
– Mouth ulcer & alopecia (proguanil)
– Fansider is no longer recommended for
chemoprophylaxis because of uncommon but
severe cutaneous reactions, including
erythema multiforme, Stevens-Johnson
syndrome, & toxic epidermal necrolysis
– Folate antagonists should be used cautiously
in the presence of renal or hepatic
dysfunction
– Although pyrimethamine is teratogenic in
animals, Fansider has been safely used in
pregnancy for therapy as an intermittent
chemoprophylactic regimen to improve
pregnancy outcomes. Intermittent preventive
therapy (IPTp) in the form of one dose
pyrimethamine (75mg) + Sulfadoxin (1500mg)
each in 2nd & 3rd trimester (gap not <1 month) is
recommended by WHO only in areas with high
P. f endemicity (P. f > 30%) for pregnant woman
– Proguanil is considered safe in pregnancy
– With the use of any folate antagonist in
pregnancy, folate supplements should be co
administered
 Halofantrine
• A phenanthrene-methanol related to quinine, is
effective against erythrocytic (but not other)
stages of all four human malarial species
• Rapidly effective against most chloroquine-
resistant strains of P falciparum
• Generally well tolerated, but use is limited by
irregular absorption & cardiac toxicity
• Most common adverse effects are abdominal
pain, diarrhoea, vomiting, cough, rash,
headache, pruritus, & elevated liver enzymes
• Dose-related prolongation of QT & PR
intervals. This effect is seen with standard dose
& is worsened by prior mefloquine therapy.
Rarely cardiac arrhythmias & death reported
• Contraindicated in patients with cardiac
conduction defects & should not be used in
those who have recently taken mefloquine; also
contraindicated in pregnancy
 Lumefantrine
• An aryl alcohol related to halofantrine
• Available as a fixed-dose combination with
artemether as Coartem
• Half-life, when used in combination, is 4.5
hours
• Coartem is highly effective in the treatment of
falciparum malaria, but it is expensive &
requires twice-daily dosing
• Despite these limitations, due to its reliable
efficacy against falciparum malaria, Coartem
has recently been selected as the first-line
therapy for malaria in African countries
• Coartem does not appear to cause the cardiac
toxicity as seen with halofantrine
 Artemisinin & its derivatives
• Artemisinin (qinghaosu) is a sesquiterpene lactone
endoperoxide, the active component of an herbal
(leaves of Artemisia annua – sweet wormwood)
medicine that has been used as an antipyretic in
China for over 2000 years
• Artemisinin is insoluble & can only be used orally
• Analogs have been synthesized to increase
solubility & improve antimalarial activity. Most
important of these analogs are –
– Artesunate (water-soluble; useful for oral, IV,
IM, & rectal administration) & Artemether
(lipid-soluble; useful for oral, IM, & rectal
administration)
• Rapidly absorbed, half-life of 1-3 hours after
oral administration
• Compounds are rapidly metabolized to the
active metabolite dihydroartemisinin
• Very rapidly acting blood schizontocides
against all human malarial parasites
• Artimisins have no effect on hepatic stages
• The antimalarial effect may result from the
production of free radicals that follows the
iron-catalyzed cleavage of the artemisinin
endoperoxide bridge in the parasite food
vacuole or from inhibition of a parasite calcium
ATPase. Artimisinin interacts with heme
resulting in the generation of free radicals that
bind to the membrane protein & damage the
parasite membrane
• Artesunate & artemether are playing an
increasingly important role in the treatment of
multidrug-resistant P falciparum malaria
• They are the only drugs reliably effective
against quinine-resistant strains
• The efficacy of artemisinins is limited by their
short plasma half-life
• Also because of their short-half-lives, they are
not useful in chemoprophylaxis
• Artesunate has also been effective in the
treatment of severe malaria when administered
rectally, offering a valuable treatment modality
when parenteral therapy is not available
• In the setting of multidrug resistance,
combination therapy with an artemisinin are:
Artemether + lumefantrine, artesunate +
amodiaquine, artesunate + mefloquine,
artesunate + sulfadoxin + pyrimethamine
• Artemisinins appear to be better tolerated than
most antimalarials
• Most commonly reported adverse effects –
nausea, vomiting & diarrhoea
• Irreversible neurotoxicity seen in animals after
doses of much higher than those used to treat
malaria
• Artemisinins should be avoided in pregnancy
because teratogenicity seen in animal studies,
but limited inadvertent use in pregnancy has
apparently not led to fetal problems
 Chemoprophylaxis/causal prophylaxis
• Drugs used for chemoprophylaxis blocks the
link between the exoerythrocytic stage & the
erythrocytic stage & thus prevents the
development of malarial attacks. The
prevention of infection by killing the
sporozoites on entry into the host is not feasible
with the presently available drugs. Prevention
of the development of clinical attacks can,
however, be effected by chemoprophylactic
drugs that kill the parasites when they emerge
from the liver after the pre-erythrocytic stage
• Drugs are – chloroquine, mefloquine,
proguanil, maloprim, pyrimethamine, dapsone,
doxycycline
Chemo Antimalarial Adult Regimen
prophylaxis tablet prophylactic
dose
Chloroquine Mefloquine 250 mg One tablet
resistance Or weekly
high Doxycycline 100 mg Daily
Or
Malarone 1 tab from 1-2 Daily
d before
travelling to 1
week after
return
Chloroquine Chloroquine 150 mg base Two tablet
resistance Plus weekly
moderate proguanil 100 mg Two tablets
daily
Chloroquine Chloroquine 150 mg base Two tablets
resistance Or once weekly
absent Proguanil 100 mg One or two
tablets once
daily
 Chemoprophylaxis dose
• Chloroquine phosphate (Children dose – 8.3
mg/kg). 300 mg of the tablet (active
chloroquine – 150 mg base) is to be taken orally
after meal once a week beginning 2 weeks
before departure. Should be continued
throughout his staying in the endemic zone &
continuing for 4 weeks after leaving the area
• Or
• Mefloquine (Tab 250 mg). 250 mg of the drug
is to be taken orally after meal once a week
beginning 2 weeks before departure, continued
throughout the stay & for at least 4 weeks after
leaving the area.
• 2nd drug: Proguanil – 200 mg once daily
(chloroquine resistant area). Start 2 days before
travel, continued throughout the stay in the
endemic zone & at least for 4 weeks after
leaving the area
• Drugs to prevent transmission
– Some drugs (e.g. primaquine, proguanil &
pyrimethamine) have the additional action of
destroying the gametocytes, preventing
transmission by the mosquito & thus
preventing the increase of the human
reservoir of the disease – but they are rarely
used for this action alone
 Education to the patient
• Chemoprophylaxis alone may not be sufficient to
prevent malaria. Other measures such as the use
of mosquito net (with permethrin soaked &
dried), screened windows, worn of long sleeves
& trousers outside the house etc. reduces the risk
of developing malaria. One should consult with
the physician if he/she develops mental
confusion, dizziness, disorientation, visual
disturbance or acute psychosis. Taking the drug
after meal may reduce the chance of GI upset.
Consuming large dose of alcohol should be
avoided. Taking bath with insect repellent soap
(permethrin 0.5% + diethyl toluamide)  gives
protection for 4-8 hours
 Acute attack
• Act on erythrocytic form of Plasmodium. In
infection with P. falciparum & P. malariae, which
have no exoerythrocytic stage, these drugs effect a
cure.
• With P. vivax & ovale, the drugs suppress the
attack but exoerythrocytic forms can cause later
relapse
• This group of drugs includes quinoline-methanols
(e.g. quinine & mefloquine), various 4-
aminoquinolines (e.g. chloroquine), the
phenanthrene halofantrine, & agents that interfere
either with the synthesis of folate (e.g. sulfone) or
with its action (pyrimethamine & proguanil) as
well as the hydroxynaphthoquinone compound
atvaquone.
• Combinations of these agents are frequently used.
Some antibiotics, such as tetracycline &
doxycycline, have proved useful when combined
with the above agents. Compounds derived from
qinghaosu, e.g. artemether, arteflene & artesunate,
have also proved effective
• Chloroquine phosphate (Tab 150 mg base). 600 mg
of the drug is to be taken orally immediately & 300
mg after 6 hours on the 1st day followed by 150 mg
twice daily for 3 days
• Plus
• Primaquine (Tab 7.5 mg). 7.5 mg of the drug is to
be taken orally twice daily for 15 days
 WHO regimen for antimalarial drugs

Day Drug Dosage

1 Chloroquine 600 mg (4 tablets) once

(150 mg base) daily
2 Chloroquine 450 mg (3 tablets) once
(150 mg base) daily
3 Chloroquine 450 mg (3 tablets) once
(150 mg base) daily
4 Primaquine 45 mg once daily
• Why clinical suppression (treatment of acute
attack) is preferred to causal prophylaxis?
– Chemoprophylaxis (causal prophylaxis)
block link between exoerythrocytic &
erythrocytic stage & thus prevent the
development of malarial attack
– True causal prophylaxis – the prevention of
infection by the killing of sporozoite on entry
into the host – is not feasible with the drugs
at present in use, though it may be achieved
in the future with vaccine
– No chemoprophylactiv regimen is 100%
effective & the choice of drug is difficult
 – Unwanted effects of some antimalarial agent
need to be born in mind & weighed against
the risk of a serious, possibly fatal,
parasitemia
– A further problem is the complexity of the
regimen, which require different drugs to be
taken at different times, & the fact that
different agents may be required for different
travel destination
• But treatment of acute attack:
– Curative
– Effective
– Specific drug schedule
– Life saving
 Fansidar
• Pyrimethamine (25 mg) acts synergistically
with sulfadoxin (500 mg) as Fansidar to inhibit
folic acid metabolism
• It is used with quinine to treat acute attack of
malaria caused by susceptible strains of P
falciparum resistant to chloroquine
• Mechanism of action:
– Acts by reciprocal potential of its two
components, achieved by a sequential
blockade of two enzymes involved in the
biosynthesis of folinic acid in the parasites
– Dosage: a single dose of pyrimethamine 75
mg + sulfadoxin 1.5 gm (3 tablets) usually
suffices
• Sulfadoxin is excreted in the urine
• Indication:
– All forms of malaria
• Toxoplasmosis
– Pneumonia due to pneumocystis carinii
– For chemoprophylaxis of malaria
• Contraindications:
– During pregnancy (because of antifolate
action)
– Pre mature or new born infants during 1st few
weeks of life (due to immaturity of enzyme
system)
– Sulfonamide hypersensitive patient
• Adverse effects:
– Any sulfonamide induced allergic reaction can
be severe, e.g. erythema multiforme, Stevens
Johnson syndrome & toxic epidermal
necrolysis. Because of its ‘antifolate’ action the
combination should not be used by pregnant
woman unless they take a folate supplement
 Management of cerebral malaria
• Diagnosis is made from cerebral manifestation
–Convulsion, hypoglycemia, difficulty in
breathing or pulmonary edema, oliguria or
acute renal failure, hyperpyrexia,
hyperparasitemia, change of behavior,
drowsiness, altered consciousness, coma,
severe anemia, circulatory collapse or shock,
hemoglobinuria, jaundice, acidosis
• Exclusion of other causes of encephalopathy
• Focal neurological signs absent
• Neck rigidity & kernigs sign absent
• Microscopic confirmation
• CSF normal
• Injection chloroquine 5 mg/kg in 500 ml of 5%
dextrose aqua over 4 hours stat & 8 hourly upto
patient can take orally for 7 days orally
• Or if chloroquine resistant –
• IV quinine dihydrochloride loading dose 20
mg/kg if not treated with quinine before
• If treated then give 10 mg/kg body weight
• It is given with 500 ml of 5% (10%) dextrose
over 4 hours & 8 hourly until patient can take
the drug orally. Total duration for 7 days
• Treatment of convulsion – diazepam IV 0.2
mg/kg
• For hypoglycemia – IV glucose 10% or 25%
• Correct fluid & electrolyte balance
• If hemoglobin < 6 gm/dl – blood transfusion
with packed red cell
• Ryles tube down for feeding
• Proper nursing care –
– Clean airway
– Frequently change of posture
– Urethral catherization
– Careful record of input/output chart
– Check speed of infusion frequently
– Monitoring of vital signs
• Treatment of pulmonary edema – propped up
position, frusemide
• Hyperpyrexia – sponging, antipyretic
• Hyparasitemia: if > 10% RBC are infected –
exchange blood transfusion
• Antibiotic – if associated infection
• If oliguria develops, frusemide or an infusion
of mannitol may forestall renal failure
• Dialysis may be needed if renal failure
develops