Antimalarial Drugs

DR VIKASENDU AGARWAL
LLRM MEDICAL COLLEGE
MEERUT

VIKASENDU AGARWAL 6/7/2011

 Antimalarial Drugs
QUINOLINES AND RELATED COMPOUNDS
4-aminoquinolines
Chloroquine
Amodiaquine
8-aminoquinoline
Primaquine
aryl aminoalcohol group
lumefantrine,quinine,mefloquine and halofantrine.
hydroxynaphthoquinone
Atovaquone
Artemisinin and its derivatives-
ArtemisininArtemetherArtesunateDihydroartemisininArtemotil
Biguanide compound - Proguanil
Tetracyclines-Tetracycline,Doxycycline
lincosamide antibiotic-Clindamycin
Sulfonamide-Sulfadoxine
Diaminopyrimidine -Pyrimethamine-used in combination with
sulfadoxine
VIKASENDU AGARWAL 6/7/2011
 Chloroquine

a 4-aminoquinoline
Virtually useless against P. falciparum infections
still maintains considerable efficacy for the
treatment of P. vivax, P. ovale and P. malariae
infections.
Chloroquine interferes with parasite haem
detoxification
Formulations:Tablets containig 100 mg or 150 mg
of chloroquine base as phosphate or sulfate.

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 Toxicity
A low safety margin,very dangerous in overdosage
Principle limiting adverse effects in practice
 unpleasant taste, which may upset children, and
 pruritus,severe in dark-skinned patients
Less common side effects
 headache,
 various skin eruptions and
 gastrointestinal disturbances, such as nausea, vomiting and diarrhoea.
Rarely CNS toxicity
 convulsions and
 mental changes
Acute overdosage-
 extremely dangerous and death can occur within a few hours.
 no specific treatment, although
 diazepam and adrenaline administered together are beneficial
VIKASENDU AGARWAL 6/7/2011
 Drug interactions

Possibility of arrhythmias with halofantrine or other

drugs prolonging QT interval;
A possible increased risk of convulsions with
mefloquine;
Reduced absorption with antacids;
An increased risk of acute dystonic reactions with
metronidazole;
A possible antagonistic effect on the antiepileptic
effects of carbamazepine and sodium valproate;

VIKASENDU AGARWAL 6/7/2011

 Amodiaquine

Mannich base 4-aminoquinoline

Mode of action similar to that of chloroquine
Effective against some chloroquine-resistant strains of P.
falciparum, although there is crossresistance.
Formulations
Tablets containing 200 mg of amodiaquine base as
hydrochloride or 153.1 mg of base as chlorohydrate.
Toxicity
Similar to those of chloroquine.
Less pruritus and G.I.side effects
A much higher risk of agranulocytosis
Hepatitis when used for prophylaxis
Large doses-cause syncope, spasticity, convulsions and
involuntary
VIKASENDU AGARWAL movements. 6/7/2011
 Quinine

An alkaloid derived from the bark of the Cinchona tree.

mechanisms of actions -inhibition of parasite haem
detoxification
Formulations
Tablets of quinine hydrochloride, quinine
dihydrochloride, quinine sulfate and quinine bisulfate
containing 82%, 82%, 82.6% and 59.2% quinine base
respectively.
Injectible solutions of quinine hydrochloride, quinine
dihydrochloride and quinine sulfate containing 82%,
82% and 82.6% quinine base respectively.
VIKASENDU AGARWAL 6/7/2011
 Toxicity

cinchonism -tinnitus, impaired high tone hearing, headache, nausea,

dizziness and dysphoria, and sometimes disturbed vision
 More severe manifestations include vomiting, abdominal pain,
diarrhoea and severe vertigo.
Massive haemolysis with renal failure (“black water fever- etiology
remains uncertain).
hyperinsulinaemic hypoglycaemia
particularly common in pregnancy (50% of quinine-treated women
with severe malaria in late pregnancy
Intravenous quinine should be given only by infusion, never
injection.
Overdosage of quinine may cause oculotoxicity, including blindness
from direct retinal toxicity, and cardiotoxicity, and can be fatal .

VIKASENDU AGARWAL 6/7/2011

 Drug interactions

causes an approximately 10% prolongation of the

electrocardiograph QT interval –drugs that may
prolong the QT interval should not be given with
quinine
Antiarrhythmics, such as flecainide and amiodarone,
should probably be avoided.
There might be an increased risk of ventricular
arrhythmias with antihistamines such as terfenadine,
and with antipsychotic drugs such as pimozide and
thioridazine
Quinine increases the plasma concentration of digoxin

VIKASENDU AGARWAL 6/7/2011

 Mefloquine

Effective against all forms of malaria.

Formulations
Mefloquine is administered by mouth as the hydrochloride salt
(250 mg base equivalent to 274 mg hydrochloride salt). Tablets
containing 250 mg base
Toxicity
G.I.-nausea, vomiting, abdominal pain, anorexia, diarrhoea,
Neuropsychiatric disturbances (seizures, encephalopathy,
psychosis) occur in approximately 1 in 1000 patients treated in
Asia and in 1 in 20 patients following severe malaria.
Mefloquine should not be given with halofantrine because it
causes QT prolongation.

VIKASENDU AGARWAL 6/7/2011

 Drug interactions

Increased risk of arrhythmias with beta blockers,

calcium channel blockers, amiodarone, pimozide,
digoxin or antidepressants;
there is also a possible increase in the risk of
convulsions with chloroquine and quinine.
Mefloquine concentrations are increased when
given with ampicillin, tetracycline and
metoclopramide.
Caution should be observed with alcohol.

VIKASENDU AGARWAL 6/7/2011

 Lumefantrine (benflumetol)

Lumefantrine is a racemic fluorine derivative developed

in China
only available in an oral preparation coformulated with
artemether.
This ACT is highly effective against multidrug resistant P.
falciparum.
Formulations
Tablets containig 20 mg of artemether and 120 mg of
lumefantrine.
Toxicity
Remarkably well tolerated
Reported side effects are generally mild – nausea,
abdominal discomfort, headache and dizziness
VIKASENDU AGARWAL 6/7/2011
 Primaquine

Effective against intrahepatic forms of all types of malaria parasite.

used to provide radical cure of P. vivax and P. ovale malaria, in combination with
a blood schizontocide
Primaquine is also gametocytocidal against P. falciparum and has significant
blood stages activity against P. vivax (and some against asexual stages of P.
falciparum).
The mechanism of action is unknown.
Formulations
Tablets containing 5.0 mg,7.5 mg or 15.0 mg of primaquine base as diphosphate.
Toxicity
most important adverse effects are haemolytic anaemia in patients with G6PD
deficiency,
Drug interactions:Drugs liable to increase the risk of haemolysis or bone marrow
suppression should be avoided.

VIKASENDU AGARWAL 6/7/2011

 Atovaquone

Active against all Plasmodium species.

It also inhibits pre-erythrocytic development in the liver, and oocyst
development in the mosquito.
It is combined with proguanil for the treatment of malaria – with which it is
synergistic.
Atovaquone interferes with cytochrome electron transport
Formulations
Tablets containing 250 mg atovaquone and 100 mg of proguanil
hydrochloride for adults.
Tablets containing 62.5 mg atovaquone and 25 mg of proguanil
hydrochloride for paediatric use.
Toxicity
Generally very well tolerated
Skin rashes, headache, fever, insomnia, nausea, diarrhoea, vomiting, raised
liver enzymes, hyponatraemia and, very rarely, haematological disturbances
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 Artemisinin and its derivatives-
Artemisinin

Artemisinin is an actone extracted from the leaves of

Artemisia annua (sweet wormwood).
Used in China for the treatment of fever for over a
thousand years.
A potent and rapidly acting blood schizontocide
Active against all Plasmodium species
An unusually broad activity against asexual parasites,
killing all stages from young rings to schizonts
In P. falciparum malaria, artemisinin also kills the
gametocytes – including the stage 4 gametocytes, whichm
are otherwise sensitive only to primaquine
VIKASENDU AGARWAL 6/7/2011
 Artemisinin

Artemisinin and its derivatives inhibit an essential

calcium adenosine triphosphatase, PfATPase 6
Should always be used as combination therapy to
protect them from resistance.
Formulations
Tablets and capsules containing 250 mg of
artemisinin.
Suppositories containing 100,200,300,400 or 500
mg of artemisinin.

VIKASENDU AGARWAL 6/7/2011

 Toxicity

Artemisinin and its derivatives are safe and

remarkably well tolerated
Type 1 hypersensitivity reactions in
approximately 1 in 3000 patients
Reports of mild gastrointestinal disturbances,
dizziness, tinnitus, reticulocytopenia,
neutropenia, elevated liver enzyme values, and
ECG abnormalities
should be avoided in first trimester patients with
uncomplicated malaria

VIKASENDU AGARWAL 6/7/2011

 Artemether

Formulations
Capsules -40 mg and tablets containing 50 mg of
artemether.
Injection 80 mg/ml for adults or 40 mg/1 ml for
paediatric use.
Coformulation with lumefantrine:
Tablets containing 20 mg of artemether and 120 mg
of lumefantrine.
Toxicity
similar to that of artemisinin

VIKASENDU AGARWAL 6/7/2011

 Artesunate
 Soluble in water but has poor stability in aqueous
solutions
 drawn up in sodium bicarbonate to form sodium
artesunate immediately before injection.
 Can be given orally, rectally or I.M./I.V. routes.
 There are no coformulations currently available.
Formulations
 Tablets containing 50 or 200 mg of artesunate.
 Injection containing 60 mg of anhydrous artesunaic acid
with a separate ampoule of 5% sodium bicarbonate
solution.
 Rectal capsules -100 mg or 400 mg of sodium
artesunate.
VIKASENDU AGARWAL 6/7/2011
 Dihydroartemisinin

Main active metabolite of the artemisinin

derivatives,
Can also be given orally and rectally as a drug in its
own right.
Formulations
Tablets containig 20mg,60 mg or 80 mg of
dihydroartemisinin.
Suppositories containig 80mg dihydroartemisinin.
Toxicity
As for artemisinin.

VIKASENDU AGARWAL 6/7/2011

 Artemotil

Ethyl ether of artemisinin

Given by intramuscular injection only.
Formulations
Ampoules containig 150 mg/2 ml solution.
Toxicity
As for artemisinin.

VIKASENDU AGARWAL 6/7/2011

 Proguanil

Metabolized in the body to the active metabolite,

cycloguanil.
Cycloguanil inhibits plasmodial dihydrofolate
reductase.
It is possibly active against pre-erythrocytic forms of
the parasite and is a slow blood schizontocide.
Proguanil also has sporontocidal activity, rendering
the gametocytes non-infective to the mosquito vector.
Proguanil is given as the hydrochloride salt in
combination with atovaquone.

VIKASENDU AGARWAL 6/7/2011

 Proguanil

Formulations
Tablets of 100 mg of proguanil hydrochloride
containing 87 mg of proguanil base.
In coformulation with atovaquone:
Tablets of 250 mg of atovaquone and 100 mg of
proguanil hydrochloride for adults.
Tablets of 62.5 mg of atovaquone and 25 mg of
proguanil hydrochloride for paediatric use.

VIKASENDU AGARWAL 6/7/2011

 Proguanil

Toxicity
Mild gastric intolerance, diarrhoea and occasional
aphthous ulceration and hair loss
Haematological changes (megaloblastic anaemia and
pancytopenia) have been reported in patients with
severe renal impairment
Use cautiously in patients with renal impairment and
the dose reduced according to the degree of
impairment.
Drug interactions
Absorption of proguanil is reduced with concomitant
administration
VIKASENDU AGARWAL of magnesium trisilicate. 6/7/2011
 Tetracycline
Derived from certain Streptomyces species
Inhibitors of aminoacyl-tRNA binding during protein synthesis.
Formulations
Capsules and tablets containing tetracycline hydrochloride, equivalent to
231 mg of tetracycline base.
Toxicity
Gastrointestinal effects, Dry mouth, glossitis,oeophageal ulceration
Overgrowth of Candida
Tetracyclines accumulate in patients with renal impairment and this may
renal failure(Doxycycline is safer).
Use of out-of-date tetracycline -- a reversible Fanconi type syndrome due to
anhydroepitetracycline.
Tetracyclines discoloration of teeth and enamel hypoplasia.
Interfere with bone growth in young infants or pregnant women.
Should therefore not be given to pregnant or lactating women, or children
aged up to 8 years.
Nephrotoxicity may be exacerbated with diuretics
Potentially hepatotoxic drugs should be avoided.
VIKASENDU AGARWAL 6/7/2011
 Doxycycline

A Tetracycline derivative
Better safety profile in patients with renal insufficiency,
where it may be used with caution
May be given orally or intravenously.
Formulations
Capsules or tablets containing 100 mg of doxycycline salt as
hydrochloride.
Toxicity
children aged up to 8 years.
Less accumulation in patients with renal impairment.
Should not be given to pregnant or lactating women, or

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 Clindamycin
A chlorinated derivative of lincomycin.
Inhibits the early stages of protein synthesis by a mechanism
similar to that of the macrolides.
May be administered by mouth as capsules or parenterally
Formulations
Capsules containing 75 mg,150 mg or 300 mg of clindamycin base
as hydrochloride.
Toxicity
Diarrhoea/pseudomembranous colitis/other G.I.side effects
Around 10% of patients develop a hypersensitivity reaction
Some parenteral formulations contain benzyl alcohol, which may
cause fatal “gasping syndrome” in neonates.
Drug interactions
Clindamycin may enhance the effects of drugs with neuromuscular
blocking activity and there is a potential danger of respiratory
depression
VIKASENDU AGARWAL 6/7/2011
 Sulfadoxine

A slowly eliminated sulfonamide.

Competitive inhibitors of dihydropteroate synthase,
Formulations
Fixed-dose combination of 20 parts sulfadoxine with 1 part pyrimethamine
Tablets 500 mg sulfadoxine + 25 mg pyrimethamine.
Ampoules containing 500 mg of sulfadoxine and 25 mg of pyrimethamine /
2.5 ml of injectable solution for intramuscular use.
Toxicity
Allergic reactions can be severe
Nausea, vomiting, anorexia and diarrhoea
Crystalluria
Cutaneous manifestations can be severe and include pruritus,
photosensitivity reactions, exfoliative dermatitis, erythema nodosum, toxic
epidermal necrolysis and Stevens-Johnson syndrome .

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 Pyrimethamine
A Diaminopyrimidine used in combination with a sulfonamide,
usually sulfadoxine or dapsone.
Antimalarial activity by inhibiting plasmodial dihydrofolate reductase
Slow-acting blood schizontocide and is also possibly active against
pre-erythrocytic forms and inhibits sporozoite development in the
mosquito vector.
Formulations
Fixed-dose combination 20 parts sulfadoxine with 1 part
pyrimethamine
Tablets containing 500 mg of sulfadoxine and 25 mg of
pyrimethamine.
Ampoules containing 500 mg of sulfadoxine and 25 mg of
pyrimethamine in 2.5 ml of injectable solution for intramuscular use.

VIKASENDU AGARWAL 6/7/2011

 Pyrimethamine

Toxicity
Prolonged periods depression of haematopoiesis Skin
rashes and hypersensitivity
Larger doses may cause gastrointestinal symptoms
Drug interactions
Administration with other folate antagonists such as
cotrimoxazole, trimethoprim, methotrexate or phenytoin
may exacerbate bone marrow depression.
Given with some benzodiazepines, there is a risk of
hepatotoxicity.

VIKASENDU AGARWAL 6/7/2011

 Artemisinin-based combination therapy

an artemisinin derivative combined with a long acting

antimalarial (amodiaquine, lumefantrine, mefloquine or
sulfadoxine-pyrimethamine).
The artemisinins produce rapid clearance of parasitaemia
and rapid resolution of symptoms,by reducing parasite
numbers 100- to 1000-fold per asexual cycle of the parasite
(a factor of approximately 10 000 in each 48-h asexual cycle
Because artemisinin and its derivatives are eliminated
rapidly, when given alone or in combination with rapidly
eliminated compounds (tetracyclines, clindamycin), a 7-day
course of treatment with an artemisinin compound is
required .

VIKASENDU AGARWAL 6/7/2011

 Artemisinin-based combination therapy

This long duration of treatment with the artemisinins can

be reduced to 3 days when given in combination with
slowly eliminated antimalarials.
With this shorter 3-day course, the complete clearance of
all parasites is dependent on the partner medicine being
effective and persisting at parasiticidal concentrations
until all the infecting parasites have been killed.
This also results in the artemisinin component being
protected from resistance by the partner medicine, while
the partner medicine is also partly protected by the
artemisinin derivative.

VIKASENDU AGARWAL 6/7/2011

 Artemisinin-based combination therapy

An additional advantage from a public health perspective

is the ability of the artemisinins to reduce gametocyte
carriage and, thus, the transmissibility of malaria.
This contributes to malaria control, particularly in areas
of low-to-moderate endemicity.
To eliminate at least 90% of the parasitaemia, a 3-day
course of the artemisinin is required to cover up to three
post-treatment asexual cycles of the parasite.
This ensures that only about 10% of the parasitamia is
present for clearance by the partner medicine, thus
reducing the potential for development of resistance.

VIKASENDU AGARWAL 6/7/2011

 Artemisinin-based combination therapy

It is the properties of the partner medicine that

determine the efficacy and choice of combination.
Resistance to the artemisinins’ partner medicines
compromises the efficacy of the ACT.

VIKASENDU AGARWAL 6/7/2011

 Artemisinin-based combination therapy

In summary, the ACT options now recommended for

treatment of uncomplicated falciparum malaria in
alphabetical order are:
artemether plus lumefantrine,
artesunate plus amodiaquine,
artesunate plus mefloquine,
artesunate plus sulfadoxine-pyrimethamine,
dihydroartemisinin plus piperaquine.

VIKASENDU AGARWAL 6/7/2011

 Artemisinin-based combination therapy

Fixed-dose combination (FDC) formulations are

strongly preferred and recommended over blistered
co-packaged or loose tablets combinations to
promote adherence totreatment.
contribute to delaying artemisinin resistance as they
avoid artemisinin monotherapies being distributed
available for all recommended ACTs, except
artesunate plus SP.

VIKASENDU AGARWAL 6/7/2011