TREATMENT OF MALARIA:

Antimalarial drugs;

1) 4 – Methoxyquinolines;
 Quinine: 10mg / kg b.w per dose 8 hourly I.V or oral); severe infection
 Quinine + Clindamycin
 Quinine + Tetracycline
 Mefloquine + Artemisinin
 Mefloquine; used alone for prophylaxis

2) 4 – Aminoquinolines;
 Chloroquine
 Amodiaquine

3) 8 – Aminoquinolines;
 Primaquine – for eradication of exoerythrocytic forms of P. Vivax,
P. Ovale and gametocidal against P. Falciparum.
(ADR: causes massive haemolysis in G 6PD – def.)
4) Sulphonamides combination;
Sulfadoxine / Pyrimethamine e.g. Fansidar
Sulphamethoxypyridazine / pyrimethamine e.g.
Metakelfin

5) Artemisinin derivatives – from Artemisia annua;

 Artemether e.g. Paluther
 Artesunate; a semi-synthetic artemisinin e.g. arsumax
 Dihydroartemisinin; the active metabolite of artemisinin
e.g. cotecxin

Artemether + lumefantrin = Coartem*

Artesunate + Mefloquine = Arteqiun
Artesunate + Amodiaquine = Larimal
Artesunate + Sulphamethoxypyridazine + Pyrimethamine = Co-Arinate
Dihydroartemisinin + Piperaquine = Duo-cotecxin
Artemisinin 62.5mg + Piperaquine 375mg = Artequick
6) Biguanides & other combinations;
 Proguanil 100mg + Atovaquone 250mg = malarone
 Proguanil alone used only in prophylaxis

7) 9 – Phenanthrenemethanols;
 Halofantrine ( Halfan)
 lumefantrine; used only in combinations
Antimalarial drugs include;
1)Quinine and related agents
2)Chloroquine
3)Amodiaquine
4)Pyrimethamine
5)Sulphadoxine
6)Proguanil
7)Mefloquine
8)Atovaquone
9)Primaquine
10)Artemisinin and derivatives
11)Halofantrine
12)Doxycycline
13)Clindamycin
 1) QUININE AND RELATED AGENTS
 Quinine has a long history stretching from Peru, and the discovery of the
cinchona tree, and the potential uses of its bark, to the current day and a
collection of derivatives that are still frequently used in the prevention and
treatment of malaria.

 Quinine is a 4 – Methoxyquinoline, an alkaloid that acts as a blood

schizonticidal and weak gametocide against Plasmodium vivax and
Plasmodium malariae.

 It is especially useful in areas where there is known to be a high level of

resistance to chloroquine, mefloquine, and sulfa drug combinations with
pyrimethamine.

 Quinine is also used in post-exposure treatment of individuals returning from an

area where malaria is endemic.
 Quinimax and quinidine are the two most commonly used alkaloids related
to quinine in the treatment or prevention of malaria.
Quinimax is a combination of four alkaloids (quinine, quinidine, cinchoine
and cinchonidine). This combination has been shown in several studies to
be more effective than quinine, supposedly due to a synergistic action
between the four cinchona derivatives.
Quinidine is a direct derivative of quinine. It is a distereoisomer, thus
having
similar anti-malarial properties to the parent compound. Quinidine is
recommended only for the treatment of severe cases of malaria.
 Mechanism of action;

As an alkaloid, it is accumulated in the food vacuoles of Plasmodium species,

especially Plasmodium falciparum.

It acts by inhibiting the hemozoin biocrystallization, thus facilitating an

aggregation of cytotoxic heme.

Quinine is more toxic as a blood schizonticidal agent than chloroquine.

 Pharmacokinetics
Doses can be given by oral, intravenous or intramuscular routes.
The oral bioavailability of quinine is 76 to 88% in healthy adults.
Quinine tablets may be administered without regard to meals.
Generally 10mg/kg b.w per dose every 8-hours is routinely given
(both I.V & oral)
Quinine is moderately protein-bound in blood of healthy subjects, ranging from
69
to 92%.
Quinine is metabolized almost exclusively via hepatic oxidative cytochrome
P450 (CYP) pathways.
Quinine is eliminated primarily via hepatic biotransformation.
Approximately 20% of quinine is excreted unchanged in urine. Because quinine
is
reabsorbed when the urine is alkaline, renal excretion of the drug is twice as rapid
when the urine is acidic than when it is alkaline.
 Adverse effects
Quinine can adversely affect almost every body system.

The most common adverse events associated with quinine use are a cluster

of

symptoms called “cinchonism”, which occurs to some degree in almost all

patients taking quinine.

Symptoms of mild cinchonism include headache, vasodilation and sweating,

nausea, tinnitus, hearing impairment, vertigo or dizziness, blurred vision, and

disturbance in color perception.

More severe symptoms of cinchonism are vomiting, diarrhea, abdominal pain,

deafness, blindness, and disturbances in cardiac rhythm or conduction.

Most symptoms of cinchonism are reversible and resolve with discontinuation

of quinine.
Hematologic: hypoprothrombinemia, hemolytic uremic syndrome (HUS),

thrombotic thrombocytopenic purpura, blackwater fever, aplastic anemia,

and lupus anticoagulant.

Neuropsychiatric: headache, diplopia, confusion, altered mental status,

seizures, coma,

Dermatologic: cutaneous rashes,

Respiratory: asthma, dyspnea, pulmonary edema.

Cardiovascular: atrioventricular block, irregular rhythm, QT prolongation

Gastrointestinal: nausea, vomiting, diarrhea, abdominal pain, gastric

irritation
Hepatobiliary: granulomatous hepatitis, hepatitis, jaundice, and abnormal

liver function tests.

Metabolic: Quinine can cause hypoglycaemia through its action of
stimulating insulin secretion

Musculoskeletal: myalgias and muscle weakness.

Renal: hemoglobinuria, renal failure, renal impairment, and acute interstitial

nephritis.
 2) CHLOROQUINE
Mechanism of action
 Chloroquine is a 4-aminoquinoline compound with a complicated and still

unclear mechanism of action.

 Chloroquine is used in malaria treatment and prophylaxis where resistance is

not encountered.

 It is believed to reach high concentrations in the vacuoles of the parasite, which,

due to its alkaline nature, raises the internal pH.

 It controls the conversion of toxic heme to hemozoin by inhibiting the

biocrystallization of hemozoin, thus poisoning the parasite through excess

levels of toxicity.
Other potential mechanisms through which it may act include interfering with the

biosynthesis of parasitic nucleic acids and the formation of a chloroquine-haem

or chloroquine-DNA complex.

The most significant level of activity found is against all forms of the schizonts

(with the obvious exception of chloroquine-resistant P. falciparum and P. vivax

strains)

Chloroquine also has a significant anti-pyretic and anti-inflammatory effect when

used to treat P. vivax infections.

Pharmacokinetics
Recommendation by the WHO, involves giving an initial dose of 10 mg/kg

followed 6–8 hours later by 5 mg/kg, then 5 mg/kg on the following 2 days.

For chemoprophylaxis: 5 mg/kg/week (single dose) or 10 mg/kg/week divided

into 6 daily doses is advised. Chloroquine is only recommended as a prophylactic

Drug in regions only affected by P. vivax and sensitive P. falciparum strains.

It is considered very safe to use during pregnancy.

Adverse effects
o gastrointestinal disturbances
o skin eruptions
o headache with visual disturbances
o hearing disorders / tinnitus
o blood dyscrasias
o skin photosensitivity
o myopathy
oNeuropathy
oHypotension
oECG changes
 3) AMODIAQUINE

Amodiaquine is a 4-aminoquinoline anti-malarial drug similar in structure and

mechanism of action to Chloroquine.

It is thought to be more effective in clearing parasites in uncomplicated malaria

than Chloroquine, thus leading to a faster rate of recovery.

The drug should be given orally in doses between 25 mg/kg and 35 mg/kg

over 3 days in a similar method to that used in Chloroquine administration.

Adverse effects

Adverse reactions are generally similar in severity and type to that seen in

Chloroquine treatment.

However, some fatal adverse effects of the drug were noted during the 1980s,

thus reducing its usage in chemoprophylaxis. The WHO's most recent advice on

the subject still maintains that the drug should be used when the potential risk of

not treating an infection outweighs the risk of developing side effects.

In addition, bradycardia, itching, nausea, vomiting, abdominal pain, blood and

hepatic disorders have been recorded.

 4) PYRIMETHAMINE
Indications
1)Treatment of Acute Malaria:
 It should not be used alone to treat acute malaria.
 Conjoint use of pyrimethamine with a sulfonamide (e.g. with sulfadoxine &
sulphamethoxypyridazine to give fansidar & metakelfin respectively)
2)Chemoprophylaxis of Malaria:
 Indicated for the chemoprophylaxis of malaria due to susceptible strains of
plasmodia.
 Resistance to pyrimethamine is however prevalent worldwide. It is not
suitable as a prophylactic agent for travelers to most areas.
3)Treatment of Toxoplasmosis:
Used conjointly with a sulfonamide, since synergism exists with this combination.
 Mechanism of Action
Pyrimethamine acts by inhibiting dihydrofolate reductase in the parasite thus

preventing the biosynthesis of purines and pyrimidines. It therefore halts the

processes of DNA synthesis, cell division and reproduction. This activity is

primarily directed on the schizonts during the hepatic and erythrocytic phases.

It does not destroy gametocytes and is highly selective against plasmodia. It

is

also active against Toxoplasma gondii.

Pyrimethamine possesses blood schizonticidal and some tissue schizonticidal

activity against malaria parasites of humans. However, the 4-amino-quinoline

compounds are more effective against the erythrocytic schizonts.

Pharmacokinetics
Pyrimethamine (Daraprim) is an antiparasitic compound available in tablet form

(25mg) for oral administration.

Pyrimethamine is well absorbed with peak levels occurring between 2 to 6 hours

following administration.

Pyrimethamine is 87% bound to human plasma proteins.

It is eliminated slowly and has a plasma half-life of approximately 96 hours.

Dose and Administration
1) Treatment of malaria
 Dosage of 25 mg daily for 2 days with a sulfonamide will initiate transmission
control and suppression of non-falciparum malaria.
 25mg pyrimethamine + 500mg sulphadoxine = Fansidar
 25mg pyrimethamine + 500mg sulphamethoxypyridazine = Metakelfin
 For Chemoprophylaxis of Malaria:
o Adults and pediatric patients over 10 years — 25 mg (1 tablet) once
weekly
o Children 4 through 10 years — 12.5 mg (1/2 tablet) once weekly
o Infants and children under 4 years — 6.25 mg (1/4 tablet) once
weekly.
2) Treatment of Toxoplasmosis:

 The adult starting dose is 50 to 75 mg of the drug daily, together with 1 to

4 g daily of a sulfonamide of the sulfapyrimidine type, e.g., sulfadoxine for

1 to 3 weeks, depending on the response of the patient and tolerance to

therapy.

 Concurrent administration of folinic acid is strongly recommended in all

patients (folinic acid dose 10mg OD)

 Adverse effects;

Mainly hypersensitivity reactions including;

oStevens-Johnson syndrome

oToxic epidermal necrolysis (TEN)

oErythema multiforme

oAnaphylaxis

Hyperphenylalaninemia, can occur particularly when pyrimethamine is

administered concomitantly with a sulfonamide.

 6)Artemesinin and derivatives
Artemisinin is an antimalarial agent extracted from the dry leaves of the Chinese

herb Artemisia annua (qinghaosu or sweet wormwood).

Artemisinin has a very rapid action and the vast majority of acute patients

treated show significant improvement within 1–3 days of receiving treatment.

It has demonstrated the fastest clearance of all anti-malarials currently used and

acts primarily on the trophozite phase, thus preventing progression of the

disease.

Semi-synthetic artemisinin derivatives (e.g. artesunate, artemether) are easier

to

use than the parent compound and are converted rapidly once in the body to the

active compound dihydroartemesinin.

 Pharmacokinetics

It is only used in combination therapy to prevent the development of resistance

for severe acute cases of drug-resistant P. falciparum.

On the first day of treatment 20 mg/kg should be given, this dose is then

reduced

to 10 mg/kg per day for the 6 following days.

 Adverse effects
Few side effects are associated with artemesinin use.

 Common adverse effects include;

oHeadaches

oNausea / vomiting

oAbnormal bleeding

oDark urine

oItching

oDrug fever
 Artemisinin Derivatives
1) Artemether;

 Artemether is a methyl ether derivative of Dihydroartemesinin.

 It is similar to Artemesinin in mode of action but demonstrates a reduced

ability as a hypnozoiticidal compound, instead acting more significantly to
decrease gametocyte carriage.

 Similar restrictions are in place, as with Artemesinin, to prevent the

development of resistance, therefore it is only used in combination therapy for
severe acute cases of drug-resistant P. falciparum.

 It should be administered in a 7 day course with 4 mg/kg given per day for 3
days, followed by 1.6 mg/kg for 3 days. Side effects of the drug are few but
include potential neurotoxicity developing if high doses are given.
2) Artesunate;

 Artesunate is a hemisuccinate derivative of the active metabolite

Dihydroartemisin.

 Currently it is the most frequently used of all the Artemesinin-type drugs.

 Its only effect is mediated through a reduction in the gametocyte transmission.

 It is used in combination therapy and is effective in cases of uncomplicated P.

falciparum.

 The dosage recommended by the WHO is a 5 or 7 day course (depending on

the predicted adherence level) of 4 mg/kg for 3 days (usually given in
combination with Mefloquine) followed by 2 mg/kg for the remaining 2 or 4
days. In large studies carried out on over 10,000 patients in Thailand no
adverse effects have been shown.
3) Dihydroartemisinin;

 Dihydroartemisinin is the active metabolite to which Artemesinin is reduced.

 It is the most effective Artemesinin compound and the least stable.

 It has a strong blood schizonticidal action and reduces gametocyte

transmission.

 It is used for therapeutic treatment of cases of resistant and uncomplicated P.

falciparum. 4 mg/kg doses are recommended on the first day of therapy

followed by 2 mg/kg for 6 days.

 As with Artesunate, no side effects to treatment have thus far been recorded.
4) Arteether;

 Arteether is an ethyl ether derivative of Dihydroartemesinin.

 It is used in combination therapy for cases of uncomplicated resistant

P. falciparum.

 The recommended dosage is 150 mg/kg per day for 3 days given by IM

injections.

 With the exception of a small number of cases demonstrating neurotoxicity

following parenteral administration no side effects have been recorded.

 7)Mefloquine
Mefloquine was developed during the Vietnam War and is chemically related to

quinine. It was developed to protect American troops against multi-drug

resistant P. falciparum.

It is a very potent blood schizonticide with a long half-life and thought to act
by

forming toxic heme complexes that damage parasitic food vacuoles.

Indication & Dosing

Mefloquine is effective in prophylaxis and for acute therapy. It is now strictly

used for resistant strains (and is usually combined with Artesunate).

A dose of 15–25 mg/kg is recommended, depending on the prevalence of

Mefloquine resistance.

The effects during pregnancy are unknown. It is not recommended for use

during the first trimester, although considered safe during the second and

third trimesters.

Mefloquine can only be taken for a period up to 6 months (due to side effects)

following which other drugs again need to be taken.

 Adverse effects
Mefloquine frequently produces side effects, including;

oGIT effects;

•nausea & vomiting

•Diarrhea / abdominal pain

oCNS effects;

•affective and anxiety disorders

•Hallucinations / dizziness

•sleep disturbances

•Psychosis

•toxic encephalopathy

•convulsions and delirium

oCardiovascular effects;

•bradycardia and sinus arrhythmia

 Drug Interaction;

Concomitant administration of Mefloquine (Lariam) and other related

compounds

(e.g., quinine, quinidine and chloroquine) may produce electrocardiographic

abnormalities and increase the risk of convulsions.

If these drugs are to be used in the initial treatment of severe malaria, Lariam

administration should be delayed at least 12 hours after the last dose.

There is evidence that the use of halofantrine after mefloquine causes a

significant lengthening of the QTc interval.

 8)Primaquine
Primaquine is a highly active 8-aminoquinoline that is used in treating all types

of malaria infection.

It is most effective against gametocytes but also acts on hypnozoites, blood

schizonticytes and the dormant plasmodia in P. vivax and P. ovale.

It is the only known drug to cure both relapsing malaria infections and acute

cases.

Mechanism of Action;
The mechanism of action is not fully understood but it is thought to mediate

some effect through creating oxygen free radicals that interfere with the

plasmodial electron transport chain during respiration.

 Adverse effects

There are few significant side effects including;

oDizziness & syncope

oAbdominal cramps

oChest tightness

oHaemolysis in G6PD-deficiency

oAnaemia

oSuppression of myeloid activity

oErythema multiforme & Steven Johnson syndrome

 9)Halofantrine
Halofantrine is a relatively new drug developed by the Walter Reed Army

Institute of Research in the 1960s. It is a phenanthrene methanol.

It is chemically related to Quinine and acts as a blood schizonticide

effective against all plasmodium parasites.

 Mechanism of Action
The mechanism of action is similar to other anti-malarials i.e. Cytotoxic

complexes are formed with ferritoporphyrin XI that cause plasmodial

membrane damage.

A dose of 8 mg/kg of Halofantrine is advised to be given in three doses at six

hour intervals for the duration of the clinical episode.

It has very variable bioavailability and has been shown to have potentially

high levels of cardiotoxicity.

It is not recommended for children under 10 kg despite data supporting the use

and demonstrating that it is well tolerated.

 Adverse effects
The most frequently experienced side-effects include;

• Nausea

•Abdominal pain & diarrhoea

•Pruritus

•Severe ventricular dysrhythmias due to prolongation of the QTc interval.

Halofantrine is not recommended for use in pregnancy and lactation, in small

children, or in patients who have taken Mefloquine previously.

 10)Proguanil
Proguanil (Chloroguanadine) is a biguanide; a synthetic derivative of
pyrimidine.
It was developed in 1945 by a British Antimalarial research group.
It has no known effect against hypnozoites therefore is not used in the
prevention of relapse.
It has a weak blood schizonticidal activity and is not recommended for
therapy of acute infection.

However it is useful in prophylaxis when combined with Atovaquone i.e.

Malarone.

The Proguanil- Chloroquine combination does not provide effective

protection

against resistant strains of P. falciparum.

Mechanism of Action & Pharmacokinetics / Adverse effects;
Proguanil has many mechanisms of action but primarily is mediated through

conversion to the active metabolite cycloguanil pamoate. This inhibits the malarial

dihydrofolate reductase enzyme.

3 mg/kg is the advised dosage per day, (hence approximate adult dosage is

200 mg).

The pharmacokinetic profile of the drugs indicates that a half dose, twice daily

maintains the plasma levels with a greater level of consistency, thus giving a

greater level of protection.

There are very few side effects to Proguanil, with slight hair loss and mouth

ulcers being occasionally reported following prophylactic use.

 11)Doxycycline
Probably one of the more prevalent antimalarial drugs prescribed, due to its

relative effectiveness and cheapness, doxycycline is a tetracycline compound

derived from oxytetracycline.

Doxycycline is used primarily for chemoprophylaxis in areas where chloroquine

resistance exists.

It can also be used in combination with quinine to treat resistant cases of

P. falciparum but has a very slow action in acute malaria, and should not be

used as monotherapy.
 Mechanism of Action;
Doxycycline is a bacteriostatic agent that acts to inhibit the process of protein

synthesis by binding to the 30S ribosomal subunit thus preventing the 50s and

30s units from bonding.

Indication & Dosing;

When treating acute cases and given in combination with quinine; 100 mg of

doxycycline should be given per day for 7 days.

In prophylactic therapy, 100 mg (adult dose) of doxycycline should be given

every

day; 1-week before exposure, during exposure and 1-week after exposure to

malaria.
 Adverse effects

The most commonly experienced side effects are;

• permanent enamel hypoplasia

• transient depression of bone growth

• gastrointestinal disturbances

• photosensitivity.

Due to its effect of bone and tooth growth it is not used in children under 8,

pregnant or lactating women and those with a known hepatic dysfunction.

 12)Clindamycin
Clindamycin is a derivative of Lincomycin, with a slow action against blood

schizonticides.

It is only used in combination with Quinine in the treatment of acute cases of

resistant P. falciparum infections and not as a prophylactic.

Being more expensive and toxic than the other antibiotic alternatives, it is
used

only in cases where the Tetracyclines are contraindicated (for example in

children).

Clindamycin should be given in conjunction with Quinine as a 300 mg dose (in

adults) four times a day for 5 days.

 Adverse Effects
The side effects recorded in patients taking Clindamycin are;

• nausea

•vomiting

•abdominal pains and cramps.

•Pseudomembranous colitis (caused by Clostridium difficile)

These adverse effects can however be alleviated by consuming large quantities

of water and food when taking the drug.

Pseudomembranous colitis also develops in some patients; this condition may

be

fatal in a small number of cases.

 13)Atovaquone
Atovaquone is only available in combination with Proguanil under the name

Malarone.

It is most commonly used as prophylaxis by travelers; also used for treatment of
acute attack of malaria.
 Chemoprophylaxis drugs:

 Proguanil (paludrine) 200mg daily for 1 – 2 days before exposure, then daily
during exposure and 4 weeks after exposure.

 Mefloquine ( larium): 250mg once weekly 1/52 before exposure , during

exposure and 4/52 post exposure.

 Chloroquine (In sensitive areas): 300mg once weekly for 1/52 before exposure,
during exposure and 4/52 after exposure

 Doxycline 100mg daily for 1/52 before exposure, during exposure and 4
weeks
after exposure.

 Malarone (proguanil + atovaquone); 1-tab OD 1-2 days before exposure,

during exposure and 4-weeks after exposure.
 Drugs used for the Prevention of Malaria in Travellers

Drug Use Adult Dosage

Chloroquine Areas without resistant P falciparum 500 mg weekly

Malarone Areas with multidrug-resistant P falciparum 1 tablet (250 mg atovaquone/100

mg proguanil) daily

Mefloquine Areas with chloroquine-resistant P falciparum 250 mg weekly

Doxycycline Areas with multidrug-resistant P falciparum 100 mg daily

Primaquine Terminal prophylaxis of P vivax and P ovale 26.3 mg (15 mg base) daily for 14
infections days after travel