2. Antimalarial Drugs.
o Malaria is the most important parasitic disease of humans and
causes hundreds of millions of illnesses per year. Four species
of plasmodium typically cause human malaria: Plasmodium
falciparum, P vivax, P malariae, and P ovale.
o A fifth species P knowlesi, is primarily a pathogen of monkeys but has
recently been recognized, it causes severe diseases in Asia.
o Although all of the latter species may cause significant illness, P falciparum
is responsible for the majority of
serious complications and deaths. Drug resistance is an important
therapeutic problem, most notably with P falciparum.
4. What is Haemozoin?
- Haemozoin or hemozoin is formed by blood-feeding parasites as the end product of their digestion. It is
usually formed by the digestion of blood. Parasites, after digesting haemoglobin, release large amounts
of free-heme, and free-heme is toxic to cells.
- So, the parasites convert the free-heme into an insoluble, crystalline form called hemozoin. Hence,
haemozoin appears to have a crystalline structure when observed under a microscope.
- Haemozoin is important for the survival of parasites, hence present and emerging antibiotics inhibit the
formation of haemozoin, thereby killing the parasites
5. CLASSIFICATION OF
ANTIMALARIALS
According to anti-malarial activity:
(i) Tissue schizonticides for causal prophylaxis:
These drugs act on the primary tissue forms of the plasmodia which after growth within the liver, initiate
the erythrocytic stage. By blocking this stage, further development of the infection can be theoretically
prevented. Pyrimethamine and Primaquine have this activity. However since it is impossible to predict the
infection before clinical symptoms begin, this mode of therapy is more theoretical than practical.
(ii) Tissue schizonticides for preventing relapse
These drugs act on the hypnozoites of P. vivax and P. ovale in the liver that cause relapse of symptoms on
reactivation. Primaquine is the prototype drug; pyrimethamine also has such activity
6. (iii) Blood schizonticides:
These drugs act on the blood forms of the parasite and thereby terminate clinical attacks of malaria. These are the
most important drugs in anti-malarialchemotherapy. These include chloroquine, quinine, mefloquine, halofantrine,
pyrimethamine, sulfadoxine, sulfones, tetracyclines etc.
(iv) Gametocytocides:
These drugs destroy the sexual forms of the parasite in the blood and thereby prevent transmission of the infection
to the mosquito. Chloroquine and quinine have gametocytocidal activity against P. vivax and P. malariae, but not
against P. falciparum. Primaquine has gametocytocidal activity against all plasmodia, including P. falciparum.
(v) Sporontocides:
These drugs prevent the development of oocysts in the mosquito and thus ablate the transmission. Primaquine and
chloroguanide have this action.
9. AMODIAQUINOLINES.
CHLOROQUINE.
• Chloroquine has been a drug of choice for both treatment and
chemoprophylaxis of malaria since the 1940s, but its usefulness against P
falciparum has been seriously compromised by drug resistance.
• It remains the drug of choice in the treatment of sensitive P falciparum and
other species of human malaria parasites.
Chemistry and Pharmacokinetics.
• Chloroquine is a synthetic 4-aminoquinoline formulated as the phosphate
salt for oral use.
• It is rapidly and almost completely absorbed from the gastrointestinal tract
and reaches maximum plasma concentrations in about 3 hours.
• It rapidly distributed to the tissues. It has a very large apparent volume of
distribution of 100–1000 L/kg and is slowly released from tissues and
metabolized.
• Chloroquine is principally excreted in the urine with an initial half-life of 3–5
days but a much longer terminal elimination half-life of 1–2 months.
10. Antimalarial Action and resistance of Chloroquine.
• When not limited by resistance, chloroquine is a highly effective blood schizonticide.
• Chloroquine is not reliably active against liver stage parasites or gametocytes.
Mechanism of action :
• Binds to and inhibits DNA and RNA polymerase; interferes with metabolism and hemoglobin
utilization by parasites; inhibits prostaglandin effects. The parasite digests the human hemoglobin
in order to get amino acid, but the problem here is that the Form complex with Hb-----deficiency of
food material.
• Chloroquine binds to Heme (or fp) to form what is known as the fp-chloroquine complex, this
complex is highly toxic to the cell and disrupts membrane function. Action of the toxic compound
results in cell lysis and ultimately parasite cell auto digestion.
11. • Resistance to chloroquine is now very common among
strains of P falciparum and uncommon but increasing for P
vivax. In P falciparum, mutations in a putative transporter,
PfCRT, are the primary mediators of resistance.
• Chloroquine resistance can be reversed by certain agents,
including verapamil, desipramine, and chlorpheniramine,
but the clinical value of resistance-reversing drugs is not
established.
12. Clinical uses of Chloroquine
• Treatment.
• Chloroquine is the drug of choice in the treatment of
uncomplicated nonfalciparum and sensitive falciparum malaria.
• It rapidly terminates fever (usually in 24–48 hours) and clears
parasitemia (in 48–72 hours) caused by sensitive parasites.
• Chloroquine has been replaced by other drugs, principally
artemisinin-based combination therapies, as the standard therapy
to treat falciparum malaria in most endemic countries.
• Chloroquine does not eliminate dormant liver forms of P vivax and
P ovale, and for that reason primaquine must be added for the
radical cure of these species.
13. Chemoprophylaxis.
• Chloroquine is the preferred chemo-prophylactic agent in
malarious regions without resistant falciparum malaria.
• Eradication of P vivax and P ovale requires a course of
primaquine to clear hepatic stages.
Amebic liver abscess: Chloroquine reaches high liver
concentrations and may be used for amebic abscesses that
fail initial therapy with metronidazole.
14. • Adverse Effects: Chloroquine is usually very well tolerated, even with
prolonged use.
Pruritus is common, primarily in Africans. Nausea, vomiting,abdominal pain,
headache, anorexia, malaise, blurring of vision,and urticaria are uncommon.
Dosing after meals may reduce some adverse effects. Rare reactions include
hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient persons.
Impaired hearing, confusion, psychosis, seizures, agranulocytosis,
exfoliative dermatitis, alopecia, bleaching of hair, hypotension, and
electrocardiographic changes.
The long-term administration of high doses of chloroquine for rheumatologic
diseases can result in irreversible ototoxicity, retinopathy, myopathy, and
peripheral neuropathy, but these are rarely seen with standard-dose weekly
chemoprophylaxis.
Intramuscular injections or intravenous infusions of chloroquine
hydrochloride can result in severe hypotension and respiratory and cardiac
arrest, and should be avoided.
15. • Contraindications & Cautions
• Chloroquine is contraindicated in patients with psoriasis or
porphyria.
• It should generally not be used in those with retinal or visual field
abnormalities or myopathy, and should be used with caution in
patients with liver, neurologic, or hematologic disorders.
• The antidiarrheal agent kaolin and calcium- and magnesium-
containing antacids interfere with the absorption of chloroquine
and should not be co-administered.
• Chloroquine is considered safe in pregnancy and for young
children.
16. Other Quinolines:
Amodiaquine is closely related to chloroquine, and it
probably shares mechanisms of action and resistance.
Amodiaquine was widely used to treat malaria because of
its low cost, limited toxicity, in some areas, effectiveness
against chloroquine-resistant strains of P falciparum, but
toxicities, including agranulocytosis, aplastic anemia, and
hepatotoxicity, have limited its use.
However, recent reevaluation has shown that serious
toxicity from amodiaquine is uncommon. The most
important current use of amodiaquine is in combination
therapy. WHO lists artesunate plus amodiaquine as a
recommended therapy for falciparum malaria.
17. Amodiaquine Continued.
oLong-term chemoprophylaxis with amodiaquine is best avoided
because of its apparent increased toxicity with long-term use.
• But short-term seasonal malaria chemoprevention with amodiaquine
plus sulfadoxine-pyrimethamine recommended by the WHO for sub-
region of Africa.
• Piperaquine is a bisquinoline that was used widely to treat
chloroquine-resistant falciparum malaria in China in the 1970s–1980s,
but its use waned after resistance became widespread.
18. Piperaquine Continued.
• More recently, piperaquine combined with
dihydroartemisinin (Artekin, Duocotecxin) showed excellent
efficacy and safety for the treatment of falciparum malaria,
although very recently decreased efficacy has been seen in
southeast Asia, linked to decreased activity of both
components of the combination.
• Piperaquine has a longer half-life (~28 days) than
amodiaquine (~14 days), mefloquine
• (~14 days), or lumefantrine (~4 days), leading to a longer
period of post-treatment prophylaxis with
dihydroartemisinin-piperaquine than with the other leading
artemisinin-based combinations; this feature should be
particularly advantageous in high transmission areas.
19. SESQUITERPINE LACTONES:ARTEMISININ & ITS
DERIVATIVES.
• Artemisinin is a sesquiterpene lactone endoperoxide the active
component of an herbal medicine that has been used as an
antipyretic in China for more than 2000 years.
• Artemisinin is insoluble and can only be used orally.
• Analogs have been synthesized to increase solubility and
improve antimalarial efficacy. The most important of these
analogs are artesunate water soluble for oral, intravenous,
intramuscular, and rectal administration.
• Artemether (lipid-soluble; oral, intramuscular, and rectal
administration),
• and dihydroartemisinin (water-soluble; oral administration).
20. • Chemistry & Pharmacokinetics.
• Artemisinin and its analogs are complex 3- and 4-ring
structures.
• They are rapidly absorbed, with peak plasma levels
occurring promptly. Half-lives after oral administration are
30–60 minutes for artesunate and dihydroartemisinin, and
2–3 hours for artemether. Artemisinin, artesunate, and
artemether are rapidly metabolized to the active
metabolite dihydroartemisinin. Drug levels appear to
decrease after a number of days of therapy.
21. • Antimalarial Action & Resistance
• The artemisinins are now widely available, but
monotherapy for the treatment of uncomplicated malaria
is strongly discouraged.
• Rather, co-formulated artemisinin-based combination
therapies are recommended to improve efficacy and
prevent the selection of artemisinin-resistant parasites.
• The oral combination regimen Coartem (artemether-
lumefantrine) as first line was approved by the U.S.Food
and Drug Administration (FDA) in 2009.
22. • Antimalarial Action & Resistance.
• Artemisinin and its analogs are very rapidly acting blood
schizonticides against all human malaria parasites.
• Artemisinins have no effect on hepatic stages. They are active
against young, but not mature gametocytes.
• The antimalarial activity of artemisinins appears to result from
the production of free radicals that follows the iron-catalyzed
cleavage of the artemisinin endoperoxide bridge.
• Mechanism of Action:
Artesunate and Artemether contain an unusual peroxide bridge
that undergoes an iron-catalyzed cleavage within the parasite
food vacuole, producing free radicals that kill the malarial
parasite. They are rapidly acting blood schizonticides, with some
activity against gametocytes, but no activity against the hepatic
stages of the malarial parasite.
23. • Clinical Uses
• Artemisinin-based combination therapy is now the
standard of care for treatment of uncomplicated
falciparum malaria in nearly all endemic areas.
• The leading regimens are highly efficacious, safe, and well
tolerated. These regimens were developed because the
short plasma half-lives of the artemisinins led to
unacceptably high recrudescence rates after short-course
therapy, which were reversed by inclusion of longer-acting
drugs. Combination therapy also helps to protect against
the selection of artemisinin resistance.
• However, with completion of dosing after 3 days, the
artemisinin components are rapidly eliminated, and so
selection of resistance to partner drugs is of concern.
24. • Clinical Uses
• Either artesunate-amodiaquine or artemetherlumefantrine
is the standard treatment for uncomplicated falciparum
malaria in most countries in Africa.
• Dihydroartemisinin and piperaquine is a newer regimen
that has shown excellent efficacy; it is a first-line therapy
for falciparum malaria in parts of Southeast Asia.
• Artemisinins also have outstanding efficacy in the
treatment of complicated falciparum malaria.
25. • Intramuscular artemether has an efficacy equivalent to
that of quinine and that intravenous artesunate is superior
to intravenous quinine in terms of parasite clearance time
and patient survival.
• Intravenous artesunate also has a superior side-effect
profile when compared with intravenous quinine or
quinidine. Thus, intravenous artesunate has replaced
quinine as the standard of care for the treatment of severe
falciparum malaria.
• Artesunate and artemether have also been effective in the
treatment of severe malaria when administered rectally,
offering a valuable treatment modality when parenteral
therapy is not available.
26. Adverse Effects & Cautions.
• The most commonly reported adverse effects are nausea,
vomiting, diarrhea, and dizziness, and these may often be due to
underlying malaria rather than the medications.
• Rare serious toxicities include neutropenia, anemia, hemolysis,
elevated liver enzymes, and allergic reactions.
• In addition, delayed hemolysis after artemisinins for severe malaria
appears to be quite common.
• WHO recommends artemisinin-based combination therapies for
the treatment of uncomplicated falciparum malaria during the
second and third trimesters of pregnancy (quinine plus
clindamycin is recommended during the first trimester) and
intravenous artesunate for the treatment of severe malaria during
all stages of pregnancy.
27. DIAMINOPYRIMIDINE:Pyrimethamine & Trimethoprime.
o Pyrimethamine, a Diamino pyrimidines analog, is an antiparasitic agent used to prevent and
cure toxoplasmosis and malaria. Pyrimethamine also used as an adjunct in the treatment of
uncomplicated, chloroquine resistant.
It is also used with dapsone as a second-line option to prevent Pneumocystis jiroveci
pneumonia in people with HIV/AIDS. It was previously used for malaria but is no longer
recommended due to resistance, its now used in combination with sulfadoxine.
Mechanism of Action
Pyrimethamine inhibits the dihydrofolate reductase of plasmodia and thereby blocks the
biosynthesis of purines and pyrimidines, which are essential for DNA synthesis and cell
multiplication.This leads to failure of nuclear division at the time of schizont formation in
erythrocytes.
28. DIAMINOPYRIMIDINE: Pyrimethamine & Trimethoprime.
Dose: Sulfadoxine 500 mg + pyrimethamine 25 mg, 3 tablets once for acute attack
• Treatment and prophylaxis of falciparum malaria resistant to chloroquine.
o Side Effects:
Pyrimethamine can cause symptoms such as nausea, vomiting, glossitis, anorexia,diarrhea. skin rashes, erythema
multiforme, Stevens-Johnson syndrome and toxicepidermal necrolysis
Indications
• Single dose treatment of uncomplicated chloroquine resistant falciparum malaria
• Patients intolerant to chloroquine.
• Malaria Chemoprophylaxis.
• First choice treatment for toxoplasmosis.
29. CINCHONA ALKALOIDS: QUININE & QUINIDINE:
Quinine and quinidine remain important therapies for
falciparum malaria especially severe disease although
toxicity may complicate therapy.
• Chemistry & Pharmacokinetics
• Quinine is derived from the bark of the cinchona tree, a
traditional remedy for intermittent fevers from South
America.
• The alkaloid quinine was purified in 1820 and has been
used in the treatment and prevention of malaria since that
time.
30. • QUININE & QUINIDINE continued.
• Quinidine,the dextrorotatory stereoisomer of quinine, is at least as
effective as parenteral quinine in the treatment of severe falciparum
malaria.
• After oral administration, quinine is rapidly absorbed, reaches peak
plasma levels in 1–3 hours, and is widely distributed in body tissues.
The use of a loading dose in severe malaria allows the achievement of
peak levels within a few hours.
• Individuals with malaria develop higher plasma levels of quinine than
healthy controls,but toxicity is not increased, apparently because of
increased protein binding. The half-life of quinine also is longer in
those with severe malaria (18 hours) than in healthy controls (11
hours).
• Quinidine has a shorter half-life than quinine, mostly as a result of
decreased protein binding.
• Quinine is primarily metabolized in the liver and excreted in the urine.
31. Antimalarial Action & Resistance
• Quinine is a rapid-acting, highly effective blood schizonticide
against the four species of human malaria parasites.
• The drug is gametocidal against P vivax and P ovale but not P
falciparum. It is not active against liver stage parasites.
• The mechanism of action of quinine is unknown.
• Resistance to quinine is common in some areas of Southeast Asia
where the drug may fail if used alone to treat falciparum malaria.
32. • Clinical Uses
Parenteral treatment of severe falciparum malaria.
• For many years quinine dihydrochloride or quinidine gluconate
were the treatments of choice for severe falciparum malaria,
although intravenous artesunate is now preferred.
• Quinine can be administered slowly intravenously or, in a dilute
solution or intramuscularly.
• Quinidine can be administered in divided doses or by continuous
intravenous infusion; treatment should begin with a loading dose to
achieve effective plasma concentrations promptly.
• Because of its cardiac toxicity and the relative unpredictability of
its pharmacokinetics, intravenous quinidine should be
administered slowly with cardiac monitoring.
• Therapy should be changed to an effective oral agent as soon as
the patient has improved sufficiently.
33. • Oral treatment of falciparum malaria.
• Quinine sulfate is appropriate therapy for uncomplicated
falciparum malaria except when the infection was transmitted
in an area without documented chloroquine resistance.
Quinine is commonly used with a second drug (most often
doxycycline or, in children, clindamycin) to shorten the
duration of use (usually to 3 days) and limit toxicity.Quinine is
not generally used to treat non-falciparum malaria.
• Malarial chemoprophylaxis—Quinine is not generally used in
chemoprophylaxis owing to its toxicity, although a daily dose
of 325 mg is effective.
• Babesiosis—Quinine is first-line therapy, in combination with
clindamycin, in the treatment of infection with Babesia
microti or other human babesial infections.
34. • Adverse Effects
• Therapeutic dosages of quinine and quinidine commonly cause
tinnitus, headache, nausea, dizziness, flushing, and visual
disturbances,a constellation of symptoms termed cinchonism.
• Hypersensitivity reactions include skin rashes, urticaria,
angioedema, and bronchospasm. Hematologic abnormalities include
hemolysis (especially with G6PD deficiency), leukopenia,
agranulocytosis, and thrombocytopenia.
• Therapeutic doses may cause hypoglycemia through stimulation of
insulin release; this is a particular problem in severe infections and in
pregnant patients, who may have increased sensitivity to insulin.
• Quinine can stimulate uterine contractions, especially in the third
trimester. However, this effect is mild, and quinine and quinidine
remain appropriate for treatment of severe falciparum malaria during
pregnancy.
• Intravenous infusions of the drugs may cause thrombophlebitis.
35. Adverse Reactions:
• Severe hypotension can follow too-rapid intravenous infusions of
quinine or quinidine. Electrocardiographic abnormalities (QT
interval prolongation) are fairly common with intravenous quinidine,
but dangerous arrhythmias are uncommon when the drug is
administered appropriately in a monitored setting.
• Blackwater fever is a rare severe illness that includes marked
hemolysis and hemoglobinuria in the setting of quinine therapy for
malaria. It appears to be due to a hypersensitivity reaction to the
drug, although its pathogenesis is uncertain.
36. • Contraindications & Cautions
• Quinine (or quinidine) should be discontinued if signs of
severe cinchonism, hemolysis, or hypersensitivity occur.
• It should be avoided if possible in patients with underlying
visual or auditory problems. It must be used with great
caution in those with underlying cardiac abnormalities.
• Quinine should not be given concurrently with mefloquine
and should be used with caution in a patient with malaria
who has recently received mefloquine.
• Absorption may be blocked by aluminum-containing
antacids.
• Quinine can raise plasma levels of warfarin and digoxin.
• Dosage must be reduced in renal insufficiency.
37. MEFLOQUINE:
Mefloquine is effective therapy for many chloroquine-resistant strains of P
falciparum and against other species.
Although toxicity is a concern, mefloquine is one of the recommended
chemoprophylactic drugs for use in most malaria-endemic regions with
chloroquine-resistant strains.
• Chemistry & Pharmacokinetics:
• Mefloquine hydrochloride 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.
• It is well absorbed, and peak plasma concentrations are reached in about
18 hours. Mefloquine is highly protein-bound, extensively distributed in
tissues, and eliminated slowly, allowing a single-dose treatment regimen.
• The terminal elimination half-life is about 20 days, allowing weekly dosing
for chemoprophylaxis. With weekly dosing, steady-state drug levels are
reached over a number of weeks.
• Mefloquine and its metabolites are slowly excreted,mainly in the feces.
38. • Antimalarial Action & Resistance
• Mefloquine has strong blood schizonticidal activity against P falciparum
and P vivax, but it is not active against hepatic stages or gametocytes.
• The mechanism of action is unknown. Sporadic resistance to
mefloquine has been reported from many areas, but resistance appears
to be uncommon except in regions of Southeast Asia with high rates of
multidrug resistance Mefloquine resistance does not appear to be
associated with resistance to chloroquine.
• Clinical Uses:
• Chemoprophylaxis:
Mefloquine is effective in prophylaxis against most strains of P
falciparum and probably all other human malarial species.
Mefloquine is among the drugs for chemoprophylaxis in all malarious
areas except those with no chloroquine resistance.
As with chloroquine, eradication of P vivax and P ovale requires a course
of primaquine.
39. • Treatment: Mefloquine is effective in treating
uncomplicated falciparum malaria. The drug is not
appropriate for treating individuals with severe or
complicated malaria, since quinine,quinidine, and
artemisinins are more rapidly active, and since
drug resistance is less likely with those agents.
• The combination of artesunate plus mefloquine showed
excellent antimalarial efficacy in regions of Southeast Asia
with some resistance to mefloquine,and this regimen is
now one of the combination therapies recommended by
the WHO for the treatment of uncomplicated falciparum
malaria.
• Artesunate-mefloquine is the first-line therapy for
uncomplicated falciparum malaria in a number of
countries in Asia and South America.
40. Adverse Effects
• Weekly dosing with mefloquine for chemoprophylaxis may cause nausea, vomiting,
dizziness, sleep and behavioral disturbances, epigastric pain, diarrhea, abdominal pain,
headache, rash, and dizziness.
• Neuropsychiatric toxicities have been reported.
Contraindications & Cautions
• Mefloquine is contraindicated in a patient with a 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, and caution is
required if quinine or quinidine is used to treat malaria after mefloquine
chemoprophylaxis.
• The CDC no longer advises against mefloquine use in patients receiving -adrenoceptor
β
antagonists.
• Mefloquine is also now considered safe in young children, and it is the only prophylaxis
other than chloroquine approved for children weighing less than 5 kg and for pregnant
women.
• Available data suggest that mefloquine is safe throughout pregnancy, although
experience in the first trimester is limited.
• Mefloquine chemoprophylaxis should be discontinued if significant neuropsychiatric
symptoms develop.
41. • Primaquine:
• Primaquine is the drug of choice for the eradication of
dormant liver forms of P vivax and P ovale and can also be
used for prophylaxis against all malarial species.
Chemistry & Pharmacokinetics:
• Primaquine phosphate is a synthetic 8-aminoquinoline.It is
well absorbed orally, reaching peak plasma levels in 1–2
hours.
• The plasma half-life is 3–8 hours and it is widely distributed
to the tissues, but only a small amount is bound there.
• It is rapidly metabolized and excreted in the urine.
42. • Antimalarial Action & Resistance
• Primaquine is active against hepatic stages of all human
malaria parasites. It is the only available agent active
against the dormant hypnozoite stages of P vivax and P
ovale.
• The drug is also gametocidal against the four human
malaria species and it has weak activity against
erythrocytic stage parasites. The mechanism of
antimalarial action is unknown. Some strains of P vivax
are relatively resistant to primaquine.
• Liver forms of these strains may not be eradicated by a
single standard treatment and may require repeated
therapy
43. Clinical Uses of Primaquine.
• Therapy (radical cure) of acute vivax and ovale malaria:
Standard therapy for these infections includes chloroquine to eradicate
erythrocytic forms and primaquine to eradicate liver hypnozoites and
prevent a subsequent relapse.
Chloroquine is given acutely, and therapy with primaquine is withheld
until the G6PD status of the patient is known. If the G6PD level is
normal, a 14-day course of primaquine is given. Prompt evaluation of
the G6PD level is helpful, since primaquine appears to be most effective
when instituted before completion of dosing with chloroquine.
• Terminal prophylaxis of vivax and ovale malaria:
Standard chemoprophylaxis does not prevent a relapse of vivax or
ovale malaria, because the hypnozoite forms of these parasites are not
eradicated by available blood schizonticides.
To diminish the likelihood of relapse, some authorities advocate the use
of primaquine after the completion of travel to an endemic area.
44. • Chemoprophylaxis of malaria: Daily treatment with 30 mg (0.5
mg/kg) of primaquine base provided good protection against
falciparum and vivax malaria, and the drug is now listed as an
alternative prophylactic regimen by the CDC.
• Gametocidal action—Primaquine renders P falciparum
gametocytes noninfective to mosquitoes. Including primaquine
with treatment for falciparum malaria is used in some areas to
decrease transmission, and routine inclusion of single low doses
of primaquine (which may be safe without testing for G6PD
deficiency) is under study.
• Pneumocystis jiroveci infection.The combination of clindamycin
and primaquine is an alternative regimen in the treatment of
pneumocystosis, particularly mild to moderate disease.
• This regimen offers improved tolerance compared with high-
dose trimethoprim-sulfamethoxazole or pentamidine, although
its efficacy against severe pneumocystis pneumonia is not well
studied.
45. Adverse Effects
• Primaquine in recommended doses is generally well tolerated.
• It infrequently causes nausea, epigastric pain, abdominal cramps,
and headache, and these symptoms are more common with higher
dosages and when the drug is taken on an empty stomach.
• More serious but rare adverse effects are leukopenia,
agranulocytosis, leukocytosis, and cardiac arrhythmias.
• Standard doses of primaquine may cause hemolysis or
methemoglobinemia (manifested by cyanosis), especially in
persons with G6PD deficiency or other hereditary metabolic
defects.
46. Contraindications & Cautions
• Primaquine should be avoided in patients with a history of granulocytopenia or
methemoglobinemia, in those receiving potentially myelosuppressive drugs (eg,
quinidine), and in those with disorders that commonly include myelosuppression.
• Patients should be tested for G6PD deficiency before primaquine is prescribed.
When a patient is deficient in G6PD,treatment strategies may include withholding
therapy and treating subsequent relapses, if they occur, with chloroquine;
treating patients with standard dosing, paying close attention to their
hematologic status; or treating with weekly primaquine (45 mg base) for 8 weeks.
• G6PD-deficient individuals of Mediterranean and Asian ancestry are most likely
to have severe deficiency, whereas those of African ancestry usually have a
milder biochemical defect.
• This difference can be taken into consideration in choosing a treatment strategy.
In any event,primaquine should be discontinued if there is evidence of hemolysis
or anemia.
• Primaquine should be avoided in pregnancy because the fetus is relatively
G6PD-deficient and thus at risk of hemolysis.
