- Chloroquine (Aralen)
- Overview/pharmacokinetics:
- 4-aminoquinoline
derivative
- Phosphate salt-oral
use; hydrochloride-parenteral use
- Rapid, complete GI
absorption; very large apparent
volume of distribution (13,000 L
= significant tissue binding)
- Crosses the placenta
- Renal excretion
(half-life 3-5 days; real
excretion enhanced by urinary
acidification
- Dosing considerations:
- Large volume of
distribution requires a loading
dose if schizonticidal
chloroquine plasma levels are
rapidly needed for management of
acute attack
- Parenteral
administration should proceed by
slow infusion or by a series of
small intramuscular doses to
avoid life-threatening
chloroquine toxicity
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- Antimalarial activity:
- highly effective;
most widely used 4-aminoquinoline
for chemoprophylaxis
- used to treat
attacks of P vivax, P ovale,
P. malariae, and sensitive
strains of P falciparum malaria
- Somewhat effective
against gametocytes of P vivax, P ovale and P.
malariae but not against
those of P falciparum
- Not active against
preerythrocytic plasmodium
- Does not provide
radical cures of P vivax
or P ovale {does not
eliminate persistent liver
parasitic stages}
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- Selective toxicity:Adverse Effects
- Generally
well tolerated during chronic
administration
(prophylaxis/treatment);
- Uncommon
Side-effects include:
- Gastrointestinal
symptoms, headache,
pruritus (particularly in
black individuals),
anorexia, blurred vision,
- Possible
long-term effects (> 100 g
accumulated)
- Opthalmological/neuromuscular
effects
- Recommendations: periodic
evaluations relative to
baseline levels
- Retinal/visual fields
changes or muscular
weakness: discontinue
medication
- Cardiovascular
ECG changes-T-wave alterations;
QRS complex widening
- Intramuscular
injections (large dose, 10 mg/kg)
& intravenous infusion:
severe hypotension, respiratory
& cardiac arrest
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- Contraindications/cautions:
- Contraindicated in patients with:
- chloroquine (Aralen)
psoriasis-may cause acute
attacks
- chloroquine
(Aralen) should not be
used in combination with
other agents which may
cause dermatitis
- porphyria-chloroquine
(Aralen) may cause acute
attacks
- retinal/visual fields
abnormalities {consider
risk-benefit in
prescribing decision}
- Cautious
Use in patients with:
- hepatic damage,
alcoholism, neurologic or
hematologic disorders
- Drug-drug
pharmacokinetic effects:
- antacids +antidiarrheal
drugs: (kaolin, magnesium
trisilicate, calcium
carbonate)-decision
should not be taken
within about four hours
before or after
chloroquine (Aralen)
- During
pregnancy:
- no reports of teratogenic
effects
- considering risk vs.
benefit: chloroquine
(Aralen) benefits appear
to outweigh possible
fetal risks
- Oral chloroquine
(Aralen): safe for
children
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- Chloroquine-Resistance:
- unknown mechanism
- probably similar to
resistance described for
multidrug-resistant cancer cells
(membrane P-glycoprotein pump)
- in vitro resistance
reversible by verapamil
(Isoptin, Calan) and
desipramine (Norpramin)
- Clinical Uses: Chloroquine
(Aralen)
- Acute
malarial attacks by P vivax,
P ovale, P. malariae and
P. falciparum (not
chloroquine (Aralen)-resistant)
- Termination by
chloroquine (Aralen) of:
- fever -- 24-48 hours
- parasitemia-48-72 hours
- Indications
for parenteral
chloroquine (Aralen):
- vomiting precludes oral
route
- peripheral asexual
parasitemia > 5%
- presents of cerebral
malaria
- Cure for P.
vivax and P
ovale malaria
requires primaquine
concurrent administration
to eliminate persistent
liver stages.
- Alternative to
chloroquine (Aralen):-hydroxycholoroquine
- Chemoprophylaxis:
- Chloroquine
(Aralen)-preferred agent
for prophylaxis against
all forms of malaria
{except where P.
falciparum exhibits
resistance to
4-aminoquinolines
- Amebiasis:
- Chloroquine
(Aralen) + emetine
(generic): alternative
for amebic hepatic
abscess
- Autoimmune
Disease:
- Long-term
chloroquine (Aralen) (or
hydroxycholoroquine):
reported useful for
management of autoimmune
disorders
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- Mefloquine (Lariam):
- Overview:mefloquine
(Lariam)
- synthetic,
4-quinoline methanol derivative
(related to quinine (Quinamm))
- Oral Route of
Administration only (local
irritation upon injection)
- Highly plasma
protein-bound
- Hepatic
clearance;very slow elimination;
half-life= 13-33 days
- Antimalarial
Properties:mefloquine (Lariam)
- Blood schizonticidal
activity against: P.
falciparum & P vivax
- Inactive against P
falciparum gametocytes or
hepatic stages of P vivax
- Mechanism of action:
unknown
- Resistance has
been reported
- Quinidine-like
cardiac effects
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- Clinical Uses: Mefloquine
(Lariam)
- Prophylaxis
of chloroquine (Aralen)-resistant P. falciparum strains
- effective against most
chloroquine
(Aralen)-resistant &
pyrimethamine
(Daraprim)-sulfadoxine
resistant P
falciparum species
- Curative protocol: four
weeks after leaving an
endemic region; used in
this way-prophylaxis
provided against P
vivax and probably
against P ovale
and P. malariae
- Curative protocol for P
vivax & P ovale
necessitates the addition
of primaquine (against
hepatic stages)
- Mefloquine
(Lariam) should be only
used in malarious regions
where chloroquine
(Aralen) is not
effective.
- Treatment
of chloroquine (Aralen)-resistant P falciparum
- Oral treatment of
mild-moderate mefloquine-susceptible P
falciparum infection
- Less rapid onset of
action compared to
quinine (Quinamm) or
quinidine-suggesting that
these drugs should be
used in treating severe
illness.
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- Adverse Reactions:mefloquine
(Lariam)
- Minor/transient adverse reaction,
including gastrointestinal
disturbances, syncope, extrasystoles.
- Transient
thrombocytopenia, leukocytosis,
and aminotransferase elevation
- Transient
neurological reactions
{convulsions, depression,
psychoses}
- Symptoms
are more likely to occur at doses
> 1000 mg -frequency = as high
as 1%
- Contraindications:mefloquine
(Lariam)
- Contraindicated in patients with
a history of:
- epilepsy
- psychiatric disturbance
- cardiac conduction
anomalies
- quinidine (and related
compound) sensitivities
- Not
appropriate for use in children
under 15 kg or under two years of
age {poorly
tolerated/unsubstantiated
efficacy in this group}
- Probably
should not be used during first
trimester of pregnancy
- Women of
child-bearing age: use
precautions against pregnancy for
at least three months following
last dosage of mefloquine.
- Neuropsychiatric disturbance
development during mefloquine
treatment: indication for
cessation of mefloquine.
- Mefloquine (Lariam) may induce
seizures in patients taking
anticonvulsant medications (e.g.
valproic acid (Depakene,
Depakote) & divalproex
sodium).
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- Primaquine (generic)
- Overview: primaquine
- synthetic,
8-aminoquinoline derivative
- well absorbed
orally
- completely
metabolized & excreted in the
urine
- major metabolite
(carboxyprimaquine) accumulates
with daily dosing--
- primaquine
and/or one of its
metabolites: responsible
for clinical activity
- Antimalarial Properties:
primaquine
- Activity
profile:primaquine
- Active against late
hepatic stages
{hypnozoites &
schizonts of P ovale &
P vivax}-provides
radical cure in these
cases
- Highly active against
primary exoerythrocytic P.
falciparum stages
- Prophylaxis (with
chloroquine (Aralen)):
protective against P
ovale & P
vivax
- Highly gametocidal
against P vivax, P
ovale, P. malariae &
P falciparum
- Mechanism of
action:primaquine
- antimalarial
activity may be secondary to
quinoline-quinone oxidants
- Other pharmacological
effects:primaquine
- myeloid
suppression (high doses)
- may affect
erythrocytes (standard doses but
in genetically susceptible
individuals)
- Resistance:primaquine
- Primaquine
relative resistance in some P
vivax strains
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- Clinical Uses:
primaquine
- Terminal P vivax &
P ovale Malaria Prophylaxis
- Primaquine + a blood
schizonticide (typically
chloroquine (Aralen)) may
allow a radical cure
{terminal
prophylaxis}-due to
effects on persistent
hepatic stages
- Radical cure of acute P
vivax & P ovale
Malaria:
- Primaquine + chloroquine
(Aralen): used to treat
these infections (2 week
primaquine duration
typical)
- Gametocidal Action:
- single primaquine dose
causes P falciparum
gametocides to become
noninfective
- Pneumocystis carinii
Pneumonia:
- Clinical
Features
- "The symptoms of
P. carinii pneumonia
(PCP) include dyspnea,
non-productive cough, and
fever. Chest
radiography demonstrates
bilateral
infiltrates.
Extrapulmonary lesions
occur in a minority
(<3%) of patients,
involving most frequently
the lymph nodes, spleen,
liver and bone
marrow. Typically,
in untreated PCP
increasing pulmonary
involvement leads to
death"-CDC
- Laboratory
Diagnosis:
- "The
specific diagnosis is
based on identification
of P. carinii in
bronchopulmonary
secretions obtained as
induced sputum or
broncho-alveolar lavage
(BAL) material. In
situations where these
two techniques cannot be
used, transbronchial
biopsy or open lung
biopsy may prove
necessary.
Microscopic
identification of
P.carinii trophozoites
and cysts is performed
with stains that
demonstrate either the
nuclei of trophozoites
and intracystic stages
(such as Giemsa) or the
cyst walls (such as the
silver stains). In
addition,
immunofluorescence
microscopy using
monoclonal antibodies can
identify the organisms
with higher sensitivity
than conventional
microscopy."-CDC
 Pneumocystis
carinii trophozoites
in broncho-alveolar
lavage (BAL) material- Pneumocystis
carinii cysts:B: 3
cysts in bronchoalveolar
material, Giemsa stain
- Cysts in lung
tissue, silver stain
- Pneumocystis
carinii cysts in
broncho-alveolar lavage
material; silver stain
- Treatment:
- "The
Medical Letter recommends
trimethoprim-sulfamethoxazole
(Bactrim) as the drug of
choice. Recommended
alternatives include
pentamidine (Pentam);
trimetrexate plus folinic
acid; trimethoprim
(generic) plus dapsone;
atovaquone (Mepron); and
primaquine plus
clindamycin
(Cleocin)."-CDC
- Primaquine +clindamycin
(Cleocin):
alternative treatment
(oral)
- Adverse Effects:
primaquine
- Few major side effects
- some gastrointestinal
disturbances, headache
- More serious side
effects include (rare):
- leukopenia/agranulocytosis
- Normal Doses:
- limited hemolysis(noted
by urinary
darkening/reddening) and
the, significant
hemolysis,
methemoglobinemia
(cyanosis evident) in
patients with variance of
glucose-6 phosphate
dehydrogenase or certain
other erythrocyte pentose
phosphate pathway
abnormalities.
- Contraindications/cautions:
- Primaquine
should not be used in patients:
- currently taking
quinidine
- having connective tissue
abnormalities
- who have history of
methemoglobinemia or
granulocytopenia
- who are pregnant
(definitely not during
first trimester)
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