Sulfonamides
& Sulfones
- Overview: sulfonamides
& sulfones
- Blood
schizonticidal activity against P.
falciparum (some strains)
- Mechanism:
dihydrofolic acid synthesis
inhibition
- Weak effects
against blood schizonts of P vivax
- Inactive against
immunocytes or liver stages of P
falciparum or P vivax.
- Synergistic
blockade of folic acid synthesis
following combination of sulfones or
sulfonamide with an antifols
- For
management of chloroquine
(Aralen)-resistant P falciparum
- pyrimethamine-sulfadoxine
(Fansidar) or
- pyrimethamine (Daraprim)-dapsone
- Major disadvantage: sulfonamides
and sulfones exhibit slow onset blood
schizonticidal activity as well as
significant adverse effects.
- Pyrimethamine-sulfadoxine
(Fansidar)
- Pharmacokinetics:
- Fansidar-well
absorbed
- Renal route of
excretion
- Antimalarial
Activity/Resistance:
- Effective against
falciparum malaria (some strains)
- For serious cases,
quinine (Quinamm) is given
concurrently since Fansidar
activity develops slowly
- Ineffective:against
vivax malaria
Quinine (Quinamm) & Quinidine
- Overview:quinine (Quinamm)
- Quinine
(Quinamm)-alkaloid from the bark of the
cinchona tree
- Quinine (Quinamm)
is now unimportant antimalarial is a
result of resistance development to other
antimalarials
- Pharmacokinetics:quinine
(Quinamm)
- rapid absorption;
wide tissue distribution
- elimination
halftime: normal individuals -- 7-12
hours; 8-21 hours in malaria infected
patients
- hepatic
metabolism (80%)
- urine excretion
- Effective
concentration range:
- ineffective < 2 ug/mL
- > 7
ug/mL-associated with
"cinchonism"
- narrow
therapeutic range: frequent side
effects associate with falciparum
malaria management with quinine (Quinamm)
- Antimalarial activity:quinine
(Quinamm)
- rapid
onset; highly effective blood
schizonticide against the four malarial
parasites: P vivax, P ovale, P
falciparum, P. malariae.
- Gametocidal
for P vivax & P ovale;
not very effective as a gametocidal agent
for P falciparum gametocytes
- No effect on
sporozoites or liver stages of any
parasite.
- Pharmacological effects: quinine
(Quinamm)
- Oral use: gastric
irritation
- Myocardial
effects similar to quinidine, but
quinine's effect less intense
- Skeletal muscle:
curare-like effect; lengthened skeletal
muscle membrane refractory.
- May be used to
reduce contracture of myotonia congenita.
- Slight oxytocic
effect (especially third trimester time
frame)
- With therapeutic doses: occasional
hypoglycemia {secondary to pancreatic
B-cell insulin release}-especially
prominent in patients who are pregnant or
with severe infections.
- Resistance: quinine (Quinamm)
- resistance for monotherapy
increasing; therapeutic failure due to
resistance of quinine (Quinamm) +
second-drug has not been confirmed.
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- Clinical Uses:quinine
(Quinamm)
- Parenteral treatment: severe
falciparum malaria
- slow, intravenous
administration of quinine
dihydrochloride (not available in
the United States)-quinidine
gluconate (Quinaglute, Quinalan)
is used instead
- alternative: dilute
intramuscular injection
acceptable
- Oral treatment of falciparum
malaria (chloroquine (Aralen)-resistant)
- management (with
other drugs) for acute P
falciparum-chloroquine (Aralen)
resistant malarial attacks
- quinine (Quinamm)
alone will not eliminate the
infection {will reduce parasitemia, however}
- quinine
(Quinamm)-less effective than
chloroquine (Aralen); quinine
(Quinamm) not used to manage
acute attacks of P ovale, P
vivax, P. malariae or
chloroquine (Aralen)-sensitive
P falciparum malaria
- Prophylaxis: quinine
(Quinamm) generally not used
- Exceptions:
- P
falciparum
chloroquine (Aralen)
resistance and:
- mefloquine (Lariam)-unavailable
- doxycycline (Vibramycin,
Doryx)-unavailable
- Other Uses:(quinine
(Quinamm)
- nighttime
leg cramps
- quinine
(Quinamm) + clindamycin
(Cleocin): for management in
cases of severe babesiosis (Babesia
microti)
- The
Medical Letter recommends
clindamycin (Cleocin)
plus quinine as the drug
regimen of choice.
It also notes that
exchange transfusion has
been used in severely ill
patients with high
parasitemias, and that
combinations including
other drugs (such as
atovaquone (Mepron),
azithromycin (Zythromax),
pentamidine (Pentam), and
trimethoprim-sulfamethoxazole
(Bactrim)) may also be
effective.-CDC reference http://www.dpd.cdc.gov/DPDx/HTML/Babesiosis.htm
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- Adverse Effects--quinine
(Quinamm)
- Gastrointestinal Effects:
- nausea,
epigastric pain, vomiting
- Cinchonism:
- occurs if
plasma levels > 7-10 ug/mL
- symptoms:-if symptoms do not
abate, discontinue quinine
(Quinamm) and obtain blood level.
- slight
visual disturbances
- mild
tinnitus
- dizziness
- headache
- nausea
- Hematologic effects:
- Rare:
(0.05%): hemolysis; they also
occur in patients with
glucose-6-phosphate dehydrogenase
deficiency
- Rare: leukopenia,
thrombocytopenic purpura, hypoprothrombinemia,
agranulocytosis, Schonlein-Henoch purpura
- Hypoglycemia:
- may occur
therapeutic doses; glucose
administration may result and
further insulin release and
hypoglycemia exacerbation.
- Other Toxicities:
- IV
quinine (Quinamm)-rare
thrombophlebitis
- rapid IV
infusion: hypotension, seizures,
ventricular fibrillation, death
- congenital malformation if
large-doesquinine (Quinamm) given
in failed abortion
- severe
toxicity: rare {may include --
fever, deafness, visual
abnormalities, CNS effects
including syncope &
confusion, quinidine-like
effects}
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Quinidine gluconate
(Quinaglute, Quinalan)
- Summary
- Dextrorotatory
diasteriomer of quinine (Quinamm)
- Quinidine gluconate
(Quinaglute, Quinalan)-typically used for
management of cardiac arrhythmias
- Also used for
parenteral treatment of severe
malaria, when parenteral quinine
(Quinamm) form is unavailable
{note: in the United States,
parenteral form of quinine
(Quinamm), quinine (Quinamm)
hydrochloride is unavailable}
- IV quinidine
gluconate: adverse effects, cautions,
contraindications
- rare:
thrombophlebitis
- potentially cardiotoxic-consider risk vs.
benefit ratio if administration
to a patient with cardiac
conduction hepatic or renal
abnormalities
- generally
contraindications/caution or
quinidine gluconate (Quinaglute,
Quinalan) similar to that for
quinine (Quinamm)
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