PRALIDOXIME CHLORIDE
DESCRIPTION:
Chemical name: 2-formyl-1-methylpyridinium chloride oxime.
Pralidoxime chloride occurs as an odorless, white, nonhygroscopic, crystalline
powder which is soluble in water to the extent of 1 g in less than 1 mL. Stable
in air, it melts between 215 deg and 225 deg C, with decomposition.
The specific activity of the drug resides in the 2-formyl-1- methylpyridinium
ion and is independent of the particular salt employed. The chloride is
preferred because of physiologic compatibility, excellent water solubility at
all temperatures, and high potency per gram, due to its low (173) molecular
weight.
Pralidoxime chloride is a cholinesterase reactivator.
Pam Chloride for intravenous injection or infusion is prepared by
cryodesiccation. Each vial contains 1 g of sterile pralidoxime chloride, and
NaOH to adjust pH, to be reconstituted with 20 mL of Sterile Water for
Injection, USP. The pH of the reconstituted solution is 3.5 to 4.5.
Intramuscular or subcutaneous injection may be used when intravenous injection
is not feasible.
ACTIONS/CLINICAL PHARMACOLOGY:
The principal action of pralidoxime is to reactivate cholinesterase (mainly
outside of the central nervous system) which has been inactivated by
phosphorylation due to an organophosphate pesticide or related compound. The
destruction of accumulated acetylcholine can then proceed, and neuromuscular
junctions will again function normally. Pralidoxime also slows the process of
"aging" of phosphorylated cholinesterase to a nonreactivatable form, and
detoxifies certain organophosphates by direct chemical reaction. The drug has
its most critical effect in relieving paralysis of the muscles of respiration.
Because pralidoxime is less effective in relieving depression of the respiratory
center, atropine is always required concomitantly to block the effect of
accumulated acetylcholine at this site. Pralidoxime relieves muscarinic signs
and symptoms, salivation, bronchospasm, etc., but this action is relatively
unimportant since atropine is adequate for this purpose.
Pralidoxime is distributed throughout the extracellular water; it is not bound
to plasma protein. The drug is rapidly excreted in the urine partly unchanged,
and partly as a metabolite produced by the liver. Consequently, pralidoxime is
relatively short acting, and repeated doses may be needed, especially where
there is any evidence of continuing absorption of the poison.
The minimum therapeutic concentration of pralidoxime in plasma is 4 mcgm/mL;
this level is reached in about 16 minutes after a single injection of 600 mg
Pam Chloride. The apparent half-life of Pam Chloride is 74 to 77
minutes.
It has been reported (REF. 1) that the supplemental use of oxime cholinesterase
reactivators (such as pralidoxime) reduces the incidence and severity of
developmental defects in chick embryos exposed to such known teratogens as
parathion, bidrin, carbachol, and neostigmine. This protective effect of the
oximes was shown to be dose related.
INDICATIONS AND USAGE:
Pam is indicated as an antidote: (1) in the treatment of poisoning due to
those pesticides and chemicals of the organophosphate class which have
anticholinesterase activity and (2) in the control of overdosage by
anticholinesterase drugs used in the treatment of myasthenia gravis.
The principal indications for the use of pralidoxime are muscle weakness and
respiratory depression. In severe poisoning, respiratory depression may be due
to muscle weakness.
CONTRAINDICATIONS:
There are no known absolute contraindications for the use of Pam. Relative
contraindications include known hypersensitivity to the drug and other
situations in which the risk of its use clearly outweighs possible benefit (see
"PRECAUTIONS").
WARNINGS:
Pam is not effective in the treatment of poisoning due to phosphorus,
inorganic phosphates, or organophosphates not having anticholinesterase
activity.
Pam is NOT indicated as an antidote for intoxication by pesticides of the
carbamate class since it may increase the toxicity of carbaryl.
PRECAUTIONS:
GENERAL
Pralidoxime has been very well tolerated in most cases, but it must be
remembered that the desperate condition of the organophosphate- poisoned patient
will generally mask such minor signs and symptoms as have been noted in normal
subjects.
Intravenous administration of Pam should be carried out slowly and,
preferably, by infusion, since certain side effects, such as tachycardia,
laryngospasm, and muscle rigidity, have been attributed in a few cases to a too-
rapid rate of injection. (See "DOSAGE AND ADMINISTRATION".)
Pam should be used with great caution in treating organophosphate
overdosage in cases of myasthenia gravis since it may precipitate a myasthenic
crisis.
Because pralidoxime is excreted in the urine, a decrease in renal function will
result in increased blood levels of the drug. Thus, the dosage of pralidoxime
should be reduced in the presence of renal insufficiency.
LABORATORY TESTS
Treatment of organophosphate poisoning should be instituted without waiting for
the results of laboratory tests. Red blood cell, plasma cholinesterase, and
urinary paranitrophenol measurements (in the case of parathion exposure) may be
helpful in confirming the diagnosis and following the course of the illness. A
reduction in red blood cell cholinesterase concentration to below 50% of normal
has been seen only with organophosphate ester poisoning.
DRUG INTERACTIONS
When atropine and pralidoxime are used together, the signs of atropinization
(flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur
earlier than might be expected when atropine is used alone. This is especially
true if the total dose of atropine has been large and the administration of
pralidoxime has been delayed. (REF. 2-4)
The following precautions should be kept in mind in the treatment of
anticholinesterase poisoning, although they do not bear directly on the use of
pralidoxime: since barbiturates are potentiated by the anticholinesterases, they
should be used cautiously in the treatment of convulsions; morphine,
theophylline, aminophylline, succinylcholine, reserpine, and phenothiazine- type
tranquilizers should be avoided in patients with organophosphate poisoning.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
Since pralidoxime chloride is indicated for short-term emergency use only, no
investigations of its potential for carcinogenesis, mutagenesis, or impairment
of fertility have been conducted by the manufacturer, or reported in the
literature.
PREGNANCY
Teratogenic Effects--Pregnancy Category C:
Animal reproduction studies have not been conducted with pralidoxime. It is also
not known whether pralidoxime can cause fetal harm when administered to a
pregnant woman or can affect reproduction capacity. Pralidoxime should be given
to a pregnant woman only if clearly needed.
NURSING MOTHERS
It is not known whether this drug is excreted in human milk. Because many drugs
are excreted in human milk, caution should be exercised when pralidoxime is
administered to a nursing woman.
PEDIATRIC USE
Safety and effectiveness in pediatric patients have not been established.
DRUG INTERACTIONS:
When atropine and pralidoxime are used together, the signs of atropinization
(flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur
earlier than might be expected when atropine is used alone. This is especially
true if the total dose of atropine has been large and the administration of
pralidoxime has been delayed. (REF. 2-4)
The following precautions should be kept in mind in the treatment of
anticholinesterase poisoning, although they do not bear directly on the use of
pralidoxime: since barbiturates are potentiated by the anticholinesterases, they
should be used cautiously in the treatment of convulsions; morphine,
theophylline, aminophylline, succinylcholine, reserpine, and phenothiazine- type
tranquilizers should be avoided in patients with organophosphate poisoning.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
Forty to 60 minutes after intramuscular injection, mild to moderate pain may be
experienced at the site of injection.
Pralidoxime may cause blurred vision, diplopia and impaired accommodation,
dizziness, headache, drowsiness, nausea, tachycardia, increased systolic and
diastolic blood pressure, hyperventilation, and muscular weakness when given
parenterally to normal volunteers who have not been exposed to
anticholinesterase poisons. In patients, it is very difficult to differentiate
the toxic effects produced by atropine or the organophosphate compounds from
those of the drug.
Elevations in SGOT and/or SGPT enzyme levels were observed in 1 of 6 normal
volunteers given 1200 mg of pralidoxime chloride intramuscularly, and in 4 of 6
volunteers given 1800 mg intramuscularly. Levels returned to normal in about 2
weeks. Transient elevations in creatine phosphokinase were observed in all
normal volunteers given the drug. A single intramuscular injection of 330 mg in
1 mL in rabbits caused myonecrosis, inflammation, and hemorrhage.
When atropine and pralidoxime are used together, the signs of atropinization may
occur earlier than might be expected when atropine is used alone. This is
especially true if the total dose of atropine has been large and the
administration of pralidoxime has been delayed. (REF. 2-4) Excitement and manic
behavior immediately following recovery of consciousness have been reported in
several cases. However, similar behavior has occurred in cases of
organophosphate poisoning that were not treated with pralidoxime. (REF. 3,5,6)
DRUG ABUSE AND DEPENDENCE:
Pralidoxime chloride is not subject to abuse and possesses no known potential
for dependence.
OVERDOSAGE:
MANIFESTATIONS OF OVERDOSAGE
Observed in normal subjects only: dizziness, blurred vision, diplopia, headache,
impaired accommodation, nausea, slight tachycardia. In therapy it has been
difficult to differentiate side effects due to the drug from those due to the
effects of the poison.
TREATMENT OF OVERDOSAGE
Artificial respiration and other supportive therapy should be administered as
needed.
ACUTE TOXICITY
IV--man TDLo: 14 mg/kg (toxic effects: CNS)
IV--rat LD50: 96 mg/kg
IM--rat LD50: 150 mg/kg
ORAL--mouse LD50: 4100 mg/kg
IP--mouse LD50: 155 mg/kg
IV--mouse LD50: 90 mg/kg
IM--mouse LD50: 180 mg/kg
IV--rabbit LD50: 95 mg/kg
IM--guinea pig LD50: 168 mg/kg
DOSAGE AND ADMINISTRATION:
ORGANOPHOSPHATE POISONING
"Pralidoxime is most effective if administered immediately after poisoning.
Generally, little is accomplished if the drug is given more than 36 hours after
termination of exposure. When the poison has been ingested, however, exposure
may continue for some time due to slow absorption from the lower bowel, and
fatal relapses have been reported after initial improvement. Continued
administration for several days may be useful in such patients. Close
supervision of the patient is indicated for at least 48 to 72 hours. If dermal
exposure has occurred, clothing should be removed and the hair and skin washed
thoroughly with sodium bicarbonate or alcohol as soon as possible. Diazepam may
be given cautiously if convulsions are not controlled by atropine." (REF. 7)
Severe poisoning (coma, cyanosis, respiratory depression) requires intensive
management. This includes the removal of secretions, airway management, the
correction of acidosis, and hypoxemia.
Atropine should be given as soon as possible after hypoxemia is improved.
Atropine should not be given in the presence of significant hypoxia due to the
risk of atropine-induced ventricular fibrillation. In adults, atropine may be
given intravenously in doses of 2 to 4 mg. This should be repeated at 5- to 10-
minute intervals until full atropinization (secretions are inhibited) or signs
of atropine toxicity appear (delirium, hyperthermia, muscle twitching).
Some degree of atropinization should be maintained for at least 48 hours, and
until any depressed blood cholinesterase activity is reversed.
Morphine, theophylline, aminophylline, and succinylcholine are contraindicated.
Tranquilizers of the reserpine or phenothiazine type are to be avoided.
After the effects of atropine become apparent, Pam may be administered.
PAM CHLORIDE INJECTION
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
Discard unused solution after a dose has been withdrawn.
In Adults, inject an initial dose of 1 to 2 g of Pam, preferably as an
infusion in 100 mL of saline, over a 15- to 30-minute period. If this is not
practical or if pulmonary edema is present, the dose should be given slowly by
intravenous injection as a 5 percent solution in water over not less than five
minutes. After about an hour, a second dose of 1 to 2 g will be indicated if
muscle weakness has not been relieved. Additional doses may be given cautiously
if muscle weakness persists.
Too-rapid administration may result in temporary worsening of cholinergic
manifestations. Injection rate should not exceed 200 mg/minute. If intravenous
administration is not feasible, intramuscular or subcutaneous injection should
be used.
In severe cases, especially after ingestion of the poison, it may be desirable
to monitor the effect of therapy electrocardiographically because of the
possibility of heart block due to the anticholinesterase. Where the poison has
been ingested, it is particularly important to take into account the likelihood
of continuing absorption from the lower bowel since this constitutes new
exposure. In such cases, additional doses of Pam (pralidoxime) may be
needed every three to eight hours. In effect, the patient should be "titrated"
with Pam as long as signs of poisoning recur. As in all cases of
organophosphate poisoning, care should be taken to keep the patient under
observation for at least 24 hours.
If convulsions interfere with respiration, they may be controlled by the slow
intravenous injection of diazepam, up to 20 mg in adults.
ANTICHOLINESTERASE OVERDOSAGE
As an antagonist to such anticholinesterases as neostigmine, pyridostigmine, and
ambenonium, which are used in the treatment of myasthenia gravis, Pam may
be given in a dosage of 1 to 2 g intravenously followed by increments of 250 mg
every five minutes.
CLINICAL STUDIES:
The use of Pam (pralidoxime) has been reported in the treatment of human
cases of poisoning by the following substances:
Azodrin
Diazinon
Dichlorvos (DDVP) with chlordane
Disulfoton
EPN
Isoflurophate
Malathion
Metasystox I(R) and Fenthion
Methyldemeton
Methylparathion
Mevinphos
Parathion
Parathion and Mevinphos
Phosphamidon
Sarin
Systox(R)
TEPP
Of these cases, over 100 were due to parathion, about a dozen each to malathion,
diazinon, and mevinphos, and a few to each of the other compounds.
REFERENCES:
1. LANDAUER, W.: Cholinomimetic teratogens. V. The effect of oximes and related
cholinesterase reactivators, Teratology 15:33 (Feb) 1977.
2. MOLLER, K.O., JENSEN-HOLM, J., and LAUSEN, H.H.: Ugeskr. Laeg. 123:501, 1961.
3. NAMBA, T., NOLTE, C.T., JACKREL, J. and GROB, D.: Poisoning due to
organophosphate insecticides. Acute and chronic manifestations, Amer. J. Med.
50:475 (Apr), 1971.
4. ARENA, J.M.: Poisoning, Toxicology Symptoms, Treatments, ed. 4, Springfield,
IL, Charles C. Thomas, 1979, p. 133.
5. BRACHFELD, J., and ZAVON, M.R.: Organic phosphate (Phosdrin(R)) intoxication.
Report of a case and the results of treatment with 2-PAM, Arch. Environ. Health
11:859, 1965.
6. HAYES, W.J., Jr.: Toxicology of Pesticides, Baltimore, The Williams & Wilkins
Company, 1975, p. 416.
7. AMA Department of Drugs: AMA Drug Evaluations, ed. 4, Chicago, American
Medical Association, 1980, p. 1455.
Manufactured by:
Ayerst Laboratories Inc.
A Wyeth-Ayerst Company
Philadelphia, PA 19101
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