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Protopam

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Protopam

CLINICAL PHARMACOLOGY

The principal action of pralidoxime chloride 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 chloride 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 chloride 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 chloride relieves muscarinic signs and symptoms, salivation, bronchospasm, etc., but this action is relatively unimportant since atropine is adequate for this purpose.

Pralidoxime chloride has been studied in animals as an antidote against numerous organophosphate pesticides, chemicals, and drugs (see Animal Pharmacology and Toxicology). Regardless of whether or not animal studies suggest that the organophosphate poison to which a particular patient has been exposed is amenable to treatment with pralidoxime chloride, the use of pralidoxime chloride should, nevertheless, be considered in any life-threatening situation resulting from poisoning by these compounds, since the limited and arbitrary conditions of pharmacologic screening do not always accurately reflect the usefulness of pralidoxime chloride in the clinical situation.

Clinical Studies

There are no adequate and well controlled clinical studies that establish the effectiveness of pralidoxime chloride as a treatment for poisoning with organophosphates having anticholinesterase activity. However, its use has been considered to be successful against poisoning with numerous pesticides, chemicals, and drugs.

Pharmacokinetics

Animal studies suggest that the minimum therapeutic concentration of pralidoxime in plasma is 4 μg/mL; this level is reached in about 16 minutes after a single injection of 600 mg pralidoxime chloride. In one study of healthy adult volunteers and patients self-poisoned with organophosphate compounds, a single intramuscular injection of 1000 mg of pralidoxime chloride resulted in mean peak plasma levels of 7.5 ± 1.7 μg/mL and 9.9 ± 2.4 μg/mL, respectively. Time to reach the mean peak plasma levels in both groups was similar, 34 minutes in healthy adults and 33 minutes in poisoned patients. Mean half-life was about 3 hours in both groups.

Some evidence suggests that a loading dose followed by continuous intravenous infusion of pralidoxime chloride may maintain therapeutic levels longer than short intermittent infusion therapy. In a cross-over study of seven healthy adults (18 – 50 years) a short intravenous infusion dose of 16 mg/kg over 30 minutes was compared to an intravenous loading dose of 4 mg/kg over 15 minutes, followed by 3.2 mg/kg/hr for 3.75 hours (for a total dose of 16 mg/kg). Results showed that the mean time over which plasma levels were maintained above 4 μg/mL was prolonged in the volunteers who received a loading dose followed by continuous infusion as compared to those who received short infusion therapy (257.5 ± 50.5 min vs. 118.0 ± 52.1 min). Use of continuous intravenous infusion in adult patients with organophosphate poisoning has been described in several case reports, with and without loading doses. Infusion rates ranged from 400 – 600 mg/hr. In one case the blood levels were 11.6 – 13.7 μg/mL when given 400 mg/hr over 5 days (measured at 5, 10 and 18 hours). In another case following an initial loading dose of 1000 mg, blood levels were 11.79 μg/mL when given 500 mg/hr and 17.26 μg/mL when given 600 mg/hr. In the latter case the pralidoxime elimination half-life was 4 hours. In two other cases blood levels were not measured.

Pralidoxime chloride is distributed throughout the extracellular water; its apparent volume of distribution at steady state has been reported to range from 0.60 to 2.7 L/kg. Pralidoxime chloride is not bound to plasma protein.

Pralidoxime chloride is relatively short acting and repeated doses may be needed, unless continuous intravenous infusion is selected. Simulations suggest that after a dose of 1000 mg given intravenously, concentrations fall below 4 μg/mL in about 1.5 hours. The short duration of action of pralidoxime chloride and the necessity for repeated doses should be considered especially where there is any evidence of continuing absorption of the poison. The apparent half-life of pralidoxime is 74 to 77 minutes. The drug is rapidly excreted in the urine by renal tubular secretion, partly unchanged, and partly as a metabolite produced by the liver. After intramuscular administration of 1000 mg of pralidoxime chloride, the renal clearance has been reported to be 7.2 ± 2.9 mL/min/kg in healthy volunteers and 3.6 ± 1.5 mL/min/kg in organophosphate-poisoned patients.

In one study of 11 organophosphate-poisoned pediatric patients (age, 0.8 to 18 years), an intravenous loading dose of 15-50 mg/kg (mean 29 mg/kg) of pralidoxime chloride followed by a continuous infusion of 10-16 mg/kg/hr (mean 14 mg/kg/hr) over 12 to 43 hours (mean 27 ± 8 hours) resulted in an average steady state plasma concentration of 22.2 mg/L (6.9 to 47.4 mg/L) and an average body clearance of 0.88 L/kg/hr (0.28 to 2.20 L/kg/hr). After the continuous infusion was discontinued, determinations of the apparent volume of distribution and half-life ranged from 1.7 to 13.8 L/kg and from 2.4 to 5.3 hours, respectively.

Animal Pharmacology And Toxicology

The following table lists chemical and trade or generic names of pesticides, chemicals, and drugs against which PROTOPAM (pralidoxime chloride) (usually administered in conjunction with atropine) has been found to have antidotal activity on the basis of animal experiments. All compounds listed are organophosphates having anticholinesterase activity. A great many additional substances are in industrial use but have been omitted because of lack of specific information.

AAT—see PARATHION
AFLIX® —see FORMOTHION
ALKRON® —see PARATHION
AMERICAN CYANAMID 3422—see PARATHION
AMITON—diethyl-S-(2-diethylaminoethyl)phosphorothiolate
ANTHIO® —see FORMOTHION
APHAMITE—see PARATHION
ARMIN—ethyl-4-nitrophenylethylphosphonate
AZINPHOS-METHYL—dimethyl-S-[(4-oxo-1,2,3,-benzotriazin-3(4 H)-yl)methyl] phosphorodithioate
MORPHOTHION—dimethyl-S-2-keto-2-(N-morpholyl)ethylphosphorodithioate
NEGUVON® —see TRICHLOROFON
NIRAN® —see PARATHION
NITROSTIGMINE—see PARATHION
O,O-DIETHYL-O-p-NITROPHENYL PHOSPHOROTHIOATE—see PARATHION
O,O-DIETHYL-O-p-NITROPHENYLTHIO PHOSPHATE—see PARATHION
OR 1191—see PHOSPHAMIDON
OS 1836—see VINYLPHOS
OXYDEMETONMETHYL—dimethyl-S-2-(ethylsulfinyl) ethyl phosphorothiolate
PARAOXON—diethyl (4-nitrophenyl) phosphate
PARATHION—diethyl (4-nitrophenyl) phosphorothionate
PENPHOS—see PARATHION
PHENCAPTON—diethyl-S-(2,5-dichlorophenylmercaptomethyl) phosphorodithioate
PHOSDRIN® —see MEVINPHOS
PHOS-KIL—see PARATHION
PHOSPHAMIDON—1-chloro-1-diethylcarbamoyl-1-propen-2-yl-dimethylphosphate
PHOSPHOLINE IODIDE® —see echothiophate iodide
PHOSPHOROTHIOIC ACID, O,O-DIETHYL-O-p-NITROPHENYL ESTER—see PARATHION
PLANTHION—see PARATHION
QUELETOX—see FENTHION
RHODIATOX® —see PARATHION
RUELENE® —4-tert-butyl-2-chlorophenylmethyl-N-methylphosphoroamidate
SARIN—isopropyl-methylphosphonofluoridate
SHELL OS 1836—see VINYLPHOS
SHELL 2046—see MEVINPHOS
SNP—see PARATHION
SOMAN—pinacolyl-methylphosphonofluoridate
SYSTOX® —diethyl-(2-ethylmercaptoethyl) phosphorothionate
TEP—see TEPP
TEPP—tetraethylpyro phosphate
THIOPHOS® —see PARATHION
TIGUVON—see FENTHION
TRICHLOROFON—dimethyl-1-hydroxy-2,2,2-trichloroethylphosphonate
VAPONA® —see DICHLORVOS
VAPOPHOS—see PARATHION
VINYLPHOS—diethyl-2-chloro-vinylphosphate


PROTOPAM (pralidoxime chloride) appears to be ineffective, or marginally effective, against poisoning by:


CIODRIN® (alpha-methylbenzyl-3-[dimethoxyphosphinyloxy]-ciscrotonate)
DIMEFOX (tetramethylphosphorodiamidic fluoride)
DIMETHOATE (dimethyl-S-[N-methylcarbamoylmethyl] phosphorodithioate)
METHYL DIAZINON (dimethyl-[2-isopropyl-4-methylpyrimidyl]-phosphorothionate)
METHYL PHENCAPTON (dimethyl-S-[2,5dichlorophenylmercaptomethyl]phosphorodithioate)
PHORATE (diethyl-S-ethylmercaptomethylphosphorodithioate) SCHRADAN (octamethylpyrophosphoramide) WEPSYN® (5-amino-1-[bis-(dimethylamino) phosphinyl]-3-phenyl-1,2,4-triazole).

Last reviewed on RxList: 10/13/2010
This monograph has been modified to include the generic and brand name in many instances.

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