Pralidoxime; Uses, Dosage, Side Effects, Interactions

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Pralidoxime is a Cholinesterase Reactivator. The mechanism of action of pralidoxime is as a Cholinesterase Reactivator. It is an antidote to organophosphate pesticides and chemicals. Organophosphates bind to the esteratic site of acetylcholinesterase, which results initially in reversible inactivation of the enzyme. If given within 24 hours, after organophosphate exposure, pralidoxime reactivates the enzyme cholinesterase by cleaving the phosphate-ester bond formed between the organophosphate and acetylcholinesterase.

Mechanism of Action of Pralidoxime

Pralidoxime is an antidote to organophosphate pesticides and chemicals. Organophosphates bind to the esteratic site of acetylcholinesterase, which results initially in reversible inactivation of the enzyme. Acetylcholinesterase inhibition causes acetylcholine to accumulate in synapses, producing continuous stimulation of cholinergic fibers throughout the nervous systems. If given within 24 hours after organophosphate exposure, pralidoxime reactivates the acetylcholinesterase by cleaving the phosphate-ester bond formed between the organophosphate and acetylcholinesterase.
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The principal pharmacologic effect of pralidoxime is a reactivation of cholinesterase which has been recently inactivated by phosphorylation as the result of exposure to certain organophosphates. Pralidoxime removes the phosphoryl group from the active site of the inhibited enzyme by nucleophilic attack, regenerating active cholinesterase and forming an oxime complex. Pralidoxime also detoxifies certain organophosphates by direct chemical reaction and probably also reacts directly with cholinesterase to protect it from inhibition. Pralidoxime must be administered before aging of the inhibited enzyme occurs; after aging is completed, phosphorylated cholinesterase cannot be reactivated, and newly synthesized cholinesterase must replace the inhibited enzyme. Pralidoxime is not equally antagonistic to all anticholinesterases, partly because the time period required for the aging of the inhibited enzyme varies and depends on the specific organophosphate bound to the cholinesterase.

American Society of Health-System Pharmacists; Drug

Indications of Pralidoxime

  • For the treatment of poisoning due to those pesticides and chemicals of the organophosphate class which has anticholinesterase activity and in the control of overdosage by anticholinesterase drugs used in the treatment of myasthenia gravis.
  • Toxic effect of organophosphate and carbamate
  • Anticholinesterase overdose
  • Organophosphate Poisoning
  • Nerve Agent Poisoning

Therapeutic Uses of Pralidoxime

  • Antidotes; Cholinesterase Reactivators
  • Protopam chloride is indicated as an antidote: 1. In the treatment of poisoning due to those pesticides and chemicals (e.g., nerve agents) of the organophosphate class which has 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 Protopam chloride are muscle weakness and respiratory depression. In severe poisoning, respiratory depression may be due to muscle weakness.
  • Pralidoxime chloride is used concomitantly with atropine for the treatment of nerve agent poisoning in the context of chemical warfare or terrorism. Pralidoxime chloride must be administered within minutes to hours following exposure to nerve agents to be effective.

Contra-Indications

  • High blood pressure
  • Kidney disease with a reduction in kidney function
  • Closed-angle glaucoma
  • Heart attack within the last 30 days
  • Atrial flutter
  • Heart disease
  • Narrowing of Opening Between Stomach and Small Intestine
  • Blockage of Urinary Bladder
  • Enlarged Prostate
  • Chronic obstructive lung disease

Allergies to

  • Pralidoxime
  • Belladonna Alkaloids

Dosage of Pralidoxime

Strengths: 1 g

Organophosphate Poisoning

Intravenous dosing (preferred route of administration)

  • Initial dose: 1 to 2 g, preferably as an IV infusion in 100 mL of normal saline, over 15 to 30 minutes; if an infusion is not practical or if pulmonary edema is present, the dose should be given slowly (over at least 5 minutes) by IV injection as a 50 mg/mL solution in Sterile Water for Injection (e.g., 1000 mg in 20 mL)
  • Second dose: 1 to 2 g may be indicated after about 1 hour if muscle weakness has not been relieved
  • Additional doses may be given every 10 to 12 hours if muscle weakness persists.

Intramuscular dosing (based on the severity of symptoms)

MILD SYMPTOMS

  • Initial dose: 600 mg IM; recommend waiting 15 minutes for pralidoxime to take effect
  • Second dose: 600 mg IM if mild symptoms persist after 15 minutes
  • Third dose: 600 mg IM (cumulative dose of 1800 mg) if mild symptoms persist after an additional 15 minutes
  • If severe symptoms develop at any time after the first dose, 2 additional 600 mg IM doses in rapid succession should be administered for a total cumulative dose of 1800 mg.

SEVERE SYMPTOMS

  • Three 600 mg IM doses in rapid succession should be administered for a total cumulative dose of 1800 mg.

PERSISTENT SYMPTOMS

  • If symptoms persist after administration of the complete 1800 mg regimen, the series may be repeated starting about 1 hour after the administration of the last injection.

Nerve Agent Poisoning

Intravenous dosing (preferred route of administration)

  • Initial dose: 1 to 2 g, preferably as an IV infusion in 100 mL of normal saline, over 15 to 30 minutes; if an infusion is not practical or if pulmonary edema is present, the dose should be given slowly (over at least 5 minutes) by IV injection as a 50 mg/mL solution in Sterile Water for Injection (e.g., 1000 mg in 20 mL)
  • Second dose: 1 to 2 g may be indicated after about 1 hour if muscle weakness has not been relieved
  • Additional doses may be given every 10 to 12 hours if muscle weakness persists.

Intramuscular dosing (based on the severity of symptoms)

MILD SYMPTOMS

  • Initial dose: 600 mg IM; recommend waiting 15 minutes for pralidoxime to take effect
  • Second dose: 600 mg IM if mild symptoms persist after 15 minutes
  • Third dose: 600 mg IM (cumulative dose of 1800 mg) if mild symptoms persist after an additional 15 minutes
  • If severe symptoms develop at any time after the first dose, 2 additional 600 mg IM doses in rapid succession should be administered for a total cumulative dose of 1800 mg.

SEVERE SYMPTOMS

  • Three 600 mg IM doses in rapid succession should be administered for a total cumulative dose of 1800 mg.

PERSISTENT SYMPTOMS

  • If symptoms persist after administration of the complete 1800 mg regimen, the series may be repeated starting about 1 hour after the administration of the last injection.

Anticholinesterase Overdose

  • Initial dose: 1 to 2 g IV slowly
  • Maintenance dose: Increments of 250 mg IV every 5 minutes as needed to control symptoms
  • The solution should be diluted to 10 to 20 mg/mL

Pediatric Dose Organophosphate Poisoning

16 years and younger

Intravenous administration (preferred method of administration)

LOADING DOSE FOLLOWED BY CONTINUOUS INFUSION

  • Loading dose: 20 to 50 mg/kg (maximum 2000 mg/dose) of a 10 to 20 mg/mL solution, intravenously over 15 to 30 minutes
  • Follow with a continuous infusion of 10 to 20 mg/kg/hour

INTERMITTENT INFUSION

  • Initial dose: 20 to 50 mg/kg (maximum 2000 mg/dose) of a 10 to 20 mg/mL solution, intravenously over 15 to 30 minutes
  • A second dose of 20 to 50 mg/kg may be indicated after about 1 hour if muscle weakness is not relieved.
  • Repeat dose every 10 to 12 hours as needed
  • If the above does is not practical or pulmonary edema is present, give dose diluted to a 50 mg/mL solution as a slow IV injection over at least 5 minutes
  • A second 20 to 50 mg/kg dose may be given after about 1 hour if muscle weakness has not been relieved.
  • Additional doses may be given every 10 to 12 hours if muscle weakness persists.

Intramuscular dosing (based on the severity of symptoms)

  • Weight under 40 kg: 15 mg/kg per single dose; 45 mg/kg total (3 injection) dose
  • Weight 40 kg and above: 600 mg per single dose; 1800 mg total (3 injections) dose

MILD SYMPTOMS

  • Give weight appropriate dose (see above) intramuscularly; allow 15 minutes for the drug to take effect
  • If symptoms persist after 15 minutes, give a second dose; allow 15 minutes for the drug to take effect.
  • If mild symptoms persist, a third dose may be given.
  • If severe symptoms develop any time after the first dose, administer two additional doses intramuscularly in rapid succession.

SEVERE SYMPTOMS

  • Administer three weight-appropriate doses intramuscularly in rapid succession.

PERSISTENT SYMPTOMS

  • If symptoms persist after the complete regimen, the series may be repeated about 1 hour after administration of the last injection.

Pediatric Dose for Nerve Agent Poisoning

16 years and younger
Intravenous administration (preferred method of administration)

LOADING DOSE FOLLOWED BY CONTINUOUS INFUSION

  • Loading dose: 20 to 50 mg/kg (maximum 2000 mg/dose) of a 10 to 20 mg/mL solution, intravenously over 15 to 30 minutes
  • Follow with a continuous infusion of 10 to 20 mg/kg/hour

INTERMITTENT INFUSION

  • Initial dose: 20 to 50 mg/kg (maximum 2000 mg/dose) of a 10 to 20 mg/mL solution, intravenously over 15 to 30 minutes
  • A second dose of 20 to 50 mg/kg may be indicated after about 1 hour if muscle weakness is not relieved.
  • Repeat dose every 10 to 12 hours as needed
  • If the above does is not practical or pulmonary edema is present, give dose diluted to a 50 mg/mL solution as a slow IV injection over at least 5 minutes
  • A second 20 to 50 mg/kg dose may be given after about 1 hour if muscle weakness has not been relieved.
  • Additional doses may be given every 10 to 12 hours if muscle weakness persists.

Intramuscular dosing (based on the severity of symptoms)

  • Weight under 40 kg: 15 mg/kg per single dose; 45 mg/kg total (3 injection) dose
  • Weight 40 kg and above: 600 mg per single dose; 1800 mg total (3 injections) dose

MILD SYMPTOMS

  • Give weight appropriate dose (see above) intramuscularly; allow 15 minutes for the drug to take effect
  • If symptoms persist after 15 minutes, give a second dose; allow 15 minutes for the drug to take effect.
  • If mild symptoms persist, a third dose may be given.
  • If severe symptoms develop any time after the first dose, administer two additional doses intramuscularly in rapid succession.

SEVERE SYMPTOMS

  • Administer three weight-appropriate doses intramuscularly in rapid succession.

PERSISTENT SYMPTOMS

  • If symptoms persist after the complete regimen, the series may be repeated about 1 hour after administration of the last injection.

Side Effects of Pralidoxime

More Common

  • Blurred or double vision
  • change in near or distance vision
  • difficult or rapid breathing
  • difficulty in focusing the eyes
  • difficulty with speaking
  • dizziness
  • fast, pounding, or irregular heartbeat or pulse
  • muscle stiffness or weakness
  • pain at the injection site (after injection into a muscle)

More Common

  • Acid or sour stomach
  • back pain
  • belching
  • cracked lips
  • diarrhea (mild)
  • dry skin
  • heartburn
  • indigestion
  • pain in the arms or legs
  • redness, swelling, or painful skin
  • scaling of the skin on the hands and feet
  • sores, ulcers, or white spots on the lips, tongue, or the inside of the mouth

Rare

  • Black, tarry stools
  • body aches or pain
  • burning, numbness, tingling, or painful sensations
  • burning pain on urination
  • chest pain
  • chills
  • cough
  • difficult or labored breathing
  • ear congestion
  • fever
  • headache
  • loss of voice
  • lower back or side pain
  • nasal congestion
  • painful or difficult urination
  • pale skin
  • red, swelling, or painful skin

Drug Interactions of Pralidoxime

Pralidoxime may interact with following drugs, supplements & may change the efficacy of drugs

  • atropine (AtroPen, Atreza, Sal-Tropine)
  • atropine
  • chlorpheniramine
  • hyoscyamine
  • phenylephrine
  • phenylpropanolamine
  • scopolamine
  • atropine
  • chlorpheniramine
  • hyoscyamine
  • phenylephrine
  • scopolamine
  • atropine
  • chlorpheniramine
  • hyoscyamine
  • pseudoephedrine
  • scopolamine
  • atropine
  • difenoxin
  • atropine
  • diphenoxylate
  • atropine
  • edrophonium
  • atropine
  • hyoscyamine
  • phenobarbital
  • scopolamine
  • atropine
  • phenobarbital
  • atropine
  • pralidoxime
  • mivacurium
  • succinylcholine

Pregnancy Category

AU TGA pregnancy category – Exempt
US FDA pregnancy category – Not assigned

Pregnancy 

US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

Drug Warning

  • IM administration of pralidoxime may produce mild pain at the injection site.
  • A rapid IV injection of pralidoxime has produced tachycardia, laryngospasm, muscle rigidity, and transient neuromuscular blockade; therefore, the drug should be administered slowly, preferably by IV infusion. IV administration of pralidoxime reportedly may also cause hypertension which is related to the dose and rate of infusion.
  • Some clinicians recommend that the patient’s blood pressure be monitored during pralidoxime therapy. For adults, IV administration of 5 mg of phentolamine mesylate reportedly quickly reverses pralidoxime-induced hypertension.

References

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