Chemistry - An opiate antagonist, naloxone HCl is structurally related to oxymorphone. It occurs as a white to slightly off-white powder with a pKa of 7.94. Naloxone is soluble in water and slightly soluble in alcohol. The pH range of commercially available injectable solutions are from 3-4.5. Naloxone HCl may also be known as N-allylnoroxymorphone HCl .
Storage/Stability/Compatibility - Naloxone HCl for injection should be stored at room temperature (15-30°C) and protected from light.
Sterile water for injection is the recommended diluent for naloxone injection. When given as an IV infusion, either D5W or normal saline should be used. Naloxone HCl injection should not be mixed with solutions containing sulfites, bisulfites, long-chain or high molecular weight anions or any solutions at alkaline pH.
Pharmacology - Naloxone is considered to be a pure opiate antagonist and it has basically no analgesic activity. The exact mechanism for its activity is not understood, but it is believed that the drug acts as a competitive antagonist by binding to the mu, kappa, and sigma opioid receptor sites. The drug apparently has its highest affinity for the mu receptor.
Naloxone reverses the majority of effects associated with high-dose opiate administration (respiratory and CNS depression). In dogs, naloxone apparently does not reverse the emetic actions of apomorphine.
Naloxone also has other pharmacologic activity at high doses, including effects on dopaminergic mechanisms (increases dopamine levels) and GABA antagonism.
Uses/Indications - Naloxone is used in veterinary medicine almost exclusively for its opiate reversal effects, but the drug is being investigated for treating other conditions (e.g., septic, hypovolemic or cardiogenic shock). Naloxone may also be employed as a test drug to see if endogenous opiate blockade will result in diminished tail-chasing or other self-mutilating behaviors.
Pharmacokinetics - Naloxone is only minimally absorbed when given orally as it is rapidly destroyed in the GI tract. Much higher doses are required if using this route of administration for any pharmacologic effect. When given IV, naloxone has a very rapid onset of action (usually 1-2 minutes). If given IM, the drug generally has an onset of action within 5 minutes of administration. The duration of action usually persists from 45-90 minutes, but may act for up to 3 hours.
Naloxone is distributed rapidly throughout the body with high levels found in the brain, kidneys, spleen, skeletal muscle, lung and heart. The drug also readily crosses the placenta.
Naloxone is metabolized in the liver, principally via glucuronidative conjugation with metabolites excreted into the urine. In humans, the serum half-life is approximately 60-100 minutes.
Contraindications/Precautions/Reproductive Safety - Naloxone is contraindicated in patients hypersensitive to it. It should be used cautiously in animals that have preexisting cardiac abnormalities or in animals that may be opioid dependent. The veterinary manufacturer states to use the drug “...cautiously in animals who have received exceedingly large doses of narcotics. ... may produce an acute withdrawal syndrome and smaller doses should be employed.” (Package Insert; P/M® Naloxone HCl Injection—P/M; Mallinckrodt)
Naloxone is generally considered to be non-teratogenic in animals, but has precipitated withdrawal in opioid-dependent human fetuses.
Adverse Effects/Warnings - At usual doses, naloxone is relatively free of adverse effects in non-opioid dependent patients. Because the duration of action of naloxone may be shorter than that of the narcotic being reversed, animals that are being treated for opioid intoxication or with symptoms of respiratory depression should be closely monitored as additional doses of naloxone and/or ventilatory support may be required.
Overdosage/Acute Toxicity - Naloxone is considered to be a very safe agent with a very wide margin of safety, but very high doses have initiated seizures (secondary to GABA antagonism?) in a few patients.
Drug Interactions - Naloxone also reverses the effects of opioid agonists/antagonists such as butorphanol, pentazocine or nalbuphine.
For opioid reversal:
a) 0.01 - 0.022 mg/kg to reverse sedative and excitatory effects of narcotic agonists. (Clark and Becht 1987)
b) 0.01 mg/kg IV to limit increases in locomotor activity secondary to narcotic agonists. (Muir 1987)
c) 0.01 - 0.02 mg/kg IV (Robinson 1987)
To reverse the effects of etorphine, morphine, and meperidine:
a,b,c) 10 mg total dose in small elephants; up to 30-50 mg in adults (Cheeran et.al. 1995; Schmidt, 1986; Smuts, 1975).
a) Cheeran,J.V., Chandrasekharan,K., and Radhakrishnan,K., 1995. Principles and Practice of Fixing Dose of Drugs for Elephants . In: Daniel,J.C. (Editor), A Week with Elephants; Proceedings of the International Seminar on Asian Elephants. Bombay Natural History Society; Oxford University Press, Bombay, India pp. 430-438
b) Schmidt,M.J., 1986. Proboscidea (Elephants). In: Fowler,M.E. (Editor), Zoo and wild animal medicine. W.B. Saunders, Philadelphia,PA, USA pp. 884-923
c) Smuts,G.L. 1975. An appraisal of naloxone
hydrochloride as a narcotic antagonist in the capture and release of wild
herbivores. J Am Vet Med Assoc 167:(7):559-561
Lance,W.R. 1991. New pharmaceutical tools for the 1990's. Proceedings of the American Association of Zoo Veterinarians 354-359
Monitoring Parameters -
1) Respiratory rate/depth
2) CNS function
3) Pain associated with opiate reversal
Client Information - Should be used with direct professional supervision only.
Dosage Forms/Preparations/FDA Approval Status/Withholding Times -
Naloxone HCl Injection 0.4 mg/ml in 10 ml vials; P/M® Naloxone HCl Injection (Schering Plough); (Rx) Approved for use in dogs.
Naloxone HCl Injection 0.4 mg/ml in 1 ml amps, syringes & 1, 2, & 10 ml vials; Narcan® (Dupont Pharm.), Generic; (Rx)
Naloxone HCl Injection 1 mg/ml in 2 ml amps, vials & 1, 5, & 10 ml vials; Narcan® (Dupont Pharm.), Generic; (Rx)
Naloxone HCl Neonatal Injection 0.02 mg/ml in 2 ml amps, & vials; Narcan® (Dupont Pharm); Generic; (Rx)
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