Discover Ketamine HCl

description of ketamine HCI:

Ketamine HCI is a dissociative anesthetic and analgesic drug that has been used in human and veterinary medicine since the 1960s. It is a phencyclidine (PCP) derivative but with far less psychotomimetic effects and abuse potential compared to PCP.

Chemical Structure and Properties

The chemical name for hydrochloride is (RS)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride. It has a molecular formula of C13H16ClNO•HCl and a molecular weight of 274.19 g/mol.

hydrochloride  base is a lipid-soluble, white crystalline powder. The hydrochloride salt form is water-soluble and used for injectable formulations. It exists as a racemic mixture of two enantiomers. hydrochloride solutions have a slightly acidic pH between 3.5-5.5 to enhance stability. It is typically formulated with preservatives like benzethonium chloride.

Mechanism of Action

hydrochloride   is classified as an N-methyl-D-aspartate (NMDA) receptor antagonist, though it also interacts with other receptors like opioid, monoaminergic, muscarinic, and voltage-gated channels.

Its primary mechanism is non-competitive inhibition of the NMDA receptor, an ionotropic glutamate receptor that mediates excitatory neurotransmission. By blocking NMDA receptors, ketamine disrupts glutamatergic neurotransmission and produces a “dissociative” effect, disconnecting the higher cortical centers from incoming sensory information.

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This NMDA antagonism is thought to underlie ketamine’s anesthetic, analgesic, psychotomimetic, and rapid antidepressant effects through modulation of glutamate neurotransmission.

Pharmacokinetics

After intravenous administration, ketamine exhibits a two-compartment model pharmacokinetics:

– Alpha phase: Rapid redistribution from the central compartment with a half-life of 10-15 minutes, corresponding to the onset of clinical effects.

– Beta phase: Slower elimination phase with a half-life of around 2-3 hours.

hydrochloride is highly protein bound (78-92%) in plasma, primarily to albumin. It undergoes extensive hepatic metabolism via N-dealkylation, hydroxylation, and conjugation pathways by cytochrome P450 enzymes.

The major metabolite norketamine is one-third to one-fifth as potent as hydrochloride and may contribute to its effects. Ketamine and metabolites are excreted in urine and bile.

Indications and Uses

FDA Approved Indications:
– Induction of general anesthesia prior to other anesthetic agents
– Sole anesthetic for diagnostic and surgical procedures not requiring muscle relaxation
– Supplement to other anesthetics like nitrous oxide

Off-Label Uses:
– Treatment-resistant depression (IV infusion)
– Chronic pain management (oral, IV, intranasal)
– Sedation in intensive care
– Neuropathic pain and complex regional pain syndrome
– Status asthmaticus and acute respiratory distress
– Procedural sedation and analgesia

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hydrochloride  produces a “dissociative anesthesia” state involving catalepsy, amnesia, and analgesia while  maintaining respiratory drive and protective airway reflexes. This unique state separates  hydrochloride from other general anesthetics.

Effects Profile
At sub-anesthetic doses, hydrochloride can produce psychoactive effects including:

– Distortions in sight, sound, and sense of time
– Feelings of detachment from environment and self (dissociation)
– Vivid dreams and hallucinations
– Increased libido
– Nausea and vomiting

At anesthetic doses, effects can include:

– Profound analgesia and amnesia
– Increased muscle tone and cardiovascular stimulation
– Respiratory depression (higher doses)
– Emergence delirium or vivid dreams upon awakening

hydrochloride   rapid antidepressant effects are believed to involve increased prefrontal brain-derived neurotrophic factor (BDNF) signaling and synaptogenesis.

For chronic pain, hydrochloride is thought to disrupt central sensitization and hyperalgesic priming through NMDA receptor inhibition.

Administration and Dosing
hydrochloride can be administered intravenously, intramuscularly, orally, intranasally, rectally, and sublingually depending on the indication.

Typical dosing for anesthesia induction is 1-4.5 mg/kg IV or 6.5-13 mg/kg IM. Lower doses of 0.1-0.8 mg/kg IV are used for analgesia or sedation.

For treatment-resistant depression, a single low-dose IV infusion of 0.5 mg/kg over 40 minutes has shown rapid antidepressant effects within hours to days.

Oral dosing for chronic pain is typically started low at 0.5 mg/kg and slowly titrated up based on response and tolerability.

Adverse Effects
Common adverse effects of ketamine include:

– Cardiovascular stimulation (hypertension, tachycardia)
– Increased muscle tone and motor incoordination
– Nausea, vomiting
– Diplopia (double vision)
– Dizziness
– Vivid dreams or emergence delirium

Serious but rare effects can include:

– Respiratory depression (higher doses)
– Increased intraocular and intracranial pressure
– Hepatotoxicity with prolonged use
– Bladder toxicity with chronic, high-dose use
– Psychosis or psychotomimetic effects

hydrochloride should be used cautiously in those with thyroid disorders, psychiatric illness, elevated intraocular or intracranial pressure, and substance abuse disorders.

Drug Interactions
hydrochloride   can dangerously potentiate respiratory depression when combined with other CNS depressants like opioids, benzodiazepines, barbiturates, or alcohol.

Inducers of CYP enzymes like rifampin may increase hydrochloride  clearance, while inhibitors like protease inhibitors may increase levels.

Cautions in Special Populations
Ketamine should be used cautiously in the elderly, pregnant patients, and those with hepatic or renal impairment. It is contraindicated in patients with untreated or uncontrolled hypertension.

Abuse Potential
Ketamine is a Schedule III controlled substance in the US due to its potential for abuse and dependence, though the risk is lower compared to PCP. Chronic, high-dose abuse can lead to bladder and cognitive impairment.

In summary, hydrochloride  is a unique anesthetic and analgesic with diverse clinical applications from anesthesia to treatment-resistant depression. While effective, it requires careful monitoring for adverse effects, drug interactions, and abuse potential, especially with off-label uses. Ongoing research continues to explore ketamine’s therapeutic potential.