KETAM

Indications

• Induction and maintenance of anesthesia
• Procedural sedation
• Pain management
• Treatment-resistant depression

Dosage

Children: In children aged 12 to 17 years, initial doses for sedation can range from 2.4 to 120 micrograms/kg/hour

Adults: For intravenous use, the adult dosage for induction of anesthesia is typically 1 to 2 mg/kg, followed by maintenance doses adjusted according to response. Continuous infusion may be maintained at 10 to 45 micrograms/kg/minute.

Mechanism of action

Ketamine primarily interacts with N-methyl-D-aspartate (NMDA) receptors, but it also affects opioid receptors, monoaminergic receptors, muscarinic receptors, and voltage-sensitive calcium ion channels. This broad interaction profile contributes to its anesthetic and analgesic properties, distinguishing it from typical general anesthetics that primarily target GABA receptors.

Pharmacodynamics

Ketamine produces a unique anesthetic state known as 'dissociative anesthesia', which includes profound analgesia, preservation of airway reflexes, and stimulation of cardiovascular and respiratory systems. It can result in slight respiratory depression and has been shown to enhance descending serotonergic pathways, providing potential antidepressant effects at sub-anesthetic doses. Ketamine also prevents central sensitization in dorsal horn neurons, contributing to its analgesic properties.

Pharmacokinetics

Ketamine is rapidly distributed throughout the body, with a large volume of distribution. It undergoes extensive hepatic metabolism primarily via CYP2B6 and CYP3A4 enzymes, yielding active metabolites such as norketamine. The elimination half-life is variable but generally ranges from 2 to 3 hours. Renal excretion is the primary route for elimination of metabolites. Care must be taken in patients with hepatic impairment, as prolonged effects may occur.

Contra-indications

• Hypersensitivity to ketamine or any component of the formulation
• Severe hypertension
• Conditions where a rise in blood pressure would be hazardous

Adverse effects

• Hallucinations
• Dysphoria
• Nausea
• Vomiting
• Increased muscle tone
• Nystagmus
• Psychotomimetic effects
• Respiratory depression
• Increased urinary frequency
• Cystitis (with long-term use)

Interactions

• Severe interaction with memantine (increases risk of CNS adverse effects)
• Unknown interaction with ergometrine (may increase risk of elevated blood pressure)

Precautions

• Use caution in patients with cardiovascular disease
• Monitor closely in patients with hepatic impairment
• Avoid in patients with a history of substance abuse
• Consider dose reduction in the elderly and those with comorbid conditions

Pregnancy

May depress neonatal respiration if used during delivery. Use with caution.

Breast-feeding

Avoid for at least 12 hours after the last dose.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Powder for solution for injection (1 mg/vial)
• Concentrated solution for injection (2 mg/vial)
• Infusion solution (1 mg/mL)

Mechanism of action

Ketamine interacts with N-methyl-D-aspartate (NMDA) receptors, opioid receptors, monoaminergic receptors, muscarinic receptors and voltage sensitive Ca ion channels. Unlike other general anaesthetic agents, ketamine does not interact with GABA receptors. Long-term ketamine abuse is known to affect the lower urinary tract and produce symptoms of cystitis. However, the pathophysiology and causative mechanism of the changes in bladder function remain unclear. The present study aimed to investigate the existence of ketamine-induced cystitis in a rat model and characterize the underlining mechanisms. Rats were assigned to blank control, normal saline (NS), low-dose ketamine (LK, 5 mg/kg), and high-dose ketamine (HK, 50 mg/kg) groups. The two experimental groups received ketamine hydrochloride daily for 16 weeks. All rats were housed individually for assessment of urinary frequency and urine volume. Urinary biomarkers were measured at different time points. Rat bladders were excised for histopathology, immunohistochemistry, and western blot analysis. Ketamine-treated rats had increased urinary frequency compared to NS-treated rats at Week 16. Urinary nitric oxide and antiproliferative factor levels were increased in ketamine-treated rats within the first 30 h after administration. After long-term ketamine administration, urinary glycoprotein GP51 and potassium levels were decreased in the HK and LK groups compared to the NS group. Ketamine-treated rats showed thickened bladder epithelial layer, increased expression of inducible nitric oxide synthase and occludin, and decreased expression of zonula occludens-1 in the bladder wall. Ketamine, or its urinary metabolites, disrupted the proliferation of bladder epithelial cells, resulting in defected bladder epithelial barrier. Subsequent leakage of urinary potassium causes a stress response in the bladder and provokes cystitis. Recreational abuse of ketamine has been associated with the emergence of a new bladder pain syndrome, ketamine-induced cystitis, characterized by chronic inflammation and urothelial ulceration. We investigated the direct effects of ketamine on normal human urothelium maintained in organ culture or as finite cell lines in vitro. Exposure of urothelium to ketamine resulted in apoptosis, with cytochrome c release from mitochondria and significant subsequent caspase 9 and 3/7 activation. The anesthetic mode-of-action for ketamine is mediated primarily through N-methyl d-aspartate receptor (NMDAR) antagonism; however, normal (nonimmortalized) human urothelial cells were unresponsive to NMDAR agonists or antagonists, and no expression of NMDAR transcript was detected. Exposure to noncytotoxic concentrations of ketamine (</=1 mmol/L) induced rapid release of ATP, which activated purinergic P2Y receptors and stimulated the inositol trisphosphate receptor to provoke transient release of calcium from the endoplasmic reticulum into the cytosol. Ketamine concentrations >1 mmol/L were cytotoxic and provoked a larger-amplitude increase in cytosolic Ca(2+) concentration that was unresolved. The sustained elevation in cytosolic Ca(2+) concentration was associated with pathological mitochondrial oxygen consumption and ATP deficiency. Damage to the urinary barrier initiates bladder pain and, in ketamine-induced cystitis, loss of urothelium from large areas of the bladder wall is a reported feature. This study offers first evidence for a mechanism of direct toxicity of ketamine to urothelial cells by activating the intrinsic apoptotic pathway. Several lines of evidence indicate that ketamine has a rapid antidepressant-like effect in rodents and humans, but underlying mechanisms are unclear. In the present study, we investigated the effect of ketamine on serotonin (5-HT) release in the rat prefrontal cortex by in vivo microdialysis. A subcutaneous administration of ketamine (5 and 25 mg/kg) significantly increased the prefrontal 5-HT level in a dose-dependent manner, which was attenu

Pharmacodynamics

Ketamine is a rapid-acting general anesthetic producing an anesthetic state characterized by profound analgesia, normal pharyngeal-laryngeal reflexes, normal or slightly enhanced skeletal muscle tone, cardiovascular and respiratory stimulation, and occasionally a transient and minimal respiratory depression. The anesthetic state produced by Ketamine has been termed as "dissociative anesthesia" in that it appears to selectively interrupt association pathways of the brain before producing somesthetic sensory blockade. It may selectively depress the thalamoneocortical system before significantly obtunding the more ancient cerebral centers and pathways (reticular-activating and limbic systems). Ketamine enhances descending inhibiting serotoninergic pathways and can exert antidepressive effects. These effects are seen in concentrations ten times lower than the needed concentration for anesthetic proposes. The effect of ketamine can be described as analgesic by the prevention of central sensitization in dorsal horn neurons as well as by the inhibition on the synthesis of nitric oxide. Ketamine can present cardiovascular changes and bronchodilatation.