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Information about Ketamine

Published on May 1, 2009

Author: drsujnanendra


Ketamine : Ketamine Dr. Sujnanendra Mishra MD (O&G) Ketamine History : 22/04/2009 Dr.Sujnanendra Mishra 2 Ketamine History Ketamine was synthesized in an attempt to find a safer anesthetic alternative to PCP, which was more likely to cause hallucinations and seizures. First synthesized by the Belgian chemist C.L. Stevens in 1962/1963, and patented by Parke Davis in 1966, Ketamine was approved by the FDA in February of 1970 In the recent past its use on humans has been dramatically curtailed because of exaggerated concern about its potential to cause emergence phenomena including out-of-body experiences in clinical practice. Ketamine : Ketamine Ketamine hydrochloride 2-(2- chlorophenyl)-2-(methlamino)-cyclohexanone hydrochloride 22/04/2009 Dr.Sujnanendra Mishra 3 Structure of Ketamine : Structure of Ketamine Ketamine is racemic Has two steroisomers R- and S+ Have different anesthetic potencies (1:3-4) but similar kinetics Structure of Ketamine : Structure of Ketamine Being a chiral compound containing an asymmetric center (chiral atom or chiral center) and with its two nonsuperimposable mirror-image forms (enantiomers). having different effects. S-Ketamine produces anesthetic effects while its enantiomer R-Ketamine produces the hallucinogenic effects. 22/04/2009 Dr.Sujnanendra Mishra 5 Slide 6: Its R- and S+ stereoisomer have different binding affinities. (S)-Ketamine has about four times greater affinity for the PCP site of the NDMA receptor than (R)-Ketamine (in guinea pig brain). The S form also seems to be better at inducing the drowsiness than the R form. Mechanism of Action : 22/04/2009 Dr.Sujnanendra Mishra 7 Mechanism of Action During normal nerve stimulation, the nerve impulse reaches the axon terminal, and Na+ and voltage dependent Ca+ gates are opened. The surge of free calcium into the axonal terminal acts as a messenger, and the contents are emptied by exocytosis into the synaptic cleft. The Ca+ is then quickly removed, and the neurotransmitter diffuses across the synaptic cleft and binds to specific protein receptors. A conformational change occurs and allows the ion channels to open and thus changing the membrane potential. Mechanism of Action : 22/04/2009 Dr.Sujnanendra Mishra 8 Mechanism of Action Glutamate is used as an excitatory amino acid neurostramitter Glutamate stimulates receptors on the postsynaptic membrane to transmit a nerve impulse When the gates are left open to long it allows more Ca+ into the cell, therefore triggering the release of more of the neurotransmitter, in this case glutamate. When present in excess, neurons become overexcited and are poisoned by the excess Ca+ and die from overstimulation via a process called excitotoxicity. NMDA-receptor antagonists, such as ketamine, bind to the receptor site where glutamate would and therefore suppress central sensitization and protects the neurons from over stimulation and cell death. Slide 9: 22/04/2009 Dr.Sujnanendra Mishra 9 Normally Acetylcholine enters to clear the neurotransmitter to allow for additional messages to be transmitted Ketamine is a nondepolarizing neuromuscular blocker, which inhibits and competes with acetylcholine from binding to its nicotinic receptor on the post synaptic membrane of the motor junction. Ketamine’s S-enantiomer (anesthetic effects) prevents the reuptake of Acetylcholine, thus allowing the receptor site to remain blocked Ketamine : 22/04/2009 Dr.Sujnanendra Mishra 10 Ketamine Pain is detected by two different types of peripheral nociceptor neurons C-fiber nociceptors with slowly conducting unmyelinated axons A-delta nociceptors thinly myelineated axons During inflammation, nociceptors become sensitized, discharge spontaneously, and produce ongoing pain. Prolonged C-fiber firing causes release of glutamate which acts on N-methyl-D-asparate (NMDA) receptors in the spinal cord. Activation of NMDA receptors causes the spinal cord neuron to become more responsive to all of its inputs, resulting in central sensitization. Ketamine : 22/04/2009 Dr.Sujnanendra Mishra 11 Ketamine Ketamine has particularly been looked at in the Wind-Up Phenomena rapidly repeated, identical noxious stimuli, which means that a simple touch input is converted into a painful sensation called allodynia. This can also mean that a pain stimuli can be magnified greatly and create a cascade of pain. The wind up seems to be mediated by the NMDA receptors and can be reduced by Ketamine. Slide 12: 22/04/2009 Dr.Sujnanendra Mishra 12 Near Death Experiences : 22/04/2009 Dr.Sujnanendra Mishra 13 Near Death Experiences Ketamine has been abused in recent years as a party drug The NDE’s are due to blockade of brain receptors for the neurotransmitter glutamate. Conditions which precipitate NDE’s are: low oxygen, low blood flow, low blood sugar, and temporal lobe epilepsy have been shown to release a flood of glutamate over activating NMDA receptors Ketamine when taken blocks the glutamate from binding and leads to a feeling of altered consciousness. Near Death Experience : 22/04/2009 Dr.Sujnanendra Mishra 14 Near Death Experience These near death experiences can be expected and vindicated because of the effect that Ketamine plays on the cortex which involves cognition and perception BENIFITS : 22/04/2009 Dr.Sujnanendra Mishra 15 BENIFITS Palliative Care Antidepressants Alcohol and substance abuse clinics Reversing tolerance of morphine in cancer patients Treatment of stroke victims, Neuro-protection Alleviation of phantom pains Management of Complex Regional Pain Syndrome Palliative Care : 22/04/2009 Dr.Sujnanendra Mishra 16 Palliative Care A small percentage of patients with far advanced diseases experience severe pain despite rapid upward titration of opioid analgesics, anti-inflammatories, or other pain modulating drugs the use of low-dose ketamine in palliative care settings where opioid-refractory pain or opioid-medicated adverse effects prevent satisfactory pain relief Ketamine is known to be a potent NMDA receptor antagonist providing some rationale for its efficacy in treating neuropathic pain and enhancing opioid analgesia Antidepressants : 22/04/2009 Dr.Sujnanendra Mishra 17 Antidepressants It is suggested that glutamate systems effect major depression and the mechanism in which the anti-depressants react in the body Clinical Neuroscience Research Unit the first placebo-controlled, double-blinded trial to assess the treatment effects of single does of an NMDA receptor antagonist in patients with depression. seven subjects, was treated for two days with intravenous treatment with ketamine or saline solutions Results : 22/04/2009 Dr.Sujnanendra Mishra 18 Results Subjects with depression evidenced significant improvement in depressive symptoms within 72 hours after ketamine but not with placebo infusion Heroin Addicts and Alcoholics : 22/04/2009 Dr.Sujnanendra Mishra 19 Heroin Addicts and Alcoholics The major components of addiction are Ibogaine and Acamprosate Ketamine produces anti-craving properties because of the NMDA receptor and its influence on the similar ligands-acamprosate and ibogaine Results : 22/04/2009 Dr.Sujnanendra Mishra 20 Results Savage and McCabe showed that LSD-assisted psychotherapy had a positive effect on the outcome of treatment of heroin addicts: 25% treated with LSD remained abstinent from opiates for one year as opposed to only 5% of the control group remaining abstinent Phantom pain : 22/04/2009 Dr.Sujnanendra Mishra 21 Phantom pain This pain is due to the hyperactivity of NMDA receptors. Ketamine is administered to block the receptor sites and alleviate the pain Those who received the ketamine infusion the stump pain was alleviated for 31 hours and were treated 4 times a day and showed no tolerance. The saline group still complained of phantom pain Complex Regional Pain Syndrome : 22/04/2009 Dr.Sujnanendra Mishra 22 Complex Regional Pain Syndrome affects between 1.5 and 7 million people little is known about this condition it appears that the pain is caused by over stimulation of a nerve receptor complex involved in the process of feeling pain Results : 22/04/2009 Dr.Sujnanendra Mishra 23 Results Alleviating all the pain was felt by 25 patients (76%) Partially eliminating the pain of 6 patients (18%) No relief was felt by 2 patients (6%) Although the relief was not indefinite, 54% said that the pain was alleviated for 3-4 months with one treatment After two treatments, 33% of the patients stated the pain was alleviated for more than 3 years!! Routes of Administration : 22/04/2009 Dr.Sujnanendra Mishra 24 Routes of Administration Routes ---Ketamine may be administered by the intravenous, intramuscular, oral, rectal, or nasal routes. (also been administered in the epidural and intrathecal spaces to achieve analgesia.) Doses, General Anesthesia -- Intravenous induction: 0.5 - 2 mg/kg -> peak effect in 30-60 seconds Intramuscular induction: 4 - 10 mg/kg -> onset 5 minutes, peak 20 minutes Maintenance: 0.5 - 1 mg/kg IV prn Or, better: 20 - 90 mcg/kg/min IV infusion Doses, Routes of AdministrationCont. : 22/04/2009 Dr.Sujnanendra Mishra 25 Doses, Routes of AdministrationCont. Sedation/analgesia 0.2 - 0.8 mg/kg IV 2 - 4 mg/kg IM 5 - 10 mcg/kg/min IV infusion Pediatric sedation-anesthesia: : 22/04/2009 Dr.Sujnanendra Mishra 26 Pediatric sedation-anesthesia: Bioavailability : 22/04/2009 Dr.Sujnanendra Mishra 27 Bioavailability Slide 28: 22/04/2009 Dr.Sujnanendra Mishra 28 Adverse Effects Most Frequent: Delirium, Hallucinations, Hypertension, Mood Changes, Nightmares, Tachyarrhythmia, Tonic-Clonic Epilepsy, Tremors, VocalizationLess Frequent: Bradycardia, Hypotension, Respiratory Depression, VomitingRare: Anaphylaxis, Anorexia, Conduction Disorder of the Heart, Diplopia, Injection Site Sequelae, Laryngismus, Nausea, Nystagmus, Obstructive Pulmonary Disease, Skin Inflammation, Skin Rash Ketamine : Ketamine Despite the side effects of Near Death Experiences, Ketamine has proved to be very beneficial and useful in the medical field both animal and human Ketamine in the future will continue to provide aid with disease pain and maybe even life time cures of certain ailments 22/04/2009 Dr.Sujnanendra Mishra 29

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