Ketamine Rebecca Gilley Fall 2005
Ketamine History • First synthesized by the Belgian chemist C.L. Stevens in 1963, and patented by Parke Davis in 1966, Ketamine was approved by the FDA in February of 1970 • It was first used on American Soldiers during the Vietnam War
Ketamine • Ketamine hydrochloride • 2-(2- chlorophenyl)-2-(methlamino)-cyclohexanone hydrochloride
Ketamine Street names • Kitty • Agent K • Special K • K
Structure of Ketamine • “Ketamine’s dual anesthetic/hallucinogenic nature comes from it being a chiral compound, with its two enantiomers having different effects. S-Ketamine produces anesthetic effects while its enantiomer R-Ketamine produces the hallucinogenic effects.
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 • 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.
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 • 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 • 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.
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 • These near death experiences can be expected and vindicated because of the effect that Ketamine plays on the cortex which involves cognition and perception
Benefits • Palliative Care • Antidepressants • Alcohol and substance abuse clinics • Reversing tolerance of morphine in cancer patients • Treatment of stroke victims • Alleviation of phantom pains • Management of Complex Regional Pain Syndrome • Neuro-protection
Chronic Pain • Chronic pain can be maintained by a state of sensitization within the central nervous system that is mediated in part by the excitatory amino acids glutamate and asparate binding to the N-methyl-D-asparate (NMDA) receptor • Queen’s Researchers have found that in extremely small doses, opioid antagonists (ketamine), normally used to block the toxic effects of opioids- instead enhance pain-killing action in experimental models. • The researchers discovered that for those who had already developed a tolerance to morphine, their tolerance was actually reduced with low doses of ketamine and pain was alleviated
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 • 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 • Subjects with depression evidenced significant improvement in depressive symptoms within 72 hours after ketamine but not with placebo infusion
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 • 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
Stroke Victims • Ketamine with it’s neuro-protective effect, mediated by antagonism of NMDA channels located on central neurons. • Such antagonism ultimately prevents calcium influx during states of neuro-cellular ischemia.
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 • 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 • 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!!
Ketamine • Effects of this drug are mediated by N-methyl-D-asparate (NMDA) receptors, opoid and muscaranic receptors. • Ketamine is a anesthetic and hallucinogenic.
Palliative Care • Antidepressants • Alcohol and substance abuse clinics • Reversing tolerance of morphine in cancer patients • Treatment of stroke victims • Alleviation of phantom pains • Management of Complex Regional Pain Syndrome.
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