KetamineKetamine

Rebecca GilleyRebecca Gilley

Fall 2005Fall 2005

Ketamine HistoryKetamine History

First synthesized by the Belgian chemist First synthesized by the Belgian chemist C.L. Stevens in 1963, and patented by C.L. Stevens in 1963, and patented by Parke Davis in 1966, Ketamine was Parke Davis in 1966, Ketamine was approved by the FDA in February of 1970 approved by the FDA in February of 1970

It was first used on American Soldiers It was first used on American Soldiers during the Vietnam War during the Vietnam War

KetamineKetamine Ketamine Ketamine

hydrochloride hydrochloride

2-(2- chlorophenyl)-2-2-(2- chlorophenyl)-2-(methlamino)-(methlamino)-cyclohexanone cyclohexanone hydrochloridehydrochloride

Ketamine Street namesKetamine Street names

KittyKitty

Agent KAgent K

Special KSpecial K

KK

Structure of KetamineStructure of Ketamine ““Ketamine’s dual Ketamine’s dual

anesthetic/hallucinogenic anesthetic/hallucinogenic nature comes from it nature comes from it being a chiral compound, being a chiral compound, with its two enantiomers with its two enantiomers having different effects. having different effects. S-Ketamine produces S-Ketamine produces anesthetic effects while anesthetic effects while its enantiomer R-its enantiomer R-Ketamine produces the Ketamine produces the hallucinogenic effects. hallucinogenic effects.

Mechanism of ActionMechanism of Action

During normal nerve stimulation, the nerve During normal nerve stimulation, the nerve impulse reaches the axon terminal, and Naimpulse reaches the axon terminal, and Na+ + and and voltage dependent Cavoltage dependent Ca+ + gates are opened.gates are opened.

The surge of free calcium into the axonal terminal The surge of free calcium into the axonal terminal acts as a messenger, and the contents are acts as a messenger, and the contents are emptied by exocytosis into the synaptic cleft.emptied by exocytosis into the synaptic cleft.

The CaThe Ca+ + is then quickly removed, and the is then quickly removed, and the neurotransmitter diffuses across the synaptic cleft neurotransmitter diffuses across the synaptic cleft and binds to specific protein receptors.and binds to specific protein receptors.

A conformational change occurs and allows the A conformational change occurs and allows the ion channels to open and thus changing the ion channels to open and thus changing the membrane potential.membrane potential.

Mechanism of ActionMechanism of Action Glutamate is used as an excitatory amino acid neurostramitterGlutamate is used as an excitatory amino acid neurostramitter

Glutamate stimulates receptors on the postsynaptic membrane Glutamate stimulates receptors on the postsynaptic membrane to transmit a nerve impulseto transmit a nerve impulse

When the gates are left open to long it allows more CaWhen the gates are left open to long it allows more Ca++ into the into the cell, therefore triggering the release of more of the cell, therefore triggering the release of more of the neurotransmitter, in this case glutamate. neurotransmitter, in this case glutamate.

When present in excess, neurons become overexcited and are When present in excess, neurons become overexcited and are poisoned by the excess Capoisoned by the excess Ca++ and die from overstimulation via a and die from overstimulation via a process called excitotoxicity.process called excitotoxicity.

NMDA-receptor antagonists, such as ketamine, bind to the NMDA-receptor antagonists, such as ketamine, bind to the receptor site where glutamate would and therefore suppress receptor site where glutamate would and therefore suppress central sensitization and protects the neurons from over central sensitization and protects the neurons from over stimulation and cell death.stimulation and cell death.

Normally Acetylcholine enters to clear the Normally Acetylcholine enters to clear the neurotransmitter to allow for additional neurotransmitter to allow for additional messages to be transmitted messages to be transmitted

Ketamine is a nondepolarizing Ketamine is a nondepolarizing neuromuscular blocker, which inhibits and neuromuscular blocker, which inhibits and competes with acetylcholine from binding to competes with acetylcholine from binding to its nicotinic receptor on the post synaptic its nicotinic receptor on the post synaptic membrane of the motor junction. membrane of the motor junction.

Ketamine’s S-enantiomer (anesthetic Ketamine’s S-enantiomer (anesthetic effects) prevents the reuptake of effects) prevents the reuptake of Acetylcholine, thus allowing the receptor site Acetylcholine, thus allowing the receptor site to remain blockedto remain blocked

Mechanism of ActionMechanism of Action

KetamineKetamine

Pain is detected by two different types of peripheral Pain is detected by two different types of peripheral nociceptor neuronsnociceptor neurons

– C-fiber nociceptors with slowly conducting unmyelinated C-fiber nociceptors with slowly conducting unmyelinated axonsaxons

– A-delta nociceptors thinly myelineated axonsA-delta nociceptors thinly myelineated axons

During inflammation, nociceptors become sensitized, During inflammation, nociceptors become sensitized, discharge spontaneously, and produce ongoing pain. discharge spontaneously, and produce ongoing pain. Prolonged C-fiber firing causes release of glutamate which Prolonged C-fiber firing causes release of glutamate which acts on N-methyl-D-asparate (NMDA) receptors in the acts on N-methyl-D-asparate (NMDA) receptors in the spinal cord. Activation of NMDA receptors causes the spinal cord. Activation of NMDA receptors causes the spinal cord neuron to become more responsive to all of its spinal cord neuron to become more responsive to all of its inputs, resulting in central sensitization. inputs, resulting in central sensitization.

KetamineKetamine

Ketamine has particularly been looked at in Ketamine has particularly been looked at in the Wind-Up Phenomenathe Wind-Up Phenomena– rapidly repeated, identical noxious stimuli, which rapidly repeated, identical noxious stimuli, which

means that a simple touch input is converted means that a simple touch input is converted into a painful sensation called allodynia. into a painful sensation called allodynia.

– This can also mean that a pain stimuli can be This can also mean that a pain stimuli can be magnified greatly and create a cascade of pain. magnified greatly and create a cascade of pain.

The wind up seems to be mediated by the The wind up seems to be mediated by the NMDA receptors and can be reduced by NMDA receptors and can be reduced by Ketamine. Ketamine.

Near Death ExperiencesNear Death Experiences Ketamine has been abused in recent years as a Ketamine has been abused in recent years as a

party drugparty drug The NDE’s are due to blockade of brain receptors The NDE’s are due to blockade of brain receptors

for the neurotransmitter glutamate. for the neurotransmitter glutamate. Conditions which precipitate NDE’s are: low oxygen, Conditions which precipitate NDE’s are: low oxygen,

low blood flow, low blood sugar, and temporal lobe low blood flow, low blood sugar, and temporal lobe epilepsy have been shown to release a flood of epilepsy have been shown to release a flood of glutamate over activating NMDA receptorsglutamate over activating NMDA receptors

Ketamine when taken blocks the glutamate from Ketamine when taken blocks the glutamate from binding and leads to a feeling of altered binding and leads to a feeling of altered consciousness. consciousness.

Near Death ExperienceNear Death Experience

These near death experiences can be These near death experiences can be expected and vindicated because of the expected and vindicated because of the effect that Ketamine plays on the cortex effect that Ketamine plays on the cortex which involves cognition and perceptionwhich involves cognition and perception

BenefitsBenefits Palliative CarePalliative Care Antidepressants Antidepressants Alcohol and substance abuse clinicsAlcohol and substance abuse clinics Reversing tolerance of morphine in cancer Reversing tolerance of morphine in cancer

patientspatients Treatment of stroke victims Treatment of stroke victims Alleviation of phantom painsAlleviation of phantom pains Management of Complex Regional Pain Management of Complex Regional Pain

Syndrome Syndrome Neuro-protectionNeuro-protection

Chronic PainChronic Pain Chronic pain can be maintained by a state of Chronic pain can be maintained by a state of

sensitization within the central nervous system sensitization within the central nervous system that is mediated in part by the excitatory amino that is mediated in part by the excitatory amino acids glutamate and asparate binding to the N-acids glutamate and asparate binding to the N-methyl-D-asparate (NMDA) receptor methyl-D-asparate (NMDA) receptor

Queen’s Researchers have found that in Queen’s Researchers have found that in extremely small doses, opioid antagonists extremely small doses, opioid antagonists (ketamine), normally used to block the toxic effects (ketamine), normally used to block the toxic effects of opioids- instead enhance pain-killing action in of opioids- instead enhance pain-killing action in experimental models. experimental models.

The researchers discovered that for those who The researchers discovered that for those who had already developed a tolerance to morphine, had already developed a tolerance to morphine, their tolerance was actually reduced with low their tolerance was actually reduced with low doses of ketamine and pain was alleviateddoses of ketamine and pain was alleviated

Palliative CarePalliative Care A small percentage of patients with far advanced A small percentage of patients with far advanced

diseases experience severe pain despite rapid diseases experience severe pain despite rapid upward titration of opioid analgesics, anti-upward titration of opioid analgesics, anti-inflammatories, or other pain modulating drugs inflammatories, or other pain modulating drugs

the use of low-dose ketamine in palliative care the use of low-dose ketamine in palliative care settings where opioid-refractory pain or opioid-settings where opioid-refractory pain or opioid-medicated adverse effects prevent satisfactory medicated adverse effects prevent satisfactory pain relief pain relief

Ketamine is known to be a potent NMDA receptor Ketamine is known to be a potent NMDA receptor antagonist providing some rationale for its efficacy antagonist providing some rationale for its efficacy in treating neuropathic pain and enhancing opioid in treating neuropathic pain and enhancing opioid analgesia analgesia

AntidepressantsAntidepressants

It is suggested that glutamate systems effect It is suggested that glutamate systems effect major depression and the mechanism in major depression and the mechanism in which the anti-depressants react in the bodywhich the anti-depressants react in the body

Clinical Neuroscience Research Unit Clinical Neuroscience Research Unit the first placebo-controlled, double-blinded trial to the first placebo-controlled, double-blinded trial to

assess the treatment effects of single does of an assess the treatment effects of single does of an NMDA receptor antagonist in patients with NMDA receptor antagonist in patients with depression. depression.

seven subjects, was treated for two days with seven subjects, was treated for two days with intravenous treatment with ketamine or saline intravenous treatment with ketamine or saline solutions solutions

ResultsResults

Subjects with depression evidenced Subjects with depression evidenced significant improvement in depressive significant improvement in depressive symptoms within 72 hours after ketamine symptoms within 72 hours after ketamine but not with placebo infusion but not with placebo infusion

Heroin Addicts and Alcoholics Heroin Addicts and Alcoholics

The major components of addiction are The major components of addiction are Ibogaine and Acamprosate Ibogaine and Acamprosate

Ketamine produces anti-craving properties Ketamine produces anti-craving properties because of the NMDA receptor and its because of the NMDA receptor and its influence on the similar ligands-influence on the similar ligands-acamprosate and ibogaine acamprosate and ibogaine

ResultsResults

Savage and McCabe showed that LSD-Savage and McCabe showed that LSD-assisted psychotherapy had a positive effect assisted psychotherapy had a positive effect on the outcome of treatment of heroin on the outcome of treatment of heroin addicts: 25% treated with LSD remained addicts: 25% treated with LSD remained abstinent from opiates for one year as abstinent from opiates for one year as opposed to only 5% of the control group opposed to only 5% of the control group remaining abstinent remaining abstinent

Stroke VictimsStroke Victims

Ketamine with it’s neuro-protective effect, Ketamine with it’s neuro-protective effect, mediated by antagonism of NMDA channels mediated by antagonism of NMDA channels located on central neurons.located on central neurons.

Such antagonism ultimately prevents Such antagonism ultimately prevents calcium influx during states of neuro-cellular calcium influx during states of neuro-cellular ischemia.ischemia.

Phantom pain Phantom pain

This pain is due to the hyperactivity of This pain is due to the hyperactivity of NMDA receptors. Ketamine is administered NMDA receptors. Ketamine is administered to block the receptor sites and alleviate the to block the receptor sites and alleviate the pain pain

Those who received the ketamine infusion Those who received the ketamine infusion the stump pain was alleviated for 31 hours the stump pain was alleviated for 31 hours and were treated 4 times a day and showed and were treated 4 times a day and showed no tolerance. The saline group still no tolerance. The saline group still complained of phantom pain complained of phantom pain

Complex Regional Pain Syndrome Complex Regional Pain Syndrome

affects between 1.5 and 7 million people affects between 1.5 and 7 million people little is known about this condition it appears little is known about this condition it appears

that the pain is caused by over stimulation of that the pain is caused by over stimulation of a nerve receptor complex involved in the a nerve receptor complex involved in the process of feeling pain process of feeling pain

ResultsResults

Alleviating all the pain was felt by 25 patients Alleviating all the pain was felt by 25 patients (76%) (76%)

Partially eliminating the pain of 6 patients (18%)Partially eliminating the pain of 6 patients (18%) No relief was felt by 2 patients (6%)No relief was felt by 2 patients (6%) Although the relief was not indefinite, 54% said Although the relief was not indefinite, 54% said

that the pain was alleviated for 3-4 months with that the pain was alleviated for 3-4 months with one treatmentone treatment

After two treatments, 33% of the patients stated After two treatments, 33% of the patients stated the pain was alleviated for more than 3 years!! the pain was alleviated for more than 3 years!!

Ketamine Ketamine

Effects of this drug are Effects of this drug are mediated by N-methyl-mediated by N-methyl-D-asparate (NMDA) D-asparate (NMDA) receptors, opoid and receptors, opoid and muscaranic receptors. muscaranic receptors.

Ketamine is a Ketamine is a anesthetic and anesthetic and hallucinogenic. hallucinogenic.

Palliative CarePalliative Care

AntidepressantsAntidepressants

Alcohol and substance abuse clinicsAlcohol and substance abuse clinics

Reversing tolerance of morphine in cancer Reversing tolerance of morphine in cancer patientspatients

Treatment of stroke victimsTreatment of stroke victims

Alleviation of phantom painsAlleviation of phantom pains

Management of Complex Regional Pain Management of Complex Regional Pain Syndrome. Syndrome.

Ketamine Ketamine

Despite the side effects of Despite the side effects of Near Death Experiences, Near Death Experiences, Ketamine has proved to be Ketamine has proved to be very beneficial and useful in very beneficial and useful in the medical field both animal the medical field both animal and human and human

Ketamine in the future will Ketamine in the future will continue to provide aid with continue to provide aid with disease pain and maybe even disease pain and maybe even life time cures of certain life time cures of certain ailmentsailments