NMDA ketamine

Psychotomimetic Drugs. Figure 2 Chemical structures of the dissociative anesthetics phencyclidine (PCP) and ketamine. Both are arylcycloalkylamine derivatives that are open channel blockers of the NMDA channel. 

Other systems also interact with glutamate. Activation of L-type voltagegated calcium channels (VGCC) occurs with NMDA receptor activation. Lamotrigine blocks several ion channels, including P- and N-type VGCC channels, an action that blocks the euphoric effects of ketamine and reduces dysphoric and cognitive effects (Hundt et al. 1998). Other modulatory sites,... 

The NRl family is composed of one subunit with nine different alternatively spliced variants. Block by NMDA channel blockers such as ketamine, MK-801 and phencyclidine is affected by which splice variant of the NRl subunit is involved, probably because the NRl splice variant affects the kinetics of channel activation (the effectiveness of any channel blocker being dependent on how much the channel is open). The glycine binding site is on the NRl subunit and the glutamate binding site is on the NR2 and NR3 subunits. 

The ion-channel blocking mechanism has been widely tested and found to be important in both pharmacology and physiology. Examples are the block of nerve and cardiac sodium channels by local anesthetics, or block of NMDA receptor channels by Mg2+ and the anesthetic ketamine. The channel-block mechanism was first used quantitatively to describe block of the squid axon K+ current by tetraethylammonium (TEA) ions. The effects of channel blockers on synaptic potentials and synaptic currents were investigated, particularly at the neuromuscular junction, and the development of the single-channel recording technique allowed channel blockages to be observed directly for the first time. 

A few infants have been treated with antagonists of the NMDA receptor, an excitatory glutamatergic receptor for which glycine is a co-agonist (see Ch. 15) [29], Ketamine and dextromethorphan have been used with inconclusive results. Some infants may have had an improvement of their irritability and electroencephalogram. One infant, treated with both benzoate and dextromethorphan, was seizure-free by 12 months of age and had only moderately delayed development. However, this favorable experience has not always been duplicated. Treatment with dextromethorphan at the recommended dosage (maximum 5mg/kg/day) seems to be well-tolerated. 

Hypofunction of NMDA receptors may contribute to the endophenotype of schizophrenia. The hypothesis that hypofunction of a subpopulation of NMDA receptors contributes to the pathophysiology of schizophrenia has gained considerable support over the last decade (see Fig. 54-1). The dissociative anesthetics including phencyclidine (PCP) and ketamine when introduced clinically 40 years ago were noted to produce a syndrome that was difficult to distinguish from schizophrenia. These agents act as noncompetitive open-channel blockers of the NMDA receptor. 

Ketamine acts as a blocker (or antagonist ) of the NMDA receptor. PCP also acts as an antagonist of the NMDA receptor, as does alcohol, although much less potently. NMDA receptors are present in numerous brain regions, and ketamine is thought to produce its effects by blocking NMDA receptors in a number of brain regions, as shown in Table 6.1. 

NMDA antagonists The combined use of memantine with other NMDA antagonists (amantadine, ketamine, and dextromethorphan) has not been systematically evaluated. Approach such use with caution. 

Memantine (Namenda) [Anti Alzheimer Agent/NMDA Receptor Antagonist] Uses Mod/ evere Alzheimer Dz Action N-methyl-D-aspartate recqjtor antagonist Dose Target 20 mg/d, start 5 mg/d, t 5 mg/d to 20 mg/d, wait >1 wk before t dose use doses if >5mg/d Caution [B, /-] Hqjatic/mild-mod renal impair Disp Tabs, sol SE Dizziness Interactions t Effects W amantadine, carbonic anhydrase inhibitors, dextromethorphan, ketamine, Na bicarbonate t effects W/ any drug, herb, food that alkalinizes urine EMS Use NaHCOs w/ caution OD May cause restlessness, hallucinations, drowsiness, and fainting symptomatic and supportive... 

The mechanisms of action of phencyclidine and ketamine are complex (Gorelick Balster, 1995). The drugs are non-competitive antagonists at NMDA receptors, and also bind to associated phencyclidine/sigma opioid receptors. They also have agonist actions at dopamine receptors, complex interactions with both nicotinic and muscarinic acetylcholine receptors and poorly understood interactions with noradrenergic and serotonergic systems. These multiple actions may combine to produce delirium and psychotic reactions. 

The uncompetitive NMDA receptor antagonist ketamine has been available for clinical use as an anaesthetic for 40 years (Domino et al. 1965). Ketamine is effective in various animal models of hyperalgesia and allodynia and has been reported to have antinociceptive effects in some of these models at doses devoid of obvious side-effects. Others, however, have reported that the effects of ketamine are only seen at doses producing ataxia (see Parsons 2001 for review). Ketamine reportedly inhibits the area of secondary hyperalgesia induced by chemical (Park et al. 1995) or thermal stimuli (Ilkjaer et al. 1996 Warncke et al. 1997) and inhibits temporal siunmation of repeated mechanical (Warncke et al. 1997) and electrical stimuli (Arendtnielsen et al. 1995 Andersen et al. 

Felsby S, Nielsen J, Arendtnielsen L, Jensen TS (1996) NMDA receptor blockade in chronic neuropathic pain a comparison of ketamine and magnesium chloride. Pain 64 283-291 Ferraguti F, Baldani-Guerra B, Corsi M, Nakanishi S, Corti C (1999) Activation of the extracellular signal-regulated kinase 2 by metabotropic glutamate receptors. Eur J Neurosci 11 2073-2082... 

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