Chapter 56

### INTRODUCTION

Ketamine is a water-soluble intravenous anesthetic that is structurally related to the psychotropic drug phencyclidine (PCP). It was first synthesized in 1962 and named “C1581” by Parke-Davis Research Laboratory. Clinical evaluation began in 1965 with approval for patient use 5 years later. In the early 1970s, ketamine was widely used as a field anesthetic by the United States during the Vietnam War.

Ketamine has an aryl cyclohexamine chemical structure in which one asymmetric carbon atom results in two optical isomers. The S(+) enantiomer is 3 times more potent and longer acting than the R(−) enantiomer. Unlike other intravenous anesthetics, ketamine produces a unique dissociative anesthetic state in which there is functional and electrophysiologic separation of the thalamocortical and limbic systems. This state is characterized by profound analgesia, amnesia, and catalepsy. The patient is unconscious but appears awake.

### PHARMACODYNAMIC PROFILE

#### Central Nervous System

The primary site of action of ketamine occurs within the thalamus and limbic system where the drug binds to N-methyl-D-aspartate (NMDA) receptors. These receptors are thought to play a major role in the relay of sensory information. Noncompetitive antagonism of NMDA receptors by ketamine results in catalepsy and high-amplitude slowing of EEG waves. However, ketamine also interacts with other CNS receptors. Binding of ketamine to the mu-opioid receptor provides its unique analgesic effects at subanesthetic doses. Not surprisingly, ketamine has cross-tolerance with morphine. However, the analgesic effect of ketamine cannot be reversed by naloxone. In addition, ketamine can bind to the sigma opioid (PCP binding site) receptor resulting in dysphoria. Lastly, ketamine interacts with muscarinic and nicotinic cholinergic receptors producing a dose-dependent potentiation of the nondepolarizing muscle relaxants. Physostigmine may reverse some of the effects of ketamine.

Historically, ketamine has been thought to increase intracranial pressure (ICP), making the drug contraindicated in patients with brain injury. An increase in mean arterial pressure (MAP) leads to higher cerebral perfusion pressure, thus raising ICP. Antagonism of the NMDA receptor causes vasodilation of the cerebral vasculature, increasing cerebral blood flow by nearly 80% and contributing to higher ICP. Preadministration of benzodiazepines or thiopental may attenuate this pressure increase. However, recent studies show that ketamine does not always cause an increase in ICP. Ketamine may actually reduce cerebral infarct volume and improve neurologic outcome in rats with brain trauma. Antagonism of the neurotoxic effects of glutamate at the NMDA receptor may serve as the underlying mechanism.

#### Cardiovascular

Ketamine is a direct myocardial depressant and vascular smooth muscle relaxant. At the same time, however, the drug also increases circulating catecholamines by decreasing neuronal reuptake. These increases in norepinephrine levels are easily blocked by alpha and beta adrenergic receptor and sympathetic ganglion blockade. Benzodiazepines may also attenuate the cardiovascular stimulating effects of ketamine. In the pulmonary vasculature, ketamine increases pulmonary vascular resistance through vasoconstriction. Overall, the cardiovascular stimulating effects of ketamine ...

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