Page 470 - Basic _ Clinical Pharmacology ( PDFDrive )

456 SECTION V Drugs That Act in the Central Nervous System

KETAMINE with a benzodiazepine may be indicated to limit the unpleasant
emergence reactions and also increase amnesia.
Ketamine (Figure 25–6) is a partially water-soluble and highly
lipid-soluble phencyclidine derivative differing from most other B. Cardiovascular Effects
intravenous anesthetics in that it produces significant analgesia. Ketamine can produce transient but significant increases in sys-
The characteristic state observed after an induction dose of ket- temic blood pressure, heart rate, and cardiac output, presumably
amine is known as “dissociative anesthesia,” wherein the patient’s by centrally mediated sympathetic stimulation. These effects,
eyes remain open with a slow nystagmic gaze (cataleptic state). Of which are associated with increased cardiac workload and myo-
the two stereoisomers, the S(+) form is more potent than the R(−) cardial oxygen consumption, are not always desirable and can
isomer, but only the racemic mixture of ketamine is available in be blunted by coadministration of benzodiazepines, opioids, or
the USA. inhaled anesthetics. Though the effect is more controversial, ket-
Ketamine’s mechanism of action is complex, but the major amine is also considered to be a direct myocardial depressant. This
effect is probably produced through inhibition of the NMDA property is usually masked by its stimulation of the sympathetic
receptor complex. nervous system but may become apparent in critically ill patients
with limited ability to increase their sympathetic nervous system
Pharmacokinetics activity.

The high lipid solubility of ketamine ensures a rapid onset of its
effect. As with other intravenous induction drugs, the effect of a C. Respiratory Effects
single bolus injection is terminated by redistribution to inactive Ketamine is not thought to produce significant respiratory depres-
tissue sites. Metabolism occurs primarily in the liver and involves sion. When it is used as a single drug, the respiratory response to
N-demethylation by the cytochrome P450 system. Norketamine, hypercapnia is preserved and blood gases remain stable. Transient
the primary active metabolite, is less potent (one third to one hypoventilation and, in rare cases, a short period of apnea can
fifth the potency of ketamine) and is subsequently hydroxylated follow rapid administration of a large intravenous dose for induc-
and conjugated into water-soluble inactive metabolites that are tion of anesthesia. The ability to protect the upper airway in the
excreted in urine. Ketamine is the only intravenous anesthetic that presence of ketamine cannot be assumed despite the presence of
has low protein binding (Table 25–2). active airway reflexes. Especially in children, the risk for laryngo-
spasm because of increased salivation must be considered; this risk
Organ System Effects can be reduced by premedication with an anticholinergic drug.
Ketamine relaxes bronchial smooth muscle and may be helpful in
If ketamine is administered as the sole anesthetic, amnesia is not patients with reactive airways and in the management of patients
as complete as with the benzodiazepines. Reflexes are often pre- experiencing bronchoconstriction.
served, but it cannot be assumed that patients are able to protect
the upper airway. The eyes remain open and the pupils are mod-
erately dilated with a nystagmic gaze. Frequently, lacrimation and Clinical Uses & Dosage
salivation are increased, and premedication with an anticholiner- Its unique properties, including profound analgesia, stimulation
gic drug may be indicated to limit this effect. of the sympathetic nervous system, bronchodilation, and minimal
respiratory depression, make ketamine an important alternative to
A. CNS Effects the other intravenous anesthetics and a desirable adjunct in many
In contrast to other intravenous anesthetics, ketamine is consid- cases despite the unpleasant psychotomimetic effects. Moreover,
ered to be a cerebral vasodilator that increases cerebral blood flow, ketamine can be administered by multiple routes (intravenous,
as well as CMRO . For these reasons, ketamine has tradition- intramuscular, oral, rectal, epidural), thus making it a useful
2
ally not been recommended for use in patients with intracranial option for premedication in mentally challenged and uncoopera-
pathology, especially increased ICP. Nevertheless, these perceived tive pediatric patients.
undesirable effects on cerebral blood flow may be blunted by the Induction of anesthesia can be achieved with ketamine,
maintenance of normocapnia. Despite the potential to produce 1–2 mg/kg intravenously or 4–6 mg/kg intramuscularly. Although
myoclonic activity, ketamine is considered an anticonvulsant and the drug is not commonly used for maintenance of anesthesia,
may be recommended for treatment of status epilepticus when its short context-sensitive half-time makes ketamine a candidate
more conventional drugs are ineffective. for this purpose. For example, general anesthesia can be achieved
Unpleasant emergence reactions after administration are the with the infusion of ketamine, 15–45 mcg/kg/min, plus 50–70%
main factor limiting ketamine’s use. Such reactions may include nitrous oxide or by ketamine alone, 30–90 mcg/kg/min.
vivid colorful dreams, hallucinations, out-of-body experiences, Small bolus doses of ketamine (0.2–0.8 mg/kg IV) may be
and increased and distorted visual, tactile, and auditory sensitiv- useful during regional anesthesia when additional analgesia is
ity. These reactions can be associated with fear and confusion, needed (eg, cesarean delivery under neuraxial anesthesia with an
but a euphoric state may also be induced, which explains the insufficient regional block). Ketamine provides effective analgesia
potential for abuse of the drug. Children usually have a lower without compromise of the airway. An infusion of a subanalgesic
incidence of and less severe emergence reactions. Combination dose of ketamine (3–5 mcg/kg/min) during general anesthesia and