Pharmacodynamics

Central Nervous System

• unconsciousness and analgesia
• "dissociative anesthesia"
  • cataleptic appearance
  • profound analgesia
  • eyes may be open
  • reflexes may be intact (corneal, cough and swallow)
  • amnesia (but not as profound as with benzodiazepines)
• onset < 30 seconds
• max effect: 1 minute (after IV injection)
• pupils dilate
• nystagmus
• lacrimation, salivation common
• skeletal muscle tone may increase
• may be purposeless but coordinated movements
• good correlation between blood concentration and CNS effects
  • need plasma level 0.6-2 mcg/ml for general anesthesia in adults
  • may need 0.8-4 mcg/ml in children
  
• 2 mg/kg -> 10-15 minutes of anesthesia with full orientation in 15-30 minutes (dose-related duration)
• S enantiomer:
  • slightly lower dose adequate
  • 10% faster hepatic biotransformation
  • slightly faster recovery
• analgesia occurs at concentrations above approximately 0.1 mcg/ml (ketamine provides built-in post-op analgesia!)
• cerebral functional disorganization
  • thalamoneocortical projection system: decreased function of cortical association areas and thalamus
  • increased function of parts of limbic system, including hippocampus (memory)
• decreased transmission in medial medullary reticular formation (affective-emotional component of nociception from cord -> brain)
• a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist
  • inhibits activation of NMDA receptor by glutamate (excitatory CNS neurotransmitter)
  • reduces presynaptic release of glutamate
  • potentiates effects of gamma-aminobutyric acid (GABA, inhibitory neurotransmitter)
  • may mediate general anesthetic effect
  • may explain part of the analgesic effect
  • may be responsible for elements of the "near death experience" (NDE) sometimes described
• opiate receptors
  • ketamine probably occupies mu and kappa opiate receptors in brain and spinal cord
  • S-(+)-ketamine has been reported to have mu opioid receptor activity
  • may explain some of analgesic effect
• increases cerebral metabolism
  • generalized EEG theta activity (signals analgesic activity)
  • petit mal seizure-like activity - hippocampus
  • increased CMRO₂
  • increased CBF
  • thiopental or diazepam block the increases in CBF and CMRO₂
  • questionably may increase ICP - clinical significance controversial
    • In the clinical setting, level II evidence indicates that ketamine does not increase intracranial pressure when used under conditions of controlled ventilation, coadministration of a gamma-aminobutyric acid (GABA) receptor agonist, and without nitrous oxide. Ketamine may thus safely be used in neurologically impaired patients.
      Compared with other anesthetics or sedatives, level II and III evidence indicates that hemodynamic stimulation induced by ketamine may improve cerebral perfusion; this could make the drug a preferred choice in sedative regimes after brain injury. Himmelseher 2005
      
    • Ketamine has generally beneficial effects on the respiratory system with no more than minimal respiratory depression.
      Ketamine does not trigger seizure activity; in fact, it much more likely prevents seizure activity by NMDA receptor antagonism.
      The preponderance of evidence favors a neuroprotective action of ketamine.
      It seems confirmed that ketamine does not increase ICP when blood pressure is controlled and mild hypocapnea is achieved. Kohrs 1998
      
    • Eight patients with traumatic brain injury were studied. In all patients, ICP monitoring was instituted before the study. Ketamine, in all three doses studied (1.5, 3, and 5 mg/kg) was associated with a significant decrease in ICP (mean +/- SD: 2 +/- 0.5 mmHg [P < 0.05], 4 +/- 1 mmHg [P < 0.05], and 5 +/- 2 mmHg [P < 0.05]) among the study patients regardless of the ketamine dose used. Albanese 1997
      
    • Anterior fontanel pressure decreased 11% during isoflurane administration, 9% during halothane administration, 10% after fentanyl, and 10% after ketamine. These changes were statistically significant, but clinically mild, and AFP remained within the normal range. Friesen 1987
      
• cerebrovascular CO₂ response intact (reducing PaCO₂ attenuates rise in ICP)
• psychological effects ("emergence reactions")
  • vivid dreaming
  • extracorporeal (floating "out-of-body") experience
  • misperceptions, misinterpretations, illusions
  • may be associated with euphoria, excitement, confusion, fear
  • occur from 1 to several hours post-op
  • 10-30% of adults
  • adults > children
  • women > men
  • more with more drug (dose-related)
  • increased susceptibility: psychosis
  • best attenuated or eliminated with benzodiazepines and, probably, propofol
  • may be ameliorated by prior "preemptive" positive suggestion

Respiratory System

• ventilatory response to CO₂ unaltered
  • 2 mg/kg may lead to brief (1-3 minutes) decrease in V_E
  • apnea rare and only at high doses
• no significant change in ABG's
• bronchodilation: bronchial smooth muscle relaxation (even in isolated bronchial muscle studies)
• increased salivation
• airway reflexes relatively intact:
  • swallow
  • cough
  • sneeze
  • gag

Cardiovascular System

• Ketamine stimulates the cardiovascular system
  • blood pressure increases
  • heart rate increases
  • cardiac output increases
  • increased MVO₂ and work (associated with appropriately increased coronary artery dilation and flow)
  • relativley unrelated to dose (0.5 mg/kg = 1.5 mg/kg)
• increases central sympathetic outflow
• increases sympathoneuronal norepinephrine release (may block this effect with barbiturates, benzodiazepines, droperidol)
• inhibits catecholamine reuptake
• in vitro: direct negative inotropic effect on isolated myocardium
• tachycardia and hypertension reduced by
  • prior benzodiazepines
  • delivering ketamine by continuous infusion rather than by boluses
  • using other general anesthetic agents concomitantly
  • beta-blockers
• congenital heart disease:
  • usually no significant change in shunt
  • usually no significant change in SPO₂
  • some increase in pulmonary artery pressure
  • pulmonary vascular resistance may increase more than systemic vascular resistance

Other

• ketamine suppresses neutrophil production of inflammatory mediators, improving blood flow *
• reduces migration of leukocytes through endothelial cells *
• suppresses proinflammatory cytokine production in whole blood *
• inhibits activity of hepatic microsomal enzymes, CYP 2D1 and CYP 3A, by 10-20% *

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