Pharmacokinetics: Ketamine (Ketalar), Etomidate (Amidate)

• Overview: ketamine (Ketalar)⁵

  • Chemically, ketamine (Ketalar,dl-2-(o-chloro-phenyl)-2-(methylamino) cyclohexanone is classified as a phencyclidine-type compound (arylcycloalkylamines, i.e.arylcyclohexylamine). 

    • Aryl refers to a molecular fragment or group attached to a molecule by an atom that is on an aromatic ring

    • Alkyl refers to a molecular fragment derived from an alkane by dropping a hydrogen atom. The general form is -C_nH_2n+1; examples would be methyl (CH₃ or ethyl (CH₂CH₃)].

  • This anesthetic has limited cardiovascular or respiratory side effects and exhibit significant analgesic effect. 

    •  However, ketamine (Ketalar) is associated with emergence hallucinations/delirium, which can include visual, proprioceptive, and auditory hallucinations. 

      • The side effects may be reduced by prior intravenous administration of benzodiazepines, particularly midazolam (Versed).

  • Ketamine (Ketalar) is an example of a molecule of a chiral carbon, and therefore has two enantiomers {two optical isomers). 

    • Consistent with the idea that anesthetics interact specifically with receptors, their differences between the biological activities of the enantiomers with one exhibiting a more rapid onset of action and higher potency. 

    • Despite this difference, ketamine (Ketalar) is used as a racemate, meaning that both enantiomers are present in a 50:50 mix.

  • Various receptor systems appear to interact with ketamine (Ketalar) including:

    • NMDA receptor (N-methyl-D-aspartate)

    • Opioid receptor

    • Adrenergic receptors

    • Muscarinic receptors,

    • Voltage-sensitive calcium ion channels. 

      • By contrast to barbiturates and benzodiazepines, ketamine (Ketalar) does not appear to interact with the GABA receptor system.

  • Ketamine (Ketalar) is more lipid-soluble by factor of 5-10 compared to thiopental (Pentothal) and has a pKa of about 7.5

  • There is no specific antagonist for ketamine (Ketalar).

    • Ketamine (Ketalar)

      Phencyclidine

      Phencyclidine 1-(1-Phenylcyclohexyl)piperidine; C17H25N

Ketamine (Ketalar): pharmacokinetics⁵

• Metabolism: the liver microsomal enzyme system metabolizes ketamine (Ketalar) involving hydroxylation and demethylation. 

  • The principal metabolite is norketamine, note below the removal of the methyl group from ketamine (Ketalar) (left), forming norketamine.

  • As an aside, the difference between epinephrine  and norepinephrine (Levophed) is that norepinephrine lacks a methyl group.  In the biosynthetic pathway, epinephrine is formed from norepinephrine (Levophed) by a methyl transferase enzyme [phenylethanolamine N-methyltransferase].

• 

• Norketamine exhibits about 25%-30% of  ketamine (Ketalar). 

  • Norketamine is subsequently metabolized by multiple hydroxylation steps.

• The high lipid solubility of ketamine (Ketalar) results in a rapid onset of action in a manner similar to that discussed earlier for other lipid-soluble IV anesthetics, e.g. thiopental (Pentothal). 

  • Similarly, recovery from the anesthetic effects is probably due to redistribution from the brain to other compartments.

  • Time to onset following IV bolus (dosage = 2 mg/kg) is about 30-60 seconds with effect lasting between 10-15 minutes. 

    • Complete recovery occurs soon thereafter.

  • Volume of distribution (V_d).  Recalling that V_d is determined by measuring plasma drug levels, it is not surprising that a highly lipid-soluble molecule would have a very large volume of distribution. 

    • Note that clearance is dependent on not only  volume of distribution but also the elimination halftime. CL = (.693*V_d)/t_1/2. 

      • By rearranging the earlier formula, t_1/2 = (0.693 · V_d)/CL. 

      • For ketamine (Ketalar), clearance is relatively high at 12-17 ml/kg/minute as a result of a fairly short elimination halftime (about 2.5 hours).

    • As noted earlier, clearance is mediated by the liver microsomal enzyme system; therefore, factors that decrease hepatic blood flow will retard clearance and prolong ketamine (Ketalar) effect. 

      • An example would be halothane (Fluothane)'s ability to reduce liver blood flow, thereby and principal prolonging ketamine (Ketalar) action.

• Ketamine (Ketalar) infusion rate: 30-90 ug/kg/minute, which would be reduced if given in combination with other CNS depressants.

Ketamine (Ketalar) pharmacology:  a summary of organ system and other effects:⁵

• CNS action: Ketamine (Ketalar) induces a unique anesthetic state referred to as dissociative anesthesia in which the patient may appear "awake" or as is frequently described "cataleptic". 

  • Specific characteristics:

    • Significant analgesia and subanesthetic doses still provide analgesia

    • Eyes remain open following administration with cough, swallow, and corneal reflexes present.

    • Amnestic properties are present but less than that observed with benzodiazepines, e.g. midazolam (Versed)

  • Anesthesia induction characteristics:

    • Increased limb muscle tone

    • Salivation, lacrimation, nystagmus, pupillary dilatation

  • CNS metabolic effects: increased metabolism, blood flow, and intracranial pressure

  • Increased electroencephalographic activity

  • Emergence syndrome: There is a significant likelihood (10%-30%) that the patient will experience unusual psychological reactions to ketamine (Ketalar) anesthesia. 

    • These reactions include illusions/hallucinations and "out of body" experiences, collectively termed emergence syndromes which may last 1-3 hours.

• Pulmonary effects are very limited. 

  • Limited pulmonary effects apply when ketamine (Ketalar) is used as the only agent; however, respiratory depression would occur in ketamine (Ketalar) is combined with other drugs which are classified as CNS depressants.

    • Ketamine (Ketalar) tends to relax bronchial smooth muscle

    • Salivation following ketamine (Ketalar) administration  may trigger laryngospasm.  Furthermore, despite retention of reflexes, aspiration may still occur

• Cardiovascular effects: The stimulant characteristics of ketamine (Ketalar) are manifest in cardiovascular responses that seem opposite to that observance most anesthetics.  

  • For example, ketamine (Ketalar) administration increases heart rate, cardiac output, and blood pressure.   

  • These effects may be relatively contraindicated in patients sensitive to the expectable increase in myocardial oxygen consumption.  

  • Drugs can reduce these positive chronotropic and hypertensive effects. 

    • Examples of drugs which can reduce these cardiovascular effects include benzodiazepines, barbiturates and adrenergic receptor blockers. 

      • The centrally acting and hypertensive agents such as clonidine (Catapres) would also be affected by reducing  central sympathetic outflow.

       

Etomidate (Amidate) Overview: ^5,6

• Etomidate (Amidate) which chemically is a carboxylated imidazole derivative is an effective IV anesthetic agent which exhibits favorable hemodynamic properties with minimal respiratory depression.  

• This drug produces rapid unconsciousness (within about 30 seconds) following IV administration. 

  • The patient will recover quickly with awakening being more rapid than with barbiturates, not including propofol (Diprivan).

• Adverse effects, however, have resulted in reduced clinical use.  

  • These adverse effects have included injection site pain (which may be prevented by local anesthetic preinjection), thrombophlebitis, myoclonus, nausea and vomiting, and inhibition of steroid synthesis.  

  • Nausea and vomiting may be especially associated with etomidate (Amidate) compared to other induction drugs and is made worse by concurrent use of opioids. 

    • This problem might be managed by avoiding etomidate (Amidate) in those patients with a known history of postoperative nausea or by pre-treatment with  antinausea medication.

• Etomidate (Amidate), a water insoluble drug which must be dissolved in propylene glycol (35%; pH 6.9) has a chiral carbon, resulting into enantiomers (stereoisomers) of which only one enantiomer is active.

  • Etomidate

• Etomidate (Amidate) pharmacokinetics: ^5,6

  •  Metabolism: Etomidate (Amidate) is metabolized by ester hydrolysis (hepatic & tissue) as well as N-dealkylation. 

    • Metabolites are inactive and excreted by renal and biliary routes.

  • Etomidate (Amidate) administration results in rapid onset, follow by an initial redistribution phase which is also rapid (initial redistribution halftime = 2.7 minutes).

    • Analysis of the concentration-decay curve suggests that a three-compartment model best fits the observed time dependent drop in plasma etomidate (Amidate) concentration. 

    • However, the initial rapid redistribution time is most pertinent for explaining the observed rapid recovery following IV administration.

  • Etomidate (Amidate) clearance ranges from 18-25 ml/kg/min.

    • Etomidate clearance can be compared to that of thiopental (Pentothal) which is a clearance of about 3.5 ml/kg/min. 

  • V_d is large, consistent with a relatively lipophilic compound which gains access to many compartments.

  • Rapid onset following IV administration is typical it has been described as "one arm-brain circulation time". 

• Etomidate (Amidate) pharmacology

  •  Summary of etomidate effects organ system: ^5,6

    • CNS:

      • Similar to observations concerning thiopental (Pentothal) and other barbiturates, etomidate (Amidate) while producing hypnosis does not produce analgesia. 

        • Also similar to the barbiturates, etomidate (Amidate) may function by interacting with GABA receptor systems.

      • Cerebral metabolism is reduced as well a cerebral blood flow following etomidate (Amidate); these effects result in a more favorable cerebral oxygen supply over demand ratio. 

        • Also intracranial pressure (ICP) is reduced by etomidate (Amidate); moreover, further ICP reduction is available by reducing P_aCO₂.

      • Activation of the EEG following the etomidate (Amidate)has been observed and this property may be the basis for epileptogenic activity. 

        • Perhaps also related is the observation that about 50% of patients receiving etomidate (Amidate) will exhibit myoclonus (spontaneous movements).

  • Pulmonary: 

    • Ventilation is depressed less with etomidate (Amidate) compared to barbiturates, but apnea may follow from rapid IV etomidate (Amidate) administration. 

    • Importantly, given that etomidate (Amidate) may be administered concommittantly with an opioid (or inhaled anesthetic), respiratory depression can occur as a result of these combinations.

  • Cardiovascular: An important distinction between etomidate (Amidate) and other induction agents is that etomidate (Amidate) has very minimal cardiovascular effects. 

    • Furthermore, during induction blood flow to the heart and oxygen consumption are both reduced which allows maintenance of the balance between oxygen supply and requirement. 

      • This advantageous property may be particularly beneficial in managing elderly patients with compromised cardiovascular status.

    • Since etomidate (Amidate) does not alter sympathetic or baroreceptor reflex function, undesirable hemodynamic effects may be induced by intubation. 

      • Accordingly, an opioid (perhaps fentanyl (Sublimaze)), as noted above, maybe given along with etomidate (Amidate).

  • Endocrine: Etomidate (Amidate) will cause postoperative suppression of adrenocortical function. 

    • This effect occurs because etomidate inhibits 11-ß-hydroxylase and 17-α-hydroxylase enzymes which are important in cortisol synthesis. 

      • Inhibition is reversible and occurs secondary to interactions between etomidate and cytochrome P450 (the hepatic microsomal enzyme system).

    • Short-term adrenocortical suppression as might occur following single induction doses is not thought to be clinically serious. 

      • However, significant adrenocortical suppression and increased mortality has been observed when etomidate (Amidate) was administered by extended,continuous infusion within the ICU setting.