Pharmacokinetics: Ketamine (Ketalar), Etomidate (Amidate)

• ⁵Overview: ketamine (Ketalar)

  • 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)]

  • On the positive side, 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.

  • A number of receptor systems appear to interact with ketamine (Ketalar) including the NMDA receptor {N-methyl-D-aspartate), the opioid receptor, adrenergic receptors, muscarinic receptors, as well as 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).

• ⁵Ketamine (Ketalar): pharmacokinetics

  • 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].}

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  • 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.

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

  • 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-- subanesthetic doses still provide analgesia; Eyes remain open 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 -- 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.

• ^5,6Overview: Etomidate (Amidate): 

  • 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.

• ^5,6Etomidate (Amidate) pharmacokinetics:

  •  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. (compared to, for example 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".  Infusion noses about 10 ug/kg/minute with etomidate (Amidate) administered often in combination with an opioid.

    • Use of etomidate (Amidate) for maintenance of anesthesia requires infusion of about 300-500 ng/ml.  The patient will awaken it concentrations of about 150-250 ng/ml.

• ^5,6Etomidate (Amidate) pharmacology-- a summary of organ system and other effects:

  • 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-alpha-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.