Intravenous Anesthetics

Question 1

Propofol is rapidly metabolized in the liver through … reactions. The inactive water-soluble metabolites are excreted through the kidneys. Certain propofol metabolites occasionally color the urine…

Answer 1

phase I (oxidation by cytochrome P450 enzymes) and phase II (mainly glucuronidation)

green

Question 2

The … are major contributors of propofol’s metabolization and together account for 40% of plasma propofol clearance

Answer 2

kidney, small intestine, and lungs

Question 3

Mechanism of action of propofol

Answer 3

The major mechanism of action of propofol is through increasing the flow of inhibitory chloride current through GABAARs. Propofol binds nonselectively to multiple sites within the transmembrane domain of the receptor. Some binding sites are shared with etomidate and others with barbiturates. These sites are distinct from the GABA and benzodiazepine binding sites on the GABAAR extracellular domains. Propofol both directly activates the GABAAR and potentiates activation of the channel by endogenous GABA.

Question 4

Mechanism of action of propofol

Answer 4

The major mechanism of action of propofol is through increasing the flow of inhibitory chloride current through GABAARs. Propofol binds nonselectively to multiple sites within the transmembrane domain of the receptor. Some binding sites are shared with etomidate and others with barbiturates. These sites are distinct from the GABA and benzodiazepine binding sites on the GABAAR extracellular domains. Propofol both directly activates the GABAAR and potentiates activation of the channel by endogenous GABA.

Question 5

Effects of propofol in the airway

Answer 5

Propofol increases upper airway collapsibility by inhibiting oropharyngeal muscles, including the genioglossus (the major tongue muscle). Consequently, upper airway obstruction frequently
occurs with sedative doses or during emergence from propofol anesthesia.
Propofol suppresses upper airway reflexes to a greater extent than other IV anesthetics, making it well suited for supraglottic airway placement or upper endoscopy procedures. Propofol also inhibits lower airway irritability and reduces the incidence of bron- choconstriction after tracheal intubation as compared with thiopental or etomidate

Question 6

Risk factors of propofol-related infusion syndrome

Answer 6

• High dosage and prolonged infusion (One must not give propofol for more than 48 hours or at a dose greater than 4 mg/kg/hour)
• Critical illness
• Elevated glucocorticoids or steroid therapy
• Dearth of carbohydrates
• Inborn errors of metabolism (especially mitocondrial)
• Young age (< 3)
• Excess lipids
• Elevated catecholamines

Question 7

Pathophysiology of propofol-related infusion syndrome

Answer 7

The mechanism responsible for PRIS remains controversial. Propofol hinders the uptake and usage of FFAs and mitochondrial activity at molecular and cellular levels. The poor balance between energy requirement and consumption is a fundamental pathogenetic process that can cause cardiac and perivascular muscle damage . One of the prevailing theories posits that propofol impairs the electron transport chain or the respiratory chain function, which in turn leads to the collapse of the body’s metabolic activities. According to various theories, propofol decouples oxidative phosphorylation and obstructs the flow of electrons in the electron transport chain running through the inner-mitochondrial membrane

Question 8

Clinical presentation of propofol-related infusion syndrome

Answer 8

• The several cardiovascular manifestations are as follows: right bundle branch block, hypotension, brugada-like syndrome ECG presentation (elevated ST segment and widening of QRS complex), ventricular tachycardia, ventricular arrhythmia, supraventricular tachycardia, atrial fibrillation, cardiogenic shock and asystole
• Metabolic acidosis, lactic acidosis, hyperkalaemia, hypertriglyceridemia, and hyperthermia
• Hepatomegaly; steatosis; elevated liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT); hyperlipidaemia; hypertriglyceridemia; and liver failure
• Acute kidney injury and renal failure
• Extreme lysis of myocytes in the entire musculoskeletal system, rhabdomyolysis

Question 9

How to avoid the pain caused by propofol infusion?

Answer 9

(1) premedication with a small dose of opioid and

(2) IV lidocaine injection (up to 1.5 mg/kg) through the same IV, with or without proximal venous occlusion, are effective to reduce pain. Lidocaine may be administered alone or as an admixture with propofol

Question 10

When combined with nitrous oxide or opioids, the therapeutic plasma propofol concentration for maintenance of anesthesia normally ranges between…
This typically requires a continuous infusion rate between …

Answer 10

2 and 8 μg/mL

100 and 200 μg/kg/min

Question 11

Subanesthetic bolus doses of propofol or a subanesthetic infusion can be used to treat postoperative nausea and vomiting (PONV) (…mg)

Answer 11

10 to 20 mg IV or 10 to 20 μg/kg/min as an infusion

Question 12

pH of thiopental and methoxihetal solutions and it’s consequences

Answer 12

After reconstitution with water or normal saline, the solutions (2.5% thiopental and 1% methohexital) are alkaline, with a pH higher than 10. Although this property prevents bacterial growth and helps increase the shelf life of the solution after reconstitution, it will lead to precipitation when mixed with acidic drug preparations such as neuromuscular blockers. These precipitates can irreversibly block IV delivery lines if mixing occurs during administration. Furthermore, accidental injection into an artery or infiltration into subcutaneous tissue will cause extreme pain and may lead to severe tissue injury

Question 13

Describe barbiturates metabolism

Answer 13

Most barbiturates undergo hepatic metabolism. The most important phase I reaction is oxidation; the result- ing metabolites are inactive and excreted in the urine (directly) or in the bile (after conjugation)

Question 14

Barbiturates should be avoided in patients with which disease?

Answer 14

Through stimulation of aminolevulinic acid synthetase, the production of porphyrins is increased. Therefore barbiturates should not be administered to patients with acute intermittent porphyria

Question 15

Unlike other IV anesthetics that bind in the GABAAR… domain, benzodiazepines bind in the… domain

Answer 15

transmembrane

extracellular

Question 16

GABAARs that respond to benzodiazepines occur almost exclusively on…, with the greatest density found in the…

This anatomic distribution explains the minimal effects of benzodiazepines outside the CNS

Answer 16

postsynaptic nerve endings in the CNS

cerebral cortex

Question 17

The primary metabolic pathway for midazolam and diazepam is… by…, a process susceptible to factors such as age, liver disease, and interaction with drugs that modulate the efficiency of the enzyme systems.
Midazolam is selectively metabolized to a single dominant metabolite,…, which has some sedative effects but undergoes rapid glucuronidation and clearance. This metabolite does not cause significant sedation in patients with normal hepatic and renal function unless midazolam is given as a prolonged infusion.

The long elimination half-time of diazepam explains the prolonged CNS effects, especially in elderly patients. In contrast, lorazepam is one of the few benzodiazepines that does not undergo oxidative metabolism and is excreted after a single step conjugation to…

Answer 17

oxidation

hepatic cytochrome P450 3A4

1-hydroxymidazolam

glucuronic acid

Question 18

Benzodiazepines effects in the CNS

Answer 18

The most important effects are the sedative-hypnotic and amnestic properties (anterograde, but not retrograde). In addition, benzodiazepines are anticonvulsants used to treat seizures. Muscle relaxation is mediated through the spinal cord and may require larger doses.

Like propofol and barbiturates, benzodiazepines decrease CMRO2 and CBF, but to a lesser extent. How- ever, midazolam is unable to produce an isoelectric EEG even at high doses, thus emphasizing that there is a ceil- ing effect on CMRO2 reduction. Patients with decreased intracranial compliance demonstrate little or no change in ICP after the administration of midazolam. Benzodiazepines have not been shown to possess neuroprotective properties

Question 19

Particularities of parenteral administration of benzodiazepines

Answer 19

Pain during IV injection and subsequent thrombophlebitis are most pronounced with diazepam. Propylene glycol, the organic solvent required to dissolve diazepam and lorazepam, is most likely responsible for pain during IM or IV adminis- tration and for the unpredictable absorption after IM injection. Midazolam is water soluble in the low pH formulation, which obviates the need for an organic solvent and decreases the likelihood of pain during injection or erratic absorption

Question 20

Clinical Scenarios for Potential Ketamine Use

Answer 20

• Sedation for painful procedures
  • Infusion for analgesia, especially with opioid-tolerant
  patients or those with anticipated difficult pain
  management
  • Intramuscular induction for uncooperative patients
  • IV induction while maintaining spontaneous respiration
  and hemodynamics
  • IV rapid-sequence induction to maintain hemodynamics

Question 21

Mechanisms of action of ketamine

Answer 21

the major anesthetic effect is produced through noncompetitive inhibition of the NMDA receptor complex

Question 22

Ketamine conventionally exists as a racemic mixture, with the … form being more potent than the …enantiomer. More recently, the … enantiomer–only formulation, appropriately named …, was approved by the FDA for major depression treatment

Answer 22

S(+)

R(−)

S(+)

esketamine

Question 23

Describe the metabolism of ketamine

Answer 23

Metabolism occurs primarily in the liver and involves N-demethylation by the cytochrome P450 system. Norketamine, the primary active metabolite, is less potent (one-third to one- fifth the potency of ketamine) and is subsequently further metabolized and excreted in urine

Question 24

What is the relation between ketamine and seizures?

Answer 24

At low doses, ketamine may facilitate seizures; however, at anesthetic doses, it is considered an anticonvulsant and may be considered for treatment of status epilepticus when more conventional drugs are ineffective.

Question 25

Ketamine is a direct myocardial depressant

T or F

Answer 25

T

Ketamine is a direct myocardial depressant, but this property is usually masked by its stimulation of the sympathetic nervous system. However, hypotension can develop in critically ill patients with limited ability to increase their sympathetic nervous system activity or patients with limited cardiovascular reserve

Question 26

How does ketamine affects the upper airway?

Answer 26

The ability to protect the upper airway in the presence of ketamine cannot be assumed despite the presence of active airway reflexes and maintenance of pharyngeal muscle tone. Frequently, lacrimation and salivation are increased, and premedication with an anticholinergic drug may be required to limit this effect. Especially in children the risk for laryngospasm may be increased because of excess salivation.

Question 27

IV and IM doses of ketamine for anesthesia induction

Answer 27

Induction of anesthesia can be achieved with ketamine, 1 to 2 mg/kg IV or 4 to 6 mg/kg IM

Question 28

Ketamine cannot be mixed with propofol in the same syringe

T or F

Answer 28

F

Ketamine can be mixed in the same syringe as propofol (“ketofol”) for procedural sedation to provide significant analgesia and to minimize the need for supplemental opioids. For example, a final ketamine concentration of 1 to 2 mg/mL in propofol can be given as a sedative infusion at a rate based on propofol dosing and titrated by the anesthesia provider to effect

Question 29

Ketamine doses for analgesia

Answer 29

Small bolus doses of ketamine (0.2 to 0.8 mg/kg IV) can provide effective analgesia without compromise of the airway (e.g., cesarean section under neuraxial anes- thesia when the regional block becomes insufficient).

An infusion of a subanesthestic dose of ketamine (3 to 5 μg/kg/min) during general anesthesia and in the early postoperative period may be useful to produce analgesia or reduce opioid tolerance and opioid-induced hyperalgesia, although not all studies examining the use of ketamine as an adjunct show the desired improvement in pain scores and recovery.

Moderate-quality evidence supports the use of moderate dose ketamine infusions (80 mg infused over 2 hours) to improve pain from com- plex regional pain syndrome.

Analgesic outcomes for other refractory pain conditions such as fibromyalgia, headaches, and phantom limb pain remain controversial. Nevertheless, ketamine infusions continue to be safely administered for these difficult-to-treat conditions

Question 30

Etomidate metabolism

Answer 30

Metabolism is primarily hepatic by ester hydrolysis to inactive metabolites, which are then excreted in urine and bile

Question 31

CNS effect of etomidate

Answer 31

Etomidate reduces CMRO2 and is, in parallel, also a potent direct cerebral vasoconstrictor resulting in decreased CBF and ICP. Despite its reduction of CMRO2, etomidate showed mixed neuroprotection results in animal studies, and human studies are lacking. Excitatory spikes on the EEG are more frequent after etomidate than from thiopental. Similar to methohexital, etomidate may activate seizure foci, manifested as fast activity on the EEG. Etomidate can be used in ECT to facilitate longer motor seizure activity

Question 32

Effects of etomidate in the endocrine system

Answer 32

Etomidate causes adrenocortical suppression by produc- ing a dose-dependent inhibition of 11β-hydroxylase, an enzyme necessary for the conversion of cholesterol to cortisol. This suppression lasts at least 4 to 8 hours after a single induction dose of etomidate, and rela- tive adrenal insufficiency may last up to 24 to 48 hours

Question 33

Movements effects that may be present after etomidate administration

Answer 33

Involuntary myoclonic movements are common from the transient imbalance of excitatory and inhibitory signaling in the thalamocortical tract and are not reflective of seizures. Myoclonus may be masked by the concomitant administration of neuromuscular blocking agents, ben- zodiazepines, and/or opioids. Awakening after a single IV dose of etomidate is rapid, with little evidence of any residual depressant effects

Question 34

Dexmedetomidine metabolism

Answer 34

Dexmedetomidine is water soluble and undergoes rapid hepatic metabolism involving N-methylation, hydroxylation, and conjugation. Inactive metabolites are excreted through urine and bile

Question 35

Dexmedetomidine effects in the CNS

Answer 35

Hypnosis presumably results from stimulation of α2-receptors in the locus ceruleus, and the analgesic effect originates at the level of the spinal cord. The sedative effect produced by dexmedetomidine has a different quality than that of other IV anesthetics: it more resembles a physiologic sleep state through activation of endogenous sleep pathways.

Dexmedetomidine decreases CBF without significant changes in ICP and CMRO2.

Tolerance and dependence can develop, and patients can exhibit withdrawal symptoms upon cessation of a prolonged infusion of dexmedetomidine. Although changes in the EEG do occur, spikes from seizure foci are not suppressed, making dexmedetomidine a useful drug for epilepsy surgery

Question 36

Dexmedetomidine effects in the immune system

Answer 36

Dexmedetomidine is capable of blunting the surgical stress response comparable to epidural anesthesia.
Dexmedetomidine infusion inhibits the release of epinephrine, norepinephrine, cortisol, and other proinflammatory factors in the blood. These antiinflammatory effects may play a part in the possible renal, myocardial, and cognitive protective effects of dexmedetomidine

Question 37

Dexmedetomidine infusion dose

Answer 37

0.5 to 1 μg/kg IV initial dose over a period of 10 to 15 minutes, followed by an infusion of 0.2 to 0.7 μg/kg/hr