IV Sedatives & Hypnotics: Anesthesia

• Intravenous sedatives and hypnotics are drugs used in anesthesia to induce calm, hypnosis, reduce anxiety, and depress the central nervous system.

Ideal Qualities of IV Anesthetic Agents

• Stability in aqueous solution.
• Lack of pain on injection and minimal venous irritation.
• Low potential for histamine release or hypersensitivity reactions.
• Rapid metabolism into inactive substances, preventing accumulation.
• Rapid, smooth onset without excitatory phenomena.
• Steep dose-response relationship for quick anesthesia depth changes.
• Rapid, smooth return of consciousness, even after prolonged use.
• Decreased cerebral metabolism without increasing intracranial pressure.
• Minimal cardiovascular and ventilatory depressant effects.
• Rapid recovery without post-operative side effects like nausea, dizziness, or prolonged sedation.

Drug Names and Mechanisms

• Benzodiazepines: GABA facilitators
  • Midazolam (Versed)
  • Diazepam (Valium)
  • Lorazepam (Ativan)
• Benzodiazepine Reversal: Benzodiazepine antagonist
  • Flumazenil (Romazicon)
• Induction Agents: GABA agonists unless otherwise stated
  • Propofol (Diprivan)
  • Etomidate (Amidate)
  • Ketamine (Ketalar): NMDA receptor inhibition
  • Dexmedetomidine (Precedex): α-2 adrenergic agonist
  • Thiopental (Pentothal)
  • Methohexital (Brevital)

Distribution Half-Life

• Alpha half-life occurs more quickly, and is more clinically significant
• Beta half-life occurs slowly and is relevant more in pharmacology textbooks

Elimination Half-Life and Clearance

• Clinically, it takes about 4 half-lives to eliminate a drug, while pharmacology textbooks may state 5.5 half-lives.
• High clearance indicates rapid elimination.

Volume of Distribution (Vd)

• Vd = theoretical compartments ECF = 14L
  • Plasma compartment 4L
  • Interstitial Fluid (IF) = 10 L
• Intracellular Fluid ICF = 28 L
• Plasma + IF + ICF = Total Body Water
• 4 + 10 + 28 = 42
• 42L/70kg or 0.6L/kg

Protein Binding

• Albumin binds to acids, is water soluble
• Protein binding and lipid solubility, refers to alpha 1 acid glycoprotein and beta globulins which bind bases.

Summary of Protein Binding

• Plasma albumin is most important. Beta-globulin and alpha-1-acid glycoprotein (AAG) also bind some drugs.
• Plasma albumin binds acidic drugs, while beta-globulin and alpha-1-acid glycoprotein bind basic drugs.
• Saturable binding can lead to a nonlinear relationship between dose and free drug concentration.
• Extensive protein binding slows drug elimination.
• Competition between drugs for protein binding is rarely clinically important.
• Protein binding > 90% is significant, protein binding < 90% is insignificant.

Propofol

• Chemical name: 2,6-diisopropyl phenol
• Prepared as: 1% solution in lipid emulsion with 10% soybean oil, 2.25% glycerol, and 1.2% purified egg lecithin.
• Characteristics: Lipophilic, milky white, and can be stored at room temperature.
• pH: 7-8.5
• Contains: 0.005% disodium edetate as a preservative and either 0.025% sodium metabisulfite or benzyl alcohol.

Propofol: Mechanism of Action

• Directly stimulates GABA-A receptors, decreasing GABA dissociation rate.
• Increases GABA binding leading to open chloride channels and hyperpolarization.
• Inhibits neuronal cell excitation.
• Antagonizes NMDA receptors.

Propofol: Pharmacokinetics

• Onset: 30-45 seconds
• Duration: 2-8 minutes
• Rapid distribution follows IV induction dose into the brain through circulation
• Prompt redistribution from central to peripheral compartments, with relatively quick wake up in 5-15 minutes.
• Primarily liver metabolism.
• Excreted by the kidneys.
• Clearance exceeds average hepatic blood flow.
• Extrahepatic metabolism in the kidneys and lungs.

Propofol: Clinical Effects

• Fully enhanced GABA inhibitory pathways.
• Targets interneurons in the cerebral cortex, brain stem, and thalamus.
• Rapid, pleasant loss of consciousness.
• Low-dose infusions result in anxiolysis, sedation, and amnesia
• Produces a dose-dependent reduction in cerebral blood flow CBF, cerebral rate of oxygen consumption CMRO2, intracranial pressure ICP, and cerebral perfusion pressure CPP.
• Has anticonvulsant activity.

Propofol: CV Effects

• Mild to moderate decrease in blood pressure in healthy patients
• Can produce significant hypotension in select patients.
• It is a CV depressant due to effects on the CNS, cardiac function, baroreceptor function, and decreases in sympathetic tone/systemic vasodilation.

Propofol: Respiratory Effects

• Transient respiratory depression which is more prominent than etomidate with induction.
• Dose-dependent respiratory depression occurs with maintenance infusion.
• Greater tidal volume reduction compared to respiratory rate.
• The frequency and duration of apnea are dependent on dose, speed of injection, patient characteristics and usage of multiple kinds of pharmaceuticals
• Minimal bronchodilating effects and no histamine release.
• Has mild antiemetic effects with continuous infusion.
• Can treat opioid induced pruritis

Propofol: Clinical Use

• Low doses produce sedation.
• Increased doses may elicit paradoxical excitation.
• Higher doses cause loss of consciousness, apnea, muscle relaxation, and loss of brainstem reflexes.
• Standard induction dose: 1-2.5 mg/kg.
• Maintenance of GA usage requires 100-200 mcg/kg/min continuous infusion.
• Sedation requires about 25-75 mcg/kg/min.

Propofol: Clinical Variability

• Elderly patients have prolonged effects and increased sensitivity due to decreased cardiac output/clearance.
• Children have larger distribution volume and require a quicker clearance.
• Morbidly obese patients should be dosed based on lean body weight.
• Chronic alcohol abusers need increased induction dose.
• Patients with CV disease may have exaggerated hemodynamic responses.

Propofol: Side Effects

• May cause myoclonus, which looks like seizures but involve involuntary muscle movements.
• Passes placental barrier leading to sedation of the neonate.
• Myoclonus is not as concerning as with etomidate
• Can cause pain on injection.
• Can cause Propofol Infusion Syndrome (PRIS)

Propofol Infusion Syndrome risk factors

• Dose > 4mg/kg/hr for > 48 hours
• Critical illness
• High-fat low-carb intake
• Catecholamine infusion
• Administration of steroids
• Inborn errors of mitochondrial fatty acid oxidation.

Propofol Infusion Syndrome symptoms

• Hypotension
• QRS widening
• Bradycardia
• Vtach
• Ischemia
• Heart failure
• Hypoxia
• Pulmonary edema
• Acute kidney injury
• Hyperkalemia
• Rhabdomyolysis
• Hyperthermia
• Fever
• discolored urine
• hepatomegaly
• steatosis
• lipidemia
• Sulfite allergy/sensitivity to sodium metabisulfite

Propofol: Egg/Nut/Soy Allergy Concerns

• Only issue is egg yolk allergy
• There is a contamination risk so one should:
  • Use an aseptic technique in drug preparation
  • Avoid multidose use from a single vial for more than one patient
• It is important to discard open propofol after six hour

Etomidate

• 35% propylene glycol based product that contains 2mg/mL
• R isomer 5x stronger than the S-isomer
• The PH is 8.1 and is 75% protein bound.
• second choice if cannot tolerate propofol, not used as infusion, only ivp

Etomidate: Mechanism of Action

• GABA-modulation to block neuroexcitation

Etomidate: Pharmacokinetics

• Induction occurs rapidly in 1 minute, and lasts 3-12 mins
• Moderate lipid solubility, large Vd allows penetration to the brain and cause hypnosis.
• Rapid redistribution to other organs and tissue causes wake up
• Metabolized via ester hydrolysis, creating inactive carboxylic acid metabolites in the liver and the plasma.
• Excreted in the urine (85%) and bile (13%)

Etomidate: CNS Clinical Effects

• Dose-dependent CNS depression.
• Decreases ICP, CBF, CMRO2, IOP, CPP
• Anti-epileptic.

Etomidate: CV Effects

• Hemodynamic stability.
• Lacks depression of the sympathetic nervous system and baroreceptor function

Etomidate: Respiratory Effects

• Dose-dependent decrease in respiratory effort, less than propofol.
• Minute volume decreases and respiratory rate increases
• Ventilatory response to CO2 is decreased.
• No effect on bronchial tone, no histamine release.
• May require supplemental steroid injection.
• Standard usage dose is 0.2-0.4 mg/kg.
• Rarely used as a continuous infusion
• Good alternative to propofol in the presence of an unstable cardiovascular system.

Etomidate: Side Effects

• Adrenocortical suppression occurs.
• Myoclonia is considered a side effect
• Pain on injection occurs 90% of the time
• Nausea/Vomiting 30-40% of the time

Etomidate: Contraindications

• Allergy
• Adrenal suppression
• Acute porphyria

Benzodiazepines

• Includes Midazolam (Versed).

Chemical Structure

• The compounds share a benzodiazepine ring system and have presence at positions 1 and 4 of two nitrogen atoms
• Share a phenyl group at position 5, with electronegative groups positioned at position 7.
• These all have similar characteristics but differ in potencies, pharmacokinetics and intensity of clinical properties. compounded with 0.8% sodium chloride and 0.01% disodium edetate and 1% benzyl alcohol as a preservative.

Benzodiazepine Clinicals

• Act as an agonist on the benzodiazepine receptor binding sites on the GABAA receptor.
• Exhibits great variation in the half-life of benzos, though Midazolam has a high clearance rate and is shorter acting compared to most.
• Rapidly metabolized by hepatic and small intestine cytochrome P450 enzymes to active and inactive metabolites
• Principal metabolite, 1-hydroxymidazolam is conjugated to 1-hydroxymidazolam glucuronide and cleared by the kidneys.

Metabolism

• Slowed in the presence of drugs that inhibit the cytochrome P450 system (cimetidine, CA channel blockers, antifungals) but this is not clinically significant.
• Clinical effects can cause anxiolysis, sedation/hypnosis, anticonvulsant activity, anterograde amnesia, spinal cord-mediated skeletal muscle relaxation.
• MAC and Anxiolysis
• Oral preparations can also be given to Children

Doses

• Typically 1-2.5 mg IV (onset 60 seconds, duration of sedation 20-80 minutes)
• Primarily employed in preoperative sedation/anxiolysis/amnesia (amnesia>sedation)

Flumazenil (Romazicon)

• Reverses Benzodiazepines
• A competitive antagonist with a high affinity for the receptor site.
• Has a Relatively short duration and half-life make re-sedation possible.
• Titrate a dose of 0.2mg IV until desired level of consciousness achieved (dose rarely exceeds 1mg).
• For Benzo overdose, use 3mg IV.

Standard Doses

• Onset 1-2 minutes
• Duration 45-90 minutes.

Side effects

• Withdrawal in chronic users.
• Mild anxiety can be observed.
• Seizures may occur so usage should be avoided in patients with known seizure disorders.

Ketamine (Ketalar)

• Primarily used to induce conscious sedation
• Is an NMDA receptor antagonist, which produces dissociative anesthesia
• Is a Phencyclidine derivative (prototype is LSD)
• Usually sold as a white crystalline salt 1% or 10% aqueous solution and has a PH of 3.3-5.5
• Inhibits activation of NMDA receptors by glutamate and decreases presynaptic release of glutamate.
• Also exerts effects at the opioid receptors, monoaminergic receptors, muscarinic receptors and voltage-sensitive sodium channels.
• Can be administered via the oral route, intranasal and rectally, though it is primarily IV.
• Routes of illicit use include snorting, smoking, swallowing or injecting.
• High lipid solubility and low plasma protein binding (12%) and IV injection rapidly distributes to highly perfused tissues, with an Onset of less than 1 minute
• Hepatic metabolism occurs (N-demethylation via cytochrome P450 enzymes) to norketamine.
• Excreted primarily in the urine, and also in bile and feces

Clinical Side Effects

• Causes Dissociative anesthesia, and Unconsciousness
• Can cause Nystagmus RAPID EYE MOVEMENTS.
• Can Increase IOP, CMRO2, CBF, ICP
• Leads to Emergence delirium, nightmares and hallucinations
• Leads to increased BP and HR due to the release of catecholamines and the decrease production of vascular nitric oxide.
• Can lead to potent Bronchodilation
• Maintains respirations and airway reflexes andIncreases salivation and respiratory secretions

Doses and Clinical Uses

• Analgesia (even in sub-hypnotic doses)
• Increases muscle tone and causes nystagmus
• Is Analgesia (in conjunction with general anesthesia or regional)
• Has been successful in Preemptive analgesia
• Can treat Burn dressing changes, and Closed reduction fractures in ER
• Can be used to induce anesthesia in special circumstances, where one may observe for Shock or CV instability, Severe dehydration/anemia, andBronchospasm
• Can be effective with Obstetric patients ( Induction of general anesthesia, and Acute bronchospasm)
• Induction of general anesthesia 0.5-2 mg/kg, with an Onset of 2-4 min with in 15-30 min duration
• Maintenance doses are commonly 0.5-1 mg/kg

Dexmedetomidine (Precedex)

• Is a presynaptic Alpha 2 agonism that decreases the release of norephinephrine and acts at the locus coeruleus leading to sedation and hypnosis
• Highly selective alpha2 agonist acting on receptors in the brain and spinal cord with 8 times greater affinity than clonidine.
• Alpha 2 receptor is 1600 times that of the affinity for the alpha1 receptor

Pharmacokinetics of Dexmedetomidine

• Its a presynaptic alpha 2 agonism that decreases the release of norephinephrine at the locus coeruleus leading to sedation and hypnosis, and with spinal effects in the dorsal horn that decrease the release of excitatory neurotransmitters like glutamate and substance P.
• Is Lipophilic and highly protein bound with a large volume of distribution thus is rapidly Redistributes to peripheral tissues.
• Hepatic metabolism occurs via both direct glucuronidation and biotransformation by cytochrome P450 enzymes and is Excreted primarily in the urine and small amount in the feces.
• Can exhibit initial increase in BP due to Alpha 1 effects (not clinically significant) but also Dose dependently decrease in BP and HR

Clinical Aspects of Dexmedetomidine

• CNS effects can include unconsciousness that resembles natural sleep with patients often being arousable, cooperative, devoid of disinhibition which makes for Easier weaning for ICU patients
• Acts as an Anxiolysis and prevents Emergence delirium
• Causes No significant respiratory depression
• Routine usage is done with 1 mcg/kg infusion over 10 minutes followed by 0.2-0.7 mcg/kg/hr during GA

Side effects

• May cause Bradycardia and/or Hypotension

Contrindications

• Known allergy should be accounted for.