Sedatives and hypnotic agents

Propofol

• Propofol is taken up by lungs and then distributed to fat
• Clearance exceeds hepatic blood flow, and volume of distribution (Vd) is very large
• Pulmonary uptake is significant, and it is metabolized by CYP450 hepatic enzymes via oxidation
• Conjugated to water-soluble metabolites and excreted by kidneys
• Dysfunction of hepatic or renal systems does not significantly impair propofol

Clinical Applications

• Induction drug of choice for anesthesia: 1.5-2.5 mg/kg, with children needing larger doses and geriatrics needing smaller doses
• Sedation: 25-100 mcg/kg/min, with prolonged infusion in pediatric patients leading to metabolic acidosis, lipemic plasma, bradycardia, and heart failure
• Maintenance: 100-300 mcg/kg/min, often combined with a short-acting opioid or inhalation agent, and associated with minimal PONV and prompt awakening

Side Effects

• Reduced PONV
• Antipruritic and anticonvulsant activity
• Attenuation of bronchoconstriction in healthy and asthmatic patients, resulting in bronchodilation
• Synergistic with other CNS depressants, e.g., synthetic opioids
• Decreases CMRO2, CBF, ICP, and preserves cerebral autoregulation in response to changes in CO2
• High doses produce burst suppression, and cortical SEE potentials are not significantly affected
• Amnestic effects are similar to Versed

Cardiovascular Effects

• Decreases systemic BP due to decreased SVR and CO
• Decreased SVR is due to relaxation of vascular smooth muscle and inhibition of sympathetic vasoconstriction
• Decreased CO is due to negative inotropic effect and inhibition of the trans-sarcolemnal calcium influx
• No change in HR, but CV effects are potentiated in hypovolemia, elderly, and LV dysfunction
• Effects are reversed by laryngosenephrine, which stimulates and can reverse the decreased BP/SVR and CO effects

Respiratory Effects

• Dose-dependent depression of RR and Vt, and central depressant response to hypoxemia
• Apnea frequently occurs, and respiratory effects are potentiated by opioids
• Hypoxic pulmonary vasoconstriction remains intact, but decreases pharyngeal contractile force, relaxing muscles in the pharynx that keep the airway open

Other Effects

• Hepatic and renal function rarely affected
• Lowers IOP during induction and intubation
• No effects on coagulation and platelet function
• Does not produce seizure activity, has anticonvulsant properties, and enhances SSE potential monitoring
• Carries a significant abuse potential, supports bacterial growth, and increases frequency of excitatory spikes

Benzodiazepines

• Provide anxiolysis, sedation, anticonvulsant actions, spinal cord-mediated relaxation, and anterograde amnesia
• GABA receptors concentrated in CNS
• Mechanism of action involves binding between the alpha and gamma subunit to increase the affinity of the receptor for GABA, resulting in increased chloride conductance and hyperpolarization of the post-synaptic cell membrane
• Ceiling effect and low toxicity, with differences in onset and duration of action reflecting differences in potency, lipid solubility, and pharmacokinetics
• All are highly protein bound to albumin and highly lipid soluble, with a decrease in adenosine degradation having cardioprotective effects
• Side effects include fatigue and drowsiness, loss of coordination and diminished cognitive function, profound amnesia, and synergistic effects with other CNS depressants

Dexmedetomidine

• A selective α2 receptor agonist with higher receptor affinity and selectivity for α2 receptors than clonidine
• Fewer hemodynamic systemic effects, with intrathecal dose: 3 ug, and no neurotoxicity reported for intrathecal or epidural administration
• Major side effects are bradycardia and hypotension

Epidural Dex

• Prolongs neuraxial sensory and motor blockade, decreases intraoperative anesthetic requirements, and improves postoperative analgesia
• Decreases heart rate and BP in C-sections, with a black box warning for hypotension and bradycardia in C-sections

Neuraxial Neostigmine

• Inhibits acetylcholinesterase and prevents the metabolism of acetylcholine, with analgesic effects due to stimulation of muscarinic cholinergic receptors
• Prolongs analgesia and minimal side effects with intrathecal (10-100 ug) or epidural (100-200 ug) use, and approved for treatment of neuropathic pain
• Side effects include dizziness, confusion, ataxia, abnormal gait, memory impairment, and suicidal ideation

Baclofen

• A GABA-B receptor agonist suppressing neuronal transmission in the cerebral cortex, basal ganglia, thalamus, cerebellum, and spinal cord
• Actions at laminae II & III, increasing potassium conductance and inhibiting calcium conductance, resulting in hyperpolarization and inhibition of glutamate and substance P release
• Intrathecal baclofen is effective in treating pain with MS, CRPS type I, and low back pain

Ketorolac

• A cyclo-oxygenase inhibitor, with COX1 and COX2 facilitating production of prostaglandins leading to hyperalgesia and allodynia after injury
• Intrathecal ketorolac appears to have little analgesia benefit

Magnesium Sulfate

• Acts on NMDA receptors by regulating calcium influx into cells, with magnesium being the natural antagonist to calcium
• Does have some analgesic effect when administered intrathecally or in the epidural space, but animal studies have reported neurotoxicity, and human safety is not proven