Sedatives and Non-opioids.docx

[IV Sedatives ] - Sedative = drug inducing a state of calm or sleep - Hypnotic = drug inducing hypnosis or sleep - Anxiolytic = drug that reduces anxiety - **Sedative-hypnotics reversibly depress the activity of the CNS** - Greater lipid solubility = greater redistribution - Rapid...

[IV Sedatives ] - Sedative = drug inducing a state of calm or sleep - Hypnotic = drug inducing hypnosis or sleep - Anxiolytic = drug that reduces anxiety - **Sedative-hypnotics reversibly depress the activity of the CNS** - Greater lipid solubility = greater redistribution - Rapid redistribution of drug leads to quick awakening - γ- Aminobutyric Acid Agonists = GABA agonists - **Propofol** - **GABA agonist** - **Produces unconsciousness in about 30 seconds** - **Rapid return to consciousness with minimal residual nervous system effects** - Preparation = emulsified in long chain egg lecithin triglycerides and soybean oil - Do not mix with lidocaine -- lidocaine is mixed with propofol to reduce pain on induction but it can create a risk of pulmonary embolism due to creation of droplets - Non-chiral - Aquavan is a more soluble formulation of the prodrug characterized by a slower onset, larger Vd, and greater potency, less pain on injection - **Mechanism of action** - **Primary = binds to GABA-A receptors. Secondary = modulates glycine receptors** - decreases the rate of GABA dissociation from the receptor - transmembrane conductance of chloride increases, inhibiting the postsynaptic membrane resulting in hyperpolarization - **Rapid awakening due to high lipid solubility of propofol. Propofol is taken up by lungs but then goes to the fat** - **Clearance exceeds hepatic blood flow** - **Vd is very large** - Pulmonary uptake is significant - Metabolized by CYP450 hepatic enzymes via oxidation - Conjugated to water-soluble metabolites and excreted by kidneys - Dysfunction of hepatic or renal systems do not really negative impair propofol - Context sensitive half time is 40 mins after 8 hour infusion - **Clinical applications** - **Induction drug of choice for anesthesia = 1.5-2.5 mg/kg** - Children need larger dose due to children having a larger Vd - Geriatrics need smaller dose due to smaller Vd and decreased clearance - **Sedation 25-100 mcg/kg/min** - Prolonged infusion of pediatric pts can lead to metabolic acidosis, lipemic plasma, bradycardia, heart failure - **Maintenance 100-300 mcg/kg/min** - Often combined with a short acting opioid or inhalation agent - GA maintenance is associated with minimal PONV and prompt awakening - Side effects - Reduced PONV - Antipruritic and anticonvulsant activity - Attenuation of bronchoconstriction in healthy and asthmatic patients -- bronchodilation - Synergistic with other CNS depressants e.g. synthetic opioids - Decreases CMRO2, CBF, ICP - High doses produce burst suppression - Preserves cerebral autoregulation in response to changes in CO2 - Cortical SEE potentials are not significantly affected - Amnestic effects are similar to versed - CV effects - Decreases in systemic BP due to decreased SVR and decreased CO - Decreased SVR = relaxation of vascular smooth muscle and inhibition of sympathetic vasoconstriction - Decreased CO = negative inotropic effect, inhibition of the trans-sarcolemnal calcium influx - No change in HR - CV effects are potentiated in hypovolemia, elderly, and LV dysfunction - Effects are reversed by laryngosenephrine -- direct DL is stimulating and can reverse the decreased BP/SVR, CO effects - Respiratory effects - Dose dependent depression of RR and Vt and central depressant response to hypoxemia - Apnea frequently occurs - Respiratory effects potentiated by opioids - Hypoxic pulmonary vasoconstriction remains intact - Decreased pharyngeal contractile force -- relaxes muscles in pharynx that keep airway open - Other effects of propofol - Hepatic and renal function rarely affected - Lowered IOP during induction and intubation - No effects on coagulation and platelet function - Does not produce seizure activity -- has anti-seizure properties - Carries a significant abuse potential - Propofol supports bacterial growth e.g. E.coli and pseudomonas aeruginosa - Prepare medication using aseptic technique - Withdraw from ampules immediately - Discard after 6 hours - **Most sedative-hypnotics have the following effects** - **Decrease CRMO2, CBF, ICP** - **EEG burst suppression** - **Propofol infusion syndrome** - Cause is unknown but may involve poisoning of the electron transport chain -- cytopathic hypoxia - Can occur in children and adults in high dose infusions of 24 hours or longer - Unexpected bradycardia should prompt measurement of ABGs and serum lactate - Other causes of acidosis should be considered if present e.g. hyperchloremic metabolic acidosis, DKA, release of limb tourniquet for 60+ mins - **Antioxidant properties of propofol by scavenging free radicals** - Reintroduction of oxygen to previously ischemic tissues leads to the formation of free radicals - Free oxygen radicals react with polyunsaturated fatty acids and cause cell membrane disruption - Propofol's phenolic hydroxyl group scavenges free radicals - **Etomidate** - **Modulates the GABA-A receptors enhancing affinity of GABA for receptor** - R isomer is 5x as potent as the S isomer - Pharmacokinetics - Large Vd - Penetrates the brain rapidly - 76% protein bound - Moderate lipid solubility - pKa 4.2 -- 99% unionized at physiologic pH - rapid hydrolysis produces a water soluble, inactive metabolite - elimination half time is 2-5 hours -- 85% excreted in urine, 10-13% excreted in bile - clinical uses - **alternative to induction with pts with CV instability** - Induction dose = 0.2-0.4 mg/kg - Pts generally wake up rapidly with little hangover - **Awakening is delayed with increased doses or infusions - greater CSHT than propofol** - Can depress adrenocortical function -- mixed data - Side effects - **Myoclonus is common after injection -- perhaps due to disinhibition of subcortical structures that normally suppress extrapyramidal motor activity** - Decreased CRMO2 by 35-45% - Decreases ICP, CBF. Direct cerebral vasoconstrictor - Increased frequency of excitatory spikes - Has anticonvulsant properties - Enhances SSE potential monitoring - **Minimal changes in HR, SV, or CO** - BP may decline up to 15% due to decreased SVR - Possible decreases in inotropy - Little impact on hepatic or renal function - IOP decreased - Apnea may occur with rapid injection - Vt decreases and RR increases - May stimulate respiratory centers - Ventilatory depressant effects are potentiated by opioids and volatile agents - Adrenal cortical suppression - Etomidate produces dose dependent inhibition of the conversion of cholesterol to cortisol - Enzyme inhibition lasts 4-8 hours - Evidence of untoward effects are controversial - Benzodiazepines provide anxiolysis, sedation, anticonvulsant actions, spinal cord mediated relaxation, and anterograde amnesia with amnesia duration lasting longer than sedation - GABA receptors concentrated in CNS - Benzos mechanism of action - **Bind between the alpha and gamma subunit to increase the affinity of the receptor for GABA** - **Increased chloride conductance results in hyperpolarization of the post-synaptic cell membrane** - Ceiling effect and low toxicity - Differences in onset and duration of action reflect differences in potency, lipid solubility, pharmacokinetics - All are highly protein bound to albumin and highly lipid soluble - Decrease adenosine degradation cardioprotective - Side effects - Fatigue and drowsiness can last up to 2 weeks - Loss of coordination and diminished cognitive function when combined with other CNS depressants - Profound amnesia - **Synergistic effects with other CNS depressants e.g. alcohol, inhaled/IV anesthetics, opioids, alpha-2 agonists** - Analgesic effects of opioids are reduced by benzos - Hypothalamic pituitary adrenal axis suppression secondary to decreased cortisol levels -- similar to etomidate - Dependence and withdrawal sx = irritability, insomnia, tremulousness - Lorazepam, oxazepam, temazepam undergo oxidation and their metabolism is less effected by aging than diazepam due to glucuronidation - Benzos may accelerate cognitive decline in elderly - Midazolam - pKA is 6.15 - In acidic solution, is water soluble - In physiologic pH, is lipid soluble -- don't have to worry about acidosis in pt affecting lipid solubility - Rapid GI absorption - Relative slow effect-site equilibration -- space doses accordingly - Elderly and obese have increased Vd - Highly protein bound 96-99% - Elimination half time = 1-4 hours with double the time in elderly - Metabolized in liver and small intestine (via CYP3A4) to active and inactive metabolites - Conjugated and eliminated by kidneys - Drugs that inhibit CYP450 enzymes slow the metabolism and increase its effects - CNS side effects - Decreased CMRO2, CBF - Cerebral vascular response to CO2 is preserved - Little change in ICP. ICP increases with laryngoscopy - Potent anticonvulsant - Respiratory Side effects - Dose-dependent decreases in ventilation -- worse effects in COPD - **Ventilatory depressant effects are potentiated when combined with opioids** - Depressed swallowing reflexes - Hemodynamic changes when used for induction are similar to thiopental - CO is stable but SVR decreases. Effects are potentiated by hypovolemia - Preoperative mediation - Give orally to peds - IV sedation - 1-2.5 mg IV with onset 30-60 sec - Peak 3-5 mins - Caution for decreased ventilation when combined with opioids and in COPD - Induction - 0.1-0.2 mg/kg over 30-60 sec - Onset is slower than thiopental and propofol - Induction with midazolam prolongs awakening - Decreases in BP are usually modest - Maintenance - **Increase in context sensitive half time reflect the duration of infusion** - Post-operative sedation - prolonged infusion transitions decreases in plasma concentration from redistribution to metabolism - clearance is delayed in elderly, obese, and hepatic disease - **Diazepam** - highly lipid soluble and protein bound - supplanted by midazolam - pain on injection - Pharmacokinetics - Rapid absorption from GI tract - Large Vd - **Duration of action is a reflection of metabolism and elimination** rather than redistribution - Metabolism = CYP450 enzymes via oxidation and eventual glucuronide conjugation to active metabolites - Active metabolites = desmethyldiazepam (principal metabolite), oxazepam, temazepam - Prolonged elimination half time with cirrhosis and elderly - **Desmethyldiazepam has half-life of 48-96 hours (long!)** - Respiratory side effects - Minimal - Decreases in Vt may cause slight increase in PaCO2 - Combining with opioids or alcohol results in exaggerated or prolonged depression of ventilation - Respiratory depression is centrally mediated - CV side effects - Minimal effects -- similar to sleep on CV - Combination with N2O does not increase CV effects - Excellent drug for delirium tremens - Effective at terminating LA induced seizures - Skeletal muscle relaxant properties mediated through inhibition of spinal gamma neurons - Lorazepam - More potent and amnestic than versed or diazepam - Similar effects - Lower lipid solubility and slower onset than midazolam and diazepam? Doesn't lipid solubility correlate with onset - Conjugates are excreted by the kidneys via hepatic glucuronidation - Elimination halftime 10-20 hours - Prolonged sedation limits utility in anesthetics where rapid awakening is desired - Not suitable for iv induction, sedation during regional anesthesia, as an anticonvulsant - Oral doses produce peak concentrations in 2-4 hours and therapeutic levels lasting 24-48 hours - May delay awakening when used for sedation for mechanical ventilation - Remimazolam = ultrashort acting benzo metabolized by non-specific tissue esterases - Has minimal to no effects on ventilation - Recommended for brief procedures - Common side effects of other benzos - Oxazepam = insomnia with night awakenings - Alprazolam = anxiety and panic attacks - Clonazepam = seizure control - Flurazepam = insomnia and daytime sedation - Temazepam = insomnia - Triazolam = insomnia marked by anterograde amnesia - **Flumazenil** - **Dose-dependent benzo competitive antagonist** - Antagonizes the benzo component of the opioid/benzo ventilatory depression - Metabolized by hepatic microsomal enzymes to inactive metabolites - Dose 0.1-0.2 mg at 60 second intervals with a total dose of 5 mg - Duration of action = 30-60 mins - Can be used as a continuous infusion - Has very weak agonistic effects - Side effects = none, but caution with benzo use for seizure disorders - Barbiturates - Thiobarbiturates = sulfur group - Oxybarbiturates = have oxygen - Phenyl barbiturates = phenyl group - Methyl barbiturates = methyl group - **Mechanism of action = potentiating GABA by allosterically increasing the affinity of GABA for the receptor** - Also influence glutamate, adenosine, and neuronal/brain nAchr - increase the duration of chloride channel opening hyperpolarization - high doses directly activate the GABA-A receptor - rapid awakening due to redistribution out of the brain - context sensitive half time is increased by prolonged infusions - re-entry to central circulation from fat and skeletal muscle prevent rapid decreases in plasma concentration - primary site of metabolism is in liver - low hepatic extraction ratio and capacity dependent elimination - no direct effect on skeletal, cardiac, or smooth muscles - Elderly pts require lower doses - Methohexital lowers the seizure threshold -- all barbiturates lower seizure threshold - Barbiturates have been used as sole agents for brief procedures - Recovery is quick but longer than with propofol - Clinical applications = treatment of increased ICP - ICP is decreased by decreasing CBF and cerebral blood volume due to cerebral vasoconstriction - Barbiturates can produce EEG burst suppression and an isoelectric EEG - Barbiturate use can result in significant hypotension - Improved survival after head trauma and global cerebral ischemia (e.g. cardiac arrest) have not been demonstrated - Side effects - Centrally mediated peripheral vasodilation and decreased sympathetic outflow cause a transient decrease in BP and increase in HR - No direct myocardial depressant effects - Central depression of ventilatory centers -- decreased response to CO2 and apnea - Thiopental produces dose-dependent decreases in SSE potentials and auditory evoked potentials - Prolonged infusions can induce hepatic microsomal enzymes - comparative potencies of barbiturates methohexital \>thiamyal\>thiopental - **Ketamine** - Produces dissociative anesthesia = eyes open, catatonic, slow nystagmus gaze - Amnesia and analgesia are intense - Carries a significant abuse potential - Chiral compound - S-ketamine produces more analgesia, rapid metabolism/recovery, less salivation, lower incidence of emergence reactions than R-ketamine - Ketamine has weak actions at the GABAA receptors - NMDA receptor - Binds to the phencyclidine site on the NMDA receptor to inhibit glutamate action - Glycine is an obligatory co-agonist with glutamate at the NMDA receptor - Opioid receptor - Interacts with mu, delta, kappa, and sigma receptors to produce analgesia - Descending monoaminergic (pain pathways) - mAchR receptor interaction produces bronchodilation and sympathomimetic effects - sodium channel interaction produces local anesthetic effects - nAchR interaction produces analgesia ? - highly lipid soluble but not significantly bound to plasma proteins - Vd high at 3L/kg - easily crosses the BBB - Has high hepatic extraction ratio and clearance - Elimination half time is intermediate at 2-3 hours - Metabolized by CYP450 enzymes (hepatic) - Demethylation to form norketamine, an active metabolite - Norketamine is hydroxylated then conjugated to be excreted by the kidneys - Enzyme induction from repeated doses may account for tolerance - Clinical applications - **Analgesia which is mediated by inhibition of dorsal horn of spinal cord NMDA receptors** - Primary spinal cord site of action is dorsal horn - Analgesia greater for somatic rather than visceral pain - Intense analgesia occurs with subanesthetic doses - Excellent agent for anesthetic management of patients with chronic pain - Induction of anesthesia - IV and IM -- IM undergoes significant 1^st^ pass effect - Consciousness returns in 10-20 mins, full orientation returns in 60-90 mins - Emergence prolonged after repeat injections or infusion - Amnesia persists 60-90 mins after return to consciousness - Precautions - Myocardial depressant effects if endogenous catecholamine stores are depleted - Sympathomimetic effects can increase MVO2 in pts with CAD - **In pre-existing cardiac disease, ketamine can unmask this and cause hypotension** - Ketamine lacks IPC effects - **May increase PVR despite beneficial bronchodilatory effects** - CNS effects - Cerebral vasoconstrictor - Despite increased excitatory activity in thalamus and limbic system, ketamine does not alter seizure threshold -- ketamine has some anticonvulsant activity - Auditory and SSE potentials are decreased by ketamine - CVS effects - **Ketamine increases sympathetic nervous system out flow causing in increase in BP, PAP, HR, CO, cardiac work, and MVO2** - Reflects increased plasma epinephrine and NE levels - Critically ill patients may still respond to ketamine with decreases in systemic blood pressure and CO due to depleted catecholamines and direct myocardial depressant effects - Emergence delirium and psychedelic effects - Incidence dose dependent at 5-30% - Risk factors are \2mg/kg IV, history of personality problems or frequent dreaming - Prevention = benzos, preop priming - **Dexemedetomidine** - Highly selective and potent alpha2 agonist - Inhibits the activity of the pontine ceruleus, a modulator of vigilance by decreasing secretion of NE - Dex = dextro isomer of medetomidine - Dex is more selective for alpha 2 receptors than clonidine with a shorter duration of action - **Produces sedation by decreasing sympathetic nervous system activity** - Pts are calm, drowsy, and easily aroused - Pharmacokinetics - Elimination half time is 2-3 hours - Highly protein bound \>90% - Undergoes extensive hepatic metabolism - Conjugated and excreted by the kidneys - Has weak inhibiting effects on CYP450 enzymes - Clinical applications - Blunts the hemodynamic response to intubation - Decreases plasma catecholamine concentrations - Potentiates inhalation agents and opioids - May cause hypotension and moderate to severe bradycardia - Does not significantly depress ventilation - Dampens thermoregulatory response to temp changes - Useful for ICU sedation [Centrally Acting Non-opioid Analgesics ] - Widespread dependence, misuse and abuse of opioids have driven exploration of alternative analgesia modalities. - Opioids have limited efficacy for managing non-cancer chronic pain. - Non-narcotic medications relieve pain by mechanisms unrelated to opioid receptors, do not cause: - Respiratory depression & other side effects are reduced - Physical dependence - Abuse - Neuroaxial use of centrally acting non-opioids agents are not federally regulated - Release of inflammatory mediators and cause changes in protein expression in the dorsal horns -- develop tolerance? - Chronic opioid use provokes the release of proinflammatory cytokines and chemokines - Non-narcotic analgesics are the basis for multimodal management of pain. - Role of Centrally Acting Non-Opioid Analgesics - Higher CSF concentrations are achieved by bypassing the blood-brain barrier. - Agents act through different mechanisms than opioids - May allow elimination or reduction in opioid - Caution: Neurotoxic effects of some compounds are unknown - Αlpha2 Adrenergic Agonists - Clonidine - Dexmedetomidine - Mechanism of Action of Αlpha2 Adrenergic Agonists - Activate α2 adrenergic receptors on sympathetic pre-ganglionic neurons reducing norepinephrine release - α2 adrenergic receptors stimulation decrease NE in brain causing decreased wakefulness, decrease BP in smooth vessels, inhibition of pain in dorsal horns - Result: leading to analgesia, hypotension, bradycardia and sedation. - Neuraxial Clonidine - Clonidine is a selective partial α2 receptor agonist - Inhibits nociceptive impulses at post-junctional α2 receptors in the dorsal horn - Neuraxial clonidine prolongs local anesthetic analgesia, and reduces postoperative opioid requirements - Prolongs sensory and motor block of LAs. - Acts synergistically with neuraxial opioids - Black box warning in obstetric patients - Anti-hyperalgesic properties - Dex: a selective α2 receptor agonist - Higher receptor affinity and selectivity for α2 receptors than clonidine - Fewer hemodynamic systemic effects - Intrathecal dose: 3 ug - No neurotoxicity reported for intrathecal or epidural administration - Major side effects are bradycardia and hypotension - Epidural Dex (2ug/kg) - Prolongs neuraxial sensory and motor blockade - Decreases intraoperative anesthetic requirements - Improves postoperative analgesia - Decreases heart and and BP in C/S - Black box warning for hypotension and bradycardia in C-sections - Neuraxial Neostigmine - Neostigmine inhibits acetylcholinesterase and prevents the metabolism of acetylcholine - Analgesic effects are d/t stimulation of muscarinic cholinergic receptors - Prolongs analgesia and minimal side effects with intrathecal (10-100 ug) or epidural (100-200 ug) use. - High incidence of nausea (50-100%) - Does not affect motor blockade - **Never any reason to use this neuraxially** - Ketamine: Mechanism of Action - Non-competitive antagonism of NMDA (glutamate) receptors in the dorsal horn - NMDA receptor agonism results in the release of glutamate, aspartate, and neurokinin - These neurotransmitters are linked to central sensitization, windup, and other elements of neuroplasticity - Ketamine counters these effects - Neuraxial Ketamine - Intrathecal use is limited by the risk of neurotoxicity - Epidural dose 10-30 mg produces excellent post op analgesia - Synergist with opioids - Use of preservative free solutions is mandatory - Side effects include headache, sedation, transient burning pain with injection -- hints at possibility of neurotoxicity - Psychogenic, respiratory, bladder dysfunction, and cardiovascular effects are minimal or absent. - Neuraxial Midazolam - Intrathecal midazolam increases the affinity of GABA for the GABAA receptor - The transmembrane conductance of chloride results in hyperpolarization of the neuron, reducing action potential propagation. - The dorsal horn of the spinal cord has a high density of GABAA receptors. - Intrathecal (1-2 mg) or epidural midazolam has an analgesic affect and may be beneficial treating perioperative and chronic pain. - Epidural midazolam reduces PONV - Tramadol - Bings to mu receptors - Inhibits serotonin and NE uptake - Droperidol - Reduces PONV - **Don't use this neuraxially** - Conopeptides: Snail poisons - Ziconotide - Selectively blocks dorsal horn voltage gated calcium channels i.e. blocks calcium channels at the spinal cord level - Inhibits norepinephrine release decreasing mean and diastolic pressures - Approved for treatment of neuropathic pain - Has a narrow therapeutic window, provokes neuropsychiatric side effects - Side effects - Dizziness - Confusion - Ataxia - Abnormal gait - Memory impairment - Suicidal ideation - **Baclofen is a GABA-B receptor agonist suppressing neuronal transmission in the cerebral cortex, basal ganglia, thalamus, cerebellum and spinal cord.** - Actions at laminae II & III - Increase potassium conductance -- hyperpolarization - Inhibit 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 - Low back pain - Ketorolac is a cyclo-oxygenase inhibitor - COX1 and COX2 facilitate production of prostaglandins leading to hyperalgesia and allodynia after injury - Intrathecal ketorolac appears to have little analgesia benefit - Magnesium sulfate act on NMDA receptors by regulation of calcium influx into cells. - Magnesium is the natural antagonist to calcium - Does have some analgesic effect when administered intrathecally or in the epidural space - **Animal studies have reported neurotoxicity and human safety is not proven.** - Glutamate is excitatory at the spinal cord level - GABA and glycine are inhibitory at the spinal cord level