QG 2 IV SEDATIVE HYPNOTICS-STUDENT.pptx

NON-GABA AGONIST SEDATIVEHYPNOTICS KETAMINE DEXMEDETOMIDINE SCOPOLAMINE DROPERIDOL 1 KETAMINE Preparations Mechanism of Action Pharmacokinetics Clinical Uses Organ System Effects CNS Cardiovascular Respiratory Side Effects 2 KETAMINE PREPARATIONS An arylcyclohexylamine resembling phencyclidine Consi...

NON-GABA AGONIST SEDATIVEHYPNOTICS KETAMINE DEXMEDETOMIDINE SCOPOLAMINE DROPERIDOL 1 KETAMINE Preparations Mechanism of Action Pharmacokinetics Clinical Uses Organ System Effects CNS Cardiovascular Respiratory Side Effects 2 KETAMINE PREPARATIONS An arylcyclohexylamine resembling phencyclidine Consists of two optical isomers S(+) ketamine R(-) ketamine Water soluble Preserved with benzethonium chloride Supplied in three strengths 1% 5% 10% 3 KETAMINE PREPARATIONS Two Isomers S(+) isomer 4x greater affinity for phencyclidine binding site on NMDA receptor than R(-) ~3x greater potency than racemic mixture More intense analgesia ~20% quicker metabolism and quicker return of cognitive function than racemic mixture Decreased salivation Decreased incidence of emergence reactions Hallucinations Nightmares Impaired memory and cognition Mood disorder Better accepted by patients Available in Europe In the United States only the racemic mixture is approved 4 KETAMINE – MECHANISM OF ACTION Produces dose-dependent CNS depression resulting in a “dissociative state” resulting in: Intense analgesia and amnesia Depending on dose, may remain conscious, or may be unconscious but appear awake in a cataleptic state Eyes open Slow, nystagmic gaze Coordinated movement of skeletal muscle – not in response to surgical pain EEG reveals dissociation between the thalamocortical and limbic systems The precise mechanism of this dissociative state is unknown, although ketamine binds with multiple CNS receptors 5 KETAMINE – MECHANISM OF ACTION Receptors affected by Ketamine NMDA Inhibits binding of glutamate with receptor Inhibits release of glutamate form presynaptic nerve terminal Opioid Strongest evidence appears to be binding of the S(+) isomer to μ receptors Monoaminergic May activate the descending inhibitory monoaminergic pathway Muscarinic Appears to act as an antagonist at muscarinic receptors Voltage gated sodium channels Mild local anesthetic-like effect Neuronal NAChR May contribute to the analgesic effect 6 KETAMINE - PHARMACOKINETICS Rapid onset of action High lipid solubility Highly unionized Poorly protein bound Increased CBF with ketamine could speed delivery of drug to the brain Brief duration of action Initially due to redistribution Large volume of distribution High HER Rapid clearance in the liver 7 KETAMINE - PHARMACOKINETICS FLOOD 8 KETAMINE - PHARMACOKINETICS Metabolism By hepatic microsomal enzymes Major pathway leads to the active metabolite norketamine ~20-30% the activity of the parent compound Ultimately hydroxylated and conjugated for urinary excretion Bioavailabliity via other routes Oral 20-30% Nasal 40-50% Tolerance with repeated dosing Chronic dosing results in induction of enzymes responsible for it’s metabolism 9 KETAMINE - PHARMACOKINETICS BARASH 10 CLINICAL USES Analgesia Greater effect on somatic than visceral pain Presumed effect via inhibition of NMDA receptors Thalamic and limbic systems Spinal nocioceptive pathways Analgesia achieved with sub-anesthetic doses 0.2 - 0.5 mg/kg IV Useful adjunct in chronic pain patients who present for surgery who may not be opioid naïve Postoperative sedation and analgesia results in: Opioid sparing effect Decreased GI side effects Dosed at 1-3 μg/kg/min IV infusion Concern with increased psychomimetic reactions 11 CLINICAL USES Induction of Anesthesia Dosing 1-2 mg/kg IV 4-8 mg/kg IM Tolerance may develop following repeated dosing Onset 30-60 seconds IV 2-4 minutes IM Duration 10-20 minutes following a single induction dose May have amnesia and disorientation for 60-90 minutes following return of consciousness 12 CLINICAL USES Indications for Ketamine Induction Hemodynamic instability Active bronchospasm Lack of IV access Need for analgesia “Inability to secure the airway” Concerns with Ketamine Induction Known coronary artery disease Severe cardiac valvular disease in which tachycardia would be harmful Elevated ICP? Emergence delerium 13 CLINICAL USES Other Considerations Small improvements in analgesia when used in the central neuraxis, but not approved for this use Does not trigger MH Sub anesthetic doses may reduce the incidence of acute opioid tolerance Potential value of low dose ketamine in depression and obsessive compulsive disorder 14 ORGAN SYSTEM EFFECTS - CNS Produces a functional disorganization of midbrain and thalamic pathways Depression of cortex and thalamic areas Stimulation of portions of the limbic system Depresses transmission of impulses in the medial medullary reticular formation Interferes with transmission of affective-emotional component of nocioception Interferes with nocioceptive central sensitization May decrease duration of pain May result in less transition to chronic pain states 15 ORGAN SYSTEM EFFECTS - CNS Ketamine produces: Increased CMRO2 Increased CBF Increased ICP Preservation of cerebrovascular responsiveness to CO2 Neuroprotection? Proposed neuroprotective effect due to NMDA receptor antagonism – unproven Question of increased apoptosis in brains of newborn animals Use in neonates questioned 16 ORGAN SYSTEM EFFECTS - CNS Emergence Reactions 10-30% incidence in adults in whom ketamine is a major portion of the anesthetic Adults > children Female > male Certain personality types (high psychotism score) Result from misperception or misinterpretation of auditory and visual stimuli Vivid dreaming Extracoporeal experience Illusions Reduced by pre or concurrent treatment with multiple other drugs Best results achieved with benzodiazipines 17 ORGAN SYSTEM EFFECTS - CNS Other Burst suppression of the EEG at high doses Nystagmus Myoclonic and other movement Evoked potentials Increased amplitude Somatosensory Decreased amplitude Auditory Visual No change in seizure threshold in epileptic patients 18 ORGAN SYSTEM EFFECTS CARDIOVASCULAR Two competing effects Direct negative inotropic effect Indirect stimulatory effect Systemic release of catecholamines Inhibition of vagal outflow Inhibition of NE reuptake at peripheral nerves and myocardium Increased NE release from post-synaptic sympathetic neurons Attenuated by: Benzodiazepines Inhaled anesthetics Propofol Beta blockade or ganglionic blockade Spinal cord transection or cervical epidural 19 ORGAN SYSTEM EFFECTS CARDIOVASCULAR Hemodynamic Effects Increased systemic BP Systolic 20-40 mmHg Diastolic somewhat less Duration 10 -20 minutes Increased pulmonary artery BP Increased heart rate Concerns Coronary artery disease Increased myocardial work and MVO2 Potentially decreased myocardial oxygen supply Pre-existing pulmonary artery hypertension Pressure ≠ Flow 20 ORGAN SYSTEM EFFECTS RESPIRATORY Minimal effect on respiratory drive Ventilatory response to CO2 maintained Brief decrease in minute ventilation following bolus dose Apnea is rare*** Upper airway muscle tone maintained Upper airway reflex relatively intact Increased salivation and tracheobronchial mucous secretion Bronchodilatory effect Drug of choice in acute bronchospasm Proposed Mechanism Increased catecholamine secretion Calcium channel blockade Inhibition of postsynaptic muscarinic receptors 21 KETAMINE – SIDE EFFECTS Emergence delirium Excessive salivation Inhibition of platelet aggregation A concern in patients with known bleeding disorders Mechanism Decreased free calcium concentration 20 inhibition of ITP Allergic reaction Rare No histamine release 22 DEXMEDETOMIDINE Preparation Mechanism of Action Pharmacokinetics Clinical Uses Organ System Effects CNS Cardiovascular Respiratory Side Effects 23 PREPARATION The S-enantiomer of medetomidine Highly specific α2 receptor agonist (α2:α1 = 1600:1) Versus Clonidine (α2:α1 = 220:1) pKa = 7.1 Highly water soluble Provided as a solution containing 100 μg/ml 24 25 MECHANISM OF ACTION – α2 AGONISM Alpha2A Effects Sedation and hypnosis Sympatholysis Analgesia Neuroprotection Hyperglycemia Diuresis Net effect is neuronal hyperpolarization Alpha2B Effects Vasoconstriction Endogenous analgesia mechanism Anti-shivering? Alpha2C Effects Feedback inhibition of adrenal catecholamine release Learning? Stress response? MECHANISM OF ACTION MILLER 26 27 MECHANISM OF ACTION Sedation Locus coeruleus Analgesia Primary site is spinal cord, but also: Supraspinal Peripheral Bradycardia Sympatholysis at the heart Hypotension Central > peripheral effects EVERS MECHANISM OF ACTION MILLER 28 29 PHARMACOKINETICS Highly protein bound (94%) Near complete hepatic biotransformation Direct glucuronidation and Metabolism by cytochrome P450 enzymes Renal excretion No effect of renal disease on pharmacokinetics Some inhibition of cytochrome P450 enzymes May slightly increase opioid concentration when given concurrently Best predicted by a three compartment model T1/2 = 2-3 hours Context-sensitive halftime 4 minutes following a 10 minute infusion 250 minutes following an 8 hour infusion CONTEXT-SENSITIVE HALF-TIME minut es 30 DEXMEDETOMIDINE - CLINICAL USES Consider the effects: Anxiolysis Sedation Analgesia Sympatholysis Decreased salivation Minimal depression of ventilation 31 DEXMEDETOMIDINE - CLINICAL USES Premedicant (preop sedation) Produces sedation and anxiolysis comparable to midazolam Greater incidence of intraoperative hypotension and bradycardia than midazolam Dosing 0.33 – 0.67 μg/kg IV 15 minutes pre-procedure 3 -4 μg/kg nasally or buccally 60 minutes pre-procedure Blunts the hemodynamic response to laryngoscopy and intubation 32 DEXMEDETOMIDINE - CLINICAL USES Sedation for Airway Management Very useful tool in the proper setting Benefits Minimal respiratory depression Difficult airway Stridor Foreign body OSA/OHS Reduces secretions in the airway Risks Pronounced sympatholysis 33 DEXMEDETOMIDINE - CLINICAL USES Sedation in the Operating Room Compared to propofol Slower onset Similar cardiorespiratory effects at equal sedation levels Longer duration Slower return of blood pressure to baseline Dosing 0.2 – 0.7 μg/kg/hour 34 DEXMEDETOMIDINE - CLINICAL USES Adjunct to General Anesthesia Reduces MAC of isoflurane by 35 -50% Improved postoperative pain control Potentially reduced nausea and vomiting Prolongs recovery when added to a propofol-based anesthetic technique Total IV Anesthesia Typically preserved respiratory function Loading dose of 1μg/kg followed by infusion of 5 – 10 μg/kg/hr 35 DEXMEDETOMIDINE - CLINICAL USES Other Uses Postop sedation Including weaning from the ventilator Additive to IV regional anesthetic Improves quality and postoperative analgesia Dosed at 0.5 μg/kg Shivering (unrelated to hypothermia) Sedation in rapid detox from opioids or cocaine withdrawal 36 ORGAN SYSTEM EFFECTS CARDIOVASCULAR Hypotension and bradycardia Central and peripheral mechanisms Central α2 agonism Imidazoline I1 receptor agonism in the medulla Attenuation of baroreceptor reflexes Peripheral α2B receptor agonism producing peripheral vasoconstriction Coronary arteries Direct vasoconstriction Increased release of nitric oxide Myocardial energetics Overall typically improved However in some patients hypotension may produce ischemia Mechanism of improved myocardial oxygen balance Decreased myocardial oxygen demand Decreased coronary perfusion pressure 37 ORGAN SYSTEM EFFECTS CARDIOVASCULAR MILLER 38 ORGAN SYSTEM EFFECTS - CNS Alpha2 agonism produces: Vasoconstriction in the cerebral vessels and a decrease in cerebral blood flow No change in CMRO2 CBF therefore becomes uncoupled from CMRO2 Despite this Dexmedetomidine appears to provide a neuroprotective effect in cerebral ischemia Benefit reversed by α2 antagonism 39 ORGAN SYSTEM EFFECTS Endocrine Blunts the neuroendocrine stress response to surgery resulting in: Decreased release of cortisol, vasopressin, epi, NE Increased release of growth hormone As an imidazoline compound blocks steroid formation, but only at concentrations 100-1000x what is used clinically Renal Diuretic effect by opposing the action of vasopressin May produce a renoprotective effect in ischemic or contrast-induced injury 40 SCOPOLAMINE Structure and PK Clinical Uses Sedation Antisialagogue Antiemetic Side Effects 41 SCOPOLAMINE Naturally occurring anticholinergic alkaloid derived from the belladonna plant Lipid soluble, tertiary amine Large volume of distribution Relatively low clearance Primarily hepatic T1/2 ~ 4.5 hours Oral bioavailabilty unpredictable so usage limited via this route 42 SCOPOLAMINE – CLINICAL USES Sedation ~100x the potency of atropine in the reticular activating system Also produces some amnesia at sedative doses Enhances the sedation produced by other drugs Typical dose = 0.3 – 0.5 mg IV or IM Antisialagogue ~3x the potency of atropine as an antisialogogue Less likely to produce tachycardic changes Dosed as above Antiemetic Transderm patch 43 SCOPOLAMINE FLOOD 44 SCOPOLAMINE – SIDE EFFECTS Mydriasis and Cycloplegia May interfere with drainage of aqueous humor Central Anticholinergic Syndrome Wide range of symptoms Restlessness and hallucinations to somnolence and unconsciousness DAWK Management Physostigmine 15-60 μg/kg IV repeated at 1-2 hour intervals Atropine fever Failure of thermoregulatory sweating Particularly problematic in infants and small children Management Physostigmine dosed as above 45 DROPERIDOL Background Organ System Effects CNS Respiratory Cardiovascular Clinical Uses Neuroleptanalgesia or anesthesia PONV Prophylaxis 46 DROPERIDOL - BACKGROUND A butyrophenone, derived from haloperidol Previously used in combination with fentanyl to produce neuroleptanalgesia or neuroleptanesthesia with the addition of an inhaled agent to improve amnesia Widely used as an antiemetic prior to a 2001 Black Box warning relating to prolonged QT interval Validity of this is and the associated case reports that led to it have been challenged Continued to see widespread use as an antiemetic in Europe and usage is again increasing in the United States 47 ORGAN SYSTEM EFFECTS - CNS Produce submaximal inhibition of GABAA receptors and full inhibition of α2 -acetylcholine receptors, producing an imbalance between dopamine and acetylcholine Results in CNS depression with: Sedation Apparent tranquility Cataleptic immobility Occasional extrapyramidal symptoms In animals: Uncoupling of CBF and CMRO 2 with: Marked reduction in CBF No change in CMRO2 48 ORGAN SYSTEM EFFECTS Respiratory Minimal effect on respiration when used alone Cardiovascular May delay myocardial repolarization and prolong the QT interval Dose dependent Likely only of consequence in a patient with other potential causes of prolonged QT Mild hypotension secondary to vasodilation with blockade of α2 receptors Little direct effect on myocardial contractility 49 DROPERIDOL – CLINICAL USES Neuroleptanalgesia Combination of a butyrophenone and an opioid Innovar = droperidol + fentanyl Goal Detached, pain-free state of immobilization Suppression of autonomic reflexes Cardiovascular stability Amnesia (in some) Neuroleptanesthesia Addition of an inhaled anesthetic improved amnesia Most often nitrous oxide 50 DROPERIDOL – CLINICAL USES Antiemetic Primary current use Dosage: 10-20 μg/kg IV (typically 0.625mg to 1.25 mg) Given at the start of an anesthetic reduced N/V by 30% Antiemetic efficacy equal to ondansetron Efficacy improved when used in combination with serotonin antagonists or dexamethasone, or both 2007 International Consensus Panel recommended droperidol as a first-line antiemetic despite the warning Sedation Routine preop sedation – not so much Agitated or psychotic patients - maybe 51 SOURCES Flood Stoelting’s Pharmacology and Physiology in Anesthetic Practice 6th edition. 2022 Barash Clinical Anesthesia 8th edition. 2017 Evers Anesthetic Pharmacology 2nd edition. 2011 Miller Miller’s Anesthesia 9th edition. 2020 52