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INTRAVENOUS SEDATIVE - HYPNOTICS NRAN 80424 SPRING 2024 RON ANDERSON, M.D. 1 KEY POINTS • Propofol, the most commonly used induction agent, increases the affinity of the GABA A receptor for GABA. In higher concentrations it may directly activate the receptor. • After prolonged propofol infusion a...

INTRAVENOUS SEDATIVE - HYPNOTICS NRAN 80424 SPRING 2024 RON ANDERSON, M.D. 1 KEY POINTS • Propofol, the most commonly used induction agent, increases the affinity of the GABA A receptor for GABA. In higher concentrations it may directly activate the receptor. • After prolonged propofol infusion awakening occurs rapidly due to a clearance which exceeds the rate of return of drug from the slow peripheral compartment (fat) to the central compartment. • Propofol is unique in having distinct antiemetic properties. • Propofol and midazolam are equally effective in producing memory impairment at similar sedation levels. • Of the induction agents, propofol produces the greatest degree of hypotension and apnea. • Etomidate provides unequaled cardiovascular stability as an induction agent. 2 KEY POINTS • A significant disadvantage to the use of etomidate, particularly as an infusion, is adrenal suppression. • The benzodiazipines have five principal effects: anxiolysis, sedation, anticonvulsant activity, skeletal muscle relaxation, and amnesia. • The barbiturates act primarily at the GABA A receptor, enhancing it’s affinity for GABA and, at high doses, directly activating the receptor. • Awakening from the barbiturates occurs prior to return of normal respirations and respiratory drive. • Ketamine, a drug with intrinsic analgesic properties produces a dissociative state. • The dominant cardiovascular effect of ketamine, in a patient with an intact autonomic nervous system and adequate catecholamine stores, is hypertension and tachycardia. 3 KEY POINTS • Dexmedetomidine, a potent α2 agonist, inhibits release of norepinephrine from the locus coeruleus. • Dexmedetomidine, as an adjunct to general anesthesia, markedly reduces MAC but is associated with a high incidence of bradycardia. 4 OUTLINE • Properties of the Ideal Anesthetic Agent • GABA Agonist Sedative-Hypnotics • • • • Propofol Etomidate Benzodiazipines Barbiturates • Non-GABA Agonist Sedative-Hypnotics • • • • Ketamine Dexmedetomidine Scopolamine Droperidol 5 PROPERTIES OF THE IDEAL ANESTHETIC • Drug compatibility and stability in solution. • Lack of pain on injection, venoirritation, or local tissue damage from extravasation. • Low potential to release histamine or precipitate hypersensitivity reactions. • Rapid, smooth onset of hypnosis without excitatory activity. • Rapid metabolism to pharmacologically inactive metabolites. • Steep dose-response curve to enhance titratability and minimize accumulation. • Lack of acute cardiovascular and respiratory depression. • Decreases CMRO2 and intracranial pressure. • Rapid, smooth return of consciousness and cognitive skills with residual analgesia. • Absence of postoperative nausea and vomiting, amnesia, psychomimetic reactions, dizziness, headache, or prolonged sedation. 6 MOST COMMONLY USED INDUCTION AGENTS • Propofol • Etomidate • Ketamine • Barbiturates • Thiopental • Methohexital • Similarities • All have rapid uptake by the brain and therefore rapid onset • All have short duration following a bolus dose • Due to redistribution from the central compartment to peripheral tissues • All undergo extensive hepatic biotransformation • All except thiopental and etomidate are appropriate for maintenance infusion • Thiopental due to it’s low hepatic extraction ratio • Etomidate due to inhibition of cortisol synthesis 7 GABA AGONIST SEDATIVEHYPNOTICS PROPOFOL ETOMIDATE BENZODIAZEPINES BARBITURATES 8 PROPOFOL Preparations Mechanism of Action Pharmacokinetics Clinical Uses Organ System Effects CNS Cardiovascular Pulmonary Hepatic and Renal IOP Coagulation Other Side Effects 9 10 PROPOFOL • First clinical trials in 1977 • 2,6-diisopropylphenol • An oil at room T0 • Insoluble in aqueous solution • Highly lipid soluble • Stable at room temperature • Insensitive to light • May be diluted in D5W PROPOFOL PREPARATIONS • Initially suspended in Cremaphor EL • Problem with anaphylactoid reactions • Now provided in an emulsion of: • • • • 1% propofol 10% soybean oil 2.25% glycerol 1.2% purified egg phosphatide • Requires the presence of a preservative to prevent bacterial growth. • Disodium edetate (Diprivan) pH adjusted to 7.0-8.5 with addition of sodium hydroxide • Sodium metabisulfite (Generic) ph 4.5-6.4 • Other formulations • 2% formula • Ampofol decreased lipid formula • Fospropofol (Aquavan) a prodrug 11 PROPOFOL MECHANISM OF ACTION • Decreases the rate of dissociation of GABA from the GABAA receptor • Increases duration of GABA–activated opening of chloride channel • Hyperpolarizes the postsynaptic cell membrane • Higher concentrations thought to directly activate GABAA receptor channels Also • • • • Increased affinity of glycine receptor for glycine Inhibition of NMDA receptors Ion channel blocking of nicotinic acetylcholine receptors in the brain Inhibition of lysophosphatidate signaling in lipid mediator receptors 12 PHARMACOKINETICS OF PROPOFOL • Hysteresis is minimal • Initial termination of action is rapid and results from redistribution of drug out of the central (or effect site) compartment • Clearance exceeds hepatic blood flow • High HER drug • Little change in propofol pharmacokinetics with hepatic or renal dysfunction • Tissue uptake and elimination in the lungs contributes to the rapid clearance • Excreted by kidneys • Elimination half life is prolonged due to slow release of drug from the slow peripheral compartment • Infusions up to 8 hours duration result in a context-sensitive half-time of < 40 minutes • Crosses the placenta but rapidly cleared from the fetal circulation 13 PHARMACOKINETICS OF PROPOFOL FLOOD BARASH 14 PROPOFOL PHARMACOKINETICS • Rapid decline in blood levels following bolus due to: • Redistribution • Elimination • Clearance is high relative to other induction agents • Propofol 30-60 ml/kg/min (20-30 ml/kg/min) • Etomidate 10-20 ml/kg/min • Ketamine 16-18 ml/kg/min IV Bolus RAPID PERIPHERAL COMPARTMENT (V2) k1 2 k1 CENTRAL COMPARTMENT (V1) 3 k2 k3 1 1 SLOW PERIPHERAL COMPARTMENT (V3) k1 0 15 PHARMACOKINETICS OF PROPOFOL • Best described with a three compartment model in which k10 is very high, but k31 is very low. • Clearance is very high • Elimination half-life 0.5-1.5 hours (4-23 hours) • A compartment exists which only very slowly releases propofol back into the central compartment • Return of small amounts of propofol from this peripheral compartment doesn’t interfere with awakening from a bolus dose or infusion IV Bolus RAPID PERIPHERAL COMPARTMENT (V2) k1 2 k1 CENTRAL COMPARTMENT (V1) 3 k2 k3 1 1 SLOW PERIPHERAL COMPARTMENT (V3) k1 0 16 Cardiac output Propofol concentration tim e 17 Cardiac Output MAP/CO Drug Level time 18 CLINICAL USES • Induction of anesthesia • Rapid induction and more complete awakening than the other induction agents • Dosing • Healthy adult 1.5-2.5 mg/kg • Unconsciousness at 2-6 μg/ml • Awakening at 1-1.5 μg/ml • Morbidly obese dosed based on lean body weight • Children require increased dose 2-3 mg/kg • Elderly require a 25-50% reduction in dose • Maintenance of anesthesia • Dosing • 100-300 μg/kg/min (100-200 μg/kg/min) • Advantages • Rapid awakening • Minimal residual sedation • Reduced postoperative N/V 19 DOSING VARIABLES • Females • Increased volume of distribution • Increased clearance • Elimination half life unchanged from males • Elderly • Decreased central compartment volume • Decreased clearance • Younger children • Increased central compartment volume • Increased clearance 20 CLINICAL USES • Sedation • Highly titratable due to: • Rapid effect-site equilibration • Short context-sensitive half-time • Dosing • Typically 25-100 μg/kg/min • SEDASYS • Computer assisted sedation system approved by the FDA for use in colonoscopy and EGD without the requirement for a trained anesthesia provider 21 CLINICAL USES – NON-HYPNOTIC • Antiemetic Effect • Postoperative nausea and vomiting is reduced when used as a component of any anesthetic technique • Postop N/V in PACU • Bolus dose 10-15mg + infusion at 10 μg/kg/min • Useful in prevention and treatment of chemotherapy related N/V • When used for induction and maintenance of anesthesia, as efficacious as ondansetron • Mechanism • Decreased serotonin levels in area postrema likely secondary to action on GABA receptors 22 CLINICAL USES – NON-HYPNOTIC • Antiemetic Effect • Postoperative nausea and vomiting is reduced when used as a component of any anesthetic technique • Postop N/V in PACU • Bolus dose 10-15mg + infusion at 10 μg/kg/min • Useful in prevention and treatment of chemotherapy related N/V • When used for induction and maintenance of anesthesia, as efficacious as ondansetron 23 CLINICAL USES – NON-HYPNOTIC • Antipruritic Effect • Effective in treatment of neuraxial opioid associated pruritis • Dose 10 mg • Anticonvulsant Activity • Termination of generalized seizure activity may be achieved with induction doses • Will shorten the duration of seizure activity with ECT • Attenuation of Bronchoconstriction • Appropriate for use in asthmatic patients • Decreased vagally-mediated bronchoconstriction seen with Diprivan (EDTA preservative), but not with the generic form containing metabisulite preservative • Analgesia • No benefit with acute nocioceptive pain, but may have use in neuropathic pain states 24 ORGAN SYSTEM EFFECTS - CNS • CMRO2 • ~36% reduction possible • Cerebrovascular autoregulation maintained • CBF • ICP • Normal baseline ICP ~30% decrease • Elevated baseline ICP ~ 30 – 50% decrease • Note: Marked drops in systemic blood pressure from large doses of propofol may impair cerebral perfusion pressure despite the reduction in ICP. 25 ORGAN SYSTEM EFFECTS - CNS • Effect on evoked potentials • Somatosensory • Decreased • Motor • Decreased • Auditory • No effect • Intraocular pressure • 30 – 40% decrease • Induction drug of choice in preventing an increase in IOP due to succinylcholine and intubation • Degree of Memory Impairment at equal sedation levels • Propofol = Midazolam > Thiopental > Fentanyl (0) 26 NEUROPROTECTION • Propofol titrated to EEG burst suppression provides cerebral protection following incomplete ischemia: • Equivalent to thiopental • Equivalent to halothane • Superior to fentanyl • Propofol at levels sufficient to produce sedation decreased infarct size when started within 1 hour of an ischemic event. • Studies on spinal cord injury • Thiopental – reduced lipid peroxidase with improved ultrastructure • Propofol – reduced lipid peroxidase with no sparing of ultrastructure injury • Mechanism • Antioxidant activity, resulting in free radical scavenging and subsequently reduced free radical induced lipid peroxidation. 27 ORGAN SYSTEM EFFECTS CARDIOVASCULAR EVERS 28 ORGAN SYSTEM EFFECTS CARDIOVASCULAR • Decreased systemic blood pressure • Direct myocardial depression • Alteration in sympathetic drive to the heart • Vasodilation • Arterial and venous • Reduction in sympathetic activity • Direct effect on vascular smooth muscle • Interference with intracellular Ca++ mobilization • Inhibition of prostacyclin synthesis in endothelium • Activation of K+ ATP channels • Increased production of nitric oxide • Possibly related to the lipid emulsion rather than the propofol • Blunted tachycardic response to hypotension 29 ORGAN SYSTEM EFFECTS CARDIOVASCULAR • Propofol induced hypotension is dose dependent, more common following bolus dosing than infusion, and is exaggerated in: • Elderly patients • Decreased LV function • Hypovolemic states • Bradycardia and asystole have occurred following propofol induction • • • • Risk of bradycardic death with propofol ~ 1.4/100,000 Likely related to a greater decrease in sympathetic tone than parasympathetic Increased incidence of the oculocardiac reflex during pediatric strabismus surgery Tachycardic response to atropine attenuated during propofol anesthesia • May require a direct acting beta agonist 30 ORGAN SYSTEM EFFECTS CARDIOVASCULAR • May suppress SVT • Not typically drug of first choice in EP lab • Preservation of myocardial oxygen supply-demand • Decreased myocardial blood flow • Decreased myocardial oxygen consumption • Ischemic preconditioning and postconditioning • May provide some myocardial protection following ischemia and reperfusion • Not as effective in preconditioning as sevoflurane • Dose-dependent effect in pre and postconditioning which may complement the use of sevoflurane 31 ORGAN SYSTEM EFFECTS RESPIRATORY EVERS 32 ORGAN SYSTEM EFFECTS RESPIRATORY • Dose dependent depression of ventilation • 25-40% of apnea following induction • Decreased tidal volume and + effect on rate with infusion • Decreased ventilator response to hypoxemia and hypercarbia • May produce bronchodilation in COPD patients • Reduces both vagally mediated and methacholine induced bronchoconstriction • In the absence of metabisulfite preservative • No inhibition of hypoxic pulmonary vasoconstriction 33 34 OTHER EFFECTS or LACK THEREOF • No potentiation of the neuromuscular blockers • Not a trigger for malignant hyperthermia • Potential for anaphylactoid reactions • Antiemetic effect • Potential for addiction • Sense of well being • Accumulation of dopamine in nucleus accumbens • Inhibition of phagocytosis and killing of S. aureus and E. coli • Despite the addition of preservative, strict aseptic technique required • Tolerance may develop, but not acutely • May temporarily abolish Parkinson’s tremor PROPOFOL SIDE EFFECTS • Pain on injection • Etomidate = methohexital > propofol > thiopental • Myoclonus /Opisthotonus • Etomidate = methohexital > propofol > thiopental • Hallucinations / sexual fantasies • Inhibition of phagocytosis and bacterial killing • Potential for bacterial growth due to emulsion 35 RECOMMENDATIONS ON HANDLING OF PROPOFOL • Aseptic technique • Disinfection of ampule or vial with isopropyl alcohol • Draw up in sterile syringe immediately after opening • Contents of an opened ampule should be discarded after 6 hours • In the ICU the tubing and unused propofol should be discarded after 12 hours 36 PROPOFOL INFUSION SYNDROME • Associated with infusion at > 75 μg/kg/min for > 24 hours • Clinical features: • • • • • • • Severe, refractory bradycardia Cardiomyopathy with acute cardiac failure Metabolic acidosis Skeletal myopathy Hyperkalemia Hepatomegaly Lipemia 37 PROPOFOL INFUSION SYNDROME • Proposed mechanism • Presumed to be due to poisoning of the electron transport chain by propofol or a metabolite which results in inadequate oxidation of long chain fatty acids • Differential Diagnosis • Metabolic acidosis of other origin • Hyperchloremic metabolic acidosis 38 FOSPROPOFOL (AQUAVAN) • Water soluble prodrug rapidly metabolized by alkaline phosphatase in the blood and mainly in tissues. • Initially proposed as a safer way for non-anesthesia providers to sedate patients for endoscopy. • Approved with the warning “Fospropofol should be administered only by persons trained in the administration of general anesthesia and not involved in the conduct of the surgical/diagnostic procedure”. 39 FOSPROPOFOL ADVANTAGES • Not prepared in a lipid emulsion • No burning on injection • No lipid load • Reduced contamination issues • Prodrug • Rate of increase in plasma concentration less dependent on rate of injection and more on hydrolysis of the prodrug to the active form. 40 FOSPROPOFOL DISADVANTAGES • Prodrug • Delayed systemic appearance of propofol from hydrolysis • Non-linear relationship between bioavailability and dose • May complicate titration of the drug • May lead to dose stacking • High interpatient variability • Lipid-free propofol derived from Fospropofol more potent and has a larger volume of distribution than lipid-bound propofol • Steep concentration-response curve • Titration critical and more difficult due to facts above 41