QG 1 IV SEDATIVE HYPNOTICS-STUDENT.pptx

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 DOSE STACKING Propofol Fospropofol ETOMIDATE Preparation Mechanism of Action Pharmacokinetics Clinical Uses Organ System Effects CNS Cardiovascular Respiratory Side Effects Myoclonus Adrenocortical Suppression 43 ETOMIDATE • An imidazole structure which is water soluble in an acidic pH and lipid soluble at physiologic pH • Preparations • Originally prepared in propylene glycol producing • Pain on injection • Venous irritation • Now also prepared in a lipid emulsion • Has essentially eliminated pain and venous irritation • Oral form for transmucosal delivery 44 ETOMIDATE MECHANISM OF ACTION • Administered as the R-isomer which has 5x the potency of the S-isomer • Mechanism • Enhances the affinity of the GABAA receptor for GABA • At supra-clinical doses may activate the GABAA receptor directly • No other known mechanisms 45 ETOMIDATE PHARMACOKINETICS  Best described by a three compartment model  Large volume of distribution  Termination of action of initial effect is redistribution  Rapidly cleared in the liver by ester hydrolysis (Clearance 18-25 ml/kg/min)  Short context-sensitive half-time  ~75% protein bound 46 ETOMIDATE CLINICAL USES • Induction of anesthesia • 0.2-0.4 mg/kg • May be of particular benefit in these settings: • • • • • Compromised cardiovascular status Questionable intravascular volume status Elevated ICP Electroconvulsive therapy Mapping of epileptogenic foci • Maintenance of anesthesia • Unlikely you will see it used in this setting due to problems with adrenocortical suppression 47 ORGAN SYSTEM EFFECTS - CNS • Improved cerebral oxygen supply-to-demand ratio • Cerebral vasoconstriction • Cerebral blood flow reduced ~ 35% • CMRO2 reduced ~45% • Maintained or improved cerebral perfusion pressure • Little to no reduction in MAP • Reduction in ICP due to decreased cerebral blood flow 48 ORGAN SYSTEM EFFECTS - CNS • Activation of epileptogenic foci • Useful in mapping seizure foci in ablative procedures • May prolong seizure duration in electroconvulsive therapy • Probably best avoided in a patient with a history of seizure disorder • Amplification of SSEP signal • Might be useful in the face of questionable SSEP recording • But consider the consequences 49 ORGAN SYSTEM EFFECTS CARDIOVASCULAR 50 ORGAN SYSTEM EFFECTS CARDIOVASCULAR • Due to lack of effect on the sympathetic nervous system and baroreceptor function, induction doses of etomidate produce minimal changes in: • • • • Heart rate Stroke volume Cardiac output Mean arterial pressure – somewhat greater, but still modest, decrease • Useful induction agent in: • Patients with poor cardiovascular function • Settings where any reduction in BP may be significant, e.g. severe cerebrovascular disease • Elevated ICP with questionable volume status • Does not effectively blunt the hemodynamic response to laryngoscopy and intubation 51 ORGAN SYSTEM EFFECTS RESPIRATORY • Less depression of ventilation than the other induction agents consisting of: • Decreased tidal volume • Increased respiratory rate • Less blunting of the ventilatory response to CO2 • Safe to use in a patient with reactive airways disease • Does not induce histamine release 52 53 ORGAN SYSTEM EFFECTS - ADRENAL • Much greater potency (20x) in steroid synthesis inhibition than as a sedative-hypnotic • Acts through inhibition of 11βhydroxylase • Suppression of adrenal steroidogenesis • Cortisol and mineralocorticoids • A single induction dose can suppress cortisol production for up to 72 hours • CORTICUS study MILLE R ETOMIDATE – SIDE EFFECTS • Excitatory Activity • Myoclonus • • • • Brief involuntary muscle contraction Due to subcortical disinhibition that normally suppresses extrapyramidal movements Seen in up to 60% of etomidate inductions Reduced by pretreatment with narcotic or benzodiazepine • Hiccupps • Pain on injection • Presumably related to the propylene glycol preparation • Eliminated with the lipid formulation • PONV • High incidence, especially when given with narcotics for outpatient procedures • Reduced somewhat with the lipid emulsion 54 ETOMIDATE DERIVATIVES (FUTURE) • Methoxycarbonyletomidate (MOC) • Hypnotic potency similar to etomidate • Shorter duration due to rapid esterase metabolism • Initial studies indicate it may not inhibit steroidogenesis • Carboetomidate • Consists of a pyrrole ring rather than an imidazole • In animals, adrenal suppression reduced to 1/1000th of etomidate 55 BENZODIAZIPINE S Structure Mechanism of Action Pharmacokinetics Clinical Uses Organ System Effects CNS Cardiovascular Respiratory Musculoskeletal Midazolam Diazepam Lorazepam Flumazenil 56 STRUCTURE • Benzene ring fused to a seven-membered diazepine ring BARASH 57 UNIQUE STRUCTURE OF MIDAZOLAM • Midazolam is distinct from the other benzodiazepines in having a substituted imidazole ring • Need to clear up a misconception that has been taught for years Lipid Soluble Water Soluble 58 THE GABAA RECEPTOR EVERS 59 BENZODIAZEPINES AT THE GABAA RECEPTOR 60 • Benzodiazipine bound by GABAA receptor facilitates binding of GABA by receptor EVERS MECHANISM OF ACTION • Enhance the affinity of the GABAA receptors for GABA, resulting in: • Increased opening of the chloride channels • Increased chloride conductance • Hyperpolarization of the postsynaptic cell membrane • Greater resistance to excitation 61 MECHANISM OF ACTION EVERS 62 63 MOA - GABAA RECEPTOR SUBTYPES • α1 Receptors • Sedation • Amnesia • Anticonvulsant properties • α2 Receptors • Anxiolysis • Muscle relaxation EVERS MOA - RECEPTOR OCCUPANCY • Drug effect is a function of receptor occupancy • < 20% anxiolysis • 30-50% sedation • > 60% unconsciousness 64 PHARMACOKINETICS OF THE BENZODIAZIPINES • Protein binding • All are highly protein bound • Volume of Distribution • Similar • Lorazepam slightly greater than the others despite it’s lower lipid solubility • Clearance • Midazolam > Lorazepam > Diazepam 65 FLOOD EFFECT OF AGE ON MIDAZOLAM REQUIREMENT MILLER 66 CONTEXT-SENSITIVE HALF-TIMES BARASH 67 METABOLISM • Midazolam • Hepatic oxidative hydroxylation of imidazole ring - rapid • Active metabolite • Diazepam • Hepatic oxidative N-demethylation – slower • Profoundly affected by cirrhosis and inhibition of cytochrome P-450 • Active metabolites • Lorazepam • Primarily hepatic glucuronidation • Unaffected by cirrhosis and inhibition of cytochrome P-450 • No active metabolite 68 INDIVIDUAL BENZODIAZEPINES Midazolam Diazepam Lorazepam Flumazenil 69 MIDAZOLAM - PHARMACOKINETICS • Oral Administration • Rapidly absorbed from GI tract • Undergoes first-pass metabolism • Short duration relative to other benzodiazepines • Rapid redistribution from central compartment • High hepatic clearance • Prolonged elimination in elderly • Decreased hepatic blood flow and enzyme activity? • Increased volume of distribution • And Obese • Increased volume of distribution 70 MIDAZOLAM - PHARMACOKINETICS • Metabolism • Rapid via hepatic oxidative hydroxylation of imidazole ring • Primary metabolite is 1-hydroxymidazolam • ~50% activity of parent compound • Conjugated to 1-hydroxymidazolam glucuronide for subsequent clearance by kidneys • May accumulate in renal insufficiency 71 MIDAZOLAM - PHARMACOKINETICS • Metabolism • Delayed in presence of drugs which inhibit cytochrome P-450 • • • • Cimetidine Erythromycin Calcium channel blockers Some anti-fungals • Hepatic clearance of midazolam is: • 10x greater than that of diazepam • 5x greater than that of lorazepam 72 DIAZEPAM - PHARMACOKINETICS • Insoluble in water so dissolved in organic solvents • Propylene glycol • Sodium benzoate • Rapid absorption from GI tract • Rapid uptake to effect site • Rapid redistribution 73 DIAZEPAM - PHARMACOKINETICS • Metabolism • Hepatic oxidative reduction of methylene group • Principle metabolites • Desmethyldiazepam* • Only slightly less potent than diazepam • Oxazepam* • Temazepam – to a lesser extent 74 DIAZEPAM - PHARMACOKINETICS • Metabolism • Inhibition of cytochrome P-450 enzymes prolongs the elimination half-time of both: • Diazepam and • Desmethyldiazepam • Cirrhosis • Prolonged elimination half-time due to: • Decreased protein binding with increased Vd • Decreased hepatic blood flow 75 LORAZEPAM - PHARMACOKINETICS • Metabolism • Via hepatic glucuronidation to inactive metabolites which are excreted by the kidneys • Relatively unaffected by inhibition of cytochrome P-450 or changes in hepatic function 76 LORAZEPAM - PHARMACOKINETICS • Unique Features • Lower lipid solubility results in: • Delayed onset of effect in CNS • Despite higher clearance and similar Vd to diazepam, effects last longer due to higher affinity of lorazepam for GABA receptor • May result in delayed emergence from sedation and prolonged amnesia 77 BENZODIAZEPINES – CLINICAL USES • Preoperative Anxiolytic • Oral premedication in adults • Diazepam 5–15 mg • Oral premedication in children • Midazolam 0.25-1.0 mg/kg • Onset 10-20 minutes (0.5 mg/kg) • Nasal Premedication • Midazolam 0.2 mg/kg 78 ORAL MIDAZOLAM IN CHILDREN FLOOD 79 BENZODIAZEPINES – CLINICAL USES • IV SEDATION • Typically well-preserved hemodynamic and respiratory function. • Caution when combined with other drugs • Amnesia > Sedation • Midazolam vs Propofol for sedation MIDAZOLAM PROPOFOL Greater Hemodynamic Stability Less Delayed Emergence More rapid Reliable Amnesia Reliable Increased Context Sensitive T1/2 Shorter 80 MIDAZOLAM DOSING GUIDELINES Midazolam Diazepam Lorazepam Induction 0.05-0.15 mg/kg 0.3-0.5 mg/kg 0.1 mg/kg Maintenance 0.05 mg/kg prn 1 mcg/kg/min 0.1 mg/kg prn 0.02 mg/kg prn Sedation 0.5-1 mg repeated 0.07 mg/kg IM 2 mg repeated 0.25 mg repeated MILLER 81 BENZODIAZEPINES – CLINICAL USES • Induction and Maintenance • Midazolam • Slower onset than thiopental or propofol, but: • Reliable amnesia • Dose required and Time of Onset affected by: • • • • Premedication Concurrent anesthetic agents ASA Physical Status classification Age 82 MIDAZOLAM - ONSET OF INDUCTION FLOOD 83 BENZODIAZEPINES – CLINICAL USES • Other Uses • Termination of seizure activity • Prophylaxis or management of delirium tremens • Skeletal muscle relaxation or lumbar disc disease • Insomnia • Anxiety • Nausea / Vomiting Prophylaxis 84 FIVE PRINCIPAL PHARMACOLOGIC EFFECTS • Anxiolysis • Sedation • Anticonvulsant • Skeletal muscle relaxation • Amnesia 85 ORGAN SYSTEM EFFECTS - CNS • CBF and CMRO2 • Both decreased and remain coupled Benzodiazepines can not produce an isoelectric EEG • Cerebral vasculature remains responsive changes in CO 2 • Little or no change in ICP • Generally considered to be an acceptable induction agent in patients with reduced intracranial compliance 86 ORGAN SYSTEM EFFECTS - CNS • Potent anticonvulsant • Management of status epilepticus • Increase seizure threshold to local anesthetic exposure • Paradoxical excitement can rarely occur • Neuroprotective activity not documented in humans 87 ORGAN SYSTEM EFFECTS CARDIOVASCULAR • Modest decrease in blood pressure • Due primarily to decreased SVR • Midazolam = Thiopental > Diazepam • Cardiac output well maintained • Does not prevent the hemodynamic response to laryngoscopy and intubation • Ceiling effect 88 ORGAN SYSTEM EFFECTS – RESPIRATORY • Produce a dose-related central respiratory depression • Ventilatory response to CO2 decreased and curve shifted to right • Decreased hypoxic drive to ventilation • Exacerbated with: • • • • COPD Concomitant use of other respiratory depressants Old age Debilitating disease • Apnea • In large doses may produce a brief apnea • Decreased muscular tone in the upper airway predisposing to obstruction 89 ORGAN SYSTEM EFFECTS MUSCULOSKELETAL • Skeletal muscle relaxation occurs via interaction of benzodiazepines with spinal internuncial neurons, not at the neuromuscular junction. 90 REMIMAZOLAM • New ultra-short acting benzodiazepine metabolized by tissue esterases. • Submitted for FDA approval summer 2019 – to my knowledge it has not yet been approved. Recent study: • 20 adult males • Infusion started at 5 mg/min x 5 minutes, followed by 3 mg/min x 15 minutes, then 1 mg/min x 15 minutes • Loss of consciousness occurred at 5 minutes • Fully alert ~ 19 minutes after infusion stopped • Steady state volume of distribution of only 35 liters • Context-sensitive half-time following a 4 hour infusion estimated at 6.8 minutes versus > 60 minutes for midazolam 91 FLUMAZENIL 92 FLUMAZENIL • Benzodiazepine receptor ligand with: • High receptor affinity • Minimal intrinsic effect • A competitive antagonist • Prevents or reverses all effects of the other benzodiazepines, in a dosedependent manner 93 FLUMAZENIL • Metabolism • Rapid clearance by hepatic microsomal enzymes • Three known metabolites with unknown activity • Uses • Reversal of residual benzodiazepine-induced sedation • Suspected benzodiazepine overdose • Dosage • 0.2 -0.5 mg incrementally to a total dose of 3.0 mg 94 BARBITURATES Mechanism of Action History Pharmacokinetics Organ System Effects CNS Cardiovascular Respiratory Contraindications Side Effects/Complications 95 BARBITURATES MECHANISM OF ACTION • GABAA • Low concentrations • Enhance effect of GABA • Decrease rate of dissociation of GABA from receptor • High concentrations • Mimic effect of GABA • Directly activate opening of the chloride channels • Also act at: • Glutamate receptors • Adenosine receptors • Neuronal NAChRs 96 HISTORY OF THE BARBITURATES 97 • 1864 - Barbituric acid synthesized by Adolph von Baeyer • No sedative properties • 1903 – Barbital synthesized by Fischer and von Mering • 1st Barbiturate with sedative properties • Very long acting and very popular as a sedative • 1920 – Somnifen • 1st Intravenous barbiturate • 1921 -1st Cinical use in Labor and Delivery • 1924 -1st Use in surgery • 1929 – Amobarbital • Intermediate-acting barbiturate widely used in North America • 1932 – Hexobarbital • 1st Ultrashort-acting barbiturate • Saw a great deal of use in Europe, but not North America • 1935 – Multiple thiobarbiturates synthesized • 1935 – Thiopental first used clinically by Ralph Waters and John Lundy • Became the preferred intravenous barbiturate due to its: • Rapid onset • Short duration • Lack of excitatory effects Thiopental…………. ”the ideal form of euthanasia in war surgery” 98 99 ULTRASHORT ACTING BARBITURATES THIOPENTAL 2.5% solution METHOHEXITAL 1% solution STRUCTURE-ACTIVITY RELATIONSHIPS Pos 1 Pos 2 Group Example Onse t Duration Problem H O Oxybarbiturates Phenobarb Slow Prolonged Excitation O Methylated Oxybarbiturates Methohexita l Rapid Short Excitation Rapid Fairly Short Rapid Very Short CH3 H CH3 S Thiobarbiturates S Methylated Thiobarbiturates Thiopental T1/2α min Clearance ml/min/kg 6 8.2 - 12 2-7 2.2 – 3.5 Extreme Excitation Adapted from MILLER 100 BARBITURATE METABOLISM • Hepatic metabolism • Primarily by oxidation • Metabolism may be influenced by drugs which induce hepatic oxidative microsomes and barbiturates may, in turn, induce these same hepatic microsomes. • Basis of recommendation that barbiturates be avoided in porphyria. • High dose thiopental may lead to accumulation of the active metabolite pentobarbital. 101 PHARMACOKINETICS • Described by either: • Physiologic models • Compartment models • In either case, termination of action of a bolus dose results from redistribution of drug out of the central circulation(compartment). IV Bolus RAPID PERIPHERAL COMPARTMENT (V2) k1 2 k1 CENTRAL COMPARTMENT (V1) 3 k2 k3 1 1 SLOW PERIPHERAL COMPARTMENT (V3) k1 0 102 CONTEXT SENSITIVE HALF TIMES • Time necessary for effect site(central compartment) concentration to decrease by 50% in relation to the duration of drug infusion. • Barbiturates, particularly thiopental, (as compared to methohexital) are extremely context sensitive. • Thiopental • Multiple bolus dosing or prolonged infusion results in saturation of clearance mechanism and a shift from first-order to zero-order kinetics. • First-order = constant fraction of drug cleared over time • Zero-order = constant amount of drug cleared over time 103 BARBITURATES vs PROPOFOL Drug Distribution T1/2 (min) Protein Binding (%) Volume of Distribution (L/kg) Clearance (mL/kg/ min) % Metabolized at Initial Awakening Thiopental 2–4 85 2.5 3.4 18 Methohexital 5–6 85 2.2 11 38 Propofol 2–4 98 2 - 10 20 - 30 70 Adapted from BARASH and EVERS 104 BARBITURATE DOSING • Thiopental induction doses • Adult 3-5 mg/kg • Child 5-6 mg/kg • Infant6-8 mg/kg • These doses must be reduced in: • • • • • • Premedicated patients Pregnancy Hypovolemia Elderly Decreased volume of central compartment Obesity Females Decreased volume of intermediate compartment 105 BARBITURATE DOSING • Thiopental infusion for increased ICP or status epilepticus. • Starting rate 2-4 mg/kg/hr • Methohexital ~ 2.5x potency of thiopental • Adult induction dose 1-2 mg/kg • Often drug of choice for ECT • Used previously as a pediatric rectal premedicant • 25 mg/kg of 10% solution via a 14 Fr catheter advanced 7-8 • Does not produce analgesia, but not antianalgesic. 106 ORGAN SYSTEM EFFECTS - CNS • Proportional decreases in CMRO2 and CBF resulting in decreased ICP. • Mean arterial pressure typically decreases less than ICP, improving cerebral perfusion. • Maximum decrease in CMRO2 obtainable with barbiturates is ~50-55%, which represents the portion of metabolic activity due to neuronal signaling and impulse traffic. • Further suppression of basal cerebral metabolic activity requires the use of hypothermia. • Useful for improving brain relaxation during neurosurgery and to increase cerebral perfusion pressure following acute brain injury. • Barbiturates not shown to be superior to other techniques for decreasing ICP following acute brain injury. 107 BARBITURATES for CEREBROPROTECTION • Investigated and found to be contraindicated following resuscitation from cardiac arrest • Used frequently in the past in anticipation of incomplete ischemia • • • • Carotid endarterectomy Temporary occlusion of cerebral arteries Profound induced hypotension Cardiopulmonary bypass • Proposed mechanisms of neuroprotective effect: • • • • Reverse steal (Robin Hood) Free radical scavenging Stabilization of liposomal membranes Blockade of excitatory amino acids (EAA) 108 BARBITURATES AS ANTICONVULSANTS • At higher concentrations, barbiturates typically produce a potent anticonvulsant effect. • Thiopental infusions have been used successfully to treat status epilepticus. • Paradoxically, at lower doses, both thiopental, and in particular, methohexital may induce seizure activity. • Particularly true in patients with an existing seizure disorder. • Methohexital in low dose has been used to induce seizure discharges in temporal lobe epilepsy, and is drug of choice for electroconvulsive therapy. 109 ORGAN SYSTEM EFFECTS CARDIOVASCULAR • Peripheral vasodilation with venous pooling • Decreased contractility • Increased heart rate (11- 36%) • Decreased cardiac output • Direct negative inotropy • Decreased filling pressure • Decreased sympathetic outflow from CNS • Cardiac index • Unchanged or reduced • Mean arterial pressure • Unchanged or slightly reduced 110 ORGAN SYSTEM EFFECTS CARDIOVASCULAR EVERS 111 ORGAN SYSTEM EFFECTS RESPIRATORY • All intravenous induction agents, with the exception of ketamine and etomidate, produce a dose-dependent respiratory depression. • Enhanced in patients with COPD. • Respiratory depression characterized by: • Decreased tidal volume • Decreased minute ventilation • A rightward shift in the CO2 response curve 112 ORGAN SYSTEM EFFECTS – RESPIRATORY • Respiratory Depression • Peak respiratory depression and maximum decrease in minute ventilation occurs ~ 60 – 90 seconds following dose. • Respiratory parameters return to near normal within 15 minutes. • Awakening occurs prior to return of normal respirations and respiratory drive. • Compounded with narcotics or other agents aboard. AWAKE ADEQUATE RESPIRATIONS 113 ORGAN SYSTEM EFFECTS RESPIRATORY • Apnea • Barbiturate induction results in apnea ~ 20% of the time. • Typically lasts 30 seconds or less. • Described as “Double Apnea” • A few seconds of apnea • Followed by a few breaths • And then a longer period of apnea 114 CONTRAINDICATIONS TO BARBITURATES • Severe cardiovascular instability or shock • Porphyria • Status asthmaticus • Respiratory obstruction or distress • Unless you’re planning to secure the airway • Inadequate equipment/ skill to manage the airway 115 PORPHYRIA • Disorders of Heme Synthesis • Multiple subtypes • Most common is Acute intermittent porphyria (~1:10,000) • Incidence ~ 1:500 in patients with psychiatric disorders • Female incidence ~ 5x that of male • Mechanism • Induction of cytochrome P-450, specifically synthesis of cytochrome protein. Heme is used up in this process decreasing the intracellular heme concentration, which results in decreased inhibitory feedback on ALA synthetase and subsequently, increased production of porphyrin. • Potential triggers • • • • • • • • Barbiturates Etomidate Ketamine Ketorolac (Toradol) Amiodarone Some Ca++ channel blockers Fasting Stress 116 117 PORPHYRIA • Symptoms • Pain in trunk, limbs, abdomen • Sensitivity to sunlight • Personality changes • Mental disorders • Seizures • Skin changes • • • • Purple coloration Fragility Blisters Retraction • Treatment • Remove triggers • Adequate hydration and carbohydrate substrate • Correction of electrolytes • Sedation • Pain management • Antiemetics • β-blockade for HTN, tachycardia • Control of seizures • Benzodiazipines or propofol • With Acute Intermittent • Systemic HTN • Renal dysfunction • If unresponsive to above: • Administration of heme SIDE EFFECTS / COMPLICATIONS • Side Effects • Cardiovascular and respiratory side effects are dose dependent • No significant differences exist between the barbiturates in terms of cardiovascular or respiratory side effects • At low blood levels thiopental has been described as having an anti-analgesic effect • Complications • • • • • Allergic reactions Garlic or onion taste on injection Local tissue irritation Rash on head, neck, trunk Excitatory phenomenon • 5x more common with methohexital than thiopental • • • • Cough Hiccough Tremors Twitching 118 OTHER USES of the BARBITURATES • Lethal Injection • Thiopental + Pavulon + KCL • Truth serum • The theory is, it depresses higher cortical brain function and • Lying is more complicated than telling the truth • Abuse potential –high • On the street, typically identified by their colors • • • • • Purple hearts Blue heavens or blue birds Yellow jackets Red Devils or red birds Rainbows 119