Pharm 2.pptx

DOSE STACKING Propofol Fospropofol ETOMIDATE Preparation Mechanism of Action Pharmacokinetics Clinical Uses Organ System Effects CNS Cardiovascular Respiratory Side Effects Myoclonus Adrenocortical Suppression 2 ETOMIDATE • An imidazole structure which is water soluble in an acidic pH and lipid...

DOSE STACKING Propofol Fospropofol ETOMIDATE Preparation Mechanism of Action Pharmacokinetics Clinical Uses Organ System Effects CNS Cardiovascular Respiratory Side Effects Myoclonus Adrenocortical Suppression 2 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 3 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 4 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 5 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 6 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 7 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 8 ORGAN SYSTEM EFFECTS CARDIOVASCULAR 9 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 10 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 11 12 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 13 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 14 BENZODIAZIPINE S Structure Mechanism of Action Pharmacokinetics Clinical Uses Organ System Effects CNS Cardiovascular Respiratory Musculoskeletal Midazolam Diazepam Lorazepam Flumazenil 15 STRUCTURE • Benzene ring fused to a seven-membered diazepine ring BARASH 16 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 17 THE GABAA RECEPTOR EVERS 18 BENZODIAZEPINES AT THE GABAA RECEPTOR 19 • 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 20 MECHANISM OF ACTION EVERS 21 22 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 23 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 24 FLOOD EFFECT OF AGE ON MIDAZOLAM REQUIREMENT MILLER 25 CONTEXT-SENSITIVE HALF-TIMES BARASH 26 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 27 INDIVIDUAL BENZODIAZEPINES Midazolam Diazepam Lorazepam Flumazenil 28 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 29 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 30 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 31 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 32 DIAZEPAM - PHARMACOKINETICS • Metabolism • Hepatic oxidative reduction of methylene group • Principle metabolites • Desmethyldiazepam* • Only slightly less potent than diazepam • Oxazepam* • Temazepam – to a lesser extent 33 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 34 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 35 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 36 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 37 ORAL MIDAZOLAM IN CHILDREN FLOOD 38 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 39 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 40 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 41 MIDAZOLAM - ONSET OF INDUCTION FLOOD 42 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 43 FIVE PRINCIPAL PHARMACOLOGIC EFFECTS • Anxiolysis • Sedation • Anticonvulsant • Skeletal muscle relaxation • Amnesia 44 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 45 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 46 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 47 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 48 ORGAN SYSTEM EFFECTS MUSCULOSKELETAL • Skeletal muscle relaxation occurs via interaction of benzodiazepines with spinal internuncial neurons, not at the neuromuscular junction. 49 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 50 FLUMAZENIL 51 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 52 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 53