Exam 1 Drugs PDF

GABA AGONIST SEDATIVE HYPNOTICS Drug propofol Drug Specifics • • • • • • • • • • • 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 Preparations o Initial...

GABA AGONIST SEDATIVE HYPNOTICS Drug propofol Drug Specifics • • • • • • • • • • • 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 Preparations o Initially suspended in Cremaphor EL § Problem with anaphylactoid reactions o Now provided in an emulsion of: § 1% propofol § 10% soybean oil § 2.25% glycerol § 1.2% purified egg phosphatide o 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 o Other formulations § 2% formula § Ampofol decreased lipid formula § Fospropofol (Aquavan) a prodrug Mechanism of Action o 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 § 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 Pharmacokinetics o Hysteresis is minimal o Initial termination of action is rapid and results from redistribution of drug out of the central (or effect site) compartment o 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 o Excreted by kidneys o Elimination half-life is prolonged due to slow release of drug from the slow peripheral compartment o 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 Rapid decline in blood levels following bolus due to § Redistribution § Elimination • Clearance is high relative to other induction agents o Propofol 30-60 ml/kg/min (20-30 ml/kg/min) o Etomidate 10-20 ml/kg/min o Ketamine 16-18 ml/kg/min o 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 Clinical Uses o Induction of anesthesia § Rapid induction and more complete awakening than the other induction agents § Dosing • Healthy adult 1.5-2.5 mg/kg o Unconsciousness at 2-6 μg/ml o 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 o Maintenance of anesthesia § Dosing • 100-300 μg/kg/min (100-200 μg/kg/min) § Advantages • Rapid awakening • Minimal residual sedation • Reduced postoperative N/V o 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 o Sedation § Highly titratable due to • Rapid effect-site equilibration • Short context-sensitive half-time § Dosing • Typically, 25-100 μg/kg/min o o • SEDASYS • Computer assisted sedation system approved by the FDA for use in colonoscopy and EGD without the requirement for a trained anesthesia provider o 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 § 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 o Antipruritic Effect § Effective in treatment of neuraxial opioid associated pruritis • Dose 10 mg o Anticonvulsant Activity § Termination of generalized seizure activity may be achieved with induction doses § Will shorten the duration of seizure activity with ECT o 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 o Analgesia § No benefit with acute nocioceptive pain, but may have use in neuropathic pain states Organ System Effects o 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 § Effect on evoked potentials • Somatosensory o Decreased § • • o Motor o Decreased • Auditory o 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) § Neuroprotection • Propofol titrated to EEG burst suppression provides cerebral protection following incomplete ischemia o Equivalent to thiopental o Equivalent to halothane o 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 o Thiopental à reduced lipid peroxidase with improved ultrastructure o Propofol à reduced lipid peroxidase with no sparing of ultrastructure injury • Mechanism o Antioxidant activity, resulting in free radical scavenging and subsequently reduced free radical induced lipid peroxidation Cardiovascular § Decreased systemic blood pressure • Direct myocardial depression o Alteration in sympathetic drive to the heart • Vasodilation o 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 o Possibly related to the lipid emulsion rather than the propofol § Blunted tachycardic response to hypotension § 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 o May require a direct acting beta agonist § 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 o Pulmonary § 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 o In the absence of metabisulfite preservative § No inhibition of hypoxic pulmonary vasoconstriction o Hepatic and Renal o IOP o Coagulation Other Side Effects o No potentiation of the neuromuscular blockers o Not a trigger for malignant hyperthermia o Potential for anaphylactoid reactions o Antiemetic effect o Potential for addiction o Sense of well being § Accumulation of dopamine in nucleus accumbens o Inhibition of phagocytosis and killing of S. aureus and E. coli § Despite the addition of preservative, strict aseptic technique required o Tolerance may develop, but not acutely o May temporarily abolish Parkinson’s tremor o Pain on injection § Etomidate = methohexital > propofol > thiopental o Myoclonus /Opisthotonus § Etomidate = methohexital > propofol > thiopental o Hallucinations / sexual fantasies o Inhibition of phagocytosis and bacterial killing o Potential for bacterial growth due to emulsion • • etomidate • • • • Recommendations on Handling o Aseptic technique § Disinfection of ampule or vial with isopropyl alcohol o Draw up in sterile syringe immediately after opening o Contents of an opened ampule should be discarded after 6 hours o In the ICU the tubing and unused propofol should be discarded after 12 hours Propofol Infusion Syndrome o Associated with infusion at > 75 μg/kg/min for > 24 hours o Clinical features § Severe, refractory bradycardia § Cardiomyopathy with acute cardiac failure § Metabolic acidosis § Skeletal myopathy § Hyperkalemia § Hepatomegaly § Lipemia o 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 o Differential Diagnosis § Metabolic acidosis of other origin § Hyperchloremic metabolic acidosis Preparation o An imidazole structure which is water soluble in an acidic pH and lipid soluble at physiologic pH o Originally prepared in propylene glycol producing § Pain on injection § Venous irritation o Now also prepared in a lipid emulsion § Has essentially eliminated pain and venous irritation o Oral form for transmucosal delivery Mechanism of Action o Administered as the R-isomer which has 5x the potency of the S-isomer o Enhances the affinity of the GABAA receptor for GABA o At supra-clinical doses may activate the GABAA receptor directly o No other known mechanisms Pharmacokinetics o Best described by a three-compartment model o Large volume of distribution o Termination of action of initial effect is redistribution o Rapidly cleared in the liver by ester hydrolysis (Clearance 18-25 ml/kg/min) o Short context-sensitive half-time o ~75% protein bound Clinical Uses o 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 Organ System Effects o CNS § Improved cerebral oxygen supply-to-demand ratio • Cerebral vasoconstriction o 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 § 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 o But consider the consequences o 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 o Ex: severe cerebrovascular disease • Elevated ICP with questionable volume status § Does not effectively blunt the hemodynamic response to laryngoscopy and intubation o 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 o Adrenal § Much greater potency (20x) in steroid synthesis inhibition than as a sedative-hypnotic • Acts through inhibition of 11β-hydroxylase o Suppression of adrenal steroidogenesis § Cortisol and mineralocorticoids o A single induction dose can suppress cortisol production for up to 72 hours • CORTICUS study o • • • benzodiazepines • • • Side Effects o 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 § Hiccups o Pain on injection § Presumably related to the propylene glycol preparation § Eliminated with the lipid formulation o PONV § High incidence, especially when given with narcotics for outpatient procedures § Reduced somewhat with the lipid emulsion o Adrenocortical Suppression Etomidate Derivatives o Methoxycarbonyletomidate (MOC) § Hypnotic potency similar to etomidate § Shorter duration due to rapid esterase metabolism § Initial studies indicate it may not inhibit steroidogenesis o Carboetomidate § Consists of a pyrrole ring rather than an imidazole § In animals, adrenal suppression reduced to 1/1000th of etomidate Structure o Benzene ring fused to a seven-membered diazepine ring o 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 GABAA Receptor o Benzodiazepine bound by GABAA receptor facilitates binding of GABA by receptor Mechanism of Action o Enhance the affinity of the GABAA receptors for GABA, resulting in § Increased opening of the chloride channels à § Increased chloride conductance à § Hyperpolarization of the postsynaptic cell membrane à § Greater resistance to excitation o GABAA Receptor § α1 Receptors • Sedation • Amnesia • Anticonvulsant properties § α2 Receptors • Anxiolysis • Muscle relaxation o Receptor Occupancy § Drug effect is a function of receptor occupancy • < 20% anxiolysis • 30-50% sedation • > 60% unconsciousness • • • • Pharmacokinetics o Protein binding § All are highly protein bound o Volume of Distribution § Similar § Lorazepam slightly greater than the others despite its lower lipid solubility o Clearance § Midazolam > Lorazepam > Diazepam Other Uses o Termination of seizure activity o Prophylaxis or management of delirium tremens o Skeletal muscle relaxation or lumbar disc disease o Insomnia o Anxiety o Nausea / Vomiting Prophylaxis 5 Principal Pharmacologic Effects o Anxiolysis o Sedation o Anticonvulsant o Skeletal muscle relaxation o Amnesia Organ System Effects o CNS § CBF and CMRO2 • Both decreased and remain coupled § Benzodiazepines cannot produce an isoelectric EEG § Cerebral vasculature remains responsive changes in CO2 § Little or no change in ICP • Generally considered to be an acceptable induction agent in patients with reduced intracranial compliance § Potent anticonvulsant • Management of status epilepticus • Increase seizure threshold to local anesthetic exposure § Paradoxical excitement can rarely occur § Neuroprotective activity not documented in humans o 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 o 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 o COPD o Concomitant use of other respiratory depressants o Old age o Debilitating disease Apnea • In large doses may produce a brief apnea § Decreased muscular tone in the upper airway predisposing to obstruction o Musculoskeletal § Skeletal muscle relaxation occurs via interaction of benzodiazepines with spinal internuncial neurons, not at the neuromuscular junction • Flumazenil o Benzodiazepine receptor ligand with § High receptor affinity § Minimal intrinsic effect o A competitive antagonist § Prevents or reverses all effects of the other benzodiazepines, in a dosedependent manner o Metabolism § Rapid clearance by hepatic microsomal enzymes § Three known metabolites with unknown activity o Uses § Reversal of residual benzodiazepine-induced sedation § Suspected benzodiazepine overdose o Dosage § 0.2 -0.5 mg incrementally to a total dose of 3.0 mg • Pharmacokinetics midazolam o Oral Administration § Rapidly absorbed from GI tract § Undergoes first-pass metabolism o Short duration relative to other benzodiazepines § Rapid redistribution from central compartment § High hepatic clearance o Prolonged elimination in elderly § Decreased hepatic blood flow and enzyme activity? § Increased volume of distribution o And Obese § Increased volume of distribution o 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 § Delayed in presence of drugs which inhibit cytochrome P450 • 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 • Clinical Uses o Preoperative Anxiolytic § Oral premedication in children § • o o diazepam • 0.25-1.0 mg/kg (0.5 mg/kg) o Onset 10-20 minutes § Nasal Premedication • 0.2 mg/kg IV Sedation § Typically, well-preserved hemodynamic and respiratory function • Caution when combined with other drugs § Amnesia > Sedation § Midazolam vs Propofol for sedation • Midazolam = o Greater hemodynamic stability o Delayed emergence o Reliable amnesia (equal) o Increase context sensitive half time Induction and Maintenance § 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 § Induction • 0.05-0.15 mg/kg § Maintenance • 0.05 mg/kg prn • 1 mcg/kg/min § Sedation • 0.5-1 mg repeated • 0.07 mg/kg IM Pharmacokinetics o Insoluble in water so dissolved in organic solvents § Propylene glycol § Sodium benzoate o Rapid absorption from GI tract o Rapid uptake to effect site o Rapid redistribution o Metabolism § Hepatic oxidative reduction of methylene group § Principle metabolites • Desmethyldiazepam* o Only slightly less potent than diazepam • Oxazepam* • Temazepam – to a lesser extent § Inhibition of cytochrome P-450 enzymes prolongs the elimination half-time of both • Diazepam and • Desmethyldiazepam § • lorazepam barbiturates • • • Cirrhosis • Prolonged elimination half-time due to: o Decreased protein binding with increased Vd o Decreased hepatic blood flow Clinical Uses o Preoperative Anxiolytic § Oral premedication in adults • 5–15 mg o Induction § 0.3-0.5 mg/kg o Maintenance § 0.1 mg/kg prn o Sedation § 2 mg repeated Pharmacokinetics o 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 o 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 • Clinical Uses o Induction § 0.1 mg/kg o Maintenance § 0.02 mg/kg prn o Sedation § 0.25 mg repeated Mechanism of Action o GABAA § Low concentrations • Enhance effect of GABA o Decrease rate of dissociation of GABA from receptor § High concentrations • Mimic effect of GABA o Directly activate opening of the chloride channels o Also act at § Glutamate receptors § Adenosine receptors § Neuronal NAChRs Pharmacokinetics o 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 o 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) Organ System Effects o 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 § Cerebroprotection • Investigated and found to be contraindicated following resuscitation from cardiac arrest • Used frequently in the past in anticipation of incomplete ischemia o Carotid endarterectomy o Temporary occlusion of cerebral arteries o Profound induced hypotension o Cardiopulmonary bypass • Proposed mechanisms of neuroprotective effect o Reverse steal (Robin Hood) o Free radical scavenging o Stabilization of liposomal membranes o Blockade of excitatory amino acids (EAA) § Anticonvulsants • At higher concentrations, barbiturates typically produce a potent anticonvulsant effect • Paradoxically, at lower doses, both thiopental, and in particular, methohexital may induce seizure activity o Particularly true in patients with an existing seizure disorder o 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 o 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 § 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 o Compounded with narcotics or other agents aboard • Awake DOES NOT = adequate respirations § Apnea • Barbiturate induction results in apnea ~ 20% of the time • Typically lasts 30 seconds or less • Described as “Double Apnea” o A few seconds of apnea o Followed by a few breaths o And then a longer period of apnea Contraindications o Severe cardiovascular instability or shock o Porphyria § Disorders of Heme Synthesis • Multiple subtypes o 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 § Symptoms • Symptoms • Pain in trunk, limbs, abdomen • Sensitivity to sunlight • Personality changes • Mental disorders • Seizures • Skin changes o Purple coloration o Fragility o Blisters o Retraction • With Acute Intermittent o Systemic HTN o Renal dysfunction § Treatment • Remove triggers • Adequate hydration and carbohydrate substrate • Correction of electrolytes • Sedation • Pain management • Antiemetics • β-blockade for HTN, tachycardia • Control of seizures o Benzodiazepines or propofol • If unresponsive to above: o Administration of heme o Status asthmaticus o Respiratory obstruction or distress § Unless you’re planning to secure the airway o Inadequate equipment/ skill to manage the airway Side Effects/Complications o 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 antianalgesic effect o 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 o Cough o Hiccough o Tremors o Twitching Other Uses Lethal Injection § Thiopental + Pavulon + KCL o Truth serum § The theory is, it depresses higher cortical brain function and § Lying is more complicated than telling the truth o Abuse potential is high § On the street, typically identified by their colors • Purple hearts • Blue heavens or blue birds • Yellow jackets • Red Devils or red birds • Rainbows • Pharmacokinetics thiopental o Metabolism § High dose thiopental may lead to accumulation of the active metabolite pentobarbital o 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 o First-order = constant fraction of drug cleared over time*** o Zero-order = constant amount of drug cleared over time*** • Dosing o Thiopental induction doses § Adult 3-5 mg/kg § Child 5-6 mg/kg § Infant 6-8 mg/kg § These doses must be reduced in • Premedicated patients • Pregnancy • Hypovolemia and Elderly o Decreased volume of central compartment • Obesity and Females o Decreased volume of intermediate compartment o Thiopental infusion for increased ICP or status epilepticus § Starting rate 2-4 mg/kg/hr • Organ System Effects o Anticonvulsants § Thiopental infusions have been used successfully to treat status epilepticus o methohexit al • • Dosing o 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 Organ System Effects o Anticonvulsants § Methohexital in low dose has been used to induce seizure discharges in temporal lobe epilepsy, and is drug of choice for electroconvulsive therapy NON-GABGA AGONIST SEDATIVE HYPNOTICS Drug Drug Specifics ketamine • • Preparations o An arylcyclohexylamine resembling phencyclidine o Consists of two optical isomers § S(+) ketamine • 4x greater affinity for phencyclidine binding site on NMDA receptor than R(-) o ~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 o Hallucinations o Nightmares o Impaired memory and cognition o Mood disorder • Better accepted by patients • Available in Europe • In the United States only the racemic mixture is approved § R(-) ketamine o Water soluble o Preserved with benzethonium chloride o Supplied in three strengths § 1% § 5% § 10% Mechanism of Action o 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 o Eyes open o 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 o 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 Pharmacokinetics o Rapid onset of action § High lipid solubility § Highly unionized § Poorly protein bound § Increased CBF with ketamine could speed delivery of drug to the brain o Brief duration of action § Initially due to redistribution • Large volume of distribution § High HER § Rapid clearance in the liver o Metabolism § By hepatic microsomal enzymes • Major pathway leads to the active metabolite norketamine o ~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 its metabolism Clinical Uses o 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 o 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 o Induction of Anesthesia § Dosing • 1-2 mg/kg IV • 4-8 mg/kg IM o Tolerance may develop following repeated dosing § Onset • 30-60 seconds IV • 2-4 minutes IM § Duration § • • • • 10-20 minutes following a single induction dose o May have amnesia and disorientation for 60-90 minutes following return of consciousness o Indications for Ketamine Induction § Hemodynamic instability § Active bronchospasm § Lack of IV access § Need for analgesia § “Inability to secure the airway” o Concerns with Ketamine Induction § Known coronary artery disease § Severe cardiac valvular disease in which tachycardia would be harmful § Elevated ICP? § Emergence delirium o 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 obsessivecompulsive disorder Organ System Effects o 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 § 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 o Use in neonates questioned § Emergence Reactions • 10-30% incidence in adults in whom ketamine is a major portion of the anesthetic o Adults > children o Female > male o Certain personality types (high psychotism score) § Result from misperception or misinterpretation of auditory and visual stimuli • Vivid dreaming o o • Extracoporeal experience • Illusions § Reduced by pre or concurrent treatment with multiple other drugs • Best results achieved with benzodiazepines § Other • Burst suppression of the EEG at high doses • Nystagmus • Myoclonic and other movement • Evoked potentials o Increased amplitude § Somatosensory o Decreased amplitude § Auditory § Visual • No change in seizure threshold in epileptic patients Cardiovascular § Two competing effects • Direct negative inotropic effect • Indirect stimulatory effect o Systemic release of catecholamines o Inhibition of vagal outflow o Inhibition of NE reuptake at peripheral nerves and myocardium o Increased NE release from post-synaptic sympathetic neurons o Attenuated by § Benzodiazepines § Inhaled anesthetics § Propofol § Beta blockade or ganglionic blockade § Spinal cord transection or cervical epidural § Hemodynamic Effects • Increased systemic BP o Systolic 20-40 mmHg o Diastolic somewhat less o Duration 10 -20 minutes • Increased pulmonary artery BP • Increased heart rate § Concerns • Coronary artery disease o Increased myocardial work and MVO2 o Potentially decreased myocardial oxygen supply • Pre-existing pulmonary artery hypertension • Pressure ≠ Flow 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 § • dexmedetomidine • • • Bronchodilatory effect • Drug of choice in acute bronchospasm • Proposed Mechanism o Increased catecholamine secretion o Calcium channel blockade o Inhibition of postsynaptic muscarinic receptors Side Effects o Emergence delirium o Excessive salivation o Inhibition of platelet aggregation § A concern in patients with known bleeding disorders § Mechanism • Decreased free calcium concentration 20 inhibition of ITP o Allergic reaction § Rare § No histamine release Preparation o The S-enantiomer of medetomidine o Highly specific α2 receptor agonist (α2: α1 = 1600:1) § Versus Clonidine (α2: α1 = 220:1) o pKa = 7.1 o Highly water soluble o Provided as a solution containing 100 μg/ml Mechanism of Action o A2 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? o Sedation § Locus coeruleus o Analgesia § Primary site is spinal cord, but also • Supraspinal • Peripheral o Bradycardia § Sympatholysis at the heart o Hypotension § Central > peripheral effects Pharmacokinetics Highly protein bound (94%) Near complete hepatic biotransformation § Direct glucuronidation and § Metabolism by cytochrome P450 enzymes o Renal excretion § No effect of renal disease on pharmacokinetics o Some inhibition of cytochrome P450 enzymes § May slightly increase opioid concentration when given concurrently o Best predicted by a three-compartment model o T1/2 = 2-3 hours o Context-sensitive half-time § 4 minutes following a 10-minute infusion § 250 minutes following an 8-hour infusion o Context Sensitive Half Time Clinical Uses o Consider the effects § Anxiolysis § Sedation § Analgesia § Sympatholysis § Decreased salivation § Minimal depression of ventilation o 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 o Sedation for Airway Management § Very useful tool in the proper setting § Benefits • Minimal respiratory depression o Difficult airway o Stridor o Foreign body o OSA/OHS • Reduces secretions in the airway § Risks • Pronounced sympatholysis o 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 o Adjunct to General Anesthesia § Reduces MAC of isoflurane by 35 -50% § Improved postoperative pain control o o • • § Potentially reduced nausea and vomiting § Prolongs recovery when added to a propofol-based anesthetic technique o Total IV Anesthesia § Typically preserved respiratory function § Loading dose of 1μg/kg followed by infusion of 5 – 10 μg/kg/hr o 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 Organ System Effects o 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 o Cardiovascular § Hypotension and bradycardia • Central and peripheral mechanisms o Central § α2 agonism § Imidazoline I1 receptor agonism in the medulla § Attenuation of baroreceptor reflexes o Peripheral § α2B receptor agonism producing peripheral vasoconstriction o Coronary arteries § Direct vasoconstriction § Increased release of nitric oxide § Myocardial energetics • Overall typically improved o However, in some patients, hypotension may produce ischemia • Mechanism of improved myocardial oxygen balance o Decreased myocardial oxygen demand o Decreased coronary perfusion pressure o Respiratory o 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 o Renal § § scopolamine • • • Droperidol • • Diuretic effect by opposing the action of vasopressin May produce a renoprotective effect in ischemic or contrast-induced injury Structure and PK o Naturally occurring anticholinergic alkaloid derived from the belladonna plant o Lipid soluble, tertiary amine o Large volume of distribution o Relatively low clearance § Primarily hepatic o T1/2 ~ 4.5 hours o Oral bioavailability unpredictable so usage limited via this route Clinical Uses o 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 o Antisialagogue § ~3x the potency of atropine as an antisialagogue § Less likely to produce tachycardic changes § Dosed as above o Antiemetic § Transdermal patch Side Effects o Mydriasis and Cycloplegia § May interfere with drainage of aqueous humor o Central Anticholinergic Syndrome § Wide range of symptoms • Restlessness and hallucinations to somnolence and unconsciousness • DAWK • Management o Physostigmine 15-60 μg/kg IV repeated at 1-2-hour intervals o Atropine fever § Failure of thermoregulatory sweating § Particularly problematic in infants and small children § Management • Physostigmine dosed as above Background o A butyrophenone, derived from haloperidol o Previously used in combination with fentanyl to produce neuroleptanalgesia or neuroleptanesthesia with the addition of an inhaled agent to improve amnesia o 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 o Continued to see widespread use as an antiemetic in Europe and usage is again increasing in the United States Organ System Effects o 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 CMRO2 with: o Marked reduction in CBF o No change in CMRO2 o Respiratory § Minimal effect on respiration when used alone o 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 Clinical Uses o 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) o Neuroleptanesthesia § Addition of an inhaled anesthetic improved amnesia • Most often nitrous oxide o Antiemetic § PONV Prophylaxis § 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 firstline antiemetic despite the warning o Sedation § Routine preop sedation – not so much § Agitated or psychotic patients - maybe § •