Pharm 3.pptx

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 1 BARBITURATES...

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 1 BARBITURATES Mechanism of Action History Pharmacokinetics Organ System Effects CNS Cardiovascular Respiratory Contraindications Side Effects/Complications 2 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 3 HISTORY OF THE BARBITURATES 4 • 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” 5 6 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 7 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. 8 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 9 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 10 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 11 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 12 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. 13 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. 14 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) 15 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. 16 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 17 ORGAN SYSTEM EFFECTS CARDIOVASCULAR EVERS 18 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 19 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 20 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 21 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 22 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 23 24 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 25 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 26 NON-GABA AGONIST SEDATIVEHYPNOTICS KETAMINE DEXMEDETOMIDINE SCOPOLAMINE DROPERIDOL 27 KETAMINE Preparations Mechanism of Action Pharmacokinetics Clinical Uses Organ System Effects CNS Cardiovascular Respiratory Side Effects 28 KETAMINE PREPARATIONS • An arylcyclohexylamine resembling phencyclidine • Consists of two optical isomers • S(+) ketamine • R(-) ketamine • Water soluble • Preserved with benzethonium chloride • Supplied in three strengths • 1% • 5% • 10% 29 KETAMINE PREPARATIONS • Two Isomers • S(+) isomer • 4x greater affinity for phencyclidine binding site on NMDA receptor than R(-) • ~3x greater potency than racemic mixture • • • • More intense analgesia ~20% quicker metabolism and quicker return of cognitive function than racemic mixture Decreased salivation Decreased incidence of emergence reactions • • • • Hallucinations Nightmares Impaired memory and cognition Mood disorder • Better accepted by patients • Available in Europe • In the United States only the racemic mixture is approved 30 KETAMINE – MECHANISM OF ACTION • Produces dose-dependent CNS depression resulting in a “dissociative state” resulting in: • Intense analgesia and amnesia • Depending on dose, may remain conscious, or may be unconscious but appear awake in a cataleptic state • Eyes open • Slow, nystagmic gaze • Coordinated movement of skeletal muscle – not in response to surgical pain • EEG reveals dissociation between the thalamocortical and limbic systems • The precise mechanism of this dissociative state is unknown, although ketamine binds with multiple CNS receptors 31 KETAMINE – MECHANISM OF ACTION • Receptors affected by Ketamine • NMDA • Inhibits binding of glutamate with receptor • Inhibits release of glutamate form presynaptic nerve terminal • Opioid • Strongest evidence appears to be binding of the S(+) isomer to μ receptors • Monoaminergic • May activate the descending inhibitory monoaminergic pathway • Muscarinic • Appears to act as an antagonist at muscarinic receptors • Voltage gated sodium channels • Mild local anesthetic-like effect • Neuronal NAChR • May contribute to the analgesic effect 32 KETAMINE - PHARMACOKINETICS • Rapid onset of action • • • • High lipid solubility Highly unionized Poorly protein bound Increased CBF with ketamine could speed delivery of drug to the brain • Brief duration of action • Initially due to redistribution • Large volume of distribution • High HER • Rapid clearance in the liver 33 KETAMINE - PHARMACOKINETICS FLOOD 34 KETAMINE - PHARMACOKINETICS • Metabolism • By hepatic microsomal enzymes • Major pathway leads to the active metabolite norketamine • ~20-30% the activity of the parent compound • Ultimately hydroxylated and conjugated for urinary excretion • Bioavailabliity via other routes • Oral 20-30% • Nasal 40-50% • Tolerance with repeated dosing • Chronic dosing results in induction of enzymes responsible for it’s metabolism 35 KETAMINE - PHARMACOKINETICS BARASH 36 CLINICAL USES • Analgesia • Greater effect on somatic than visceral pain • Presumed effect via inhibition of NMDA receptors • Thalamic and limbic systems • Spinal nocioceptive pathways • Analgesia achieved with sub-anesthetic doses • 0.2 - 0.5 mg/kg IV • Useful adjunct in chronic pain patients who present for surgery who may not be opioid naïve • Postoperative sedation and analgesia results in: • • • • Opioid sparing effect Decreased GI side effects Dosed at 1-3 μg/kg/min IV infusion Concern with increased psychomimetic reactions 37 CLINICAL USES • Induction of Anesthesia • Dosing • 1-2 mg/kg IV • 4-8 mg/kg IM • Tolerance may develop following repeated dosing • Onset • 30-60 seconds IV • 2-4 minutes IM • Duration • 10-20 minutes following a single induction dose • May have amnesia and disorientation for 60-90 minutes following return of consciousness 38 CLINICAL USES • Indications for Ketamine Induction • • • • • Hemodynamic instability Active bronchospasm Lack of IV access Need for analgesia “Inability to secure the airway” • Concerns with Ketamine Induction • • • • Known coronary artery disease Severe cardiac valvular disease in which tachycardia would be harmful Elevated ICP? Emergence delerium 39 CLINICAL USES • Other Considerations • Small improvements in analgesia when used in the central neuraxis, but not approved for this use • Does not trigger MH • Sub anesthetic doses may reduce the incidence of acute opioid tolerance • Potential value of low dose ketamine in depression and obsessive compulsive disorder 40 ORGAN SYSTEM EFFECTS - CNS • Produces a functional disorganization of midbrain and thalamic pathways • Depression of cortex and thalamic areas • Stimulation of portions of the limbic system • Depresses transmission of impulses in the medial medullary reticular formation • Interferes with transmission of affective-emotional component of nocioception • Interferes with nocioceptive central sensitization • May decrease duration of pain • May result in less transition to chronic pain states 41 ORGAN SYSTEM EFFECTS - CNS • Ketamine produces: • • • • Increased CMRO2 Increased CBF Increased ICP Preservation of cerebrovascular responsiveness to CO2 • Neuroprotection? • Proposed neuroprotective effect due to NMDA receptor antagonism – unproven • Question of increased apoptosis in brains of newborn animals • Use in neonates questioned 42 ORGAN SYSTEM EFFECTS - CNS • Emergence Reactions • 10-30% incidence in adults in whom ketamine is a major portion of the anesthetic • Adults > children • Female > male • Certain personality types (high psychotism score) • Result from misperception or misinterpretation of auditory and visual stimuli • Vivid dreaming • Extracoporeal experience • Illusions • Reduced by pre or concurrent treatment with multiple other drugs • Best results achieved with benzodiazipines 43 ORGAN SYSTEM EFFECTS - CNS • Other • • • • Burst suppression of the EEG at high doses Nystagmus Myoclonic and other movement Evoked potentials • Increased amplitude • Somatosensory • Decreased amplitude • Auditory • Visual • No change in seizure threshold in epileptic patients 44 ORGAN SYSTEM EFFECTS CARDIOVASCULAR • Two competing effects • Direct negative inotropic effect • Indirect stimulatory effect • • • • Systemic release of catecholamines Inhibition of vagal outflow Inhibition of NE reuptake at peripheral nerves and myocardium Increased NE release from post-synaptic sympathetic neurons • Attenuated by: • Benzodiazepines • Inhaled anesthetics • Propofol • Beta blockade or ganglionic blockade • Spinal cord transection or cervical epidural 45 ORGAN SYSTEM EFFECTS CARDIOVASCULAR • Hemodynamic Effects • Increased systemic BP • Systolic 20-40 mmHg • Diastolic somewhat less • Duration 10 -20 minutes • Increased pulmonary artery BP • Increased heart rate • Concerns • Coronary artery disease • Increased myocardial work and MVO2 • Potentially decreased myocardial oxygen supply • Pre-existing pulmonary artery hypertension • Pressure ≠ Flow 46 ORGAN SYSTEM EFFECTS RESPIRATORY • Minimal effect on respiratory drive • Ventilatory response to CO2 maintained • Brief decrease in minute ventilation following bolus dose • Apnea is rare*** • Upper airway muscle tone maintained • Upper airway reflex relatively intact • Increased salivation and tracheobronchial mucous secretion • Bronchodilatory effect • Drug of choice in acute bronchospasm • Proposed Mechanism • Increased catecholamine secretion • Calcium channel blockade • Inhibition of postsynaptic muscarinic receptors 47 KETAMINE – SIDE EFFECTS • Emergence delirium • Excessive salivation • Inhibition of platelet aggregation • A concern in patients with known bleeding disorders • Mechanism • Decreased free calcium concentration 20 inhibition of ITP • Allergic reaction • Rare • No histamine release 48 DEXMEDETOMIDINE Preparation Mechanism of Action Pharmacokinetics Clinical Uses Organ System Effects CNS Cardiovascular Respiratory Side Effects 49 PREPARATION • The S-enantiomer of medetomidine • Highly specific α2 receptor agonist (α2:α1 = 1600:1) • Versus Clonidine (α2:α1 = 220:1) • pKa = 7.1 • Highly water soluble • Provided as a solution containing 100 μg/ml 50 51 MECHANISM OF ACTION – α2 AGONISM • Alpha2A Effects • • • • • • Sedation and hypnosis Sympatholysis Analgesia Neuroprotection Hyperglycemia Diuresis • Net effect is neuronal hyperpolarization • Alpha2B Effects • Vasoconstriction • Endogenous analgesia mechanism • Anti-shivering? • Alpha2C Effects • Feedback inhibition of adrenal catecholamine release • Learning? • Stress response? MECHANISM OF ACTION MILLER 52 53 MECHANISM OF ACTION • Sedation • Locus coeruleus • Analgesia • Primary site is spinal cord, but also: • Supraspinal • Peripheral • Bradycardia • Sympatholysis at the heart • Hypotension • Central > peripheral effects EVERS MECHANISM OF ACTION MILLER 54 55 PHARMACOKINETICS • Highly protein bound (94%) • Near complete hepatic biotransformation • Direct glucuronidation and • Metabolism by cytochrome P450 enzymes • Renal excretion • No effect of renal disease on pharmacokinetics • Some inhibition of cytochrome P450 enzymes • May slightly increase opioid concentration when given concurrently • Best predicted by a three compartment model • T1/2 = 2-3 hours • Context-sensitive halftime • 4 minutes following a 10 minute infusion • 250 minutes following an 8 hour infusion CONTEXT-SENSITIVE HALF-TIME minut es 56 DEXMEDETOMIDINE - CLINICAL USES • Consider the effects: • Anxiolysis • Sedation • Analgesia • Sympatholysis • Decreased salivation • Minimal depression of ventilation 57 DEXMEDETOMIDINE - CLINICAL USES • Premedicant (preop sedation) • Produces sedation and anxiolysis comparable to midazolam • Greater incidence of intraoperative hypotension and bradycardia than midazolam • Dosing • 0.33 – 0.67 μg/kg IV 15 minutes pre-procedure • 3 -4 μg/kg nasally or buccally 60 minutes pre-procedure • Blunts the hemodynamic response to laryngoscopy and intubation 58 DEXMEDETOMIDINE - CLINICAL USES • Sedation for Airway Management • Very useful tool in the proper setting • Benefits • Minimal respiratory depression • Difficult airway • Stridor • Foreign body • OSA/OHS • Reduces secretions in the airway • Risks • Pronounced sympatholysis 59 DEXMEDETOMIDINE - CLINICAL USES • Sedation in the Operating Room • Compared to propofol • • • • Slower onset Similar cardiorespiratory effects at equal sedation levels Longer duration Slower return of blood pressure to baseline • Dosing • 0.2 – 0.7 μg/kg/hour 60 DEXMEDETOMIDINE - CLINICAL USES • Adjunct to General Anesthesia • • • • Reduces MAC of isoflurane by 35 -50% Improved postoperative pain control Potentially reduced nausea and vomiting Prolongs recovery when added to a propofol-based anesthetic technique • Total IV Anesthesia • Typically preserved respiratory function • Loading dose of 1μg/kg followed by infusion of 5 – 10 μg/kg/hr 61 DEXMEDETOMIDINE - CLINICAL USES • Other Uses • Postop sedation • Including weaning from the ventilator • Additive to IV regional anesthetic • Improves quality and postoperative analgesia • Dosed at 0.5 μg/kg • Shivering (unrelated to hypothermia) • Sedation in rapid detox from opioids or cocaine withdrawal 62 ORGAN SYSTEM EFFECTS CARDIOVASCULAR • Hypotension and bradycardia • Central and peripheral mechanisms • Central • α2 agonism • Imidazoline I1 receptor agonism in the medulla • Attenuation of baroreceptor reflexes • Peripheral • α2B receptor agonism producing peripheral vasoconstriction • Coronary arteries • Direct vasoconstriction • Increased release of nitric oxide • Myocardial energetics • Overall typically improved • However in some patients hypotension may produce ischemia • Mechanism of improved myocardial oxygen balance • Decreased myocardial oxygen demand • Decreased coronary perfusion pressure 63 ORGAN SYSTEM EFFECTS CARDIOVASCULAR MILLER 64 ORGAN SYSTEM EFFECTS - CNS • Alpha2 agonism produces: • Vasoconstriction in the cerebral vessels and a decrease in cerebral blood flow • No change in CMRO2 • CBF therefore becomes uncoupled from CMRO2 • Despite this • Dexmedetomidine appears to provide a neuroprotective effect in cerebral ischemia • Benefit reversed by α2 antagonism 65 ORGAN SYSTEM EFFECTS • Endocrine • Blunts the neuroendocrine stress response to surgery resulting in: • Decreased release of cortisol, vasopressin, epi, NE • Increased release of growth hormone • As an imidazoline compound blocks steroid formation, but only at concentrations 100-1000x what is used clinically • Renal • Diuretic effect by opposing the action of vasopressin • May produce a renoprotective effect in ischemic or contrast-induced injury 66 SCOPOLAMINE Structure and PK Clinical Uses Sedation Antisialagogue Antiemetic Side Effects 67 SCOPOLAMINE • Naturally occurring anticholinergic alkaloid derived from the belladonna plant • Lipid soluble, tertiary amine • Large volume of distribution • Relatively low clearance • Primarily hepatic • T1/2 ~ 4.5 hours • Oral bioavailabilty unpredictable so usage limited via this route 68 SCOPOLAMINE – CLINICAL USES • Sedation • • • • ~100x the potency of atropine in the reticular activating system Also produces some amnesia at sedative doses Enhances the sedation produced by other drugs Typical dose = 0.3 – 0.5 mg IV or IM • Antisialagogue • ~3x the potency of atropine as an antisialogogue • Less likely to produce tachycardic changes • Dosed as above • Antiemetic • Transderm patch 69 SCOPOLAMINE FLOOD 70 SCOPOLAMINE – SIDE EFFECTS • Mydriasis and Cycloplegia • May interfere with drainage of aqueous humor • Central Anticholinergic Syndrome • Wide range of symptoms • Restlessness and hallucinations to somnolence and unconsciousness • DAWK • Management • Physostigmine 15-60 μg/kg IV repeated at 1-2 hour intervals • Atropine fever • Failure of thermoregulatory sweating • Particularly problematic in infants and small children • Management • Physostigmine dosed as above 71 DROPERIDOL Background Organ System Effects CNS Respiratory Cardiovascular Clinical Uses Neuroleptanalgesia or anesthesia PONV Prophylaxis 72 DROPERIDOL - BACKGROUND • A butyrophenone, derived from haloperidol • Previously used in combination with fentanyl to produce neuroleptanalgesia or neuroleptanesthesia with the addition of an inhaled agent to improve amnesia • Widely used as an antiemetic prior to a 2001 Black Box warning relating to prolonged QT interval • Validity of this is and the associated case reports that led to it have been challenged • Continued to see widespread use as an antiemetic in Europe and usage is again increasing in the United States 73 ORGAN SYSTEM EFFECTS - CNS • Produce submaximal inhibition of GABAA receptors and full inhibition of α2 -acetylcholine receptors, producing an imbalance between dopamine and acetylcholine • Results in CNS depression with: • • • • Sedation Apparent tranquility Cataleptic immobility Occasional extrapyramidal symptoms • In animals: • Uncoupling of CBF and CMRO 2 with: • Marked reduction in CBF • No change in CMRO2 74 ORGAN SYSTEM EFFECTS • Respiratory • Minimal effect on respiration when used alone • Cardiovascular • May delay myocardial repolarization and prolong the QT interval • Dose dependent • Likely only of consequence in a patient with other potential causes of prolonged QT • Mild hypotension secondary to vasodilation with blockade of α2 receptors • Little direct effect on myocardial contractility 75 DROPERIDOL – CLINICAL USES • Neuroleptanalgesia • Combination of a butyrophenone and an opioid • Innovar = droperidol + fentanyl • Goal • • • • Detached, pain-free state of immobilization Suppression of autonomic reflexes Cardiovascular stability Amnesia (in some) • Neuroleptanesthesia • Addition of an inhaled anesthetic improved amnesia • Most often nitrous oxide 76 DROPERIDOL – CLINICAL USES • Antiemetic • Primary current use • Dosage: • 10-20 μg/kg IV (typically 0.625mg to 1.25 mg) • Given at the start of an anesthetic reduced N/V by 30% • Antiemetic efficacy equal to ondansetron • Efficacy improved when used in combination with serotonin antagonists or dexamethasone, or both • 2007 International Consensus Panel recommended droperidol as a first-line antiemetic despite the warning • Sedation • Routine preop sedation – not so much • Agitated or psychotic patients - maybe 77 SOURCES • Flood Stoelting’s Pharmacology and Physiology in Anesthetic Practice 6th edition. 2022 • Barash Clinical Anesthesia 8th edition. 2017 • Evers Anesthetic Pharmacology 2nd edition. 2011 • Miller Miller’s Anesthesia 9th edition. 2020 78