Pharmacotherapeutics for Minimal and Moderate Sedation

Transcription

1 Pharmacotherapeutics for Minimal and Moderate Sedation Daniel Becker, D.D.S. Miami Valley Hospital Analgesia Anesthesia Pain A neurologic or pharmacologic state in which painful stimuli are moderated. Loss of sensation resulting from pharmacologic depression of nerve function or from neurologic dysfunction. Consciousness Anxiolysis Sedation Hypnosis Reduction in fear or apprehension. Sleepiness or drowsiness. Unconsciousness; a state of sleep. Becker DE. Pharmacotherapeutics 1

2 What is General Anesthesia Stage I II III IV Description Analgesia Excitement Surgical Impending Death Say Goodbye to Guedel s Ether Stages! General anesthesia is a collection of "component" changes in behavior or perception. The components of the anesthetic state include amnesia, immobility in response to noxious stimulation, attenuation of autonomic responses to noxious stimulation, analgesia, and unconsciousness. Patel PM, et al. Goodman & Gilman s 2011 What is General Anesthesia Each component of GA accomplished at different sites within the CNS It is now clear that general anesthesia consists of separable and at least partially independent components, each of which involves distinct, but possibly overlapping, mechanisms at different sites in the central nervous system (CNS) and with variations in relative potencies between specific agents. Miller s Anesthesia 8 th ed Becker DE. Pharmacotherapeutics 2

3 Many Drugs Are Called: General Anesthetics Agent General Anesthesia Hypnosis Analgesia (areflexia) Volatiles Yes Yes But ARE They? Sedatives Yes No Opioids Unpredictable Yes Sedation vs General Anesthesia Sedation follows a continuum. Minimal Sedation (Anxiolysis) Moderate Sedation Deep Sedation Unconscious But General Anesthesia is Distinct! A drug-induced loss of consciousness during which patients are not aroused, even by painful stimulation. Complete analgesia is present! Unconsciousness + Complete Analgesia Becker DE. Pharmacotherapeutics 3

4 Levels of Sedation Level Description Characteristics 1 Minimal Awake but calm (Little evidence of drowsiness) 2 Moderate Awake but sedated. (Slowed or slurred speech) 3 Moderate Asleep but easily aroused.(verbally) 4 Deep Asleep but difficult to arouse. (Shake/Shout) 5 Deep Asleep and unarousable Your intent is to never exceed a level of moderate (Conscious) sedation However, you must be capable of recognizing and managing a deeply sedated (Unconscious) patient should it inadvertently occur. Absorption Diffusion of drug from site of administration into the bloodstream PO vs IV? Drug * * Distribution Diffusion of drug from bloodstream into body tissues * * * * Elimination Removal of active drug from the bloodstream: excretion (renal) or biotransformation (hepatic) PO vs IV? PO vs IV? Becker DE. Pharmacotherapeutics 4

5 Time-Concentration Distribution (T 1/2α ) vs Elimination (T 1/2β ) Stambaugh JE, et al. J Clin Pharmacol 1976;16: Meperidine (1 mg/kg) Drug T 1/2 β (hr) Drug T 1/2 β (hr) Drug T 1/2 β (hr) Diazepam Midazolam Propofol 4-7 Lorazepam Flumazenil Ketamine BUT: Distribution T 1/2α ranges from 3-30 minutes Duration for Sedation? Distribution/Redistribution Onset as drug enters brain Offset as drug leaves brain Predicated on Serum Level Distribution or Elimination? Relative Lipid Solubility Elimination Slower than distribution Determines recovery 4 Half-lives T 1/2 T 1/2 Unrelated to Lipid Solubility Becker DE. Pharmacotherapeutics 5

6 Duration of Sedation Determined more by distribution, not elimination! Brain Distribution Brain, Kidney, Liver Redistribution Drug Absorption Serum Concentration Clearance T 1/2 Distribution Muscle, Viscera Distribution Bone, Adipose Pharmacokinetic Summary Elimination ( T 1/2 ) does not predict duration of procedural sedation. Duration of procedural sedation is mostly related to redistribution Greater lipid solubility, shorter duration Parent drugs and metabolites vary in activity and their elimination half lives. Pros & Cons for long T 1/2 May provide prolonged anxiolysis. May extend residual sluggishness. T 1/2β must be considered for postoperative and at home recovery. Becker DE. Pharmacotherapeutics 6

7 Pharmacodynamics Drug Action: Mechanism for effects Primarily act at receptors Drugs/Classes Benzodiazepines Propofol, Barbiturates Antihistamines Opioids Mechanisms of Action Agonists potentiating GABA-mediated chloride ion influx Agonists directly increase chloride ion influx Antagonize excitatory histamine and acetylcholine receptors Agonists at mu and kappa opioid receptors Effects of Sedatives Sedation is Primary Effect for All Secondary Effects may Vary by Class All Classes of Sedatives Dose-dependent sedation and respiratory depression Dependence with chronic use Paradoxical excitation Benzodiazepines Antihistamines Unique Effects Anticonvulsant Antiemetic Anterograde Amnesia Anticholinergic Becker DE. Pharmacotherapeutics 7

8 Benzodiazepines Action: Agonists at BZ Receptors, Potentiating GABA-Mediated Effects GABA A Receptor Complex protein forming Cl - ion channel Many subunits and binding sites ( receptors ) Hyperpolarization Benzodiazepines Respiratory Side Effects Minimal depression of respiratory system when administered alone BUT airway obstruction can occur Higher doses can depress hypoxemic drive Concern for COPD and Obstructive Sleep Apnea Cardiovascular Side Effects Minimal depression of CVS system administered alone Higher doses can decrease BP and reflex increase HR Becker DE. Pharmacotherapeutics 8

9 Benzodiazepines All comparable in their sedative efficacy Differ pharmacokinetically Lipid solubility Patterns of clearance L = >24hr I = hr S = < 6 hr * Pharmacokinetic Drug Interactions CYP3A4 enzymes inhibited by: Antiretrovirals Macrolides azole antifungals Verapamil & Diltiazem Grapefruit juice They can delay hepatic clearance and elevate serum concentrations of: Midazolam Triazolam Alprazolam Becker DE. Pharmacotherapeutics 9

10 Benzodiazepine Comparisons Lorazepam Diazepam Triazolam Midazolam Elimination Half Life (T 1/2β ) hr hr hr hr Peak Serum Level (PO) 2-4 hr hr hr hr Duration (PO) 3-4 hr 2-3 hr 1-2 hr 1 hr Suggested Dosages: Minimal Sedation (mg PO) Not Indicated Moderate sedation (mg PO) 3-4mg mg/kg Moderate sedation Poor (mg IV increment) Titration All doses halved for elderly. Minimal sedation doses OK at home; HS or Preop. Moderate sedation doses should be administered at office. Z-Compounds Zolpidem (Ambien), Zaleplon (Sonata), et. al. Pharmacologically similar to benzodiazepines, but differ in chemical structures Zolpidem 10 mg ~ Triazolam 0.25 mg in potency ZolpiMist Oral spray Intermezzo Sublingual lozenger Sublinox Sublingual tablet Becker DE. Pharmacotherapeutics 10

11 Antihistamines Sedation and antiemetic due to central blockade of excitatory cholinergic and histaminergic receptors Dopamine blockade contraindicated for patients with Parkinson s disease, and also may account for EPS reactions in other patients. Avoid any anticholinergic in elderly or dementia Pharmacodynamics Hydroxyzine Diphenhydramine Promethazine Cholinergic Blockade Histaminic Blockade Dopaminergic Blockade Alpha Blockade PO Dosage mg 25-50mg 25-50mg IV Increments (Dilute to 10 mg/ml) mg to 50mg Opioids [ Avoid in PO Regimens! ] Opioid receptors inhibit Ca ++ influx that triggers excitatory neurotransmitter release Sedation less predictable and titratable than BZs Potentiate sedation AND respiratory depression Meperidine Nalbuphine* Fentanyl Pharmacodynamics Mu Receptor Agonist Antagonist Agonist Kappa Receptor Agonist Agonist Agonist Anticholinergic; Withdrawal May produce Unique Negative inotropic; syndrome in skeletal muscle Considerations Histamine release opioid-dependent rigidity patients Relative Potency 100 mg 10 mg 0.1 mg (100 mcg) IV Increments 25 mg x mg x 4 25 mcg x 4 * No DEA restrictions. Ceiling effect but not until ~30 mg; otherwise all effects equivalent. Avoid if opioid dependent!!!! Becker DE. Pharmacotherapeutics 11

12 Summary for IV Drug Dilution I.V. Increments (Total) Diazepam 5 mg/ml mg (? ) Midazolam 1 mg/ ml 1-2 mg (? ) Total amount depends on duration of appointment. Diphenhydramine 10 mg/ml mg (50mg) Promethazine 10 mg/ml mg (50mg) Exceeding this amount provides little benefit and increases risk for anticholinergic syndrome. Nalbuphine 2.5 mg/ ml 2.5 mg (10mg) Meperidine 25 mg/ml 25 mg (100 mg) Fentanyl 25 mcg/ml 25 mcg (100 mcg) Exceeding this amount significantly increases risk for PONV When to Give Up! [ DE Becker: Personal recommendations ] When treatment cannot be commenced with the patient cooperative following: PO Techniques: (Includes any pre-office doses) 0.75 mg triazolam or 30 mg diazepam or 6 mg lorazepam (Plus 50 mg hydroxyzine acceptable) Plus N 2 O titration IV Techniques: (Doses presume proper titration) 10 mg midazolam Plus 50 mg diphenhydramine or promethazine Plus 100 mcg fentanyl or equivalent opioid Becker DE. Pharmacotherapeutics 12

13 Limitations for Moderate Sedation Some patients cannot be managed using moderate sedation regimens. They simply will not cooperate while conscious! All will have some degree of sedation and anxiolysis. Explain: I cannot safely administer any further medication. Do you want to continue or we can arrange hospital or out-patient management using an anesthesiologist. Financial considerations are NOT your responsibility! Propofol / Methohexital Agonists at distinct receptors on the GABA complex Low doses potentiate GABA, like benzodiazepines Higher doses open channel directly, independent of GABA CNS Depression Propofol BZs Increasing Dose Becker DE. Pharmacotherapeutics 13

14 Ketamine Antagonist at NMDA Receptors Subclass of glutamate receptor Regulates communication between limbic and thalamocortical regions. Ketamine N methyl D aspartate (NMDA) Inhibiting this communication results in Dissociative Sedation & Anesthesia Analgesia via mu receptors accomplished at low doses Negative Effects Methohexital Propofol Midazolam Ketamine Ventilation Heart Rate MAP Nausea Residual Sedation Becker DE, Rosenberg MB, Phero JC. Intern Anesth Clinics 2013; 51(2) Becker DE. Pharmacotherapeutics 14

15 Methohexital Drug Moderate Sedation Deep Sedation/ General Anesthesia Typical Serum Conc. (mcg/ml) Propofol Loading (mg/kg) * 1-2 Infusion (mcg/kg/min) Typical Serum Conc. (mcg/ml) Ketamine Loading (mg/kg) * 1-2 Infusion (mcg/kg/min) Typical Serum Conc. (mcg/ml) Loading (mg/kg) * 1-2 Infusion (mcg/kg/min) * Low dosage range is suggested for intermittent titration techniques Advanced Agents Are you comfortable and competent in managing an unconscious patient? Do you have a well-trained 3 rd person supporting the airway and Continuously monitoring ventilation? Becker DE. Pharmacotherapeutics 15