Anesthestics - sedative drugs during sedation

Sedative Hypnotic Drugs Fast Refreshing Review

1. Anesthetic sedative And hypnotic drugs Dr Mohamed AbdulRazik alsaaid ali Anesthesia Department Rashid hospital Trauma Center

2. Introduction Procedural Sedation And Analgesia (PSA) A Technique Used, To Minimize Discomfort And Apprehension During Procedure With Appropriate Non-Pharmacological & Pharmacological Interventions To Facilitate The Effective Performance Of A Procedure.

3. Effective Procedural Sedation Requirements Analgesia : Pain Experienced By The Patient Should Be Treated With Analgesia Rather Than Sedation. Anxiolysis : Pharmacological Methods Of Reducing Anxiety Are Often Very Effective And Include Consideration Of The Environment And Patient Comfort. Sedation : For Most Procedures, The Level Of Required Sedation Will Be Moderate To Deep, This Should Be Determined In Advance. Amnesia : A Degree Of Amnesia Will Minimize Unpleasant Memories Associated With The Procedure.

4. IDEAL SEDATIVE AGENT Maintain Respiratory Drive. Provide Adequate Sedation (Somnolence). Provide Adequate Analgesia. Provide Anxiolysis. Provide Amnesia Of Unpleasant Sensations. Have A Rapid Onset And Short Recovery Time With Predictable Results. W ould Have No Adverse Effects. Have An Antidote.

5. Good Practice of Sedation The Use Of Sedative Drugs Does Not Abolish The Need For Good Communication Skills With The Patient And A Sympathetic Manner . No One Technique Is Suitable For All Patients . The Simplest And Safest Technique Is The Rule. Titrating A Drug/Drugs To Effect Is Critical To Safety . The Initial Dose Must Have Taken Full Effect Before An Additional Dose Is Given. While Over-Sedation Must Be Avoided, Under-Sedation Will Have An Adverse Effect On The Patient And The Delivery Of Effective Treatment. As A General Rule, Single Drugs Are Easier To Titrate To Effect And Safer Than Sequential Administration Of Two Or More Drugs. Multiple Anesthetic Drug Techniques Should Only Be Considered By Those Skilled In Their Use, Where There Is Clear Clinical Justification.

6. Choice of Sedation Agents The Appropriate Choice Of Pharmacological Agents For PSA Depends On: The Nature Of The Procedure. The Planned Level Of Sedation. Training And Familiarity Of The Sedating Practitioner With Potential Pharmacological Agents. Patient Factors. The Local Environment.

7. Drugs used in Moderate Sedation BENZODIAZEPINES KETAMINE ETOMIDATE PROPOFOL KETOFOL CHLORAL HYDRATE DEXMEDETOMIDINE

8. BENZODIAZEPINES A Category Of Drugs Widely Used In Anesthesia As Anxiolytics, Sedatives, & Hypnotics They Exert Their Action Through GABA-A Receptors, Which Are The Key Targets That Mediate Most Of The Clinically Important Effects Of IV Anesthetics Commonly Used In Sedation/Anesthesia: Midazolam, Diazepam, Lorazepam, And Temazepam Remimazolam , An Ultrashort-acting GABA-A Receptor Agonist, May Be A Useful Benzodiazepine In Future Anesthetic

9. DIAZEPAM Long-Acting BZD Mild To Moderate, Procedural Anxiolysis, and Amnesia. Dosage : Oral 5-10mg, IV 2mg Increments Advantages : Reversible Disadvantages : Poorly Soluble In Water Dilution In Water Causes Cloudiness But Not Affect Potency, Active Metabolites With Long Half Life Respiration Depression, Excessive Sedation, And Hypotension

10. MIDAZOLAM After Oral Ingestion , Midazolam Is Absorbed Completely, And The Peak Plasma Concentration Is Achieved In 30 To 80 Mins After IV Administration , Midazolam Is Rapidly Distributed, With A Distribution Half Life Of 6 To 15 Mins The Elimination Half-life Ranges From 1.7 To 3.5 Hours The Pharmacokinetics Of Midazolam Is Affected By Obesity, Age, And Hepatic Dysfunction Midazolam Is Metabolized By Liver In Patients With Renal Impairment, Its Main Metabolite And Its Conjugated Metabolite Can Cause Profound Sedation

11. Midazolam Has Hypnotic, Sedative, Anxiolytic, Amnestic , Anticonvulsant , And Centrally Produced Muscle- Relaxing Properties . It Produces Dose-related Central Respiratory System Depression: Through An Effect On The Muscular Tone Leading To An Increased Risk Of Upper Airway Obstruction. It Flattens The Response Of The Respiratory Curve To CO2. Benzodiazepines And Opioids Produce Additive Or Super - Additive (Synergistic) Respiratory Depression, Even Though They Act At Different Receptors Old Age, Debilitating Disease, And Other Respiratory Depressant Drugs Increase The Incidence And Degree Of Respiratory Depression And Apnea By Benzodiazepines.

12. KETAMINE Pharmacologic Class: Antagonist Of The NMDA Receptor Bioavailability Is 93% After Parenteral Administration IV Or IM Metabolized By Hepatic Microsomal Enzymes Produces Dose-related Unconsciousness And Analgesia

13. A Trance-like Cataleptic State Induced By The Dissociative Agent Ketamine Characterized By Profound Analgesia And Amnesia, With Retention Of Protective Airway Reflexes, Spontaneous Respiration, And Cardiopulmonary Stability Sedation Spectrum Dissociative Sedation The Anesthetized State Has Been Termed Dissociative Anesthesia Because Patients Who Receive Ketamine Alone Appear To Be In A Cataleptic State, In Contrast To Other States Of Anesthesia That Resemble Normal Sleep.

14. Profound Analgesia Maintain Many Reflexes Lacrimation And Salivation Are Common Increase Skeletal Muscle Tone The Duration After A Single IV Administration Of A General Anesthetic Dose (2 mg/kg) Is 10 To 15 Minutes Full Orientation To Person, Place, And Time Occurs Within 15 To 30 Minutes Concomitant Administration Of Benzodiazepines, Which Is A Common Practice, May Prolong The Effect Of Ketamine And Minimize Its Side-effects

15. Adverse effects: Sympathomimetic Reactions Transient Hypertension (10 - 50% Increase From Baseline & 5 - 10% Incidence) Transient Tachycardia Laryngospasm. Ketamine Maintain Airway Reflexes. Any Secretion In Oropharynx Can Cause Laryngospasm 3. Emergence Phenomena Ranges (Frequency 0­‐30%) Vivid, Possibly Frightening, Hallucinations During Emergence From Anesthesia Adults > Children Risk Increases With: Single Dose ≥ 2.5 mg/kg IV And Total Dose ≥ 5 mg/kg IV Treatment/Prevention: Pretreatment With Midazolam 0.05 mg/kg IV Or Propofol 10 – 20 mg 4. Contraindicated In ICP, Psychiatrics, Ischemic Cardiac Patients

16. PROPOFOL Non - ­Barbiturate Hypnotic Sedative Ɣ - ­Aminobutyric Acid A (GABA-A) Receptor Agonist Global Central Nervous System Depression NMDA Receptor Antagonism Leads To Amnestic Effects The Color Of Solution Is Milky White Available In 1% And 2% Concentration Emulsion Is Isotonic And Has A Ph Of 4.5-6.4 It Is Preservative Free So Should Be Used Within 6hrs After Opening The Vial Because There Have Been Death Reports Following The Use Of Contaminated Solution Of Propofol (As Egg Lecithin Is A Good Media For Bacterial Growth) Injection Can Be Very Painful (This Can Be Prevented By Pre-anesthetizing The Vein Mucosa By 2 ml Xylocaine)

17. Effects on Organ Systems Cardiovascular Hypotension Due To Drop In SVR (Inhibition Of Sympathetic Vasoconstrictor Activity), Preload And Cardiac Contractility Respiratory Profound Fall In Tidal Volume Leading To Apnea In Many Patients. Inhibits Hypoxic Ventilatory Drive And Depresses The Normal Response To Hypercarbia. Induces Bronchodilatation Hypotension, Apnea, Airway Obstruction, And/Or Oxygen Desaturation Can Occur, Especially With A Rapid Bolus Injection

18. Contraindications Egg Allergy Is Not A Contraindication For Its Use!! Obstetrical Procedures( Propofol Crosses The Placenta; And May Be Associated With Neonatal Depression ) Propofol Is Not Recommended For Use In Nursing Mothers Because Propofol Has Been Reported To Be Excreted In Human Milk, And The Effects Of Oral Absorption Of Small Amounts Of Propofol Are Still Not Known

19. KETOFOL Mixing Propofol & Ketamine To Produce A 1:1 “ Ketofol ” Solution: Propofol 10mg + Ketamine 10mg/ Ml Dose: 0.5mg/kg - 0.75mg/kg Of Both Agents Benefits: Lower Doses Of Each Sedative Results In Decreased Dose‐related Side Effects Opposing Actions May Moderate Each Effect

20. Adverse Events of Ketofol Compared to Ketamine

21. Adverse Events of Ketofol Compared to Propofol

22. ETOMIDATE Pharmacologic Class: GABA Receptor Agonist. Maintain Respiratory Drive At Anesthetic Doses Cardiovascular Stability Onset: 1min Duration: 5-15 Min Initial Dosing: 0.1 mg/kg IV Repeat Dosing/Titration: 1-2 Mg IV Every10 Min Route: IV Reversal: No Safety Implications: Limited Effects On Cardiovascular And Hemodynamic Function Even In Patients With Comorbid Diseases The Carrier Vehicle Is Propylene Glycol, It Can Cause Pain And There Is Possibility For The Development Of Thrombophlebitis When Administered Via A Peripheral Vein Side Effect : Emergence Nausea/Vomiting, Adrenal Suppression, Myoclonus/Seizure Activity

23. Chloral Hydrate A Medication Used To Calm Patient. It Belongs To A Class Of Drugs Known As Hypnotics - A Pure Sedative Hypnotic With No Analgesic Properties. It May Produce A State Of Disinhibition With An Agitated Response To Noxious Stimuli.  It Is Used As An Adjunct For Painful Therapeutic Procedures. Most Effective In Children. Administration Oral: May Dilute Syrup In Water Or Other Oral Liquid (Fruit Juice) To Minimize Gastric Irritation. 50-75 mg/kg (0.5g – 1.0g) PO Given 30 Minutes Before Sedation. Maximum Single Or Total Daily Dose: 2 Grams/Day PO. Onset Of Action Occurs Within 0.5—1 Hour, With A Duration Of Action Of Approximately 4—8 Hours. Oral: Well Absorbed. Avoid Use In Elderly Metabolism Rapidly Hepatic Metabolized By Alcohol Dehydrogenase To Trichloroethanol (Active Metabolite); Trichloroethanol Undergoes Glucuronidation In The Liver; Variable Amounts Hepatically And Renally Metabolised To Trichloroacetic Acid (Inactive) Crosses The Placenta And Is Distributed Into Breast Milk.

24. Mechanism Of Action Is Unknown. CNS depressant Effect Appears To Be Due To Its Active Metabolite, Trichloroethanol . BP And Respiration Are Depressed Only Slightly More Than In Normal Sleep, And Reflexes Are Not Significantly Depressed. High Doses Of Chloral Hydrate Induce Respiratory And Vasomotor Depression. Cautious Use With Other Sedatives Or Opioids – May Increase The Risk Of Respiratory Complications.  Contraindications Hypersensitivity To Chloral Hydrate Or Any Component Of The Formulation; Marked Hepatic Or Renal Impairment. Antagonist None Available.

25. Dexmedetomidine In December 1999, Dexmedetomidine Was Approved As The Most Recent Agent As A Short-term Sedative. An Alpha 2 Adrenergic Receptor Agonist. Has Several Beneficial Actions During The Perioperative Period. Improved Side Effect Profiles. Allows Psychomotor Function To Be Preserved While Letting The Patient Rest Comfortably. Provides A New Concept For The Administration Of Perioperative Anesthesia And Analgesia. Adrenergic Receptors Are Divided Into Two General Categories: Α And Β. Each Of These Has Been Further Subdivided Into At Least Two Subtypes: Α1 And Α2, And Β1, Β2, And Β3. Dexmedetomidine Has A 1600:1 Preference For Α2 Receptors Relative To Α1 Receptors.

26. The Site For The Sedative Action Is In The Locus Ceruleus Of The Brain Stem , Whereas The Principal Site For The Analgesic Action Is Probably In The Spinal Cord ( They Cannot Be Used As Sole Analgesic ). In The Heart, The Dominant Action Of Α 2 Agonists Is A Decrease In Tachycardia (Through Block Of The Cardio- Accelerator Nerve) And Bradycardia (Through A Vagus Nerve ( X th ) Action). In The Peripheral Vasculature, There Are Both A Vasodilatory Action Via Sympatholytic Effect And Vaso - Constriction Mediated Through The Receptors In The Smooth Muscle Cells. The Mechanism For The Anti Shivering And Diuretic Actions Have Yet To Be Discovered. Physiology of Dexmedetomidine There Is Clear Evidence For Both A Peripheral And A Supraspinal Site Of Action.

27. Pharmacokinetics Rapid Distribution Phase – With Half-life 6 Min Elimination Half-life Of 2.0 - 2.5 Hours Protein Binding – 94 % Metabolism –Complete Biotransformation In The Liver With No Known Active Or Toxic Metabolites. The Metabolites Are Eliminated To The Extent Of 95% In The Urine. Pharmacokinetics Similar In Young Adults And Elderly. (IV) Onset Of Action After Approximately 15 Minutes. Peak Concentrations Within 1 Hour After Continuous IV. No Accumulation After Long Infusion Time. It Is Also Absorbed Systemically Through The Transdermal, Oral, Or Intramuscular Routes Bioavailability Orally 82% And IM 100%.

28. Pharmacodynamics Hemodynamic CNS Respiratory Metabolic Organ Protective Biphasic, Dose-Dependent Sedation Limited Respiratory Effects, Leading To A Wide Safety Margin. Suppresses Shivering Reduction In Perioperative Myocardial Ischemia Episode. Hypertension Hypnosis Hypercapnic Arousal Is Preserved Neuroprotective Properties Of Cerebral Ischemia Hypotension Anxiolysis Apnea Threshold Is Actually Decreased Decrease Heart Rate Amnesia Analgesia.

29. TOXICOLOGY AND SIDE-EFFECTs The Teratogenic Effects Have Not Been Adequately Studied At This Time. Drug Does Cross The Placenta And Should Be Used During Pregnancy Only If The Benefits Justify The Risk To The Fetus. The Adverse Effects Include Initial Hypertension, Nausea, Bradycardia, Atrial Fibrillation. Overdose (Rapid Infusion) May Cause First Degree Or Second-degree Atrioventricular Block. Most Of The Adverse Events Use Occur During Or Shortly After Loading Dose. Prolonged Infusion May Cause Delayed Recovery. Contraindications : Caution With Patient With Advanced Heart Block Ventricular Dysfunction, Conductive Arrhythmias Shock, Hypovolemia Clearance Is Lower In Hepatic Impairment Severe Cardiovascular Impairment Patients With Thermogenic Impairment (High Risk For Hypothermia  Use Active Warming ).

30. Induction Sedation : Loading Dose Of 0.3 – 0.5 mcg/kg In 10mins. Peak Effect Starts 6 mins After Loading Dose. Potentiates All Sedation Drugs ! (↓ Dose Of Other Drugs) Maintenance Of Anesthesia : 0.3 – 0.5 mcg/kg/ hr. Infusion. Precautions Never Give Bolus (Causes Severe Bradycardia/Hypertension). Always End Infusion 20 – 30 Mins Before End Of Procedure. Patients Require 2 - 4 Hrs. Recovery Time Drug Interaction Vagal Effects Can Be Counteracted By Atropine

31. Conscious Sedation Procedures Using Intravenous Midazolam for Dental Care in Patients with Different Cognitive Profiles: A Prospective Study of Effectiveness and Safety, PLOS.Org . Published: August 5, 2013 Ketofol: A Combination of Ketamine and Propofol. J Anesth Crit Care Open Access 1(5): 00031. DOI: 10.15406/ jaccoa.2014.01.00031 EBM consult: Sedatives and Hypnotics used in anesthesia and procedural sedation Morgan & Mikhail’s Clinical Anesthesiology , 5 th Edition, Chapter 9, Intravenous Anesthetics Procedural sedation: A review of sedative agents, monitoring, and management of complications Saudi J Anaesth . 2011 Oct-Dec; 5(4): 395–410. Safety and Efficacy of the Moderate Sedation During Flexible Bronchoscopic Procedure, Medicine (Baltimore). 2015 Oct; 94(40): e1459. Clinical Pharmacokinetics And Pharmacodynamics Of Dexmedetomidine. M. A. S. Weerink Et Al. Clin Pharmacokinet 2017 April , DOI 10.1007/S40262-017-0507-7. Update On Dexmedetomidine: Use In Nonintubated Patients Requiring Sedation For Surgical Procedures Therapeutics And Clinical Risk Management. Shukry And Miller Et Al, 2010; 6:111–121. Conscious Sedation Using Dexmedetomidine For Percutaneous Transcatheter Closure Of Atrial Septal Defects: A Single Center Experience. Desai PM. Et Al Ann Card Anaesth 2016;19:463-7. Dexmedetomidine In Current Anaesthesia Practice- A Review. Journal Of Clinical And Diagnostic Research. 2014 Oct, Vol-8(10): GE01-GE04 References