INTRAVENOUS ANESTHESIA presentation for anesthesia

intravenous anesthesia

1. INTRAVENOUS ANESTHESIA Presentor : Dr. Anish Duwal(PGY1) Moderator : Dr. Jenny Bajracharya

2. Propofol 2,6 Di-Isopropyl Phenol Milky White pH 7 Stable at room temperature To be diluted with 5% Dextrose

3. 1% propofol 10% soybean oil (Medium ) 1.2% purified egg phospholipid (Emulsifier ) 2.25% of glycerol ( Tonicity-adjusting agent ) Sodium hydroxide ( Change the pH ) EDTA (Bacteriostatic agent )

4. Fospropofol Water-soluble prodrug of propofol Fospropofol Propofol (Prodrug) (Active metabolite) 1.86 mg of fospropofol sodium is the molar equivalent of 1 mg propofol Not associated with pain on injection Mild to moderate perineal paresthesias and pruritis minutes after a bolus injection of fospropofol ( due to Formaldehyde byproduct ) More potent , Slower onset , More Vd

5. Mechanism of action Sedative hypnotic GABA A Modulator Increases binding affinity of GABA for the GABAA receptor Coupled to a chloride channel Activation of the receptor leads to hyperpolarization of the nerve membrane. No direct action on spinal cord

6. Pharmacokinetics Intravenous administration for the induction of general anesthesia and for moderate to deep sedation Rapid onset of action Produce unconsciousness within 30 seconds Recovery from propofol is more rapid Minimal residual CNS effect Fast blood brain barrier achieved

7. Hepatic clearance: 30-60 ml/kg/min [If 50 kg patient= 1500-3000 ml/min] But, Hepatic blood flow : 800-1200 ml/min As propofol hepatic clearance > Hepatic blood flow, Extrahepatic elimination does occur i.e Renal and Pulmonary Under hepatic clearance, Propofol glucoronidation Inactive metabolites (Water soluble excreted in urine)

8. T 1/2 = 30 – 90 min Context sensitive half life : 40 minutes Drug Interactions: Midazolam can reduce the required propofol dose by more than 10% Hence , Many clinicians administer a small amount of midazolam ( eg , 30 mcg/kg) prior to induction with propofol

9. Pharmacokinetics of propofol may be altered by various factors (e.g., gender, weight, preexisting disease, age, and concomitant medication ) Reduced cardiac output ( in elderly) ; hence Low Vd Decreased elimination Decreased Induction Dose In a hemorrhagic shock , propofol concentrations increased 20 %. Women have a larger volume of distribution and higher clearance rates Relatively larger central compartment volume (50%) and a more rapid clearance (in children ) ; hence large dose requirement

10. Pharmacodynamics Effects on CNS : Decreases cerebral blood flow Decreases intracranial pressure Provide a comparable degree of cerebral protection Reduces intraocular pressure Has anticonvulsant properties

11. Effects on Cardiovascular system Decreases Arterial blood pressure Decrease in preload and cardiac contractility Markedly impairs the normal arterial baroreflex response to hypotension Rarely, Vagally mediated reflex bradycardia Heart rate unaffected Decrease in arterial blood pressure from propofol during the infusion phase is much less than intravenous bolus dose.

12. Effects on Respiratory system Profound respiratory depressant Causes apnea following an induction dose Inhibits hypoxic ventilatory drive and depresses the normal response to hypercarbia Depression of Upper airway reflexes Decreases tidal volume Increases respiratory frequency Induces bronchodilation in patients with COPD Potentiates hypoxic pulmonary vasoconstriction

13. Other Effects Does not trigger malignant hyperthermia Does not enhance neuromuscular blockade Possesses significant antiemetic activity ( 10 mg in adults ) Associated with the development of pancreatitis, which may be related to hypertriglyceridemia Intralipid : excellent culture medium, Hence , More infection associated with propofol

14. Uses Induction : Intravenous induction dose is 1 to 2.5 mg/kg. in elderly patients ; 1 mg/kg (with premedication) 1.75 mg/kg (without premedication) In children ; 2-3 mg/kg

15. Maintenance : After an induction dose, an infusion dose : 100 to 200 μg /kg/min If 50 kg patient ; 5 – 10 mg/min 300 - 600 mg/ hr 30 – 60 ml/ hr

16. For Sedation : 30-60 μ g/kg/min Infusion should be individually titrated to the desired effect In 50 kg patient; 1.5 – 3 mg / min 90 – 180 mg / hr 9 – 18 ml / hr Recommended maximal dose of propofol infusion rate : 80 μg /kg/min

17. SIDE EFFECTS AND CONTRAINDICATIONS Allergic reaction Abuse Potential During induction : Pain on injection Myoclonus Apnea Hypotension rarely, Thrombophlebitis of the vein Potential risks to fetal brain development Bacterial growth : E.Coli & Pseudomonas aerogenosa

18. Propofol Infusion Syndrome Rare but lethal syndrome Associated with infusion of propofol at 4 mg/kg/h or more for 48 hours or longer Acute refractory bradycardia leading to asystole Along with 1 or more of following: Metabolic acidosis (base deficit >10 mmol/ L−1) Rhabdomyolysis Hyperlipidemia Enlarged or fatty liver

19. Ketamine Structural analogue of phencyclidine One-tenth as potent, yet retains many of phencyclidine’s psychotomimetic effects Highly lipid soluble

20. Mechanism of action Inhibit N-methyl-D-aspartate (NMDA) channels and neuronal hyperpolarization-activated cationic (HCN1 ) channels Functionally “dissociates” sensory impulses from the limbic cortex (which is involved with the awareness of sensation) Patient to appear conscious ( eg , eye opening, swallowing, muscle contracture) but unable to process or respond to sensory input Additional actions on endogenous analgesic pathways

21. Pharmacokinetics Administered orally, nasally, rectally, subcutaneously, and epidurally, but in usual clinical practice it is given intravenously or intramuscularly Peak plasma levels are usually achieved within 10 to 15 min after intramuscular injection Orally bioavailability : 20 – 30 % Nasally bioavailability : 40% to 50%

22. Ketamine increase in cerebral blood flow and cardiac output Hence, rapid brain uptake and subsequent redistribution Awakening is due to redistribution from brain to peripheral compartments. Biotransformed in the liver to several metabolites, one of which is Norketamine End products of ketamine biotransformation are excreted renally.

23. Pharmacodynamics Effects on CNS : Increase in CMRO2 Increases cerebral blood flow Increases Intracranial pressure Dilates pupil moderately and causes nystagmus Lacrimation and Salivation common

24. Emergence reactions: Vivid dreaming Extracorporeal experiences (sense of floating out of body) Illusions (misinterpretation of a real, external sensory experience) Occurs in 1st hour then abates Benzodiazepine attenuates incidence & severity of Emergence rxn Antidepressant effects : 0.5 mg/kg, given as a 40-minute infusion

25. Effects on Cardiovascular system : Increases arterial blood pressure, heart rate, and cardiac output Increases in pulmonary artery pressure and myocardial work Causes systemic release of catecholamines Inhibition of the vagal nerve Inhibition of norepinephrine reuptake at peripheral nerves Direct myocardial depressant ; use cautiously in patient with depleted catecholamine stores

26. Effects on Respiratory system: Minimal response on the central respiratory drive Response to CO2 preserved Transient (1-3 minutes) decrease in minute ventilation after the bolus administration Relaxes bronchial smooth muscle Increases oral secretions Can produce upper airway obstruction followed by laryngospasm

27. Uses Induction and Maintenance of Anesthesia Desirable in: Unstable cardiovascular patients suffering from hypovolemia Hemorrhagic shock Cardiovascular depression in sepsis Reactive airway disease Trauma patients with extensive blood loss In children with difficult vein access

28. Sedation and analgesia Dose : 0.3-0.6 mg/kg IV over 2-3 min 2-4 mg/kg IM 0.5 to 1 mg/kg via Epidural / Caudal (Safety controversial) During burn dressing changes , debridement procedures Supplementation of regional anesthesia

29. Side Effects Increases HR, BP ,CO Stimulates oral secretion ( Antisialogue ; Glycopyrolate helpful ) Increases ICP and IOP Increases muscle tone Potentiation of Neuromuscular blockade

30. Contraindications Raised ICP Raised IOP and Penetrating eye injuries Psychiatric disorders As sole anesthetic agent in Hypertensives, IHD and CVA patients

31. Benzodiazepines Widely used in anesthesia as Anxiolytics Sedatives Hypnotics Exert their action through GABA A receptor Eg ; Diazepam, Lorazepam, Temazepam, Midazolam, Remimazolam Flumazenil : Benzodiazepine–receptor antagonist Initial dose is 0.2 mg IV (8 to 15 g/ kg IV) 0.1 mg IV (max 1 mg IV) may be administered at 60-sec intervals

32. Physicochemical Characteristics High lipophilicity of the compounds accounts for the rapid CNS effect and relatively large volumes of distribution.

33. Pharmacokinetics Influenced by age, gender, race, obesity, enzyme induction, and hepatic and renal disease Administered orally, intravenously, intramuscularly Midazolam : Oral bioavailability < 50% Peak plasma concentration : 30 to 80 minutes Lorazepam : Oral bioavailability : 90%. Peak plasma concentrations : approximately 2 hours Diazepam : Oral bioavailability :94% Peak plasma concentrations : 60 minutes.

34. Rely on the liver for biotransformation into water-soluble glucuronidated end products. Metabolites of benzodiazepines are excreted chiefly in the urine.

35. Pharmacodynamics Effects on CNS : Reduce the CMRO2 Reduces cerebral blood flow Reduces Intracranial pressure Effective in controlling seizures Produces anterograde amnesia Mild muscle-relaxing property No direct analgesic properties

36. Effects on Respiratory system : Depress the ventilatory response to CO2 Affect muscular tone leading to an increased risk of upper airway obstruction. Depress the hypoxic ventilatory response

37. Effects on Cardiovascular System: Decrease arterial blood pressure Heart rate maintained Ventricular filling pressures maintained Cardiac output maintained Stress of endotracheal intubation and surgery not blocked

38. Uses PREMEDICATION : Midazolam: 7.5 - 15 mg (Oral ) 0.025 mg/kg (Pediatric ) Diazepam : 5 - 10 mg (Oral ) Lorazepam : 2 - 4 mg (Oral ) Temazepam : 10 - 20 mg (Oral )

39. Induction and Maintenance of Anesthesia : Onset: 30- 60 seconds for Midazolam

40. Sedation : Midazolam : 0.5 – 1 mg repeated 0.07 mg/kg IM Diazepam : 2 mg repeated Lorazepam : 0.25 mg repeated Long-term IV administration of midazolam (loading dose 0.5 to 4 mg IV and maintenance dose 1 to 7 mg per hour IV) produce sedation in intubated patients

41. Nausea and Vomiting Prophylaxis : 0.075 mg/kg after induction of anesthesia Combination of midazolam with dexamethasone proved more effective Side Effects and Contraindications: Respiratory depression Venous irritation and thrombophlebitis Prolonged interval of postoperative amnesia

42. Drug Interactions As cytochrome P450 is often involved in the metabolism of the benzodiazepines ; Cimetidine , Erythromycin reduces metabolism Omeprazole, Ciprofloxacin increase the plasma half-life of diazepam Synergistic interaction by combination of opioids and benzodiazepines Benzodiazepines reduce the minimum alveolar concentration of volatile anesthetics as much as 30%

43. Barbiturates Derived from Barbituric acid Two major classes : Oxybarbiturates : Methohexital Thiobarbiturates : Thiopental & Thioamyl

44. Mechanism of action Enhance transmission of inhibitory neurotransmitters (GABA) Suppress transmission of excitatory neurotransmitters (acetylcholine and glutamate) Depress the reticular activating system in brainstem which controls consciousness

45. Pharmacokinetics Prior to the introduction of propofol, Barbiturates frequently administered intravenously for induction of general anesthesia in adults and children Rectal methohexital has been used for induction in children. Dosage:

46. Induction doses determined by redistribution, not by metabolism or elimination Thiopental’s great lipid solubility and high nonionized fraction (60%) account for rapid brain uptake (within 30 s) Less dose required in : Hypovolemic shock Elderly patient Severe liver disease or malnutrition Acidosis Loss of consciousness within 30 sec. and Awaken within 20 min.

47. Metabolised hepatically by: Oxidation ( most important ) N-dealkylation Desulfuration Destruction of the barbituric acid ring Metabolites readily excreted in the urine Or; as glucuronic acid conjugated in the bile But , Phenobarbital metabolite excreted renally.

48. Pharmacodynamics Effects on CNS: Dose-related depression of cerebral metabolic oxygen consumption rate (CMRO2) Decrease cerebral blood flow Decrease intracranial pressure Neuroprotective CPP preserved as ICP decreases more than MAP

49. Effects on Cardiovascular system : Transient decrease in BP Compensatory increase in HR Should be avoided in Hypovolemia, Congestive heart failure, β- adrenergic blockade (baroreceptor response blunted or absent ) as Cardiac Output and Blood pressure (BP) may fall drastically Can prolong QT interval , hence , should be avoided in ventricular dysrhythmias & Acidotic patient.

50. Effects on Respiratory System : Dose-related central respiratory depression Decrease ventilatory response to hypercapnia and hypoxia In thiopental , “Double apnea “ seen. Initial apnea of a few seconds upon drug administration, succeeded by a few breaths of reasonably adequate tidal volume, followed by a more prolonged period of apnea ~25 secs. Incompletely depress airway reflex responses

51. Uses Induction and Maintenance of Anesthesia Cerebral Protection Refractory seizures Providing anesthesia during Electroconvulsive Therapy

52. Side effects Intra-arterial Injection Immediate, intense vasoconstriction and excruciating pain that radiates along the distribution of the artery. Severe Vasoconstriction may obscure distal arterial pulses. Gangrene and permanent nerve damage may occur Mechanism of Damage: Due to be the precipitation of thiopental crystals, inflammatory response and arteritis microembolization that follows, results in occlusion of the distal circulation. Treatment Immediate attempts to dilute the drug --- injection of saline Prevention of arterial spasm & sustain adequate blood flow with vasodilators as lidocaine, papaverine stellate ganglion block or brachial plexus block CYP inducer , hence changes metabolism of other drugs

53. Contraindications Acute Intermittent Porphyria Aminolevulonic acid induced Cardiovascular collapse Impending coma ( Hepatic failure, Renal failure, Diabetes) Adrenocortical failure Myxedema Severe anemia

54. Etomidate Carboxylated imidazole derivative Chemically unrelated to any other drug To increase its solubility it is formulated as a 0.2% solution either in 35% propylene glycol Or, in a lipid emulsion Original formulation painful

55. Mechanism of action Depresses the reticular activating system Mimics the inhibitory effects of GABA Bind to a subunit of the GABAA receptor, increasing the receptor’s affinity for GABA Disinhibitory effects on the parts of the nervous system that control extrapyramidal motor activity Hence, 30 – 60 % incidence of myoclonus

56. Pharmacokinetics Available only for intravenous administration Despite highly protein bound, very rapid onset of action due to its great lipid solubility and large nonionized fraction at physiological pH Hepatic microsomal enzymes and plasma esterases rapidly hydrolyze etomidate to an inactive metabolite End products primarily excreted in the urine.

57. Pharmacokinetics Effects on CNS: Decreases CMRO2 Decreases cerebral blood flow Decreases intracranial pressure Cerebral perfusion pressure is well maintained produces increased EEG activity in epileptogenic foci Useful for intraoperative mapping of seizure foci before surgical ablation Postoperative nausea and vomiting Lacks analgesic properties

58. Effects on Cardiovascular system: Minimal effects Mild decline in arterial blood pressure Myocardial contractility and cardiac output usually unchanged May not ablate sympathetic response to laryngoscopy

59. Effects on Respiratory system: Minimal effect on ventilation Does not induce histamine release in healthy patients or in patients with reactive airway disease. Ventilatory response to CO2 is depressed Produces a brief period of hyperventilation, sometimes followed by a similarly brief period of apnea

60. Effects on Endocrine system: Dose-dependent reversible inhibition of the enzyme 11β-hydroxylase Inhibit cortisol and aldosterone synthesis Concentrations associated with adrenal cortical suppression are less than 10 ng/mL, which are much lower than the concentrations needed for hypnosis (more than 200 ng/mL)

61. Uses Induction of anesthesia Dose : 0.2 to 0.6 mg/kg Induction dose is reduced by premedication with an opiate, a benzodiazepine, or a barbiturate Appropriate in patients with Cardiovascular disease Reactive airway disease Intracranial hypertension Maintenance Brief deep sedation such as prior to placement of retrobulbar blocks

62. Side effects Post operative nausea vomiting Pain on injection Myoclonic movement Hiccup Adrenocortical suppression Allergic reaction Epilepsy

63. Dexmedotomidine α2- adrenergic agonist Used for : Anxiolysis Sedation Analgesia Loading dose : 1 mcg/kg 5 to 10 min Maintenance dose : 0.2 to 1.4 mcg/kg/h

64. References Millers Anesthesia 9 th Edition Morgan and Mikhail’s Clinical Anesthesiology 6 th Edition STOELTING’S HANDBOOK OF Pharmacology and Physiology in Anesthetic Practice THIRD EDITION

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