Anesthesia Review PDF (2nd Edition) by Kaushik Jothinath

Anesthesia Review Anesthesia Review Second Edition Kaushik Jothinath MBBS DNB FIACTA FCA Consultant Pediatric Cardiac Anesthesiologist G Kuppuswamy Naidu Memorial Hospital Coimbatore, Tamil Nadu, India JAYPEE BROTHERS M...

Anesthesia Review Anesthesia Review Second Edition Kaushik Jothinath MBBS DNB FIACTA FCA Consultant Pediatric Cardiac Anesthesiologist G Kuppuswamy Naidu Memorial Hospital Coimbatore, Tamil Nadu, India JAYPEE BROTHERS MEDICAL PUBLISHERS The Health Sciences Publisher New Delhi | London  Jaypee Brothers Medical Publishers (P) Ltd Headquarters Jaypee Brothers Medical Publishers (P) Ltd 4838/24, Ansari Road, Daryaganj New Delhi 110 002, India Phone: +91-11-43574357 Fax: +91-11-43574314 Email: [email protected] Overseas Office J.P. Medical Ltd 83 Victoria Street, London SW1H 0HW (UK) Phone: +44 20 3170 8910 Fax: +44 (0)20 3008 6180 Email: [email protected] Website: www.jaypeebrothers.com Website: www.jaypeedigital.com © 2021, Jaypee Brothers Medical Publishers The views and opinions expressed in this book are solely those of the original contributor(s)/author(s) and do not necessarily represent those of editor(s) of the book. All rights reserved. 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Inquiries for bulk sales may be solicited at: [email protected] Anesthesia Review First Edition: 2016 Second Edition: 2021 ISBN 978-93-90020-75-1 AT THY LOTUS FEET   Preface It was during my postgraduate years that I realized that the subject of anesthesiology does not have a comprehensive and examination-oriented book. The pursuit of DNB as a postgraduation degree itself is an arduous task, owing to the difficult work schedule, and high expectations from the students at the time of examinations. This problem is compounded manifold for the subject of anesthesiology, as it is a discipline in which the students have to have a wide base of knowledge. Most of the textbooks available today are not student-friendly as there is a lot of information in them, from which the examinee has to pick and retain in memory only those details which are necessary. As a result, there is a whole lot of unwanted information to which he is subjected, which may be confusing at the time of examinations. Secondly, there is no single textbook which gives all the details in an examination-oriented format. As a result, the student is forced to study from several different textbooks spanning multiple subjects. Also, owing to the importance of knowledge of various clinical guidelines, it becomes mandatory for the anesthesiology examinee to be familiar with the latest guidelines across a wide variety of disciplines. I have attempted to address these problems by compiling a book, which is student-friendly, well researched and is based on the most recent clinical practice guidelines. This book has been written to cater to the DNB anesthesiology board examinations in a comprehensive and point-based system. Also, most of the references are from standard textbooks in order to prevent confusion arising due to numerous research papers published in the recent past. Therefore, the information has been provided in a highly concise, crisp and readable manner to help you crack the anesthesiology boards. Hope you enjoy reading it and wishing you all the best to crack your boards!! Kaushik Jothinath  Acknowledgments My humble gratitude to my teacher, father figure and guiding spirit, Dr Krishnadasan, without whom this book would not have materialized. Your encouragement and motivation have been vital in bringing forth this second edition. I am also indebted to Dr Sathya Swaroop Patnaik for his help during those difficult years when life looked uncertain. He was an invaluable guide and helping hand, who showed me the way during this arduous journey. Bhishma sir, the man who lives up to his name, will always be remembered for the exceptional moral support he gave, during those years. I sincerely acknowledge all my anesthesiology professors Dr Debadas Bagchi, Dr Pandey, Dr Anand, Dr Hemadri, Dr Kolli S Challam, Dr Prabhakar, Dr Jayashree Simha, Dr Iyer, Dr Vasanth Nayak, Dr Prabhakar, Dr Parameshwar, Dr Suma, Dr Murthy, Dr Rehana, Dr Jalaja, Dr Ramachandra, Dr Sowmini, Dr Kumaresan, Dr Manjunath, Dr Niranjan, Dr Vaishali and Dr Anita for their enormous help and guidance during the formative years of this book. I am also immensely thankful to my mentors Dr Vindhya Kumar, Dr Shivananda N.V and Dr Nagaraj. I have been immensely lucky to have learnt the art of anesthesia from you all. My humble gratitude to the CEO of GKNM hospital Dr. Raghupathy Veluswamy for the immense support given to me for the second edition of this book. I would also like to thank my teachers in the department of Anesthesiology, GKNM hospital, Dr Rajani Sundar, Dr Soundaravalli Balakrishnan, Dr Sai Gopalakrishnan, Dr Anandhi Arul and Dr Palaniappan for being the sturdy, unrelenting backbone behind the entire process of giving shape to the second edition. I am also thankful to my colleagues Dr Karthik Babu, Dr Manikandan and Dr Naresh Kumar from GKNM Hospitals for their valuable guidance and support. I sincerely acknowledge Dr S Muralidharan, Dr P Chandrashekhar, Dr Sundar Ramanathan, Dr Madhav Rao and Dr Shobha Menon from GKNM Hospitals for their valuable inputs into this book. My acknowledgement would be incomplete if I do not mention my colleague and friend Dr Vijayakumar Raju who inspires everyone around with his sheer hard work and will power as a congenital heart surgeon. I will be indebted to my closest friend Mahesh T. Venkataramani, whose constant inputs and feedback at various stages made this book what it is My biggest source of strength has been my group of friends, Dr Satya Swaroop Patnaik, Dr Anoop Pothen John, Dr Gokulakrishnan, Dr Aamir Farooq Siddique, Dr Abhinay Indrakumar Reddy and Dr Sandeepan. I also appreciate the continuous moral support given by my parents and wife during this process. Thank you for your patience. I am also thankful to all my colleagues and staff at Sri Sathya Sai Institute of Higher Medical Sciences, Manipal Hospital and GKNM hospital for rendering a helping hand. I appreciate Shri Jitendar P Vij (Group Chairman) and Mr Ankit Vij (Managing Director), M/S Jaypee Brothers Medical Publishers (P) Ltd, for their patience, encouragement and punctuality for publishing this book. I would also like to thank Ms Chetna Malhotra Vohra (Associate Director–Content and Strategy), Ms Saima Rashid (Publishing Manager) and Mr Santosh Kumar (Commissioning Editor) from Jaypee Brothers for their thoughtful insights into making this second edition a more user friendly version. Finally I would like to thank all my students for making the first edition of this book an enormous success story. I owe this book to everyone who contributed directly or indirectly. Any oversight is purely unintentional.  Contents 1. Anesthetic Pharmacology.................................................................................................................................................1 2. Neuroanesthesia..............................................................................................................................................................79 3. Cardiac Anesthesia........................................................................................................................................................211 4. Anesthesia for Respiratory Disease............................................................................................................................478 5. Anesthesia for Endocrine Disorders...........................................................................................................................638 6. Anesthesia and the Kidney..........................................................................................................................................678 7. Anesthesia and Liver.....................................................................................................................................................717 8. Pain and Regional Anesthesia.....................................................................................................................................743 9. Machine and Monitors..................................................................................................................................................782 10. Ophthalmic Anesthesia.................................................................................................................................................853 11. Obstetric Anesthesia......................................................................................................................................................864 12. Miscellaneous Topics.....................................................................................................................................................985 13. Pediatric Anesthesia....................................................................................................................................................1073 14. ICU and Mechanical Ventilation...............................................................................................................................1124 15. Perioperative Fluid Therapy and Blood Transfusion.............................................................................................1240 16. Transplant Anesthesia.................................................................................................................................................1324 DNB Question Papers....................................................................................................................................................1361  1 CHAPTER Anesthetic Pharmacology DRUG INTERACTIONS ™™ Drugs forming toxic compounds: Halogenated agents + Baralyme → CO + heat Classification Sevoflurane + Baralyme → Sevo-olefin ™™ Pharmaceutical interactions NO + O2 → NO2 (toxic at > 10 ppm concentration) ™™ Pharmacokinetic interactions: Pharmacokinetic Interactions Absorption Distribution I. Absorption Cardiac output alterations ™™ Altered mechanism of absorption: Ion trapping Oral tetracycline inactivated with Mg2+/Ca2+/ Al3+ antacids Protein binding Oral anti-diarrheals (kaolin/pectin) absorb Metabolism digoxin Hepatic biotransformation Bile acid binding residue cholestyramine binds Elimination to warfarin and reduces absorption ™™ Pharmacodynamic interactions: ™™ Reduced regional perfusion: Affecting hemodynamics Reduced local anesthetic absorption when adren- Affecting analgesia/hypnosis aline added Problems Due to Drug Interactions II. Distribution ™™ Cardiac output altering distribution: ™™ One drug may antagonize action of other Thiopentone/propofol/remifentanyl causes ™™ Toxicity due to drug interaction reduced cardiac output ™™ Reduced therapeutic window of warfarin/digoxin/ Volatile anesthetics reduce cardiac output and theophylline have increased CNS effect ™™ Unable to identify the drug producing clinical effect ™™ Ion trapping: ™™ Increased idiosyncratic reactions: MAO inhibitors Drug induced changes in pH causing altered with meperidine distribution Antacids/H2 blockers/proton pump inhibitors Pharmaceutical Interaction reduce absorption of acidic drugs Introduction Altered urinary pH affects renal clearance of drugs Chemical/physical interaction which occurs before a drug is administered/absorbed systemically. ™ ™ Plasma protein binding: Displacement of bilirubin by sulphonamides Types causing kernicterus ™™ Incompatibility between two drugs in solution: Displacement of warfarin by phenylbutazone/ Thiopentone precipitates when given with succ- phenytoin inylcholine III. Metabolism Sodium bicarbonate reduces solubility of bupi- ™™ Acetylcholine esterases/nonspecific esterases: vacaine and precipitates it Neostigmine/pyridostigmine increases succi- Sodium bicarbonate inactivates catecholamines nylcholine effects 2 Anesthesia Review Neostigmine increases action of ester local Etomidate inhibits cytochrome P450 dependant anesthetics: 17 α hydroxylase and 11 β hydroxylase –– Procaine This causes reduced synthesis of cortisol and –– Cocaine aldosterone –– Tetracaine ™™ Enzyme inducers: ™™ MAO inhibitors interaction: Phenobarbitone They increase action of indirect acting sympatho- Phenytoin mimetics: Rifampicin –– Ephedrine Carbamezipine –– Amphetamine Ethanol They may cause hypertensive crises due to ™™ Enzyme inhibitors: tyramine present in aged cottage cheese: Wine Cimetidine and cheese reaction Ketoconazole They increase action of direct acting sympatho- Erythromycin mimetics to a lesser extent: Disulfiram –– Epinephrine, Ritonavir –– Norepinephrine When given with meperidine it causes serotonin V. Elimination syndrome: ™™ Ion trapping: Phenobarbital (weak acid) excretion is –– Excitation and hyperpyrexia increased in acidic urine –– HTN, diaphoresis, rigidity ™™ Ion secretion: –– Seizures, coma and death Probenecid inhibits secretion of penicillin IV. Hepatic Biotransformation Quinidine reduces Vd and clearance of digoxin ™™ Drugs with high extraction ratio (ER ≥ 0.7): Pharmacodynamic Interactions Examples of drugs with high ER: I. Additive Interactions –– Lidocaine ™™ Occurs when drugs with similar mechanism of –– Propranolol action are combined Blood flow to liver is rate limiting as metabolism is at maximum ™™ Rocuronium + vecuronium: Additive effect Lidocaine concentration increases due to: ™™ 2 volatile anesthetics or N2O + VA: Additive effect –– Reduced hepatic blood flow due to reduced II. Antagonistic Interaction cardiac output ™™ SCH + NDMR –– Vasopressors: Isoproterenol and noradrena- ™™ Neostigmine + NDMR line ™™ Flumazenil + Benzodiazepines ™™ Drugs with low extraction ratio (ER ≤ 0.3): ™™ Naloxone + opioid Examples of drugs with low ER: –– Diazepam ™™ Butorphanol + midazolam: increased sedation but –– Mepivacaine less anterograde amnesia than midazolam alone –– Alfentanyl III. Synergistic Interaction Activity of hepatic enzymes is rate limiting as ™™ Small doses of 2 drugs producing larger effects enzyme induction can increase metabolism ™™ Opioid potentiation by NSAIDs Midazolam and fentanyl are competitive ™™ NDMR potentiation by volatile anesthetics inhibitors of CYP3A4 ™™ Aminosteriod + benzylisoquinoline NDMR Propofol inhibits CYP3A4 and reduces clearance of midazolam by 37% IV. Pharmacodynamic Interactions Affecting Hemody- Erythromycin increases effect of alfentanyl namics Cimetidine inhibits metabolism of warfarin, ™™ Tricyclic antidepressants can increase effects of diazepam, phenytoin and morphine direct/indirect acting agonists Ketoconazole inhibits clearance of midazolam, ™™ β2 agonists may cause tachycardia and ectopic theophylline, warfarin and digoxin rhythms  Anesthetic Pharmacology 3 V. Interactions Affecting Analgesia/Hypnosis ™™ Solution has highly alkaline bacteriostatic properties ™™ Opioid – hypnotic: with pH of 10.8 and pKa of 7.6 Fentanyl reduces barbiturate need ™™ Reconstitution: Opioids potentiate propofol Should not be reconstituted with Lactated ™™ Opioid – Benzodiazepine: Ringers or acidic solutions Fentanyl potentiates midazolam This will cause a reduction in alkalinity of the ™™ Opioid – volatile anesthetic: solution Thus, barbiturates will precipitate as free acids Fentanyl at 1.67 ng/mL blood concentration reduces isoflurane MAC by 50% Once reconstituted, it can be used for 1 week if refrigerated Butorphanol and nalbuphine also reduces MAC ™™ Benzodiazepine – hypnotic Mechanism of Action Thiopentone potentiates midazolam ™™ Two principle mechanisms of action: Propofol hypnosis increased with midazolam Enhancement of synaptic actions of inhibitory ™™ α2 agonist interaction: neurotransmitters: GABA receptors Dexmedetomidine potentiates opioids and Blockade of synaptic actions of excitatory benzodiazepines (BZDs) neurotransmitters: Dexmedetomidine reduces halothane MAC by –– Inhibits synaptic transmission of glutamate, almost 100% adenosine receptors ™™ Three way interactions: –– This blocks excitatory CNS transmission Propofol dose reduces by 86% in combination ™™ At GABAA receptors: with midazolam and alfentanyl Positive allosteric modulation: Enflurane MAC reduces with dexmedetomidine –– Thiopentone binds to GABAA receptor and fentanyl –– This increases channel opening time of Cl- channels THIOPENTONE –– Thus chloride conductance through the ion channel increases Introduction –– This causes hyperpolarization of the cell ™™ Introduced by Waters and Lundy in 1934 membrane ™™ Thio-barbiturate which is commonly used as a –– Thus, threshold of excitability of postsynap- hypnotic inducing agent tic neuron is increased Reduces dissociation of GABA from receptors: Chemistry –– Occurs at lower concentrations ™™ Derivative of barbituric acid formed by condensation –– Rate of dissociation of GABA from GABAA of urea and malonic acid receptor is reduced ™™ Oxygen in barbituric acid replaced by: –– This causes sustained inhibition of RAS Sulphur at urea derived carbon position 2 –– This may be responsible for hypnotic action Branched chain group at carbon position 5 of thiopentone ™™ This gives the drug short duration of action Mimics GABA action by directly stimulating GABAA receptors ™™ S (–) isomers of thiopental are more potent than R (+) isomers Pharmacodynamics ™™ Commercial preparations are racemic mixtures ™™ Central nervous system: Cerebro-protective effect: Sedation Presentation Rapid induction of anesthesia ™™ Hygroscopic yellow powder Antalgesic in lower doses: Reduces pain threshold ™™ Clinically used as 2.5% solution Anti-convulsant ™™ Contains thiopentone with 6% anhydrous Na2CO3 Depresses respiratory center stored under atmosphere of nitrogen Depresses vasomotor center ™™ Nitrogen prevents precipitation of insoluble acid Retrograde amnesia: Midazolam causes anterograde formed by atmospheric carbon dioxide amnesia 4 Anesthesia Review Reduced cerebral blood flow, cerebral vasocon- Rapid onset of action as: striction –– High blood flow to brain Reduces ICP, depresses cerebral metabolism –– Lipophilicity of drug Reduces intra-ocular pressure –– Low degree of ionization ™™ Respiratory system: ™™ Redistribution: Depresses respiratory center: Initial high uptake of drug by the brain causes –– Causes transient apnea plasma concentration to decrease –– This is followed by a more prolonged period This results in reversal of the concentration of respiratory depression gradient Preserves laryngeal reflexes This causes movement of the drug back into Coughing, laryngeal spasm, bronchoconstriction blood subsequently especially in asthmatics Accounts for the brief duration of anesthesia Reduces ventilatory response to hypercarbia following bolus dose of thiopentone ™™ Cardiovascular system: ™™ Metabolism: Hypotension and tachycardia Hepatic metabolism with extraction ratio of 0.15 Negative inotropism (low) Reduces cardiac output by about 20% Indicates that approximately 15% of the drug Reduces peripheral vascular resistance presented to the liver is extracted Oxidation results in formation of active metabo- ™™ Genitourinary system: lite pentobarbital Reduces renal plasma flow Initially after bolus dose, decay follows first Increases ADH secretion order kinetics Reduces urine output With longer infusions and higher doses hepatic Uterine tone is unaffected metabolic capacity is exceeded Crosses blood-placental barrier This results in zero order kinetics Fetal plasma concentration is lower and more Thiopentone causes hepatic enzyme induction delayed ™™ Excretion: ™™ Autonomic nervous system: Predominantly in urine Reduces intestinal activity Excreted as inactive metabolic Constriction of splanchnic vasculature Less than 1% is directly eliminated unchanged Inhibits vasomotor center in urine Constriction of pupil followed by dilatation Loss of pupillary and eyelash reflexes Implications of Pharmacokinetics ™™ Metabolic: Transient reduction in K+ levels ™™ Dose should be reduced in CRF and liver failure patients as serum albumin will be low: More amount Dosage of free drug in circulation ™™ Intravenous: given as 2.5% solution (25 mg/mL) in a ™™ Concurrent administration of warfarin and aspirin dose of 3–5 mg/kg may displace thiopentone from proteins resulting in ™™ Can be given rectally as 5–10% solution in a dose of toxicity 50 mg/kg body weight ™™ Dose should be reduced in hypovolemia as blood flow to skeletal muscle is reduced while brain and Pharmacokinetics heart perfusion is maintained ™™ Onset of action: within one brain arm circulation time Clinical Uses (30 seconds) ™™ Induction of anesthesia: ™™ Duration of action: 5–10 minutes 3–5 mg/kg IV is induction dose ™™ Absorption: Absorbed when given orally/rectally Loss of consciousness (LOC) occurs in one brain- ™™ Distribution: arm circulation time (30 seconds) 72–86% protein bound, mostly to albumin LOC lasts for around 5–15 minutes Volume of distribution 2.5 L/kg ™™ Treatment of raised ICT: Lipid soluble, un-ionized form of the drug Produces cerebral vasoconstriction and reduces crosses BBB cerebral blood flow  Anesthetic Pharmacology 5 37.5 mg/kg thiopentone required to produce ™™ Intra-arterial injection: iso-electric EEG Clinical features: Hemodynamic instability may complicate high –– Immediate intense pain dose thiopentone –– Vasoconstriction with blanching of extremity Thiopentone is preferred to isoflurane for raised ICT –– This can result in cyanosis and gangrene Isoflurane requires 2 MAC to produce equivalent Mechanism of action: EEG suppression –– Endothelial damage causes inflammatory ™™ Cerebral protection: response Useful in focal ischemia, but not global cerebral –– This leads to arteritis and micro-emboliza- ischemia like in cardiac arrest tion causing occlusion of artery Reduces incidence of neuropsychiatric complica- Treatment and prevention: tions following cardiopulmonary bypass –– Use only 2.5% solution thiopentone Cerebral protection occurs due to: –– Let angio-catheter remain in place –– Reduction in CMRO2 –– If angio-catheter has been removed: –– Reverse steal phenomenon (Robin Hood ▪▪ Inject vasodilator into more proximal loca- effect) on CBF tion in artery –– Free radical scavenging ▪▪ Injected more proximally because affected –– Stabilization of lysosomal membranes artery will be in spasm –– Excitatory amino acid receptor blockade –– Inject saline into angio-catheter to dilute the ™™ To verify wet epidural tap: drug ™™ Used to verify if the fluid coming out of the epidural –– Lidocaine, apaverine and phenoxyben- catheter is CSF or LA zamine used to produce vasodilation ™™ Local anesthetic (LA) solutions are highly acidic –– Heparin/urokinase is considered if throm- preparations bosis occurs ™™ If fluid coming out of catheter is LA solution, –– Sympathetic blockade: stellate ganglion/ thiopentone being highly alkaline will precipitate brachial plexus block may be used on being added ™™ Allergic reaction: Side Effects May occur even without prior exposure to thiopentone ™™ Cardiovascular: Aggressive and early therapy with epinephrine, Myocardial depression especially when given in fluids and steroids high doses Unusually high mortality rate Hypotension due to peripheral venodilatation ™™ Immuno-suppression: Histamine release: Hypotension Bone marrow suppression and leucopenia occurs Heat loss and hypothermia due to vasodilation Also inhibits neutrophil function ™™ Respiratory: Occurs with long term and high dose adminis- Transient apnea tration Bronchospasm/laryngospasm during intubation Results in increased incidence of nosocomial if inadequate depression of laryngeal reflexes by infections barbiturates ™™ Liver: Modest reduction in hepatic blood flow Contraindications ™™ Kidney: Modest reduction in renal blood flow and ™™ Porphyria: GFR Thiopentone causes hepatic enzyme induction ™™ Tolerance Thus, it may stimulate the enzyme δ– aminole- ™™ Venous thrombosis: vulinic acid synthetase Due to deposition of barbiturate crystals in the This is the enzyme responsible for production of vein porphyrins Occurs frequently when vecuronium is given Thus, acute worsening of porphyria may result after thiopentone injection ™™ Status asthmaticus Diluting thiopentone injection to 2.5% reduces ™™ Shock, pericardial tamponade this incidence ™™ Uncompensated myocardial disease 6 Anesthesia Review PROPOFOL –– Preservatives: None because of low lipids –– Equipotent to diprivan but causes more pain Introduction or injection Propofol is a substituted isopropylphenol which is –– Less bacterial growth commonly used as an induction agent in anesthesia. Aquavan: Chemistry –– Alternative to lipid emulsion formulations ™™ Chemically 2–6 disopropylphenol –– It is water soluble ™™ Propofol unlike ketamine and thiopentone is a non- –– Contains pro-drug fospropofol (phosphoryl- chiral compound ated pro-drug) –– Propofol is liberated after hydrolysis by al- Presentation kaline phosphatases ™™ Propofol is an oily compound which is insoluble in –– Prevents lipid associated side effects like: water ▪▪ Pain, hypertriglyceridemia ™™ Therefore, it requires a lipid vehicle for emulsification ▪▪ Pulmonary embolism ™™ Commercial preparations contain propofol molecule, –– Properties: a carrier and preservative compound ▪▪ Larger Vd ™™ Preservatives are used because the lipid carrier acts ▪▪ Higher potency as a potent medium for bacterial growth ▪▪ Longer time to peak effect ▪▪ Prolonged pharmacological action Preparations Non-lipid formulations with cyclodextrin carrier: ™™ There are various preparations for propofol depend- –– Structurally sugar molecules ing on: –– Forms guest-host complexes which migrate Carrier molecule between hydrophilic center of the cyclodex- Propofol concentration trin molecular and the water soluble phase Preservative compound –– After injection, propofol migrates out of the ™™ The various preparations are: cydodextrin into blood Generic propofol: 2% formulations: –– Contents: –– Contains 2% propofol and medium to long ▪▪ 1% propofol chain fatty acids ▪▪ 2.25% glycerol –– Decreased incidence of pain on injection due ▪▪ 10% soyabean oil to long chain and medium chains ▪▪ 1.2% egg phosphatide –– Mixing of propofol with any drug is not rec- –– Preservative used: sodium metabisulfite ommended –– pH: 4.5–6.5 –– May be mixed with lignocaine to reduce Cremophor EL: pain on injection –– Earlier used as the carrier –– This may result in coalescence of oil droplets –– Withdrawn due to anaphylaxis causing pulmonary embolism Diprivan: –– Contents: Mechanism of Action ▪▪ 1% propofol ™™ GABAA receptor: ▪▪ 2.25% glycerol Propofol binds to β subunit of GABAA receptor ▪▪ 10% soyabean oil α and γ2 subunits also contribute to modulatory ▪▪ 1.2% egg phosphatide effects of propofol on GABAA –– Preservatives: NaOH, disodium edetate Prevents dissociation of GABA from the receptor (EDTA) This causes prolonged activation of the receptor –– pH: 7–8.5 Chloride influx occurs as a result causing hy- Ampofol low-lipid emulsion perpolarization and inhibition of post-synaptic –– Contents: neurons ▪▪ 1% propofol ™™ Inhibits ACH release in hippocampus through ▪▪ 0.6% egg lecithin GABAA action ▪▪ 0.5% soyabean oil ™™ Inhibits NMDA receptor  Anesthetic Pharmacology 7 Pharmacodynamics Produces bronchodilation and reduces intraop- erative wheezing ™™ Central nervous system: Hypoxic pulmonary vasoconstriction is intact Rapid smooth induction but attenuated Rapid and clear headed recovery Laryngeal reflexes are lost Cerebroprotective: ™™ Hepatic and renal functions: –– Antioxidant properties Prolonged infusion: –– Reduces intra-cranial pressure, CMRO2 and –– Causes hepatocellular injury resulting in cerebral perfusion pressure acidosis Cerebrovascular autoregulation and reaction to –– Increases phenols in urine: changes in PaCO2 not affected ▪▪ This causes phenol urea resulting in green Produces burst suppression on EEG: Anti-con- color urine vulsant ▪▪ However, it does not alter renal function Produces same degree of memory impairment as Urinary uric acid excretion increases resulting in midazolam turbid urine Seizures and abnormal motor activity may Decreases hepatic blood flow sometimes occur ™™ Intraocular pressure: Tolerance occurs to repeated dosing Decreases intraocular pressure following intuba- Increases dopamine in nucleus accumbens: Results tion in drug abuse Potentiates oculo-cardiac reflex ™™ Cardiovascular system: ™™ Coagulation: Does not alter coagulation profile Decrease in: –– Arterial blood pressure: Pharmacokinetics ▪▪ Reduction in systolic, diastolic and mean ™™ Distribution: pressures Volume of distribution 3.5–4.5 L/kg ▪▪ Effects exaggerated in old patients, hypo- 97% is plasma protein bound volemia and LV dysfunction due to CAD Onset of action: 30–45 seconds (one brain-arm ▪▪ Inhibits baroreceptor reflex to hypotension circulation time) –– PVR: Due to more impotent inhibition of Duration of unconsciousness produced is around sympathetic nervous tone 10 minutes –– Cardiac output, stroke volume index and ™™ Metabolism: Undergoes hepatic and extra-hepatic cardiac index: metabolism: ▪▪ Occurs due to reduced intracellular Ca2+ Hepatic metabolism: availability –– Rapid metabolism ▪▪ This is secondary to inhibition of trans- –– Conjugation to soluble, inactive compounds sarcolemmal Ca2+ influx with glucuronide and sulfate Heart rate: –– Cytochrome P450 actions: –– May increase, decrease or remain unchanged ▪▪ Ring hydroxylation occurs forming 4-hy- –– Response depends on hypotension and ba- droxypropofol roreceptor suppression ▪▪ This has one-third the hypnotic activity of –– Causes bradycardia and asystole sometimes propofol –– Heart rate response to atropine is attenuated Extrahepatic metabolism: –– Bradycardia is reversed by isoprenaline –– Lungs: Does not alter SA node or AV node function: safe ▪▪ Are responsible for 30% uptake and first in WPW syndrome and ablative procedures pass elimination after bolus dose Suppresses supra-ventricular tachycardia ▪▪ Propofol is metabolized to 2-disopropyl- Potentiates oculocardiac reflex quinol ™™ Respiratory system: –– Kidney and brain: Contains UDP-glucuronyl Produces short duration apnea (30–60 sec) after transferase induction in 25–30% patients ™™ Excretion: Decreases tidal volume and frequency of breathing Less than 0.3% excreted unchanged in kidneys Response to CO2 and hypoxemia is reduced by Metabolites are also excreted in kidney direct action on carotid body receptors 2% is eliminated in feces 8 Anesthesia Review No influence of renal dysfunction on renal Immediate Side Effects clearance ™™ Hypotension and bradycardia: augmented by Hepatic dysfunction also does not affect elimina- concomitant opioids tion ™™ Pain on injection: ™™ Fospropofol Most common side effect Endothelial cell alkaline phosphatase hydrolyses it to release propofol Occurs especially on injection into smaller veins Each mg of fospropofol liberates 0.54 mg of Preventive measures: propofol –– Inject into larger veins –– Avoid veins on dorsum of hand Clinical Uses –– Pretreatment with opioids/NSAIDs ™™ Induction of anesthesia: –– Prior administration of 1% lidocaine Results in rapid induction with rapid and smooth –– Change carrier composition to long and me- recovery dium chain fatty acids Induction dose: 1.5–2.5 mg/kg IV in adults ™™ Allergic reactions: Higher doses in children due to higher central Was more with cremaphor-EL which was with- compartment volume and clearance rate drawn from production Complete awakening results without residual Occurs due to isopropyl side chain and phenol CNS effects nucleus ™™ Intravenous sedation: ™™ Proconvulsant action: 25–100 µg/kg/min IV infusion Spontaneous excitatory activity due to increased Prompt recovery occurs following stoppage of subcortical activity infusion Caution in administration of propofol with Low incidence of postoperative nausea and poorly controlled epileptic patients vomiting Myoclonus associated with meningismus occurs ™™ Maintenance of anesthesia: in some cases 100–300 µg/kg/min IV infusion Side Effects on Prolonged Administration Used only for short procedures Longer procedures (72 hours): propofol not ™™ Bacterial growth: preferred due to higher cost Lipid carrier is a potent culture medium ™™ Non-hypnotic therapeutic applications: Supports the growth of E. coli and pseudomonas Antiemetic effects: Preventive measures: –– Due to: –– Aseptic technique: Disinfect neck of ampule ▪▪ Reduced release of glutamate and aspar- with 70% isopropyl alcohol tate in olfactory cortex – – Withdraw drug with sterile syringe ▪▪ Inhibits CTZ and vagal nuclei – – Discard unused contests within 6 hours ▪▪ Has anti-dopaminergic properties – – Flush IV cannula after administration of drug ▪▪ Also reduces serotonin levels in area postrema ™™ Abuse potential: –– 10–15 mg given IV (sub-hypnotic doses) Due to dopamine accumulation in nucleus accum- Effective for PONV especially if non-vagal in bens nature and chemotherapy induced vomiting Causes intense dreaming, amorous behavior and ™™ Antipruritc actions: sexual fantasies 10 mg propofol given IV Hallucinations occur on recovery from effects of Due to ability to depress spinal cord activity propofol Used for: ™ ™ Propofol infusion syndrome –– Pruritis due to intrathecal opioids ™™ Pancreatitis: Due to prolonged administration of –– Cholestatic jaundice associated pruritis preparations with lipid carriers ™™ Anticonvulsant: 1 mg/kg IV reduces seizure ™ ™ Thrombophlebitis in rare cases duration in patients undergoing ECT ™™ Hypertriglyceridemia ™™ Chronic intractable headache: 20–30 mg IV given ™™ Immunosuppression: every 3–4 minutes (maximum 400 mg) Inhibits phagocytosis and killing of bacteria ™™ Also used for laryngospasm and for cerebroprotection Reduces proliferative lymphocyte activity  Anesthetic Pharmacology 9 PROPOFOL INFUSION SYNDROME Clinical Features ™™ Profound metabolic acidosis (base deficit > 10 Introduction mmol/l) Features which occurs in patients receiving propofol in- ™™ Lactic acidosis fusions for long duration (> 48 hrs). ™™ Hyperkalemia Incidence ™™ Hyperlipidemia hypertriglyceridemia ™™ More common in children ™™ Acute refractory bradycardia, sinus arrest, asystole ™™ Cardiomyopathy, cardiac failure, hypotension ™™ More common if used for sedation in TBI ™™ Fatty liver, hepatomegaly ™™ Can occur with prolonged infusion (> 48 hrs) ™™ Skeletal myopathy, rhabdomyolysis Risk Factors ™™ Acute renal failure ™™ Pediatric age group Early Markers ™™ Cumulative dose: ™™ Unexplained metabolic acidosis > 75 µg/kg/min ™™ Elevated serum lactate > 4 mg/kg/hr ™™ Elevated creatinine kinase ™™ Duration of infusion > 48 hrs ™™ Elevated myoglobin levels ™™ Severe inciting illness ™™ Hyperlipidemia CNS origin (TBI) ™™ ECG changes (ST segment elevation in V1 to V3) Sepsis Investigations Respiratory origin Pancreatitis ™™ ABG for metabolic acidosis ™™ Triglycerides ™™ Catecholamines/corticosteroid supplementation ™™ Lactate ™™ Inadequate delivery of carbohydrates ™™ Creatinine kinase ™™ Subclinical mitochondrial disease ™™ Myoglobin Pathophysiology Prevention ™™ Avoid high dose propofol ™™ Minimize duration of infusion ™™ Avoid infusion in: Children Mitochondrial disease ™™ Early and adequate carbohydrate intake ™™ Avoid lipid overload ™™ High index of suspicion – serum triglycerides after 2 days of continuous infusion Treatment ™™ Mainly supportive ™™ Stop propofol infusion ™™ Start alternative sedation ™™ Hemodynamic maintenance: IV crystalloids/colloids Vasopressors/inotropes Transvenous pacing ™™ Nutritional support: Avoid additional lipids Add dextrose to IV fluids (4–8 mg/kg/hr glucose) 10 Anesthesia Review ™™ Renal support: Decreases presynaptic glutamate release Dialysis Potentiates GABA effect Continuous renal replacement therapy ™™ Opioid receptors: Interacts with µ, k and δ receptors ™™ Maintain oxygenation ™™ Monoaminergic receptor: Interacts and thus ™™ ECMO has been tried interferes with pain pathway ™™ Muscarinic receptors: KETAMINE Acts as an antagonist at muscarinic receptors Introduction This causes the bronchodilator and delirious effects of ketamine This is a phencyclidine derivative widely used for in- ™™ Sodium channels: Attributes mild local anesthetic duction of anesthesia. like properties Chemistry ™™ Cytokines: ™™ Phencyclidine derivative Suppresses neutrophil production of cytokines Also, directly inhibits cytokines in circulation ™™ Two optical isomers: causing analgesic properties S (+) and R (–) ketamine Racemic mixture of the two is usually used Pharmacokinetics commercially ™™ Distribution: Isomers are pharmacodynamically and pharma- Less plasma protein bound cokinetically different Large volume of distribution (Vd = 3 L/kg) No. Property S (+) Isomer R (–) Isomer Rapid onset of action as: 1. Action More intense Less intense –– Highly lipid soluble (5–10 times that of thio- 2. Potency Analgesia is four Less potent pentone) time more potent –– Ketamine induced vasodilatation: 3. Metabolism Rapid hepatic Slower biotransformation biotransformation ▪▪ Causes increased cerebral blood flow 4. Recovery More rapid Slower ▪▪ This causes increased drug delivery 5. Emergence Lower incidence Higher incidence Onset of action 30–60 seconds reaction ™™ Redistribution: 6. Salivation Less More Following initial rapid distribution to CNS, the 7. EEG suppression More potent Less potent plasma concentration falls 8. Apoptosis More anti-apoptotic Less The drug then re-enters plasma from the central 9. Therapeutic index More Less compartment and gets redistributed to the less 10. Affinity More receptor Less affinity perfused areas ™™ Metabolism: Preparation Occurs through cytochrome P450 enzyme ™™ Available in 1%, 5% and 10% concentrations Demethylated to form nor-ketamine ™™ It is partially water soluble, 5 to 19 times as lipid Nor-ketamine has one-third to one-fifth the soluble as thiopentone activity of ketamine ™™ Preparation has a pKa of 7.5 Nor-ketamine is hydroxylated and conjugated ™™ Preservative: with glucuronide Benzethonium chloride used as preservative which is Ketamine can also induce cytochrome P450 neurotoxic enzyme S (+) isomer preparations do not have preserva- This causes tolerance and drug dependence tive (less neurotoxic) High hepatic clearance rate (more than 1 L/min) Only these preservative free preparations are Reduction in hepatic blood flow reduces used for intrathecal administration metabolism ™™ Excretion: Mechanism of Action Less than 4% is excreted unchanged in urine ™™ NMDA receptor: Less than 5% is excreted in feces Causes non-competitive inhibition of NMDA Remaining conjugated metabolites excreted via receptor urine  Anesthetic Pharmacology 11 Pharmacodynamics ™™ Autonomic nervous system: ™™ Central nervous system: Pupillary dilation, nystagmus Analgesia: Increased salivation and lacrimation –– Greater for somatic non-visceral pain ™ ™ Cardiovascular system: –– Reduces spinal cord sensitization by block- Blood pressure: ing NMDA receptors in dorsal horn –– Increases blood pressure –– Also reduces transmission of impulses in –– SBP increases by 20–40 mm Hg, DBP by medullary RAS: Important for affective com- smaller amount ponent of pain –– Rise in BP occurs progressively during first Anesthesia: Called Dissociative Anesthesia: 3–5 minutes –– Definition: Cataleptic state where profound –– This is followed by a fall over next 20–30 analgesia and amnesia occurs even though minutes patient appears conscious and maintains Critically ill patients: protective reflexes –– In these patients catecholamine stores are ex- –– Mechanism: hausted ▪▪ Causes dissociation between thalamo- –– Direct negative inotropic effect of ketamine cortical tract and limbic system may manifest in critically ill patients ▪▪ Inhibition of thalamo-cortical tract occurs –– Administration on ketamine may therefore with stimulation of limbic system cause cardiovascular collapse ▪▪ This causes functional disorganization of Also increases heart rate, cardiac output, cardiac nonspecific pathways in midbrain and work, myocardial oxygen demand thalamus Enhances arrhythmogenicity of adrenaline –– Characteristics: Mechanisms of cardiovascular effect: ▪▪ It is a cataleptic state –– Direct stimulation of CNS resulting in ▪▪ Open eyes with slow and nystagmic gaze increased central sympathetic flow ▪▪ Appears awake but non-communicative –– Inhibition of baroreceptor reflex through ▪▪ Various degrees of hypertonus and pur- NMDA receptors in nucleus tractus solitarius poseless skeletal muscle movements –– Inhibition of nor-epinephrine reuptake in ▪▪ Amnesia: No recall of surgery/anesthesia post-ganglionic sympathetic nervous sys- ▪▪ Cough, swallowing and corneal reflexes tem: results in increased plasma catecho- are present lamine concentration ▪▪ Reflexes should not be assumed to be pro- ™™ Respiratory system: tective ▪▪ Profound analgesia present Ventilation: Intracranial pressure: –– No significant depression of ventilation –– Potent vasodilator occurs –– Increases cerebral blood flow by 60% – – Has no effect on central respiratory drive –– Increases ICP in normo-capneic patients – – Ventilatory response to CO2 is preserved –– May cause reduction in ICP in ventilated pa- – – Breathing frequency reduced for 2–3 min- tients utes after administration –– Cerebrovascular response to CO2 is pre- –– Apneacan occur with large dose/with con- served comitant benzodiazepines Neuro-protection: Upper airway reflexes: –– Antagonist of NMDA receptors – – Airway reflexes are preserved –– This causes neuro-protection in cerebral is- – – However airway is not completely protected chemic states as silent aspiration may occur EEG: Salivary and tracheo-bronchial secretions: –– Abolishes α-rhythm –– Ketamine increases trachea-bronchial and –– β-rhythm slowly progresses to δ-rhythm, salivary secretion which coincides with loss of consciousness –– Secretions are especially problematic in chil- –– High doses cause burst suppression pattern dren as it causes laryngospasm –– Has anti-convulsant activity though myo- –– Pretreatment with anti-sialogogues manda- clonus may present occasionally tory 12 Anesthesia Review Bronchodilation: –– Hypovolemic shock –– May be useful in asthmatics –– Known asthmatics/bronchospasm –– Bronchodilation occurs due to: –– Congenital heart disease especially with ▪▪ Reduced uptake of catecholamines right to left shunts ▪▪ Increasedlevels of circulating catechola- –– Septic shock, provided catecholamine stores mines are intact ▪▪ Muscarinic antagonism ™™ Sedation: ▪▪ Inhibition of Ca2+ channel 2 mg/kg/hr IV effusion used for postoperative ™™ Coagulation: Inhibits platelet aggregation by sedation reducing formation of inositol 1, 4, 5 – triphosphate Especially useful in pediatric patients for: ™™ Hepatic and renal function: Not significantly altered –– Cardiac catheterization –– Radiotherapy/radiological studies Clinical Uses –– Dressing change –– Dental work ™™ Analgesia: ™™ Adjunct to regional anesthesia: 0.2–5 mg/kg IV analgesic dose of ketamine 0.5 mg/kg IV given along with 0.03 mg/kg Indications: midazolam –– Cancer pain Used during application of painful blocks –– Chronic central and peripheral neuropathic ™™ Reversal of opioid tolerance: pain Useful in reversing opioid tolerance –– Fibromyalgia, migraine Acts through interactions between NMDA, nitric –– Phantom limb and ischemic limb pain oxide pathway, and µ-opioid receptors –– Complex regional pain syndrome ™™ Improvement of mental depression: ™™ Neuraxial analgesia: Postoperative depression unproved in patients 0.5–1 mg/kg neuraxial dose of ketamine with mental depression Mechanism of action: Improves depression apart from providing –– Due to systemic and spinal effects analgesia in chronic pain syndrome –– Spinal effects: ™™ Restless legs syndrome: Inhibits neuro-inflammation ▪▪ Action on spinal opioid receptors in spinal cord ▪▪ LA action through sodium channels Affinity of ketamine is 10,000 times weaker than Contraindications morphine ™™ Raised ICP, head trauma S (+) isomer preparations with no preservative ™™ Open ocular injury: As ketamine increases IOP is used ™™ Ocular examination/operations: As ketamine causes Preservative in the racemic mixture formulation nystagmus is neurotoxic ™™ Schizophrenia, delirium tremens ™™ Induction of anesthesia: ™™ Coronary artery disease Induction doses: ™™ Pulmonary hypertension, right heart failure –– 1–2 mg/kg IV dose ™™ Systemic hypertension –– 4–8 mg/kg IM dose ™™ Vascular aneurysmal surgery Consciousness is lost in 30–60 seconds after IV administration Side Effects Loss of consciousness occurs 2–4 minutes after ™™ Central nervous system: IM administration Raised intracranial pressure, myoclonus Return of consciousness occurs after 10–20 minutes Nystagmus, raised intraocular pressure Full orientation attained 60–90 minutes after last ™™ Central nervous system: Raised systemic BP, dose tachycardia No retrograde amnesia present ™™ Respiratory: Preferred agent in: Transient apnea in rare cases –– Children Sialorrhea and laryngospasm especially in –– Skin grafting/debridement/burn dressing children  Anesthetic Pharmacology 13 ™™ Allergic reactions: very rare Diazepam/midazolam ™™ Tolerance and drug abuse Verapamil ™™ Increased bleeding tendency ™™ Enhances neuromuscular blocking actions of non- ™™ Emergence reaction: depolarizing drugs Description: Emergence from ketamine anes- ™™ Pancuronium enhances cardiac stimulating thesia is associated with visual, auditory and properties proprioceptive illusions which may progress to ™™ Succinylcholine apnea may be prolonged delirium ™™ Seizures when aminophylline is given along with Clinical features: ketamine –– Transient cortical blindness, altered short ™™ When used with tricyclic antidepressants (TCAs): term memory TCAs and ketamine prevent nor-epinephrine –– Vivid and brightly colored dreams with mor- reuptake bid content and nightmares This results in severe hypotension, cardiac failure –– Hallucinations: and myocardial ischemia ▪▪ May occur upto 24 hours after administra- tion of ketamine ETOMIDATE ▪▪ Usually disappear within a few hours Introduction –– Extra-corporeal experiences: ▪▪ Patient feels a sensation of floating out of ™™ Initially developed as an anti-fungal agent body ™™ Hypnotic activity discovered later during animal ▪▪ This is due to lack of appreciation of grav- testing ity ™™ First introduced as an induction agent to clinical ▪▪ Occurs due to reduced somatic and pro- practice in 1972 prioceptive sensation ™™ Unique properties of hemodynamic stability with Incidence: Increased incidence in: minimal respiratory depression –– Females Chemistry –– Age more than 15 years: As children are un- able to communicate the dreams occurance ™™ Carboxylated imidazole –– Dosage more than 2 mg/kg IV ™™ Structurally unrelated to other anesthetic agents –– History of personality problems/frequent ™™ Structurally R- (+) -pentylethyl-1H-imidazole-% dreaming carboxylate sulphate Mechanisms: –– Due to depression of inferior colliculus and Presentation medical geniculate body ™™ Imidazole ring causes lipid solubility at physiological –– This causes mis-interpretation of auditory pH and visual stimuli resulting in illusions ™™ At acidic pH however, it becomes water soluble –– Extra-corporeal experiences due to ĸ- ™™ Thus, it is formulated as a 0.2% solution with 35% receptor stimulation propylene glycol for injection Prevention: –– Pretreatment with benzodiazepines: Mida- ™™ This may be responsible for pain on injection zolam best –– Co-administration of thiopental, inhaled anesthetics or propofol –– Benzodiazepines given 5 minutes IV before ketamine usage –– Prospective discussion with patients about side effects Drug Interactions ™™ Hemodynamic depression rather than stimulation when used with: Fig. 1: Etomidate. Inhaled agents 14 Anesthesia Review Mechanism of Action ™™ Endocrine system: ™™ Positive modulation of GABA receptor: Transiently inhibit enzymes involved in cortisol Occurs at clinical doses and aldosterone synthesis R+ isomer of etomidate binds to GABAA receptor Results in decreased cortisol synthesis and This increases the receptors affinity for GABA adrenocortical suppression Thus lower concentration of GABA is required to Dose-dependant reversible inhibition of 11β- activate the GABAA receptor hydroxylase ™™ Allosteric agonism: Adrenal suppression may last upto 72 hours Occurs at high, supraclinical doses following induction Etomidate directly activates GABAA receptor Adrenal suppression action of etomidate more ™™ Disinhibitory effects: potent compared to sedation May have disinhibitory effect extrapyramidal Pharmacokinetics pathways Myoclonus seen in 30–60% of patients on ™™ Onset of action: induction with etomidate Very rapid onset of action due to high lipid solubility Pharmacodynamics Large unionized fraction at physiological pH ™™ Central nervous system: contributes to rapid onset Decreases CMRO2 (45%), cerebral blood flow Hypnosis achieved in one brain-arm circulation (34%) time Produces a decline in intracranial pressure (50%) ™™ Duration of action: Cerebral perfusion pressure increased or main- Provides hypnosis for 5–10 minutes tained Awakening occurs predominantly due to redis- PONV more common than propofol or barbitu- tribution rate Lacks analgesic properties ™™ Absorption: Associated with grand mal seizures Oral transmucosal administration has been used EEG activity increases in epileptogenic foci in the past ™™ Cardiovascular system: Rectal administration has also been attempted Minimal effects on cardiovascular system- makes Available currently only for intravenous it a unique drug injection Hemodynamic stability due to lack of effect on ™™ Distribution: sympathetic nervous system Highly protein bound (75% plasma protein Causes mild reduction in peripheral vascular bound) resistance, mean arterial pressure Large peripheral Vd of 74.9 L/kg Myocardial contractility and cardiac output are ™™ Metabolism: usually unchanged By hepatic microsomal enzymes and plasma Maintains myocardial oxygen demand-supply esterases ratio High hepatic extraction ratio 0.5 + 0.9 Useful in patients with valvular heart disease, IHD with poor cardiac function Rapidly hydrolyzed to carboxylic acid and an ethanol leaving group ™™ Respiratory system: Less effects on respiratory system ™™ Excretion: Induction usually does not cause apnea unless Elimination T1/2 of 2.9–5.3 hours opioids have been administered Primarily excreted in urine May be associated with brief period of hyper- Renal excretion: 2% excreted unchanged, 85% as ventilation following induction metabolites Does not induce histamine release Biliary elimination: 13% as metabolites  Anesthetic Pharmacology 15 Clinical Uses Steroid supplementation provided no benefits in ™™ Induction of anesthesia: these patients Especially useful in those with poor cardiovas- Other studies have reported conflicting results cular reserve Larger well designed trials are required to define Reasonable choice during neurosurgical proce- the impact of single dose etomidate in critically dures ill patients Useful in trauma patients with questionable intravascular volume status MIDAZOLAM ™™ Short term sedation: Introduction Useful in hemodynamically unstable patients This is a commonly used short acting benzodiazepine. Useful for cardioversion, primary percutaneous intervention Chemistry ™™ Maintenance of anesthesia: not used now due to ™™ Water soluble compound adrenal suppression ™™ Imidazole ring present which accounts for: ™™ Treatment of Cushings syndrome Water solubility ™™ Intraoperative mapping of seizure foci: Short duration of action Useful to map foci prior surgical ablation Rapid metabolism This is due to property of enhancing EEG activity ™™ Non-chiral in nature: no isomers in epileptogenic foci Dosage Preparation ™™ Can be used in doses of 0.2–0.6 mg/kg IV for induction ™™ Clear, colorless solution ™™ Usual induction dose is 0.3 mg/kg IV ™™ 1/2/5 mg/mL of solution for IV injection ™™ 0.04–0.05 mg/kg/hr infusion in refractory cases of ™™ Midazolam syrup preparation has 2 mg/mL Cushings ™™ Acidic pH of 3.5 ™™ Compatible with lactated Ringers solution Adverse Effects ™™ Characterized by pH dependant ring opening ™™ Emergence delirium phenomenon: ™™ Pain on injection: At pH less than 4, ring remains open and thus it More with aqueous preparations compared with is water soluble propylene glycol At pH more than 4 (physiological pH), ring Reduced with cyclodextrin and medium chain closes and it becomes a highly lipid soluble drug FA formulations Reduced by IV xylocard 20–40 mg immediately Mechanism of Action prior to etomidate injection ™™ Acts mainly through BZD receptors: ™™ Nausea and vomiting Found at synapses concentrated in cortex and ™™ Myoclonus: mid-brain Reduced by premedication with midazolam These are closely related to GABAA receptors Split dose induction has been useful in some BZD receptors facilitate GABAA receptor opening studies This opens up chloride channels: Causes hyper- Thiopentone and dexmedetomidine have also polarization of the synaptic membrane been useful ™™ Kappa opioid agonist activity which explains spinal Magnesium sulphate 60–90 seconds prior to in- analgesia jection reduces myoclonic activity Routes of Administration Validation ™™ Oral administration: 0.25 mg/kg given as 2 mg/mL ™™ CORTICUS trial: syrup Corticosteroid Therapy of Septic Shock trial ™™ Intramuscular administration: 0.07–0.08 mg/kg Enrolled 500 septic shock patients, 20% of whom received etomidate ™™ Intravenous administration: 0.02–0.03 mg/kg Observed that patients receiving etomidate had ™™ Intrathecal administration: 0.3–2 mg given usually higher 28-day mortality ™™ Epidural administration: 0.03–0.05 mg/kg 16 Anesthesia Review Pharmacodynamics Short duration of action due to: –– High lipid solubility ™™ Central nervous system: –– Rapid redistribution Hypnosis, sedation, anxiolysis –– Short context sensitive half time: can be used Anterograde amnesia which is more potent and for continuous infusion longer lasting than sedative effect ™™ Metabolism: Reduces cerebral metabolic oxygen requirements By hepatic and small intestinal by cytochrome which has a ceiling effect P450 Reduces cerebral blood flow, especially in regions Converted to 1 and 4 hydroxy-midazolam associated with arousal, attention and memory 1-hydroxy-midazolam has half the activity of Little or no change in intra-cranial pressure midazolam Potent anticonvulsant, no cerebroprotective This may be responsible for prolonged sedation effects in renal insufficiency When administered intrathecally or epidurally, it Metabolism is slowed in the presence of has anti-nociceptive effect cytochrome P450 inhibitors: Muscle relaxant through actions on spinal –– Cimetidine, erythromycin internuncial gamma neurons –– Calcium channel blockers, antifungal drugs ™™ Cardiovascular system: Hepatic clearance is also reduced by concomitant Reduces systolic BP by 5% and diastolic BP by fentanyl administration 10% Finally 1 and 4 OH-midazolamare conjugated No effect on cardiac output: most useful in with glucuronide congestive cardiac failure ™™ Excretion: Reduces peripheral vascular resistance In urine as glucuronide conjugates Renal impairment has little effect Increases heart rate Elimination half life of 1.5–3.5 hours ™™ Respiratory system: ™™ Onset of action within 30–60 seconds Reduction in tidal volume but increase in ™™ Peak effect within 3–5 minutes respiratory rate ™™ Duration of action 15–80 minutes Dose dependant reduction in ventilation with 0.15 mg/kg IV Uses Transient apnea with doses more than 0.15 mg/kg ™™ Preoperative medication: Impaired ventilatory response to hypercapnea Most commonly used premedication in children Better avoided in COPD patients for conscious sedation Ventilatory depression more when 0.05 mg/kg IV Oral midazolam syrup 2 mg/mL in dose of 0.25 used for induction mg/kg ™™ Others: Administered at least 20 minutes prior to surgery Reduces hepatic and renal blood flow ™™ Intravenous sedation: Reduces adrenergic but not cortisol response to 0.03–0.05 mg/kg given IV stress Continuous IV infusion can be used at 4 µg/kg/min Inhibits phagocytosis and leucocyte bactericidal Useful for: activity –– Endoscopy and procedures performed un- der local anesthesia Pharmacokinetics –– Monitored anesthesia care Used with caution in patients with COPD and ™™ Absorption: old age Absorbed well and very quickly when given ™™ Induction of anesthesia: orally 0.1–0.2 mg/kg IV Oral bioavailability 50% Causes slower onset of unconsciousness com- IM bioavailability 80–100% pared with thiopental ™™ Distribution: Onset can be quickened by prior administration Vd of 1–1.5 L/kg may increase to 3 L/kg in of opioids critically ill patients Fentanyl 50 or 100 µg IV can be given preceding 96% plasma protein bound midazolam by 1–3 minutes  Anesthetic Pharmacology 17 ™™ Maintenance of anesthesia: ™™ 10 mg suppository or 2/4 mg/mL solution available 0.25 to 1 mg/kg/hour for rectal administration Used as supplement to opioids and propofol ™™ Clear yellow solution with 5 mg/mL for IM/IV Reduces MAC of volatile agents by around 15% injection Produces gradual awakening which is rarely ™™ Insoluble in water and thus dissolved in organic associated with nausea or emergence reactions solvent like propylene glycol ™™ Post-operative sedation: 1–7 mg/hr IV in intubated ™™ Slightly acidic with pH of 6.6–6.9 patients ™™ Also available as soyabean formulation for IV ™™ Paradoxical vocal cord motion: injection Causes non-organic upper airway obstruction and stridor Mechanism of Action Midazolam 0.5–1 mg IV can be used effectively ™™ Acts mainly through BZD receptors: ™™ Chronic pain including de-afferentiation syndrome Found at synapses concentrated in cortex and mid-brain Side Effects These are closely related to GABAA receptors ™™ Occasional discomfort at site of injection BZD receptors facilitate GABAA receptor opening ™™ Ventilatory depression and apnea especially with This opens up chloride channels: causes hyper- doses > 0.15 mg/kg polarization of the synaptic membrane ™™ Withdrawal phenomenon like irritation and ™™ Kappa opioid agonist activity which explains spinal insomnia in prolonged infusions analgesia ™™ Transient apnea in geriatric patients and those with Routes of Administration COPD ™™ Oral dose of up to 60 mg/day in divided doses in ™™ May accelerate cognitive decline in elderly patients with long term use adults ™™ Intravenous dose: 5–20 mg, increasing according to ™™ May inhibit platelet aggregation by causing con- formational change in platelet membranes clinical effect ™™ Rectally used in children with febrile seizures Drug Interactions Pharmacodynamics ™™ Antacids and food reduce absorption from GIT ™™ Central nervous system: ™™ Cimetidine, erythromycin, calcium channel blockers Anxiolytic and decreases aggression inhibit metabolism of midazolam Paradoxical excitement may occur ™™ Metabolism of midazolam is also inhibited by Sedation, hypnosis, anterograde amnesia fentanyl Anticonvulsant activity: ™™ Alcohol, inhaled anesthetics, opioids and α2 agonist –– Act by selectively inhibiting limbic syste