Intravenous Induction Agents by Dr. Animesh
- 1. Intravenous Induction Agents By Dr. Animesh Aman Singh Moderator-Dr. Ram Gopal Maurya
- 2. What are i.v induction drugs? Drugs,when given intravenously in an appropriate dose,cause rapid loss of consciousness. Rapid onset:Often described as occurring within"ONE ARM- BRAINCIRCULATION TIME” The time taken for the drug to travel from the site of injection (usually the arm)to the brain,where they have their effect.
- 3. History HEXOBARBITAL:The first ultra short acting barbiturateThe first successful i.v anesthetic Introduced by Weese in Germany in 1932. THIOPENTAL:Introduced in 1935 by Lundy in Minnesota &Waters in Wisconsin. Thiopental-widely accepted because of lack of excitatory myoclonicmovements seen with hexobarbitone
- 4. PROPOFOL-launched in 1986 under the brand name DIPRIVAN KETAMINE-was first synthesized in 1962 by Calvin StevensFirst human use was in 1969. METHOHEXITAL-a shorter-acting barbiturate with central nervous system- stimulating properties,was introduced in 1956 for electroconvulsive therapy (ECT).
- 5. USES of Intravenous anesthetics Induction and maintenance of anesthesia As a sole anesthetic for short procedures Intravenous infusion-to maintain anesthesia for longer procedures e.g.TIVA(Total intravenous anesthesia) To provide sedation in places like ICU
- 6. From induction to wake up:what happens to abolus of IV induction drug? Bolus of i.v induction agent enters blood stream A percentage of drug is bound to plasma proteins &the rest is UNBOUND(protein binding depends on lipid solubility °ree of ionization) The drug is carried in the Venous blood to the right side of the heart.
- 7. Drug reaches Left side of the heart through pulmonary circulation Systemic circulation High proportion of initial bolus is delivered to CEREBRAL CIRCULATION(as majority of cardiac output is diverted to brain,liver &kidney)
- 8. The drug then passes along a concentration gradient from the blood into the brain. The rate of this transfer is dependent on a number of factors: the arterial concentration of the unbound free drug the lipid solubility of the drug the degree of ionization. Unbound,lipid soluble,unionized molecules cross the blood brain barrier the quickest.
- 9. Drug starts exerting its effect once it penetrates CNS tissue Each drug acts at a specific receptor (e.g GABA-A,NMDA and Ach receptors) The drug then starts to diffuse in to other tissues that do not have such a richblood supply(e.g Skeletal muscle)
- 10. This secondary tissue uptake,causes the plasma concentration to fall,allowing drug to diffuse out of the CNS down the resulting reverse concentration gradient This initial REDISTRIBUTION-leads to the rapid wake up seen after a singledose of an induction drug Metabolism and plasma clearance have a much less important role following a single bolus,but are more important following infusions and repeat doses of a drug.
- 11. Drug distribution in various tissues against time following an i.v bolus of thiopental
- 12. How is this different in states of reducedcardiac output? When cardiac output is reduced(Shock,Elderly)the body compensates by diverting an increased proportion of the cardiac output to the cerebral circulation,as preservation of cerebral blood flow in these situations is important. A greater proportion of any given drug will enter the cerebral circulation As a result,the dose of induction drug must always be reduced. Since global cardiac output is reduced,the time taken for an induction drug toreach the brain and exert its effect is prolonged* Key to SAFE INDUCTION:SLOW titration of a REDUCED dose of drug
- 13. Properties of an IDEAL induction agent Physical properties Water soluble & stable in solution Stable on exposure to light Long shelf life No pain on intravenous injection Painful when injected into an artery Non-irritant when injected subcutaneously Low incidence of thrombophlebitis Cheap
- 14. Pharmacokinetic properties Rapid onset in one arm-brain circulation time Rapid redistribution to vessel rich tissue Rapid clearance and metabolism No active metabolites
- 15. Pharmacodynamic properties High therapeutic ratio(ratio of toxic dose:minimally effective dose ) Minimal cardiovascular and respiratory effects No histamine release/hypersensitivity reactions No emetic effects No involuntary movements No emergence nightmares No hang over effect No adrenocortical suppression Safe to use in porphyria
- 16. Classification The commonest drugs currently in use can be classified according to theirchemical structure and include: Barbiturates-THIOPENTAL,METHOHEXITAL Phenols -PROPOFOL Imidazoles -ETOMIDATE Phencyclidines -KETAMINE Benzodiazepines-MIDAZOLAM,DIAZEPAM,LORAZEPAM Others-Dexmedetomidine
- 17. They can also be classified based on the onset of their action as: Rapidly acting(within one arm brain circulation time)- Thiopentone,Propofol,Etomidate Slow acting (those that take longer than one arm-brain circulation time)-Ketamine,Midazolam
- 18. EXTRA POINTS α half life denotes time taken to redistribute the drug from central compartment to peripheral tissues. β-half-life denotes redistribution of the drug from the muscle group to less vascular tissues. γ-half life denotes elimination of the drug from the body. The patient wakens from anaesthesia when the plasma concentration reduces at the end of alpha half life even though it is not eliminated from the body.
- 19. PROPOFOL
- 20. PROPOFOL Chemical Structure-2,6 Di isopropyl phenol Availablity-Single-patient use vials of 200 mg of propofol per 20 mL,500 mg of propofol per 50 mL 1 or 2%aqueous emulsion(tiny fat droplets in suspension,hence the white colour) Highly lipid soluble Contains- 10%Soybean oil, 1.2%Egg Lecithin and 2.25%Glycerol(an osmotic agent)
- 21. Propofol The emulsion is an excellent medium for bacterial growth EDTA or Sodium Benzoate are added to impede bacterial growth Propofol causes pain in injection PROPOFOLLIPURO-preparation of propofol containing both long &medium chain triglycerides in 1:1 ratio.Reduces pain on injection FOSPROPOFOL-A water soluble methylphopshorylated prodrug of propofol No Pain on injection.But slow onset of action
- 22. Propofol Physicochemical &pharmacokinetic properties pKa-11 Volume of distribution-4.6 L/Kg Clearance-25 ml/Kg/min Protein binding-98% Water solubility-No pH 7.0-8.5
- 23. Propofol Mechanism of action-Activation of chloride channels of GABA receptors thus enhancing inhibitory synaptic transmission.It also inhibits NMDA subtypeof glutamate receptors. Onset of action-One arm brain circulation time(15 -20 seconds) Duration of action-3 to 5 min when given i.v Half life: a half life-3-5 min β half life-20-50 min y half life-200-500 min
- 24. Propofol Context sensitive half time:Appox.10 minutes when infused for less than 3 hours &less than 40 minutes when infused for upto 8 hours Elimination:Propofol is metabolized by conjugation to glucuronide&sulfate by liver. Propofol also undergoes Extra hepatic metabolism in kidneyand lungs (30%)
- 25. PROPOFOL:Effects on the body CNS:Dose dependent depression of CNS End point for induction-Loss of response to verbal commands Can be used an anti-convulsant Reduces Cerebral metabolic rate Reduces Cerebral blood flow through auto-regulation Reduces Intracranial pressure Can cause some involuntary movements during induction
- 26. PROPOFOL CVS:Causes hypotension due to peripheral vasodilatation The fall in blood pressure is dose dependent and is most marked in theelderly and in shocked patients. This can be minimized by slow injection-avoiding inadvertent overdose. RS:Causes transient apnea Obtunds airway reflexes well GIT:Propofol has antiemetic properties
- 27. Propofol:Uses,Dose &Route Induction of anaesthesia:2-2.5 mg/Kg in adults;2.5-3 mg/Kg in children Maintenance of anaesthesia:At a dose of 50-150μg/Kg/min Conscious sedation:@50-75μg/Kg/min Sole anaesthetic for short procedures e.g.Cardioversion Very useful in Day care anaesthesia and surgery Useful in patients susceptible to Malignant hyperthermia Can be used as an Anticonvulsant
- 28. PROPOFOL Total intravenous anaesthesia (TIVA):A plasma concentration of 2.5 to 8μg/ml is required. This can be achieved as follows-1 mg/Kg bolus→10 mg/kg/hr for 10 min — 8mg/kg/hr for next10 minutes6 mg/kg/hr thereafter.→ This is expected to give a plasma conc.of propofol of 3 μg/ml. Sedation of critically ill patient in ICU:1-3 mg/kg/hr. Can also be used as antipruritic &antiemetic:10-20 mg boluses every 5-10 minutes Safe in patients susceptible to porphyrias.
- 29. PROPOFOL:Adverse effects &Caution Hypotension Allergic reaction to Egg protein Pain on injection(can be reduced with lignocaine 20 mg added to 20ml ) Caution in patients who are hypovolemic Susceptible to growth of micro-organisms:Tubings and unused propofol injectable emulsions should be discarded after 12 hours. Can cause involuntary epileptiform movements.
- 30. Propofol Infusion Syndrome Occurs due to prolonged infusion in small children and infantsUsually when used in excess of 4 mg/kg/hr for>48 hours Propofol interferes with mitochondrial mechanisms Features:METABOLIC ACIDOSIS,hyperkalemia,RHABDOMYOLYSIS,Renal failure,hepatomegaly,cardiac failure(RBBB &asystole)Hyperlipidemia. Management:Cardiorespiratory support Hemodialysis.
- 31. BARBITURATES Barbiturates-broadly classified as a)Thiobarbiturates:Sulphur at C2 e.g.Thiopental,thiamylal b)Oxybarbiturates:Oxygen at C2 e.g.Methohexital Formulated as racemic mixtures of their water soluble sodium salts Use“Sodium carbonate”to maintain alkaline pH 10-11 High alkalinity-Severe tissue damage (intra arterial injections) Precipitation of drugs that are weak bases(vecuronium)
- 33. Thiopentone Sodium Ultra-short acting barbiturate Available as Hygroscopic,pale YELLOW powder Ampoules commonly contain-500mg or 1000mg of sodium thiopental + 6%sodium carbonate in an inert atmosphere of nitrogen. (to prevent precipitation of insoluble acid form of barbiturate by atmospheric CO2) Reconstituted with 20ml of water-2.5%solution(25mg/ml)with a pH of 10.8. The alkaline solution is bacteriostatic and safe to keep for 48 hours
- 34. Thiopentone Sodium Mechanism of action: Mainly through interaction with inhibitory neurotransmitter-GABA in CNS GABAA receptor has 5 glycoprotein subunits Activation of GABAA receptor Increase in transmembrane Chloride channel conductance Hyperpolarization of post-synaptic neurons “FUNCTIONAL INHIBITION OF POST-SYNAPTIC NEURONS”
- 35. Thiopentone Sodium-Uses &Dose Always given intravenously (i.v) Can be given through rectal route for sedation,but theabsorption is erratic. For induction of anaesthesia:4-5 mg/Kg in adults. Children require slightly higher doses (5-6 mg/Kg)due to larger volume of distribution(Vd)
- 36. Thiopentone Sodium-Uses &Dose Status Epilepticus-Single bolus of 3-5 mg/Kg to treat an episode ofconvulsion f/b INFUSION(3-5mg/Kg/hr)in status epilepticus refractory to conventional treatment. Cerebral protection-Bolus of 3 mg/Kg followed by an infusionof 5-6 mg/Kg/hr to protect ischemic brain in neurosurgical patients
- 37. Thiopentone Sodium Onset of action:One arm-brain circulation time (15-20 sec) Duration of action: a Half life -10 min β Half life -45 min γ Half life -6-20 hrs Elimination:Metabolized by LIVER &excreted by KIDNEY Clearance:3.4 ml/Kg/min Volume of distribution:2.5 liters/Kg
- 38. Thiopentone Sodium Following repeated doses or infusions of thiopental,metabolism follows zero order kinetics i.e.,a constant amount of drug is being eliminated per unit time,irrespective of the plasma concentration. Some drugs are metabolized by frst order kinetics;a constant fraction of drug is eliminated per unit time,i.e.dependent on plasma concentration. Zero order kinetics occur when the metabolic pathways become saturated leading to an accumulation of the active drug and delayed recovery
- 39. Effects on Body Central Nervous System: Dose dependent depression of CNS End point of induction-Loss of"EYELASH REFLEX" Reduces CMRO2&CBF thereby reducing ICP It is a potent anti-convulsant It is an ANTANALGESIC-decreases the threshold to pain
- 40. Effect on body Cardiovascular system: Causes Hypotension due to peripheral vasodilatation Causes increase in Heart rate -Baroreceptor reflexmediated sympathetic stimulation Higher doses have negative inotropic effect &should be used with caution in hypovolemic and IHD patients
- 41. Effect on body Respiratory system: Causes transient apnea Produces dose dependent decrease in both tidal volume &minute ventilation The medullary center ventilator responses to both hypoxia &hypercapnia are reduced May not obtund airway reflexes well-hence unsuitable for use while inserting an LMA(can cause coughing &laryngospasm) Histamine release can occur-can precipitate bronchospasm
- 42. Thiopentone-Adverse effects Inadvertent intra-arterial injection of thiopentone-causes intense spasm of the artery &therefore must be avoided.If occurs, a)Stop further injection but keep cannula in place b)Inject saline into the cannula &flush it c)Inject through same cannula,preservative free LIGNOCAINE to reduce pain,PAPAVERINE 40-80 mg to provide local vasodilatation,HEPARIN to preventthrombus formation d)Stellate ganglion block or brachial plexus block to achieve sympatholysis if intensepain &if tissue perfusion is in jeopardy.
- 43. Thiopentone-Adverse effects Thiopentone is contraindicated in Patients with PORPHYRIAS Stimulation of mitochondrial enzyme-“δ Amino levulinic acid Reductase”,the rate limiting enzyme in porphyrin biosynthesis,can exacerbate AIP(Acute intermittent porphyria) Manifestations: 1.Abdominal pain 2.Psychiatric symptoms like hysteria 3.Motor neuropathies. 4.CNS symptoms like seizures,mental status changes,cortical blindness &coma
- 44. Thiopentone-Adverse effects Thiopentone should be avoided in patients with sulpha drug allergy Extravasation of thiopentone at i.v site can cause local tissue destruction Thiopentone can be used safely in cesarean deliveries But doses greater than 8 mg/Kg can cause neonatal depression due to placental transfer of the drug
- 46. Etomidate Chemical Structure-Carboxylated IMIDAZOLE ester. Weak Base &poorly water soluble Formulated as a Hyperosmotic solution in 35%Propylene glycol* Prepared as pharmacologically active R(+)isomer Available as lipid emulsion 10ml at a conc.of 2mg/ml Pain on injection is common and there is a high rate of thrombophlebitis in the post operative period.
- 47. Etomidate Mechanism of action:Activation of Chloride channels ofGABAA receptors Enhancing inhibitory synaptic transmission Onset of action: One arm-brain circulation time (15-20 sec) Duration:3-5 minutes when given i.v Dosage:For induction of anaesthesia 0.2-0.4 mg/Kg i.v
- 48. Etomidate : Effects on the body CNS: Dose dependent depression of CNS Can produce involuntary movements during induction. Recovery is RAPID due to REDISTRIBUTION. CVS:IV agent with LEAST cardiovascular depression Only small reduction in BP&HR-very CARDIOSTABLE Used in shock,elderly and cardiovascularly compromised patients.
- 49. Etomidate : Effects on the body RS: Transient apnea occurs with induction doses. Can cause cough or hiccups. Hence not ideal for insertion of supraglottic airway devices* GIT: Increased incidence of Nausea &Vomiting Metabolized by hepatic and plasma esterase to yield inactive metabolites. Excretion is predominantly urinary and the elimination half life varies from 1-5 hours.
- 50. Etomidate : Adverse effects Pain on iniection & Thrombophlebitis Recovery is frequently unpleasant and accompanied by nausea and vomiting Adreno-cortical suppression Etomidate inhibits 11-β-hydroxylase, an enzyme important in adrenal steroid production. A single induction dose blocks the normal stress-induced increase in adrenal cortisol production for4-8 hours, and up to 24 hours in elderly and debilitated patients. Continuous infusion of etomidate for sedation in critically ill patients has been shown to increase mortality. No increase in mortality has been identified following a single dose during induction of anesthesia.
- 52. KETAMINE HYDROCHLORIDE Chemical Structure-Phencyclidine derivative AVAILABILTY: vials containing 10 mg/ml&50 mg/ml Preservative free ketamine is available for use for Central neuraxial blockade. Produces DISSOCIATIVE ANAESTHESIA-dissociation between thalamocortical & limbic systems Dissociative anaesthesia resembles a cataleptic state in which the eyes remain open with a slow nystagmus gaze.
- 53. Structure activity relationships Presence of asymmetric carbon atom results in the existence of two OPTICAL ISOMERS of ketamine: S(+)&R(-)forms. Most frequently used preparation of ketamine -Racemic mixture S(+)ketamine produces (when compared to R(-)form): a)More intense analgesia b)More rapid metabolism &thus recovery c)Less salivation d)Lower incidence of emergence reactions Preservative used -BENZETHENIUM CHLORIDE
- 55. Mechanism of action: a)Inhibits N-methyl-D-aspartate (NMDA)receptors which have been activated by Glutamate,an excitatory neurotransmitter. b)Also inhibits SEROTONIN &MUSCARINIC receptors c)It is an agonist of μ type of opioid receptors Onset of action:30-60 sec when given i.v,5 min when given i.m&25-45 min when given orally Duration of action:10-15 min when given i.v(a half life-10-15 min, γ half life-2- 3 hours) KETAMINE HYDROCHLORIDE
- 56. Induction of anaesthesia:1-2 mg/Kg. Particularly useful in a)Bronchial asthma- Bronchodilatory effect b)Tetralogy of fallot- Maintains SVR(systemic vascular resistance) c)Hypovolemic patients. Analgesia:0.5 mg/Kg bolus followed by infusion @3μg/Kg/min* Premedication:I.m-3-5 mg/Kg(onset time-5 min),Nasal-3-6 mg/Kg(onset time-5 min),Orally-3-10 mg/Kg(onset-20-45 min) KETAMINE :Uses,Dose &Route
- 57. As a Bronchodilator: for treatment of Status asthmaticus @30- 40μg/Kg/min As a sole anesthetic for short procedures-Can be given as infusion @15-45μg/Kg/min with 50%Nitrous oxide @30-90 μg/Kg/min without Nitrous oxide POINTS TO REMEMBER WITH USE OF KETAMINE: *Ketamine can produce “Hallucinations &Increase in secretions” Hence ketamine administration should be preceded by a benzodiazepine like midazolam &an anti-sialo gogue like Glycopyrrolate. KETAMINE :Uses,Dose &Route
- 58. Central Nervous system: Produces "Dissociative anaesthesia“ resembling a cataleptic state. Causes Functional &Electrophysiological dissociation of Thalamocortical system(depressed)from Limbic system(stimulated). This produces intense analgesia &amnesia as the sensory impulses from the body do not reach the cortex. Increases CMRO2,CBF and thereby increases Intracranial pressure. Also increases the intraocular pressure. KETAMINE :Effects on the body
- 59. Cardiovascular system:DUAL EFFECT a)HYPERTENSION &TACHYCARDIA-by indirect stimulation of sympathetic system causing release of catecholamines. b)In larger doses or patients with depressed sympathetic system, can cause hypotension due to direct myocardial depression Respiratory system: Very good BRONCHODILATOR, But does not obtund airway reflexes well. GIT: Increases secretions especially Salivary &bronchial KETAMINE :Effects on the body
- 60. Hallucinations : also called “Emergence reactions” Occur due to ketamine induced depression of auditory and visual relay nuclei, leading to misperception/misinterpretation of auditory and visual stimuli. Muscle rigidity due to increased muscle tone Hypertension and tachycardia. KETAMINE :Adverse effects
- 62. Midazolam Hydrochloride Chemical Nature-Water soluble Benzodiazepine with an IMIDAZOLE ring in its structure, that accounts for stability in aqueous solutions & rapid metabolism. The solubility of midazolam is pH dependent. At pH 3.5,imidazole ring is open →WATER SOLUBLE. At body pH imidazole ring closes LIPID SOLUBLE →RAPID ONSET Availability:5 ml vials containing 1 mg/ml&1 ml ampoules containing 5 mg/ml* It doesn't cause pain on injection.
- 64. Midazolam Hydrochloride Mechanism of action: Activation of Chloride channels of GABA receptors enhancing inhibitory synaptic transmission. Onset of action:30-60 seconds Duration of action:1 hour when given i.v *Elimination: Metabolized in liver by hydroxylation &conjugation, The metabolite “HYDROXYMIDAZOLAM” has no clinically significant side effects.
- 65. Midazolam : Uses,Dose &Route Induction of anesthesia:0.1-0.2 mg/Kg intravenously Commonly used to supplement to regional anesthesia for SEDATION For PREMEDICATION: Midazolam is given in a dose of 0.5 mg/Kg ORALLY,upto a maximum dose of 10 mg,to easily separate children from parents. This is usually possible in 15 to 30 minutes Popular drug for sedating critically ill patients in the ICU as it is cardiostable. Also used as an ANTICONVULSANT
- 66. Midazolam : Effects on the body CNS: Dose dependent depression of the CNS* CVS: Relatively CARDIOSTABLE Doesn't affect Heart rate and Blood pressure much RS: doesn't produce change in respiration at usual doses CAUTION: To be used with caution in patients with HYPOVOLEMIA as it may aggravate hypotension
- 67. Flumazenil Competitive benzodiazepine antagonist *Available in vials containing 0.1 mg/ml Usually given in 100 μg boluses Onset of action:2 min Duration: about an hour Adverse effects: Nausea, Vomiting, Agitation, seizures.
- 68. Dexmedetomidine Dexmedetomidine is a potent a2 adrenergic agonist. It is shorter acting than clonidine and much more selective for a2 vs. a1 receptors (dexmedetomidine 5 1620:1; clonidine 220:1). MECHANISM OF ACTION- One of the highest densities of a2receptors is located in the pontine locus ceruleus, an important nucleus mediating sympathetic nervous system function, vigilance, memory, analgesia, and arousal. The sedative effects produced by dexmedetomidine are largely due to inhibition of this nucleus.
- 69. Dexmedetomidine Dexmedetomidine, acting on a2 receptors, produces sedation by decreasing sympathetic nervous system activity and the level of arousal. The result is a calm patient who can be easily aroused to full consciousness. Available forms-Dexmedetomidine 50mcg/0.5ml, 100mcg/ml and 200mcg/2ml
- 70. Dexmedetomidine Pharmacokinetics Elimination half-time of dexmedetomidine is 2 to 3 hours Dexmedetomidine is highly protein bound (.90%) and undergoes extensive hepatic metabolism. The resulting methyl and glucuronide conjugates are excreted by the kidneys.
- 71. Dexmedetomidine CLINICAL USES- Pretreatment with dexmedetomidine attenuates hemodynamic responses to tracheal intubation, decreases plasma catecholamine concentrations during anesthesia, decreases perioperative requirements for inhaled anesthetics and opioids, and increases the likelihood of hypotension.
- 72. Dexmedetomidine Decreases inhalational MAC In Patients isoflurane MAC was decreased 35% and 48% by dexmedetomidine plasma concentrations of 0.3 ng/mL and 0.6 ng/mL, respectively Despite marked dose-dependent analgesia and sedation produced by this drug, there is only mild depression of ventilation.
- 73. Dexmedetomidine Dexmedetomidine in high doses (loading dose of 1 mcg/kg IV followed by 5 to 10 mcg/kg/hour IV) produces total IV anesthesia without associated depression of ventilation. The preservation of breathing provides a potential anesthetic technique for patients with a difficult upper airway. Addition of 0.5 mcg/kg dexmedetomidine to lidocaine being administered to produce IV regional anesthesia improves the quality of anesthesia and postoperative analgesia without causing side effects. Severe bradycardia may follow the administration of dexmedetomidine and cardiac arrest has been reported in a patient receiving a dexmedetomidine infusion as a supplement to general anesthesia.
- 74. Dexmedetomidine Postoperative Sedation Dexmedetomidine (0.2 to 0.7 mg/kg/hour IV) is useful for sedation of postoperative critical care patients in an ICU environment, particularly when mechanical ventilation via a tracheal tube is necessary. dexmedetomidine infusions do not result in clinically significant depression of ventilation and sedation exhibits some similarity with natural sleep. Tracheal extubation, dexmedetomidine-sedated patients breathe spontaneously and appear calm and relaxed. Because of its sympatholytic and vagomimetic actions, dexmedetomidine may be accompanied by systemic hypotension and bradycardia.
- 75. References Robert K.Stoelting,Simon C Hillier. Pharmacology and physiology in anesthetic practice.5th Edition. Morgan &Mikhail's Clinical Anesthesiology.5th Edition. Ronald D Miller,Elske sitsen,Marije reekers Intravenous Anesthetics.8th edition.