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Intavenous Anaesthetic Agents

Intavenous Anaesthetic Agents. Dr.C.N.Chandra Sekhar. Intravenous Anaesthetic Agents. Induction with IV Anaesthetic agents is smoother and rapid than inhalational agents. Intravenous Anaesthetic Agents. Properties of the Ideal IV Anaesthetic Agent:

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Intavenous Anaesthetic Agents

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  1. Intavenous Anaesthetic Agents Dr.C.N.Chandra Sekhar

  2. Intravenous Anaesthetic Agents • Induction with IV Anaesthetic agents is smoother and rapid than inhalational agents

  3. Intravenous Anaesthetic Agents • Properties of the Ideal IV Anaesthetic Agent: • Rapid onset – mainly unionized at blood pH - highly lipid soluble • Rapid recovery –Rapid redistribution • Analgesic at subanaesthetic Concentration • Minimal CV and Resp. depression • No emetic effects • No emergence phenomena • No Interaction with NMBD

  4. Intravenous Anaesthetic Agents • Properties of the Ideal IV Anaesthetic Agent: • No pain on injection • No venous sequelae • Safe if injected inadvertantly into an artery • No toxic effects on other organs • No release of Histamine • No hypersensitivity reactions • Water soluble formulation • Long shelf-life • No stimulation of Porphyrias.

  5. Intravenous Anaesthetic Agents • Pharmacokinetics of IV Anaesthetic Agents: • After IV  rapid  in plasma conc. slower decline • Anaesthesia is produced by diffusion of drug from arterial blood across BBB into the brain

  6. Intravenous Anaesthetic Agents • Rate of transfer into the brain and anaesthetic effect is regulated by: • 1.Protein binding • 2.Blood flow to the brain • 3.Extracellular pH & pKa of the drug • 4.The relative solubilities of the drug in lipid and water • 5.Speed of Injection

  7. Intravenous Anaesthetic Agents • 1.Protein Binding: Only unbound drug is free to cross the BBB • Low plasma protein • Displacement from proteins by other drugs increase free drug conc. • Hyperventilation decreases protein binding and increases anaesthetic effect

  8. Intravenous Anaesthetic Agents • 2.Blood Flow to the Brain: • Reduced blood flow reduced delivery of the drug. • If CBF is decreased due to low Cardiac output---initial blood conc. Higher than N, i.e Anaesthetic effect may be delayed but enhanced.

  9. Intravenous Anaesthetic Agents • 3.Extracellular pH & pKa of the drug: • Only non-ionized fraction of the drug penetrates the lipid BBB • The potency of the drug depends on the degree of ionization at the pH of extracellular fluid & pKa of the drug.

  10. Intravenous Anaesthetic Agents • 4.The relative solubilities of the drug in lipid and Water: • High lipid solubility enhances transfer into brain. • 5.Speed of Injection: • Rapid IV adminstration  high initial conc. increases speed of induction and extent of CV and Resp.side effects

  11. Pool Lean % of Dose Viscera Fat 0.06 0.125 025 0.5 1 2 4 8 16 32 128 mts

  12. Classification of Intravenous Anaesthetics • Rapidly acting agents: • Barbiturates • Methohexital • Thiobarbiturates- thiopental, thiamylal • Imidazole compounds: eg.etomidate • Sterically hindered alkyl phenols: eg. Propofol • Steroids: eg. Eltanalone, Althesin, Minaxolone • Eugenol: eg. Propanidid

  13. Classification of Intravenous Anaesthetics • Slower- acting agents: • Ketamine • Benzodiazepines:- Diazepam, flunitrazepam, midazolam • Large-dose opioids:- Fentanyl, Alfentanil, Sufentanil, remifentanil • Neurolept combinations:- Opioid + Neuroleptic

  14. O ‖C N R C=O C R N C ‖ O R

  15. Thiopental Sodium • Chemical Structure:- • Sodium 5-ethyl – 5(1-methylbutyl) – 2 thiobarbiturate • Physical properties & Presentation:- • Sulphur analogue of pentobarbital • Taste = bitter • Colour = yellowish • State = powder • Smell = garlic

  16. Thiopental • Stored in Nitrogen to prevent chemical reaction with atmospheric CO2 • 6% anhydrous sodium carbonate to increase solubility in water • 2.5% solution pH : 10.8 • Solution is hypotonic • Prepared solution can be kept for 24 hrs. • Oil/water partition coefficient 4.7 • pKa is 7.6

  17. Thiopental • Central Nervous System:- • Onset <30sec after IV injection • delayed if CO is low • Progressive depression of CNS and spinal cord reflexes • Hypnotic action – potent • Analgesic effect – poor • CMR • CBF  • CBV  • ICP 

  18. Thiopental - CNS • Recovery of consciousness occurs at high blood concentrations if a large dose is given or if the drug is injected rapidly (acute tolerance) • Consciousness regained in 5-10mts. • At subanaesthetic conc. • Antanalgesic effect • Reduces pain threshold • Potent anticonvulsant • Sympathetic effect depressed more than parasympathetic. • Tachycardia

  19. Thiopentone • Cardiovascular System:- • Myocardial contractility depressed • Peripheral vasodilation • Hypotension • HR

  20. Thiopentone • Respiratory System:- • Ventilatory drive  • In spont.Vent. Vf  & Vt  •  in bronchial muscle tone • Laryngospasm

  21. Thiopentone • Skeletal muscle:- •  tone at high blood concentrations • No direct effect on NMJ • Uterus & Placenta:- • Contractions suppressed at high doses • Crosses the placenta rapidly • Foetal blood conc. Not reach upto mother’s • Eye:- • IOP  by 40% • Pupils = dilates first and then constricts • Light reflex present until surgical anaesthesia is reached • Corneal,conjunctival,eyelash and eyelid reflexes abolished

  22. Thiopentone • Hepatorenal Function:- • Transient impairement of liver and kidney functions. • Hepatic microsomal enzymes are induced  metabolism & elimination of other drugs.

  23. Thiopentone • Pharmacokinetics:- • 75-85% drug is protein bound (mostly albumin) • Protein binding affected by pH I.e by alkalemia • Conc. Of free drug  in hyperventilation • Diffuses readily into CNS because of high lipid solubility. • Predominantly unionized (61%) at body pH • Consciousness returns when the brain concentration returns to a threshold value( vary from patient to patient)

  24. Thiopentone • Pharmacokinetics:- (contd….) • Metabolism occurs in Liver • Metabolites excreted in Urine • Terminal elimination half-life 11.5 hrs. • Metabolism is a Zero order process • 30% of original drug remain after 24 hrs. • Hangover effect common • Elimination impaired in elderly • In obese dose should be based on lean body mass as distribution to fat is slow.

  25. Thiopentone • Dosage & adminstration:- • Adminstered as 2.5% solution • Initially 1-2 ml injected • Healthy adults: 4 mg/kg administered over 15-20 sec. • Loss of eye reflex within 30sec • Supplementary dose 50-100mg slowly • Children 6 mg/kg • Elderly patients 2.5 – 3 mg/kg • Induction smooth, preceded by the taste of garlic • No other drugs should be mixed with Thiopentone

  26. Thiopentone • Adverse Effects:- • Hypotension • Respiratory depression • Tissue necrosis • Intra-arterial injection • Laryngospasm • Bronchospasm • Allergic reactions • Thombophlebitis

  27. Thiopentone • Indications:- • Induction of Anaesthesia • Maintenance of Anaestheisa • Treatment of Status epilepticus • Reduce intracranial pressure

  28. Thiopentone • Absolute Contraindications: • Airway Obstruction • Porphyria • Hypersensitivity reaction to Baribiturates

  29. Thiopentone • Precautions:- • Cardiovascular disease • Severe hepatic disease • Renal disease • Muscle disease • Reduced metabolic rate • Obstetrics • Outpatient anaesthesia • Adrenocortical insufficiency • Extremes of age • asthma

  30. Thiopentone

  31. Propofol • Indications: • For induction and Maintenance of General anaesthesia • Sedation in Intensive Care Unit and during Regional anaesthesia techniques • For treatment of refractory nausea and vomiting in patients receiving chemotherapy • Treatment of status epilepticus

  32. Propofol • Mode of Action:- Unclear. Potentiates the inhibitory transmitters glycine and GABA

  33. Propofol • Routes of Adminstration and Dose: • Intravenous bolus dose 1.5 – 2.5 mg/kg for induction • Maintenance 4-12mg/kg/hour • For children induction dose should be increased by 50% and Manintenance infusion by 25-50%

  34. Propofol • Consciousness lost in 30 sec. • Recovery about 10mts after a single dose • Plasma concentration of 2-6mcg/ml associated with hypnosis. • Plasma conc. of 0.5 – 1.5 mcg/ml associated with sedation.

  35. Propofol- pharmacodynamics CVS: - -15-25% drop in Blood pressure and SVR without comp. Increase in HR -20% decrease in Cardiac output -attenuates laryngoscopic response -Vasodilatation due to NO release

  36. Propofol- pharmacodynamics • Respiratory System: • Apnea for variable duration • Decreased laryngeal reflexes • Infusion decreases the TV and  RR • Depresses ventilatory response to CO2 • Bronchodilatation due to direct effect • Preserves the mechanism of hypoxic pulm.vaso constriction

  37. Propofol- pharmacodynamics • Central Nervous System:- • Smooth,rapid induction with rapid and clear headed recovery • Intracranial pressure,cerebral perfusion pressure, cerebral oxygen consumption reduced • GIT:- • Propofol has got intrinsic antiemetic properties, mediated by antagonism of dopamine D2 receptors.

  38. Propofol- Pharmacodynamics • Renal:- • Causes reduction in excretion of Na+ ions • Metabolic:- • Longterm use causes hypertriglyceridemia

  39. Propofol • Toxicity and side effects:- • Pain on injection seen in 28% subjects • Epileptiform movements • Facial parasthesias • Bradycardia • Neurological sequelae in children after longterm use of propofol for sedation • Quinol metabolites give green colour to urine

  40. Propofol-Pharmacokinetics • Distribution:- • 97% protein bound in plasma • VD is 700 – 1500 L • Distribution half-life is 1.3 – 4.1minutes. • Metabolism:- • Rapidly metabolised in the liver • Primarily to inactive glucuronide and sulphate conjugates and the corresponding quinol. • Renal and hepatic disease have no significant effect on the metabolism.

  41. Propofol • Chemical:- 2,6 – diisopropylphenol • Presentation:- White oil in water emulsion containing 1 to 2% propofol in soyabean oil and purified egg phosphatide • Main Action:- Hypnotic

  42. Ketamine Hydrochloride • 1965 • Phencyclidine derivative • Dissociative anaesthesia • Chemical structure:- • 2(o-chlorophenyl)-2(methylamino)-cyclohexanone hydrochloride

  43. Ketamine • Physical characteristics & presentation:- • Soluble in water • 1% with NaCl for istonicity • 5 & 10% with benzothonium chloride 0.1mg/kg as preservative • pH of the solution 3.5 – 5.5 • pKa of Ketamine 7.5

  44. Ketamine • Central Nervous System:- • Extremely lipid soluble • After IV • Onset: 30-60 sec • Duration: 10-15 min • After IM • Onset: 3-4 mts. • Duration: 15-25mts • Potent analgesic at subanaesthetic doses

  45. Ketamine • Central Nervous System:- (contd…) • Amnesia persists 1 hr. after recovery of consciousness • Induction smooth • Emergence delirium,restlessness,disorientation & agitation • EEG changes – loss of alpha activity & predominant theta activity • CMR • CBF  • CBV  • ICP 

  46. Ketamine • Cardiovascular System:- • Arterial pressure  by 25% • HR  by 20% • CO may increase • Myocardial O2 consumption  •  Myocardial sensitivity to Epinephrine • Vasodilatation in tissues innervated by -adrenergic receptors & vasoconstriction in those with - receptors

  47. Ketamine • Respiratory System:- • Transient apnoea • Pharyngeal & laryngeal reflexes, patent airway maintained • Bronchial muscle is dilated

  48. Ketamine • Skeletal Muscle:- • Muscle tone  • GI system:- • Salivation is increased • Uterus & Placenta:- • Crosses placenta readily • Eye:- • IOP 

  49. Ketamine • Pharmacokinetics:- • 12% is bound to protein • Initial peak conc.after IV injection decreases after drug distributes • Metabolism is by liver demethylation & hydroxylation of cyclohexanone ring (nor-ketamine is the active metabolite) • 80% of injected drug excreted as glucuronides

  50. Ketamine • Pharmacokinetics:- contd…… • 2.5% excreted unchanged in urine • Elimination half-life 2.5hrs. • Peak conc. Achieved after 20 mts. After IM inj.

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