Intavenous Anaesthetic Agents

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.