Propofol vs stp

Propofol vs stp

1. Basic Pharmacology of Propofol; Propofol Vs. Thiopentone Presenter- Dr. Suresh Pradhan Moderator- Dr. Yogesh Dhakal

2. Propofol substituted isopropylphenol (2,6-di-isopropylphenol)

3. History was first prepared in early 1970s in the UK by Imperial Chemical Industries as ICI 35868 Clinical trials followed in 1977, first by Kay and Rolly , using a form of soulbilised in cremophor EL confirmed the potential of propofol as an anesthetic agent

4. due to anaphylactic reactions to cremophor , this formulation was withdrawn and reformulated as emulsion of a soya oil/propofol mixture in water the emulsified formulation was re-launched in 1986 by ICI (now AstraZeneca) under the brand name Diprivan is used for induction and maintenance of anesthesia and for sedation in and outside the operating room

5. Physicochemical Characteristics comes as sterile, non-pyrogenic milky white emulsion in vials or ampoules is highly lipid soluble and is insoluble in an aqueous solution numerous formulations are available commercially

6. the most common formulation 1% propofol 10% soybean oil 1.2% purified egg phospholipid added as emulsifier 2.25% of glycerol as a tonicity-adjusting agent sodium hydroxide to adjust the pH

7. following concerns regarding microbial growth in the emulsion, ethylenediaminetetraacetic acid (EDTA) was added for its bacteriostatic activities in Europe, a 2% formulation and a formulation in which the emulsion contains a mixture of medium-chain and long chain triglycerides also are available

8. all formulations commercially available are stable at room temperature not light sensitive may be diluted with 5% dextrose in water

9. Commercial Preparations Diprivan emulsion form contains ethylenediaminetetraacetic acid (EDTA-0.005%)- acts as bacteriostatic agent contains sodium hydroxide to adjust pH to 7-8.5

10. Amloflo Low lipid emulsion preparation of propofol Contains 5% soyabean oil and 6% egg lecithin Doesnot require preservative or microbial growth retardant Equipotent to Diprivan , but associated with higher incidence if pain on injection

11. Fospropofol ( Lusedra / Aquavan ) water soluble phosphorylated prodrug of propofol approved in 2008 by FDA for use as anesthetic agent rapidly broken down by endothelial cell surface enzyme alkaline phosphatase to form propofol 1 mg fospropofol will liberate 0.54mg of propofol

12. Features: does not produce pain at the injection site has higher volume of distribution longer time to peak effect higher potency more prolonged pharmacodynamics effects

13. Non-lipid formulation uses cyclodextrins as solubilizing agent cyclodextrins are ring sugar molecules that form guest host complexes migrating between the hydrophilic center of the cyclodextrin molecule and water soluble phase allows propofol which is poorly soluble in water to be presented in injectable form after injection, propofol migrates out of cyclodextrin into the blood

14. Mechanism of Action selective modulator of gamma amino butyric acid (GABA A ) receptors causes wide spread inhibition of N-methyl-D-Aspartate (NMDA) receptor through allosteric modulation rather than by open channel gating increases dopamine concentration in the nucleus acumens resulting in sense of well being in the patient

15. decreases serotonin levels in the area postrema through action on GABA receptors resulting in its anti-emetic effect depresses spinal cord activity manifesting as its anti-pruritic effect

16. Pharmacokinetics available only for intravenous administration molecular weight of 178.27 isotonic Pka - 11 protein-binding- 95-98%

17. Distribution three compartment phase linear model after intravenous injection following an IV bolus dose, the highly lipid soluble propofol rapidly equilibrates between the plasma and the brain, accounting for the rapid onset of anesthesia

18. Phase of Rapid Distribution is rapidly distributed to highly perfused organs like kidneys, heart, lungs, liver awakening from a single bolus dose is rapid due to a very short initial distribution half-life (1-8 mins) and rapid clearance plasma level of propofol decreases

19. Phase of Slow Distribution is rapidly redistributed form the brain/ other highly perfused areas to other body tissues—first to muscle and then slowly to adipose tissues

20. Phase of Terminal Elimination drug is slowly released from the deep compartment with limited perfusion (adipose tissue) to plasma

21. Metabolism Rapidly metabolized in liver by conjugation to glucuronide and sulphate to produce water soluble inactive compounds, which are excreted by kidneys Exhibits a high systemic clearance that exceeds hepatic blood flow, implying existence of hepatic clearance

22. Also oxidized by liver cytochrome to 4-hydroxypropofol which is then glucuronidated or sulphated to inactive compounds Pulmonary uptake of propofol is significant and influences the initial availability Extra-hepatic metabolism is also reported-mainly by kidneys and lungs.

23. Kidneys may metabolize propofol upto 30% Lungs play important role in extrahepatic metabolism 30% of uptake and first pass elimination after bolus dose 20-30% after continuous infusion Less than 1% propofol is excreted unchanged in urine and only 2% is excreted in faeces

24. Onset of hypnosis- takes one arm brain circulation time; peak effect- within 90-100 seconds Duration of effect- 5-10 mins Elimination half life-0.5-1.5 hours

25. Context sensitive half life of infusions lasting upto 8hrs is less than 40 mins Is minimally influenced by the duration of infusion Readily crosses placenta but is rapidly cleared from the neonatal circulation

26. Basic Pharmacology of Propofol; Propofol Vs. Thiopentone contd ….

27. Pharmacodynamics Central Nervous System Effects dose dependent depression of cerebral cortex, ascending reticular activating system and medullary center resulting in sedation hypnosis amnesia anesthesia respiratory depression

28. decrease in cerebral metabolic oxygen consumption, cerebral blood flow and ICP along with decrease in cerebral perfusion pressure anticonvulsant effect anti-emetic effect antipruritic properties has no analgesic effect

29. Cardiovascular effects MAP-fall in MAP due to a drop in systemic vascular resistance preload cardiac contractility Cardiac Output decrease more significantly in hypovolemic patients cardiac disease on beta-blockers at the extremes of age hypertensive patients in treatment

30. Respiratory System dose dependent respiratory depression (first depth, then rate) inhibits hypoxic ventilatory drive and depresses the normal response to hypercarbia laryngeal and cough reflexes are blunted

31. Hepatic and Renal Function does not adversely affect hepatic or renal function as reflected by measurements of liver transaminase enzymes or creatinine concentrations

32. Neuromuscular Junction provides minimal muscle relaxation though good intubating condition may be obtained with propofol use alone

33. Eyes decreases intraocular pressure by 30-40% more than with Thiopentone more useful in blunting increase in IOP due to succinylcholine or laryngoscopy

34. Pregnancy & Lactation no effect on uterine muscle tone crosses placenta-equilibrium between foetus and mother within 2-3 minutes not recommended for use in lactating mother

35. Uses of Propofol induction of anesthesia most commonly used IV induction agent 1-2.5mg/kg, dose reduced with increasing age blood level: 2-6mcg/ml

36. maintainence of Anesthesia bolus of 10-40mg repeated every few minutes, or continuous infusion at 50-100mcg/kg/min IV when combined with N2O or opiate or 100-300 mcg/kg/min when it is used alone is preferred anesthetic agent for TIVA in conjugation with opioids

37. sedation for short surgical procedure or icu sedation/conscious sedation dose- 25-75mcg/kg/min IV preferred drug in day care surgery sedation antiemetic effect 10-20mg IV bolus, can be repeated every 5-10 mins

38. antipruritic effect 10mg IV is effective in the treatment if pruritis associated with neuraxial opioids or cholelithiasis anti- convulsant activity induction is occasionally accompanied by excitatory phenomena such as muscle twitching, spontaneous movement, opisthotonus , or hiccupping these reactions may occasionally mimic tonic– clonic seizures propofol has anticonvulsant properties and has been used successfully to terminate status epilepticus

39. attenuation of bronchospasm acts as a bronchodilator preservative sodium metabisulfite may produce bronchoconstriction in asthmatics anti-oxidant- beneficial in acute lung injury

40. Side Effects bradycardia and asystole have been reported dose dependent depression of ventilation with apnea allergic reactions lactic acidosis- after prolonged infusions >75mcg/kg/min for longer than 24 hrs risk of infection, pain on injection, hypertriglyceridemia with prolonged administration

41. Propofol Infusion Syndrome (PRIS) a rare but lethal complication if propofol infusion at dose 4mg/kg/ hr or more for 48 hrs or longer initially described in children, but later on also found in critically ill patients

42. presentation- acute refractory bradycardia leading to asystole in the presence of one or more of the following: metabolic acidosis rhabdomyolysis hyperlipidemia enlarged/ fatty liver

43. other features may include cardiomyopathy with acute cardiac failure skeletal myopathy hyperkalemia hyperlipidemia

44. major risk factors: poor oxygen delivery sepsis serious cerebral injury high propofol dose; cumulative dose of propofol age

45. severe critical illness of CNS or respiratory origin infusion of catecholamines infusion of corticosteroids inadequate delivery of carbohydrates subclinical mitochondrial disease

46. Proposed mechanisms / Pathophysiology proposed pathophysiology of PRIS remains controversial is likely multifactorial one of the leading hypotheses involves impaired electron transport chain function caused by propofol which eventually causes metabolic collapse of the body

47. Management early recognition of the manifestations is the key to managing PRIS if PRIS is suspected, propofol should be discontinued and an alternative sedative agent initiated general measures to support cardiac (vasopressors and inotropes) and renal function should be initiated promptly in patients with suspected PRIS

48. hemodialysis or hemofiltration have been suggested to decrease the plasma concentrations of circulating metabolic acids and lipids use of extracorporeal membrane oxygenation (ECMO) for combined respiratory and circulatory support

49. Propofol Vs. Thiopentone

50. Properties PROPOFOL THIOPENTONE chemistry ALKYLPHENOL THIOBARBITURATE consistency Emulsion milky white Sodium salts(6% sodiumcarbonate ) yellow amorphous powder solubility Lipid soluble Lipid soluble pH 7 10.5 of 2.5%

51. Properties PROPOFOL THIOPENTONE pKa 11 7.6 unionised % 99.97% 61% onset One arm –brain time15-30 sec 10-15 peak 90-100 sec 90-100 sec awakening 5-10 min 5-10 min rapid fall in plasma conc. after bolus redistribution & elimination redistribution

52. Properties PROPOFOL THIOPENTONE Protein binding 98% 85% Metabolism & excretion LIVER Glucuronite sulphate KIDNEY LIVER Oxidation N- dealkylation Desulfuration Destruction of barbituric acid ring KIDNEY & BILE

53. Properties PROPOFOL THIOPENTONE Metabolite Inactive pentabarbital Extrahepatic metabolism lung absent Clearance ml/kg/min 20-30 3-4

54. Properties PROPOFOL THIOPENTONE Context sensitive half time(for infusion lasting upto 8 hrs <40 min <150min MOA GABA GABA Induction 1-2.5 mg/kg 3-5 adult 5-6 children 6-7 infant

55. Properties PROPOFOL THIOPENTONE Neuroprotective Reduce infarct size when given immediately or 1 hr after ischemic insult Decrease 2 demand Preserve CPP ROBINHOOD phenomenon Free radical scavenging Emergence reaction + -- Antiemetic + --

56. Properties PROPOFOL THIOPENTONE BP Dec.25-40% dec HR N / dec . Dec(10-36%) CO dec dec CMRO2 dec dec CBF dec dec ICP dec dec

57. Properties PROPOFOL THIOPENTONE Apnea ++ dose dependent (20-30%) ++ bronchodilation + -- anticonvulsant + + antipruritic + -- Chronic refractory headache + --

58. properties PROPOFOL THIOPENTONE Pain on injection ++ + Hypotension ++ + apnea ++ + bronchospasm -- + Allergic reaction + + thrombophlebitis + ++

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