Propofol - pharmacology, MOA USES, SIDE EFFECTS

Propofol - pharmacology, MOA USES, SIDE EFFECTS

1. DR ZIKRULLAH PROPOFOL

2. INTRODUCTION Propofol is the most frequently used intravenous anaesthetic today. Work in the early 1970’s on the substituted derivatives of phenol with hypnotic properties results in the development of 2,6-di-isopropofol The first clinical trial, reported by Kay and Rolly in 1977, confirmed the potential of propofol as an anaesthetic induction agent

3. Propofol is insoluble in water and was therefore initially prepared with Cremophor EL As Cremophor EL was associated with side effects in form of hypersensitive reactions, the drug was reformulated as a lipid emulsion and relaunched in 1986 with brand name Diprivan (Di – IsoPRopyl - IV- ANaesthetic )

4. Physical properties Propofol is a white ,oil in water, isotonic emulsion for intravenous injection only Highly lipid soluble Insoluble in water

5. Chemical Nature Propofol is a substituted isopropyl phenol ( 2,6-diisopropyl phenol)

6. AVAILABLE PREPARATIONS

7. Available as 1% solution of propofol in an aqueous solution of 10% soybean oil (oil phase) 2.25% glycerol 1.2% purified egg phosphatide (emulsifying agent) Available in a strength of 10 mg per ml in 10ml , 20ml , 50ml vials and 100ml bottle and 20ml ampoule.

8. GENERIC FORMULATION This preparation uses sodium metabisulfite (0.25 mg/ml )as preservative The pH is low  4.5 - 6.4

9. It has the preservative disodium edetate (0.005%) Uses sodium hydroxide to adjust pH to 7 to 8.5 DIPRIVAN

10. A low lipid emulsion of propofol contain 5% soybean oil 0.6% egg lecithin Higher incidence of pain on injection, Doesn't need a preservative or microbial growth retardant Equipotent to diprivan . AMPOFOL

11. Fospropofol ( Aquavan ) Prodrug Phosphono-o-methyl-2,6-diisoprpylphenol Undergo hydrolysis by endothelial cell surface alkaline phosphatases liberating propofol , phosphate and formaldehyde 1mg of fospropofol would liberate 0.54 mg of propofol Alternative to emulsion formulation to reduce associated side effects (pain on injection, risk of infection, hypertriglyceridemia , pulmonary embolism) Phosphate Monoesters, Hemisuccinate groups added to the parent compound to increase its water solubility

12. Non Lipid Formulations CYCLODEXTRINS as solublizing agents is used. Cyclodextrin are ring sugars, and form a carrier (host) complex to carry guest drugs ( propofol ) This makes propofol water soluble Propofol migrates out of the cyclodextrin ring in the blood.

13. Pharmaco kinetics

14. Absoption Available only for iv administration. Distribution - High lipid solubility Awakening from a single bolus dose is rapid due to a very short initial distribution half life(2-8)min. Biotransformation - Rate of clearence exceeds hepatic blood flow suggesting extrahepatic site of metabolism.

15. Metabolism Metabolism occurs at hepatic (mainly) and extrahepatic sites. Hepatic Inactive, water soluble sulphate and glucoronic acid metabolite, excreted by kidney Extrahepatic lung- pulmonary uptake of propofol occurs in first pass but most of drug is released back in circulation . kidney/ brain – glucoronidation is major metabolic pathway.

16. Excretion Metabolites are primarily excreted in urine. The elimination half time is 0.5 – 1.5 hrs The context sensitive half time of propofol infusion lasting upto 8 hrs is < 40 min

17. Mechanism of action It is relatively selective modulator of GABA A receptors (ß subunit) Exerts its sedative hypnotic effects through a GABA A receptor interaction

18. INTERACTION OF PROPOFOL with GABA receptor Decrease the rate of dissociation of the inhibitory neurotransmitter, GABA from the receptor Increase the duration of the GABA activated opening of the chloride channel Hyperpolarisation of cell membranes.

19. EFFECTS ON ORGAN SYSTEMS

20. CNS Propofol decreases cerebral blood flow intracranial pressure cerebral metabolic rate for oxygen(CMRO2) Cerebrovascular auto regulation in responses to changes in systemic BP and reactivity of the cerebral blood flow to changes in PaCO2 are not affected by Propofol

21. GABA A receptor mediated CNS depression. Inhibits NMDA subtype of glutamate receptors through modulation of sodium channel gating. Sense of well being, Pleasure seeking behaviour which leads to its abuse potential is due to increased dopamine concentration in Nucleus Accumbens . Tolerance to propofol doesn't develop in children undergoing repeated exposure to the drug during radiation therapy

22. CVS Decreases systemic BP Decrease in BP is often accompanied by corresponding changes in cardiac output. Vasodilation is due to Reduction in sympathetic activity Direct effect on intracellular smooth muscle calcium mobilization Inhibition of prostacyclin synthesis in endothelial cells Reduction in angiotensin II elicited Ca++ entry Activation of K+ ATP channels and stimulation of nitric oxide

23. A negative ionotropic effect of propofol may result from a decrease in intracellular calcium availability secondary to inhibition of trans- sclerolemmal Ca+ influx. The BP effect of propofol may be exaggerated in hypovolumic Patienst , elderly, and Patients with compromised LVF due to CAD Adequate hydration before rapid IV infusion is recommended to minimize the BP effect.

24. Propofol may decrease sympath .N. system activity to a greater extent than parasympathetic. N. system activity resulting in a predominant of the latter It doesn’t alter SA or AV node function in normal patients or in Pt of WPW syndrome - acceptable drug during ablative period Baroreceptor reflex control of heart rate may be depressed by propofol .

25. Profound bradycardia and asystole reported in healthy adult Pt despite prophylactic anticholinergics Risk of bradycardia – related death during propofol anaesthesia has been estimated to 1.4 in 100,000 Heart rate responses to IV administration of atropine may be attenuated in Pt receiving propofol due to suppression of sympathetic nervous system by propofol Treatment may require beta agonist such as isoproterenol

26. Respiratory System Dose dependant depression of ventilation Apnea occurring in 25 – 35 % of patient after induction of anaesthesia . Opioids in premedication enhance ventilatory depressant effect A maintenance infusion of propofol decreases tidal volume and frequency of breathing Ventilatory response to CO2 and hypoxemia are decreased

27. Propofol depresses the ventilatory response to hypercapnia due to an effect at the central chemoreceptors Peripheral chemoreceptor reflex response to CO2 remain intact Propofol can produce broncho -dilatation and decrease the incidence of intraop wheezing in Pt of asthma Hypoxic pulmonary vasoconstriction seems to remain intact

28. Hepatic and renal system Prolonged infusions have been associated with hepatocellular injury accompanied by lactic acidosis, bradyarrthythmia and rhabdomyolysis Prolonged infusion may also result in excretion of green urine, reflecting the presence of phenols in the urine  this discoloration doesn’t alter renal function

29. Uric acid in urine is increased  cloudy urine. This is d/t uric acid crystallization in urine at low pH and temperature not considered to be detrimental or indicative of adverse renal effect of propofol IOP Causes significant decrease in IOP

30. Doesn’t alter tests of coagulation or platelet function Inhibits platelet aggregation that is induced by proinflammatory lipid mediators including thromboxaneA2 and platelet activating factor COAGULATION

31. USES OF PROPOFOL

32. Induction Of Anaesthesia Drug of choice for day care surgery For healthy adult  1.5 – 2.5 mg / kg body wt Blood level of 2- 6 m g /ml producing unconsciousness Children  Require higher induction dose d/t larger central distribution volume and higher clearance rate

33. Elderly  Require lower induction dose (25 – 50%) d/t smaller central distribution volume and decreased clearance rate Awakening typically occurs at plasma concentration of 1.0 to 1.5 m g/ml

34. Maintenance of Anaesthesia Dose  100 – 300 m g / kg / min IVI combined with nitrous oxide or an opioid

35. INTRAVENOUS SEDATION Conscious sedation  25 – 100 m g / kg / min IVI Produces minimal analgesic and amnestic effects Conventional patient controlled analgesia delivery system set to deliver 0.7 mg / kg doses of propofol with a 3 min lockout period is an alternative to continuous sedation technique Propofol also provides antioxidant property which is esp. beneficial for ICU Pt.

36. TOTAL INTRAVENOUS ANAESTHESIA (TIVA) Bristol infusion regimen  (after induction) Is based on lean body wt 10 mg/kg / hr infusion for first 10 min 8 mg / kg / hr for the next 10 min Final maintenance level of 6 mg / kg / hr using 67 % nitrous oxide in oxygen

37. NON HYPNOTIC THERAPEUTIC APPLICATIONS Antiemetic effects Sub hypnotic doses, 10 - 20 mg IV, repeat 5 – 10 min, or start infusion @ 10 m g / kg /min Useful esp. if PONV is not of vagal origin Effective against chemotherpy induced nausea and vomiting More effective in preventing nausea and vomiting than ondansetron when used to induce and maintain anaesthesia Mechanism: Modulate subcortical pathways Direct depressant effect on vomiting centre Decreased serotonin level in area postrema through GABA receptor activation

38. Antipruritic action  Propofol 10.0 mg IV Effective in the treatment of pruritus associated with nueroaxial opioids or cholestasis . Mechanism: D epress the spinal cord activity.

39. Anticonvulsive action GABA mediated presynaptic and post synaptic inhibition of chloride ion channel. Propofol in doses of > 1 mg / kg IVI decreases seizure duration 35 – 45 % of Pt undergoing ECT.

40. Attenuation of bronchoconstriction Propofol decreases the prevalence of wheezing after induction of anaesthesia and tracheal intubation, in healthy and asthmatic Pt Preparations of propofol using meta- bisulfite as preservative causes bronchoconstriction in asthmatics

41. ADVERSE EFFECTS Pain on injection : is reduced by using a large vein, avoiding veins in the dorsum of the hand by prior lignocaine or short acting opioid administration (mixing in same syringe might cause pulm embolism – not recommended) Changing composition of carrier fat emulsion for propofol to medium chain triglyceride.

42. Apnoea Greater incidence of apnoea lasting longer than 30 sec, increased by addition of opioid . Decrease in arterial BP: Most significant side effect Addition of opioid augments fall in BP Thrombophlebitis in the injected vein Pulmonary Embolism Hypertriglyceridemia Myoclonus More frequently seen in propofol than thiopentone

43. Propofol infusion syndrome Rare but lethal complication Associated with propofol infusion of > 75 m g /kg /min for 24 hr or more. C/F  Acute refractory bradycardia leading to asystole Cardiomyopathy with acute cardiac failure Metabolic acidosis Rhabdomyolysis , hyperlipidemia,enlarged or fatty liver Skeletal myopathy , hyperkalemia , hepatomegaly and lipaemia

44. Mechanism: Cytopathic hypoxia of electron transport chain Impaired oxidation of long chain fatty acids Propofol metabolite in susceptible patients Risk Factors: Poor O2 delivery Sepsis Serious Cerebral Injury High propofol dosage Treatment: Metabolic Acidosis is reversible in in early stages with discontinuation of propofol Cardiogenic shock may require assistance with extracorpreal membrane oxygenation

45. Allergic Reactions Allergic component include phenyl nucleus and diisopropyl side chain Bacterial Growth: Propofol strongly supports the growth of E.coli and Pseudomonas aeruginosa , Postoperative surgical infection is attributed to extrinsic contamination of propofol

46. Recommendations for Safe Propofol Use: Aseptic Technique in handling propofol as reflected by disinfecting ampule neck surface or vial rubber stopper by 70% alcohol To be withdrawn in a sterile syringe immediately after opening and administered promptly Contents of opened ampule to be discarded if they are not used with in 6 hours In ICU, tubing and unused portin of propofol must be discarded after 12 hours.

47. Contraindications No absolute contraindication Not to be used in Pt known to be hypersensitivity to propofol injection or its components Not recommended in children less than 3 yrs of age

48. INTERACTIONS Induction dose is reduced when premeditation is done with narcotics ( morphine, meperidine and fentanyl ) and opioid -sedative combination ( BZD, barbiturates) These agents also enhanced decrease in systolic diastolic and mean arterial BP and cardiac output. Inhalational agents enhance anaesthetic action of propofol . No significant interaction with neuromuscular blockers, local anaesthetics analgesics

49. Not recommended for obstetric anaesthesia as it crosses the placenta and may cause neonatal depression Has been used for termination of pregnancy in first trimester Safety in lactation has not been established Effects on fetus and pregnancy

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