Propofol ppt nandini

Propofol and anaesthesia

1. Propofol

2. Introduction Propofol is famously called as “Milk of Amnesia”. Most common intravenous agent used for induction and maintenance of Anaesthesia . Preferred drug in Day care surgeries. Also used for sedation in intubated and mechanically ventilated patients in ICU. The best choice in TIVA.

3. Preparations Diprivan (1%)- 10% soyabean oil, 2.25% glycerol, 1.2% egg phosphatide , 0.005%disodium edenate . Ampofol (low lipid emulsion)- 5%soyabean oil, 0.6% egg lecithin Diprifusor TCI devices Propofol lipura Fospropofol ( Lusedra / Aquavan )

4. Physical and chemical properties Milky white coloured , sterile , non pyrogenic oil in water emulsion Highly lipid soluble Slightly water soluble Molecular weight -178.271 D Octanol water partition coefficient-6761:1 at pH- 6 to8.5 Isotonic, pH-7-8.5 2,6- diisopropylphenol (C12H18O) Weak acid, unionized, Pka-11 Protein binding-95-98%

5. 2,6-diisopropylphenol

6. Mechanism of action Main Site of action - GABAa -BZD: Chloride receptor complex in CNS - Binding of propofol to GABAa receptor causes prolongation of action of GABA and increased duration of opening of chloride channel resulting in hyperpolarization of postsynaptic cell membrane and functional inhibition of post synaptic neurons. Acts on hippocampus and prefrontal cortex . Principal action responsible for sedation and hypnosis.

7. Mechanism of Action Widespread inhibition of NMDA(N-methyl-D- aspartate ) receptor through sodium channel gating. Acts on GABA a and glycine receptors on dorsal horn of spinal cord and inhibits the excitatory action. Increases Dopamine concentration in nucleus accumbens which is responsible for sense of well being, drug abuse potential and pleasure seeking behaviour . Decreases serotonin levels in area postrema – anti emetic effect.

8. Pharmacokinetics Absorption- Intravenous Volume of distribution-3.5-4-5 L/kg Distribution- explained by three compartment linear model Rapidly equilibrates between plasma and brain accounting for rapid onset of anaesthesia (one brain arm circulation time) Onset-<40 seconds, peak effect -90-100 seconds, initial redistribution half life-2-8minutes. Phase 1/very rapid distribution(half life- 1-8min)- rapidly distributed to highly perfused organs like heart , lungs, kidneys and liver. Phase 2/slow distribution(half life-30 -60 min)- rapidly distributed from highly perfused tissues to muscle and fat. Phase 3/terminal elimination(half life-4 to24 hrs)-slowly released from deep compartment with limited perfusion (fat) to plasma and is metabolized.

9. Pharmacokinetics Elimination half time- 0.5 hrs -1.5 hrs Context sensitive half time- <40 min-8 hrs Short effect-site equilibration time Clearance rate-30-60ml/kg/min Metabolism- propofol is extensively metabolized by liver .It undergoes conjugation by UDP- glucoronosyl transferase to form inactive, water soluble sulfate and glucoronic acid metabolites which are excreted by the kidneys. Propofol may also undergo ring hydroxylation by cytochrome-P450 to form 4- hydroxypropofol which is then glucoronidated or sulfated. Extra-hepatic metabolism- Lungs-30% uptake( propofol converted to 2,6-diisopropyl-1,4-quinol) and kidneys -30%uptake. Less than 1%propofol is excreted unchanged in urine and only 2%in faeces . No dosage adjustments are needed for patients with renal or hepatic failure Geriatrics age-related decrease in volume of distribution Decresed rate of plasma clearance cardiorespiratory effects including hypotension, apnea, airway obstruction, and/or oxygen desaturation

10. Pharmacokinetics Blood levels of propofol during surgery required for unconsciousness- 2-5 ug /ml. Patient becomes awake at plasma level less than 1.5 ug /ml. ED90 for anaesthesia is 3.2ug/ml when used with 67% of nitrous oxide. Larger doses required in children- higher clearance rate(25%) and larger central compartment volume(50%).

11. Pharmacodynamics CNS- decrease in cerebral metabolic oxygen consumption, cerebral blood flow, ICP and cerebral perfusion pressure. Cerebral autoregulation and reactivity to increased PaCO2 is maintained. CVS- decreases SVR by 30%, decreases SBP by 25-40% along with decrease in COP. Propofol blocks/resets baroreceptors , so there is little (no) compensatory tachycardia due to decrease in mean BP. A central cholinergic response may be responsible for bradycardia . If ventilation is assisted or controlled(CPAP), there is increase in the incidence and degree of depression on COP.

12. Pharmacodynamics RS- dose dependent respiratory depression(first reduction in tidal volume associated with tachypnoea followed by apnoea ). Apnoeaoccure in 25-30% of patients depending on the dose and use of concomitant drugs like opoids , BZP . Decreased sensitvity of respiratory centre to increase in CO2 and hypoxia via carotid body chemoreceptors . Laryngeal and cough reflexes are depressed. Propofol has a bronchodilator effect through direct action on muscaranic action and attenuating vagal response. Attenuates the magnitude of hypoxic pulmonary vasoconstriction.

13. Pharmacodynamics Liver- blood flow is decreased. Prolonged infusions have been associated with hepatocellular injury accompanied by lactic acidosis, bradydysarrythmias and rhabdomolysis . Kidney- vasoconstriction of splanchnic and renal blood vessels which causes decrease in RBF and GFR. Prolonged infusions results in green urine due to phenols in urine and due to increased uric acid crystals in urine. Eyes- decrease in IOP by 30-40%, helps in blunting increase in IOP due to succinylcholine or laryngoscopy . Pregnant uterus- crosses placenta (equilibrium between mother and foetus is 2-3 min) and causes neonatal depression.

14. INDICATIONS AND USAGE: induction and maintenance of anesthesia Monitored anaesthesia care(MAC) sedation Combined sedation and regional anaesthesia Short surgical procedure, ICU sedation ,conscious sedation.

15. Non- Anaesthetic Uses Anti-emetic- 10-20 mg IV ,can be repeated every 5-10 min or start infusion of 10 ug /kg/min. Anti- pruritic - 10 mg IV is effective in the treatment of pruritis associated with neuraxial opoids and cholelithiasis . Attenuation of bronchospasm - Hence, useful in asthamatics . Antioxidant- beneficial in acute lung injury.

16. Induction of General Anesthesia Healthy Adults Less Than 55 Years of Age: 40 mg every 10 seconds until induction onset (2-2.5 mg/kg). Elderly, Debilitated, or ASA III/IV Patients: 20 mg every 10 seconds until induction onset (1-1.5 mg/kg). Cardiac Anesthesia: 20 mg every 10 seconds until induction onset (0.5-1.5 mg/kg). Neurosurgical Patients: 20 mg every 10 seconds until induction onset (1-2 mg/kg). Pediatric Patients - healthy, from 3-16 years of age: 2.5-3.5 mg/kg administered over 20-30 seconds.

17. Maintenance of General Anesthesia Healthy Adults Less Than 55 Years of Age: 100-200 μg /kg/min (6-12 mg/kg/h). Elderly, Debilitated, ASA III/IV Patients: 50-100 μg /kg/min (3-6 mg/kg/h). Pediatric Patients - healthy, from 2 months to 16 years of age: 125-300 μg /kg/min (7.5-18 mg/kg/h) Cardiac Anesthesia, Most Patients Require: Primary propofol injectable emulsion with secondary opioid : 100-150 μg /kg/min. Low-dose propofol injectable emulsion with primary opioid : 50-100 μg /kg/min. Neurosurgical Patients: 100-200 μg /kg/min (6-12 mg/kg/h).

18. MAC sedation Initiation of MAC sedation- Healthy adults <55 yrs of age: most patients require an infusion of 100-150 ug /kg/min(6-9mg/kg/hr) for 3-5min or a slow injection of 0.5 mg/kg over 3-5 min followed immediately by a maintenance infusion. Elderly , debiliated , neurosurgical or ASA- III/IV patients- require doses similar to healthy adults but rapid boluses are to be avoided. Maintenance of MAC sedation- Healthy adults <55 yrs of age: 25-75 ug /kg/min(1.5-4.5 mg/kg/hr)or incremental doses of 10 mg or 20 mg. Elderly , debiliated , neurosurgical or ASA- III/IV patients- require 80% of the usual adult dose, but rapid boluses are to be avoided.

19. ICU sedation 2 % aqueous solution of propofol is used in ICU for initiation and maintenance of sedation in intubated and mechanically ventilated patients Initiation: 5 ug /kg/min(0.3 mg/kg/hr) for at least 5 min with subsequent increments of 5-10 ug /kg/min(0.3-0.6 mg/kg/hr) over 5-10 min. Maintenance: 5-50 ug /kg/min(0.3-3 mg/kg/hr) or higher my be required.

20. Adverse Effects Airway Copious secretions Laryngospasm Respiratory Apnea, respiratory depression Hiccough Bronchospasm Cardiovascular Hypotension Dysrhythmias, bradycardia or tachycardia

21. Adverse Effects Central Nervous System Headache Dizziness, euphoria, confusion Clonic / myoclonic movements Seizures, disinhibition Other Pain or burning at the injection site is common especially when the IV is in a small peripheral vein Green urine

22. Adverse Effects Transient local pain: larger veins; prior injection of IV lidocaine (1 ml of a 1% solution), not exceeding 20 mg lidocaine /200mg propofol . Post operative unconsciousness. rare reports of pulmonary edema. unexplained postoperative pancreatitis Pediatric patients no vagolytic activity Reports of bradycardia , asystole , and rarely, cardiac arrest have been associated with propofol particularly when fentanyl is given anticholinergic agents

23. Drug Abuse Potential Propofol is known to have effects like amorous behaviour , intense dreaming and hallucinations. The famous legendary singer Michael Jackson died due to acute propofol and benzodiazepine intoxication .  

24. Propofol Infusion Syndrome It has been described in pediatric and adult patients receiving prolonged infusions of propofol at >75ug/kg/min(>5 mg/kg/hr) for>24-48 hrs. It is a rare but lethal complication . Basic pathology-mitochondrial toxicity(impaired oxidation of long chain fatty acids affecting electron transport chain), impaired tissue oxygenation and carbohydrate deficiency. Presentation- acute refractory bradycardia leaading to asystole in presence of one or more of the following: metabolic acidosis(base deficit>10 mmol /l), hyperlipedemia , rhabdomyolysis , enlarged or fatty liver, cardiomyopathy with acute cardiac failure and hyperkalemia . Treatment- prompt recognition of symptoms and discontinuation of propofol infusion. ECMO(extra corporeal membrane oxygenation) has been described in treatment of some patients.

25. Contraindications Absolute contraindications: Known hypersensitvity to propofol or any of its components. Allergies to egg, egg products, soyabeans or soy products. Disorders of fat metabolism. Relative contraindications: Untreated hypertensive, hypovolemia and compromised left ventricular function. Paediatric patients <3 yrs. Pregnant or lactating mother. Known case of epilepsy. Patients undergoing neurosurgery such as pallidotomy as it temporary abolishes tremors in patients of parkinsonism.

26. DRUG INTERACTIONS: dose requirements reduced : Premedication with narcotics ( e.g., morphine, meperidine , and fentanyl , etc.) In pediatric patients, administration of fentanyl concomitantly with propofol may result in serious bradycardia combinations of opioids and sedatives ( e.g., benzodiazepines, barbiturates, chloral hydrate, droperidol , etc.) more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output

27. DRUG INTERACTIONS: reduced in the presence nitrous oxide inhalational agents ( e.g., isoflurane , enflurane , and halothane) has not been extensively evaluated does not cause a clinically significant change in onset, intensity or duration of action of the commonly used neuromuscular blocking agents ( e.g., succinylcholine and nondepolarizing muscle relaxants). Coadministration of 10 microg kg(-1) midazolam decreases the dose and time required to achieve hypnosis with propofol induction without delaying emergence from anesthesia. Additional administration of flumazenil further shortens the time to emerge from midazolam-propofol anesthesia

28. The interaction between fentanyl and propofol during emergence from anesthesia: monitoring with the EEG-Bispectral index. Journal of Clinical Anesthesia Volume 15 • Number 2 • March 2003 Copyright © 2003 Elsevier CONCLUSIONS: The plasma levels of fentanyl affect the concentrations of propofol required for patients to regain consciousness. The BIS values for wakefulness are unaltered at the different combinations of propofol and fentanyl concentrations. Thus, the BIS appears to be a useful and consistent indicator for level of consciousness during emergence from propofol/fentanyl intravenous anesthesia

29. References Pharmacology and physiology in Anaesthetic practice- fourth edition- Stoelting . Miller’s Anaesthesia - seventh edition. Lee’s synopsis of Anaesthesia . Journal of Clinical Anesthesia Volume 13 • Number 4 • June 2001 Copyright © 2001 Elsevier