Propofol. Dr Prashant Kumar. MD (Anaesthesiology & Critical Care, UCMS, Delhi)

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1 Dr Prashant Kumar MD (Anaesthesiology & Critical Care, UCMS, Delhi) Class: Non barbiturate short acting intravenous anaesthetic agent, alkyl phenol Structure: 2,6 di-isopropylphenol Preparation and Properties: 1. Propofol comes as sterile, nonpyrogenic emulsion (1% strength) in vials or ampoules. 2. It is very slightly soluble in water and, thus is formulated in a white, oil-in-water emulsion. 3. The pka is 11. The octanol/water partition coefficient for Propofol is 6761:1 at a ph of Each 1 ml of solution contains: Propofol (1%)= 10mg/ml, Soyabean oil= 10% (100mg/ml, emulsifier), Glycerol= 2.25% (22.5mg/ml, as a tonicity- adjusting agent) and Purified egg lecithin (phospholipids) = 1.2%(12 mg/ml, emulsifier). It also contains Sodium hydroxide to adjust ph. 5. The emulsion is isotonic and has a ph of

2 6. Commercially available propofol contains no anti microbial preservatives these days. Strict asepsis must be followed, it must be drawn aseptically into a sterile syringe or volumetric infusion device immediately after the container is opened. There have been reports in which failure to use aseptic technique when handling of Propofol was associated with microbial contamination of the product and with fever, infection/ sepsis, other life-threatening illness, and/or death. 7. Unused propofol should be discarded within 6 hours of opening vials. (The emulsion is sterile only for 6 hours). 8. Compatibility and Stability: Propofol should not be mixed with other therapeutic agents prior to administration. 9. Dilution Prior to Administration: a. If a dilute solution is required, it is compatible with 5% dextrose in water. b. Changes in dilutent may theoretically result in slight changes in pharmacokinetics, cracking of the emulsion, spontaneous degradation of propofol, and possibly changes in pharmacologic effects. c. The diluted concentration of propofol should not be less than 2mg/ml to preserve the emulsion base. d. In diluted form it has been shown to be more stable when in contact with glass than with plastic (95% potency after 2 hours of running infusion in plastic). 10. Administration with Other Fluids: Compatibility of Propofol with the co- administration of blood/serum/plasma has not been established. When administered using a y-type infusion set, Propofol has been shown to be compatible with the following intravenous fluids: - - 5% Dextrose Injection, USP - Lactated Ringers Injection, USP - Lactated Ringers and 5% Dextrose Injection - 5% Dextrose and 0.45% Sodium Chloride Injection, USP - 5% Dextrose and 0.2% Sodium Chloride Injection, USP 11. Administration with Lidocaine: If lidocaine is to be administered to minimize pain on injection of Propofol, it is recommended that it be administered prior to Propofol administration or that it be added to Propofol immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg Propofol. But mixing of drugs may result in coalescence of oil droplets which may pose the risk of pulmonary embolism. 12. Container should be shaken before use. 2

3 13. It must not be administered through microbiological filter or through same IV catheter as for blood or plasma. 14. All formulations are stable at room temperature and are not light sensitive. Store below 25 0 C, do not freeze. Commercial Preparations of Propofol: 1. Diprivan: This emulsion form also contains sodium EDTA (0.0005%),which acts as bacteriostatic against some bacteria along with some other antimicrobial agents. It also contains sodium hydroxide to adjust ph to 7 to Generic Formulation: Some newer generic formulations contain sodium metabifulfite (0.25 mg/ml) or benzyl alcohol to retard the rate of growth of micro-organisms in the event of accidental extrinsic contamination. These have lower ph (4.5 to 6.4). 3. Amlofol: Low lipid emulsion preparation of propofol contains 5% of soybean oil and 0.6% egg lecithin. It does not require a preservative or microbial growth retardant. This formulation is equipotent to Diprivan, but associated with higher incidence of pain on injection. 4. Fospropofol (Lusedra/ Aquavan): A water-soluble phosphorylated prodrug form of propofol, approved in 2008 by FDA for use as anaesthetic agent in humans. Fospropofol is rapidly broken down by endothelial cell surface enzyme alkaline phosphatase to form propofol. 1mg of fospropofol would liberate 0.54mg of propofol. This new formulation may not produce the pain at injection site that often occurs with the traditional form of the drug. Compared with propofol emulsion, fospropofol has slightly large volume of distribution, longer time to peak effect, higher potency and more prolonged pharmacodynamic effect. 5. A nonlipid formulation of propofol uses cyclodextrins as solubilising agent. Cyclodextrins are ring sugar molecules that form guest (propofol)- host complexes migrating between the hydrophilic centre of the cyclodextrin molecule and water soluble phase. This allows propofol, which is poorly soluble in water, to be presented in an injectable form. After injection, propofol migrates out of cyclodextrin into the blood. 6. In European countries, 2% formulation and an emulsion formulation containing a mixture of medium- and long- chain triglycerides are also available. 3

4 History: 1. It was first prepared in early 1970s in the UK by Imperial Chemical Industries as ICI Clinical trials followed in 1977, first by Kay and Rolly, using a form solubilised in cremophor EL confirmed the potential of propofol as an anaesthetic to induce anaesthesia. 3. However, due to anaphylactic reactions to cremophor, this formulation was withdrawn from the market and subsequently reformulated as an emulsion of a soya oil/propofol mixture in water. 4. The emulsified formulation was re-launched in 1986 by ICI (now AstraZeneca) under the brand name Diprivan (abbreviated version of diisopropyl intravenous anaesthetic). Mechanism of action: Ultra short-acting anaesthetics depress the central nervous system (CNS) to produce hypnosis and anaesthesia without analgesia: 1. Site of action: GABA A : BZD: Chloride receptor complex in CNS Binding of propofol to GABA A receptor causes prolongation of action of GABA and increased duration of opening of chloride channel resulting in hyperpolarisation of postsynaptic cell membrane and functional inhibition of postsynaptic neurons. 2. It causes wide spread inhibition of NMDA (N- methyl- D Aspartate) receptor through sodium channel gating. 3. Propofol increases dopamine concentration in the nucleus acumens (phenomenon associated with drug abuse and pleasure seeking behaviour) resulting in a sense of well being in a patient. 4. It also decreases serotonin levels in the area postrema through action on GABA receptors resulting in its anti emetic effect. 5. Depresses spinal cord activity (anti pruritic effect) 4

5 Pharmacokinetics: 1. Molecular weight pka The octanol/water partition coefficient for Propofol is 6761:1 at a ph of Absorption: Only Intravenous 5. Volume of distribution at steady-state (Vd): L/kg 6. Protein binding: 95% 98% 7. 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 anaesthesia (one-arm-to-brain circulation time) Phase 1/very rapid distribution: (half life 1-8 minutes): Then the drug is rapidly distributed to other highly perfused organs like kidneys, heart, lungs and liver. Awakening from a single bolus dose is rapid due to a very short initial distribution half-life (2 8 min) and rapid clearance. Plasma level of propofol decreases. Phase 2/slow distribution: (half life minutes) Drugs are rapidly redistributed from the brain/other highly perfused area to other body tissues first to muscle, and then slowly to fat. Phase 3/ terminal elimination: (half-life from 4 to 24 h) Depending on the study conditions using bolus or infusion dosing, drug is slowly released from deep compartment with limited perfusion (fat) to plasma, and it is metabolised. Blood level of propofol required during surgery is 2-5 µg/ml, while patient becomes awake at plasma level less than 1.5µg/ml. Because required decrease in concentration for awakening after anaesthesia or sedation is less than 50%, recovery from propofol remain rapid even after prolonged infusions. The context sensitive half time for propofol for infusion of up to 8 hours is less than 40 minutes. But, longer duration of infusion may result in accumulation of drug in fat stores, and longer time may be required for elimination. The figure below illustrates 5

6 the fall of plasma Propofol levels following infusions of various durations to provide ICU sedation. 8. Metabolism: Propofol is rapidly metabolised in the liver by conjugation to glucuronide and sulphate to produce water- soluble inactive compounds, which are excreted by kidneys. Propofol exhibits a high systemic clearance that exceeds hepatic blood flow ( l/min), implying existence of extra hepatic clearance. Propofol may also be oxidized by liver cytochrome to 4-hydroxypropofol (active component with 1/3 rd activity), which is then glucuronidated or sulphated into inactive compounds. Extra hepatic metabolism is also reported, mainly by kidneys and lungs. Kidney may metabolise propofol up to 30%. Lungs also play important role in extra hepatic metabolism and account for approximately 30% of uptake and first pass elimination after bolus dose and 20-30% after continuous infusion. Less than 1% propofol is excreted unchanged in urine and only 2% is excreted in faeces. 9. Onset of Hypnosis: one arm- brain circulation Peak effect: sec Duration of effect: 5-10 minutes 6

7 Uses: 1. Induction of Anaesthesia: a. It is the most commonly used IV induction agent, has replaced thiopentone for this purpose b. Dose: 1-2.5mg/kg IV dose reduced with increasing age c. Blood level: 2-6µg/ml 2. Maintenance of Anaesthesia: a. A bolus of 10-40mg repeated every few minutes or b. Continuous ( )µg/kg/min IV combined with N 2 O or opiate c. Preferred anaesthetic drug for TIVA (Total Intravenous Anaesthesia) technique in conjugation with short acting opioids. 3. Sedation: a. For short surgical procedure or ICU sedation/ conscious sedation b µg/kg/min IV c. Preferred drug in Day care surgery sedation 4. Antiemetic effect: a mg IV, can be repeated every 5-10 minutes or start infusion of 10µg/kg/minute 5. Antipruritic effect: a. 10mg IV is effective in the treatment of pruritis associated with neuraxial opioids or cholelithiasis. b. Mechanism of antipruritic effect is due to depression of spinal cord activity. 6. Anticonvulsant activity: a. Theoretically propofol may produce seizure. 7

8 b. It has anti epileptic activity due to GABA mediated pre- and post- synaptic inhibition of chloride ion channels. dose > 1mg/kg body wt decreases seizure duration. 7. Attenuation of Bronchospasm: a. Propofol acts as bronchodilator. b. Its preservative sodium metabisulfite may produce bronchoconstriction in asthmatics. 8. Anti- oxidant: a. Beneficial in acute lung injury. Contraindications: Absolute contraindications: 1. Patients with a known hypersensitivity to Propofol or any of its components. 2. Propofol is contraindicated in patients with allergies to eggs, egg products, soybeans or soy products. 3. Disorders of fat metabolism Relative contraindications: 1. Patients undergoing stereotactic neurosurgery such as pallidotomy, as it temporary abolishes tremors in patients with Parkinsonism. 2. Known case of Epilepsy 3. Untreated hypertensive, hypovolemia, compromised Left ventricle function 4. Hepatic or Renal impairment 5. Pregnant and lactating mother 6. Paediatric patients age < 3years. 8

9 Advantages: 1. Pleasant, smooth and rapid induction 2. Loss of cough reflex and laryngeal reflex 3. Quicker and complete recovery and psychomotor function compared with thiopentone, regardless of the anaesthetic used for maintenance of anaesthesia. 4. Absence of stage of delirium 5. Depth of anaesthesia can be increased rapidly. 6. Less PONV (post- operative nausea vomiting) 7. Short Context sensitive half time: may be used as continuous infusion for long period. 8. Blunts stress response 9. It has antioxidant properties. 10. Amnesic properties 11. Does not trigger malignant hyperthermia 12. Does not influence secretion of cortisol. Disadvantages: 1. Pain at site of injection 2. Allergic reactions 3. CVS and Respiratory depression including apnoea 4. Expensive than thiopentone 5. Chances of infection if strict asepsis is not taken. 6. Propofol emulsion syndrome on prolong infusion. Pharmacodynamics: 1. Central Nervous System a. Dose dependent depression of cerebral cortex, ascending reticular activating system and medullary centre resulting in sedation, hypnosis, amnesia, anaesthesia, respiratory depression. b. Decrease in Cerebral metabolic oxygen consumption, Cerebral blood flow and ICP along with decrease in cerebral perfusion pressure. c. Normal cerebral reactivity to carbon dioxide and autoregulation is maintained. d. Neuro-protective effect of propofol remains controversial (antioxidant properties, attenuating calcium, sodium, potassium, ATP changes during hypoxia). 9

10 e. Dose dependent anticonvulsant effect is present. Seizure after propofol has been reported during induction, emergence, and rarely post- operatively. f. It does not alter brainstem auditory evoked potentials. However, propofol prolongs latency and decreases amplitude of wave in dose dependent manner. g. It has no ant-analgesic property i.e. does not produce pain. h. Autonomic Nervous System: Decreases sympathetic activity greater than parasympathetic system. 2. Cardiovascular System: a. Myocardial depression: dose dependent b. Systolic BP: 25-40% decrease in SBP. Similar changes in Mean BP and DBP. Due to direct vasodilatation. c. Propofol blocks/ reset Baroreceptors, so there is little (no) compensatory tachycardia due to decrease in mean BP. Propofol attenuates heart rate response to atropine: Bradycardia. d. Cardiac Output: Decreases, more significant in hypovolemic patients, cardiac disease, on beta blockers, hypertensive patients on treatment 3. Respiratory System: a. Dose dependent respiratory depression (first reduction in tidal volume associated with tachypnoea followed by apnoea). b. Apnoea occurs in 25-30% of patients depending on dose. Duration of apnoea depend upon dose, concomitant drugs like opioids, BZP, and may be more than 30 seconds. c. Decreased sensitivity of respiratory centre to increase in carbon dioxide, and hypoxia via carotid body chemoreceptors. d. Laryngeal reflexes and cough reflexes are depressed. e. Propofol has bronchodilatory effect through direct action on muscarinic action as well as attenuating vagal response. f. Propofol also attenuates the magnitude of hypoxic pulmonary vasoconstriction. 4. Liver: a. Blood flow is decreased. 5. Kidney: a. Constriction of splanchnic and renal blood vessels: decrease in RBF and GFR. 10

11 b. Prolonged infusion of propofol results in green urine due to phenols in urine, cloudy urine due to increased uric acid in urine (crystallization of uric acid at low ph and temperature). Presence of these does not affect renal function. 6. GIT: No direct effect 7. NM Junction: a. Minimal muscle relaxation though good intubating condition may be obtained with propofol use alone. 8. Eye: a. Decrease in IOP (intra ocular pressure, 30-40%) is more than thiopentone, so more useful in blunting increase in IOP due to Succinyl choline or laryngoscopy. 9. Pregnant Uterus: a. Propofol have no effect on uterine muscle tone. b. Crosses placenta (equilibrium between mother and foetus within 2-3 minutes) and causes neonatal depression. 10. Other Properties: a. Propofol does not trigger malignant hyperthermia. b. Propofol after single dose does depress cortisol synthesis or alter the normal response to ACTH. c. It has antioxidant properties like vitamin E. d. It has anti pruritic effect. e. It does not alter coagulation. Precautions to Consider: 1. Allergic reaction and/or related problems: Contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. 2. Carcinogenicity/Mutagenicity: Propofol does not seem to have carcinogenic and mutagenic potential. 3. Fertility: Propofol does not seem to have effect on fertility. 4. Pregnancy: Propofol is not recommended for obstetrics, including caesarean section deliveries. Propofol crosses the placenta, and as with other general anaesthetic agents, the administration of Propofol may be associated with neonatal depression. Adequate and well- 11

12 controlled studies in humans have not been done to determine whether propofol is teratogenic. FDA Pregnancy Category B. 5. Breast-feeding mother: Propofol is not recommended for use in nursing mothers because Propofol has been reported to be excreted in human milk and the effects of oral absorption of small amounts of Propofol are not known. 6. Paediatrics Children require larger induction dose due to high plasma clearance and greater central volume of distribution. Propofol is not recommended for the induction of anaesthesia in patients younger than 3 years of age and for the maintenance of anaesthesia in patients younger than 2 months of age as safety and effectiveness have not been established. 7. Geriatrics: With increasing patient age, the dose decreases. This does not appear to be an age-related change in pharmacodynamics or brain sensitivity. But with increasing age, pharmacokinetic changes are such that, for a given IV bolus dose, higher peak plasma concentrations occur, which can explain the decreased dose requirement. These higher peak plasma concentrations in the elderly can predispose patients to cardiorespiratory effects including hypotension, apnoea, airway obstruction, and/or arterial oxygen desaturation. The higher plasma levels reflect age-related decreased in volume of distribution and inter-compartmental clearance. Lower doses are therefore recommended for initiation and maintenance of sedation and anaesthesia in elderly patients. 8. Organ Failure: The pharmacokinetics of Propofol does not appear to be different in people with chronic hepatic cirrhosis or chronic renal impairment compared to adults with normal hepatic and renal function. The effects of acute hepatic or renal failure on the pharmacokinetics of Propofol have not been studied. 9. Seizure disorder: When Propofol is administered to an epileptic patient, there is a risk of seizure during the recovery phase. 10. Obese patients: There may be prolonged effect due to accumulation of drug in fat on prolonged infusion. 11. Drug administration requires caution when administered to patients with disorders of lipid metabolism such as primary hyperlipoproteinemia, diabetic hyperlipidemia, and pancreatitis. 12. Drug Abuse and Dependence: Rare cases of self-administration of Propofol by health care professionals have been reported, including some fatalities. 12

13 Adverse Effects: Local: 1. Pain on injection: Attention should be paid to minimize pain on administration of Propofol. a. Transient local pain can be minimized if the larger veins of the forearm or antecubital fossa are used. b. Pain during intravenous injection may also be reduced by prior injection of IV lidocaine (1 ml of a 1% solution). Adding lignocaine with propofol may cause instability of emulsion and reduced drug potency. Therefore, it is recommended that lidocaine be administered prior to Propofol administration or it should be added to Propofol immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg Propofol. c. Prior administration of potent short acting opioids. d. Other drugs tried with different efficacy: NSAIDs, ketamine, esmolol/ metoprolol, magnesium, clonidine/ ephedrine combination, dexamethasone, metoclopromide. 2. Phlebitis or thrombosis have been reported rarely (<1%). 3. Intra-arterial injection in animals did not induce local tissue effects or vascular complications. 4. Intentional injection into subcutaneous or perivascular tissues of animals caused minimal tissue reaction. Systemic: 1. Clinical features of anaphylaxis, including angioedema, bronchospasm, erythema, and hypotension, occur rarely due to allergy to components of emulsion or due to phenyl nucleus and diisopropyl side chain of propofol. 2. CNS: Perioperative myoclonia, hallucination, sexual fantasies, convulsions and opisthotonos have been reported. 13

14 3. CVS: hypotension, bradycardia, asystole (no vagolytic activity). Paediatric patients are susceptible to this effect, particularly when fentanyl is given concomitantly. The intravenous administration of anticholinergic agents (e.g., atropine or glycopyrrolate) should be considered to modify potential increases in vagal tone due to concomitant agents (e.g., succinylcholine) or surgical stimuli. 4. Respiratory system: Apnoea 5. GIT: Rarely, cases of unexplained postoperative pancreatitis (requiring hospital admission) have been reported after anaesthesia in which Propofol was one of the induction agents used. Due to a variety of confounding factors in these cases, including concomitant medications, a causal relationship to Propofol is unclear ml of Propofol contains approximately 0.1 g of fat (1.1 kcal). 7. Abuse Potentials 8. Bacterial growth: a. Intralipid that acts as solvent for propofol is excellent medium for bacterial growth. b. Support growth of E. coli, pseudomonas aeruginosa and other bacteria, so may cause sepsis. c. Some preparation contains anti- bacterial or bacteriostatic components. 9. Propofol Infusion Syndrome: a. A rare but lethal complication of propofol infusion at dose more than 4mg/kg/hr or more for 48 hours or longer. b. Initially described in children, but later on also found in critically ill patients. c. Presentation: acute refractory bradycardia leading to asystole, in the presence of one or more of following: metabolic acidosis (base deficit > 10mmol/L), rhabdomyolysis, hyperlipidemia and enlarged or fatty liver. d. Other features may include: cardiomyopathy with acute cardiac failure, skeletal myopathy, hyperkalemia, hepatomegaly, and lipidemia. 14

15 e. Major risk factors: poor oxygen delivery, sepsis, serious cerebral injury and high propofol dose. f. Basic Pathology: mitochondrial toxicity/ defect, impaired tissue oxygenation, carbohydrate deficiency. Drug Interactions 1. The induction dose requirements of Propofol may be reduced in patients with intramuscular or intravenous premedication, particularly with opioids and sedatives (e.g., benzodiazepines, barbiturates, chloral hydrate, droperidol, etc). These agents may increase the anaesthetic or sedative effects of Propofol and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output, post- operative respiratory depression. 2. Bradycardia with fentanyl and vecuronium. 15