Thiopentone and propofol

intravenous drugs

1. THIOPENTONE

2. Derived from babituric acid - urea and malonic acid In No 2- Retaining oxygen atom called Oxybarbiturate and replacement of this atom by Sulphar atom is called Thiobarbiturate. In No 5- Phenyl group causes anticonvulsant activity, hypnotic activity.

3. Bacteriostatic property due to highly alkaline pH. Commercial preparation of barbiturates often contain a mixture of 6 part of anhydrous Na2Co3 . It prevents precipitation of insoluble acidic form of barbiturates by atmospheric CO2. Powdered form of thiopentone is stable at room temperature indefinitely Refrigerated solution of thiopentone are stable up to 2 weeks. At 22 degree celcius ; 6 days

4. PREPARATION Sodium thiopentone ( Racemic mixtures ) is prepared by dissolving a yellowish powder in sterile water to provide a 2.5% solution ( ie 25mg/ml). In this concentration 20mls of solution will contain 500mg. Diluent for reconstitution 0.9% NS STERILE WATER 5%DEXTROSE SOLUTION

5. Barbiturates are prepared commercially from highly alkaline solution as sodium salts that are readily soluble in water and saline. Ph of 2.5% solution of Thiopentone is 10.5. Incompatible with mixture with drugs which are acidic in solution such as opioids catecholamines neuromuscular blocking drugs

6. Dose ED 50 = 2.2 – 2.7 mg / Kg Induction dose: Adults : 3-6 mg/kg given I/V over 5- 15 sec. Sedation dose: 0.5 to 1.5 mg/kg I/V. Neonates:2-3 mg/kg. Rectal dose:-30-50 mg/kg IV maintenance infusion: 50-100 mg every 10-12 min Most frequently admnistered I/V for induction in adults and childern . It can be used rectally in case of children

7. MECHANISM OF ACTION Ultra short-acting barbiturate anaesthetics depress the central nervous system (CNS) to produce hypnosis and anaesthesia without analgesia. Site of action: GABA: BZD: Chloride receptor complex in CNS When GABA A receptors are activated, trans-membrane chloride conductance increases, resulting in hyperpolarisation of post- synaptic cell membrane and functional inhibition of post synaptic neurons.

8. Pharmacokinetics Distribution determined by- Lipid solubility Protein binding(80%) Degree of ionization(60%) Maximal brain uptake of thiopentone occurs in 30 sec . It decreases over next 5 min to one-half the initial peak concentration due to redistribution from brain to other tissues. Rapid awakening after I/V induction-REDISTRIBUTION. After 30 min, ~ 10 % remains in the brain due to redistribution.

9. Protein binding: — Protein binding parallels to lipid solubility (i.e. unionized component). Thiopentone is a highly lipid soluble drug with high protein binding, with binding to albumin ranging from 72 to 86%. Decreased protein binding due to H ypoproteinemia (cirrhosis of liver) U raemia or aspirin, phenylbutazone may lead to increased free fraction of the drug; hence enhanced effect.

10. S keletal muscles most prominent site for redistribution . Equilibrium with muscle reached in 15 min after I/V injection. Fat is the only compartment in which thiopentone continues to remain 30 min after injection. Fat is potential reservoir for maintaining plasma concentration of drug. Redistribution of thiopentone is most important for awakening . Metabolized in liver to hydroxythiopental and carboxylic acid an is water soluble .

11. PHARMACODYNAMICS Central Nervous System Dose dependent depression of cerebral cortex, ascending reticular activating system and medullary centre resulting in sedation, hypnosis, anaesthesia, respiratory depression. Decrease in Cerebral metabolic oxygen consumption, Cerebral blood flow and ICP Anticonvulsant effect Stimulates CTZ, so nausea and vomiting It has no analgesic property

12. Facilitate CSF absorption which results in reduction in CSF volume this combined with decrease in CBF, makes thiopentone highly effective in lowering ICT. Decrease in intracranial pressure exceeds the decline in cerebral arterial pressure ,thus results in increase cerebral perfusion pressure(CPP).

13. CVS Myocardial depression: dose dependent Mean BP: There is either a fall in or no change in mean arterial blood pressure depending on volume status. Compensatory increase in heart rate due to decrease in mean BP

14. Liver: Blood flow is not affected (rather increases hepatic blood flow) unless there is hypoxia. Induction of microsomal enzymes Induction of aminolevulinic acid synthetase stimulate the formation porphyrins,which may precipitate acute intermittent porphyria in susceptible individuals Kidney: D ecrease in renal blood flow and GFR GIT: Decrease in peristalsis.

15. Eye: Pupil first dilate and then constrict Sensitivity to light remains until the patients is deep enough to permit skin incision. At this stage, eyeballs are centrally placed. Decrease in IOP. Loss of eyelash reflex is the sign of induction of anaesthesia.

16. Indications I nduction M aintenance of anesthesia P remedication Pre- anaesthetic Sedation: Rectal suspension Sedation Convulsions (treatment)—Thiopental for injection (3mg/kg)(GTCS) states Narcoanalysis Cerebral protection: Thiopental for injection is indicated to protect the brain from the effects of hypoxia and ischemia following head injuries and other related conditions

17. CONTRAINDICATIONS When the patient has respiratory obstruction or an inadequate airway C ardiovascular instability Status asthmaticus Porphyria Without proper equipment (IV instrumentation) and airway equipment (means of artificial ventilation), thiopental should not be administered. H ypersensitivity

18. Side/Adverse Effects Local: On intravenous/ perivenous injection, it may cause pain, swelling, ulceration, hematoma due to its high pH (highly alkaline). Treatment is 10ml of 1% xylocaine with hydralase 1000U into area (causes vasodilatation and absorption of drug).

19. Accidental intra- arterial injection: The pH of 2.5% drug solution is 10.5 (strong alkali). When it is injected into artery and mixed with blood (pH= 7.4= less alkaline) it gets precipitated as solid crystals of thiopentone and haemoglobin. It results in local inflammation and blocks small arterioles, causes vasospasm due to local release of noradrenaline.

20. Arteriospasm S evere pain B lanching of the arm and fingers. O edema, U lceration G angrene of hand/ arm may follow. Onset of unconsciousness is delayed.

21. C orrective measures S top the injection. Leave the needle in place (do not take out needle otherwise we may lose artery access). Inject 500U heparin (it reverses alkalinity and prevents thrombosis). Inject 5 ml xylocaine 1- 2% into the artery. Dilute the injected Pentothal (Thiopental Sodium for Injection, USP) by removing the tourniquet and any restrictive garments and flush with normal saline. Inject the artery with a dilute solution (10- 20ml) of papaverine, 40 to 80 mg, or 10 mL of 1% procaine, to inhibit smooth muscle spasm.

22. Continue anaesthesia with Halothane (vasodilator) Postpone surgery if possible. Oral anticoagulants may be required. If necessary, perform sympathetic block of the brachial plexus and/or stellate ganglion to relieve pain and assist in opening collateral circulation. Papaverine can be injected into the subclavian artery, if desired. Consider local infiltration of an alpha-adrenergic blocking agent such as phentolamine into the vasospastic area.

23. Handling The powder is soluble in distilled water, normal saline and alcohol. It should be reconstituted in distilled water or normal saline to prevent precipitation . Store below 25 celsius ,in dry place, protect from light. Avoid Lactated Ringer’s solution. It should be prepared as 2.5% solution as higher concentrated solution will result in higher pH (more alkaline solution). Solution of 2.5% in distilled water is isotonic.

24. The bacteriostatic properties of commercial preparations are due to their highly alkaline pH. It does not contain anti- bacterial agents. The powder form is stable at room temperature . Cloudy solution should be discarded.

25. Propofol

26. Preprations of Propofol 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) prodrug

27. G roup alkylphenols The formulation most commonly used is that of 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 change the pH may be diluted with 5% dextrose in water Sometimes EDTA (inhibit microorganism)

28. Milky white coloured , sterile , non pyrogenic , oil in water emulsion Highly lipid soluble , Slightly water soluble Isotonic pH- 6 to8.5 2,6- diisopropylphenol(C12H18O) Weak acid, unionized, Pka-11 Protein binding-95-98%

29. PHARMACOKINETICS Propofol is oxidized to 1,4-diisopropyl quinol in the liver Propofol is oxidized to 1,4-diisopropyl quinol in the liver. In duction of anesthesia starts within 40 seconds from the start of injection (the time for one arm-brain circulation) Propofol is hemodynamic depressant R educe hepatic blood flo w therefore it reduce s metaboliz am of other drugs by the liver .

30. Propofol Half life elemination 4-7 hours. Clearance 20-30 mg/kg/min Volume of distribution 2-10 L/kg

31. T hree-compartment models . After a single bolus dose, blood propofol levels decrease rapidly as a result of redistribution and elimination. Onset-<40 seconds, peak effect -90-100 seconds P ropofol is described by a three-compartment model give initial and slow distribution half-lives of Phase 1- 2 to 8 minutes Phase 2 - 30 to 70 minutes muscle and fat Phase 3 - elimination half-life of 4 to 23.5 hours .

32. Compartment distribution

33. Geriatric Age P atients 80 years old or older generally need 50% of the propofol dose of patients 20 years old to target the same level of sedation or hypnosis . Older individuals - decreased clearance rates and a smaller central compartment volume. R educed cardiac output.

34. Effect in children Children have larger central compartment volume (50%) and a more rapid clearance (25%). Children less than 3 years of age have larger central compartment and systemic clearance values than in adults or older children. Th erefore larger dose are require d in this age group.

35. Opioids and Bendzodiazepines In the presence of a sedative Benzodiazepines( midazolam ) , blood propofol concentrations become elevated by approximately 25% Opioids increase s blood propofol concentrations through a reduction in the elimination and distribution clearance of propofol.

36. In ICU daily titration o f propofol dosage to achieve only the minimum effective therapeutic concentration, rapid awakening within 10 minutes to 15 minutes can occur even after long-term administration.

37. PHARMACODYNAMICS Central Nervous System The hypnotic action of propofol is mostly mediated b y enhancing γ-aminobutyric acid (GABA)-induced chloride current through its binding to the β subunit of the GABA A receptor. Sites on the β1, β2, and β3 subunits of the transmembrane domains are crucial for the hypnotic action of propofol

38. Other CNS effects of propofol Propofol decreases intracranial pressure (ICP) . The decrease in ICP (30% to 50%) is associated with significant decreases in cerebral perfusion pressure (CPP) . Head-injured patients should be restricted to doses providing mild to moderate sedation (i.e., blood concentration of 2 μg/mL, infusion of 1.5-4.5 mg/kg/hr) Neuroprotective effects - Reduce the metabolic oxygen as it maintain the balance between energy supply and demand. Increase the tolerance to hypoxia by the neuronal tissue

39. The onset of hypnosis after a dose of 2.5 mg/kg is rapid (one arm–brain circulation), with a peak effect seen at 90 to 100 seconds. ED50 of propofol for loss of consciousness is 1 to 1.5 mg/kg after a bolus. The duration of hypnosis 5 to 10 minutes after 2 to 2.5 mg/kg. Effect of age induction dose, which is highest at younger than 2 years (95% effective dose [ED95], 2.88 mg/kg) D ecreases with increasing age.

40. Propofol causes a concentration-dependent decrease in the bispectral index (BIS), 50% and 95% of patients unable to respond to a verbal command at a BIS of 63 and 51, respectively. The concentration at which 50% of volunteers failed to respond to verbal command is 2.35 μg/mL .

41. Propofol infusions of at least 2 mg/kg/hour were necessary to provide amnesia. Drug abuse because it increases DOPAMINE in nucleus acumens. Propofol is used as a sedative in the intensive care unit (ICU); in 20% to 40% of patients, the propofol dosage regimen must be repeatedly adjusted upward to maintain the same effect

42. Effects on the Respiratory System Apnea can occur during induction dose of propofol . I ncidence and duration of apnea depend on dose, speed of injection, and concomitant premedication. It occurs for more than 30 seconds, 40 % decrease in Tidal volume , 20% increase in respiratory rate)

43. Cardiovascular effects Decreses cardiac activity by 25% - 40% Baroreflex blunted while induction, therefore no tachycardic response to hypotension Attenuates the heart rate response to atropine in a dose-dependent manner. It also suppresses atrial (supraventricular) tachycardias and probably should be avoided during electrophysiologic studies.

44. Propofol versus volatile anesthetics in patients who undergo cardiac surg ry. L arge dose of propofol (120 μg/kg/minute) or a small dose of propofol (60 μg/kg/minute) during card iacsurgery , or titrating isoflurane throughout the operation, showed improved hemodynamic function in the large-dose propofol group compared with the isoflurane or small-dose propofol group. Isoflurane preconditioning, combined with propofol postconditioning, attenuating postis c hemic myocardial reperfusion injury .

45. Metabolic effects During prolonged infusion in ICU to older patient serum triglyceride concentrations should be routinely monitored. The sedation guidelines of the American College of Critical Care Medicine also recommend “that patients receiving propofol for long term sedation should be monitored for unexplained metabolic acidosis or arrhythmias. The recommended maximal dose of propofol infusion rate is 80 μg/kg/minute (<5 mg/kg/hour). No dosage adjustments are needed for patients with renal or hepatic failure

46. 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 .

47. Propofol infusion syndrome Risk factor D ecreased oxygen delivery to tissues serious neurological injury sepsi s high dosages of one or more of the steroids, inotropes high-dose infusions of propofol (greater than 5 mg/kg/h for greater than 48h). The syndrome has also been reported following large-dose in short-term infusions during surgical anesthesia.

48. R are but lethal syndrome associated with infusion of propofol at 4 mg/kg/hour or more for 48 hours or longer. The clinical features A cute refractory bradycardia leading to asystole in the presence of one or more of the following: M etabolic acidosis (base deficit >10 mmol/L) , R habdomyolysis, H yperlipidemia, fatty liver. ECG changes ST segment elevation

49. TARGET CONTROLLED INFUSIONS IN ANESTHESIA E ffect site (Brain) concentration targeting where the calculated c oncentration of the drug at the effect site . When the effect site concentration is set the system will administer a bolus to rapidly fill the central compartment producing a step-wise increase in plasma concentration thereby increasing the effector site concentration.

50. The TCI systems repeat the calculations and alter the rate of infusion every 10 seconds. In the 3-compartment model, 3 superimposed infusions are required: two first order exponentially decreasing infusions to match drug that is removed from the central to the peripheral compartments by distribution and a third infusion at a constant rate to replace drug removed by elimination .

51. Indications I nduction and maintenance of anesthesia Monitored anaesthesia care(MAC) sedation Combined sedation and regional anaesthesia Short surgical procedure, ICU sedation C onscious sedation. Induction in malignant hyperthermia

52. Non Anesthetic use Antiemitic effects (10- 15mg IV) Antipruritic Effects 10mg Anticonvulsant activity 1mg/kg IV Bronchoconstriction Antioxdant

53. Side effects Pain on injection site Bradicardia Hypertirglyceridemia Allergic reaction Lactic acidosis Abuse potential Proconvulsant activity Bacterial Growth- Pseudomonas , E.coli, Candida albicans Green colour urine (prolong infision)

54. Labor and Delivery Propofol is not recommended for obstetrics, including cesarean section deliveries. Propofol crosses the placenta, and as with other general anesthetic agents, Propofol is associated with neonatal depression

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

56. Maintenance of General Anesthesia: Infusion Healthy Adults Less Than 55 Years of Age: 6 mg/kg/h to 12 mg/kg/h Elderly, Debilitated, ASA-PS III or IV Patients: 3 mg/kg/h to 6 mg/kg/h Cardiac Anesthesia: Most patients require: Pr opofol with Secondary Opioid –100 mcg/kg/min to 150 mcg/kg/min. Low-Dose Propofol with Primary Opioid – 50mcg/kg/min to 100 mcg/kg/min. Neurosurgical Patients: 6 mg/kg/h to 12 mg/kg/h Pediatric Patients - healthy, from 2 months of age to 16 years of age: 7.5 mg/kg/h to 18 mg/kg/h Following the first half hour of maintenance, if clinical signs of light anesthesia are not present, the infusion rate should be decrease d

57. Monitored Anesthesia Care (MAC) Sedation During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration. Initiation of MAC Sedation: Healthy Adults Less Than 55 Years of Age: Slow infusion or slow injection techniques are recommended to avoid apnea or hypotension. Doase require ment 6 mg/kg/h to 9 mg/kg/h for 3 minutes to 5 minutes followed immediately by a maintenance infusion(1.5 mg/kg/h to 4.5 mg/kg/h) or incremental bolus doses of 10 mg . In Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients:Most patients require 80% of the usual adult dose.

58. Initiation and Maintenance of ICU Sedation in Intubated, Mechanically Ventilated Adult Patients - Because of the residual effects of previous anesthetic or sedative agents, in most patients the initial infusion should be 5 mcg/kg/min (0.3 mg/kg/h) for at least 5 minutes. Subsequent increments of 0.3mg/kg/k to 0.6 mg/kg/h over 5 minutes to 10 minutes may be for desired clinical effect is achieved. Maintenance rates of 0.3 mg/kg/h to 3 mg/kg/h or higher may be required. Should not exceed 4 mg/kg/hour unless the benefits outweigh the risks Maintenance of MAC Sedation: Healthy Adults Less Than 55 Years of Age: A variable rate infusion technique is preferable over an intermittent bolus technique.

59. Evaluation of CNS function should be done daily throughout maintenance to determine the minimum dose of propofol required for sedation. The tubing and any unused popofol drug product should be discarded after 12 hours because propofol contains no preservatives and is capable of supporting growth of microorganisms .

60. Handling Administration with Lidocaine It should be given prior to propofol administration or or It can be added to Propofol immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg Propofol

61. Administration with Other Fluids I t should not be diluted to a concentration less than 2 mg/mL compatible with the following intravenous fluids. - 5% Dextrose Injection (prefered) - Lactated Ringers Injection - Lactated Ringers and 5% Dextrose Injection - 5% Dextrose and 0.45% Sodium Chloride Injection - 5% Dextrose and 0.2% Sodium Chloride Injection

62. Precautions before opening Parenteral drug should be inspected visually for particulate matter and discoloration and expiry date prior to administration . Store below 25 celsius, Don't freez. Propofol should only be administered through a filter with a pore size of 5 micron or greater. Strict aseptic technique must always be maintained during handling. Propofol is a single access parenteral product (single patient infusion vial) which contains 0.005% disodium edetate to inhibit the rate of growth of microorganisms, up to 12 hours.

63. The vial rubber stopper should be disinfected using 70% isopropyl alcohol. Propofol should be drawn into a sterile syringe immediately after a vial is opened. When withdrawing Propofol from vials, a sterile vent spike should be used. The syringe should be labelled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vial has been opened.

64. Propofol must be prepared for single-patient use only. Any unused Propofol drug product, reservoirs, dedicated administration tubing and/or solutions containing Propofol must be discarded at the end of the anesthetic procedure or at 12 hours The IV line should be flushed every 12 hours and at the end of the anesthetic procedure to remove residual Propofol.