Propofol and Etomidate. - Rahul (1).pptx

PROPOFOL ETOMIDATE

1. Propofol & Etomidate Moderator – Dr. Archana(professor) Presented by - Dr. Rahul Kumar

2. PROPOFOL Group - Sedative Hypnotic iv induction agent Chemical Properties  - Highly lipid soluble but water insoluble Pharmacokinetics   Onset: 30-40 seconds   Protein binding: 98%   Volume of distribution: 3-4L/Kg Therapeutic Half Life - 10 Minutes

3. Formulations Intravenous route only Most used formulation is  1% propofol  10% soybean oil and 1.2% eff phospholipid(emulsifier)  2.25% glycerol (tonic adjusting agent)  NaOH to change the pH of the solution. This preparation can be diluted with 5% dextrose. A water-soluble prodrug called fospropofol is also available. It is metabolised in the liver and yields 1mg of propofol for every 1.86mg of fospropofol. Low lipid formulations of Propofol containing 5% soybean oil and 0.6% egg lecithin have also been developed.

4. Mechanism of Action Selective modulator of GABA-A receptors, with additional action at glycine receptors, thereby potentiating the action of these inhibitory neurotransmitters. It decreases the rate of dissociation of GABA from its receptor, thereby increasing the duration of the GABA-activated opening of the chloride channel resulting in hyperpolarization of post-synaptic cell membranes and functional inhibition of the post-synaptic neuron.  The other proposed mechanisms of action of Propofol are: Widespread inhibition of NMDA receptors Increases dopamine concentration in nucleus accumbens Decreases serotonin in area postrema - anti emetic effec t

5. Metabolism Propofol is oxidised to 1,4-disopropyquinol in the liver, which is then conjugated to glucuronic acid. The clearance of propofol is higher than the hepatic blood flow, due to extra hepatic metabolism. The kidney accounts for 30% and the lung also metabolises a variable amount.  Propofol reduces hepatic blood flow, reducing the clearance of other drugs, and inhibits CYP3A4, instantaneously reducing the clearance of midazolam. In turn, midazolam also reduces the clearance of propofol.

6. Pharmacokinetics Distribution Occurs in3 phases - Alpha - 1 phase distribution to highly perfused organs; 2-8 minutes, Alpha - 2 phase redistribution to other body tissues; 30-70 minutes, and Beta - 1phase (elimination by metabolism; 4-23 hours )

7. Pharmacodynamics Central Nervous System Rapid smooth induction Rapid and clear headed recovery Cerebroprotective Antioxidant properties  Reduces intra-cranial pressure, CMRO2 and cerebral perfusion pressure Produces same degree of memory impairment as midazolam Seizures and abnormal motor activity may sometimes occur  Tolerance occurs to repeated dosing Increases dopamine in nucleus accumbens: Results in drug abuse

8. Pharmacodynamics Cardiovascular System Decrease in: Arterial blood pressure: Reduction in systolic, diastolic and mean pressures Effects exaggerated in old patients, hypovolemia and LV dysfunction due to CAD Inhibits baroreceptor reflex to hypotension  PVR: Due to more impotent inhibition of sympathetic nervous tone Cardiac output, stroke volume index and cardiac index: Occurs due to reduced intracellular Ca2+ availability  This is secondary to inhibition of transsarcolemmal Ca2+ influx  Heart rate May increase, decrease or remain unchanged Response depends on hypotension and baroreceptor suppression  Causes bradycardia and asystole sometimes Heart rate response to atropine is attenuated  Bradycardia is reversed by isoprenaline Does not alter SA node or AV node function: safe in WPW syndrome Potentiates oculocardiac reflex

9. Pharmacodynamics Respiratory System Produces short duration apnea (30–60 sec) after induction in 25–30% patients Decreases tidal volume and frequency of breathing Response to CO2 and hypoxemia is reduced by direct action on carotid body receptors Hypoxic pulmonary vasoconstriction is intact but attenuated.

10. Pharmacodynamics Hepatic and Renal Functions Prolonged infusion: Causes hepatocellular injury resulting in acidosis  Increases phenols in urine: This causes phenol urea resulting in green color urine  However, it does not alter renal function  Urinary uric acid excretion increases resulting in turbid urine Decreases hepatic blood flow

11. Pharmacodynamics Intraocular Pressure Decreases intraocular pressure following intubation Potentiates oculo-cardiac reflex Pharmacodynamics Intraocular Pressure Decreases intraocular pressure following intubation Potentiates oculo-cardiac reflex Coagulation Does not alter coagulation profile

12. Uses and Dosage Induction of anaesthesia: 1.5 -2.5 mg/kg, which needs to be reduced to 1-1.5 mg/kg in elderly patients. Maintenance of anaesthesia: 100-300 g/kg/min following an induction bolus. (Plasma concentrations of 2-6 ug/ml for surgery, with levels < 1.5 µg /ml causing awakening). Various protocols including the Marsh Schneider and Minto, and Kataria protocol for paediatric populations are available for syringe pump administered TIVA, using a bolus elimination transfer dosing method based on two or three compartment models. Conscious sedation: Loading dose of 0.5 to 1 mg/kg, followed by an infusion of 25 - 75 μg/kg/min. Anti-emesis: Sub-hypnotic doses of Propofol (10 - 20 mg) may be used to treat PONV.

13. Adverse Effects Pain on Injection (28%): May be reduced by addition of lignocaine 1( ml of 1%), cooling the drug, or by injection into a large vein Profound bradycardia, Hypotension Risk of infection Abuse potential Hyperlipidaemia Pancreatitis with prolonged infusion Propofol Infusion Syndrome (PRIS): In children receiving prolonged high-dose infusions of Propofol ie 4 mg/kg/hr for 48 hours or longer, a severe metabolic (lactic) acidosis, with rhabdomyolysis, skeletal myopathy and hyperkalemia noticed in some patients. It is characterized by acute refractory bradycardia, asystole, myoclonus and apnea. Predisposing factors are genetic disorders impairing fatty acid metabolism. Lipemia is an early sign of the syndrome.

14. ETOMIDATE Group - Sedative Hypnotic, Imidazole ring derivative Chemical Properties  - The imidazole ring provides water solubility in acidic solutions and lipid solubility at physiological pH. Pharmacokinetics    Onset: 10-65 seconds   Protein binding: 75%   Volume of distribution: 2.5 - 4.5 L/Kg   Elimination Half Life: 2.9-5.3 Hrs   Duration of action: 6 - 10 minutes Therapeutic Half Life: 15-20 minutes

15. Formulations Etomidate is formulated either in propylene glycol or as a lipid emulsion of triglycerides which is associated with much less pain. No dilution is required for administration.  The pH of the emulsion is 8.1 and the propylene glycol formulation has a pH of 6.

16. Mechanism of action It acts on GABA-A receptors to modulate fast inhibitory transmission in the CNS. The R (+) enantiomer of Etomidate is ten times as potent as the S(-) enantiomer.

17. Metabolism By plasma and hepatic esterases to inactive metabolites.

18. Pharmacokinetics Onset: 10 - 65 seconds (one arm-brain circulation) Duration of action: 6 - 10 minutes Termination of action by redistribution to fat and then to muscle Protein binding: 75% Elimination Half Life: 2.9-5.3 Hrs Vd: 2.5-4.5 lit/kg Therapeutic Half Life: 15 - 20 Mins

19. Pharmacodynamics Central Nervous System Decreases CMRO2 (45%), cerebral blood flow (34%) Produces a decline in intracranial pressure (50%) Cerebral perfusion pressure increased or maintained PONV more common than propofol or barbiturate Lacks analgesic properties Associated with grand mal seizures EEG activity increases in epileptogenic foci

20. Pharmacodynamics Cardiovascular System Minimal effects on cardiovascular system- makes it a unique drug Hemodynamic stability due to lack of effect on sympathetic nervous system Causes mild reduction in peripheral vascular resistance, mean arterial pressure Myocardial contractility and cardiac output are usually unchanged Maintains myocardial oxygen demand-supply ratio Useful in patients with valvular heart disease, IHD with poor cardiac function

21. Pharmacodynamics Respiratory System Less effects on respiratory system Induction usually does not cause apnea unless opioids have been administered May be associated with brief period of hyperventilation following induction Does not induce histamine release

22. Pharmacodynamics Endocrine System Transiently inhibit enzymes involved in cortisol and aldosterone synthesis Results in decreased cortisol synthesis and adrenocortical suppression Dose-dependant reversible inhibition of 11βhydroxylase Adrenal suppression may last upto 72 hours following induction Adrenal suppression action of etomidate more potent compared to sedation

23. Usages and Dosage Etomidate has a place in anaesthesia because of its safe cardiovascular profile.  It has proven especially useful in valvular or ischemic heart disease. The myocardial supply to demand ratio is well maintained. Induction of anaesthesia (0.2-0.6 mg/kg VI reduced to 0.2 mg/kg in the elderly)

24. Adverse Effects Pain on injection (much less with the lipid emulsion) Myoclonus Adrenal suppression- Etomidate reversibly suppresses 11-a- Hydroxylase which is important in adrenal steroid production. This leads to primary adrenal suppression. Continuous infusions of Etomidate were associated with increased mortality in the ICU, which is why the drug is now used only as a single dose. The subgroup analysis of CORTICUS study showed that Etomidate caused adrenal suppression for 48 Hrs after single use also. This adverse effect has been used therapeutically in the stabilization of patients prior to surgery with Cushing's syndrome. Increased bleeding time due to antiplatelet activity

25. Contraindications and Special Points Adrenal insufficiency Use for ICU sedation Special Point Novel Etomidate derivates- Methoxycarbonyl etomidate and carboetomidate are experimental drugs. They cause reduced adrenocortical suppression, decreased PONV and decreased Myocionus.

26. Thank you