propofol and etomidate

1. Dr . zikrullah

2. INTRODUCTION
 Work in the early 1970’s on substituted
derivatives of phenol with hypnotic
properties resulted in development of 2,6-
diisopropofol.
 First clinical trial in 1977 by Kay and Rolly
confirmed the potential of propofol as an
anaesthetic agent

3. PHYSIOCHEMICAL CHARACTERISTICS
 Group- Alkyl Phenol
 Chemical structure:
2,6- di iso-propylphenol
 Molecular Mass- 178.271
g/mol
 pH- 7-8.5
 Stable at room
temperature

4. MECHANISM OF ACTION
 Propofol exerts its sedative hypnotic effects
by binding to βsubunit of GABA-A receptor.
 Activation of GABA receptor leads to an
increased transmembrane chloride
conductance, resulting in hyper-polarisation
of postsynaptic cell membrane and
inhibition of postsynaptic neuron.

5. Transmembrane chloride
conductance increases
Hyperpolarisation of
postsynaptic cell membrane
and inhibiton of neurons
GABA receptor activation
↓
↓

6. PHARMACOKINETICS
 pH-7, pKa- 11 (in water)
 Highly lipid soluble.
 Exists in unionized form.
 After bolus dose whole blood level decrease
rapidly due to redistribution and
elimination.
 Initial distribution half life is 2 – 8 min

7.  Rapid distribution to tissues and rapid
hepatic clearance by oxidative metabolism
by cytochrome P-450 results in inactive
water soluble sulfate and glucuronic acid
metabolites that are excreted by kidneys.
 Propofol readily crosses the placenta but
rapidly clears from the neonatal
circulation.

8. FACTORS AFFECTING PHARMACOKINETICS
 Gender - Women have higher volume of
distribution and higher clearance rates.
 Age-Children:-Large central compartment
volume and more rapid clearance.
Elderly:people have decreased
clearance rates but small central
compartment.

9.  Pre existing disease
 Hepatic disease : clearance is unchanged
but elimination half life is prolonged.
 Renal disease: kinetics is unaltered
 Concomitant medication
Fentanyl : decrease clearance rates and VD
Alfentanyl :propofol conc decrease with
alfentanyl.

10. METABOLISM
 Metabolism is both hepatic and extrahepatic
 Hepatic: Rapid and extensive.
Conjugated to glucoronide and sulphate to
produce water soluble compounds excreted by
kidneys
 Propofol also undergoes ring hydroxylation by
cytochrome P-450 to form 4-hydroxypropofol.

11. CNS
 Propofol is primarily a hypnotic acts on
GABA
Onset of hypnosis after doses of 2.5mg/kg is
rapid with in 13 sec, peak effect at 90-100 sec
 Duration of hypnosis is dose dependent 5-10
minutes after 2-2.5mg/kg dose
Median effective doseED50 of propofol for
loss of consciousness is 1-1.5mg/kg .

12.  Sedative effect Propofol acts on GABA
receptors in the Hippocampus and inhibits
acetylcholine release in the Hippocampus
and prefrontal cortex
 Propofol does not alter brain stem evoked
potentials.
 Neuro protection: scavenges free redical and
protect from hypoxic injury

13.  Decreases ICP
In normal patients by 30%
In patients with increased ICP- 30%-50% and
significantly reduces the cerebral perfusion
 Decreases CMRO2 by 36%
 Decreases CBF

14. CVS
 Decrease systemic BP
 At 2-2.5mg/kg 25%-40% decrease in BP
due to vasodilation and myocardial
depression.
 Relaxation of smooth muscle due to
inhibition of sympathetic vasoconstrictor
nerve activity

15.  Negative ionotropic effect due to decrease
intracellular calcium.
 Decrease in cardiac output/cardiac
index(15%), systemic vascular
resistance(15%-25%), stroke volume(20%)
and left ventricular stroke work index(30%).

16. RESPIRATORY SYSTEM
 Dose dependent depression of
ventilation,with apnea in 25%-35% patients
after induction.
 Incidence of prolonged apnea >30seconds
seen with addition of an opiate.
 In patients of asthma bronchodilatation and
decreased incidence of intraoperative
wheezing.

17. HEPATIC ,RENAL AND EYE
 Does not affect hepatic and renal function
 Prolonged infusion may cause green
coloured urine due to presence of phenols
 Decrease in intra ocular pressure
immediately after induction

18. PREPARATION 1% propofol
(10mg/ml)/2% propofol
(20mg/ml)
 Oil in water emulsion
 10% soyabean oil (oil
phase)
 2.25% Glycerol
 1.2% Purified egg
phosphatide
(emulsifying agent )
 0.005% disodium
edetate/ metabisulfite

19.  DIPRIVAN: utilizes preservative 0.005% di-
sodium edetate with sodium hydroxide to
adjust the pH to 7-8.5.
 Generic formulation incorporates sodium
metabisulphite (0.25mg/ml) as the
preservative and has lower pH(4.5-6.4)

20. DOSAGE
 Induction- 1-2mg/kg IV with blood levels of
2-6μg/ml.Increased in children, alcoholics
and anxious patients and decreased in
elderly(25%-50% decrease) and when used
with other medications
 Awakening occurs at plasma conc 1.0-
1.5μg/ml

21.  Maintenance- 50-300μg/kg/min IV
 IV Sedation- 25-75 μg/kg/min
 Antiemetic- 10-20mg IV or infusion of
10mcg/kg/min

22. USES
 Intravenous sedation
 Dose: 25-100μg/kg/min
 Prompt recovery without residual sedation
and low incidence of nausea and vomiting
 Sedation of patients during mechanical
ventilation in ICU.
• Day care surgery: Induction agent of choice

23.  Post operative patients-
Controls stress responses
Modulates postoperative hemodynamic.
Anticonvulsant and amnesic property.
 Maintenance of anaesthesia
dose-50 to 300mcg/kg/mincombined with
short acting opioids

24. Antiemetic effects
10-15mg IV single dose followed by
10μg/kg/min.
Subhypnotic doses: Effective in post
operative and chemotherapy induced
nausea and vomiting
Mechanism: modulates subcortical
pathways decreasing serotonin level.

25.  Antipruritic effect
Dose: 10mg IV
In treatment of pruritus associated with
neuraxial opioids or cholestasis
Mechanism: depresses spinal cord activity
 Anti convulsant effect
Dose: >1mg/kg
Decreases seizure duration by 35%-45% in
patients undergoing ECT

26.  Attenuation of Bronchoconstriction
Decreases prevalence of wheezing after
induction in healthy and asthmatic patients
Propofol formulation with metabisulphite
as preservative may cause
bronchoconstriction in asthmatics and in
patients with h/o smoking.

27. PRECAUTIONS
 Pregnancy
 Lactaion
 Elderly
 Lipid metabolism disorders
 Status epilepticus
 Raised ICT or decreased cerebral
perfusion pressure
 ASA Ⅲ/Ⅳ

28. SIDE EFFECTS
 Allergic reactions due to phenyl and
diisopropyl group
 Pain on injection site
 Most common side effect
 Avoid veins on the dorsum of hand.
 Add lidocaine to the solution or use before
injecting the solution

29.  Bacterial Growth
 E.coli, Psuedomonas Aeruginosa and
Candida
 Aseptic precautions when using the
preparation
 Not to be used beyond 6hrs
 0.005% sodium edetate used as
preservative

30.  CVS: Hypotension, decreased cardiac output
and hypertension in children
Bradycardia related death
 CNS: Amorous behavior, movement
hypotonia, neuropathy, ophisthotonus
Pro convulsant activity: Prolonged
myoclonus associated with meningismus .

31. Propofol infusion syndrome
Metabolic acidosis, acute cardiomyopathy and
skeletal myopathy associated with prolonged
(>48hrs) high dose (>5mg/kg/hr) infusion.
Occurs due to failure of free fatty acid (FFA)
metabolism secondary to inhibition of both FFA
entry into mitochondria.

33. INTRODUCTION
 Nonbarbiturate intravenous anaesthetic agent.
 Etomidate discovered at Janssen Pharma in
1964.
 It is a carboxylated imidazole containing comp.
 Imidazole nucleus renders etomidate water
soluble at an acidic pH and lipid soluble at
physiological pH

34. COMMERCIAL PREPARATION
 Available only for iv use
 Each ml contains etomidate 2mg
,propylene glycol 35% v/v.
 pH of solution is about 6.9 .
 causes pain on injection which can be
lessened by prior injection of lidocaine.

35. Mechanism of action
 It acts on GABA-A receptor by bonding
directly to specific site on protein and
enhancing affinity of inhibitory
neurotransmitter GABA .
 It is unique amongst injected and inhaled
anaesthetic agents in being administered as
a single isomer.

36. PHARMACOKINETICS
 It has large VD
 Distribution is favoured by its moderate
lipid solubility and exists as a weak base.
 It penetrates brain rapidly reaching peak
level within one minute after i.v induction.
 About 76% is bound to albumin
independent of the plasma concentration of
the drug.

37. METABOLISM
 Rapidly metabolized by hydrolysis resulting
in a water soluble, pharmacologically
inactive comp.
 Hepatic microsomal enzymes and plasma
esterases are responsible for this hydrolysis
 10-13% is excreted in bile.
 Elimination half time is of 2-5 hrs

38. USES
 Intravenous anesthetic agent
 Cardiovascular stable anesthetic agent.
 Induction dose: 0.2 – 0.4mg/Kg
 Involuntary myoclonic movements are
common during the induction period result
of alteration in the balance of inhibitory and
excitatory influences on the thalamocortical
tract.

39.  myoclonic like activity can be attenuated by
prior administration of an opioid.
 No analgesia is produced.

40. EFFECT ON CNS
• Etomidate decreases
-Cerebral metabolic rate.
-Cerebral blood flow.
-Intracranial pressure
• It produces a pattern on EEG.
• May activate seizure foci.
• Used with caution in patients of focal
epilepsy.

41. EFFECT ON CVS
• Cardiovascular stability is the characteristic.
• Minimal changes in heart rate, stroke volume
and cardiac output.
• Mean arterial pressure decreases up to 15%
because of decrease in SVR
• Administration to acutely hypovolemic
patients can result in sudden hypotension.

42. EFFECT ON RESPIRATORY SYSTEM
• The depressant effect of etomidate on
ventilation is less than Barbiturate
• Depression of ventilation may be
exaggerated when it is combined with
inhaled anesthetics or opioids.

43. SIDE EFFECTS
PAIN ON INJECTION
 Attenuated with use of etomidate utilizing a
lipid emulsion
MYOCLONUS
 Preoperatively administration of opioid or
benzodiazepine decreases incidence of
myoclonus.

44. ADRENOCORTICAL SUPPRESSION :-
 Dose dependent inhibition of the conversion of
cholesterol to cortisol by inhibiting 11-beta-
hydroxylase.
 It lasts for 4-8 hours after an induction dose.
• Should be used cautiously in patients of
hemorrhage sepsis which require intact cortisol
response.

45. DRUG INTERACTION
 Fentanyl increases the plasma level and
prolongs elimination half- life of
etomidate.
 Opioids decrease the myoclonus
characteristic of an etomidate induction.

46. THANK YOU