Propofol & Etomidate - pharmacology and its use

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(inwater)
Highlylipidsoluble.
Existsinunionizedform.
Afterbolusdosewholebloodleveldecrease
rapidlyduetoredistributionand
elimination.
Initial distribution half life is 2–8 min

7. Rapiddistributiontotissuesandrapid
hepaticclearancebyoxidativemetabolism
bycytochromeP-450resultsininactive
watersolublesulfateandglucuronicacid
metabolitesthatareexcretedbykidneys.
Propofolreadilycrossestheplacentabut
rapidlyclearsfromtheneonatal
circulation.

8. FACTORS AFFECTING PHARMACOKINETICS
Gender-Womenhavehighervolumeof
distributionandhigherclearancerates.
Age-Children:-Largecentralcompartment
volumeandmorerapidclearance.
Elderly:people have decreased
clearance ratesbutsmallcentral
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
Metabolismisbothhepaticandextrahepatic
Hepatic: Rapid and extensive.
Conjugatedtoglucoronideandsulphateto
producewatersolublecompoundsexcretedby
kidneys
Propofolalsoundergoesringhydroxylationby
cytochromeP-450toform4-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
Durationofhypnosisisdosedependent5-10
minutesafter2-2.5mg/kgdose
MedianeffectivedoseED50ofpropofolfor
lossofconsciousnessis1-1.5mg/kg.

12. SedativeeffectPropofolactsonGABA
receptorsintheHippocampusandinhibits
acetylcholinereleaseintheHippocampus
andprefrontalcortex
Propofoldoesnotalterbrainstemevoked
potentials.
Neuroprotection:scavengesfreeredicaland
protectfromhypoxicinjury

13. Decreases ICP
In normal patients by 30%
InpatientswithincreasedICP-30%-50%and
significantlyreducesthecerebralperfusion
DecreasesCMRO2by36%
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. Propofolinfusion syndrome
Metabolic acidosis, acute cardiomyopathyand
skeletal myopathyassociated 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
Nonbarbiturateintravenous anaesthetic agent.
Etomidatediscovered at Janssen Pharmain
1964.
It is a carboxylatedimidazolecontaining comp.
Imidazolenucleus 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 etomidateon
ventilation is less than Barbiturate
•Depression of ventilation may be
exaggerated when it is combined with
inhaled anestheticsor 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 cortisolby inhibiting 11-beta-
hydroxylase.
It lasts for 4-8 hours after an induction dose.
•Should be used cautiously in patients of
hemorrhagesepsis 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