intravenous induction agents

1. Dr. Deepali Jamgade
Dr.Pradeepa Chevala
Guided by: DR . S MANIMALA RAO

2. 1872
•PIERRE-CYPRIEN ORE’ (French Surgeon) used chloral hydrate
1864
•ADOLF VON BAYER – On Saint Barbara’s Day discovered barbituric
acid. Coined the term Barbitute as acombination of Barbara and
urea. (no sedative properties)
•1n 1903 – Emil fischer discovered hexobarbital. Helmut Weese
studied it
1934
•John Lundy of clinic of mayo studied sod .thiopental – balanced
anesthesia
•In 1941 – pearl harbour – many deaths with use of STP due to
cardiovascular depressant effects.

3. 1956 - Replacements like
• HYDROXYDIONE (steroid; thrombophlebitis)
• ALTHESIN (mixture of alphaxolone and alphadolone; has rapid onset and
recovery; rejected because of hypersensitivty reactions)
• PROPANIDID (solubilized in Cremephor EL; rejected because of hypersensitivity
reactions)
In 1973 – Etomidate – minimal hemodynamic depression . Used
use in pts with severe CVS disease
1962 – 1978
• Ketamine – unique as it does not cause CVS depression but post op
hallnications are present
• Benzodiazepines were studied for anxiolysis without same degree of sedation
as thiopentone ;1963 – diazepam 1978 - midazolam
1977
• Propofol was discovered
• Alkylphenol compound with antiemetic properties and depressionof laryngeal
reflexes so easy placement of supraglottic airways

6.  What are i.v. induction agent ?
 Agent cause a rapid reversible loss of consciousness.
 TIME :- “one arm-brain (A→B)circulation time” this time
also depend on cardiac output and ejection fraction .
Normal A → B circulation time is 15-20 sec.
 They are used:
 To induce anaesthesia prior to other drugs being given to
maintain anaesthesia.
 To maintain anaesthesia for longer procedures by
intravenous infusion. To provide sedation. Use for day care
/ short / opd procedure

7. Drug conc. In CNS decreased and patient becomes awake (due to redistribution of
drug)
Repeat intermittent bolus Continuous sedation required
Unbound high lipid soluble and unionized drug crosses BBB quickly
Drug conc. Increases in VRG
organs
Slowly sec. uptake by diffussion
to other tissue
Drug injected in vein reaches the blood
Some % bind to protein Rest % of drug free/unbound

10. Several factors :-
Route of administration
 Age ( ↓ with age )
 Lean body mass ( fat free ) (muscular > fatty
)
 ↓ in low cardiac output state( body
compensate to accordingly to maintain
cerebral perfusion )
 ↓ in Hypoprotenemia ( nutritional,
nephropathy , PIH )

11.  Rapid onset and offset
 Analgesia at subanesthetic dose
 Minimal cardio respiratory depression
 No emetic effect
 No excitatory and emergence phenomenon
 No interaction with N-M blocking agent
 No pain on injection
 No venous sequel ( venous thrombosis)
 No toxic effect on other organs
 No release of histamine ( bronchospasm )
 Water soluble formulation and long self life
 No hypersensitivity
 No stimulation of porphyria
 No adrenocortical suppression

12. GABAA RECEPTOR
HIGHEST NUMBER IN OLFACTORY BULB,
CEREBRAL CORTEX, CEREBELLUM,
HIPPOCAMPUS, SUBSTANTIA NIGRA,
INF. COLLICULUS
LOWER DENSITY IN STRIATUM , LOWER
BRAIN STEM AND SPINS
ALPHA 1 – CAUSES
Sedation ,
anterograde amnesia
, and anticonvulsant
properties.
ALPHA 2 – causes
anxiolysis ms.
Relaxant

13.  Major inhibitory Neuro-transmitter in the CNS
= GABA
 Active GABA A receptor => Cl - influx =>
Hyperpolarisation
 Propofol & barbiturates slow GABA A receptor
dissociation
 Benzodiazepines increase GABA A to receptor
coupling
 Ketamine acts at NMDA receptor
 These effects lead to sedative & hypnotic
effects

14.  Increasing dose => sedation => hypnosis
 All iv anesthetics affect other organ systems
 Potential for respiratory depression
 Potential for CVS depression
 Potential for altered CBF/ICP
 Hypovolemia => severe hemodynamic effects
seen due to decreased blood pool
 Use lower doses!

15. Rapid onset and rapid offset , no excitatory
effect .
 Yellow amorphous powder , in atmosphere
of nitrogen
 Ultra short acting barbiturate.
 @C5
-aryl or alkyl group (hypnotic)
-phenyl gr. (anti convulsant)
 @ C2
-O2 (oxybarb.)
-Sulfur (thiobarbiturate)
@C1-
 Replacement of oxygen at C2 with sulphur.
 Diluted to 2.5 % solution ,can be stored for
48 hr ↓refrigerator , Concentration >5 %
cause pain
 Highly Alkaline pH 10.5, contain 6 %
NaHCO3
 ↓ in alkalinity cause ppt of solution , so
avoid to dilute in acidic solution , RL .
 Co-adm of vec, atra , midaz , alfentanil
form ppt in I.V. line and occlude the vein

16.  Sedation & Hypnosis by interaction with
inhibitory neurotransmitters GABA on GABAA
receptor.
 GABA facilitatory & GABA mimetic action.
 GABAA receptor has 5 glycoprotein sub unit.
 Increases GABA mediated transmembrane conductance
of Cl– ion, Causes hyperpolarization & inhibition of
post synaptic neuron.

17.  At low concentrations, barbiturates enhance the effects of GABA,
decreasing the rate of dissociation of GABA from its receptor–
sedative-hypnotic effects of the barbiturates.
 At higher concentrations, the barbiturates directly activate the
chloride channels without the binding of GABA, acting as the
agonist itself.
 The GABA-mimetic effect at slightly higher concentrations may
be responsible for what is termed barbiturate anesthesia.

18.  Onset of action of i.v. injection - 10-20 sec.
peak 30-40 sec. duration for awakening 5-15 min.
 Prompt awakening after single i.v. inj. is due to rapid
redistribution to lean body tissue (muscle)
 Volume of distribution is 2.5 Lit. per Kg.
 Ultimate elimination due to hepatic metabolism.
 Effect site equilibration time is rapid.
Brain – 30 Sec. Muscle – 15 Min. Fat > 30 Min.
 Context sensitive half life is prolonged.

19.  Excretion-< 1% excreted unchanged in the
urine
 Volume of distribution – 2.5L/Kg
 Rapid distribution half life – 8.5 Min
 Slow distribution half life – 62.7 Min
 Elimination Half Life 11.6 Hours
 Clearance(3.4ml/kg/min)
 Prolonged in obese
patient,elderly,pregnancy.
 Short in paediatric patient.

20. 1) Redistribution
- Lipid solubility (most important factor)
High Lipid Solubility makes it to cross blood brain
barrier & lean body tissue rapidly.
- Protein Binding
Highly bound to albumin & other plasma protein 72 – 86% Binding.
Only unbound fraction crosses Blood-Brain-Barrier.
-Ionization
Only non-ionized part crosses BBB.
Thiopentone has pKA 7.6 so 61% of it is non-ionized at physiologic PH
-Conc. Gradient between CSF and Plasma

21. 2)Metabolism
By liver microsomal enzymes mainly, Slightly in CNS & kidney. 10
– 24 % Metabolised each hour.
OXIDATION of Aryl, Alkyl or Phenyl moeity @ C5
N-DEALKYLATION
DESULFURATION
DESTRUCTION of Barbituric ring
 Conjugation with glucoronide to hydroxythiopentol & carboxylic
acid derivatives to form water soluble metabolites.
 Excreted in urine

22.  Act on GABA a receptor lead to Cl influx –
hyperpolarisation of cell membrane -
↑threshold of excitability of post synaptic
neuron .
 This is highly lipid soluble drug cross BBB –
fast onset of axon
 AT plasma pH around 50 % unionized drug ; in
acidosis condition unionized % ↑; dose
requirement ↓
 Dose dependent↓ CBF, ↓ ICP, ↓ CMRO 2
 CPP= (MAP-ICP ) but { ↓ICP > ↓MAP } ; CPP
preserve

23.  Sedation and loss of consciousness
 retrograde amnesia and depression of vasomotor
centre.
 Induction and maintenance of anesthesia
 Rate of adm α onset
 Termination of effect take 5-10 min to awake (
after bolus )
 Awakening depend on :-
 Volume of distribution
 Plasma concentration
 Redistribution and Clearance
 Alteration in metabolism
 CNS sensitivity ↑ with age

24.  Pupil and eye :- initially pupil contract but then
dilate .
 Pupillary response is lost with surgical anaesthesia .
 loss of eyelash reflex is commonly used as endpoint
for adequate induction dose .
 Following traumatic brain injury, infusion of
thiopental to produce a “barbiturate coma” lowers
intracranial pressure and may improve neurological
outcome.
 Anticonvulsant property
 Thiopental have no analgesic action and may be
antianalgesic in low dose .
 Burst suppression of EEG can be induced with high
doses when used in treatment of status epilepticus or
intractable rise in ICP following head injury .

25.  Dose related resp depression ,peak resp depression
after (1-1.5 min) after adm of bolus dose .
 More susceptible patient ch lung disease , Airway
obst
 Apnea :- transient apnea for 25 sec only in 20 %
cases.
 Double apnea :- 1 st during adm of drug > transient
>after 4-5 breath 2 nd apnea last for longer period .
 during this period ventilation must be assessed –
controlled ventilation .
 ↓minute ventilation , ↓ sensitivity to raised CO2
 Airway reflexes preserved not suitable for LMA
insertion ,may cause coughing and laryngospasm
 C/I in St. asthmaticus

26.  When choosing an induction agent, the
primary goals are as follows:
(1) to preserve maternal blood pressure,
cardiac output, and uterine blood flow;
(2) to minimize fetal and neonatal
depression;
(3) to ensure maternal hypnosis and
amnesia.

27. Umbilical blood and maternal blood concentration equal by the time of delivery
At this dose fetal brain
suppression does not occur
Fetal CNS depression occur at
>= 8mg/kg
Haemodynamic effect unlikely at this dose in normal pregnant women
Within 30 sec drug can be found
in umbilical cord
Umbilical venous blood
concentration peaks in 1 min
Thiopental <4 mg/kg; prompt,reliable induction
Reach in maternal blood, induce
patient
Readily cross the placenta

28.  First effect dose dependent peripheral
vasodilatation
 - ve inotropic effect - ↓ Ca to myocardial fiber
 ↓BP
 ↓ CO (↓venous return , vasodilatation, -ve
inotropic effect , ↓CNS symp outflow )
 Tachycardia ( 10-36 %) Via baroreceptor
mediated symp reflex in response to ↓ CO & BP
 CAD patient on induction ↑HR - ↑myocardial
demand of O2
 ECG changes :-prolonged QT , flattened T wave
,vent arrhythmia
eg - acidotic patient ,long term dialysis ,
Cirrhosis

29. Indications
 Induction of anaesthesia
 Control convulsions
 Decreased ICP
 Neuroprotection
Contraindications
 ABSOLUTE
 COPD
 Severe asthama
 porphyria
 Previous hypersensitivity
 Allergy to sulphur
PRECAUTIONS :
 Stenotic valvular disease
 Severe hepatic disease
 Renal impairment

30.  Anticonvulsant
for rapid control of status epilepticus
dose 0.5 – 2 mg/kg. repeated as needed
 Treatment of increased intracranial pressure
 CMRO2 by 55%, CBF
dose 1 – 4 mg/kg i.v.
CPP is maintained

31. ADVANTAGE :-
Rapid induction
Don’t sensitize
myocardium to
adrenaline
No nausea and vomiting
Other uses
Anticonvulsant In
psychiatric patient
Narcoanalysis
DISADVANTAGE :-
Pharyngeal and
laryngeal reflex
persist →apnea –
controlled ventilation
Resp depression
Hypotension
Poor analgesic and
muscle relaxant
Gangrene and necrosis
Shivering and delirium

32. Stop injection
immediately ,
leave the canula insitu ,
and dilute with
immediate inj of saline
Give intra-arterial inj of
LA + vasodilator
Lidocaine 50 mg ( 5 ml of
1 %) + phenoxybenzamine
( α blocker)0.5 mg bolus
or 50-200 µg/min
infusion.
Consider systemic
papaverine 40-80 mg
Consider sympathetic
block ( brachial plexus
block or stellate ganglion
block )
Start i.v heparin infusion
Give intra arterial
hydrocort Postpone
surgery Consult vascular
surgeon

33. •diazepam was synthesised by Sternbach in 1959
DIAZEPAM
•by Bell in 1961
OXAZEPAM,
•by Fryer and Walser in 1976
MIDAZOLAM
•existence of BZR was first discussed in Milan in 1971
•isolation and receptor-ligand interaction were demonstrated in
1977
•this has resulted in the generation of a number of new ligands and
a specific antagonist
BENZODIAZEPINE RECEPTOR
(BZR)

34. DIAZEPAM MIDAZOLAM
COMPOSITION milliliter of diazepam
solution (5 mg)
contains propylene
glycol 0.4 mL,
alcohol 0.1 mL,
benzyl alcohol
0.015 mL, and
sodium
benzoate/benzoic
acid in water for
injection
(pH 6.2 to 6.9)
solution (1 or
5 mg/mL) contains
0.8% sodium chloride
and 0.01% disodium
edetate,
with 1% benzyl
alcohol as a
preservative.
The pH is adjusted to
3 with hydrochloric
acid and sodium
hydroxide

35. DIAZEPAM MIDAZOLAM
MOLECULAR
WEIGHT
284.7 362
PKa 3.3 6.2
WATER SOLUBLE NO YES
LIPID SOLUBLE YES
HIGHLY LIPOPHILIC
YES
HIGHLY LIPOPHILIC
(DUE TO IMIDAZOLE
RING)

36. DIAZEPAM MIDAZOLAM
EQUIVALENT DOSE
(mg)
0.3 – 0.5 0.15 - 0.3
VOLUME OF
DISTRIBUTION
(L/KG)
1 - 1.5 0.3 – 0.5
PROTEIN BINDING 96 -98 % 96 -98 %
CLEARANCE
(ml/kg/min)
0.2 - 0.5 6 - 8

37. DIAZEPAM MIDAZOLAM
MECHANISM Oxidation of methylene
group of diazepine ring;
Finally glucuronidation of
metabolite
Oxidation at imidazole
ring;
And further glucuronidation
METABOLITES 1.Desmethyldiazepam
2.Oxazepam
3.temazepam
1. 1-hyddroxymidazolam
2. 4-hydroxymidazolam
ELIMINATION Kidney
(e.t1/2 21-37 hours)
Increased in cimetidine
use, old age , cirrhosis of
liver
Kidney
(e.t1/2 1-4 hours)
Increased in cimetidine
,erythromycin ,CC Blockers
, old age , cirrhosis of liver
(mainly by hepatic microsomal oxidation and glucoronide conjugation)

39. CNS EFFECTS RESPIRATORY EFFECTS
 Dose dependent↓ CBF, ↓
CMRO 2 (ratio maintained
by midazolam)
 Increase in seizure
initiation threshold
 20% - Anxiolysis
 30-50% - sedation
 60% - unconsciousness
SLEEP CYCLE-
 alpha activity is decreased
 increase in low voltage,
fast activity, especially beta
 the amplitude of somato-
sensory EP's is reduced
 "pre-anaesthetic" doses-
↓alveolar ventilation
 the peak onset of
ventilatory depression
following midazolam (0.15
-0.3 mg/kg) is at ~ 3 min
and lasts for ~ 15 mins
 in patients with
obstructive pulmonary
disease - respiratory
depression, CO2 retention
and narcosis
 decreases the MAC of
inhalational anaesthetics

40.  in "pre-anaesthetic" doses they decrease the BP and increase HR
 decrease peripheral resistance - flunitrazepam - midazolam
 decrease LV work and cardiac output - diazepam – lorazepam
 baroreceptor reflexes generally remain intact, though, there is
some depression
the hypotensive effect is minimal and usually less than that seen
with thiopentone
the effect is possibly slightly greater with midazolam and is dose
related
 in patients with elevated cardiac filling pressures, both
midazolam and diazepam produce a "nitroglycerine like" effect,
reducing preload and increasing cardiac output
 diazepam increases coronary blood flow in man, possibly by
increasing interstitial concentrations of adenosine

41.  INTRAVENOUS SEDATION
 ORAL SEDATION
 INDUCTION OF ANAESTHESIA
DIAZEPAM MIDAZOLAM
INDUCTION 0.3 – 0.5 mg/kg
(Given in 5 to 15
sec; induction in
39 sec)
0.05 – 0.15 mg/kg
(Given in 5 to 15
sec; induction in
28 sec)
MAINTAINENCE 0.1 mg/kg 0.05 mg/kg
SEDATION 2 mg 0.5 - 1 mg

42. ADVANTAGES DISADVANTAGES
 Better amnesia ( 1-2
hours)
 Smoother
haemodynamic course
(in healthy patients)
 Less opioid
requirement
 Less dosage required
if used with opioids
 Accumulate in blood
 Prolonged arousal time
compared to other I.v
induction agents
 In hemodynamically
compromised patients cvs
depression.
 Dosage affected by age,
sex , gender , obesity ,
enzyme induction ,
hepatic and renal diseases
 Longer context sensitive
half life.

44.  Ketamine is a phencyclidine derivative
 Rapid onset 30-60 sec ;
 high lipid soluble ( 5× thiopental )
 Hypnosis ,amnesia Dissociative anaesthesia , intense
analgesic ( SOMATIC > VISCERAL ), ,rapid clearance
 Cardio stimulation property
 Minimal effect on resp system
 Sympathomimetic effect
 IOA choice for ASA – IV and hemodynamic
compromised state the possibility of emergence
delirium limits the clinical usefulness of ketamine.
 Ketamine has advantages over Propofol and
etomidate in being water soluble

45.  NMDA Receptors antagonist :-
 Opioid Receptors:-
 Muscarinic Receptors:-
 The fact that ketamine produces anticholinergic
symptoms (emergence delirium, Bronchodilation,
sympathomimetics action) suggests that an
antagonist effect of ketamine at muscarinic
receptors is more likely than an agonist effect.
 Sodium Channels:- Consistent with its mild local
anesthetic-like properties, ketamine interacts
with voltage-gated sodium channels sharing a
binding site with local anesthetics

46. Induction of general anesthesia 0.5-2 mg/kg IV;
4-6 mg/kg IM
Maintenance of general
anesthesia
0.5-1 mg/kg IV with N2O 50% in
O2
15-45 µg/kg/min IV with N2O 50-
70% in O2
30-90 µg/kg/min IV without N2O
Sedation and analgesia 0.2-0.8 mg/kg IV over 2-
3 min 2-4 mg/kg IM
Preemptive/preventive analgesia 0.15-0.25 mg/kg IV
Intra thecal ketamine 0.5-0.75 mg/kg

47. Emergence phenomenon (psychadelic effect) visual , auditory, propioceptive and
confusional illusion ,delirium and cortical blindness
Bodily detachment /
dissociative anesthesia
Preventive measures
LOC in 30-60 sec i.v and 2-4 min after i.m (end point Nystagmus in horizontal
gaze)
Consciousness regain in (10-
20)min
Full orientation in (60-90)min
Ketamine water soluble; consider dose dependending factor
1-2mg/kg i.v and 4-6 mg/kg i.m Apnea rare but can be there

48.  ↑CMRO2, ↑ ICP(d/t ↑symp tone ),↑IOT,↑ CBF
(↑CBF> ↑CMRO2)
 Dissociative anaesthesia ( cataleptic state )
 Corneal , cough , swallow reflex +nt
 Amnesia not prominent as compare with BZD
↑muscle tone , purposeless movement , Ө wave
on EEG , petit mal type seizure activity in
hippocampus
 Primary site of axon in CNS thalamoneocortical
projection system .
 Depress cortical and thalamus function Stimulate
limbic and hippocampal function

49.  Associated with vivid dreaming , sense of floating of body,
illusion , ext sensory experience , excitement , confusion ,
euphoria , fear .
 Occur with ketamine due to depression of auditory and
visual relay nuclei .
 The loss of skin and musculoskeletal sensations results in a
decreased ability to perceive gravity, thereby producing a
sensation of bodily detachment or floating in space.
 These feature last for 1 hr.
 Factor affecting emergence reaction
 Age ( adult > child )
 Gender( female > male )
 Dose (↑)
 Concurrent drug ( BZD priming 5 min before ketamine )
 Preop counseling

50.  Sympathomimetic action ↑BP, ↑HR , ↑ CO
 ↑ SBP is 20 to 40 mm Hg, with a slightly increase in DBP, increases
progressively during the first 3 to 5 minutes after an intravenous
injection of ketamine and then decreases to predrug levels over
the next 10 to 20 minutes.
 ↑ myocardial O2 demand – provided by adequate CO &↓ coronary
vascular resistance .
 These effect are more apparent in 1 st bolus dose than 2 nd dose
.
 Ketamine ↑ pul artery pressure – caution use in left side stenotic
valvular lesion .
 Tachycardia and hypertension by ketamine can be prevented by
premedication with BZD or continuous inhalational agent
 Cautiously use in IHD
 Useful in pt of cong heart Ds even in whom propensity for R-L
shunt exist

51.  Min effect on central resp drive
 Transient (1-3 ) min ↓ in minute ventilation
 Large dose produce apnea
 Bronchial muscle relaxant { when given in patient of
bronchospasm – pul compliance increased }
 Bronchodilation make this a potentially useful drug for the
rapid intravenous induction of anesthesia in patients with
asthma.
 Ketamine as effective as halothane
 Resp problem in children are due to ↑ secretion ( salivation
)-cause upper airway obstruction – laryngospasm
 Increase pulmonayl artery pressure
 Preserve cough and upper airway reflex so not useful with
LMA

52.  When choosing an induction agent, the
primary goals are as follows:
(1) to preserve maternal blood pressure,
cardiac output, and uterine blood flow;
(2) to minimize fetal and neonatal
depression; and
(3) to ensure maternal hypnosis and amnesia.

53. Fetal outcome same in both induction with ketamine or thio
Provide both analgesia and hypnosis,maternal awareness less as compared to
thiopentone alone
Ketamine rapidly cross the placenta and
at max conc in fetal blood in 1.5 to 2 mins
Large dose (>1 mg/kg) increased uterine
tone
Ketamine excellent choice for i.v induction in LSCS at 1mg/kg
Rapid onset, sympathomimetic Best in hypovolemia and asthama patient

54.  ADVANTAGE
 increase HR,BP,CO
 In asthmatic
 For short procedure
 Combination with BZD
can use in cardiac
catheterization and
angiography .
 In OPD surgical
procedure
 Good analgesic property
 DISADVANTAGE
 limb movement and
Nystagmus
 Emergence phenomenon
in 50 %
 Hypertensive
 Increased ICP , IOT
 Uterine stimulation
 Schizophrenia ,
psychosis
 Poor muscle relaxation

55.  INDICATION
 CVS except IHD and Resp.
disorder
 Hemodynamic compromised (
pericarditis , cardiac
tamponade , CM , shock )
 Traumatic and septic shock
 As component in TIVA with
midaz and propofol provide
better hemodynamic stability
 In cancer patient ,
neuropathy
 Phantom or ischaemic limb
pain
 Fibromyalgia , visceral pain
 Migraine
 CONTRAINDICATION
 ↑ ICP , SOL brain
 Large size Infarct
 Ophthalmic injury
 IHD
 Vascular aneurysm
 Schizophrenia

56.  Most frequently use I.V. anaesthetic drug today
 Milky white ;
 pH 7.0 - 8.5 ;
 isotonic to plasma
 Fospropofol prodrug
 Stable at room temp ;
 Not light sensitive
 Dilution :- water insoluble ;
 Compatible in DNS Dilution cause cracking of emulsion ,
spontaneous degradation
 Concern regarding microbial growth in emulsion – disodium
edetate (0.005%) added to retard the bact. Growth
 Sedation in and outside of OT
 Concern regarding induction and emergence myoclonic ,jerk
 Painful injection in small vessel take care of it

57.  2,6 –di-isopropylphenol
 Rapid onset 15-45 sec and offset , rapid offset even
after prolonged infusion ( small context sensitive half
time )
 Metabolize in liver with Glucuronide and sulfate
conjugation .
 Extra hepatic metabolism + lung ; inactive
metabolite Mainly excreted by kidney
 Propofol causes the most marked fall in blood
pressure of all the induction drugs. This is mainly due
to systemic vasodilatation. There may be an
accompanying slight increase in heart rate. The fall
in blood pressure is dose dependent and is most
marked in the elderly and in shocked patients. This
can be minimized by slow injection – avoiding
inadvertent overdose.

58.  By the removal of Cremophor consists of 1%
(wt/ vol ) Propofol 10% soybean oil 2.25%
glycerol 1.2% purified egg phosphatide To
prevent microbial growth in the emulsion,
disodium edetate (0.005%) was added as a
retardant of bacterial growth.
 If a dilute solution of propofol is required, it
is compatible with 5% dextrose in water.
 Fospropofol (Aquavan)soon going to be
approved by FDA, a phosphorylated prodrug
of Propofol,

59. Clinical use Dose
Induction of general
anaesthesia
•1-2.5mg/kg,dose reduced with increasing
age,induction dose in 2 yr(2.9mg/kg),in 6-
12 yr(2.2 mg/kg)
Maintainance of
general anaesthesia
100-200mcg/kg/min without N2O & opiates
50-150mcg/kg/min with n2O & opiate
Sedation(with little
analgesic & amnesic)
25-75 mcg/kg/min I.V.,concious sedation
Antiemetic 10-20mg I.V.can repeat every 5-10 min
orstart 10mcg/kg/min infusion

60.  Dose and therapeutic conc dependent action
 Hypnotic action by enhancing GABA induced chloride
current
 Onset with 2.5 mg/kg 15-30 sec with peak effect in 90-100
sec.
 Duration of hypnosis 5-10 min depending on redistribution
and Vd
 Subhypnotic dose – sedation and amnesia infusion
@2mg/kg/hr
 Propofol have shown direct depressant effect on neuron of
spinal cord
 sense of well being ( ↑dopamine conc in nucleus
accumbence- phenomenon seen in drug abuser and
pleasure seeking behavior.
 Antiemetic action may be explained by ↓in serotonin level
.

61.  ↓ ICP , acutely ↓ IOP -(propofol >Thio )effective in
preventing raised IOP with scolin and intubation
response
 Neuroprotective role ↓ controversies ;due to
antioxidant axn by inhibiting lipid peroxidation
 Just or 1 hr after to ischemic insult produce
reduction in size of infarct at sedation dose @ 25-75
µg/kg/min as compared to awake control with
intralipid.
 Burst suppression @blood level > 8µg/ml –better
neurological outcome and less brain injury
 EEG effect – ( α → ϒ → Ө ) wave Seizure like activity
reported mainly on induction and emergence . Dose
dependent anticonvulsant activity +nt

62.  On induction dose and rate of adm dependent↓ BP
(25-40 %) in comparable dose (propofol >Thiopental)
 ↓ SBP and DBP , ↓ MAP
 ↓ CO, ↓ SV , ↓ SVR ( 15-25 %)
 HR ↓(-10 +_10 % ) to baseline; Propofol either may
reset or may inhibit the baroreflex, reducing the
tachycardia response to hypotension
 MAP ↓ ( -10-40 %)
 Propofol at high concentrations (10 µg/mL) abolishes
the inotropic effect of α but not β adrenoreceptor
stimulation, and enhances the lusitropic (relaxation)
effect of β stimulation
 CNS induced ↓ sympathetic drive on heart - cardio
depression

63.  In patient with valvular lesion ↓( PA and PCWP ) – due
to ↓ pre and afterload .
 cardio depression ( bolus > infusion )
 Continuous Infusion cause significant ↓ in myocardial
blood flow and oxygen demand
 For better hemodynamic stability use one or more
additive induction agent ( fentanyl , Midazolam )with
propofol .
 Bradycardia-related Death:-Profound bradycardia
and asystole after the administration of Propofol
despite prophylactic Anticholinergics. thus suggesting
that Propofol induce a suppression of sympathetic
nervous system activity. The treatment of Propofol-
induced bradycardia may require the administration
of a β-agonist, such as isoproterenol.

64.  Profound resp depressant
 Apnea occur depend on dose , speed of injection,
concomitant premedication
 Occur in 25- 30 % cases ,may last for >30 sec ,may ↑by
adding opiate in premedication
 Apnea risk max in this agent than other
 Apnea precedes with marked ↓ TV and tachypnoea.
 A maintenance infusion (100 µg/kg/min) results in a 40%
↓TV and a 20% ↑ RR ,
 Propofol (50 to 120 µg/kg/min) also depresses the
Ventilatory response to hypoxia, presumably by a direct
action on carotid body chemoreceptor
 Reduces airway and pharyngeal reflexes- use with LMA
 Bronchoconstriction ( thiopental > propofol
),Bronchodilation prevent intraop wheeze.

65.  Proconvulsant Activity:-The majority of reported
Propofol-induced seizures during the induction of
anesthesia or emergence from anesthesia reflect
spontaneous excitatory movements of sub cortical
origin.
 Abuse Potential :-Intense dreaming activity, amorous
behaviour, and hallucinations have been reported
during recovery from the effects of Propofol.
 Bacterial Growth:-growth of Escherichia coli and
Pseudomonas aeruginosa.
 Pain on Injection:-As little as 0.2 mg/kg of lidocaine
(mixed with the propofol) is effective in reducing but
not eliminating this discomfort.
 Mini – Bier Block –APPLY tourniquet give 1mg /kg of
lidocaine 15-20 sec before propofol adm then remove
tourniquet

66.  Complication in prolonged infusion patient
 Propofol infusion syndrome(PIS) in (pediatric
> adult) patients receiving prolonged high-
dose infusions of Propofol (>75 µg/kg per
minute) for longer than 24 hours.
 Associated with :-
 metabolic acidosis,
 lipidaemia,
 cardiac arrhythmias
 Unexpected tachycardia
 Increase mortality

67. Significant bradycardia with scoline
Induction with propofol@1-2mg/kg
Marked decrease in B.P Decrease uteroplacental circulation

68. Advantages
 Rapid induction
 Anti emetic effect
 TIVA
 Agent of choice for
day care surgery
Disadvantages
 Induction apnoea
 Hypotension
 Dose dependant
bradycardia
 Dose dependant resp
depression
 Pain during injection
 It is also euphorigenic
but does not have
residual psychotic
effects like Ketamine

69.  Etomidate is a carboxylated imidazole & prepared as a fat emulsion,
 its effects on GABA A receptors
 Etomidate A→B circulation time 1 min,
 The clearance of etomidate is about five times that for thiopental;
 Likewise, the context-sensitive half-time of etomidate is less likely to be
increased by continuous infusion, as compared with thiopental.
 Etomidate (0.2 to 0.4 mg/kg IV) IOC especially in the presence of an
unstable cardiovascular system.
 Involuntary myoclonic movements are common during the induction due
to alterations in the balance of inhibitory and excitatory influences on
the thalamocortical tract.
 Awakening after a single intravenous dose of etomidate is more rapid
than after barbiturates.
 The principal limiting factor in the clinical use of etomidate for the
induction of anesthesia is the ability of this drug to transiently depress
adrenocortical function

70. Clinical use Dose
Induction of general anaesthesia 0.2-0.6mg/kg I.V
Maintainance of general
anaesthesia
10mcg/kg/min I.V. with N2o & an
opiate
Sedation & Analgesia Limited to periods of brief
sedation because of inhibition of
steriod synthesis

71.  ↓ CBF , ↓ CMR02 , ↓ ICP
 Myoclonus (spontaneous movements) occurs
in 50% to 80% of patients receiving etomidate
in the absence of premedication. etomidate-
induced Myoclonus appears to be
disinhibition of subcortical structures that
normally suppress extra pyramidal motor
activity.

72.  Cardiovascular stability (minimal changes in
heart rate, stroke volume, cardiac output) is
characteristic of induction of anesthesia
using 0.3 mg/kg IV of etomidate So it may
differ from most other intravenous
anesthetics in that depressive effects on
myocardial contractility are minimal at the
concentrations needed for the production of
anesthesia.

73.  The depressant effects of etomidate on
ventilation seem to be less than those of
barbiturates, although apnea may
occasionally accompany a rapid intravenous
injection of the drug.

74.  Limitation of etomidate Etomidate causes
adrenocortical suppression by producing a
dose-dependent inhibition of the conversion
of cholesterol to cortisol

75. properties PROPOFOL THIOPENTONE KETAMINE
chemistry ALKYLPHENOL THIOBARBITURATE ARYLCYCLOHEXYL
AMINE
consistency Emulsion milky
white
Sodium salts(6%
sodium
carbonate)yellow
amorphous powder
Clear aquaous
solution
solubility Lipid soluble Lipid soluble Lipid soluble
ph 7 10.5 of 2.5% 3.5-5.5
pka 11 7.6 7.5
Unionised % 99.97% 61% 55.7%
onset One arm –brain
time15-30 sec
10-15 30-60
peak 90-100 sec 90-100 sec 90-100sec
awakening 5-10 min 5-10 min 10-20 min
Rapid fall in
plasma conc.
After bolus
Redistribution &
elimination
redistribution redistribution

76. properties PROPOFOL THIOPENTONE KETAMINE
Protein binding 98% 85% 60%
Metabolism &
excretion
LIVER
Glucuronite
sulphate
KIDNEY
LIVER
Oxidation
N-dealkylation
Desulfuration
Destruction of
barbituric acid
ring
KIDNEY & BILE
LIVER
Norketamine
Hydroxynorketam
ine
KIDNEY
metabolite Inactive pentabarbital Norketamine 20-
30%
Extrahepatic
metabolism
lung absent absent
Clearance
ml/kg/min
20-30 3-4 12-14

77. properties PROPOFOL THIOPENTONE KETAMINE
Content
sensitive half
time(for
infusion lasting
upto 8 hrs
<40 min <150min <40 min
MOA GABA GABA NMDA(thalamoc
ortical &
limbic)
Induction 1-2.5 mg/kg 3-5 adult
5-6 children
6-7 infant
0.5-2 mg/kg
maintenance 50-
150ug/kg/min
15-
45ug/kg/min
sedation 25-
75ug/kg/min
0.2-0.8mg/kg
analgesia 25-
75ug/kg/min
Conscious
sedation
0.2-0.8mg/kg

78. properties PROPOFOL THIOPENTONE KETAMINE
Neuroprotective Reduce infarct
size when adm
immediately or
1 hr after
ischemic insult
Decrese 02
demand
Preserve CPP
ROBINHOOD
phenomenon
Free radical
scavenging
Improve
perfusion in
incomplete
cerebral
ischemia
Dissociative
anasthesia
- -- +
Emergence
reaction
+ -- +
Upper airway
reflexes
-- -- +
Salivation &
lacrimation
-- -- ++
antiemetic + -- -
Sk musle tone -- -- increase
relaxant -- -- +

79. propeties PROPOFOL THIOPENTONE KETAMINE
BP Dec.25-40% dec increase
HR N /dec. Dec(10-36%) inc
CO Dec. dec inc
CMRO2 Dec. dec inc
CBF Dec. dec inc
ICP Dec. dec inc
ICP Dec. dec inc
APNEA ++dose
dependent (20-
30%)
++ Higher dose
Min ventilation dec dec inc
bronchodilation + -- +
anticonvulsant + + --
antipruritic + -- --
Chronic
refractory
headache
+ -- --

80. properties PROPOFOL THIOPENTONE KETAMINE
Pain on
injection
++ + --
Hypotension ++ + --
apnea ++ + +/-
bronchospasm -- + --
Allergic
reaction
+ + --
thrombophlebit
is
+ ++ --

81.  A patient with intestinal obstruction requires
an emergency laparotomy. Which induction
drug would you use?

82.  Any patient with intestinal obstruction must
be assumed to have a potentially full
stomach.
 Traditionally a rapid sequence induction
would be performed with preoxygenation ,
cricoid pressure, thiopental and
suxamethonium.
 Thiopental is chosen due to its rapid, well
defined onset at a predetermined dose. This
is also the method of choice of induction for
caesarean section.

83.  A patient requires a burns dressing change.
Which induction drug would you use?

84.  Ketamine is an ideal drug to be used for
minor procedures.
 For burns dressing changes, a sub-
anaesthetic dose can be used. It will provide
sedation and analgesia, preserving the
protective airway reflexes.
 Ketamine is often combined with
benzodiazepine premedication to reduce the
dose requirement and emergence reactions,
and sometimes an anti-sialagogue (e.g.
glycopyrrolate, glycopyrronium bromide) to
reduce airway secretions

85.  A patient with a history of heart failure
requires a general anaesthetic. Which
induction drug would you choose?

86.  drug of choice would be etomidate due to its
limited effect on the cardiovascular system.
However some anaesthetists avoid etomidate all
together due to its effect on steroid synthesis.
 Ketamine could also be considered due to its
relative cardiovascular stability.
 Propofol and thiopental are also options, but
potentially cause more cardiac depression. The
important issue is that which ever induction drug
is used, the lowest possible dose is given, it is
given slowly and it is titrated to effect.
 Intra-arterial blood pressure monitoring should
be considered if available.

87.  A patient with porphyria comes for an
inguinal hernia repair and is requesting a
general anaesthetic. Which induction drug
would you use?

88.  A patient with porphyria comes for an inguinal hernia
repair and is requesting a general anaesthetic. Which
induction drug would you use?
 The porphyrias are a group of disease characterised
by overproduction and excretion of porphyrins
(intermediate compounds produced during
haemoprotein synthesis).
 Acute attacks may be precipitated by drugs, stress,
infection, alcohol, pregnancy and starvation.
 Propofol would be the ideal induction drug to use in
this case – being safe to use in patients with
porphyria.
 Thiopental and etomidate should be avoided as they
can precipitate a porphyric crisis

89.  An adult patient requires sedation on the
intensive care unit. Which of the induction
drugs would be appropriate to run as an
infusion?

90.  A propofol infusion would be appropriate.
Midazolam could also be given in addition, or
as an alternative to propofol.
 Thiopental should be avoided due to
accumulation, and etomidate should be
avoided due its effect on adrenal steroid
hormone synthesis.

91. THANK YOU