iv agents used for induction of general anaesthesia, sedation under standard monitored anesthesia care, ICU sedation

1. Intravenous
inductional agents
DR SHIV SUNDAR CHAKRABORTY
SVMCH & RC , PONDICHERRY

2. Goals of GA
 Hypnosis (unconsciousness)
 Amnesia
 Analgesia
 Muscle relaxation
 Inhibition of nociceptive reflexes
 Reduction of certain autonomic reflexes
(gag reflex, tachycardia, vasoconstriction)

3. Phases of General Anaesthesia
Stage I: Disorientation, altered consciousness
Stage II: Excitatory stage,
 delirium, uncontrolled movement,
 irregular breathing.
 Goal is to move through this stage as rapidly as possible.

4. Stage III: Surgical anesthesia; return of
regular respiration.
 Plane 1: “light” anesthesia, reflexes, swallowing reflexes.
 Plane 2: Loss of blink reflex, regular respiration (diaphragmatic and chest). Surgical procedures can
be performed at this stage.
 Plane 3: Deep anesthesia. Shallow breathing, assisted ventilation needed. Level of anesthesia for
painful surgeries (e.g.; abdominal exploratory procedures).
 Plane 4: Diaphragmatic respiration only, assisted ventilation is required. Cardiovascular impairment.

5. Stage IV: Too deep;
 essentially an overdose and represents anaesthetic crisis.
 This is the stage between respiratory arrest and death due to circulatory
collapse.

6. Classification
Iv anaesthethetics
barbiturates
thiopentone methohexital
amobarbital
benzodiazepines
Diazepam,lorazepam,midazolam
etomidate ketamine propafol

7. GABA receptor complex
 g- amino butyric acid is inhibitory neurotransmitter
 Oligomeric complex of 5 glycoprotein subunits
 Assemble to form cl- channel with GABA A receptor
 Activation of GABA receptors increases cl conductance
hyperpolarization of post synaptic neuron
excitability of post synaptic neuron

9. Barbiturates
Mechanism of action
 Increases duration of opening of cl- channel in GABA
receptor (gabamimetic)
 Depress reticular activating system in brain stem
 RAS helps to maintain wakefulness

10. Other targets :
 Adenosine receptors
 Neuronal nicotinic acetyl ch receptors
 nAChRs are not critical targets ( Downie et al : 2000)
 At NMJ high dose decrease sensitivity of post synaptic membranes to depolarising action of
acetyl ch

11. Structure – activity
Substitution at carbon C5 determines hypnotic
potency & anticonvulsant activity.
Phenyl group in phenobarbital is
anticonvulsive
Longer the branched chain more the potency
Urea + malonic acid = barbituric acid

12.  Replacing oxygen with sulphur atom at C2
(thiopentone)
 ‘Thio’ group also increases the potency
 Thiopentone have greater potency & shorter
duration of action than pentobarbital
 Replacing with methyl group ( methohexital)

13. Preparation
 hygroscopic (attracts moisture from the atmosphere)
 pale yellow powder.
 Ampoules contain 500mg of sodium thiopental
 6% sodium carbonate in an inert atmosphere of nitrogen
 Reconstituted 20ml of water this yields a 2.5% solution (25mg/ml) with a pH of 10.8.
 alkaline solution is bacteriostatic

14. Cont..
 These highly alkaline solution are incompatible for mixture with opioids,
catecholamine's, NMB drugs (acidic)
 Thiopentone , methohexital are available in racemic mixture
 Although , S(-) isomer is more potent than R(-)
 S(-) isomer causes excessive muscular activity

15. Stability of commercial preparation
 Refrigerated solution of thiopentone are stable up to 2 weeks
 Solution of methohexital are stable up to 6 weeks
 At 22 degree C thiopental is stable & sterile for 6 days (Haws et al)

16. Pharmacokinetics
Protein binding
Highly protein bound - 72-86 %
Hypoalbuminemia ( cirrhosis, CKD, neonates)
Displacement of binding sites
by aspirin,phenyl butazone increased unbound fraction foetal acidosis stressful
delivery
enhanced drug effect

17. Distribution
Factors affecting distribution:-
 Lipid solubility
 Protein binding
 Degree of ionization
 Tissue blood flow
In hypovolemia, there is decreased blood flow to skeletal muscle & fat
whereas flow to brain & cardiac are maintained, leads to exaggerated brain &
cardiac suppression.

18. Distribution to brain
 Maximal brain uptake within 30 sec (rapid effect site equilibration)
 10 % total dose received in 30 sec
 Next 5 min half of initial peak concentration (redistribution)
 Redistribution to other tissue responsible for early awakening
 Prompt brain uptake is because of its high lipid solubility

19. Distribution to Sk Ms & fat
 Sk Ms is initial site for redistribution of thiopentone
 Equilibrium in Ms is seen within 15 mins
 Low perfusion(shock) & elderly ,dose of thiopentone should be reduced
 Maximal deposition in fat is present after 2.5 hrs
 Fat is potential reservoir of drug( maintains plasma concentration)
 Repeated doses can cause cumulative effect later
 Dose of thiopentone should be calculated on lean body mass

21. Ionization
 Pk of thiopentone (7.6) is near blood PH
 Acidosis nonionised form more lipid soluble cns effect
 Alkalosis decrease barbiturate effect
Metabolic acidosis has more influence on distribution has respiratory acidosis
Metabolic acidosis H+ H+ cant cross BBB intracellular PH unchanged
unionised form
Respiratory acidosis Co2 Co2 diffusion similar change extracellular & intracellular ph
ionised form

22. Metabolism
 Thiopentone is metabolised in liver into hydroxythiopental & carboxylic acid
 They are water soluble & have little cns activity
 Metabolism of methohexital is more rapid than thiopentone
 Recovery with methohexital is faster (less lipid soluble)
 Clearance of thiopentone in cirrhosis is equal to normal pt ( Pandele et al 1983)

23. Renal excretion
 < 1 % thiopentone is excreted unchanged in urine
 High lipid solubility favours reabsorption
 High protein binding limits filtration
 Osmotic diuresis & alkalinisation hastens phenobarbital excretion

24. Elimination half life :-
 Thiopentone – 11.6 hrs , methohexital – 3.9 hrs
 Shorter elimination ½ life of methohexital is due to rapid hepatic clearance
 Elimination ½ life of thiopentone is prolonged in obese pt
 Elimination ½ life of thiopentone is prolonged in pregnancy due to increased protein binding
 Elimination ½ life of thiopentone for paediatric is shorter than adults

25. Effects on CNS :-
 Barbiturates constricts cerebral blood vessels decrease ICP > aterial BP
cerebral perfusion pressure
 Barbiturates also decrease cerebral O2 consumption
 Decrease in blood flow is not detrimental
 Lowers pain threshold ( antianalgesic)
 Small dose can cause paradoxical excitement in elderly or in presence of pain

26. Clinical uses :-
 Induction of anaesthesia
Thiopentone = 3-6 mg/kg (iv)
Methohexital = 1-2 mg/kg (iv)
 Pentobarbital ( premedication) = 2-4 mg/kg(IM), 3 mg/kg (rectal)
 Prolong infusion (barbiturate coma) saturates peripheral compartments,
duration of action then directly depends on elimination ( context
sensitivity)
 Thiopentone has long context sensitive half life

27. Treatment of increased ICP
 Decrease ICP even when mannitol & hyperventilation have failed to reduce
effectively
 Induction in pt with increased ICP
 Hazard of high dose thiopentone ( 37.5mg/kg) is hypotension
 Hypotension can cause decreased CPP
 Inotropic support is often required

28. Cerebroprotection
 50 – 100 mg thiopentone rapidly controls grand mal seizures
 Profound EEG suppression
 Low voltage fast activity to high voltage slow activity
 Protect from transient ischemia ( embolism)
 Avg dose of 39.5 mg/kg iv of thiopentone is used after cardiopulmonary bypass to maintain
isoelectric EEG.
 Doesn’t protect from global ischemia (cardiac arrest)
 Methohexital is used to produce seizure activity in pt of psychomotor epilepsy, undergoing
temporal lobe resection of seizure producing areas

29. Effects on CVS
Barbiturates depress medullary VMC sympathetic tone peripheral
vasodilation
CO & BP venous return
carotid sinus baroreceptor tachycardia (maintain CO)
Pt with hypovolemia, CHF, B blockers have
accentuated hypotension (uncompensated ), slow iv

30. Effects on respiration
 Dose dependant depression of medulla & pontine RC
 Decrease sensitivity of medullary rc to CO2
 Inadequate plane may provoke laryngospasm & bronchospasm during
intubation
 During awakening tidal vol & RR are decreased.

31. Liver
 Modest decrease in hepatic blood flow
 Increases liver microsomal protein ( enzyme induction)
 Increased metabolism of oral anticoagulants, phenytoin, TCA, vit K
 Phenobarbitone used in kernicterus( increase glucoronyl tranferase)
 Exaggeration of acute intermittent porphyria( D ALA synthase)

32. Allergic & immunological effects
 Incidence of allergic rxn of thiopentone is 1/30,000 pt ( Clarke 1981)
 High mortality, H/o chronic atopy
 Increased incidence of nosocomial infection
 Bone marrow suppression
 Leukopenia
 Inhibits ntF-KB, impair neutrophils ( reduces antibacterial host defence)

33. Intra arterial injection
 Immediate vasoconstriction, pain (radiates along artery)
 2.5% soln is safer
 Thiopentone crystals leads to arteritis, thrombosis
 Leave needle intact
 Injection of normal saline
 Lidocaine , papaverine,heparin
 Stellate ganglion block

34. BENZODIAZEPINES
 They have seven membered diazepine ring
 5 aryl substituent & 1,4 diazepine ring
Principal pharmacologic effect
 Anxiolysis
 Sedation
 Anticonvulsant action
 Spinal chord mediated sk ms relaxation
 Anterograde amnesia ( Ashton 1994)

35. Mechanism of action
 a1 subunits of GABA A – sedative effect
 a2 subunits of GABA A- anxiolytic activity
GABA A
receptor
a1 subunit
Cerebral cortex, cerebellar
cortex,thalamus
a2 subunit
Hippocampus, amygdala

36. Cont..
 Drug induced increased affinity of receptor for GABA
 Increase cl- conductance
 Post synaptic neuron more resistant to excitation

37. BZD effect on nucleoside transport
 Inhibits nucleoside transporter
 Thus, decrease degradation of adenosine
 Adenosine has cardio protective mechanism
 Coronary vasodilator
 Reduces cardiac O2 demand

38. MIDAZOLAM
 IMIDAZOLE ring (stable in aqueous soln.)
 pK is 6.15
 pH dependent ring opening phenomenon
 At physiological pH it is highly lipid soluble
 pH >4 – lipid soluble
 pH<4 – water soluble
 Compatible with RL & other acidic drugs

39. Pharmacokinetics
 Slow effect site equilibration time ( 0.9- 5.6 mins)
 High lipid soluble
 Rapid redistribution ( short duration of action)
 Context sn ½ time of midazolam is shorter than diazepam , so it can be
used for prolonged sedation as infusion in icu’s.
 Elimination ½ time is 1-4 hrs
 Etime is prolonged in elderly ( age related decrease in hepatic BF)

40. Metabolism
 Rapid , liver & intestine ( p450 – CYP3A4 enzyme activity)
 1 hydroxyl midazolam
 Glucoronide metabolite has little seductive effect
 Delayed ( cimetidine,erythromycin,ccb,antifungals )
 Clearance is delayed if fentanyl is co administered

41. Effects on CNS
 Decreases CMR O2 & CBF
 Unable to produce isoelectric EEG
 Dose related CBF to regions functioning with arousal, attention, memory
 Cerebral vasomotor response to CO2 is preserved
 Potent in status epilepticus

42. Ventilatory effects
 Dose dependent ( 0.15 mg/kg)
 Increase depression in copd
 If >0.15 mg/kg + opioid – transient apnoea
 Depress swallowing reflex
 Depress upper airway activity

43. Effects on CVS
 Dose (0.2 mg/kg) produces greater decrease in SBP than diazepam of 0.5
mg/kg
 BP changes are due to sys vasodilation
 No change in CO ( beneficial for CHF)
 Does not prevent pressor response to intubation

44. Clinical uses:-
 Preop medicine for children (0.25 mg/kg)
 Intravenous sedation 1-2.5 mg iv
 Induction of anaesthesia (0.1-0.2 mg/kg iv / 30-60 sec)
 Facilated induction with fentanyl (50 -100 mcg iv )
 Decrease dose in elderly
 Post op sedation: LD – 0.5-4 mg iv MD – 1-7 mg/hr
 O.5 – 1 mg/kg treat paradoxical VC motion

45. DIAZEPAM
 Dissolved in organic solvents ( propylene glycol, Na benzoate )
 pH 6.6-6.9
 Dilution with water causes cloudiness ( potency unaffected)
 Injection IM/IV painful

46. Pharmacokinetics
 Peak conc in 1 hr adults / 15 – 30 mins in children
 Rapid brain uptake
 Rapid redistribution to fat
 Obese women Vd > men
 Crosses placenta
 High protein bound ( HD not effective)

47. Metabolism
 Oxidative pathway of N methylation
 Desmethyl diazepam & oxazepam & little temazepam
 Metabolites contribute to return of drowsiness a/f 8 hrs
 Enterohepatic circulation also favour recur of sedation
 Elimination ½ life 21 – 37 hrs
 Liver failure increases E half life

48. Effects & uses:-
 Minimal depression on ventilation
 0.5 – 1 mg/kg minimal decrease in BP,CO
 Transient decrease of baroreceptor response of HR
 In addition with N20 no adverse cardiac changes
 muscle relaxation ( spinal internuncial neurons)

49. Anticonvulsant activity
 0.1 mg/kg abolishes lidocaine induced seizures
 Treat delirium tremens & status epilepticus
 Diazepam selectively inhibits activity in limbic system & hippocampus
 If diazepam is given then long acting Fosphenytoin should also be given

50. Other BZD:-
Lorazepam
 More potent sedative than midazolam
 Max anterograde amnesia
 Slow onset ( disadvantage)
 Delayed weaning from ventilator
Alprazolam – Anxiolysis,preop med
Clonazepam – myoclonic & infantile spasms
Zolpidem, zaleplon – delayed sleep onset

51. FLUMAZENIL
 1,4- imidazobenzodiazepine derivate
 competitive BZD antagonist (min agonistic activity)
 Initial dose 8-15 mcg/kg iv
 If further required 0.1 mg iv upto 1mg every 60 sec
 Maintain wakefulness = 0.1-0.4 mg/hr infusion

52. Propafol
 2,6- di isopropyl phenol
 Needs lipid vehicle for emulsification
 10% soyabean oil + 2.25% glycerol+ 1.2% purified egg phosphatide
 Supports bacteria growth (discard after 6 hrs)
 Increase triglyceride level on infusion
 Na metabisulfite preservative ( generic)
 Lidocaine can be added to reduce pain

53. Fospropafol
 Water soluble prodrug of propafol
 Reduce the disadvantages of the lipid emulsion of propafol

54. Cont..
 Endothelial cell – alkaline phosphatase
 Dose dependent sedative effects
 Fospropafol has higher potency
 Larger Vd

55. Mechanism of action
 Selective modulator of GABA A receptor
 Decrease rate of dissociation of GABA
 Doesn't alter spinal motor excitability

56. Pharmacokinetics
Clearance
 Hepatic p450 cyt oxd (rapid & extensive)
 Extra hepatic (lungs)
 Metabolite – 4- hydroxypropafol
 Short context sensitive life ( minimal influence by duration of infusion)
 Kidney plays major role in elimination
 Crosses placenta

57. Clinical uses:-
 Induction DOC (1.5 -2.5mg/kg iv)
 25 – 50 % reduce dose in elderly
 Complete awakening without residual effects
 Part of balanced or total anaesthetic
 IVS in ICU’S ( 100 mcg/kg/min )
 Maintenance ( 100-300 mcg/kg/min )
 >1mg/kg reduce 35 -45% seizure duration in ECT

58. Non hypnotic uses:-
 Decreased postop nausea & vomiting (10 – 15 mg iv)
 Effective in chemotherapy induced nausea & vomiting ( effective than
odansetron)
 Depress subcortical areas
 10 mg iv antipruritic ( neuraxial opioids & cholestasis)
 >1mg/kg reduce 35 -45% seizure duration in ECT
 Attenuation of bronchoconstriction (compared to thiopentone)
 Metabisulfite can cause bronchoconstriction in asthma

59. Systemic effects:-
 Decrease CMR O2 , CBF, ICP
 Decrease Systemic BP (relax vascular sm – inhibit Ca+ influx)
 Propafol is more effective than thiopentone in blunting pressor response to intubation & LMA
 Pressor response to ephedrine is augmented
 Apnoea in 25 -35% pt a/f induction
 Prolong infusion green urine ( phenol )
 Increase urine uric acid
 Decrease IOP ( useful in laparoscopic sx)
 Inhibits platelet aggregation

60. Bradycardia – Related Death
 Profound bradycardia & asystole have been seen in healthy adult individual
after induction , despite prophylactic anticholinergics (Egan & Brock ; 1991,
James et al 1989,Tramer et al 1997c)
 Risk is about 1.4 / 1,00,000
 Refractory bradycardia in children in icu have been see (Dearlove & Dobson
1995, Bray 1995)
 In this cases isoproterenol may be required

61. Side effects:-
 Allergic reaction (phenyl nucleus & di isopropyl side chain)
 Propofol infusion syndrome
 Prolonged myoclonus associated with meningismus
 Abuse potential (intense dreaming)
 Bacterial contamination ( E.coli, P.Areruginosa)

62. Propofol infusion syndrome
 Lactic acidosis during high dose infusion(>75mcg/kg/min)
 Unexpected tachycardia > ABG > lactate level
 Cytopathic hypoxia of ETC
 Impaired oxd of Long chain FA
D/D:
1. Mitochondrial myopathy
2. Hyperchloremic metabolic acidosis
3. Diabetic acidosis
4. Release of tourniquet

63. Antioxidant properties
 Potent antioxidant property that resemble Vit E
 Phenolic hydroxyl group scavenges free radicle
 Inhibits lipid peroxidation
 Scavenges peroxynitrite ( supress phagocytosis)
 Helpful in acute lung injury
 Post ischemic dysfuntion, myocardial stunning
 Attenuates lipid peroxidation in CABG

64. ETOMIDATE
 Carboxylated imidazole compound
 Physiologic pH lipid soluble
 35% propylene glycol (pain on injection)
 R isomer > S isomer
 Metabolized to carboxylic acid
 85% excreted in urine, 15% in bile
 elimination ½ life varies from 1 – 5 hours

65. Effects & uses:-
 Standard induction dose is 0.3mg/kg
 Recovery is rapid due to redistribution to muscle and fat.
 Involuntary movements which may be mistaken for generalized seizure
 Small reduction in the cardiac output and blood pressure
 Post operative nausea and vomiting is common

66. Adreno-cortical suppression
 inhibits 11-B-hydroxylase
 Blocks conversion of cholesterol to cortisol
 Single induction dose blocks the normal stress-induced cortisol production for
4-8 hours
 Up to 24 hours in elderly and debilitated patients.
 Continuous infusion of etomidate for sedation in critically ill patients has been
shown to increase mortality
 use of etomidate has declined in recent years due to a perceived potential
morbidity.

67. KETAMINE
 Derivative of phencyclidine
 Racemic mixture of the 2 stereo-isomers
 R- and S+ ketamine
 S ketamine has recently become available due to its
more desirable pharmacological properties
 Prepared in a slightly acidic solution (pH 3.5–5.5)
containing 10, 50 or 100mg of Ketamine per ml.

68. Mechanism of action
 Non-competitive antagonism at NMDA receptor in brain and spinal cord.
Other receptors :-
 Opioid ( antagonist at mu, agonist at kappa)
 Monoaminergic (antinociceptive function)
 Muscarinic (emergence delirium, bronchodilation, sympathomimetic actions)
 Na + channels & L-type Ca2+ channels (mild LA property)

70. pharmacokinetics
 Rapid onset, short duration
 High lipid soluble
 Peak conc. Within 1 min (iv) & 5min (IM)
 Low protein bound
 High hepatic clearance ( 1 Lit/min)
 Large Vd( 3 Lit/kg)
 Elimination ½ life 2-3 hrs

71. Effects & uses:-
Analgesia (0.2-0.5 mg/kg iv)
 Somatic pain > visceral
 Thalamic & limbic system activity
 Inhibition of spinal nociceptive pathway
Postop sedation & analgesia (1-2 mg/kg/hr)
Synergistic effect with epidural opioid & LA

72. Induction
 1-2 mg/kg IV or 4-8 mg/kg IM (unconsciousness in 1-2min)
 Duration of action of a single dose is approximately 5-10 min
 Combination of propofol & ketamine is more hemodynamically stable
than with fentanyl
 Combination of diazepam & ketamine can be used in CAD pt
 Safe for malignant hyperthermia
 Avoided in pulmonary htn

73. Cont..
 Subanesthetic doses prevent & reverse morphine induced tolerance
 Improve post op depression
 Single case report shown improvement in restless leg syndrome after oral ketamine(Kapur
& Friedman ,2002)

74. Effect on CNS
 Traditionally thought to increase CBF, CMR O2, ICP
 Increase CBF by 60 % in normocapnia
 In settings of hyperventilation & avoiding hypercapnia ketamine was found to
have some beneficial effect on brain
 This action is because action on NMDA receptors
 Several clinical studies have been done
 Abolish a activity, domination of theta activity in EEG

75. Clinical trials (neuro protective effect of
ketamine)
 Ant. Frontanelle pressure reduced in ventilated preterm neonates in NICU a/f
giving 2 mg/kg of ketamine (Friesen et al 1987)
 Pt undergoing cerebral aneurysm resection or craniotomy ,1mg/kg of
ketamine did not increase MCA blood flow velocity & reduce ICP modestly
(Mayberg 1995)

76. Systemic effects :-
Increase hemodynamic
 Systemic BP
 Pulmonary AP
 CO
 Cardiac work
 Myocardial O2 requirement
Vasoconstriction maintains SBP at cost of tissue perfusion
Increase sympathetic outflow
Decrease need of inotropes in sepsis (decrease catecholamine uptake)

77. Other organs:-
 Upper airway tone maintained
 Bronchodilator (effective as halothane & enflurane)
 Increase bronchial secretion
 Inhibits platelet aggregation

78. Preconditioning
 Activate K+ ATP channels
 Mimics ischemic preconditioning
 Decrease infract size
 Improve stunned myocardium ( ischemic reperfused viable)
 R isomer blocks this preconditioning
 Opioids & volatile elicit early & late preconditioning

79. Emergence delirium(Psychedelic effect)
Emergence associated with
 Visual & auditory hallucination
 Confusional illusion
 Transient cortical blindness
 Morbid dreams ,vivid colours
 Can occur upto 24 hrs in some pt.
Mechanism – depression of inferior colliculus , MGN & kappa receptors

80. Incidence & RF :-
 5 – 30 %
 Age > 15 yrs
 Females
 Dose > 2mg/kg
 H/o mental illness
Midazolam & proper counselling

81. References:-
1. Intravenous drugs used for the induction of anaesthesia ;Dr Tom Lupton, Dr
Oliver Pratt, Salford Royal Hospitals NHS Foundation Trust, Salford, UK.
2. Pharmacology & Physiology in Anaesthetic practice 4th ed, Robert K
stoelting, Simon C Hiller
Thank you