1. IV Induction Agents
Jed Wolpaw MD, M.Ed

2. History
1656 Percival Christopher Wren and Daniel Johann Major tried injecting wine and beer into a dog’s vein.
Early 1900s Hedonal, ether, chloroform into veins—syncope, cyanosis, pulmonary edema
Bier tried novacaine in veins—Bier block
1936 Thiopental
Jarman 1946 &Miller’s Anesthesia 8th edition

3. Propofol Propofol a) Mechanism of Action
b) Pharmacokinetics and Pharmacodynamics
c) Metabolism and Excretion
d) Effect on Circulation
e) Effect on Respiration
f) Effect on Other Organs
g) Side Effects and Toxicity
h) Indications and Contraindications

4. Propofol History Introduced in 1970s, now most widely used IV hypnotic
Developed in UK, initially 1977 caused anaphylaxis
Relaunched as emulsion in soybean oil in 1986

5. Mechanism of Action Alkylphenol derivative
Enhances GABA-induced chloride currents through binding to B subunit of GABA-A receptor.
At lower concentrations has indirect effect-potentiates activation by GABA
At higher concentrations activates GABA-A directly
Also inhibits NMDA glutamate receptors
Increases dopamine in nucleus accumbens (sense of well-being)
Decreases serotonin in area postrema (anti-emetic)

6. Pharmacokinetics
Oxidized and conjugated in liver and then excreted by kidneys
There is some extra-hepatic clearance likely in kidneys and lungs
Competitive inhibitor of CYP3A4, increases duration of action of midazolam
After single bolus dose levels decrease rapidly due to redistribution and elimination with initial distribution half-life 2-8min
Context sensitive half-time 10 minutes for infusions up to 3 hours and 40 minutes for 3-8hours.
Starts to reduce EEG activity in 20 seconds, peak effect in 90 seconds
Because of decreased cardiac output and therefore decreased hepatic blood flow, can impair its own clearance

7. Pharmacokinetics Greater reduction in cardiac output in older patients
80 y/o needs 50% the dose of a 20 y/o to get same effect
Even though it is cleared hepatically no dose reduction needed in hepatic disease due to efficient clearance and extra-hepatic clearance
Increases plasma levels of midazolam and remifentanil

8. Context sensitive half-time

9. Pharmacodynamics
Onset of hypnosis after dose of 2.5mg/kg is 20 seconds with peak effect 90 seconds
ED50 for loss of consciousness is 1-1.5mg/kg
Duration of action is dose dependent, after 2mg/kg lasts 5-8 min
Highest dose needed in less than 2 y/o
Can suppress seizures but can also cause them
Decreases ICP by 30-50% and decreases CPP, decreases intraocular pressure by 30-40%
Cerebral autoregulation relatively intact

10. Effects on respiration
Induction dose produces apnea for 30 seconds or longer with other medications
Maintenance infusion decrease tidal volume by 40% and increases RR by 20% even up to 200mcg/kg/min
May have some bronchodilatory properties

11. Effects on cardiovascular system
Decreased BP by 25-40% due to decreased CO and SVR
HR can go up or down by about 10%-inhibits baroreceptor reflex tachycardia that would normally results from hypotension
Hemodynamic effect lags behind hypnotic effect (twice as long)
Can suppress atrial tachycardias-avoid in EP studies
Reduces myocardial blood flow and O2 consumption preserving supply to demand ratio
May have some cardioprotective effects at higher doses and in combination with inhaled anesthetics

12. Use Induction Maintenance Sedation Anti-emetic
1-2.5mg/kg based on lean body mass, adjusted for age, reduced with premed
Maintenance
50-150mcg/kg/min based on total body weight, adjusted to individual (older and sicker patients require much less)
Sedation
25-75mcg/kg/min
Anti-emetic
10-20mg IV intermittently or infusion of 10mcg/kg/min
Infusions>30mcg/kg/min usually cause amnesia

13. Advantages
Does not prolong neuromuscular blockade but large doses may provide good intubating conditions without paralysis
Not an MH trigger
No adrenal suppression
Pleasant dreams
Anti-emetic even at low doses (10mcg/kg/min)
When used as maintenance in breast surgery was more effective than 4mg Zofran at preventing PONV
Also relieves pruritis from opiates and from cholestasis

14. Adverse effects
Anaphylactoid reactions, especially in people with multiple allergies
Pancreatitis-likely from hypertriglyceridemia-older, longer duration, higher dose
Pain on injection-rare thrombophlebitis of vein
Propofol infusion syndrome
Usually doses >70mcg/kg/min for >48h
Acute bradycardia leading to asystole with metabolic acidisos, rhabdo, hyperlipidemia, fatty liver, hyperkalemia
Likely a genetic disorder involving fatty acid metabolism is involved

15. Barbiturates a) Mechanism of Action
b) Pharmacokinetics and Pharmacodynamics
c) Metabolism and Excretion
d) Effect on Circulation
e) Effect on Respiration
f) Effect on Other Organs
g) Side Effects and Toxicity
h) Indications and Contraindications

16. Uses
Thiopental: Induction, cerebral protection (e.g. status epilepticus)
Methohexital: Induction, especially for ECT
Phenobarbital: Seizure suppression

17. Mechanism of Action
Bind to GABA-A receptor and enhance GABA effect (low doses) and directly stimulate (high doses) causing increased chloride current and hyperpolarization
Reduces CMRO2, ICP and CBF but preserves CPP due to greater drop in ICP than MAP

18. Pharmacokinetics
All hepatically metabolized then excreted in urine except phenobarbital (60-90% renal unchanged)
Rapid redistribution terminates action of single dose
Much longer context sensitive half-time than propofol

19. Pharmacodynamics
Single dose lasts 5-10 minutes, redistributes to lean tissues
Wake up is faster after methohexital than thiopental due to greater hepatic uptake
Longer recovery of barbiturates in general led to replacement by propofol

20. Respiratory and CV Effects
Dose dependent depression, apnea after induction dose
Peripheral vasodilation and negative inotropy
Increased HR 10-36% from baroreceptor reflex, can be harmful in cardiac disease
Can prolong QT interval
In hypovolemia can reduce CO by 70%

21. Adverse effects Garlic or onion tastes Allergic reactions
Local tissue irritation or rarely necrosis
Induction of P450 system
Bronchoconstriction in asthmatics

22. Dosing Thiopental 3-4mg/kg with onset in 10-30 seconds
Methohexital 1-1.5mg/kg with similar onset

23. Benzodiazepines Midazolam (short acting)
Lorazepam and Temazepam (intermediate)
Diazepam (long acting)
Flumazenil (antidote, shorter half life than most of the benzos)

24. Mechanism of Action Bind to GABA-A receptor, enhance response to GABA
Leading to hypnotic, sedative, anxiolytic, amnestic, anticonvulsant, muscle- relaxation properties
Increase seizure threshold
Maintain normal CBF to CMRO2

25. Pharmacokinetics Midazolam Lorazepam Remimazolam
Rapid onset <1min, peak 2-3 min
Distribution half life 6-15 min
Hepatically metabolized by CYP system including active metabolite 1- hydroxymidazolam
Not an issue with normal renal function but in renal impairment can build up
Lorazepam
Conjugated in liver (not by CYP) to inactive compounds so renal impairment doesn’t prolong action but liver failure can
Infusion can cause propylene glycol toxicity
Remimazolam
New, cleared by non-specific tissue esterases

26. Effects on respiratory system
Reduce muscular tone in upper airway leading to risk for obstruction
Reduce response to increased CO2
Reduce hypoxic response
Synergistic effect with opioids
Midazolam PO has little effect on respiration

27. Cardiovascular effects
Small decrease in SVR leading to small drop in BP
Preserved baroreceptor reflexes
CO maintained
In patients with increased filling pressures can act like nitroglycerin and decrease filling pressures and increase CO

28. Uses and doses Premedication: anxiolysis, amnesia, reduced PONV
Midazolam mg PO or 0.5-2mg IV
Lorazepam 2-4mg PO or mg IV
ICU sedation
Avoid if possible due to delirium, prolonged action
Induction of anesthesia
Midazolam 0.3mg/kg adjusted for age
Reduction of PONV
IV doses as low as 1mg after induction

29. Adverse effects
Lorazepam and Diazepam can cause venous irritation and thrombophlebitis
All can have extended effects
Post-operative delirium
Give appearance of sleep without restorative sleep

30. Flumazenil Competitive antagonist
Short half-life, may get rebound effect of agonist, can use infusion (30- 60mcg/min)
Rapid onset, 1-3 min, lasts 3-30 min
Can cause seizures in patients on chronic benzos

31. Flumazenil

32. KETAMINE
Synthesized in 1962, first used in humans in 1965, released for clinical use 1970
Phencyclidine-bines to NMDA Receptor
Racemic mixture of S and R ketamine. S isomer is more potent and has fewer psychomimetic effects
Only 20% bioavailability after oral use 2/2 first pass metabolism

33. Mechanism of action
Acts at NMDA receptors, opioid receptors and monoaminergic receptors
Most important is inhibition of NMDA glutamine input to GABA system centrally as well as in spinal cord where it also inhibits ACh release
Produced “dissociative anesthesia” because patients may not appear asleep (eyes open, reflexes intact)

34. Pharmacokinetics
Metabolized in liver to norketamine and hydroxynorketamine
Norketamine has some activity but less than ketamine
Metabolites excreted in urine
Bioavailability orally is 20-30%, intranasally is 40-50%

35. Ketamine action

36. Pharmacodynamics
Onset in seconds, peak in 1 minute, duration about 8-10min for anesthetic properties, min for full orientation
Pupils dilate, nystagmus
Lacrimation and salivation
Increased muscle tone, purposeless movements
Prolonged by benzos

37. Advantages for post-op analgesia
Sub-anesthetic doses can produce analgesia
Inhibits central hypersensitization
Attenuates acute tolerance to opioids and opioid induced hyperalgesia

38. Effects on CNS Increases CMRO2, CBF and ICP
Preserves responsiveness to CO2
Emergence reactions 10-30% after pure or partial ketamine anesthetic
Vivid dreams, extracorporeal experiences, hallucinations
Last 1 to several hours
Can be reduced by benzo co-administration

39. Effect on Respiratory system
Transient decrease in minute ventilation after bolus (2mg/kg) but rarely apnea
Bronchial smooth muscle relaxant-improves compliance in asthma
Can also directly treat status asthmaticus
Increased salivation, can be modulated by atropine or glycopyrrolate

40. Cardiovascular effects
Usually causes increased BP, HR and CO
Direct cardiodepressant effect
Indirect stimulant effect by activation of sympathetic nervous system causing release of catechols, inhibition of vagus, inhibition of NE reuptake
Can cause pulmonary hypertension
If presynaptic catechol stores are depleted, cardiac depression will dominate
Propofol and benzos blunt hemodynamic effects such as tachycardia
Bolus is more likely to cause than infusion

41. Uses Induction Pain management Sedation
In hemodynamically unstable patients or bronchoconstriction
Good in tamponade
Pain management
Part of multimodal regimen, reduces opiate use
Chronic pain
Management of acute procedures like fracture reduction
Sedation
Great in pediatrics, fewer emergence reactions

42. Doses Induction: 0.5-2mg/kg IV or 4-6mg/kg IM
Maintenance 30-90mcg/kg/min
Sedation mg/kg of 2-3min or 2-4 mg/kg IM

43. Adverse effects Increased ICP and IOP
Increased myocardial O2 consumption
Repeated abuse can cause liver and renal toxicity
Preservative, chlorobutanol, is neurotoxic, can’t be given neuraxially, but S- ketamine comes in preservative free formulation

44. ETOMIDATE First clinical use in 1972 Widespread use in 1970s
Began to taper off in 1980s with reports of adrenal suppression

45. Mechanism of Action
GABA-A facilitation (lower dose of GABA required to activate receptor)
At higher doses can activate receptor independently

46. Pharmacokinetics
Cleared by Liver by ester hydrolysis then excreted by kidneys and in bile, metabolites not active
Initial offset is due to redistribution so liver disease doesn’t alter it
Initial dose (0.3mg/kg) lasts 6-8 min
Clearance not altered by hypovolemia
Short context sensitive half-time (less than propofol) but limited by adrenal suppression

47. Effects on CNS
Reduces CBF by 34% and CMRO2 by 45% with no change in MAP
CPP maintained or increased with improved cerebral O2 supply: demand
Acutely decreases ICP by 50% if elevated (back to normal) but transient effect

48. Respiratory effects
Induction dosing (0.3mg/kg) produces brief hyperventilation then brief apnea
Ventilatory response to CO2 depressed

49. Cardiovascular effects
Very hemodynamically stable even in hemorrhagic shock model
Can see hypertension, tachycardia but less than ketamine
Maintains myocardial O2 supply to demand ratio
Has no analgesic effect so needs to be given with opiate to prevent HTN response to intubation

50. Endocrine effects
Dose dependent inhibition of 11B-hydroxylase, decreased cortisol and mineralocorticoids
Occurs at lower doses than hypnosis by more than 20x so suppression lasts much longer, up to 72h
Can be used to treat hypercortisolemia

51. Endocrine suppression

52. Uses and Doses Induction (0.2-0.6mg/kg)
Less if given with premed
Good in trauma with potential hemorrhage or unstable hemodynamics
Can produce longer seizures in ECT
No longer used for prolonged sedation

53. Adverse effects High rate of nausea and vomiting Pain on injection
Myoclonus (up to 70%), reduced by versed or magnesium prior
Hiccups

54. Dexmedetomidine
Alpha-2 receptor agonist, 1600:1 compared to 220:1 alpha-2 to alpha-2 compared to clonidine
Used for sedation, anxiolysis, withdrawal, delirium
S-enantiomer of medetomidine-used in veterinary medicine

55. Pharmacokinetics
Almost complete biotransformation in liver with P450 system involvement
Clearance is impaired in liver failure but not renal impairment due to inactive metabolites
Severe renal disease sedative effect may be stronger due to decreased protein binding
Context sensitive half time 4 minute after 10 min infusion and 250 minutes after 8 hour infusion
So tapering probably not needed

56. Effects on CNS
Sedative hypnotic effect through action on alpha-2 receptors in brain and spinal cord
Independent of GABA system
More natural sleep patterns than other drugs
May have reduced rates of delirium
Suppresses pain transmission in spinal cord
Reduces post-op narcotic requirements by 50% when on infusion
Reduces MAC
Can enhance neuraxial blockade like clonidine epidurally
Reduces CBF but unclear effect on CMRO2, autoregulation preserved
Overall effect on supply:demand unknown
Doesn’t reduce evoked potentials or seizure activity so can use in neuromonitoring or seizure mapping

57. Effects on Cardiovascular system
Bradycardia (30% reduction), Reduced CO up to 35%
Can see initial increase in BP with bolus loading dose from blocking peripheral alpha receptors

58. Uses and doses ICU sedation: 0.2-1.5 mcg/kg/hour
Premed: mcg/kg slowly to prevent bradycardia
Good as adjunct for awake crani
Opioid sparing effects good for bariatric patients
Awake fiberoptic intubation: sedation without respiratory depression and some dry mouth make it ideal
Has been used to treat withdrawal and delirium, unclear data
Weaning from vent in ICU

59. Adverse effects
Bradycardia, hypotension, prolonged duration