This document discusses the pharmacology of several intravenous anesthetics used for general anesthesia induction and maintenance. It provides a brief history of intravenous anesthetics and covers the pharmacokinetic properties and organ system effects of thiopental, benzodiazepines like midazolam, opioids, ketamine, etomidate, and propofol. For each drug, the document discusses mechanisms of action, distribution, metabolism and elimination, and clinical applications.

1. General Anesthetics III:
Pharmacology of Intravenous
Anesthetics
Brooks Gentry, M.D.
Associate Professor
Departments of Anesthesiology, and
Pharmacology and Toxicology

2. History
Mid-seventeenth century
– Wren “stupefied” a dog by injecting
opium
1845 Rynd invented the hollow needle
1930’s Thiopental first used
1990’s At least 10 drugs used for
induction of general anesthesia

3. Learning Objectives
 Compare the contributions of distribution and
metabolism to duration of iv anesthetic effects
 Describe organ system effects for iv anesthetics
– Use this information to make decisions on clinical use
of these drugs
 Compare iv anesthetics based on general
pharmacokinetic properties

4. Drug Disposition
Absorption, distribution, metabolism and
elimination
– Distribution
»Results in termination of effects of most
anesthetics
– Metabolism & elimination
»Play a small role in termination of effects

5. Distribution
With the IV medications,
assume a BOLUS (rapid)
administration!!

6. Distribution
Definition: Initial dispersion of drug into
different body compartments
– from low volume/high flow compartments
to high volume/low flow compartments
Determines early, rapid decline in
anesthetic concentrations
Affected by alterations in physiology
– hemodynamics, disease states, etc.

7. Distribution
Price, 1960
Redistribution
Time (min)
0.1 1.0 10.0 100.0
%
of
Dose
0
20
40
60
80
100
Blood
Fat
Lean
Viscera
Like Figure 25-6, Katzung

8. Metabolism & Elimination
Biotransformation and elimination of
most anesthetics is slow
– Many have long elimination half-lives,
but short effects
– Duration of effects is dose-dependent
» Anesthetic doses result in brief effects
» Redosing used to prolong effects

9. Thiopental

10. Thiopental: “Truth serum”
 Thiopental
– Most frequently used barbiturate
– Ultrashort acting drug, BUT
– Has a long elimination half-life
» Duration of action is dose-related; anesthetic induction
dose lasts 5 minutes
 Knowledge of pharmacology of thiopental is
important
– Most commonly used induction agent
– Redistribution terminates effect

11. Thiopental: History
1934: Recommended for use in wartime
– Compact, easily prepared, nonexplosive
1943 Editorial: Thiopental caused numerous
deaths at Pearl Harbor
– “ideal form of euthanasia”
Case report: successful use in gunshot victim
– Method of administration vs. inherent toxicity
caused poor outcomes

12. Thiopental
Rapid unconsciousness
Good amnesia, poor analgesia
Poor muscle relaxation
Pleasant induction for the patient

13. Thiopental: Mechanism of Action
Binds to GABAA receptor
– Increases chloride ion flux into cell
– Stimulates inhibitory neuronal systems

14. Thiopental: Mechanism of Action
GABA schematic
From Textbook of Intravenous Anesthesia; PF White, Ed

15. Thiopental: Organ System Effects
CNS
– Reduces cerebral metabolism, and
oxygen utilization
– Reduces cerebral blood flow
» Related to oxygen consumption changes
» Reduces blood volume and intracranial
pressure, not cerebral perfusion pressure
– Protects the brain against
hypoxic/ischemic injury

16. Thiopental: Organ System Effects
 Cardiovascular
– Direct effects
» Peripheral vasculature:
 blood pressure, vascular resistance and cardiac output may
decrease transiently in normal patients
 venodilation may result in hypotension in patients in shock
 venodilation occurs due to increased venous capacitance
» Myocardium: direct depressant which lowers myocardial
contractility
– Indirect effects
» Heart rate increased via barostatic reflex

17. Thiopental: Organ System Effects
Patients with high sympathetic tone will
experience large drop in blood pressure
– e.g., hypovolemia and heart failure
– due to redistribution of cardiac output
– Example: shock in a victim of repeatedly
being run over by a ski boat

18. Thiopental: Organ System Effects
Respiratory
– Depress respiration in dose-dependent fashion
» Depress responses to hypoxemia & hypercapnia
– Muscle relaxants required due to retention of
tracheal/laryngeal reflexes
» Hiccups
– Thiopental depresses mucociliary clearance

19. Thiopental: Organ System Effects
Kidney, liver and GI track
– Decreased renal blood flow & glomerular
filtration rate
– No effects on liver and GI track

20. Thiopental: Clinical Uses
General anesthetic induction
Brain protection

21. Benzodiazepines

22. Benzodiazepines
Midazolam and lorazepam
– Best amnestic agents
– Excellent anxiolytics, anti-convulsants,
muscle relaxants

23. Benzodiazepines: Mechanism of Action
Bind to distinct sites on GABAA receptor
Effects are concentration dependent
– 20% receptor occupancy gives anxiolysis
– 30 - 50% occupancy gives sedation
– 60% occupancy gives hypnosis or
unconsciousness

24. Midazolam: Physicochemical Properties
In vial: pH = 3.5
– Allows the imidazole ring to remain open
– Maintains water solubility
In plasma: pKa = 6.2
– On injection , the ring closes and the
basic drug becomes 94% unionized
– Increases lipid solubility, which
decreases time to onset of action

25. Midazolam: Organ System Effects
CNS
– Dose-related effects on cerebral metabolism
and blood flow
– Raises seizure threshold
» Good anticonvulsant
– EEG: b activity
– Antegrade, not retrograde amnesia

26. Midazolam: Organ System Effects
CV
– Hypotensive effect similar to thiopental
– Hypotension exaggerated in hypovolemia
– Synergistic sedative effect exists with
opioids
Respiration
– Hypnotic dose causes apnea
– Amnestic dose gives minimal depression

27. Benzodiazepines: Uses
Premedication before anesthesia
Conscious (or unconscious - heavy)
sedation
Induction of anesthesia

28. Opioids

29. Opioids: Actions
Analgesics with some hypnotic action
– Not reliable for amnesia
– Jim Lehrer
Used for premedication, induction &
maintenance of anesthesia, and
postoperative pain control

30. Opioids: Mechanism of Action
Analgesic action is via m receptors
– G-protein linked receptors
Examples: adrenergic, dopaminergic,
serotonergic, Opioid, cannabinoid

31. Opioids: Effects
Pruritis
– Nose and whole body
– I.V., intrathecal, epidural routes
Chest wall rigidity
– “Fight or flight”
Patients “forget to breathe”

32. Opioids: Agents
Morphine:
– Used in all phases of anesthesia
– IM, IV, intrathecally, epidurally
Meperidine
– Used primarily postoperatively
– IM, IV, intrathecally, epidurally

33. Opioids: Agents
Fentanyl and sufentanil
– Used pre-, intra- and postoperatively
– IV, intrathecally, epidurally
Alfentanil
– Used intraoperatively as IV infusion

34. Opioids: Agents
Remifentanil
– Shortest acting opioid
» Termination of action is due to elimination,
not redistribution
» Metabolism is via non-specific esterases
» Actions stop within 8 min of stopping
infusion, even after prolonged infusions
» Commonly used neuroanesthetic

35. Ketamine

36. Ketamine: Mechanism of Action
Arylcyclohexylamine - like PCP
Non-competitive NMDA antagonist
– only intravenous agent discussed that
works predominately via inhibition of
stimulatory neuronal systems
“Dissociative” anesthetic
– An individual’s cognitive function is
‘separated’ from his physical being

37. Ketamine: Organ System Effects
CNS
– Unpleasant dreams, hallucinations & delirium
» Incidence higher in adults, females, habitual
dreamers, psychological problems
» Benzodiazepines, barbiturates, N2O reduce
incidence of these effects
– Increases intracranial pressure 1 - 60 mmHg
» In patients with intracranial disease

38. Ketamine: Organ System Effects
CV
– Central sympathetic stimulation results in
increased heart rate, blood pressure,
epinephrine and nor-epi levels
» Offers an advantage over thiobarbiturates when
sympathetic stimulation is helpful
– Direct myocardial depressant

39. Ketamine: Organ System Effects
Ventilation
– Small doses given slowly result in minimal
ventilatory depression
» Profound analgesia reduces airway reflexes
– Rapid infusion, or combination with
benzodiazepines potentiates depressant effects
– Sympathetic stimulation results in
bronchodilation via direct smooth muscle
effects

40. Ketamine: Organ System Effects
Salivary and tracheobronchial secretions
are markedly increased
– Reduced with atropine or glycopyrrolate
Nonpurposeful tonic, clonic, and athetoid
movements occur
– Make determination of anesthetic depth
difficult
Nystagmus and phonation occur

41. Etomidate

42. Etomidate: Mechanism of Action
Imidazole derivative
Activates GABAA receptors

43. Etomidate: Organ System Effects
CNS
– Lowers cerebral blood flow and thus
intracranial pressure
– Lowers cerebral metabolic rate for
oxygen (CMRO2)
Respiration
– Minimal ventilatory depressant
– Lower incidence of apnea
» good for short procedures

44. Etomidate: Organ System Effects
Cardiovascular Effects
– Minimal changes in all parameters
– Well suited to use in patients with
cardiovascular risk factors
» Best when hemodynamic stability is a must
Musculoskeletal System
– Myoclonus

45. Propofol

46. Propofol
Originally designed as an organic
solvent – a cleaner
– Not a good cleaner
A pharmaceutical company screened
compounds based on lipid solubility
– The co. bought the rights to the
compound and have sold $ millions

47. Propofol: Mechanism of Action
Diisopropyl phenol
Some action at GABAA complex
– Binds to a distinct site
May enhance Cl- conductance at
glycine receptors

48. Propofol: Organ System Effects
CNS
– Reduces cerebral blood flow and metabolism
– Autoregulation is maintained in animal
studies, along with response to changes in
cardiac output

49. Propofol: Organ System Effects
CV
– Decreased mean blood pressure, vascular
resistance, heart rate, & cardiac output;
central venous pressure unchanged
– CABG patients: no deleterious changes
in myocardial blood flow or metabolism

50. Propofol: Effects
Burns on injection
– Phenol component
Extremely fast-acting
– Conversations resumed in recovery
– Clearance exceeds hepatic blood flow
Euphoric
– Patients feel better the next day
“Milk of amnesia”

51. Pharmacokinetics
Drug
Thiopental Midazolam Ketamine Etomidate Propofol
Volume of
distribution
(L/kg)
2.5 1.7 2 – 5 3.5 3 - 12
Elimination
clearance
(ml/kg/min)
3.4 10 12 – 19 18 30
Elimination
half-life (hr)
8.4 2–4 2.5–3.1 2.9–3.5 0.5-1

52. Pharmacokinetics
Drug
Remifentanil Fentanyl Sufentanil Morphine Meperidine
Volume of
distribution
(L/kg)
0.4 3 3 3 3
Elimination
clearance
(ml/kg/min)
50 15 15 15 15
Elimination
half-life (hr) 0.17–0.33 3.1–6.6 2.2–4.6 1.7–3.3 3-5

53. Summary
Anesthetics have multiple effects
Distribution terminates majority of effects
Disease processes, physiology determine
effect of a given dose

54. General References
 Barash, Cullen and Stoelting. Clinical
Anesthesia
 White Ed. Textbook of Intravenous Anesthesia
 Stoelting. Pharmacology & Physiology in
Anesthesia Practice
 Katzung. Basic & Clinical Pharmacology
 Pratt & Taylor. Principles of Drug Action
 Eger. Anesthetic Uptake and Action