anesthetic agents

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