1. Clinical Pharmacology of Inhaled Anesthetics
Department of Anesthesiology
University of Ottawa
Core Program Lecture Series
September 2003

2. A note for those at the lecture
Those I was able to keep awake might notice that I’ve added/modified a couple of the slides to better reflect the information in the latest versions of your text books.
Much the material on CV and RS effects can be annoyingly inconsistent between texts and editions
For those who asked about “protection” and volatile anesthesia I’ve appended a couple of recent articles “for your interest”
“FYI” means that I won’t examine you on this stuff but the Royal College might!
This stuff is relatively new and part of a broader area of research in ischemic preconditioning – you know, rat stuff
Thanks for attending!

3. Objectives I Chemical structure Structure - function relationships
Physiochemical properties
Mechanism of action
Pharmacokinetics of Inhaled Agents
Uptake and Distribution
Fa/Fi curves, and factors which affect them
Metabolism of Inhalation Anesthetics

4. Objectives II Definition of MAC Factors which affect MAC
Cardiovascular effects
Pulmonary effects
CNS effects
Neuromuscular effects
Hepatic effects
Renal effects
Uterine effects
Marrow effects

5. The reality There’s an awful lot of stuff here - none of it is “new”
All of it is in the textbooks
Barash 4th Edition
Chapter 15. Inhalation Anesthesia
Miller 5th Edition
Chapter 3. Mechanisms of Action
Chapter 4. Uptake and Distribution
Chapter 5a. Cardiovascular Pharmacology
Chapter 5b. Pulmonary Pharmacology
Chapter 6. Metabolism and Toxicity
Much of it requires rote memorization
Some of it useful - all of it “test-able”
I can’t cover all of it in 3 hours

6. Greg’s goals for this lecture
Inflict my view of what you should know
Put this in a clinical (read: useful) context
Explain that which needs explaining
Leave the memory work to you
Be back on my porch, beer in hand, by 1730

7. Chemical structure I
Nitrous Oxide
Halothane
Diethyl Ether

8. Fun with chemistry Halogenation reduces flammability
Fluorination reduces solubility
Trifluorcarbon groups add stability
Alkanes precipitate arrythmias

9. Chemical structure II
Isoflurane
Sevoflurane
Desflurane

10. Physical characteristics
Please cram the contents of the appropriate table 15.1 from Barash 4th Ed the night before the exam. Take home points include:
desflurane boils at 24 OC
halothane is preserved with thymol
vapor pressures are needed for some exam questions
knowledge of blood:gas partition coefficients may actually be useful

11. Partition coefficients
Represent the relative affinity of a gas for 2 different substances (solubility)
Measured at equilibrium so partial pressures are equal, but...
The amounts of gas dissolved in each substance (concentration) aren’t equal.
We most commonly refer to blood:gas pc
The larger the number, the more soluble in blood

12. Blood:gas partition coefficients
Table Barash 4th Edition. p378.

13. The blood:gas pc is useful, really.
Anesthesia is related to the partial pressure of the gas in the brain.
If a drug is dissolved in blood, it isn’t available as a gas
More molecules of a soluble gas are required to saturate liquid phase before increasing partial pressure
Speed of onset/offset closely related to solubility
The lower the blood:gas pc - the faster the onset

14. Uptake and distribution
Anesthesia depends upon brain partial pressure
Alveolar partial pressure (PA) = Pbrain
The faster PA approaches the desired level the faster the patient is anesthetized
PA is a balance between delivery of drug to the alveolus and uptake of that drug into the blood
Time for an analogy

15. a b
To induce anesthesia the bucket (PA) must be full. Unfortunately the bucket has a leak (uptake). To fill the bucket you must either (a) pour it in faster (increase delivery) or (b) slow down the leak (decrease uptake).

16. Factors influencing delivery
Alveolar ventilation
Breathing system
volume
fresh gas flow
Inspired partial pressure (PI)
concentration effect
second gas effect

17. Concentration and 2nd gas effects

18. Factors influencing uptake
Solubility (blood:gas pc)
Cardiac output
Alveolar-venous pressure gradient
For those of you who like formulae:
Uptake =  • Q • (PA-Pv)/BP

19. FA/FI Curves

20. V/Q distribution and uptake
Ventilation < perfusion
blood leaving shunt dilutes PA from normal lung
induction with low solubility agent will be delayed
little difference with soluble agents (slow anyway)
Ventilation > perfusion
uptake is decreased which enhances rise in FA
may speed induction for soluble agents
less difference with low solubility agents (fast anyway)

21. Nitrous Oxide N20 leaves blood 34x more than N2 absorbed
Sure, other agents are more soluble but we don’t give them at 70% end-tidal concentration
distension of closed air spaces
70% N2O will double a pneumo in 10 minutes

22. Mechanism of Action Meyer-Overton Theory Protein Receptor Hypothesis
lipid soluble agent spreads membranes distorting membrane proteins (ie ion channels).
Protein Receptor Hypothesis
inhaled agent binds to membrane protein and changes ion conductance
Neurotransmitter Availability
inhaled agent prevents breakdown of GABA
Greg’s Postulate
if more than one theory - then no one really knows

23. Metabolism of inhaled anesthetics
Fairly small component of elimination
Occurs at cytochrome p450
Inducible
Oxidative
o-dealkylation
dehalogenation
epoxidation
Reductive
occurs only with halothane in hypoxic conditions

24. Three determinants of metabolism
Chemical structure
ether bond
carbon-halogen bond
Hepatic enzyme activity
Blood concentration

25. Metabolism of inhaled anesthetics II
Table Barash 4th Edition. p378.

26. Break

27. Minimum alveolar concentration
Alveolar concentration required to prevent movement in 50% of subjects
standard stimulus
represents brain concentration
consistent within and between species
additive

28. MAC Values
Table Barash 4th Edition. p378.

29. Factors increasing MAC
Hyperthermia
Chronic ETOH abuse
Hypernatremia
Increased CNS transmitters
MAOI
Amphetamine
Cocaine
Ephedrine
L-DOPA
Table Barash 4th Edition. P389

30. Factors decreasing MAC
Increasing age
Hypothermia
Hyponatremia
Hypotension (MAP<50mmHg)
Pregnancy
Hypoxemia (<38 mmHg)
O2 content (<4.3 ml O2/dl)
Metabolic acidosis
Narcotics
Ketamine
Benzodiazepines
2 agonists
LiCO3
Local anesthetics
ETOH (acute)
And many more...
Table Barash 4th Edition. P390

31. Factors with no influence on MAC
Duration of anesthesia
Sex
Alkalosis
PCO2
Hypertension
Anemia
Potassium
Magnseium
And others

32. Effects on organ systems
Cardiovascular
Pulmonary
CNS
Neuromuscular
Hepatic
Renal
Uterine
Miscellaneous

33. Inhaled anesthetics and the CV system
Effect can be hard to quantify
In vitro and in vivo effects can be quite different
Sympathetic stimulation
Baroreceptor reflexes
Animal model vs human subject
Information provided in this lecture is a broad overview.
Please refer to Miller for a detailed discussion of the topic

34. Blood pressure All decrease BP, except N2O
Effect caused by a combination of
Vasodilation
Myocardial depression’
Decreased CNS tone
Relative contribution of each is drug dependent

35. Heart rate Effects variable and agent-specific halothane decreases HR
Sevoflurane and enflurane neutral
Desflurane associated with transient tachycardia
occurs with rapid increases in MAC
associated with increases in serum catecholamines
similar effect may be seen with isoflurane

36. Myocardial contractility
All volatile anesthetics are direct myocardial depressants in vitro, including N2O.
Effect on circulation in vivo modified by effects on pulmonary circulation and sympathetic stimulation.
As best as we can tell, at 1 MAC anesthetics depress contractility in the following order
H = E > I = D = S.

37. Cardiac output
Despite myocardial depression cardiac output is well-maintained with isoflurane and desflurane
preservation of heart rate
greater reduction in SVR
preservation of baroreceptor reflexes

38. Systemic vascular resistance
All are direct vasodilators, except N2O
relax vascular smooth muscle
cAMP - Ca2+and or nitric oxide involved
variable effects on individual vascular beds

39. Dysrhytmias Halothane potentiates catecholamine-related dysrhythmias
ED50 of epinehrine producing dysrhythmias at 1.25 MAC
halothane 2.1 g•kg-1
isoflurane 6.9 g•kg-1
enflurane 10.9 g•kg-1
Lidocaine doubles ED50 of epinephrine
Children somewhat more resistant

40. Coronary blood flow Isoflurane is a potent coronary vasodilator
In theory, dilation of normal coronary vessels can direct blood flow away from stenotic coronaries
Steal-prone anatomy
total occlusion of 1 major coronary vessel
collateral perfusion with 90% stenosis
In practice, doesn’t seem to be a problem

41. Respiratory pattern Increased frequency Decreased tidal volume
Decreased minute ventilation
Attributed (in cats) to sensitization of pulmonary stretch receptors - not supported in humans

42. Mechanoreceptors
Sense tension in muscles/tendons in intercostal muscles
Increased resistance detected and increased respiratory effort recruited
Responses to inspiratory and expiratory loads diminished
Further inhibition in patients with COPD

43. Chemoreceptors Apneic threshold raised Response to PCO2 blunted
PCO2 increased while spontaneously ventilating
E>D=I>S=H
hypoxic drive abolished by 0.1 MAC

44. Bronchial musculature
Reduce vagal tone
Direct relaxation
increased cAMP (but not via adrenoreceptor mediated)
When bronchospastic, a dose dependent reduction in Raw occurs with most agents

45. Hypoxic pulmonary vasoconstriction
Inhaled anesthetics appear to blunt HPV and increase shunt
Shunt and PO2 appear unchanged in studies of inhaled anesthetics during one lung ventilation
Intrinsic changes in HPV confounded by
changes in cardiac output
pulmonary artery pressure
position

46. Central nervous system
Increase cerebral blood flow
Increase ICP
Decreased CMRO2
Decreased frequency - increased voltage on EEG
2 MAC enflurane increases seizure activity
Decreased amplitude - increased latency on SSEP

47. Neuromuscular function
Skeletal muscle relaxation
Potentiate NDMR
Trigger MH

48. Hepatic Hepatic arterial blood flow decreased by halothane
Clearance of drugs decreased in keeping with reductions in hepatic blood flow
Hepatotoxicity
mild, transient, postoperative increase in LFTs
? due to transient hypoxia ± reductive metabolites
massive hepatic necrosis
oxidative metabolite binds to hepatocyte
repeat exposure leads to immune-mediated necrosis

49. Renal Dose-dependent decreases in
renal blood flow
glomerular filtration rate
urine output
Related to changes in CO and BP not ADH
Fluoride nephrotoxicity at serum conc. 50 mol/l
F- opposes ADH leading to polyuria
methoxyflurane 2.5 MAC-hours
enflurane 9.6 MAC-hours

50. Obstetrical N2O has no effect
Halogenated volatiles lead to dose-dependent
uterine relaxation
reductions in uterine blood flow

51. Miscellaneous N2O-related myelosupression if >12 hr exposure
inhibition of methionine-synthetase
megaloblastic anemia
Inhaled anesthetics, N2O in particular, decrease leukocyte function
Teratogenesis with prolonged exposure in rats
Increased risk (RR = 1.3) of spontaneous abortion with chronic exposure to N20