Clinical Pharmacology of
Inhaled Anesthetics
Dr. Greg Bryson
Dept of Anesthesiology
The Ottawa Hospital
2012.09.27
Objectives I
•
•
•
•
•
•
•
Chemical structure
Structure - function relationships
Physiochemical properties
Definition of MAC
Factors which affect MAC
Mechanism of action
Uptake and Distribution
Objectives II
• Fa/Fi curves, and factors which affect them
• Physiological effects of inhalation anesthetics:
– Cardiovascular system
– Respiratory system
– Central nervous system
– Neuromuscular junction
– Others
• Metabolism/toxicity of inhalation anesthetics
The reality
•
•
•
•
•
•
You use these drugs every day
If you don’t know them – no one else does
None of this stuff is “new”
All of it is in the textbooks
Some of it is useful – some is “on the exam”
I can’t cover all of it in 3 hours
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
Take my daughter to cross country practice
Reference material
• Miller 7th Edition
– Chapter 20. Inhaled Anesthetics. Mechanisms
of Action.
– Chapter 21. Inhaled Anesthetics. Uptake and
Distribution.
– Chapter 22. Pulmonary Pharmacology.
– Chapter 23. Cardiovascular Pharmacology.
– Chapter 24. Inhaled Anesthetics. Metabolism
and Toxicity.
Chemical structure I
Xe
Nitrous Oxide
Xenon
Halothane
Diethyl Ether
Fun with chemistry
•
•
•
•
Alkanes precipitate arrythmias
Halogenation reduces flammability
Fluorination reduces solubility
Trifluorcarbon groups add stability
Chemical structure II
F
Cl
H
F
Enflurane
Isoflurane
Desflurane
Sevoflurane
Physical characteristics
• Please cram the contents of table 15.1 from
Barash 5th 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
(uptake and distribution)
Vapor pressure and vaporizer
Fig 25-17. Miller 7th Ed
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.
• The larger the number, the more soluble it is
in the first substance
Key Physical Properties
Drug
Nitrous Oxide
Xenon
MAC
105
71
Oil:Gas PC Blood:Gas PC
1.4
1.9
0.47
0.14
Desflurane
6.0
19
0.45
Sevoflurane
1.71
53
0.65
Enflurane
*1.68
*97
1.4
Isoflurane
1.15
90
1.8
Halothane
*0.74
*224
2.5
Tables 21.1 and 24.1. Miller 7th Ed
* Old textbooks on my shelf
Mechanism of Action
Meyer-Overton
Protein-interference
Fig 20-2 Miller 7th Ed
Mechanism of action II
• Protein Receptor Hypothesis
– ligand-gated ion channels (GABA, glycine,
NMDA-glutamate)
– voltage-gated ion channels (Na, K, Ca)
– G-proteins (guanine nucleotide)
– Protein kinase C
• Site of action
– Brain v spinal cord (amnesia v immobility)
– Axonal v synaptic
– Pre v post synaptic
Minimum alveolar concentration
• Alveolar concentration required to prevent
movement in 50% of subjects
• standard stimulus
• represents brain concentration
• consistent within and between species
• Additive
• Variants
– BAR (1.7 – 2.0 MAC)
– Awake (0.3 -0.5 MAC)
Factors decreasing MAC
•
•
•
•
•
•
•
•
Increasing age (6% per decade)
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 15.5. Barash 5th Edition
Factors increasing MAC
•
•
•
•
Hyperthermia
Chronic ETOH abuse
Hypernatremia
Increased CNS transmitters
– MAOI
– Amphetamine
– Cocaine
– Ephedrine
– L-DOPA
Table 15.4. Barash 5th Edition.
Factors with no
influence on MAC
•
•
•
•
•
•
•
•
•
Duration of anesthesia
Sex
Alkalosis
PCO2
Hypertension
Anemia
Potassium
Magnseium
And others
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
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).
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
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
FA/FI Curves
Agent
Blood:Gas PC
Nitrous Oxide
0.47
Desflurane
0.45
Sevoflurane
0.65
Isoflurane
1.8
Methoxyflurane
12
Factors influencing delivery
• Alveolar ventilation
• Breathing system
– volume
– fresh gas flow
• Inspired partial pressure (PI)
– concentration effect
– second gas effect
Minute ventilation and uptake
Figure 21-5. Miller 7th Ed
Cardiac Output and Uptake
Fig 21-7. Miller 7th Ed
Concentration and 2nd gas effects
54%
Fig 21.3 Miller 7th Ed
Concentration and 2nd Gas Effects
Fig 21.4. Miller 7th Ed
V/Q distribution and uptake
• Ventilation < perfusion (shunt)
– 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 (dead space)
– uptake is decreased which enhances rise in FA
– may speed induction for soluble agents
– less difference with low solubility agents (fast
anyway)
Endobronchial intubation
Figs 21 – 11 and 12. Miller 7th Ed.
Break
Objectives II
• Physiological effects of inhalation anesthetics:
– Cardiovascular system
– Respiratory system
– Central nervous system
– Neuromuscular junction
– Others
• Metabolism/toxicity of inhalation anesthetics
Effects on organ systems
•
•
•
•
•
•
•
•
Cardiovascular (Ch 23)
Pulmonary (Ch 22)
CNS (Ch 13)
Neuromuscular
Hepatic (Ch 66)
Renal (Ch 45)
Uterine (ch 69)
Miscellaneous
Inhaled anesthetics - CV system
• Effect is hard to quantify
• In vitro and in vivo effects often quite different
– Sympathetic stimulation
– Baroreceptor reflexes
– Animal model vs human subject
• Information provided in this lecture is a broad
overview.
• Chapter 23, Miller 7th Ed for details
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.
• Ca++ hemostasis in sarcoplasmic reticulum
• As best as we can tell, at 1 MAC anesthetics
depress contractility in the following order
– H = E > I = D = S.
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
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
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
Systemic vascular resistance
•
•
•
•
All are direct vasodilators, except N2O
relax vascular smooth muscle
cAMP - Ca++and/or nitric oxide involved
variable effects on individual vascular beds
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
– Sevo + Des similar to isoflurane
• Lidocaine doubles ED50 of epinephrine
• Children somewhat more resistant
Chapter 2. Stoelting P&P. 2nd Ed
Chapter 5. Barash 5th ED
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
Myocardial protection
• Ischemic preconditioning
• Volatiles appear able to replicate the effect
• Activation of mitochondrial KATP channels
– maintain Ca++ hemostasis
– prevent mitochondrial Ca++ overload
• Inhibition of adenosine 1 (A1) receptors and
guanine inhibitory (Gi) proteins abolish protection
• Free radical scavenging (ROS)
Respiratory system
• Volatile anesthetics affect all aspects of RS
• With exception of bronchodilation, none good.
• For all the gory details (Chapter 22. Miller 7th
Ed)
Bronchial musculature
• Reduce vagal tone
• Direct relaxation
– decreased intracellular Ca++
– decreased sensitivity to Ca++
• When bronchospastic, a dose dependent
reduction in Raw occurs with most agents
• Exception is Xenon
– Increased viscosity causes increased Raw
Mucociliary function + surfactant
• Volatile anesthetics decrease ciliary beat
• Decreased mucus clearance
• Decreased production of phosphatidylcholine
– PC used to make surfactant
– occurs in as little as 4 hours
– reversible in 2 hours
Pulmonary blood flow
• Intrinsic vasodilators
• Hypoxic pulmonary vasoconstriction
• Intrinsic changes in HPV confounded by
– changes in cardiac output
– pulmonary artery pressure
– position
• Shunt and PO2 appear unchanged in studies of
inhaled anesthetics during one lung ventilation
Control of ventilation
• All decrease tidal volume
• Most increase frequency
• Net effect is:
– decrease minute ventilation
– increased PaCO2 (E>D=I>S=H)
• Xenon appears to do the opposite
• Decreased sensitivity and response to
– Hypoxia
– Hypercarbia
– Inspiratory and expiratory loads
Lung volumes
• Decreased FRC
– decreased intercostal muscle activity
– phasic expiratory muscle activity
• Cephalad displacement of dependent
diaphragm
• Dependent atelectasis
Enclosed Air Spaces
Agent
Nitrous Oxide
Nitrogen
Blood:Gas PC
0.47
0.014
• 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
Fig 21-13 Miller 7th Ed.
Central nervous system
• Increase cerebral blood flow (halo worst)
• Increase ICP – related to increase in CBF
• Decreased CMRO2 – uncoupled
.
• Decreased frequency - increased voltage on EEG
• 2 MAC enflurane increases seizure activity
• Decreased amplitude - increased latency on SSEP
Neuromuscular function
• Skeletal muscle relaxation
• Potentiate NDMR
• Trigger MH
Hepatic
• Volatile anesthetics increase hepatic arterial
blood flow – decrease portal blood flow
• Halothane is the exception – decreases arterial
flow.
• Clearance of drugs decreased in keeping with
alteration in hepatic blood flow
Renal
• Dose-dependent decreases in
– renal blood flow
– glomerular filtration rate
– urine output
• Related to changes in CO and BP not ADH
Obstetrical
• N2O has no effect
• Halogenated volatiles lead to dose-dependent
– uterine relaxation
– reductions in uterine blood flow
.
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
Three determinants of metabolism
• Chemical structure
– ether bond
– carbon-halogen bond
• Hepatic enzyme activity
– Cytochrome P450 (CP2E1
– Inducible
• Blood concentration
Metabolism of inhaled anesthetics II
Agent
Halothane
Sevoflurane
Enflurane
Isoflurane
Desflurane
Nitrous Oxide
Xenon
% Metabolized
20
2-5
2.4
0.2
0.02
0.004
0.000
Table 15-1. Barash 5th Edition.
Hepatic toxicity
• Hepatotoxicity comes in 2 forms
• mild, transient, postoperative increase in LFTs
– ? due to transient hypoxia ± reductive
metabolites
• massive hepatic necrosis
– oxidative metabolite (TFA) binds to hepatocyte
– repeat exposure leads to immune-mediated
necrosis
• Largely a disorder of halothane (metabolism)
• Some evidence for other volatiles and HCFCs
Fluoride nephrotxicity
•
•
•
•
Oxidative metabolism releases inorganic fluoride
Toxic at serum concentrations 50 mol/l
F- opposes ADH leading to polyuria
Duration and intensity of exposure important
– methoxyflurane 2.5 MAC-hours (renal
metabolism)
– enflurane 9.6 MAC-hours
– sevoflurane ?
Sevofluane and compound A
•
•
•
•
•
Reaction with alkaline, hot, C02 absorbents
FGF related to heating of absorbent
Baralyme > soda lime
25 – 50 ppm yields ATN in rats
Rats have 20 – 30 times more -lyase
– thionoacyl fluoride metabolite is toxic
• Human studies have not demonstrated ATN
Carbon monoxide
• Interaction with dry, basic CO2 absorbent
• Monday morning syndrome
• All volatiles generate CO
– desflurane>enflurane>isoflurane>>>sevo+hal
othane
– Baralyme (20% BaOH) > soda lime (CaOH, NaOH)
– We use ???
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
Conclusion
• Damn, there is a lot to
cover here.
• Some overlap with other
core lectures
• PLEASE summarize as
you read
• When in doubt…blame Gproteins and cytosolic Ca