Clinical Pharmacology of Inhaled Anesthetics

Dr. Greg BrysonDept of AnesthesiologyThe Ottawa Hospital2012.09.27

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

Nitrous Oxide

Diethyl EtherHalothane

Xenon

Xe

Fun with chemistry

• Alkanes precipitate arrythmias • Halogenation reduces flammability• Fluorination reduces solubility• Trifluorcarbon groups add stability

Chemical structure II

Isoflurane

Sevoflurane

Desflurane

F

FH

Cl

Enflurane

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 MAC Oil:Gas PC Blood:Gas PC

Nitrous Oxide 105 1.4 0.47

Xenon 71 1.9 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 2.5Tables 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

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).

a

b

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

Fig 21.3 Miller 7th Ed

54%

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

• 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

Agent Blood:Gas PCNitrous Oxide 0.47Nitrogen 0.014

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

Table 15-1. Barash 5th Edition.

Agent % MetabolizedHalothane 20Sevoflurane 2-5Enflurane 2.4Isoflurane 0.2Desflurane 0.02Nitrous Oxide 0.004Xenon 0.000

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+halothane

– 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 G-proteins and cytosolic Ca