pharmacology of therapeutic gases and inhalational anesthetics

Pharmacology of Therapeutic Gases and

Inhalational Anesthetics

www.freelivedoctor.com

OUTLINE

•Therapeutic gases

•Introduction and historical perspective

•Mechanisms of action

•Potency and pharmacokinetics


OBJECTIVES

• To understand the indications for and uses of common therapeutic gases.

• To be familiar with the mechanisms of action (or major theories) of general anesthetics.

• To grasp the role of solubility and pharmacokinetics in inhaled anesthetic action.


THERAPEUTIC GASES: Oxygen

•Hypoxia can result from:–Ineffective uptake–Inadequate delivery to tissues–Impaired utilization

•Administered to prevent hypoxic injury

•Can have toxic effects


O2 Delivery Devices100% O2 Flow Rate

(L/min) Estimated FiO2

Nasal Cannulae1 0.242 0.283 0.324 0.365 0.406 0.44

Simple Facemask5–6 0.406–7 0.507–8 0.60

Mask w/ Reservoir Bag

6 0.607 0.708 0.809 ≥0.8010 ≥0.80www.freelivedoctor.com

Hemoglobin O2 Saturation Curve


THERAPEUTIC GASES: Nitric Oxide

Important cell signaling molecule, activates sGC

Can preferentially dilate pulmonary vasculature

Administered to newborns with persistent pulmonary hypertension

Under investigation for numerous disease states

Can have toxic effects due to NO2 or MetHb


THERAPEUTIC GASES: Helium

•Pulmonary Function Testing

•Imaging studies

•Laser surgery on airway


THERAPEUTIC GASES: CO•CO is produced endogenously by Heme Oxygenase

The pathway of heme metabolism

•Therapeutic and toxic properties mediated by binding to metalloproteinswww.freelivedoctor.com

THERAPEUTIC GASES: COPotential signaling pathways activated by CO leading to tissue protection

Ryter, S. W. et al. Physiol. Rev. 86: 583-650 2006


What Is General Anesthesia?

Generalized reversible depression of the central nervous system such that perception of all senses is ablated

Reversible condition of comfort, quiescence, and physiological stability in a patient before, during, and after performance of a procedure that otherwise would be painful, frightening, or hazardous


Desirable Components of Anesthesia

1. Immobility in response to noxious stimulus2. Amnesia3. Analgesia4. Unconsciousness5. Muscle relaxation6. Loss of autonomic reflexes7. Anxiolysis


Effects of General Anesthesia

Low Dose Effects

•Amnesia

•Euphoria

•Analgesia

•Hypnosis

•Excitation

•Hyperreflexia

High Dose Effects

•Deep sedation

•Muscle relaxation

•Diminished motor responses

•Diminished autonomic responses

•Myocardial protection from ischemia

•Cardiovascular/respiratory depression

•Hypothermia


Before Anesthetics

•Surgery uncommon•Surgical pain relief

• alcohol, opium• physical methods (ice, ischemia)• unconsciousness (blow to head, strangulation)• simple restraint most common


HISTORY OF ANESTHESIA•1540 Paracelsus, a Swiss physician and alchemist, sweetens the feed of fowl with “sweet oil of vitriol” (diethyl ether) “and besides, it has associated with it such sweetness that it is taken even by chickens and they fall asleep from it for a while but awaken later without harm.”

•1790 Humphry Davy uses nitrous oxide to relieve his headache and tooth pain

•1824 Henry Hill Hickman uses carbon dioxide to partially asphyxiate to the point of insensibility several animal species. Delivers an address to the Royal Society: “Letter on suspended animation – with the view to ascertaining its probable utility in surgical operations on human subjects”

•1830s Crawford Long and others engage in ether frolics. Insensibility to pain is noted

•1844 Nitrous oxide is used by Horace Wells for tooth extraction

•1846 TG Morton: First public demonstration of ether administration for excision of neck mass

•1850s Chloroform begins to be used in England for surgery and childbirth


“Gentlemen, this is no humbug.”


HISTORY OF ANESTHESIA•1929 Waters introduces cyclopropane into clinical practice at Wisconsin – explosive!

•1951 Halothane synthesized to be nonflammable, but causes cardiac dysrhythmias

•1973 Enflurane – convulsant at high concentrations

•1981 Isoflurane – little toxicity, oldest volatile agent in common use today

•1990 Sevoflurane introduced into clinical practice

•1993 Desflurane introduced


1.Rapid and pleasant induction2.Rapid changes in the depth of anesthesia3.Adequate muscle relaxation4.Wide margin of safety5.Absence of toxic/adverse effects

CHARACTERISTICS OF ANIDEAL ANESTHETIC

No single agent yet identified is an ideal anesthetic


Intravenous agentsprimarily used for induction

•Barbiturates •Benzodiazepines•Etomidate•Ketamine•Propofol

CLASSIFICATION OF GENERAL ANESTHETICS


INTRAVENOUS ANESTHETICS

• Rapid onset (seconds)

• Rapid awakening (minutes)

• Redistribution determines duration of action


Inhalational agentsprimarily used for maintenance

•Volatile agentsIsofluraneSevofluraneDesfluraneHalothane, Enflurane

•Anesthetic gasesNitrous Oxide - currently usedXenon - in the future?

CLASSIFICATION OF GENERAL ANESTHETICS


• MAC: minimum alveolar concentration • MAC is the concentration of anesthetic that produces

immobility in 50% of patients exposed to a noxious stimulus.

• MACawake: MAC at which response to commands are lost

• amnesia, loss of awareness

• MACBAR: blunt autonomic response• MACintubation: response to intubation

Measures of Anesthetic Potency


MAC values are useful

•Allows comparison of anesthetics

•Important clinical endpoints

•Consistent and reproducible


Therapeutic Index

•Margin of safety very small

•TI: 2-4dose that produces circulatory failure may be 2-4X that for anesthetic dose

•Some of the most dangerous drugs in common clinical use


General anesthesia can be caused by a remarkable number of structurally diverse molecules

Unitary Hypothesis


Meyer-Overton Correlation

1903: Meyer and Overton note very strong correlation between solubility in olive oil and anesthetic potency


Meyer-Overton rule

The correlation of anesthetic potency with lipid

solubility provides a means of predicting anesthetic

potency. This correlation has traditionally been

interpreted as meaning that primary anesthetic

action sites are lipid portions of nerve membranes.

Molecular Actions of General Anesthetics


Nonspecific Theory

Unitary hypothesis + Myer-Overton Rule =

Anesthetics act nonspecifically on hydrophobic lipid components of cells


General anesthetic potencies in animals can be

correlated well with their ability to inhibit the

activity of certain soluble enzymes, such as

firefly luciferase. The finding shook the

foundation of lipid theory, and opened a new

chapter for protein theory.

Proteins: molecular targets of general anesthetics Franks & Lieb 1984

Nature. 310:599-601www.freelivedoctor.com

Protein Theory

of General Anesthesia


Molecular Sites of Action•Ligand-gated ion channels

•GABAA receptorActivity is enhanced by intravenous and volatile agents

•Glycine receptorActivity is enhanced by volatile agents

•NMDA receptorBlocked by nitrous oxide, xenon, cyclopropane, volatile agents

•nACh receptorBlocked by volatile agents

•Voltage-gated ion channels•Calcium channels – synaptic function impaired by volatile agents•Sodium channels – impaired function

•Background channels•Tandem pore-domain potassium channels

Activated by volatile agents


Xe

Isoflurane

Halothane

......Cellular (synapses)

Molecular(lipids &

receptors)

Molecular Mechanism(s) of General Anesthesia


A Working Hypothesis

• Anesthetics enhance inhibitory postsynaptic channel activity (GABAA and glycine receptors)

• Anesthetics inhibit excitatory synaptic channel activity (nicotinic acetylcholine and glutamate receptors)


MACROSCOPIC SITES OF ACTION

• Anesthetic induced ablation of movement in response to pain is mediated primarily by spinal cord.– Cervical transection or decerebration does not alter MAC– Selective administration to cord causes immobility

• Anesthetic induced amnesia is mediated by higher brain structures (e.g., hippocampus)

• Anesthetic induced sedation mediated by tuberomammillary nucleus of hypothalamus


Inhaled Anesthetics - Pharmacokinetics

•Partial pressure vs. Concentration

Partial pressure in a mixture of gases is

the portion of the total pressure supplied

by gas

•Amount of gas in blood or tissue is

dependent on the solubility of the gas in

that solvent.

•Solvent/gas partition coefficient


Properties of Inhaled Anesthetics

Lesspotent

Morepotent

ANESTHETIC MAC(atm) (oil/gas) (oil/gas) x MAC

Nitrous oxide

1.01 1.4 1.4

Desflurane 0.06 19 1.1

Sevoflurane 0.02 51 1.0

Ether 0.019 65 1.2

Enflurane 0.0168 98 1.6

Isoflurane 0.0114 98 1.1

Halothane 0.0077 224 1.7


Induction Speed

•Determined by rate that alveolar partial pressure

equilibrates with inspired partial pressure

•Solubility (less soluble, faster)

•Ventilation rate (increased rate, faster)

•Cardiac output (decreased output, faster)

•Inspired concentration (higher concentration, faster)


Induction Speed


Anesthetic Uptake and Distribution

•Vessel Rich Group (VRG)

•CNS and visceral organs

•High blood flow (75%) and low capacity

•Muscle Group (MG)

•Skin and muscle

•Moderate flow and high capacity

•Fat Group (FG)

•Low flow and high capacity

•Vessel Poor Group

•Bone, cartilage, ligaments

•Low flow and low capacity


Anesthetic of the Future: Xenon

•Rare gas extracted from air

•Very expensive to produce

•Close to ideal anesthetic

•Low blood and tissue solubility

(rapid induction/recovery)

•Potent

•Not metabolized

•Nonflammable

•Minimal side effects


pharmacology of therapeutic gases and inhalational anesthetics

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