Introduction Into CRNA School Pharmacology: Inhaled Anesthetics

 

 

Anesthesia Gases

Currently Used

• Sevoflurane (Ultane)
• Desflurane (Suprane)
• Isoflurane (Forane)
• Nitrous Oxide

 

No Longer in Use

• Halothane (Fluothane)
• Methoxyflurane (Penthrane)

CRNA School Prep Course

History of Inhaled Anesthetic Gases

• Either – Valerious Cordus (1540) synthesized and wrote the formula for the purified form of ether by using ethyl alcohol (CH₃CH₂OH) and sulfuric acid (H₂SO₄). Diethyl ether was the first publicly demonstrated inhalational anesthetic of the modern era. William Morton (1846) gave a presentation at a Massachusetts Hospital, where he introduced a vaporizer that could convert diethyl ether (CH₃CH₂OCH₃CH₃) into a gaseous form. The presentation was successful, and by the end of the year there were ether anesthetics being given all over London.

• Nitrous Oxide – Joseph priestly (1773) was a chemist who purified Nitrous Oxide N₂O by burning ammonium (NH₄+) in the presence of iron (Fe) molecules. Samuel Colt (1835) traveled the country selling hits of nitrous oxide for 25 cents a piece. He used this money to pay for a government patent. His invention was the Colt revolver, which he sold to the U.S. government.

• Chloroform –  Jean Baptiste Andre Dumas (1834) purified Chloroform (CHCl₃), however it was Sir James Simpson (1847), who really advocated for its use. He was looking for an anesthetic that did not have the problems that ether had such as slow onset and nausea.

 

 

Qualities of Inhaled Anesthetics

Why Use A Gas

• Very fast onset

• Easily titrated

• High potency

• Little to no metabolism

• Easily measured

 

How do They Work

• The Reticular Activating System (RAS): located in the brainstem is responsible for wakefulness and sleep-wake transition. Inhaled anesthetics alter ion motion across the lipid bilayer causing hyperpolarization of post and pre-synaptic neurons. This inhibits synaptic transmission resulting in inhibition of the Reticular Activating System (RAS).

• Direct agonist of gamma-aminobutyric acid (GABA) receptors.

• N-Methyl-D-aspartate (NMDA) receptor antagonist.

• Potentiate glycine receptors.

• Nicotinic acetylcholine receptors (nACH) receptors are inhibited.

• H-HT₃ (serotonin) receptors are inhibited.

 

How Are They Measured

• Minimum alveolar concentration (MAC): lowest concentration of anesthetic that prevents movement in 50% of patients in response to surgical stimulus. Each gas has its own unique MAC value. (Sevoflurane: 2%, Desflurane: 6%, Isoflurane 1.5%)

• MACawake (0.3 x MAC): alveolar concentration of anesthetic at which a patient will open their eyes to commands.

• MACbar (1.5 x MAC): alveolar concentration of anesthetic that blunts adrenergic responses to noxious stimuli.

 

Factors That Increase MAC

• Hyperthermia

• Increased CNS Transmitters: (stress, pain, monoamine oxidase inhibitors (MAOIs).

• Certain antibiotics: (cyclosporins)

• Acute amphetamine use

• Frequent alcohol consumption

 

Factors That Decrease MAC

• Hypothermia

• Hypoxia

• Elderly

• Decreased CNS transmitters

• Pregnancy: MAC decreased by 30%

• Anemia: (< 4.3 ml O2/dl blood)

• Hyponatremia: decreases the cell’s resting membrane potential. Certain medications: (opioids, benzodiazepines, alpha-2 agonists, calcium channel blockers, and hydralazine)

 CRNA School: Induction Agents

 

 

Physiologic Effects of Inhaled Anesthetics

Cardiovascular

• Mean arterial pressure (MAP): decreased due  to a decreased systemic vascular resistance (SVR)

• Cardiac output (CO): minimal decrease

• Circulating catecholamines: decreases in circulating norepinephrine and epinephrine.

• Central venous pressure (CVP): increased except for sevoflurane.

• Heart rate: desflurane & isoflurane cause increase in heart rate.

• Baroreceptors: slight depression.

 

Respiratory

• Pulmonary vascular resistance (PVR): not altered

• Minute ventilation (MV): net decrease

• Tidal volume (VT): decreased

• Respiratory rate: increased

• Ventilatory response to carbon dioxide (CO₂): the PaCO₂ at which the body’s normal drive to breathe is completely blocked. Every patient’s apneic threshold is different based on a number of physiologic factors. Each patient’s apneic threshold is 4-5 mmHg PaCO₂ below a their normal resting end tidal carbon dioxide level (ETCO₂)

• Ventilatory response to arterial hypoxemia: decreased

• Airway resistance: decreased

• Bronchoconstriction: this results from parasympathetic nervous system (PNS) stimulation by increased cyclic guanosine monophosphate (cGMP).

• Functional Residual Capacity (FRC): this is the volume of air present in the lungs at the end of passive expiration. Volatile anesthetics decrease FRC due to relaxation of intercostal muscle tone, and change in diaphragm position.

• Mucociliary movement: the patients ability to expel mucus is impaired. This is important to CRNAs, because it can cause an impaired airway.

 

Central Nervous System

• Brain waves: decreased amplitude & frequency

• Amnesia: occurs at 0.4 MAC

• Prolonged impaired cognitive function: none

• Cerebral Metabolic Oxygen Requirements (CMRO₂): decreased

• Cerebral vascular resistance: decreased

• Cerebral Blood Flow (CBF): increased

• Cerebral Spinal Fluid (CSF): increased

• Somatosensory evoked potentials (SSEPs): increased latency & amplitude

• Visual evoked potentials (VEPs): increased latency & amplitude

• Motor evoked potentials (MEPs): increased latency & amplitude

 

Hepatic

• Halothane hepatitis: Antitrifluoroacetylated (TFA) protein antibodies get formed the first time a person is administered halothane. The second time they receive halothane the body would react to it would producing an immune response resulting in halothane hepatitis. This is only an issue seen with Halothane.

• Hepatotoxic: methoxyflurane

• Formation of “Compound A” (sevoflurane)

 

Renal

• Renal blood flow (RBF): reduced as a result of the drop in mean arterial pressure (MAP).

• Nephrotoxic: Enthrane

 

Skeletal Muscle

• Relax skeletal muscle: this augments neuromuscular blockers such as (rocuronium), which are commonly used by Certified Registered Nurse Anesthetist (CRNAs).

• Skeletal muscle blood flow: increased synergistic effects with neuromuscular paralytics.

• Neuromuscular monitoring: decreased train of four (TOF) and sustained tetanus monitoring with the nerve stimulator.

 

Other Effects

• “Coronary Steal Syndrome”: volatile anesthetics relax blood vessels diverting blood away from ischemic areas in the heart, and redistributing it to non-ischemic tissue. Isoflurane (coronary artery vasodilator) was originally held off the market due to this “Coronary Steal Syndrome”. Clinically, this is only a issue if a patient is already cardiac compromised, which can exacerbate this effect. As long as the CRNA keeps the mean arterial pressure (MAP), and adequate oxygenation is maintained “Coronary Steal Syndrome” will be prevented.

• “Inhaled Anesthetic Preconditioning” (APC): volatile anesthetics reduce vascular re-perfusion damage during or following a myocardial infarction. This reduces myocardial infarct size, ST segment depression, and the incidence of dysrhythmias during a ischemic cardiac event.

• Malignant Hyperthermia (MH): a potentially fatal condition that can be caused by all volatile anesthetics and succinylcholine (Anectine), which is a depolarizing neuromuscular blocker. The result is an accelerated metabolism of skeletal muscle caused buy elevated calcium levels leading to uncoordinated contraction of all skeletal muscles. This only occurs in a small percentage of the population. The Certified Registered Nurse Anesthetist (CRNA) could expect to see increased end tidal carbon dioxide (ETCO₂), elevated temperatures, masseter muscle rigidity, rapid heart rate, and metabolic acidosis. Immediate treatment with the drug Dantrolene (2.5 mg/kg) intravenously by the CRNA will usually reverses the signs of MH.

 

 

 

Isoflurane (1981)

Chemistry

• IUPAC: (RS)-2-chloro-2-(difluoromethoxy)-1,1,1-trifluoro-ethane

• Halogenated methyl ethyl ether Isomer of enflurane

• Vapor Pressure: 240 mmHg

• Blood:Gas Coefficient: 1.46

 

Minimal Alveolar Concentration (MAC)

• MAC: 1.5%

 

Qualities

• Still in use today.

• Intermediate solubility in blood.

• High potency

• Doesn’t break down in soda lime.

• Clear and nonflammable liquid at room temperature.

• Physically stable: no detectable deterioration during 5 years of storage or on exposure to soda lime or sunlight.

 

Metabolism

• Defluorination occurs in liver.

• Resistant to kidney metabolism.

• Unlikely to cause organ toxicity.

 

Contraindications

• Patients with a history of malignant hyperthermia.

 

Airway Effects

• Pungent odor (very irritating to airways).

 

Cardiovascular Effects

• Accused of dilating coronary arteries. “Coronary Steal Syndrome” Potential neurodegeneration in infants. Increased risk when combined with nitrous oxide (N₂0) and benzodiazepines such as (Versed).

 

Vaporizer

• Conventional



 

Desflurane (1982)

Chemistry

• IUPAC: 2-(difluoromethoxy)-1,1,1,2-tetrafluoro-ethane.

• Slightly different from isoflurane: has fluorine atom on α-ethyl component of isoflurane.

• Vapor Pressure: 669 mmHg

• Blood:Gas Coefficient: 0.42

 

Minimal Alveolar Concentration (MAC)

• MAC: 6%

 

Qualities

• Poorly soluble resulting in a rapid onset and offset.

• Carbon monoxide production in soda lime.

• High cost: however due to its very fast onset/offset it is actually believed to be more cost effective by increasing surgical turnover times.

 

Metabolism

• Defluorination occurs in liver.

• Unlikely to cause organ toxicity.

 

Contraindications

• Patients with a history of malignant hyperthermia.

 

Airway Effects

• Very pungent: administration of greater than 1 MAC can cause airway irritation, increased salivation, breath-holding, coughing, and laryngospasms.

 

Cardiovascular Effects

• Sympathetic nervous system (SNS) stimulation with high concentrations.

 

Vaporizer

• Due to its very high vapor pressure, desflurane requires a special Dual Gas blender in order for it to be administered safely.



 

 

Sevoflurane (1994)

 

Chemistry

• IUPAC: 1,1,1,3,3,3-Hexafluoro-2-(fluoromethoxy)propane

• Halogenated methyl ethyl ether

• Isomer of enflurane

• Vapor Pressure: 157 mmHg

• Blood:Gas Coefficient: 0.65

 

Minimal Alveolar Concentration (MAC)

• MAC: 2%

 

Qualities

• Commonly used

• Great safety record

• Onset/Offset: very fast (2nd only to desflurane)

• Low blood:Gas solubility

• High potency

• Physically stable

 

Metabolism

• Defluorination occurs in liver The anesthesia machine uses strong bases in the carbon dioxide (CO₂) absorbents, which interact with sevoflurane to form a substance called “Compound A”. This has been found to be nephrotoxic in rats. However current research shows that this is not an issue with humans.

 

Contraindications

• Patients with a history of malignant hyperthermia.

• No potential to produce hepatotoxicity, unless patient has been previously exposed to halothane and developed the neoantigen antibody (anti- iC₃b).

• Breaks down into inorganic fluoride (F^–) and hexafluoroisopropanol (CF₃)₂CHOH, which may have some renal implications.

 

Airway Effects

• Non-pungent: has the least airway irritation of all inhaled anesthetics.

 

Cardiovascular Effects

• Accused of dilating coronary arteries. “Coronary Steal Syndrome”

 

Vaporizer

• Conventional

 

 

 

Nitrous Oxide (1773)

Chemistry

• IUPAC: Dinitrogen monoxide

• Very soluble Low-molecular weight

• Vapor Pressure: 38,770 mmHg

• Blood:Gas Coefficient: 0.46

 

Minimal Alveolar Concentration (MAC)

• MAC: 105%

 

Qualities

• Odorless

• Low potency

• Increased risk of nausea

• Poor amnestic

• Nonflammable

• Combined with opioids or volatile anesthetics for general anesthesia.

• Prominent analgesic effects, but poor amnestic.

• Minimal to no skeletal muscle relaxation

 

Metabolism

• Potential depression of bone marrow function with > 24 hour exposure. This is only a problem with abuse.

 

Contraindications

• Nitrous oxide (N₂O) leaves the blood to enter an air-filled cavity 34 x faster than nitric oxide (N₂), which can cause increased volume and pressure in of air-filled cavities such as the inner ear. Surgeries where expansion of air-filled cavities must be avoided (tympanic membrane grafting, craniotomies, retinal detachment repair, laparoscopic cases, existing pneumothorax, and surgeries requiring patient be in sitting position.

 

Airway Effects

• Airway irritability: very mild

 

Cardiovascular Effects

• Stimulates the sympathetic nervous system (SNS). This can result in mydriasis, increased body temperature, diaphoresis, increased right atrial pressures vasoconstriction, and increased systemic vascular resistance (SVR)

 

Respiratory Effects

• Inhibition of norepinephrine uptake by the lungs.

• “2nd Gas Effect”: nitrous oxide will increase the alveolar pressure of a concurrently administered inhaled anesthetic such as sevoflurane. This allows for a very fast onset of anesthesia when nitrous oxide is combined with another anesthesia gas.

• “Fink effect” (Diffusion hypoxia): occurs during emergence from anesthesia, when large amounts of nitrous oxide crosses from the blood into the alveolus. This dilutes the existing oxygen (O₂) concentration in the alveoli resulting in hypoxia. This is prevented by certified Registered Nurse Anesthetist and anesthesiologist by administering 100% oxygen (O₂) during emergence.

 

 

 

Halothane (1956)

Chemistry

• IUPAC: 2-bromo-2-chloro-1,1,1-trifluoroethane

• Halothane is an halogenated alkane derivative. Alkanes are arrhythmogenic, and can cause cardiac arrhythmias specially in presence of catecholamines.

• Vapor Pressure: 244 mmHg

• Blood:Gas Coefficient: 2.3

 

Minimal Alveolar Concentration (MAC)

• MAC: 0.74%

 

Qualities

• No longer used

• Clear, nonflammable, and liquid at room temp.

 

Non-pungent

• Stored in amber-colored bottles: when exposed to light the chemical structures breakdown into Hydrochloric acid (HCL), Chloride (Cl^–), Bromide (Br-), and Phosgene (COCl₂).

 

Metabolism

• Halothane hepatitis: Antitrifluoroacetylated (TFA) protein antibodies get formed the first time a person is administered halothane. The second time they receive this agent the body would react to it, producing an immune response resulting in halothane hepatitis.

 

Contraindications

• People who were exposed to halothane in the past may have this neoantigen antibody (anti- iC₃b), which will be activated if they are exposed to isoflurane or sevoflurane. Exposure to these volatile agents can trigger another hepatitis event.

 

Airway Effects

• Very low airway irritability

 

Cardiovascular Effects

• Arrhythmogenic: can cause cardiac arrhythmias, especially in presence of drugs that mimic catecholamines (i.e epinephrine).

 

Vaporizer

• Conventional

 

 

 

Methoxyflurane (1960)

Chemistry

• IUPAC: 2,2-dichloro-1,1-difluoro-1-methoxyethane methyl ethyl ether

• Vapor Pressure: 25mmHg

• Blood:Gas Coefficient: 12

 

Minimal Alveolar Concentration (MAC)

• MAC: 0.2%

 

Qualities

• No longer used

• Very soluble: this was problematic, because it required it to be administered in very high amounts in order to achieve adequate anesthesia.

 

Metabolism

• Hepatic mechanism resulted in increased plasma concentrations of fluoride which were nephrotoxic and hepatotoxic.

• Defluorination occurs in the kidneys

 

Contraindications

• High concentration of fluoride was damaging to the kidneys and liver which made this a poor anesthetic agent. Produced high output renal failure causing it to be pulled from market very quickly.

 

Cardiovascular Effects

• Does not contain the same arrhythmogenic properties as halothane.

• Methoxyflurane will not enhance dysrhythmias in presence of catecholamines such as epinephrine.

 

Vaporizer

• Conventional