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Transcript
Lecture 21: Pharmacology of General Anesthetics
Timothy Beer (Modified by Dave Reilly 2013)
GENERAL ANESTHETICS
1) General anesthesia = behavioral syndrome
a. Amnesia, hypnosis, immobility, arousals blockade
2) Theories (NO single molecular mechanism—still a PHARMACOLOGIC ENIGMA)
a. Lipid solubility = physical property that correlates best w/ anesthetic potency
i. Primary site of action = LIPID BILAYER of cell membrane
b. Protein theory = interact directly w/ proteins
i. Luciferase inhibition correlates w/ anesthetic potency
c. Sites of action
i. Spinal cord = mediates immobility
ii. Cortex = mediates cognition, memory, sleep, learning
1. Reticular activation system, hippocampus, amygdala, thalamus
iii. Neuronal level (axons or synapses)
1. Excitatory and/or inhibitory
iv. Molecular level = ion channels (ligand gated, voltage gated, leak)
v. Cellular level = disrupts the transmission of neuronal impulse in the CNS (blocking synaptic
transmission)
3) Classification = according to receptor action
a. IV induction drugs (most potent)
i. Barbiturates, propofol, benzodiazepenes
ii. MOA = GABA-A receptors
b. Volatile anesthetics (less potent)
i. Ethers, substituted hydrocarbons
ii. Targets = GABA-A, glycine, NMDA, K+ channels
c. Xenon, nitrous oxide, ketamine
i. Minimal effect on GABA-A receptor but marked blockade of NMDA action
4) Sensitivity to volatile agents vary
a. Genetic predisposition, ethnicity
5) Surgery procedure and general anesthesia
a. Induction  maintenance  emergence
Inhalation agents
a. Advantages
i. Provides all needs (anesthesia, analgesia, immobility)
ii. Low cost as a single drug
iii. Administration and elimination via lungs
1. Always accessible because respiration and gas exchange is vital to life
2. Reliable means to control delivery or removal (breath by breath)
b. MINIMAL ALVEOLAR CONCENTRATION (MAC) = measure of POTENCY
iv. Define = MAC of an anesthetic that prevents movements in 50% of the subjects in response to
a standard surgical stimulus
v. Halothane = 0.75%; desflurane = 6.0%
vi. MAC ↓ w/ age, ↓ w/ narcotics, ↓ w/ ↓ temperature
1)
2)
3)
4)
c. Administration = always w/ O2
vii. Often used in combo w/ other drugs (barbiturates, narcotics, muscle relaxants)
viii. Requires special equipment to deliver accurate dose
d. Factors affecting the uptake of an inhaled agent
ix. ↑ concentration = ↑ uptake
x. ↑ alveolar ventilation = ↑ uptake
xi. ↑ solubility = ↓ uptake
1. Solubility = relative affinity (relative [anesthetic]) for two phases
a. [blood] 2x that in gas = affinity for blood is 2x the affinity in the gas phase
2. Halothane = 2.4; desflurane = 0.45
3. Lower solubility = more rapid induction (sleep) and more rapid emergence (recovery)
xii. ↑CO = ↓ uptake
e. Respiratory effects (of all halogenated hydrocarbons)
xiii. ↓ bronchial smooth muscle tone
xiv. ↓ PVR
xv. Depress mucocilliary fxn
xvi. ↓ tidal volume and ↑ respiratory frequency
xvii. Depress respiratory response to CO2
xviii. Block respiratory drive due to hypoxemia  can cause respiratory arrest.
f. Cardiovascular effects
xix. All depress myocardial contractility
xx. Effects on BP and CO vary based on effects on HR and SVR
g. Malignant Hyperthermia
xxi. Rare but often fatal complication of halogenated anesthetics
xxii. Autosomal recessive mutation in Ryanidine Receptor 1 (RyR1)  uncontrolled release of
calcium into the sarcoplasmic reticulum  uncoupled cycling of ATP ultimately results in:
1. Tachycardia, Hyperthermia, hypercarbia, rigidity, metabolic acidosis and death.
xxiii. Treatment: Dantrolene and ice.
Obsolete drugs
a. Ether (flammable), chloroform (hepatic toxicity), ethyl chloride (arrhythmia), cyclopropane
(explosive), fluroxene (flammable), methoxyfiurane (renal toxicity)
Halothane = first fluorinated anesthetic to gain popularity
a. Highly potent, non-flammable, low pungency
b. SE = myocardial and hepatotoxicity (not used as much anymore)
Drugs used today = —flurane (especially sevo-, des-, iso-)
a. Halogenated, non-flammable, and safe
Nitrous Oxide
a. N2O MAC = 105% (cannot be used as a general anesthetic by itself)
i. Used in combo w/ IV narcotics, anesthetics, and muscle relaxants
b. Desirable properties
i. NOT metabolized, respiratory elimination, and does not trigger MH
ii. LOW solubility
iii. NO resp irritation w/ MINIMAL CV and NMJ effects
c. Undesirable properties
i. LOW potency, HIGH MAC, MILD analgesia
ii. Inactivation of methionine synthetase (cannot be given to CA pts)
d. SE = cerebral vasodilation (↑ ICP midly)
i. Avoid in pneumothorax (fills up physiologic spaces  expands cavities)
5) Isoflurane
a. MAC = 1.28% w/ minimal metabolism
b. ↑ free fluoride levels (NO significance) and NO renal dysfxn
c. Minimal effects on ICP = used for neurosurgical cases
d. Potentiates muscle relaxation
e. SE = EEG suppression (at high concentrations), trigger MH (rare), ↑ HR, ↓ BP, ↓ SVR (significant)
i. BUT little effect on CO
6) Sevolurane = most commonly used agent
a. Low solubility (rapid onset offset agent) and non pungent (ideal for inhalation)
b. MAC = 1.7
c. Drug interactions
i. 5% is metabolized by CYP450 2E1 and can degrade to compound A in CO2 absorbers
d. SE = can induce MH (rare)
e. Respiratory depressant, does NOT change ICP, ↑ GFR and hepatic blood flow
f. Highly metabolized = may lead to high fluoride levels in renal impaired pts
i. NOT for pts w/ kidney dysfxn
g. Little effect on HR but ↓ BP (via ↓ SVR); does NOT sensitize to catecholamines
7) Desflurane
a. LEAST blood:gas solubility coefficient = most rapid induction and emergence.
b. Minimal biotransformation w/ MAC = 6.0
c. BUT! Pungency = airway irritation and even bronchospasm (NOT for children)
d. SE = ↑ HR, ↓ BP, and small ↓ in CO, sympathetic burst (unique)
i. Sympathetic burst = ↑ HR and BP due to rapid ↑ in [Desflurane]
Intravenous agents
a. All CNS depressants can act as general anesthetics in high doses
b. Clinically used = ketamine, propofol, etomidate
c. Ketamine = IV, IM, PO
ii. Metabolism = oxidation and demethylation
iii. MOA = muscarinic receptor antagonist and opiate receptor agonist
1. Blocks NMDA receptors in dorsal horn (associated w/ pain “windup”)
iv. Produces “dissociation anesthesia” = pain-free and unconscious but show nystagmus and
random movements
v. ↑ ICP and produces emergence rxns and hallucinations
vi. CV effects = direct myocardial depressant and ↑ BP and HR
vii. Respiratory effects = normal response to CO2 and bronchial SM relaxant
d. Propofol = most commonly used IV anesthetic
viii. Widely used as an induction agent (provides complete anesthetic)
ix. Faster and “cleaner” recovery than barbiturates and ketamines
1. Also anti-emetic properties (very important)
x. Depresses BP and respiration
e. Etomidate (non barbiturate hypnotic)
xi. Minimal CV effects (good in severe trauma case) – good to maintain CV stability
xii. Causes reversible adrenocortical suppression after a single dose