During graduate school I was asked to give this lecture for pharmacy students. Describes aspects of local and general anesthetics including intravenous and inhaled forms of the latter.
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Basic of Anesthetics
1. PHARM 539 Pcol III
12-6-2012
Kellie Jaremko
6th year MDPhD Student in Neuroscience
Kellie.jaremko@jefferson.edu
2. First identified in ~1800s
Cocaine was isolated in 1860 and in 1884
Carl Koller noted its numbing properties
as a topical ophthalmic agent
▪ In 1905 Procaine the first synthetic LOCAL
anesthetic was produced
Nitrous Oxide, diethyl ether, & chloroform
all introduced into medical practice in the
mid 1800s
▪ These allowed for the development of major
surgical opportunities since they were no longer
limited by pain and shock with use of GENERAL
anesthetics
3. Peripheral Nerve Anatomy
Local Anesthetics
• Perineurium is the hardest for LAs to
penetrate
• Clinically higher concentration than in-
vitro would predict gets to site of action
• Blocking synaptic transmission in this
order: small myelinated (Aδ fibers)
unmyelinated fibers (C fibers/
nociceptors) myelinated large axons
(sensory then motor nerves)
4. Prototypical
Local
Anesthetics
Local Anesthetics (LA): Chemical Aspects
Aromatic Group:
Related to hydrophobicity
Increase by adding
alkyl groups
Moderate hydrophobicity is
ideal for a balance between
Permeability through
membrane & binding
to hydrophobic binding
sites
Diffusion from
membrane to binding
site
5. Prototypical
Local
Anesthetics
Local Anesthetics (LA): Chemical Aspects
Tertiary Amine Group:
Makes LAs weak bases
with pKa ~ 8-10
At Physiological PH ~7.4
more protonated but some
still neutral
Neutral: crosses
membrane easier
Protonated: binds site
of action more
strongly dissociates
slower
Benzocaine is atypical with
no basic group
6. Prototypical
Local
Anesthetics
Local Anesthetics (LA): Chemical Aspects
Ester vs. Amide Linking
Group:
Esters rapidly
hydrolyzed by non
specific esterases
in plasma and
tissues; ultimately
excreted by kidney
Amides are more
stable with longer
plasma half lives;
metabolized by
P450 enzymes in
liver then cleared
by kidneys
7. Local Anesthetic Binding to Different Conformations (States) of the Sodium Channel
Local Anesthetics (LA): Mechanism of Action
8. Tonic and Phasic (Use-Dependent) Inhibition
Local Anesthetics (LA): Mechanism of Action
• Phasic block is especially helpful
when local damage causes
spontaneous nociceptor firing and
application of LA inhibits this
more than the tonic block of
unaffected sensory/motor nerves
at that site.
• LAs can also interact with
potassium channels, calcium
channels, uncouple g-proteins and
inhibit substance P, bradykinin and
glutamate receptors
9. Topical Anesthesia
Pain relief for mucous membranes or skin it is applied to
Infiltration Anesthesia
To numb skin or surface via an injection intradermally or subcutaneously
Due to acidic solution there is a sting at injection but combination with
sodium bicarbonate can reduce this pain
Peripheral Nerve Block
Major (brachial plexus) vs. Minor (radial nerve)
Requires much higher dosage than would be needed for application to
unsheathed nerve
Central Nerve Block
Epidural and Spinal (intrathecal)
Intravenous RegionalAnesthesia (Bier’s Block)
Use tourniquet above block to prevent systemic toxicity
Used for hand and arm surgery
10. LA absorbed by local tissues and redistributed to systemic
circulation
To limit this and subsequent toxicity vasoconstrictors (epinephrine or
felypressin) are often applied to
▪ 1) Increase local concentration of LA for prolonged effects
▪ 2) Decrease amount of LA in systemic circulation and toxic effects
▪ NOT given at peripheral extremities where blood flow is limited so as not to risk
hypoxia at injury
▪ Mepivacaine has less vasodilation and prilocane has none, therefore doesn’t
require adjunct
GeneralToxicity Risks:
Local irritation at site of inject with possible damage to muscle cells
from intramuscular injection
CNS effects:
▪ Initial excitation (due to blockade of inhibitory pathways) with possible
convulsions & tremors
▪ depression at higher levels of LA in CNS when all pathways depressed
Cardiac effects:
▪ Low doses= antiarrhythmics via reducing conduction velocity
▪ Dose-dependent decreases in cardiac contractility
11. Only naturally occurring LA
Ester-linked
Medium onset and duration (~1hr plasma half-life)
Indications: for topical ophthalmic application, otolaryngology (ENT)
procedures, or spray for upper respiratory tract anesthesia
Formulations & Dosage:
Flakes, crystals, 135mg tablets, premade topical solutions
Max safe dose is 200mg or 2-3mg/kg
Used in combination asTAC (with tetracaine & adrenaline)
Drug Interactions & Contraindications:
Dihydroergotamine (ergot alkaloid for migraines increased blood
pressure)
Phenelzine, Selegiline, (monoamine oxidase inhibitor
antidepressantsevere hypertensive reactions can occur)
Epinephrine ( with other Las, EpiPen for anaphylactic allergic reaction,
risk of life threatening cardiac arrhythmias)
Cons:
Highly addictive
Inhibits catecholamine uptake in CNS
Large cardiotoxic potential
12. Long acting highly potent due to high
hydrophobicity
Ester-linked
Released slowly from tissues so metabolized slowly
Generally a 1% solution given as an injection
Indications: for spinal and ENT (especially nose
surgeries and topical (cornea) anesthesia
Drug Interactions:
Hyaluronidase (a spreading substance used to improve
uptake of drugs given under the skin shorter duration
LA effects and increased systemic LA side effects)
Sodium Nitrite/Amyl nitrite/ sodium thiosulfate
(treatment for cyanide poisoning but can also cause
methemoglobin formation so together
methemoglobinemia)
13. 0.5% tetracaine + 1:200,000 epinephrine solution+ 11.8% cocaine
A few drops of solution can be applied directly to a wound
(<10cm) prior to suturing a laceration followed by constant
pressure for 10-20mins
Most effective in head, neck, and scalp injuries in pediatric emergency
situations
Benefits include: ease of application, patient comfort during irrigation
and suturing and avoidance of wound distortion present with
injections of local anesthetics/
14. Aka Novocain
1st synthetic LA
Ester-linked
Medium onset
short duration (<1 hr)
Low hydrophobicity:
Low tissue accumulation
Low potency
Indications: dental procedures but more rarely now (1% procaine
hydrochloride solution), subarachnoid (spinal) block (10% procaine
hydrochloride solution)
Drug Interactions:
Sodium Nitrite/Amyl nitrite/ sodium thiosulfate (treatment for cyanide
poisoning but can also cause methemoglobin formation so together
methemoglobinemia)
Hyaluronidase
Prilocaine & lidocaine local anesthetics
PABA is a metabolite
Commonly found in sunscreen
Can be an allergen ~hypersensitivity contact dermatitis
Blocks sulfonamide antibiotic efficacy
15. Rapid onset with medium duration of action (1-2hrs)
Amide-linked
Low pKa so mainly neutral at physiological pH
Indications:Widely used for nerve blocks, at infiltration, spinal, epidural, and topical
anesthesia
Also used intravenously for treating ventricular dysrhythmias
CNS adverse effects include tinnitus, drowsiness, twitching and possibly seizures
Drug Interactions:
Increased Risk of Seizures from combining with:
▪ Bupropion (antidepressant)
▪ Sodium Biphosphate (a bowel cleansing agent for constipation pre-op)
▪ Tramadol (pain reliever)
▪ Ionhexol and Metrizamide (iodinated contrast media)
Cleared by CYP450 enzyme in liver so increased blood levels both drugs and increased cardiac/CNS
toxicity:
▪ Saquinavir, Amprenavir (antiretroviral drugs for HIV)
▪ Conivaptan (used to treat hyponatremia)
Dihydroergotamine
Sodium Nitrite/Amyl nitrite/ sodium thiosulfate
Other antiarrhythmic like Dronedarone and Dofetilide due to additive effect
Arbutamine(an ionotropica cardiac agent with lidocaine may cause ventricular arrhythmias)
Prilocaine is like lidocaine but has its own vasoconstrictive properties
16. 5 % lidocaine transdermal patch
12 hours on 12 hours off per any 24 hour period
Indications:
▪ Post- herpatic neuralgia or pain after Shingles (herpes
zoster)
▪ Recent studies suggest it is beneficial
▪ Low Back pain
▪ Osteoarthritis knee pain
17. A 5% oil emulsion containing 2.5% of each lidocaine and prilocaine
FYI: Eutectic Mixture= the melting point of the mixture is lower than the
melting point of the individual ingredients
▪ Lidocaine and prilocaine are solids but in this mix in a non-aqueous solution there
is a higher concentration of anesthetic possible.
Can be a cream or on a cellulose disk (patch)
Indications: local analgesia prior to catheterization or procedures
involving genital mucosal membranes, pre-treatment for
infiltration analgesia, lumbar puncture, venipuncture, dental
procedures
NOT for ophthalmic use
Side Effects: same as for drugs individually plus
Paleness (37%) or redness(30%) at site
Burning sensation (17%)
18. Slow onset but long duration of action (~2hrs)
Amide-linked
Has chiral center so enantiomers with levobupivacaine safer form
High risk of cardiotoxicity
Formulations: As an isotonic solution with sodium chloride ranging in
concentration from 0.25%- 0.75% with or without epinephrine
Indications: Used for labor and post-operative anesthesia, dental & eye
procedures
Not in children or handicapped due to increased self-inflicted post-operative
injury
Drug Interactions:
Hyaluronidase
Propranolol (non-selective beta blocker
increased risk of side effects)
St. John’sWort
19. The most commonly used local anesthetic in
dentistry is lidocaine
Gaffen et. al. study of Ontario Dentists (2009)
▪ 37.3% used lidocaine with epinephrine
▪ 27% used articaine with epinephrine
▪ Articaine has been widely used in Europe and Canada although only
approved in a 4% solution in US in 2000. Similar to prilocaine and
both have increased risk of nerve paresthesia (“pins and needles”
feeling)
Ngan et. al. (2001) also found among pediatric
dentists in the US lidocaine was the preferred local
anesthetic
Mepivacaine (2% solution, amide LA) is used
when a vasoconstrictor cannot be given
20. 1) Resident AP is preparing a patient for a surgical
procedure to resect liver cancer.
Catheterization is required so AP reaches for
the lidocaine cream. His attending
recommends EMLA cream instead because of
its:
a) Decreased side effect profile
b) Higher concentration of anesthetic properties per
application
c) More balanced pH to reduce the sting of application
d) Ester-linkage and metabolism which bypasses the
liver
21.
22. Designed to induce a reversible depression of the
CNS where perception of all sensations are blocked
Loss of consciousness
Amnesia
Immobility
Analgesia
& with adjuvants: anxiolysis, muscle relaxation, & loss of
autonomic reflexes
Inhaled versus Intravenous agents…
23. Potency is one factor
that determines
progression through
these stages
Inversely related to the
Minimum Alveolar
Concentration (MAC) or
the partial pressure
required in the alveoli to
abolish a response to
surgical incision in 50%
of patients
24. The Meyer–Overton Rule & Lipid Solubility
• λ (oil/gas) coefficient describes
the solubility of a GA into lipids
and is related to potency
• MAC x λ (oil/gas) = a constant
such that MAC= 1.3/ λ (oil/gas)
• This led to the lipid hypothesis of
how anesthetics worked:
Anesthesia was achieved when a
specific concentration of
anesthetics were in the lipid
membranes such that the bilayer
fluidity was disturbed altering
excitability no proof of a
mechanism so largely discredited
25. Actions of Anesthetics on (Ligand-Gated) Ion Channels
• Potentiate action of Inhibitory Receptors
• Mainly GABAA Receptors
• Two-Pore Potassium channels (Not
affected by intravenous anesthetics)
• Inhibit excitatory receptors
• NMDA Glutamate Receptors by Xenon,
Nitrous Oxide and Ketamine
26. When you first breathe in a specific amount of inhaled
anesthetic that is administered (PI) it mixes with the
residual volume of gas in the lungs so that the
concentration at the alveoli (Palv) is less
With subsequent breaths Palv comes closer to equilibrium
with PI
The λ (blood/gas) coefficient or solubility of an anesthetic
in the blood determines the rate of induction/recovery
The lower the λ (blood/gas) coefficient the slower the
absorption into the blood is so Palv will equal the PI sooner
Ventilation rate also affects the rate of absorption
Additionally due to optimized gas exchange at the alveoli Palv
~ Part
Tissue distribution of an anesthetic depends upon blood
flow to the area of interest (cardiac output) since
equilibration of the partial pressure of arterial anesthetic
Part with the tissue can occur in the span of time the blood
traverses the capillary bed
27. Ventilation-Limited
Anesthetics
High λ (blood/gas)
coefficient
High rate of uptake
prevents the rise of Palv
Slow Induction and
recovery
Includes: diethyl ether,
enflurane, isoflurane,
halothane
Perfusion-Limited
Anesthetics
Low λ (blood/gas)
coefficient
Slow rate of uptake
expedites the rise of Palv
Fast Induction and
recovery
Includes: Nitrous oxide,
desflurane, sevoflurane
28. Effects of Changes in Ventilation and Cardiac Output
on the Rate at Which Alveolar Partial Pressure Rises
Toward Inspired Partial Pressure
• Increasing ventilation accelerates equilibration and
induction
• Increasing cardiac output slows equilibration
• The effects of these cardiovascular changes are more
substantial for anesthetics with high λ(blood/gas)
coefficients like halothane
• Fast inducers like nitrous oxide equilibrate so
fast that changes are not felt to the same extent
• λ(oil/gas) coefficients indicate an anesthetic’s fat
solubility
• Affects potency
• Distribution kinetics: high lipid solubility causes
slower recovery due to slow reversal and release
from fat stores that have absorbed the drug
29. High λ (blood/gas) Slow induction
High λ (oil/gas) 1) high potency (low MAC)
and 2) slow recovery with “hangover” effect
Non-irritating smell
Used in pediatrics but rarely
Toxicity:
Metabolites can result in fatal hepatotoxicity
with an incidence of 1: 35,000 adults
Malignant Hyperthermia
30. • Due to inherited autosomal
dominant mutation in gene for
the Ryanodine Calcium
Channel on the Sarcoplasmic
reticulum
• ~1/30,000 risk
• Caused by halogenated
anesthetics in these individuals
• Uncontrolled release of
calcium into muscle cells
constant contractions
tetany & heat production
death
• Treated with Dantrolene that
blocks calcium release from SR
31. Lower λ (blood/gas) Faster Induction
Lower λ (oil/gas) Less Potent but less in fat so easier
recovery
Metabolism & SubsequentToxicity:
isoflurane<enflurane< halothane
Enflurane:
Slight increased risk renal toxicity,
Risk of epilepsy-like seizures
Isoflurane:
Most widely used general anesthetic
Can be an irritant to respiratory tract
May precipitate myocardial ischemia in patients with coronary
artery disease due to vasodilation
32. Extremely low λ (blood/gas) Very Fast Induction
Very Low λ (oil/gas) Such low potency (MAC~1
atm)MUST be combined with other agents
Very good recovery
Toxicity:
Safe at low doses
Enters and accumulates in gaseous cavities potentially
expanding them so avoid in pneumothorax, obstructed
intestines or in the case of an air embolus
Prolonged or repeated exposure (>6hrs) inactivates
methionine synthase needed for DNA and protein
synthesis bone marrow depression, anemia
▪ AVOID in patients with B12 deficiency
33. Lower λ (blood/gas) Faster Induction than older agents
High λ (oil/gas) Increased Potency
Desflurane:
Faster onset and recovery than isoflurane
Used for day-case outpatient surgery
Not metabolized much so decreased toxicity
Reparatory irritant coughing and bronchospasm and increase
sympathetic activity
▪ AVOID in ischemic heart disease
Sevoflurane:
More potent than desflurane
NO respiratory irritation
Small amount of metabolism (3%)
Can be chemically unstable if machinery contains carbon dioxide
absorbents that can create a nephrotoxin but better machinery
improving usage
34. High λ (blood/gas) Slow Induction
High λ (oil/gas) High Potency
Easy to administer and control
Analgesic and muscle relaxant properties
VERY flammable & explosive
Post-operative nausea and vomiting
Irritant to respiratory tract
Obsolete in developed countries but still used
where modern facilities are not available
35. Much faster induction
(seconds to minutes)
Not as reversible i.e.. Can’t
clear by increasing ventilation
of oxygen
Rapid metabolism but
elimination from body is slow
so not generally used to
maintain anesthesia
36. Fast onset (30s) and fast recovery
Possible to use as continuous infusion for short day
procedures with less nausea than inhaled anesthetics
Risks andToxicity:
Pain at injection site
Cardiovascular and respiratory depression
Propofol Infusion Syndrome (1/300): when high doses have
been given for a prolonged period, particularly to sick
patients-especially children-in intensive care units.
▪ severe metabolic acidosis, skeletal muscle necrosis
(rhabdomyolysis), hyperkalaemia, lipaemia, hepatomegaly, renal
failure, arrhythmia and cardiovascular collapse
37. Thiopental
A barbiturate
Causes unconsciousness in 20seconds and lasts only 5-
10minutes due to high lipid solubility.
Largely replaced by Propofol
Risk of precipitating porphyria
Etomidate
Fast onset and fairly fast recovery
Less cardiovascular and respiratory depression than
thiopental
Can cause unpleasant excitatory effects during induction
and pain at injection site, as well as adrenocortical
depression
38. Takes 1-2minutes for effects
Causes a dissociative amnesia: sensory loss, analgesia, and amnesia,
without complete loss of consciousness
Increases Cardiac Output through increased sympathetic outflow
Indications: General anesthesia as an adjuvant, procedural sedation,
(Non-FDA approved: bronchospasm and rapid sequence intubation i.e..
Emergency situations)
Toxicity &Warnings:
Unpleasant hallucinations, delirium, and irrational behaviors
May increase intracranial pressure soAVOID n patients with risk of cerebral
ischemia
Drug Interactions:
Hydromorphone, oxycodone, and tramadol (pain killers that also depress
CNS)
St. John’sWort
Non-selective MAOIs (phenelzine &selegiline; ancedotal hyper and hypo
tension cases with general anesthetics)
39. 2) High anesthetic potency is associated with which chemical
properties:
a) High λ(blood/gas) coefficient and extreme
hydrophobicity
b) Low λ(oil/gas) coefficient and moderate
hydrophobicity
c) High λ(oil/gas) coefficient and moderate
hydrophobicity
d) High λ(blood/gas) coefficient and High λ(blood/gas)
coefficient
e) Low λ(oil/gas) coefficient and low hydrophobicity
40. Know the general mechanism of action of each class of
anesthetics
Local anesthetics bind to the intracellular side of sodium
channels in all states except the resting state to block excitatory
nerve transmission
General anesthetics must either decrease excitatory neuronal
signals by blocking glutamate receptors (NMDAr) and/or
increase inhibitory GABA activity
Know major drug interactions and adverse effects
Know what makes special drugs in each class and subtype
good for complicated patients & situations
EX: when vasocontrictors are contraindicated or best
anesthetics for short procedures etc.
Hinweis der Redaktion
1. Local anesthetics (LAs) are injected or otherwise applied outside the peripheral nerve epineurium (the outermost sheath of connective tissue containing blood vessels, adipose tissue, fibroblasts, and mast cells). 2. LA molecules must cross the epineurium to reach the perineurium, another epithelial membrane, which organizes nerve fibers into fascicles. The perineurium is the most difficult layer for local anesthetics to penetrate, because of the tight junctions between its cells. 3. LAs then pass through the endoneurium, which envelops the myelinated and unmyelinated fibers, Schwann cells, and capillaries. Only LAs that have passed through these three sheaths can reach the neuronal membranes where the voltage-gated sodium channels reside. Clinically, a high concentration of local anesthetic must be applied because only a fraction of the molecules reach the target site.
Procaine (A) and lidocaine (B) are prototypical ester-linked and amide-linked local anesthetics, respectively. Local anesthetics have an aromatic group on one end and an amine on the other end of the molecule; these two groups are connected by an ester (-RCOOR′) or amide (-RHNCOR′) linkage. In solution at high pH, the equilibrium between the basic (neutral) and acidic (charged) forms of a local anesthetic favors the basic form. At low pH, the equilibrium favors the acidic form. At intermediate (physiologic) pH, nearly equal concentrations of the basic and acidic forms are present. Generally, ester-linked local anesthetics are easily hydrolyzed to a carboxylic acid (RCOOH) and an alcohol (HOR′) in the presence of water and esterases. In comparison, amides are far more stable in solution. Consequently, amide-linked local anesthetics generally have a longer duration of action than do ester-linked anesthetics.
Procaine (A) and lidocaine (B) are prototypical ester-linked and amide-linked local anesthetics, respectively. Local anesthetics have an aromatic group on one end and an amine on the other end of the molecule; these two groups are connected by an ester (-RCOOR′) or amide (-RHNCOR′) linkage. In solution at high pH, the equilibrium between the basic (neutral) and acidic (charged) forms of a local anesthetic favors the basic form. At low pH, the equilibrium favors the acidic form. At intermediate (physiologic) pH, nearly equal concentrations of the basic and acidic forms are present. Generally, ester-linked local anesthetics are easily hydrolyzed to a carboxylic acid (RCOOH) and an alcohol (HOR′) in the presence of water and esterases. In comparison, amides are far more stable in solution. Consequently, amide-linked local anesthetics generally have a longer duration of action than do ester-linked anesthetics.
Procaine (A) and lidocaine (B) are prototypical ester-linked and amide-linked local anesthetics, respectively. Local anesthetics have an aromatic group on one end and an amine on the other end of the molecule; these two groups are connected by an ester (-RCOOR′) or amide (-RHNCOR′) linkage. In solution at high pH, the equilibrium between the basic (neutral) and acidic (charged) forms of a local anesthetic favors the basic form. At low pH, the equilibrium favors the acidic form. At intermediate (physiologic) pH, nearly equal concentrations of the basic and acidic forms are present. Generally, ester-linked local anesthetics are easily hydrolyzed to a carboxylic acid (RCOOH) and an alcohol (HOR′) in the presence of water and esterases. In comparison, amides are far more stable in solution. Consequently, amide-linked local anesthetics generally have a longer duration of action than do ester-linked anesthetics.
1st figure: Local anesthetic action. An injected local anesthetic exists in equilibrium as a quaternary salt (BH+) and tertiary base (B). The proportion of each is determined by the pKa of the anesthetic and the pH of the tissue. The lipid-soluble base (B) is essential for penetration of both the epineurium and neuronal membrane. Once the molecule reaches the axoplasm of the neuron, the amine gains a hydrogen ion, and this ionized, quaternary form (BH+) is responsible for the actual blockade of the sodium channel. The equilibrium between (BH+) and (B) is determined by the pH of the tissues and the pKa of the anesthetic (pH/pKa).
A. The sodium channel is composed of one polypeptide chain that has four repeating units. One region, known as the S4 region, has many positively charged amino acids (lysine and arginine). These residues give the channel its voltage dependence. At rest, the pore is closed. When the membrane is depolarized, the charged residues move in response to the change in the electric field. This results in several conformational changes (intermediate closed states) that culminate in channel opening. After about 1 ms (the channel open time), the 3–4 amino acid “linker region” plugs the open channel, yielding the inactivated conformation. The inactivated conformation returns to the resting state only when the membrane is repolarized; this conformational change involves the return of the S4 region to its original position and the expulsion of the linker region. The time required for the channel to return from the inactivated state to the resting state is known as the refractory period; during this period, the sodium channel is incapable of being activated. B. The binding of local anesthetic (LA) alters the properties of the intermediate forms assumed by the sodium channel. Sodium channels in any of the conformations (resting, closed, open, or inactivated) can bind local anesthetic molecules, although the resting state has a low affinity for LA, while the other three states have a high affinity for LA. LA can dissociate from the channel–LA complex in any conformational state, or the channel can undergo conformational changes while associated with the LA molecule. Ultimately, the channel–LA complex must dissociate, and the sodium channel must return to the resting state to become activated. LA binding extends the refractory period, including both the time required for dissociation of the LA molecule from the sodium channel and the time required for the channel to return to the resting state.
A. In tonic block, depolarizations occur with low frequency, and there is sufficient time between depolarizations for equilibrium binding of local anesthetic (LA) molecules to the various states of the sodium channel to be reestablished. When a depolarization occurs, resting channels (which have low affinity for LA) are converted into open channels and inactivated channels (both of which have high affinity for LA). Thus, there is an increase in the number of LA-bound channels. Once the depolarization ends, there is enough time before the next depolarization for equilibrium between LA molecules and sodium channels to be reestablished, and virtually all of the channels return to the resting and unbound state. B. In phasic block, depolarizations occur with high frequency, and there is not sufficient time between depolarizations for equilibrium to be reestablished. After each depolarization, a new baseline is established that has more LA-bound channels than the previous baseline, leading eventually to conduction failure. Because high-frequency stimulation of nociceptors occurs in areas of tissue damage, phasic (use-dependent) block causes actively firing nociceptors to be inhibited more effectively than nerve fibers that are only occasionally firing. The frequency dependence of phasic block depends on the rate at which LA dissociates from its binding site on the channel.
pi
The deepening anesthetic state can be divided into four stages, based on observations with diethyl ether. The analgesia of stage I is variable and depends on the particular anesthetic agent. With fast induction, the patient passes rapidly through the undesirable “excitement” phase (stage II). Surgery is generally undertaken in stage III. The anesthesiologist must take care to avoid stage IV, which begins with respiratory arrest. Cardiac arrest occurs later in stage IV. During recovery from anesthesia, the patient progresses through the stages in reverse.
Molecules with a larger oil/gas partition coefficient [λ(oil/gas)] are more potent general anesthetics. This log–log plot shows the very tight correlation between lipid solubility [λ(oil/gas)] and anesthetic potency over five orders of magnitude. Note that even such gases as xenon and nitrogen can act as general anesthetics when breathed at high enough partial pressures. The equation describing the line is: Potency = λ(oil/gas)/1.3. Recall that Potency = 1/MAC.
Anesthetics potentiate the action of endogenous agonists at inhibitory receptors, such as GABAA and glycine receptors, and inhibit the action of endogenous agonists at excitatory receptors, such as nicotinic acetylcholine, 5-HT3, and NMDA glutamate receptors. At GABAA receptors, anesthetics both decrease the EC50 of GABA (i.e., GABA becomes more potent) and increase the maximum response (i.e., GABA becomes more efficacious). The latter effect is thought to be due to the ability of anesthetics to stabilize the open state of the receptor channel. At excitatory receptors, anesthetics decrease the maximum response while leaving the EC50 unchanged; these are the pharmacologic hallmarks of noncompetitive inhibition.
The rate of equilibration of the alveolar partial pressure with the inspired partial pressure can be affected by changes in ventilation (A) and cardiac output (B). Increasing ventilation from 2 L/min (dashed lines) to 8 L/min (solid lines) accelerates equilibration. On the other hand, increasing cardiac output from 2 L/min (dashed lines) to 18 L/min (solid lines) slows equilibration. Both effects are much larger for more blood-soluble gases, such as halothane and diethyl ether, which have rather slow induction times. For nitrous oxide, the rate of equilibration is so fast that any changes caused by hyperventilation or decreased cardiac output are small. The dashed horizontal line represents 63% equilibration of Palv with PI; the time required for each curve to cross this line represents τ{Palv→PI}.