General Anesthetics
Michael H. Ossipov, Ph.D.
Department of Pharmacology
Surgery Before Anesthesia
Fun and Frolics led to Early Anesthesia
History of Anesthesia
(150 years old)
Joseph Priestly – discovers N2O in 1773
Crawford W. Long – 1842. Country Dr. in Georgia first used ether for neck
surgery. Did not publicize, in part because of concerns about negative fallout
from “frolics”. Tried to claim credit after Morton’s demonstration but…
Important lesson learned – if you don’t publish it, it didn’t happen.
Sir Humphrey Davy – experimented with N2O, reported loss of pain, euphoria
Traveling shows with N2O (1830’s – 1840’s)
Colt (of Colt 45 fame)
Horace Wells 1844. Demonstrated N2O for tooth extraction – deemed a failure
because patient “reacted”.
History of Anesthesia
William Morton, dentist – first demonstration of successful
surgical anesthesia with ether 1846
John C. Warren, surgeon at MGH says “Gentlemen, this is no
humbug!” – birth of modern anesthesia
Dr. John Snow administers chloroform to Queen Victoria (1853)–
popularizes anesthesia for childbirth in UK
He becomes the first anesthesia specialist.
Note that ether became anesthesia of choice in US, chloroform in UK
Anesthesia
• Allow surgical, obstetrical and diagnostic
procedures to be performed in a manner which is
painless to the patient
• Allow control of factors such as physiologic
functions and patient movement
Anesthetic techniques
•
•
•
•
General anesthesia
Regional anesthesia
Local anesthesia
Conscious Sedation (monitored anesthesia
care)
What is “Anesthesia”
• No universally accepted definition
• Usually thought to consist of:
–
–
–
–
–
Oblivion
Amnesia
Analgesia
Lack of Movement
Hemodynamic Stability
What is “Anesthesia”
• Sensory
-Absence of intraoperative pain
• Cognitive:
-Absence of intraoperative awareness
-Absence of recall of intraoperative events
• Motor:
-Absence of movement
-Adequate muscular relaxation
• Autonomic:
-Absence of hemodynamic response
-Absence of tearing, flushing, sweating
Goals of General Anesthesia
•
•
•
•
Hypnosis (unconsciousness)
Amnesia
Analgesia
Immobility/decreased muscle tone
– (relaxation of skeletal muscle)
• Inhibition of nociceptive reflexes
• Reduction of certain autonomic reflexes
– (gag reflex, tachycardia, vasoconstriction)
Desired Effects Of General Anesthesia
(Balanced Anesthesia)
•
•
•
•
•
•
Rapid induction
Sleep
Analgesia
Secretion control
Muscle relaxation
Rapid reversal
StagesofOfGeneral
General Anesthesia
Phases
Anesthesia
• Induction- initial entry to surgical anesthesia
• Maintenance- continuous monitoring and
medication
– Maintain depth of anesthesia, ventilation, fluid balance,
hemodynamic control, hoemostasis
• Emergence- resumption of normal CNS function
– Extubation, resumption of normal respiration
Stages Of General Anesthesia
Phases
of General Anesthesia
Stage I: Disorientation, altered consciousness
Stage II: Excitatory stage, delirium, uncontrolled movement, irregular breathing.
Goal is to move through this stage as rapidly as possible.
Stage III: Surgical anesthesia; return of regular respiration.
Plane 1: “light” anesthesia, reflexes, swallowing reflexes.
Plane 2: Loss of blink reflex, regular respiration (diaphragmatic and
chest). Surgical procedures can be performed at this stage.
Plane 3: Deep anesthesia. Shallow breathing, assisted ventilation
needed. Level of anesthesia for painful surgeries (e.g.; abdominal
exploratory procedures).
Plane 4: Diaphragmatic respiration only, assisted ventilation is required.
Cardiovascular impairment.
Stage IV: Too deep; essentially an overdose and represents anesthetic crisis.
This is the stage between respiratory arrest and death due to circulatory
collapse.
Routes of Induction
•Intravenous
–Safe, pleasant and rapid
•Mask
–Common for children under 10
–Most inhalational agents are pungent, evoke coughing and
gagging
•Avoids the need to start an intravenous catheter
before induction of anesthesia
–Patients may receive oral sedation for separation from
parents/caregivers
•Intramuscular
–Used in uncooperative patients
Anesthetic Techniques
• Inhalation anesthesia
– Anesthetics in gaseous state are taken up by
inhalation
• Total intravenous anesthesia
• Inhalation plus intravenous (“Balanced
Anesthesia”)
– Most common
Anesthetic drugs have rapid onset and offset
• “Minute to minute” control is the “holy grail” of general anesthesia
• Allows rapid adjustment of the depth of anesthesia
• Ability to awaken the patient promptly at the end of the surgical
procedure
• Requires inhalation anesthetics and short-acting intravenous drugs
Anesthetic Depth
• During the maintenance phase, anesthetic doses are adjusted
based upon signs of the depth of anesthesia
• Most important parameter for monitoring is blood pressure
• There is no proven monitor of consciousness
Selection of anesthetic technique
• Safest for the patient
• Appropriate duration
– i.v. induction agents for short procedures
• Facilitates surgical procedure
• Most acceptable to the patient
– General vs. regional techniques
• Associated costs
MAC – Minimal Alveolar Concentration
• "The alveolar concentration of an inhaled anesthetic that prevents movement
in 50% of patients in response to a standardized stimulus (eg, surgical
incision)."
• A measure of relative potency and standard for experimental studies.
• MAC values remain constant regardless of stimuli, weight, sex, and even
across species
• Steep DRC: 50% respond at 1 MAC but 99% at 1.3 MAC
• MAC values for different agents are approximately additive. (0.7 MAC N2O +
0.6 MAC halothane = 1.3 MAC total)
• "MAC awake," (when 50% of patients open their eyes on request) is
approximately 0.3.
• Light anesthesia is 0.8 to 1.2 MAC, often supplemented with adjuvant i.v.
drugs
Factors Affecting MAC
•
•
•
•
Circadian rhythm
Body temperature
Age
Other drugs
– Prior use
– Recent use
How do Inhalational Anesthetics Work?
Surprisingly, the mechanism of action is still largely unknown.
• "Anesthetics have been used for 160 years, and how they work is one of the great
mysteries of neuroscience," James Sonner, M.D. (UCSF)
• Anesthesia research "has been for a long time a science of untestable hypotheses," Neil
L. Harrison, M.D. (Cornell University)
How do Inhalational Anesthetics Work?
Meyer-Overton observation: There is a strong linear correlation between lipid solubility
and anesthetic potency (MAC)
How do Inhalational Anesthetics Work?
•Membrane Stabilization Theory:
– Site of action in lipid phase of cell membranes (membrane stabilizing
effect) or
– Hydrophobic regions of membrane-bound proteins
– May induce transition from gel to liquid crystalline state of
phospholipids
– Supported by NMR and electron-spin resonance studies
– Anesthesia can be reduced by high pressure
How do Inhalational Anesthetics Work?
•Promiscuous Receptor Agonist Theory: Anesthetics may act at
GABA receptors, NMDA receptors, other receptors
• May act directly on ion channels
• May act in hydrophobic pouches of proteins associated
with receptors
• May effect allosteric interaction to alter affinity for ligands
•Immobility is due to a spinal mechanism, but site is unknown
• “Overall, the data can be explained by supposing that the primary target sites underlying
general anesthesia are amphiphilic pockets of circumscribed dimensions on particularly sensitive
proteins in the central nervous system.” – Franks and Lieb, Environmental Health Perspectives
87:199-205, 1990.
Receptors Possibly Mediating CNS
Effects Of Inhaled Anesthetics
• Potentiation of
inhibitory ‘receptors’
– GABAA
– Glycine
– Potassium channels
• Inhibition of
excitatory ‘receptors’
–
–
–
–
NMDA (glutamate)
AMPA (glutamate)
Nicotinic acetylcholine
Sodium channels
Inferred from demonstration of effect on receptor at clinically relevant
concentrations and lack of effect in absence of receptor
Inhaled Anesthetics
• Gases
– Nitrous oxide
– Present in the gaseous state at room temperature and pressure
– Supplied as compressed gas
Inhaled Anesthetics
• Volatile anesthetics
– Present as liquids at
room temperature and
pressure
– Vaporized into gases
for administration
Inhaled Anesthetics
• Volatile anesthetics
– Present as liquids at
room temperature and
pressure – BUT NOT
ALWAYS!
– Vaporized into gases for
administration
Concentration of Inhaled Anesthetics
Determines Dose
• Partial pressure (mmHg)
– Applies to gas phase or to dissolved gases
• Volumes %
– Percentage of total gas volume contributed by
anesthetic
– Percentage of total gas molecules contributed by
anesthetic
– Partial pressure/atmospheric pressure
Solubility of Inhaled Anesthetics
Determines Dose and Time-course
• Ratio of concentration in one phase to that in a
second phase at equilibrium
• Important solubility coefficients for inhaled
anesthetics
– Lower blood-gas partition coefficient leads to faster
induction and emergence
– Higher oil-gas partition coefficient leads to increased
potency
Chemistry
(CF3)2CH-O-CH3
10%, excellent anesthesia
CF3CHFCF2-O-CH3
5%, light anesthesia, tremors
CF3CH2-O-CF2CH2F
3%, convulsions
CF3CH2-O-CH2CF3 (Indoklon)
0.25%, marked convulsions
CF3CF2-O-CF2CF3 Inert
From: F.G. Rudo and J.C. Krantz, Br. J. Anaesth. (1974), 46, 181
Inhaled Anesthetics
Inhaled Anesthetics - Historical
•Ether – Slow onset, recovery, explosive
•Chloroform – Slow onset, very toxic
•Cyclopropane – Fast onset, but very explosive
•Halothane (Fluothane) – first halogenated ether (non-flammable)
• 50% metabolism by P450, induction of hepatic microsomal
enzymes; TFA, chloride, bromide released
• Myocardial depressant (SA node), sensitization of myocardium to
catecholamines
• Hepatotoxic
•Methoxyflurane (Penthrane) - 50 to 70% metabolized
• Diffuses into fatty tissue
• Releases fluoride, oxalic acid
• Renotoxic
Inhaled Anesthetics – Currently
• Enflurane (Ethrane) Rapid, smooth induction and maintenance
• 2-10% metabolized in liver
• Introduced as replacement for halothane, “canabilized” to make
way for isoflurane
• Isoflurane (Forane) smooth and rapid induction and emergence
• Very little metabolism (0.2%)
• Control of Cerebral blood flow and Intracranial pressure
• Potentiates muscle relaxants, Uterine relaxation
• CO maintained, arrhythmias uncommon, epinephrine can be used
with isoflurane; Preferential vasodilation of small coronary vessels
can lead to “coronary steal”
• No reports of hepatotoxicity or renotoxicity
• Most widely employed
Inhaled Anesthetics – New Kids on the Block
• Desflurane (Suprane) – Very fast onset and offset (minute-to minute
control) because of its low solubility in blood
• Differs from isoflurane by replacing one Cl with F
• Minimal metabolism
• Very pungent - breath holding, coughing, and laryngeal spasm; not
used for induction
• No change in cardiac output; tachycardia with rapid increase in
concentration, No coronary steal
• Degrades to form CO in dessicated soda-lime (Ba2OH /NaOH/KOH; not
Ca2OH)
• Fast recovery – responsive within 5-10 minutes
Inhaled Anesthetics – New Kids on the Block
• Sevoflurane (Ultane) – Low solubility and low pungency = excellent
induction agent
• Significant metabolism (5%; 10x > isoflurane); forms inorganic fluoride
and hexafluoroisopropranolol
• No tachycardia, Prolong Q-T interval, reduce CO, little tachycardia
• Soda-lime (not Ca2OH) degrades sevoflurane into “Compound A”
• Nephrotoxic in rats
• Occurs with dessicated CO2 absorbant
• Increased at higher temp, high conc, time
• No evidence of clinical toxicity
• Metallic/environmental impurities can form HF
Inhaled Anesthetics – Currently
• Nitrous Oxide is still widely used
• Potent analgesic (NMDA antagonist)
• MAC ~ 120%
• Used ad adjunct to supplement other inhalationals
• Xenon
• Also a potent analgesia (NMDA antagonist)
• MAC is around 80%
• Just an atom – what about mechanism of action?
Malignant Hyperthermia
Malignant hyperthermia (MH) is a pharmacogenetic hypermetabolic state of skeletal
muscle induced in susceptible individuals by inhalational anesthetics and/or
succinylcholine (and maybe by stress or exercise).
• Genetic susceptibility-Ca+ channel defect (CACNA1S) or RYR1
(ryanodine receptor)
• Excess calcium ion leads to excessive ATP breakdown/depletion,
lactate production, increased CO2 production, increased VO2, and,
eventually, to myonecrosis and rhabdomyolysis, arrhythmias, renal
failure
• May be fatal if not treated with dantrolene – increases reuptake of
Ca++ in Sarcoplasmic Reticulum
• Signs: tachycardia + tachypnea + ETCO2 increasing + metabolic
acidosis; also hyperthermia, muscle rigidity, sweating, arrhythmia
• Detection:
– Caffeine-halothane contracture testing (CHCT) of biopsied muscle;
– Genetic testing for 19 known mutations associated with MH
Intravenous Anesthetics
•Most exert their actions by potentiating GABAA receptor
•GABAergic actions may be similar to those of volatile
anesthetics, but act at different sites on receptor
•High-efficacy opiods (fentanyl series) also employed
•Malignant hyperthermia is NOT a factor with these
Intravenous Anesthetics
Organ Effects
• Most decrease cerebral metabolism and
intracranial pressure. Often used in the
treatment of patients at risk for cerebral
ischemia or intracranial hypertension.
• Most cause respiratory depression
• May cause apnea after induction of
anesthesia
Cardiovascular Effects
• Barbiturates, benzodiazepines and propofol
cause cardiovascular depression.
• Those drugs which do not typically depress
the cardiovascular system can do so in a
patient who is compromised but
compensating using increased sympathetic
nervous system activity.
Intravenous Anesthetics - Barbiturates
Ideal: Rapid Onset, short-acting
Thiopental (pentathol)- previously almost universally used
For over 60 years was the standard against which other injectable induction
agents/anesthetics were compared
Others: Suritol (thiamylal); Brevital (methohexital)
Act at GABA receptors (inhibitory), potentiate endogenous GABA activity at the
receptor, direct effect on Cl channel at higher concentrations.
Effect terminated not by metabolism but by redistribution
repeated administration or prolonged infusion approached equlibrium at
redistribution sites. Redistribution not effective in terminating action, led to
many deaths.
Build-up in adipose tissue = very long emergence from
anesthesia (e.g.; one case took 4 days to emerge)
Propofol (Diprivan)
• Originally formulated in egg lecithin emulsion
• anaphylactoid reactions
• Current formulation: 1% propofol in 10% soybean oil, 2.25%
glycerol, 1.2% egg phosphatide
• Pain on injection
• Onset within 1 minute of injection
• Not analgesic
• Enhances activity of GABA receptors (probably)
• Vasodilation, respiratory depression, apnea (25% to 40%)
• Induction and maintenance of anesthesia or sedation
• Rapid emergence from anesthesia
• Antiemetic effect
• Feeling of well-being
• Widely used for ambulatory surgery
Etomidate (Amidate)
• Insoluble in water, formulated in 35% propylene glycol (pain on
injection)
• Little respiratory depression
• Minimal cardiovascular effects
• Rapid induction (arm-to-brain time), duration 5 to 15 minutes
• Most commonly used for induction of anesthesia in patients with
cardiovascular compromise; or where cardiovascular stability is most
important
• Metabolized to carboxylic acid, 85% excreted in urine, 15% in bile
• Rapid emergence from anesthesia
• Adverse effects: Pain, emesis, involuntary myoclonic movements,
inhibition of adrenal steroid synthesis
Ketamine
• Chemically and pharmacologically related to PCP
• Inhibits NMDA receptors
• Analgesic, dissociative anesthesia
• Cataleptic appearance, eyes open, reflexes intact, purposeless but
coordinated movements
• Stimulates sympathetic nervous system
• Indirectly stimulates cardiovascular system, Direct myocardial depressant
• Increases cerebral metabolism and intracranial pressure
• Lowers seizure threshold
• Psychomimetic – “emergence reactions”
• vivid dreaming extracorporeal (floating "out-of-body") experience
misperceptions, misinterpretations, illusions
• may be associated with euphoria, excitement, confusion, fear
Benzodiazepines
•Diazepam (Valium, requires non-aqueous vehicle, pain on
injection); Replaced by Midazolam (Versed) which is watersoluble.
•Rapidly redistributed, but slowly metabolized
•Useful for sedation, amnesia
-Not analgesic, can be sole anesthetic for non-painful
procedures (endoscopies, cardiac catheterization)
-Does not produce surgical anesthesia alone
•Commonly used for preoperative sedation and anxiolysis
•Can be used for induction of anesthesia
•Safe – minimal respiratory and cardiovascular depression
when used alone, but they can potentiate effects of other
anesthetics (e.g.; opioids)
•Rapid administration can cause transient apnea
Opioids
•i.v. fentanyl, sufentanil, alfentanil, remifentanyl or morphine
•Usually in combination with inhalant or benzodiazepine
•Respiratory depression, delayed recovery, nausea and vomiting postop
•Little cardiovascular depression; Provide more stable hemodynamics
•Smooth emergence (except for N & V)
•Excellent Analgesic: intra-operative analgesia and decrease early
postoperative pain
–Remifentanil: has ester linkage, metabolized rapidly by nonspecific esterases
(t1/2 = 4 minutes; fentanyl t1/2 = 3.5 hours)
–Rapid onset and recovery
–Recovery is independent of dose and duration – offers the high degree of
“minute to minute” control
Conscious sedation
• A term used to describe sedation for
diagnostic and therapeutic procedures
throughout the hospital.
• Ambiguous because no one really
knows how to measure consciousness
in the setting of a patient receiving
sedation.
Depth of sedation
Conscious sedation
•Each health care facility should have policies and procedures
defining conscious sedation and specifying the procedures and
training required for its use.
•Before sedating patients one should review and follow these
policies and procedures.
•One should also understand sedative medications and have the
knowledge and skills required for the treatment of possible
complications (e.g. apnea).
Conscious sedation
•The most common mistake is to over-sedate the patient. If the
patient is comfortable, there is no need for more medication.
•The safest method of sedation is to carefully titrate sedative
medications in divided doses.
•Allow enough time between doses to assess the effects of the
previous dose.
•Administer medications until the desired level of sedation is
reached, but not past the point where the patient is capable of
responding verbally.
•Midazolam and fentanyl are among the easiest drugs to use.
Midazolam provides sedation and anxiolysis and fentanyl
provides analgesia.
What is Balanced Anesthesia?
• Use specific drugs for each component
• Sensory
• N20, opioids, ketamine for analgesia
• Cognitive:
• Produce amnesia, and preferably unconsciousness, with N2O, .25.5 MAC of an inhaled agent, or an IV hypnotic (propofol,
midazolam, diazepam, thiopental)
• Motor:
• Muscle relaxants as needed
• Autonomic:
• If sensory and cognitive components are adequate, usually no
additional medication will be needed for autonomic stability. If
some is needed, often a beta blocker +/- vasodilator is used.
What is Balanced Anesthesia?
• Garbage Anesthesia (everything but the
kitchen sink)
• LOT2 (Little Of This, Little of That)
• Mixed Technique
• The Usual
Isoflurane Concentration (%)
MAC Reduction
2.00
1.50
1.00
0.50
0.00
0
10
20
30
40
50
60
Target Remifentanil Concentration (ng/ml)
S=success (no response to skin incision) F=failure (response to skin incision)
Lang et al, Anesthesiology 85, 721-728, 1996
Bolus Dose Equivalents
•
•
•
•
Fentanyl 100 mg (1.5 mg/kg)
Remifentanil 35 mg (0.5 mg/kg)
Alfentanil 500 mg (7 mg/kg)
Sufentanil 12 mg (0.2 mg/kg)
What is the role of N2O?
• Excellent analgesic in sub-MAC doses
• MAC is around 110%.
• MACasleep tends to be about 60% of MAC.
• MACasleep for N2O is 68-73%
• Well tolerated by most patients but bad news if you are subject to
migraine.
• At N2O concentrations of 70%, there may be no need for additional
drugs to ensure lack of awareness.
• Has the fastest elimination of any hypnotic agent
used in anesthesia.
• If you want your patients to wake up quickly, keep them within
N2O of being awake!
Simple Combinations
• Morphine
• 10 mg iv 3-5 minutes prior to induction
• Additional 5 mg 45 minutes before the end of the
procedure, if it lasts longer than 2 hours
• Propofol
• 2-3 mg/kg on induction
• N2O
• 70%
• Sevoflurane
• 0.3-0.6%
• Relaxant of choice
Simple Combinations
• Fentanyl
• 75-150 on induction
• 25-50 mg now and then during the case
• Propofol
• 2-3 mg/kg on induction
• N2O
• 70%
• Sevoflurane
• 0.3-0.6%
• Relaxant of choice
Local/Regional Anesthetics
Michael H. Ossipov, Ph.D.
Department of Pharmacology
General concepts
•Cocaine isolated from Erythroxylon coca plant in Andes
•Von Anrep (1880) discovers local anesthetic property, suggests
clinical use
•Koller introduces cocaine in opthalmology
•Freud uses cocaine to wean Karl Koller off morphine
•Halstead demonstrates infiltration anesthesia with cocaine
•Rapidly accepted in dentistry
General concepts
• Halstead (1885) shows cocaine blocks
nerve conduction in nerve trunks
• Corning (1885) demonstrates spinal block
in dogs
• 1905: Procaine (NOVOCAINE) synthesized
– analog of cocaine but without euphoric
effects, retains vasoconstrictor effect
– Slow onset, fast offset, ester-type (allergic
reactions)
General concepts
• First “modern” LA (1940s): lidocaine
(lignocaine in UK; XYLOCAINE)
– Amide type (hypoallergenic)
– Quick onset, fairly long duration (hrs)
– Most widely used local anesthetic in US today,
along with bupivacaine and tetracaine
General concepts
• Cause transient and reversible loss of
sensation in a circumscribed area of the body
– Very safe, almost no reports of permanent nerve
damage from local anesthetics
• Interfere with nerve conduction
• Block all types of fibers (axons) in a nerve
(sensory, motor, autonomic)
Local anesthetics: Uses
•
•
•
•
•
Topical anesthesia (cream, ointments, EMLA)
Peripheral nerve blockade
Intravenous regional anesthesia
Spinal and epidural anesthesia
Systemic uses (antiarrhythmics, treatment of
pain syndromes)
Structure
•All local anesthetics are weak
bases. They all contain:
•An aromatic group (confers
lipophilicity)
diffusion
across
membranes,
duration,
toxicity
increases with
lipophilicity
•An intermediate chain, either an
ester or an amide; and
•An amine group (confers
hydrophilic properties)
– charged form is the
major active form
Structure
•Formulated as HCl salt (acidic) for
solubility, stability
•But, uncharged (unprotonated N)
form required to traverse tissue to
site of action
•pH of formulation is irrelevant since
drug ends up in interstitial fluid
•Quaternary analogs, low pH bathing
medium suggests major form active
at site is cationic, but both charged
and uncharged species are active
PKa
% RN at PH
7.4
Onset in
minutes
Mepivicaine
7.6
40
2 to 4
Etidocaine
7.7
33
2 to 4
Articaine
7.8
29
2 to 4
Lidocaine
7.9
25
2 to 4
Prilocaine
7.9
25
2 to 4
Bupivicaine
8.1
18
5 to 8
Procaine
9.1
2
14 to 18
H 2N
O
C 2H 5
COCH 2CH 2
N
O

H
H 2N
C2H5
COCH 2CH 2
N
+
C2H5
C 2H 5
Cationic acid
Log Base = pH – p Ka
Acid
+ H
Nonionized base
Lipoid barriers
[1.0]
(nerve sheath)
(Henderson-Hasselbalch equation)
Extracellular
fluid
Base
Acid
[1.0]
*
[3.1]
Acid
[2.5]
For procaine (p K a = 8.9)
at tissue pH (7.4)
Nerve membrane
Base =
0.03
Acid
Axoplasm
Base
Structure
Structure
Mode of action
•
•
•
•
Block sodium channels
Bind to specific sites on channel protein
Prevent formation of open channel
Inhibit influx of sodium ions into the
neuron
• Reduce depolarization of membrane in
response to action potential
• Prevent propagation of action potential
Mode of action
Mode of action
Mode of action
Sensitivity of fiber types
• Unmyelinated are more sensitive than myelinated nerve
fibers
• Smaller fibers are generally more sensitive than largediameter peripheral nerve trunks
• Smaller fibers have smaller “critical lengths” than larger
fibers (mm range)
• Accounts for faster onset, slower offset of local
anesthesia
• Overlap between block of C-fibers and Ad-fibers.
Choice of local anesthetics
•
•
•
•
•
Onset
Duration
Regional anesthetic technique
Sensory vs. motor block
Potential for toxicity
Clinical use
Esters
Procaine
Chloroprocaine
Tetracaine
Amides
Lidocaine
Mepivacaine
Bupivacaine
Ropivacaine
Etidocaine
Onset
Duration
Slow
Fast
Slow
Short
Short
Long
Fast
Fast
Moderate
Moderate
Fast
Moderate
Moderate
Long
Long
Long
Choice of local anesthetics
Technique
Topical
Infiltration
Peripheral nerve block
Spinal
Epidural
I.V. regional anesthesia
Appropriate drugs
Cocaine, tetracaine, lidocaine
Procaine, lidocaine, mepivacaine,
bupivacaine, ropivacaine,
etidocaine
Chloroprocaine, lidocaine,
mepivacaine, bupivacaine,
ropivacaine, etidocaine
Procaine, tetracaine, lidocaine,
bupivacaine
Chloroprocaine, lidocaine,
bupivacaine, ropivacaine,
etidocaine
Lidocaine
Factors influencing anesthetic activity
• Needle in appropriate location (most
important)
• Dose of local anesthetic
• Time since injection
• Use of vasoconstrictors
• pH adjustment
• Nerve block enhanced in pregnancy
Redistribution and metabolism
•
•
•
•
Rapidly redistributed
More slowly metabolized and eliminated
Esters hydrolyzed by plasma cholinesterase
Amides primarily metabolized in the liver
Local anesthetic toxicity
• Allergy
• CNS toxicity
• Cardiovascular toxicity
Allergy
• Ester local anesthetics may produce true
allergic reactions
– Typically manifested as skin rashes or
bronchospasm. May be as severe as anaphylaxis
– Due to metabolism to ρ-aminobenzoic acid
• True allergic reactions to amides are
extremely rare.
Systemic toxicity
• Results from high systemic levels
• First symptoms are generally CNS
disturbances (restlessness, tremor,
convulsions) - treat with benzodiazepines
• Cardiovascular toxicity generally later
CNS symptoms
• Tinnitus
• Lightheadedness, Dizziness
• Numbness of the mouth and tongue, metal taste
in the mouth
• Muscle twitching
• Irrational behavior and speech
• Generalized seizures
• Coma
Cardiovascular toxicity
•
•
•
•
Depressed myocardial contractility
Systemic vasodilation
Hypotension
Arrhythmias, including ventricular fibrillation
(bupivicaine)
Avoiding systemic toxicity
• Use acceptable total dose
• Avoid intravascular administration (aspirate
before injecting)
• Administer drug in divided doses
Maximum safe doses of local
anesthetics in adults
Anesthetic
Dose (mg)
Procaine
Chloroprocaine
Tetracaine
Lidocaine
Mepivicaine
Bupivacaine
500
600
100 (topical)
300
300
175
Uses of Local Anesthetics
•Topical anesthesia
- Anesthesia of mucous membranes (ears, nose,
mouth, genitourinary, bronchotrachial)
- Lidocaine, tetracaine, cocaine (ENT only)
•EMLA (eutectic mixture of local anesthetics)
cream formed from lidocaine (2.5%) & prilocaine
(2.5%) penetrates skin to 5mm within 1 hr, permits superficial
procedures, skin graft harvesting
•Infiltration Anesthesia
- lidocaine, procaine, bupivacaine (with or
w/o epinephrine)
- block nerve at relatively small area
- anesthesia without immobilization or
disruption of bodily functions
- use of epinephrine at end arteries (i.e.;
fingers, toes) can cause severe vasoconstriction leading to
Uses of Local Anesthetics
•Nerve block anesthesia
- Inject anesthetic around plexus (e.g.; brachial
plexus for shoulder and upper arm) to anesthetize a larger area
- Lidocaine, mepivacaine for blocks of 2 to 4 hrs,
bupivacaine for longer
•Bier Block (intravenous)
- useful for arms, possible in legs
- Lidocaine is drug of choice, prilocaine can be used
- limb is exsanguinated with elastic bandage,
infiltrated with anesthetic
- tourniquet restricts circulation
- done for less than 2 hrs due to ischemia, pain from
touniquet
Uses of Local Anesthetics
•Spinal anesthesia
- Inject anesthetic into lower CSF (below L2)
- used mainly for lower abdomen, legs, “saddle
block”
- Lidocaine (short procedures), bupivacaine
(intermediate to long), tetracaine (long procedures)
- Rostral spread causes sympathetic block, desirable
for bowel surgery
- risk of respiratory depression, postural headache
Uses of Local Anesthetics
•Epidural anesthesia
- Inject anesthetic into epidural space
- Bupivacaine, lidocaine, etidocaine, chloroprocaine
- selective action of spinal nerve roots in area of
injection
- selectively anesthetize sacral, lumbar, thoracic or
cervical regions
- nerve affected can be determined by concentration
- High conc: sympathetic, somatic sensory, somatic
motor
- Intermediate: somatic sensory, no motor block
- low conc: preganglionic sympathetic fibers
- used mainly for lower abdomen, legs, “saddle
block”
- Lidocaine (short procedures), bupivacaine
(intermediate to long), tetracaine (long procedures)
- Rostral spread causes sympathetic block, desirable
Neuromuscular Blocking Drugs
Michael H. Ossipov, Ph.D.
Department of Pharmacology
Neuromuscular blocking drugs
• Extract of vines (Strychnos toxifera; also
Chondrodendron species)
• Used by indegenous peoples of Amazon basin in
poison arrows (not orally active, so food is safe to
eat)
• Brought to Europe by Sir Walter Raleigh, others
• Curare-type drugs: Tubocurare (bamboo tubes),
Gourd curare, Pot curare
• Brody (1811) showed curare is not lethal is animal is
ventilated
• Harley (1850) used curare for tetanus and strychnine
poisoning
• Harold King (1935) isolates d-tubocurarine from a
museum sample – determines structure.
Neuromuscular blocking drugs
• Block synaptic transmission at the
neuromuscular junction
• Affect synaptic transmission only at skeletal
muscle
– Does not affect nerve transmission, action
potential generation
• Act at nicotinic acetylcholine receptor NII
Neuromuscular blocking drugs
(CH3)3N+-(CH2)6-N+(CH3)3
Hexamethonium
(ganglionic)
(CH3)3N+-(CH2)10-N+(CH3)3
Decamethonium
(motor endplate)
Neuromuscular blocking drugs
• Acetylcholine is released from motor neurons in
discrete quanta
• Causes “all-or-none” rapid opening of Na+/K+ channels
(duration 1 msec)
• Development of miniature end-plate potentials (mEPP)
• Summate to form EPP and muscle action potential –
results in muscle contraction
• ACh is rapidly hydrolyzed by acetylcholinesterase; no
rebinding to receptor occurs unless AChE inhibitor is
present
Non-depolarizing Neuromuscular blocking drugs
• Competetive antagonist of the nicotinic 2
receptor
• Blocks ACh from acting at motor end-plate
– Reduction to 70% of initial EPP needed to
prevent muscle action potential
• Muscle is insensitive to added Ach, but
reactive to K+ or electrical current
• AChE inhibitors increase presence of ACh,
shifting equilibrium to favor displacing the
antagonist from motor end-plate
Nondepolarizing drugs: Metabolism
• Important in patients with impaired organ
clearance or plasmacholinesterase deficiency
• Hepatic metabolism and renal excretion (most
common)
• Atracurium, cis-atracurium: nonenzymatic
(Hoffman elimination)
• Mivacurium: plasma cholinesterase
Depolarizing Neuromuscular blocking drugs
• Succinylcholine, decamethonium
• Bind to motor end-plate and cause
immediate and persistent depolarization
• Initial contraction, fasciculations
• Muscle is then in a depolarized, refractory
state
• Desensitization of Ach receptors
• Insensitive to K+, electrical stimulation
• Paralyzes skeletal more than respiratory
muscles
Succinlycholine: Pharmacokinetics
• Fast onset (1 min)
• Short duration of action (2 to 3 min)
• Rapidly hydrolyzed by plasma
cholinesterase
Succinlycholine: Clinical uses
• Tracheal intubation
• Indicated when rapid onset is desired
(patient with a full stomach)
• Indicated when a short duration is desired
(potentially difficult airway)
Succinylcholine: Side effects
• Prolonged neuromuscular blockade
– In patients lacking pseudocholinesterase
• Treat by maintaining ventilation until it wears off hours
later
Succinylcholine: Phase II block
•
•
•
•
Prolonged exposure to succinlycholine
Features of nondepolarizing blockade
May take several hours to resolve
May occur in patients unable to metabolize
succinylcholine (cholinesterase defects,
inhibitors)
• Harmless if recognized
Acetylcholinesterase inhibitors
• Acetylcholinesterase inhibitors have
muscarinic effects
–
–
–
–
Bronchospasm
Urination
Intestinal cramping
Bradycardia
• Prevented by muscarinic blocking agent
Selection of muscle relexant:
• Onset and duration
• Route of metabolism and elimination
Monitoring NM blockade
• Stimulate nerve
• Measure motor
response (twitch)
• Depolarizing
neuromuscular
blocker
– Strength of twitch
• Nondepolarizing
neuromuscular
blocker
– Strength of twitch
– Decrease in strength
of twitch with
repeated stimulation