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 UKHe 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

PhasesStagesofOfGeneralGeneralAnesthesiaAnesthesia

• 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 AnesthesiaStage 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 CNSEffects 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 AnestheticsDetermines 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 AnestheticsDetermines 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 - BarbituratesIdeal: Rapid Onset, short-acting

Thiopental (pentathol)- previously almost universally usedFor 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 redistributionrepeated 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 water-soluble.•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 post-op•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 “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

MAC Reduction

Isof

lura

ne C

once

ntra

tion

(%

) 2.00

1.50

1.00

0.50

0.00 0 10 20 30 40 50 60

Target

Remifentanil Concentratio

n (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 g (1.5 g/kg) • Remifentanil 35 g (0.5

g/kg)

• Alfentanil 500 g (7 g/kg) • Sufentanil 12 g (0.2 g/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 g 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

Mepivicaine 7.6

Etidocaine 7.7

Articaine 7.8

Lidocaine 7.9

Prilocaine 7.9

Bupivicaine 8.1

Procaine 9.1

% RN at PH Onset in7.4 minutes

40 2 to4

33 2 to4

29 2 to4

25 2 to4

25 2 to4

18 5 to8

2 14 to 18

O C2H

5 ⊕ O C 2

H 5

H 2 N COCH 2CH 2 H 2 N COCH 2CH 2 N +N H + H

C 2 H

5 C 2 H 5Cationic acid

Log Base

Acid = pH – p

Ka

(Henderson-Hasselbalch equation)

For procaine (p Ka =

8.9) at tissue pH

(7.4)

BaseAcid = 0.03

Nonionized base

Lipoid barriers

(nerve sheath)

ExtracellularBase

fluid

Nerve membrane * [3.1]

Axoplasm Base Acid [2.5]

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 large-diameter 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 Aδ-fibers.

Choice of local anesthetics

• Onset • Duration • Regional anesthetic technique • Sensory vs. motor block • Potential for toxicity

Clinical useOnset Duration

EstersProcaine Slow ShortChloroprocaine Fast ShortTetracaine Slow LongAmidesLidocaine Fast ModerateMepivacaine Fast ModerateBupivacaine Moderate LongRopivacaine Moderate LongEtidocaine Fast Long

Choice of local anesthetics

Technique Appropriate drugsTopical Cocaine, tetracaine, lidocaineInfiltration Procaine, lidocaine, mepivacaine,

bupivacaine, ropivacaine,

Peripheral nerve blocketidocaineChloroprocaine, lidocaine,mepivacaine, bupivacaine,

Spinalropivacaine, etidocaineProcaine, tetracaine, lidocaine,

EpiduralbupivacaineChloroprocaine, lidocaine,bupivacaine, ropivacaine,

I.V. regional anesthesiaetidocaineLidocaine

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 500

Chloroprocaine 600

Tetracaine 100 (topical)

Lidocaine 300

Mepivicaine 300

Bupivacaine 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 gangrene

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)