general anesthetics

General Anesthetics

Surgery Before Anesthesia

Fun and Frolics led to Early Anesthesia

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(150 years old)

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

History of Anesthesia

• General anesthesia• Regional anesthesia• Local anesthesia• Conscious Sedation (monitored anesthesia

care)

Anesthetic techniques

• No universally accepted definition• Usually thought to consist of:

– 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

What is “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)

Goals of General Anesthesia

• Rapid induction• Sleep• Analgesia• Secretion control• Muscle relaxation• Rapid reversal

Desired Effects Of General Anesthesia (Balanced 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

Phases of General AnesthesiaStages 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.

Phases of General AnesthesiaStages Of General Anesthesia

•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

Routes of Induction

• Inhalation anesthesia – Anesthetics in gaseous state are taken up by

inhalation

• Total intravenous anesthesia• Inhalation plus intravenous (“Balanced

Anesthesia”)– Most common

Anesthetic Techniques

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

•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

Anesthetic Depth

• 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

Selection of anesthetic technique

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.

• 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

• Circadian rhythm• Body temperature• Age • Other drugs

– Prior use– Recent use

Factors Affecting MAC

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

–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

•“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.

• 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

Receptors Possibly Mediating CNS Effects Of Inhaled Anesthetics

Inhaled Anesthetics

• Gases– Nitrous oxide– Present in the gaseous state at room temperature and pressure– Supplied as compressed gas

• 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

Inhaled Anesthetics

• 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

Concentration of Inhaled Anesthetics Determines Dose

• 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

Solubility of Inhaled Anesthetics Determines Dose and Time-course

Chemistry(CF3)2CH-O-CH3

10%, excellent anesthesia

CF3CHFCF2-O-CH3

5%, light anesthesia, tremors

CF3CH2-O-CF2CH2F3%, convulsions

CF3CH2-O-CH2CF3 (Indoklon)0.25%, marked convulsions

CF3CF2-O-CF2CF3 InertFrom: F.G. Rudo and J.C. Krantz, Br. J. Anaesth. (1974), 46, 181

Inhaled Anesthetics

•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; 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

Inhaled Anesthetics - Historical

•Enflurane (Ethrane) Rapid, smooth induction and maintenance

• 2-10% metabolized in liver

• Introduced as replacement for halothane

•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

Inhaled Anesthetics – Currently

•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

• Degrades to form CO in dessicated soda-lime (Ba2OH

/NaOH/KOH; not Ca2OH)

• Fast recovery – responsive within 5-10 minutes

Inhaled Anesthetics

•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

•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?

Inhaled Anesthetics – Currently

• 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

Malignant HyperthermiaMalignant 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).

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

• 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

Organ 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.

Cardiovascular Effects

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 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.

0.00

0.50

1.00

1.50

2.00

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)

Isof

lura

ne C

once

ntra

tion

(%)

MAC Reduction

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

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)• Peripheral nerve blockade• Intravenous regional anesthesia• Spinal and epidural anesthesia• Systemic uses (antiarrhythmics, treatment of

pain syndromes)

StructureAll 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 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

•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

O

COCHH N2

CCH22

H

H

2

N5

C 52

HC 52

HC 52

O

COCHH N2 CH22 N H + H+

Nonionized baseCationic acid

BaseAcid

Log = pH – pKa

(Henderson-Hasselbalch equation)

BaseAcid

0.03=

For procaine (pK = 8.9)at tissue pH (7.4)

a

Base Acid

Lipoid barriers (nerve sheath)

Extracellular fluid

Axoplasm Base Acid

*Nerve membrane

[1.0]

[2.5]

[1.0]

[3.1]

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

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 A-fibers.

Choice of local anesthetics

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

Clinical use Onset Duration Esters Procaine Slow Short Chloroprocaine Fast Short Tetracaine Slow Long Amides Lidocaine Fast Moderate Mepivacaine Fast Moderate Bupivacaine Moderate Long Ropivacaine Moderate Long Etidocaine Fast Long

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

bupivacaine, ropivacaine,etidocaine

Peripheral nerve block Chloroprocaine, lidocaine,mepivacaine, bupivacaine,ropivacaine, etidocaine

Spinal Procaine, tetracaine, lidocaine,bupivacaine

Epidural Chloroprocaine, lidocaine,bupivacaine, ropivacaine,etidocaine

I.V. regional anesthesia Lidocaine

Choice of local anesthetics

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

•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 for bowel surgery

- risk of respiratory depression, postural headache

Uses of Local Anesthetics

Neuromuscular Blocking Drugs

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• 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 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