General Anesthetics
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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 N 2 O in 1773

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General Anesthetics

Michael H. Ossipov, Ph.D.

Department of Pharmacology




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)


Rapid induction

Sleep

Analgesia

Secretion control

Muscle relaxation

Rapid reversal

Desired Effects Of General Anesthesia

(Balanced Anesthesia)


Phases of General Anesthesia

Stages Of General 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.


Potentiation of inhibitory ‘receptors’

GABAA

Glycine

Potassium channels

Inhibition of excitatory ‘receptors’

NMDA (glutamate)

AMPA (glutamate)

Nicotinic acetylcholine

Sodium channels

Receptors Possibly Mediating CNS

Effects Of Inhaled Anesthetics

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
Chemistry Time-course

(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 Time-course


Inhaled Anesthetics - Historical Time-course

  • 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 Time-course

  • 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 Time-course

  • 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 Time-course

  • 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 Time-course

  • 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 Time-course

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 Time-course

  • 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



Organ Effects Time-course

  • 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 Time-course

  • 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 Time-course

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) Time-course

  • 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) Time-course

  • 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 Time-course

  • 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 Time-course

  • 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 Time-course

  • 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
Conscious sedation Time-course

  • 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
Depth of sedation Time-course


Conscious sedation1
Conscious sedation Time-course

  • 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 sedation2
Conscious sedation Time-course

  • 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
What is Balanced Anesthesia? Time-course

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 anesthesia1
What is Balanced Anesthesia? Time-course

Garbage Anesthesia (everything but the kitchen sink)

LOT2 (Little Of This, Little of That)

Mixed Technique

The Usual


Mac reduction
MAC Reduction Time-course

Lang et al, Anesthesiology 85, 721-728, 1996


Bolus dose equivalents
Bolus Dose Equivalents Time-course

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 n 2 o
What is the role of N Time-course2O?

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
Simple Combinations Time-course

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 combinations1
Simple Combinations Time-course

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 Time-course

Michael H. Ossipov, Ph.D.

Department of Pharmacology


General concepts
General concepts Time-course

  • 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 concepts1
General concepts Time-course

  • 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 concepts2
General concepts Time-course

  • 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 concepts3
General concepts Time-course

  • 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
Local anesthetics: Uses Time-course

Topical anesthesia (cream, ointments, EMLA)

Peripheral nerve blockade

Intravenous regional anesthesia

Spinal and epidural anesthesia

Systemic uses (antiarrhythmics, treatment of pain syndromes)


Structure
Structure Time-course

  • 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


  • Structure1
    Structure Time-course

    • 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


    C Time-course

    H

    O

    2

    5

    C

    H

    5

    2

    H

    N

    COCH

    CH

    N

    2

    2

    2

    C

    H

    2

    5

    C

    H

    2

    5

    O

    +

    H

    N

    COCH

    CH

    N

    H

    +

    H

    2

    2

    2

    Cationic acid

    Nonionized base

    [1.0]

    Base

    Log

    Lipoid barriers

    (nerve sheath)

    = pH – p

    K

    a

    Acid

    (Henderson-Hasselbalch equation)

    Extracellular

    Base Acid

    [1.0]

    fluid

    For procaine (p

    K

    = 8.9)

    a

    at tissue pH (7.4)

    Nerve membrane

    [3.1]

    *

    Base

    Axoplasm

    Base Acid

    [2.5]

    =

    0.03

    Acid


    Structure2
    Structure Time-course


    Structure3
    Structure Time-course


    Mode of action
    Mode of action Time-course

    • 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 action1
    Mode of action Time-course


    Mode of action2
    Mode of action Time-course


    Mode of action3
    Mode of action Time-course


    Sensitivity of fiber types
    Sensitivity of fiber types Time-course

    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 Ad-fibers.


    Choice of local anesthetics
    Choice of local anesthetics Time-course

    Onset

    Duration

    Regional anesthetic technique

    Sensory vs. motor block

    Potential for toxicity


    Clinical use
    Clinical use Time-course



    Factors influencing anesthetic activity
    Factors influencing anesthetic activity Time-course

    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
    Redistribution and metabolism Time-course

    Rapidly redistributed

    More slowly metabolized and eliminated

    Esters hydrolyzed by plasma cholinesterase

    Amides primarily metabolized in the liver


    Local anesthetic toxicity
    Local anesthetic toxicity Time-course

    Allergy

    CNS toxicity

    Cardiovascular toxicity


    Allergy
    Allergy Time-course

    • 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
    Systemic toxicity Time-course

    Results from high systemic levels

    First symptoms are generally CNS disturbances (restlessness, tremor, convulsions) - treat with benzodiazepines

    Cardiovascular toxicity generally later


    Cns symptoms
    CNS symptoms Time-course

    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
    Cardiovascular toxicity Time-course

    Depressed myocardial contractility

    Systemic vasodilation

    Hypotension

    Arrhythmias, including ventricular fibrillation (bupivicaine)


    Avoiding systemic toxicity
    Avoiding systemic toxicity Time-course

    Use acceptable total dose

    Avoid intravascular administration (aspirate before injecting)

    Administer drug in divided doses



    Uses of Local Anesthetics Time-course

    • 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 Time-course

    • 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 Time-course

    • 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 Time-course

    • 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


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    Neuromuscular Blocking Drugs

    Michael H. Ossipov, Ph.D.

    Department of Pharmacology


    Neuromuscular blocking drugs

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    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 drugs1

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    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 drugs2

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    Neuromuscular blocking drugs

    (CH3)3N+-(CH2)6-N+(CH3)3

    Hexamethonium

    (ganglionic)

    (CH3)3N+-(CH2)10-N+(CH3)3

    Decamethonium

    (motor endplate)


    Neuromuscular blocking drugs3

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    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

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    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

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    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

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    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

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    Succinlycholine: Pharmacokinetics

    • Fast onset (1 min)

    • Short duration of action (2 to 3 min)

    • Rapidly hydrolyzed by plasma cholinesterase


    Succinlycholine clinical uses

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    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

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    Succinylcholine: Side effects

    • Prolonged neuromuscular blockade

      • In patients lacking pseudocholinesterase

        • Treat by maintaining ventilation until it wears off hours later


    Succinylcholine phase ii block

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    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

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    Acetylcholinesterase inhibitors

    • Acetylcholinesterase inhibitors have muscarinic effects

      • Bronchospasm

      • Urination

      • Intestinal cramping

      • Bradycardia

    • Prevented by muscarinic blocking agent


    Selection of muscle relexant

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    Selection of muscle relexant:

    • Onset and duration

    • Route of metabolism and elimination


    Monitoring nm blockade

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    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


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