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					MCMP 407

           General Anesthesia


   Sleep induction
   Loss of pain responses
   Amnesia
   Skeletal muscle relaxation
   Loss of reflexes
MCMP 407

      General Anesthesia

       Stages of Anesthesia
        Stage I
              Analgesia
        Stage II
              Disinhibition
        Stage III
              Surgical anesthesia
        Stage IV
              Medullary depression
MCMP 407

   Types of anesthetics

   I. Inhalation anesthetics

   II. Intravenous anesthetics

   III. Local anesthetics
 MCMP 407
I. Inhalation anesthetics

Mechanisms of Action
 Activate K+ channels
 Block Na+ channels
 Disrupt membrane lipids
 In general, all general anesthetics increase the
  cellular threshold for firing, thus decreasing
  neuronal activity.
    MCMP 407
    I. Inhalation anesthetics

                  CH3CH2          O     CH2CH3

Ether (diethyl ether)
   Spontaneously explosive
   Irritant to respiratory tract
   High incidence of nausea and vomiting during induction
    and post-surgical emergence
    MCMP 407
    I. Inhalation anesthetics
                               O
Nitrous Oxide
    Rapid onset           N       N
    Good analgesia
    Used for short procedures and in combination
     with other anesthetics
    Supplied in blue cylinders
    MCMP 407
    I. Inhalation anesthetics

                                                   F    Br
Halothane (Fluothane)
                                              F    C    CH
    Volatile liquid
    Narrow margin of safety                        F Cl
    Less analgesia and muscle relaxation
    Hepatotoxic
    Reduced cardiac output leads to decrease in mean
     arterial pressure
    Increased sensitization of myocardium to catecholamines
    MCMP 407
I. Inhalation anesthetics

Enflurane (Ethrane)                             F   F        F
   Similar to Halothane                    H   C   C    O   CH
   Less toxicities                             Cl F         F




                                                F   H        F
Isoflurane (Forane)
                                            F   C   C    O   CH
   Volatile liquid
   Decrease mean arterial pressure             F   Cl       F
    resulting from a decrease in systemic
    vascular resistance
  MCMP 407
I. Inhalation anesthetics

Pharmacokinetics
   The concentration of a gas in a mixture of gases is
    proportional to the partial pressure
   Inverse relationship between blood:gas solubility and rate
    of induction

                    Alveoli   Blood       Brain


Nitrous oxide
(low solubility)




Halothane
(high solubility)
 MCMP 407
I. Inhalation anesthetics
Pharmacokinetics
   Increase in inspired anesthetic concentration will
    increase rate of induction
   Direct relationship between ventilation rate and induction
    rate
   Inverse relationship between blood flow to lungs and rate
    of onset
   MAC=minimum concentration in alveoli needed to
    eliminate pain response in 50% of patients

Elimination
 Redistribution from brain to blood to air
 Anesthetics that are relatively insoluble in blood and
   brain are eliminated faster
    MCMP 407
I. Inhalation anesthetics
Side Effects
   Reduce metabolic rate of the brain
   Decrease cerebral vascular resistance thus increasing
    cerebral blood flow = increase in intracranial pressure

   Malignant Hyperthermia
        Rare, genetically susceptible
        Tachycardia, hypertension, hyperkalemia, muscle rigidity,
         and hyperthermia
        Due to massive release of Ca++
        Treat with dantrolene (Dantrium), lower elevated
         temperature, and restore electrolyte imbalance
MCMP 407
II. Intravenous anesthetics

                                                  Cl
Ketamine (Ketaject, Ketalar)
   Block glutamate receptors
   Dissociative anesthesia:
      Catatonia, analgesia, and amnesia          HN
       without loss of consciousness                         O
                                                       CH3
      Post-op emergence phenomena:
         disorientation, sensory and perceptual
           illusions, vivid dreams
   Cardiac stimulant
MCMP 407
II. Intravenous anesthetics

Etomidate (Amidate)                                             N
   Non-barbiturate                                     O
   Rapid onset                              C2H5   O   C   N
   Minimal cardiovascular and respiratory
    toxicities                                              CHCH3
   High incidence of nausea and vomiting
MCMP 407
II. Intravenous anesthetics

    Propofol (Diprivan)                CH(CH3)2
       Mechanism similar to ethanol
       Rapid onset and recovery         OH
       Mild hypotension
       Antiemetic activity            CH(CH3)2


    Short-acting barbiturates
       Thiopental (Pentothal)


    Benzodiazepines
       Midazolam (Versed)
MCMP 407
III. Local anesthetics
   Blockade of sensory transmission to brain from a
    localized area
   Blockade of voltage-sensitive Na+ channels
   Use-dependent block
   Administer to site of action
       Decrease spread and metabolism by co-administering with a1-
        adrenergic receptor agonist (exception….cocaine)


                               O
                                                    C2H5
                H 2N           C    O   CH2 CH2 N
                                                    C2H5

                               Procaine
MCMP 407
III. Local anesthetics

      Structure-Activity Relationships
         Benzoic acid derivatives (Esters)
         Aniline derivatives (Amides)


     R
                    Ester/Amide   X   NH      R
MCMP 407
III. Local anesthetics

      Structure-Activity Relationships
                         O
                                                 C2H5
           H 2N          C    O   CH2 CH2 N
                                                 C2H5

                   Procaine (Novocain)


                    CH3
                              O           C2H5
                         NH   C   CH2 N
                                          C2H5
                    CH3

                  Lidocaine (Xylocaine, etc.)
    MCMP 407
III. Local anesthetics

         Structure-Activity Relationships

   Direct correlation between lipid solubility AND potency
    as well as rate of onset
   Local anesthetics are weak bases (pKa’s ~8.0-9.0)



         Why are local anesthetics less
          effective in infected tissues?
 MCMP 407




            See Katzung, Page 220




 Activation gate (m gate) is      With inactivaton gate closed, drug
  voltage-dependent                 can access channel through the
 Open channel allows access to     membrane
  drug binding site (R) from       Closing of the channel (m gate) is
  cytoplasm                         distinct from inactivation and
 Inactivation gate (h gate)        blocks access to drug binding site
  causes channel to be             Thus, local anesthetics bind
  refractory                        preferentially to the
                                    open/inactivated state
    MCMP 407
  III. Local anesthetics
Drug                                  Duration of Action
Esters
 Cocaine                                  Medium
 Procaine (Novocain)                       Short
 Tetracaine (Pontocaine)                   Long
 Benzocaine                           Topical use only
Amides
 Lidocaine (Xylocaine)                     Medium
 Mepivacaine (Carbocaine, Isocaine)        Medium
 Bupivacaine (Marcaine)                     Long
MCMP 407
III. Local anesthetics
Techniques of administration
   Topical: benzocaine, lidocaine, tetracaine
   Infiltration: lidocaine, procaine, bupivacaine
   Nerve block: lidocaine, mepivacaine
   Spinal:   bupivacaine, tetracaine

   Epidural:    bupivacaine

   Caudal: lidocaine, bupivacaine
MCMP 407
III. Local anesthetics

Toxicities:
 CNS-sedation, restlessness, nystagmus, convulsions
 Cardiovascular- cardiac block, arrhythmias,
  vasodilation (except cocaine)
 Allergic reactions-more common with esters

				
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posted:4/23/2008
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