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General anesthetics (Signs and stages of GAs (Stage of delirium: (Motor…

- - - - Intercostal ventilation weakens, then ceases, and only the diaphragmatic ventilation remains
        
        The pupil dilates gradually
        
        Various reflexes disappear:
        
        Corneal reflex: in plane 2 (no blinking upon stimulation of the cornea)
        
        Peritoneal reflex: in plane 3 (No abdominal muscle contraction upon perit stimulation
        
        Pupillary refles: in plane 4 (no pupillary constriction upon light
  - - - The heart stops (vasomotor center paralysis)
- - - - (1900s) The potency of inhalation anesthetics is directly related to their lipid solubility. They act by dissolving in the lipid membrane of the CNS, and the anesthesia develops
        when the conc. if high in the neuronal cell memb.
    - - (1980s) Benzodiazepines and barbiturates produce hypnotic effect by activating the GABA-A receptors -> Cl influx -> neuronal hyperpolarzation and is inhibitory.
    - - (1990s) We found out that most anesthetics activate the GABA-A. Drugs also affect other ligand ion-channels
    - - (Early 2000s) Anesthetics activate TREK-1, which is a 2 pore background K channel, causing K efflux and neuronal hyperpolarization
  - - - Inhalation anesthetics, except nitrous oxide
      - I.v. anesthetics, except ketamine
    - - Inhalation anesthetics, except nitrous oxide
  - - - All inhalation anesthetics
      - Barbiturates type i.v. anesthetics
    - - Nitrous oxide
      - Ketamine
- - - - Potency
        
        The more lipophilic, the more potent they are (the lower is their MAC value)
  - - - Diffusion across the alveolar membrane (follwing the conc. gradient), rapid absorption (due to the large alveolar surface, short diffusion distance)
    - - from the blood tissue (incl the brain)
        
        Less lipophilic are less dissolved in blood lipids -> less retained in the blood -> equilibrate rapidly between the blood and tissue -> the anestheric conc. in the brain is reacphed rapidly -> rapid induction of anesthesia at 1.3 MAC
        
        More lipophilic more dissolved in blood lipids -> more retained in the blood -> equilibrate slowly between the blood and tissue, incl brain -> slow induction of anestheis at 1.3 MAC
        
        However one may facilitate induction by: Transiently increasing the inhaled conc. or increasing the minute ventilation.
    - - Largely by exhalation. Halothane is also eliminated by biotransformation. Speed of elimination determines the speed of recovery from anesthesia after GA inhalation has stopped.
      - Slow for highly lipophilic anesthetics, as they are retained the brain and adipose tissue
      - Rapid for less lipophilic anesthetics, as they are less retained the brain and adipose tissue
  - - - Ether
        
        Diethyl ether
        
        Not used to the flammability and explosiveness of its vapor.
        
        Undesirable properties
        
        Light sensitive: light induces peroxidation of ether; ether peroxides are toxic (prevent by keeping in cans).
        
        Causes strong excitation during the stage of delirium.
        
        Irritates the airways → induces hypersecretion (like isoflurane and desflurane; prevented by atropine).
        
        Excites the vomiting center → postoperative vomiting.
        
        Advantages
        
        Ether produces good muscle relaxation.
        
        Ether is a safe anesthetic. It does not have severe toxic effects (e.g., hepato- and nephrotoxicity), and it does not depress cardiac contractility and respiration markedly (mechanical ventilation is not required)
        
        Divinyl ether
        
        Rarely used due to flammability. More potent then diethyl ether, and is less irritative to the airway. May be used for short anesthesia to reach the stage of analgesia for a short surgical intervention
      - Halogenated hydrocarbons: Halothane (Br-, Cl- and F-substituted) – highly lipid sol.
        
        Chloroform
        
        CHCL3. Queen victoria delivered her 8th child on it. No longer used due to its hepato- and cardiotoxicity. The hepatotoxic metabolite is phosgene, which is bormed by oxidative dehalogenation.
        
        Halothane
        
        Is the only inhlaltional anesthetic agent containing a bromine atom, its used as drastically curtailed due to its idiosyncrastic hepatotoxicity.
        
        Advantages
        
        It is non-flammable (just like any other halogenated hydrocarbon and halogenated ether)
        
        It causes “smooth induction” with virtually no stage of delirium
        
        It rarely induces postoperative nausea and vomiting
        
        It has bronchodilatory effect, like all halog. inhal. anesthetics – last resort in st. asthmaticus
        
        Disadvantages
        
        Insufficient decrease of muscle tone (easily overcome by muscle relaxants)
        
        Adverse effects: 2 common (predictable) and 2 rare (unpredictable)
        
        Common and predictable adverse effects of halothane
        
        Cardiac adverse effect
        
        Cardiodepressive effect
        
        manifested in decreased heart rate and decreased contractility
        
        halothane decreases cardiac output by 20-50%
        
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        Slightly sensitizes the heart to catecholamines
        
        Exogenous catecholamine may provoke arrhythmias (this is uncommon in children)
        
        Respiratory adverse effect
        
        Halothane reduces the respir. minute volume by inducing rapid shallow respiration leading to increase pCO2, and decrease pO2
        
        This necessitates assisted ventilation (i.e., use of anesthesia machine which also contains a ventilator)
        
        Halothane impairs the mucociliary clearance → mucus retention, postoperative respiratory infections
        
        Rare and inpredictable adverse effect of halothane:
        
        Halothane hepatitis – an immunologically determined reaction
        
        An idiosyncratic reaction = rare (1 in 10 000 cases; higher after repeated use), unpredictable reaction
        
        Symptoms start 2-5 days after anesthesia: fever, nausea; elevation of ALT, eosinophilia
        
        Hepatic failure rate may be as high as 50%
        
        Mechanism
        
        oxidative debromination (20% of dose) by CYP2El to reactive trifluoro-acetylchloride
        (a reactive electrophilic acyl chloride) → covalent binding to hepatic proteins = neoantigene formation
        → immune hepatitis
        
        On theoretical basis, disulfiram pretreatment has been recommended before halothane anesthesia to prevent
        hepatitis. Disulfiram is a potent inhibitor of CYP2E1 (not only of aldehyde dehydrogenase) and thus
        decreases formation of trifluoro-acetylchloride.
        
        Malignant hyperthermia (MHT) – a genetically determined reactio
        
        MHT may be caused by any halogenated inhalation anesthetic and also by succinylcholine
        
        Symptoms
        
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        Pathomechanism
        
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        Therapy
        
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      - Halogenated ethers: Cl- and F-substituted (more lipid sol.): enflurane, isoflurane - Only F-substituted (less lipid soluble): desflurane, sevoflurane
      - All halogenated inhalators have respiratory depressive effect, Necessiating mechanical ventilation. Halothane and enflurane also produce negative inotropic effect.
      - Halogenated ethers
        
        Enflurance
        
        Use has been diminished
        
        Advantages
        
        Like ether
        
        Enflurane has a good muscle relaxant effect
        
        Enflurane does not sensibilize the heart toward catecholamines
        
        Like halothane
        
        Enflurane is not flammable
        
        Enflurane smoothly induces anesthesia
        
        Disadvantages
        
        Like ether
        
        Enflurane mildly stimulates the tracheobronchial secretions
        
        Enflurane may cause postoperative nausea and vomiting (10%)
        
        Like halothane
        
        Enflurane decreases cardiac contractility (but not the heart rate)
        
        it causes a moderate decrease in cardiac output and blood pressure
        
        it causes a moderate decrease in cardiac output and blood pressure
        
        Rare adverse effect
        
        Tonic-clonic seizures
        
        Sometimes signs can only be detected by EEG
        
        We will see high voltage, high frequency activity, "spike and dome complexes"
        
        Seizures are short and self limiting
        
        Hyperventilation should be avoided, because it causes hypocarbia (↓pCO2)
        which sensitizes the CNS to enflurane-induced seizures
        
        CO2 in the brain causes two effects
        
        Anticonvulsive effect (remember the carbonic anhydrase inhibitor acetazolamide also ↑CO2 and is used as
        an adjuvant to antiepipleptics); therefore, ↓CO2 is proconvulsive
        
        Vasodilatory effect; therefore, ↓CO2 causes vasoconstriction – desirable in brain surgery
        
        Biotransformation
        
        2-5% of dose undergoes dehalogenation
        
        Isoflurane
        
        Most commonly used anesthetic
        
        Properties similar to enflurance, except for 5
        
        Isoflurane’s dehalogenation in the body is only 0.2% – there is no reason to fear toxic metabolite
        
        Isoflurane does not cause cardiac depression → cardiac output is well maintained
        
        decreases BP because it reduces peripheral vascular resistance
        
        increases the heart rate, but arrhythmias are not precipitated
        
        Isoflurane does not induce seizures
        
        Isoflurane is a preferred anesthetic for BRAIN SURGERY for 2 reasons
        
        It decreases O2 demand/utilization by the brain
        
        Although isoflurane slightly ↑ the cerebral blood flow (CBF), the CBF and ICP can be ↓ by inducing
        hypocarbia (low pCO2) with hyperventilation. (Hypocarbia causes cerebral vasoconstriction.)
        
        An unfavorable property: isoflurane has pungent odor and irritates airways. This necessitates induction
        with an i.v. anesthetic
        
        Methoxyflurane
        
        Used to induce stage of analgesia, but not for GA
        
        It is the most lipid soluble and the most potent inhalant anesthetic
        
        It has nephrotoxic effects
        
        Clinical presentation: "High-output renal failure", a concentrating defect (ADH-refractory polyuria)
        
        Mortality rate: 20%, survivors slowly recover (it may take years)
        
        Increased susceptibility: after long anesthesia, in patients with existing renal disease, in older patents, and
        after treatment with CYP inducers
        
        Mechanism
        
        50-70% of methoxyflurane (MF) undergoes biotransformation via CYP-catalyzed. O-demethylation and subsequent oxidative dehalogenations. Its extensive biotransformation is mainly due
        to large accumulation of methoxyflurane in fat → prolonged release of MF from the fat → prolonged
        delivery of MF to the liver for biotransformation
        
        Nephrotoxic methoxyflurane metabolites: Methoxyfluoroacetic acid, dichloroacetic acid, oxalic acid, and
        fluoride ion. Note: Oxalic acid is also one of the nephrotoxic metabolites of ethylene glycol
        
        Desflurane (Suprane) and sevoflurane
        
        Common properties
        
        Ethers containing only fluorine substitutions
        
        They have lower lipid solubility and blood solubility than halothane, enflurane and isoflurane consequently
        
        they induce anesthesia more rapidly
        
        recovery from anesthesia is also more rapid
        
        They do not cause cardiac depression
        
        Causes
        
        hypotension (due to vasodilatation)
        
        respiratory depression
        
        Differences:
        
        Desflurane
        
        induces anesthesia most rapidly out of all volatile liquid anesthetics (as it is the least lipophilic)
        
        not used for anesthesia induction because it irritates the airways and causes coughing, breath
        holding, secretions and laryngospasm.
        
        In contrast, sevoflurane has a pleasant odor and can be used for induction
        
        Sevoflurane
        
        can react with the CO2 absorber Ba(OH)2 (Baralyme) in the anesthesia machine
        
        Adverse outcomes
        
        causes an exothermic reaction with the CO2 absorber
        
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        In the basic CO2 absorber, sevoflurane is dehydrofluorinated to form “compound A”
        
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- - - - it is flammable and explosive
      - it sensitizes the heart to catecholamines, and can induce arrhythmias, including
        ventricular fibrillation
  - - - N2O is nonflammable, not explosive
      - It lacks harmful effects under proper use
      - It does not induce malignant hyperthermia
      - Of the inhalation anesthetics, N2O is least likely to increase cerebral blood flow and intracranial pressure
      - It promotes induction and recovery when combined with halothane
    - - N2O is very weak → used only in combination with other general anesthetics
      - It has no muscle relaxant activity → use muscle relaxant
      - It may cause 3 adverse effects
        
        Diffusional hypoxia
        
        occurs when N2O inhalation is discontinued and air inhalation is started
        
        Reason
        
        N2O is rapidly released from the blood into the alveolar space
        
        → it dilutes O2 there → ↓ alveolar pO2 → ↓ arterial pO2. Easily prevented by O2 inhalation
        
        Expansion of closed air pockets
        
        in the body by replacing the N2 in these closed air spaces
        
        Reason
        
        arge amounts of N2O moves into the pocket readily, while N2 moves out from the pocket into
        the blood slowly, due to the much lower blood/gas partition coefficient for N2 (0.01) than for
        N2O (0.5)
        
        Air pocket
        
        occluded middle air, cyst in the lung or kidney, pneumothorax, and formed during
        pneumoencephalography. Avoid N2O in these conditions
        
        N2O oxidizes Co(I) to Co (II) in methycobalamin
        
        inactivates methylcobalamin for use by methionine synthase
        
        This may be harmful only after extremely prolonged or repeated use of N2O
        
        Consequence
        
        symptoms of vit. B12 deficiency
        
        megaloblastic anemia
        
        neuropathy
    - - For anesthesia
        
        combination with other inhalation anesthetics (e.g., halothane, enflurane, isoflurane)
        
        The MAC value of the anesthetic is reduced by 60% when 70% N2O is added → unwanted effects of the
        combined anesthetic (e.g., circulatory respiratory depression) are also reduced
      - For inducing euphoria
        
        in order to relieve chronic pain
        
        in patients with tetanus
        
        in cancer patients with pain
    - - N2O (laughing gas) induces euphoria; addiction may occur
      - Non-medical use
        
        At elevated temperatures, nitrous oxide is a powerful oxidizer; it is also used as an oxidizer in rocketry and
        in motor racing to increase the power output of engines
        
        Nitrous oxide is a greenhouse gas. Together with others (e.g., water vapor, CO2, methane), it absorbs the thermal
        infrared radiation originating from reflection of sunlight from the Earth’s surface back towards the space, thereby
        trapping this radiation (and the heat) in the lower atmosphere
- - - - Thalamic neurons with GABA-A - R
        
        GAs decrease thalamocortical excitatory signaling
      - Hypothalamic tuberomammillary nucleus neurons with GABA-A - R and excitatory projections to the cerebral cortex, whereby these TMN neurons directly increase cortical activation and arousal
        
        GAs decrease excitatory signaling by TMN neurons to the cortex
      - Cortex at specific regions
        
        GAs suppress cortical activity directly
      - Causes
        
        Sedative effect, unconsciousness, loss of arousability
    - - Causes
        
        Analgesia
    - - Causes
        
        Amnesia
    - - Causes
        
        Muscle relaxation (immobility)