anesthetics I-II Flashcards
Physicochemical properties of inhaled general anesthetics that determine anesthetic potency.
Volatile anesthetics are uncharged, nonpolar molecules with seemingly unrelated structures. More potent general anesthetics are more soluble in oil. Ie. nitrous oxide is very insoluble, whereas methoxyflurane is very oil soluble
define potency of anesthetics
potency=1/MAC (MAC = Minimum Alveolar Concentration of a GA that produces insensibility to pain in 50% of subjects)
Current thinking regarding the mechanism of action of inhaled anesthetics in producing anesthesia.
There is a lipid theory and a protein theory
Lipid theory of inhaled anesthetics
Suggests that volatile general anesthetics exert their effects by partitioning into the lipid component of the nerve cell membrane
protein theory of inhaled anesthetics
Proposes that anesthetics act via interactions with hydrophobic pockets in membrane proteins. The fundamental idea is that partitioning of volatile anesthetic into the cell membrane perturbs the normal function of integral membrane proteins, possibly causing depressed membrane excitability.
Anesthetic size cut-off and how this relates the mechanism
For a series of structurally-related compounds that differ only in size, only compounds below a certain size cut-off have anesthetic effects. This can be explained by assuming that anesthetic molecules must fit into pockets of specific size within membrane proteins, such as ion channels. This supports the protein theory
Action of volatile anesthetics on the nervous system
General anesthetics depress neuronal excitability in the CNS. The best described effect is a potentiation of GABAA receptor activity which prologs inhibitory postsynaptic potentials. Also, potentiation of brainstem glycine receptors, inhibition of nicotinic receptors and potentiation of TASK-1 K channels
role of conduction block in anesthesia
Impaired conduction of action potentials ONLY occurs at concentrations above clinical range, so conduction block does not underlie anesthesia. Conduction in peripheral nervous system is normal in anesthetized patients
Brain regions involved in general anesthesia
Hypothalamic nuclei involved in sleep, reticular formation of brainstem (pain sensation, alertness and sleep), hippocampus (memory)
anesthetic concentrations
Because the pockets are not specific binding sites, volatile anesthetics exert clinically-relevant effects only at concentrations much higher (∼1-100 mM) than those needed for drugs with specific binding sitesBecause the pockets are not specific binding sites, volatile anesthetics exert clinically-relevant effects only at concentrations much higher (∼1-100 mM) than those needed for drugs with specific binding sitesBecause the pockets are not specific binding sites, volatile anesthetics exert clinically-relevant effects only at concentrations much higher (∼1-100 mM) than those needed for drugs with specific binding sitesBecause the pockets are not specific binding sites, volatile anesthetics exert clinically-relevant effects only at concentrations much higher (∼1-100 mM) than those needed for drugs with specific binding sites
Ideal characteristics of a general anesthetic.
rapid and smooth onset of action, a rapid recovery from anesthesia upon termination of drug administration, and the drug would have a wide margin for safe use as well.
Signs and stages in the development of general anesthesia.
- Stage I – analgesia • Stage II – excitement, delirium
- Stage III – surgical anesthesia (this stage is not reached by N2O) Plane 1-regular, metronomic respirations. Plane 2- onset of muscular relaxation, fixed pupils. Plane 3- good muscular relaxation, depressed excursion of intercostal muscles during respiration. Plane 4- diaphragmatic breathing only, dilated pupils • Stage IV – medullary paralysis-Respiratory failure, vasomotor collapse and resulting circulatory failure lead to death within minutes.• Stage I – analgesia • Stage II – excitement, delirium
- Stage III – surgical anesthesia (this stage is not reached by N2O) Plane 1-regular, metronomic respirations. Plane 2- onset of muscular relaxation, fixed pupils. Plane 3- good muscular relaxation, depressed excursion of intercostal muscles during respiration. Plane 4- diaphragmatic breathing only, dilated pupils • Stage IV – medullary paralysis-Respiratory failure, vasomotor collapse and resulting circulatory failure lead to death within minutes.• Stage I – analgesia • Stage II – excitement, delirium
- Stage III – surgical anesthesia (this stage is not reached by N2O) Plane 1-regular, metronomic respirations. Plane 2- onset of muscular relaxation, fixed pupils. Plane 3- good muscular relaxation, depressed excursion of intercostal muscles during respiration. Plane 4- diaphragmatic breathing only, dilated pupils • Stage IV – medullary paralysis-Respiratory failure, vasomotor collapse and resulting circulatory failure lead to death within minutes.• Stage I – analgesia • Stage II – excitement, delirium
- Stage III – surgical anesthesia (this stage is not reached by N2O) Plane 1-regular, metronomic respirations. Plane 2- onset of muscular relaxation, fixed pupils. Plane 3- good muscular relaxation, depressed excursion of intercostal muscles during respiration. Plane 4- diaphragmatic breathing only, dilated pupils • Stage IV – medullary paralysis-Respiratory failure, vasomotor collapse and resulting circulatory failure lead to death within minutes.
Descending depression
progressive loss of function from higher (e.g., cognition and consciousness) to lower (e.g., respiratory control) levels within the central nervous system. Seen with general anesthesia
Sequence of events following general anesthesia progression
• alteration of consciousness and often analgesia • loss of temperature regulation • unconsciousness • effects on eye motion, pupil size and light reflex • loss of muscle tone • respiratory failure • cardiovascular failure • coma and death
time course of surgical anesthesia
• Induction: time between initiation of administration of anesthetic and attainment of surgical anesthesia, that is, until Stage III is reached • Maintenance: time during which surgical anesthesia is in effect (surgery carried out during this period) • Recovery: time following termination of administration of anesthetic until complete recovery of patient from anesthesia
depth of anesthesia depends on…
concentration of anesthetic in brain
The rate at which an effective concentration of anesthetic is reached in the brain depends upon…
(1) concentration of the anesthetic in inspired air, (2) alveolar ventilation rate, (3) pulmonary blood flow (cardiac output) (4) blood:gas partition coefficient, and (5) potency (oil:gas partition coefficient).
What is the maintenance stage of inhaled anesthesia
A steady state condition in which the anesthetic gas partial pressure in lung = anesthetic gas partial pressure in blood = anesthetic gas partial pressure in body tissues. In other words, no net uptake or loss of anesthetic occurs during this time. At steady state, the concentration of anesthetic in the brain is determined solely by the inspired anesthetic concentration.
Four phases of reaching steady state anesthesia
(I) lung factors, (II) uptake of anesthetic by blood from alveoli, (III) uptake from blood to body tissues, and (IV) tissue distribution.
Discuss phase 1 of steady state anesthesia
lung factors: The rate of increase in anesthesia partial pressure is proportional to rate of ventilation, so over ventilation increases rate of induction of anesthsia. Also, respiratory depression can prolong recovery time
How is depth of anesthesia affected by ventilation rate
it is not affected at all
Discuss phase 2 of reaching steady state anesthesia
uptake by blood from alveoli: rate of uptake is inversely related to anesthetic’s solubility in blood and pulmonary blood flow/cardiac output
How is solubility in blood measured
blood:gas partition coefficient (λ)- concentration of anesthetic in blood divided by anesthetic concentration in the inspired gas mixture at equilibrium
Is induction of anesthesia faster or slower for a more soluble anesthetic gas?
Slower- Higher GA solubility in blood, means that more anesthetic must be dissolved in blood in order to reach stage III, surgical anesthesia.
How does pulmonary blood flow affect initial rise in arterial anesthetic gas concentration
Increased pulmonary flow slows the initial rise in arterial anesthetic gas conc. b/c the faster blood passes through lungs, the less time there is for anesthetic to diffuse into blood. With time, the blood becomes loaded with anesthetic
Discuss phase 3 of reaching steady state anesthesia
uptake from arterial blood to body tissues, particularly brain: The rate of uptake into body tissues depends upon (1) anesthetic gas solubility in body tissues, (2) tissue blood flow, and (3) partial pressures of anesthetic in blood and in tissues
How is solubility in tissue expressed and what are the values for lean vs fatty tissues
This is expressed as the tissue:blood (brain:blood) partition coefficient. Tissue:blood partition coefficients are ∼1 for lean tissues (brain, heart, muscle, skin), and»_space;1 for fatty tissues.This is expressed as the tissue:blood (brain:blood) partition coefficient. Tissue:blood partition coefficients are ∼1 for lean tissues (brain, heart, muscle, skin), and»_space;1 for fatty tissues.This is expressed as the tissue:blood (brain:blood) partition coefficient. Tissue:blood partition coefficients are ∼1 for lean tissues (brain, heart, muscle, skin), and»_space;1 for fatty tissues.
How does tissue blood flow determine uptake of anesthesia from blood into tissues
The higher the blood flow, the faster the delivery of anesthetic. This is determined by cardiac output.
How does partial pressure of anesthetic in blood and tissues affect uptake into tissues
In early stages of anesthesia, the rate of uptake is rapid because this rate depends upon the difference in partial pressure between blood and tissue, which is initially large. As anesthesia develops, tissue levels of anesthetic rise, the difference in partial pressure gets smaller, and the rate of anesthetic uptake from blood into tissue decreases
Anesthetics permation into brain
General anesthetics freely permeate the blood-brain barrier: concentration of volatile anesthetic in brain – the organ targeted in a functional sense by general anesthetics – is in equilibrium with the concentration in arterial blood.
Discuss tissue distribution in vessel rich group of tissues
Vessel-rich group: highly vascularized tissues such as brain, heart, kidney, liver and endocrine glands. Uptake rate into these tissues is very high (minutes) because these tissues are very well perfused. Thus uptake into body tissue as a whole is dominated initially by the rate of uptake into this vessel-rich group.
Discuss tissue distribution in muscle group of tissues
Muscle group: includes muscle and skin. Uptake into these tissues occurs over 2-4 hours. Uptake is slower into this tissue group because perfusion is lower than in the vessel-rich group.
Discuss tissue distribution in fat group of tissues
Fat group: Inhaled anesthetic uptake occurs very slowly in fatty tissue owing to (i) the enormous amount of anesthetic that can be dissolved in fatty tissue, and (ii) the low perfusion. High lipid solubility of volatile anesthetics accounts for the huge anesthetic storage capacity of fatty tissue. Ultimately, the fat group comes to dominate the rate of uptake of gaseous anesthetic into total body tissue
Which tissue group determines recovery time from anesthesia
Fat group- The longer the required duration of anesthesia, the greater the loading of fatty tissue with volatile anesthetic. The consequence of this is that recovery from long-duration anesthesia will be long because unloading anesthetic from fatty tissue is slow
Methods of elimination of volatile anesthetics
clearance by lungs is major route. Determined by cardiac output and respiration. Metabolism is not important in terminating action, but hepatic metabolism does contribute to adverse reactions
Nitrous oxide - potency, use
Low potency anesthetic, but excellent analgesic. Used in “balanced anesthesia”: N2O combined with barbiturate + opioid. Used alone, exhibits rapid onset (3-5 minutes), rapid recovery
concentration effect of nitrous oxide
Uptake rate is faster than predicted b/c large volume is taken out of lung into blood, pulling more N2O gas into lung.
Diffusion hypoxia from nitrous oxide
when anesthetic administration is terminated Large N2O volume leaving blood expands lung and dilutes alveolar O2 - hypoxia
Second gas effect from nitrous oxide
Huge volume uptake rate of N2O sucks more of both gases into lungs Thus, uptake of halothane is increased over expected value alone
nitrous oxide advantages, contraindications
Increases cerebral blood flow less than other agents – consideration if patient has a head injury. Contraindications: respiratory obstruction, especially chronic obstructive respiratory disease pregnancy – epidemiological studies suggest mildly increased risks of miscarriage, infertility
Halothan- potency, side effects
Moderately to highly potent; poor analgesic. May cause respiratory/cardiac failure (arrythmias), can be hepatotoxic and may cause malignant hyperthermia
Signs of hepatotoxicity from halothane
2-5 days after anesthesia, fever, anorexia and nausea/vomiting Death occurs in 50% of these patients Repeated exposure to halothane significantly increases the risk
Cause and treatment of malignant hyperthermia
Inherited disorder, mutations in ryanodine receptors in skeletal muscle. Ryanodine receptors (RyR): Ca2+ release channels, key in muscle contraction. Treat: ice water immersion, dantrolene to block RyR and relax muscle. Use IV anesthetic if family history
Isoflurane - advantages, disadvantages
Most widely used inhaled anesthetic. Advantages: more potent, less hepatotoxicity and renal toxicity, little seizure propensity. Minimal myocardial depression, good muscle relaxant. Disadvantage: more pungent odor than halothane, triggers coughing
Sevoflurane- advantages, disadvantages
Pleasant odor – no coughing – so can be used for induction. Drawback: chemically unstable, releases fluoride ions, which are toxic to kidneys
Thiopental- MOA, onset, recovery
IV anesthetic. Short acting barbiturate that potentiates GABA activity. Rapid onset (15-20 seconds), fast induction and recovery due to high lipid solubility
Propofol- MOA, onset, recovery, benefits
IV anesthetic. Potentiates GABA receptor activity. Rapid onset, faster recovery than thiopental. Less nausea
Etomidate- MOA, advantage, onset, recovery, negatives
IV anesthetic. Nonbarbiturate hypnotic lacking analgesic properties, potentiates GABA receptor activity. Minimal depression of cardio and respiratory function. Loss of conciousness in seconds, recovery within 3 minutes. Can cause involuntary movements, nausea, vomiting, pain
Ketamine- MOA, onset, advantage
IV adjunct. NMDA antagonist. Slow effect (2-5 minutes). Potent bronchodilator (good for asthma), post operative psychic disturbance
Anti-anxiety meds used for surgery
Benzodiazepines (diazepam (valium)) used for sedative purposes, Barbiturats (pentobarbital) used infrequently
induction agents for surgery
thiopental, propofol
Analgesics for surgery
opioids- morphine, fentanyl
neuromuscular blockers used for surgery
relax skeletal muscle- vecuronium
anticholinergic drugs used for surgery
reduce GA induced hypotension, bradycardia and excess salivary secretions that can choke patient. Glycopyrrolate
Anti-emetics for surgery
ondansetron (5-HT receptor antagonist)
