General Anesthetics Flashcards
Signs and stages in the development of general anesthesia
Stage I – analgesia
Stage II – excitement, delirium
Stage III – surgical anesthesia
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
Differences between tissue groups that are important in determining uptake of general anesthetics
Vessel-rich group: highly vascularized tissues (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.
Muscle group: (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.
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.
Characteristics of more potent GAs
More soluble in oil
MAC and its relationship to potency
Minimum Alveolar Concentration of a GA that produces insensibility to pain in 50% of subjects
Potency is proportional to 1/MAC
Actions of GAs in the therapeutic range
Duration of GABAa-recptor mediated inhibitory synaptic current is prolonged
Potentiation of glycine receptors (increased inhibitory transmission)
Inhibition of brain nicotinic ACh receptors (decreased excitatory transmission)
Potentiation of TASK-1 K+ channels that set resting potential (decrease excitability)
Actions of GAs that ONLY occur in higher doses than therapeutic ranges
Impaired conduction of action potentials: conduction block DOES NOT underlie anesthesia (in therapeutic doses). Conduction in peripheral nervous system is normal in anesthetized patients.
Inhalational anesthetics act on voltage-gated Na+, Ca2+ and K+ channels , but only at anesthetic levels substantially higher than that needed to induce surgical anesthesia.
What areas of the brain are suspected to be especially affected by GAs?
hypothalamic nuclei involved in sleep
reticular formation of the brainstem- involved in control of pain sensation, alertness and sleep and because damage to this region can cause unconsciousness
hippocampus- The amnesia of postoperative patients probably involves this because short-term memory
Protein theory of GA action
Volatile GAs (i) partition into the membrane, and (ii) enter hydrophobic pockets in various membrane proteins such as GABAA receptors, other ion channels and perhaps proteins involved in neurotransmitter release.
Volatile GA occupancy of hydrophobic pockets in membrane proteins alters the function of these proteins, depressing central nervous system function and producing general anesthesia.
Volatile anesthetics and intravenous anesthetics potentiate GABAergic IPSPs in the CNS, and this effect seems to be key in anesthesia.
The hydrophobic protein pockets within which volatile anesthetics bind are not specific binding sites, but pocket size does account for the size cut-off for volatile anesthetics.
Because these 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.
What factors determine the rate at which an effective concentration of anesthetic is reached in the brain?
(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)
4 phases in the uptake of volatile anesthetic
(I) lung factors
(II) uptake of anesthetic by blood from alveoli
(III) uptake from blood to body tissues
(IV) tissue distribution
Lung factors affecting uptake of volatile anesthetic
Rate of increase in the partial pressure of anesthetic gas in the alveoli and pulmonary capillary blood is proportional to the rate of ventilation
The depth of anesthesia is not affected by ventilation rate
Rate of ventilation also affects recovery from GA, so respiratory depression can prolong recovery time
Uptake of anesthetic by blood from alveoli
Uptake rate is determined by:
i. the solubility in blood of anesthetic gas: The blood:gas partition coefficient (λ) is a measure of the solubility of anesthetic gas in blood. The blood:gas partition coefficient is defined as the concentration of anesthetic in blood divided by anesthetic concentration in the inspired gas mixture
ii. pulmonary blood flow = cardiac output
Initial rise in arterial anesthetic gas concentration is slowed by increased pulmonary flow (cardiac output) – the faster that blood passes through the lungs, the less time there is for anesthetic to diffuse into the blood, and hence the lower the concentration of anesthetic in blood at early times after onset of administration of anesthetic.
Is the induction of anesthesia is slower or faster 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
The compartment size into which the anesthetic dissolves is larger for a more soluble anesthetic gas than it is for a less soluble one.
How is the rt of transfer of volatile anesthetic from alveoli to blood related to solubitily and pulmonary blood flow?
Inversely related to both!
Uptake from arterial blood to body tissues, particularly brain
The rate of uptake into tissues depends upon:
(1) anesthetic gas solubility in body tissues: 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.
(2) tissue blood flow: higher the blood flow, the faster the delivery of anesthetic
(3) partial pressures of anesthetic in blood and in tissues: faster rate when the difference in partial pressures is higher
Pharmacokinetics of elimination of inhalational general anesthetics
Clearance by lungs is major route of removal for the volatile anesthetics
Elimination is not under the control of the physician, but is instead determined by cardiac output and respiration of the patient
In general, metabolism (in the liver) of volatile anesthetics is not important in terminating volatile anesthetic action
Products of hepatic metabolism of volatile anesthetics are often important as instigators of adverse reaction to volatile anesthetics
Characteristics of an idea GA?
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
Rationale for combination use of GA?
No single GA possesses all desirable properties, so a combination of drugs is used in modern anesthesiological practice to achieve optimal behavior.
Specific drug combinations are designed to take advantage of the desirable properties of individual drugs while attenuating undesirable side effects
Nitrous oxide
Gaseous anesthetic
Low potency anesthetic, but excellent analgesic
MAC for N2O is 105%: N2O cannot be used as a sole anesthetic agent
Rapid onset (3-5 minutes), rapid recovery
Desflurane (on drug list but not in ppt)
Volatile anesthetic
Relatively recently developed volatile anesthetic
Drawback: desflurane has a pungent odor, causing airway irritation and coughing
Contraindicated in patients with a predisposition to malignant hyperthermia
Enflurane (on drug list but not in ppt)
Volatile anesthetic
Excellent analgesic
Induction and recovery are moderately fast
Good muscle relaxant
Most common use is as general anesthetic for maintenance of anesthesia in adults
Main drawback is that it can trigger seizures, either during induction or recovery
Halothane
Volatile anesthetic
Until recently, most widely used inhalational anesthetic Moderately to highly potent; poor analgesic
Untoward effects:
(i) Respiratory and cardiovascular failure (arrhythmias)
(ii) Hepatotoxic
(iii) Malignant hyperthermia and central core disease
Isoflurane
Volatile anesthetic
Has become most widely used inhalational anesthetic
Advantages: Somewhat more potent, less incidence of hepatotoxicity, renal toxicity ,little seizure propensity
More pungent odor than halothane, triggers coughing – use IV agents to overcome
Sevoflurane
Volatile anesthetic
Pleasant odor – no coughing – so can be used for induction
Drawback: chemically unstable, releases fluoride ions, which are toxic to kidneys
Propofol
Intravenous anesthetic
Potentiates GABAA receptor activity
Rapid onset anesthetic, similar in speed to thiopental
Faster recovery than for thiopental
Rapid metabolism
Seems to produce less nausea in the post-operative patient
Etomidate (on drug list but not in ppt)
Intravenous anesthetic
Nonbarbiturate hypnotic lacking analgesic properties
Potentiates GABAA receptor activity
Used primarily for induction of general anesthesia and in “balanced anesthesia”
Minimal depression of cardiovascular and respiratory function
Can cause involuntary patient movements during induction
High incidence of nausea with vomiting, and pain, on injection
Thiopental (on drug list but not in ppt)
Intravenous anesthetic
Very commonly used to induce general anesthesia
Ultra-short acting barbiturate
Potentiates GABAA receptor activity, prolonging IPSP duration at GABAergic synapses
Rapid deep anesthesia (20 sec), avoiding excitation/delirium
Diazepam
Intravenous adjunct
Anti-anxiety agent (benzodiazepine)
Ondansetron
Intravenous adjunct
Anti-emetic: reduce post-operative nausea and vomiting (common problem)
5-HT3–type serotonin receptor antagonist
Fentanyl
Intravenous adjunct
Analgesic
Opioid
Advantageously short duration of action
Glycopyrrolate
Intravenous adjunct
Anticholinergic drug
Reduce GA-induced hypotension, bradycardia, and excess
salivary secretions that can choke patient during anesthesia
Ketamine (on drug list but not in ppt)
Intravenous GA
Produces dissociative anesthesia characterized by catatonia, amnesia, and analgesia
Problems with “emergence phenomena” of disorientation and hallucination
Antagonist of the NMDA-subtype of glutamate receptor
Effect is to inhibit excitatory, glutamatergic synaptic transmission in the central nervous system
No action on GABAA receptor
Morphine
Intravenous adjunct
Analgesic
Opioid
Neuromuscular Blocking Agents
Intravenous adjunct
Relax skeletal muscle, particularly for abdominal surgeries
Dantrolene sodium
For malignant hyperthermia
Block RyR and relax muscle
Pharmacokinetics of N2O
(i) Concentration effect: Big anesthetic vol. taken out of lung into blood, sucks more N2O gas into lung. Uptake rate is faster than predicted
(ii) Diffusion hypoxia: when anesthetic administration is terminated Large N2O volume leaving blood expands lung and dilutes alveolar O2 - hypoxia
(iii) Second gas effect: Like concentration effect, but with 2 gaseous GAs (75% N2O, 1% halothane) Huge volume uptake rate of N2O sucks more of both gases into lungs Thus, uptake of halothane is increased over expected value alone
Therapeutic index of GA
Very narrow
Doses that are 2-4x amount needed for surgical anesthesia can cause circulatory failure
