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MSII Pharmacology > Unit 3 - General Anesthetics > Flashcards

Unit 3 - General Anesthetics Flashcards

1
Q

what is the likely mechanism for immobility in response to noxious stimuli?

A

inhibition of the spinal cord

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2
Q

what is the likely mechanism for unconsciousness?

A

depressing the thalamic neurons and blocking thalamo-cortical communication

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3
Q

what do volatile anesthetics do to glutamate release? GABA release? glycine release?

A
  • inhibit glutamate release
  • increase and decrease GABA release
  • increase glycine affinity
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4
Q

what does the GABA-A receptor look like? similar structures? postsynaptic response?

A

member of super-family that includes nAChR, 5HT3, and glycine receptors

  • 5 non-identical subunits
  • mediate postsynaptic response by selectively allowing Cl- ions to enter, thus hyperpolarizing neurons
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5
Q

what does the glutamate receptor look like?

A

tetrameric protein with structurally related subunits

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6
Q

what are NMDA receptors? what do volatile anesthetics, ketamine, or N2O do?

A

glutamate-activated ion channels that conduct Na+, K+, and Ca++

  • modulate long-term synaptic responses
  • VA, ketamine, and N2O inhibit NMDA (ketamine potently and selectively, N2O selectively)
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7
Q

what drugs increase the frequency/length of time Cl- channels remain open? what channels are these important for?

A

barbiturates, propofol, and volatile anesthetics affect GABA-activated ion channels in this way

  • produce conformational change in GABA-A receptor that increases GABA affinity
  • liekly don’t bind to GABA binding site
  • 3 classes of drugs bind to different sites on GABA-A receptor
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8
Q

what drugs potentiate glycine activated currents?

A

propofol, alphaxalone, pentobarbitol

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9
Q

explain the Meyer-overton rule

A

potency of anesthetic gases is directly related to their solubility in olive oil
-however, this doesn’t affect their efficacy

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10
Q

what is the unitary theory of anesthesia?

A

since a variety of structurally unrelated drugs obey the same Meyer-Overton rule, they must bind at the same hydrophobic site

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11
Q

what is firefly luciferase and how is it involved in anesthesia?

A

water soluble protein that is inhibited by anesthetics in clinically relevant concentrations
-anesthetics bind to hydrophobic pockets on proteins

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12
Q

what are chloroform, halothane, and methoxyflurane?

A

older inhaled anesthetics no longer used today

  • chloroform; diethyl ether that was flammable and caused liver toxicity
  • halothane: alkane that is dysrhythmogenic, toxic to liver, and caused hypotension
  • methoxyflurane: methyl ethyl ether that caused both liver and kidney toxicity
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13
Q

what are chemical properties about desflurane that are important?

A

the boiling point is lower than the others (room temperature), and ventriculo-peritoneal shut pressure is higher than the others
-the MAC is also the highest of all (except for N2O)

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14
Q

ADME of inhaled anesthetics

A

Absorbed from alveoli into pulmonary capillary blood (uptake)
Distributed to site of action (brain) and reservoirs (vessel-rich group, muscle, fat)
Metabolized variously
Eliminated principally via lungs

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15
Q

why is partial pressure important in anesthesiology?

A

equilibriation between two phases (alveoli:blood, blood:brain) means that the same partial pressure of an anesthetic gas exists in both phases (but concentration may be different)

  • PP gradients propel anesthetic to brain
  • general anesthesia requires having an optimal and constant Pbr of inhaled anesthetic gas
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16
Q

what are factors that increase alveolar partial pressure? what determines PA?

A

PA is determined by delivery of anesthetic to alveoli minus uptake of anesthetic into blood

  • increased by delivery to alveoli and less uptake by blood
  • -increased delivery to alveoli: higher inhaled partial pressure and alveolar ventilation, but decreased functional residual capacity
  • -decreased uptake by blood: less blood solubility of agent, less CO, and less d(PA - Pa)
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17
Q

what is the 2nd gas effect?

A

ability of high volume uptake of one gas (N2O) to accelerate rate of increase in PA of a second gas (potent anesthetic agent)
-large volume uptake of N2O increases concentration of remaining gases (O2 and anesthetic) in resulting smaller lung volume

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18
Q

what is the speed of anesthetic induction determined by?

A

rate of rise of alveolar concentration of anesthetic agent (FA/FI)
-poorly soluble agents rapidly achieve high alveolar concentration, thus induction occurs more quickly

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19
Q

what is the minimum alveolar concentration? when does loss of awareness and recall occur?

A

concentration at which 50% of patients will not move in response to surgical incision, likely due to action on spinal cord

  • obeys Meyer-Overton rule (related to solubility in olive oil)
  • MACs are additive
  • loss of awareness and recall occurs at 0.4 to 0.5 MAC
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20
Q

what increases MAC? (more needed)

A
  • hyperthermia
  • pheomelanin (red hair)
  • high CNS catecholamine lvels (stress)
  • cyclosporine
  • hypernatremia
  • high CNS nt (MAOis, cocaine, ephedrine, L-DOPA)
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21
Q

what decreases MAC? (less needed)

A
  • hypothermia
  • increased age
  • decreased CNS catecholamine levels
  • opioids, anxiolytics, a2 agonists, lidocaine
  • hyponatremia
  • pregnancy, post-partum period
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22
Q

what is N2O?

A

nitrous oxide analgesic (doesn’t produce muscle relaxation)

  • relatively insoluble in blood, so if used alone, would need >100%
  • associated with post-op N/V
  • inactivates B12
  • accumulates in closed, air-containing spaces (bowel, middle ear, phemothoraces, air emboli, endotracheal tube cuffs)
  • adverse effects on embryonic development
  • used frequently for mask induction in children, and with volatile agents for maintenance
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23
Q

what is isoflurane?

A 
most potent (MAC 1.17%), somewhat pungent volatile agent
-mask induction is difficult, but it is the gold standard for maintenance of general anesthesia
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24
Q

what is desflurane?

A

least soluble, least potent of volatile agents

  • has Fl- instead of Cl- in isoflurane (complete fluorination of ether)
  • -decreases blood and tissue solubility (like N2O) for rapid emergency
  • -decreases potency (MAC 6.6%, 5x isoflurane)
  • most pungent of volatile agents
  • -with mask induction: coughing, salivation, breath holding, laryngospasm
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25
Q

what is sevoflurane?

A

sweet-smelling, non-pungent, bronchodilator (middle solubility and potency)

  • used for mask induction in children and adults
  • more soluble than desflurane, but less than isoflurane, and half as potent as isoflurane (MAC 1.8%)
  • metabolized into inorganic Fl- (but becomes nephrotoxic Compound A in rats)
  • can form CO when exposed to strong bases present in dry CO2 absorbers (exothermic RXN)
26
Q

what are Guedel’s 4 stages of CNS depression?

A

I: analgesia + amnesia
II: excitement/delirium: increased HR, RR, BP
III: surgical anesthesia
IV: medullary depression: without support of respiration and circulation, death ensues

27
Q

what are CNS effects of volatile agents?

A
  1. dose-dependent depression of:
    - EEG
    - sensory evoked potentials (increased latency, decreased amplitude)
    - motor evoked potentials
    - cerebral metabolic rate
  2. dose dependent increase in:
    - cerebral blood flow (may be blunted by hypocapnia made by deliberate hyperventilation)
    - increase in intracranial pressure parallels CBF
28
Q

what are cardiovascular effects of volatile agents?

A
  1. dose-dependent decreases in systemic vascular resistance and arterial blood pressure
  2. redistribution of blood flow
    - more to brain, muscle, and skin
    - less to liver, kidnneys, gut
  3. increased HR (5-10%) by isoflurane and desflurane)
    - likely due to puncency stimulating airway receptors and eliciting reflex tachycardia
  4. minimal effects on myocardial contractility
29
Q

what are respiratory effects of volatile agents?

A
  1. dose-dependent decrease in TV and ventilatory response to hypoxia and hypercapnia
    - blunted response of usually protective effect of CO2 or less O2
  2. dose-dependent increase in respiratory rate
  3. relaxation of airway smooth muscle (bronchodilation)
30
Q

what are neuromuscular effects of volatile agents?

A
  1. directly relax skeletal muscle
  2. potentiate effects of neuromuscular blockers
  3. trigger malignant hyperthermia in susceptible patients
31
Q

what are barbituates?

A

IV anesthetic prepared as aqueous solutions of Na+ salt

  • rapid onset, short duration of action, but only to induce
  • -provide only hypnosis/sedation
  • -hypnotic effect terminated by redistribution of drug from brain to muscle and fat
  • dose based on LBM
32
Q

how do barbiturates produce hypnosis?

A
  1. enhance actions of inhibitory nt
    - bind to GABA-A receptors to enhance Cl- conductance
    - act as direct agonist at higher concentrations
  2. inhibiting actions of excitatory nt
    - antagonist of NMDA-glutamate receptors
33
Q

how are barbiturates and propofol similar?

A
  • dose-dependent decreases in blood pressure due to vasodilation
  • dose dependent respiratory depression
  • barbiturates are negative inotropes
34
Q

what is propofol?

A

IV anesthetic “milk of amnesia” most commonly used IV anesthetic for hypnosis

  • insoluble in aqueous solution including soybean oil and egg
  • rapid onset and offset
  • metabolized in liver and lung, excreted in kidney
  • unique anti-emetic properties at sub-hypnotic doses
  • used for induction and maintenace of general anesthesia, and sedation in ICU
35
Q

how does propofol induce hypnosis?

A
  • hypnosis mediated via GABA agonist activity
  • -enhances GABA-induced Cl- currents
  • a2 receptor activity may also contribute
  • inhibits NMDA-glutamate receptors
  • directly depresses spinal cord neurons via action at GABA-A and glycine receptors
36
Q

does propofol trigger malignant hyperthermia? bacterial growth?

A

no malignant hyperthermia, but emulsion supports bacterial growth and must be thrown out if exposed

37
Q

what is propofol infusion syndrome?

A

in critically ill patients getting high doses > 48 hours

  • associated with administration of catecholamines and glucocorticoids in these patients
  • metabolic acidosis, myocardial failure, rhabdomyolysis, hyperkalemia, renal failure
  • unclear etiology, perhaps impaired FA oxidation
38
Q

what is etomidate?

A

IV anesthetic carboxylated imidazole structurally unrelated to any of the others

  • only D-isomer has anesthetic activity, which is primarily hypnosis due to GABA-antagonism
  • associated with pain on induction due to propylene glycol solvent (causes anepileptic myoclonus)
  • -due to subcortical disinibition
  • ester hydrolysis in liver
  • post-op N/V
  • NO analgesic activity
39
Q

what does etomidate do to cortisol? cardiorespiratory depression?

A

single dose inhibits cortisol synthesis
-not appropriate for continuous infusion

minimal cardiorespiratory depression; agent of choice in patients with minimal cardiac reserve

40
Q

what is ketamine? metabolism? ASE?

A

racemic mixture of phencyclidines (S+ more potent for dose-related anesthetic, analgesic, and unconsciousness)

  • metabolized by P450 enzymes to norketamine (1/3 to 1/5 as potent)
  • can administer orally, intranasally, rectally, IM, or IV
  • ASE: nystagmus, lacrimation, and salivation, with increased muscle tone with uncoordinated movement
  • -eyes remian open; corneal, cough, and swallow reflex intact but not protective
  • undesirable emergence delirium attenuated by benzodiazepines
41
Q

what is dissociative anesthesia

A

produced by ketamine

-patients appear to be in cataleptic state

42
Q

what is the primary site of CNS action of ketamine?

A

thalamo-neocortical projection system

  • depresses neuronal function in parts of cortex and thalamus
  • stimulates part of limbic system including hippocampus
  • causes functional disorgnization
  • may occupy opiate receptors in brain and spinal cord
  • is NMDA-glutamate receptor antagonist
43
Q

unique effects of ketamine on cardiovascular system?

A
  1. directly stimulates SNS
  2. increased systemic and pulmonary vascular resistance and pressure (no HTN)
  3. increased HR
  4. cardiac work and O2 consumption
    - not used in patients with CAD
  5. cerebral blood flow and intracranial pressure
    - not use din patients with intracranial mass lesions
44
Q

what is ketamine used for?

A

excellent bronchodilator

  • used as induction agent in patients with reactive airway disease (asthma), hypovolemia (trauma), cardiomyopathy, cardiac tamponade, restrictive pericarditis, congenital heart disease
  • used for IM induction in pediatric and developmentally delayed adult patients (ketamine dart)
45
Q

what are ketamine-unique uses?

A
  1. sedative/anesthetic for pediatric procedures
    - cardiac cath, radiation therapy, X-ray studies, dressing changes, dental procedures
  2. combined with propofol for IV procedural sedation
  3. as adjuvant to general anesthesia to decrease opioid use
  4. post-op analgesia in small doses to decrease opioid use
  5. as part of multimodal pain therapy regimen in chronic pain patients
46
Q

what is dexmedetomidine?

A

a2 adrenergic agonist (high specificity)

  • metabolized by liver, excreted in urine and feces
  • FDA approved for sedation <24 hours in ventilated ICU patients
  • binds to a2A/B receptors in locus ceruleus and spinal cord to produce sedation, sympatholysis, and analgesia
  • quality of sedation is different compared with GABA acting drugs
  • -easy to wake up and feel rested
  • -simiarlity to natural sleep (not REM)
  • primary site of analgesic action spinal cord
  • -systemic and epidural/spinal administration demonstrates narcotic sparring
47
Q

what are off-label uses for dexmedetomidine?

A
  1. procedural sedation in OR (awake intubation, craniotomies)
  2. adjunct to general anesthesia, especially in patients susceptible to narcotic-induced post-op respiratory depression (bariatric surgery)
  3. withdrawal/detoxification
48
Q

what does dexmedetomidine do to the respiratory system?

A

limited depression, thus wide margin of safety

49
Q

what are neuromuscular blocking agents?

A

interrupt transmission of nerve impulses at NMJ to prevent muscles from contracting
-can be depolarizers (to mimic ACh), or non-depolarizers (interfere with action of ACh)

50
Q

what are the chemical classes of non-depolarizing drugs?

A
  1. benzilisoquinolinium compounds (curare, atracurium)

2. amino steroid comppounds (pancuronium)

51
Q

explain the chemical structure of NMBs

A

all structurally related to ACh

  • contain quarternary ammonium structure N+
  • -positive charge attracts them to muscarinic and nicotinic ACh receptors
52
Q

what does succinylcholine do?

A

depolarizing NMB that stimulates and opens ion channels of all ACh receptors

  • muscle groups contract in disorganized fashion (fasciculations)
  • only NMB with rapid onset and ultra-short duration of action
  • used to facilitate intubation
  • action terminated by diffusion away from NMJ
  • -rapid hydrolysis by pseudocholinesterase; but if patient doesn’t have adequate AChase, they will be affected longer
53
Q

what are side effects of succinylcholine?

A
  1. stimulation of all cholinergic autonomic receptors –> cardiac dysrhythmias
  2. hyperkalemia (K+ leaves cells during depolarization)
    - can be life-threatening if pre-existing neuromuscular disease
  3. increased intraocular, intracranial, and intragastric pressure
  4. myalgias
  5. masseter spasm
54
Q

what factors affect NMB reversal?

A
  1. depth of blockade (recommendation to see some recovery prior to anti-cholinesterase administration)
  2. duration of action of non-depolarizer (shorter acting NMBs are more easily reversed)
  3. choice and dose of anti-cholinesterase
    - edrophonium (fastest onset)
    - neostigmine (more complete antagonism and most commonly used)
    - pyridostigmine (longer duration of action)
55
Q

explain what “Train of Four” is?

A

reduction in muscle response during electrical nerve stimulus reflects type and degree of blockade

  • non-depolarizing has TOF ratio < 1 (wait for 1-2 twitches prior to reversal)
  • depolarizing has TOF ratio of 1 (A = B)
56
Q

what is pancuronium?

A

bis-quartenary non-depolarizing NMB supplied as liquid

  • onset in 3-5 minutes, action for 60-90 minutes
  • 80% excreted unchanged in urine (some metabolism in liver)
  • avoid use in patients with renal insufficiency
  • modest increase in heart rate (vagolytic)
57
Q

what is vecuronium?

A

mono-quartenary non-depolarizing NMB supplied as powder (must be reconstituted for use)

  • onset in 3-5 minutes, action for 20-35 minutes
  • hepatic metabolism and excretion (renal excretion 30%)
  • devoid of circulatory effects
58
Q

what is rocuronium?

A

mono-quartenary non-depolarizing NMB supplied as liquid

  • onset 1-2 minutes, action for 20-35 minutes
  • -can speed onset and increase duration of action by increasing dose
  • -can be used as alternative to succinylcholine in rapid sequence intubation
  • 50% excreted unchanged in bile, some renal excretion
  • devoid of cardiovascular side effects
59
Q

what is Sugammadex? side effects?

A

1st selective relaxant binding agent

  • 3D structure resembles donut with hydrophobic interior
  • interior cavity traps rocuronium, forming stable complex which effects rapid reversal of blockade
  • no effect on AChase, so no need for anti-muscarinic
  • allows faster, more complete recovery compared to neostigmine
  • ASE: decreased BP; N/V, dry mouth
60
Q

what is unique about isoquinoline NMBs? examples?

A

undergo spontaneous, non-enzymatic degradation to be used in patients with renal or liver dysfunction

  • atracurium: onset in 3-5 minutes, with 20-35 minutes of action
  • -causes histamine release with brisk injection
  • -transient increase in HR, decreased BP
  • cisatracurium: onset in 3-5 minutes, with 20-35 minutes of action
  • -NO histamine release, and devoid of cardiovascular effects

MSII Pharmacology (43 decks)

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