Unit 3 - General Anesthetics

Question 1

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

Answer 1

inhibition of the spinal cord

Question 2

what is the likely mechanism for unconsciousness?

Answer 2

depressing the thalamic neurons and blocking thalamo-cortical communication

Question 3

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

Answer 3

• inhibit glutamate release
• increase and decrease GABA release
• increase glycine affinity

Question 4

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

Answer 4

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

Question 5

what does the glutamate receptor look like?

Answer 5

tetrameric protein with structurally related subunits

Question 6

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

Answer 6

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)

Question 7

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

Answer 7

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

Question 8

what drugs potentiate glycine activated currents?

Answer 8

propofol, alphaxalone, pentobarbitol

Question 9

explain the Meyer-overton rule

Answer 9

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

Question 10

what is the unitary theory of anesthesia?

Answer 10

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

Question 11

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

Answer 11

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

Question 12

what are chloroform, halothane, and methoxyflurane?

Answer 12

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

Question 13

what are chemical properties about desflurane that are important?

Answer 13

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)

Question 14

ADME of inhaled anesthetics

Answer 14

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

Question 15

why is partial pressure important in anesthesiology?

Answer 15

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

Question 16

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

Answer 16

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)

Question 17

what is the 2nd gas effect?

Answer 17

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

Question 18

what is the speed of anesthetic induction determined by?

Answer 18

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

Question 19

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

Answer 19

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

Question 20

what increases MAC? (more needed)

Answer 20

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

Question 21

what decreases MAC? (less needed)

Answer 21

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

Question 22

what is N2O?

Answer 22

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

Question 23

what is isoflurane?

Answer 23

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

Question 24

what is desflurane?

Answer 24

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

Question 25

what is sevoflurane?

Answer 25

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)

Question 26

what are Guedel's 4 stages of CNS depression?

Answer 26

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

Question 27

what are CNS effects of volatile agents?

Answer 27

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

Question 28

what are cardiovascular effects of volatile agents?

Answer 28

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

Question 29

what are respiratory effects of volatile agents?

Answer 29

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)

Question 30

what are neuromuscular effects of volatile agents?

Answer 30

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

Question 31

what are barbituates?

Answer 31

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

Question 32

how do barbiturates produce hypnosis?

Answer 32

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

Question 33

how are barbiturates and propofol similar?

Answer 33

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

Question 34

what is propofol?

Answer 34

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

Question 35

how does propofol induce hypnosis?

Answer 35

- 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

Question 36

does propofol trigger malignant hyperthermia? bacterial growth?

Answer 36

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

Question 37

what is propofol infusion syndrome?

Answer 37

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

Question 38

what is etomidate?

Answer 38

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

Question 39

what does etomidate do to cortisol? cardiorespiratory depression?

Answer 39

single dose inhibits cortisol synthesis -not appropriate for continuous infusion minimal cardiorespiratory depression; agent of choice in patients with minimal cardiac reserve

Question 40

what is ketamine? metabolism? ASE?

Answer 40

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

Question 41

what is dissociative anesthesia

Answer 41

produced by ketamine | -patients appear to be in cataleptic state

Question 42

what is the primary site of CNS action of ketamine?

Answer 42

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

Question 43

unique effects of ketamine on cardiovascular system?

Answer 43

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

Question 44

what is ketamine used for?

Answer 44

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)

Question 45

what are ketamine-unique uses?

Answer 45

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

Question 46

what is dexmedetomidine?

Answer 46

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

Question 47

what are off-label uses for dexmedetomidine?

Answer 47

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

Question 48

what does dexmedetomidine do to the respiratory system?

Answer 48

limited depression, thus wide margin of safety

Question 49

what are neuromuscular blocking agents?

Answer 49

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)

Question 50

what are the chemical classes of non-depolarizing drugs?

Answer 50

1. benzilisoquinolinium compounds (curare, atracurium) | 2. amino steroid comppounds (pancuronium)

Question 51

explain the chemical structure of NMBs

Answer 51

all structurally related to ACh - contain quarternary ammonium structure N+ - -positive charge attracts them to muscarinic and nicotinic ACh receptors

Question 52

what does succinylcholine do?

Answer 52

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

Question 53

what are side effects of succinylcholine?

Answer 53

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

Question 54

what factors affect NMB reversal?

Answer 54

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)

Question 55

explain what "Train of Four" is?

Answer 55

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)

Question 56

what is pancuronium?

Answer 56

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)

Question 57

what is vecuronium?

Answer 57

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

Question 58

what is rocuronium?

Answer 58

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

Question 59

what is Sugammadex? side effects?

Answer 59

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

Question 60

what is unique about isoquinoline NMBs? examples?

Answer 60

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