Flashcards in Unit 3 - General Anesthetics Deck (60):
what is the likely mechanism for immobility in response to noxious stimuli?
inhibition of the spinal cord
what is the likely mechanism for unconsciousness?
depressing the thalamic neurons and blocking thalamo-cortical communication
what do volatile anesthetics do to glutamate release? GABA release? glycine release?
-inhibit glutamate release
-increase and decrease GABA release
-increase glycine affinity
what does the GABA-A receptor look like? similar structures? postsynaptic response?
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
what does the glutamate receptor look like?
tetrameric protein with structurally related subunits
what are NMDA receptors? what do volatile anesthetics, ketamine, or N2O do?
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)
what drugs increase the frequency/length of time Cl- channels remain open? what channels are these important for?
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
what drugs potentiate glycine activated currents?
propofol, alphaxalone, pentobarbitol
explain the Meyer-overton rule
potency of anesthetic gases is directly related to their solubility in olive oil
-however, this doesn't affect their efficacy
what is the unitary theory of anesthesia?
since a variety of structurally unrelated drugs obey the same Meyer-Overton rule, they must bind at the same hydrophobic site
what is firefly luciferase and how is it involved in anesthesia?
water soluble protein that is inhibited by anesthetics in clinically relevant concentrations
-anesthetics bind to hydrophobic pockets on proteins
what are chloroform, halothane, and methoxyflurane?
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
what are chemical properties about desflurane that are important?
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)
ADME of inhaled anesthetics
Absorbed from alveoli into pulmonary capillary blood (uptake)
Distributed to site of action (brain) and reservoirs (vessel-rich group, muscle, fat)
Eliminated principally via lungs
why is partial pressure important in anesthesiology?
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
what are factors that increase alveolar partial pressure? what determines PA?
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)
what is the 2nd gas effect?
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
what is the speed of anesthetic induction determined by?
rate of rise of alveolar concentration of anesthetic agent (FA/FI)
-poorly soluble agents rapidly achieve high alveolar concentration, thus induction occurs more quickly
what is the minimum alveolar concentration? when does loss of awareness and recall occur?
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
what increases MAC? (more needed)
-pheomelanin (red hair)
-high CNS catecholamine lvels (stress)
-high CNS nt (MAOis, cocaine, ephedrine, L-DOPA)
what decreases MAC? (less needed)
-decreased CNS catecholamine levels
-opioids, anxiolytics, a2 agonists, lidocaine
-pregnancy, post-partum period
what is N2O?
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
-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
what is isoflurane?
most potent (MAC 1.17%), somewhat pungent volatile agent
-mask induction is difficult, but it is the gold standard for maintenance of general anesthesia
what is desflurane?
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
what is sevoflurane?
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)
what are Guedel's 4 stages of CNS depression?
I: analgesia + amnesia
II: excitement/delirium: increased HR, RR, BP
III: surgical anesthesia
IV: medullary depression: without support of respiration and circulation, death ensues
what are CNS effects of volatile agents?
1. dose-dependent depression of:
-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
what are cardiovascular effects of volatile agents?
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
what are respiratory effects of volatile agents?
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)
what are neuromuscular effects of volatile agents?
1. directly relax skeletal muscle
2. potentiate effects of neuromuscular blockers
3. trigger malignant hyperthermia in susceptible patients
what are barbituates?
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
how do barbiturates produce hypnosis?
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
how are barbiturates and propofol similar?
-dose-dependent decreases in blood pressure due to vasodilation
-dose dependent respiratory depression
-barbiturates are negative inotropes
what is propofol?
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
how does propofol induce hypnosis?
-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
does propofol trigger malignant hyperthermia? bacterial growth?
no malignant hyperthermia, but emulsion supports bacterial growth and must be thrown out if exposed
what is propofol infusion syndrome?
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
what is etomidate?
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
-NO analgesic activity
what does etomidate do to cortisol? cardiorespiratory depression?
single dose inhibits cortisol synthesis
-not appropriate for continuous infusion
minimal cardiorespiratory depression; agent of choice in patients with minimal cardiac reserve
what is ketamine? metabolism? ASE?
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
what is dissociative anesthesia
produced by ketamine
-patients appear to be in cataleptic state
what is the primary site of CNS action of ketamine?
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
unique effects of ketamine on cardiovascular system?
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
what is ketamine used for?
-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)
what are ketamine-unique uses?
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
what is dexmedetomidine?
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
what are off-label uses for dexmedetomidine?
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)
what does dexmedetomidine do to the respiratory system?
limited depression, thus wide margin of safety
what are neuromuscular blocking agents?
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)
what are the chemical classes of non-depolarizing drugs?
1. benzilisoquinolinium compounds (curare, atracurium)
2. amino steroid comppounds (pancuronium)
explain the chemical structure of NMBs
all structurally related to ACh
-contain quarternary ammonium structure N+
--positive charge attracts them to muscarinic and nicotinic ACh receptors
what does succinylcholine do?
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
what are side effects of succinylcholine?
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
5. masseter spasm
what factors affect NMB reversal?
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)
explain what "Train of Four" is?
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)
what is pancuronium?
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)
what is vecuronium?
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
what is rocuronium?
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
what is Sugammadex? side effects?
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