12-04 Anesthesia

Question 1

What are the 5 effects of the drug combos that make up general anesthesia?

Answer 1

1. unconsciousness
2. amnesia
3. analgesia
4. inhibition of autonomic reflexes
5. SKM relaxation

Question 2

describe the major steps in conducting general anesthesia

Answer 2

Induction - time from initiation to desired [agent] in brain; may start w/ benzo; give propofol to obtain unconsciousness (#1); succinylcholine or rocuronium to paralyze SKM (#5) if intubation required;

Maintenance of Anesthesia - period maintained anesthetized w/ mix of IV/inhaled agents; opioid like fentanyl can be co-administered; monitor vitals

Recovery - can give neostigmine to reverse SKM paralysis

Question 3

pharmacokinetics of inhaled anesthetics depends on?

Answer 3

1)inhalation technique
—a) conc. inhaled, and
—b) rate of alv. vent (want alv conc = inspired conc…faster that happens, faster you’re out)
2) solubility of agent (least soluble is fastest onset)
3) incr in CO will incr delivery to OTHER tissues b/c cerebral blood flow doesn’t ∆ much
4) alvelolar-venous partial P diffs: the more agent is distributed to body the this diff the longer to get equilibrium between systemic and cerebral circulation
5) elimination - reversal is same speed as onset b/c they are eliminated in large part via lungs (halothane 40% via liver, others less)

Question 4

cardiac toxicity of inhaled anesthetics?

Answer 4

halogenated agented decr contractility and MAP

—use “–flurane’s” to preserve CO, and decr pre- and after-load in pts s/p MI

Question 5

renal toxicity of inhaled anesthetics?

Answer 5

decr GFR and urine flow

Question 6

hepatic toxicity of inhaled anesthetics?

Answer 6

some ∆ liver enzymes but rarely long-term

Question 7

respiratory toxicity of inhaled anesthetics?

Answer 7

inhaled agents (‘cept N2O) cause dose-dep dec in tidal vol but incr in RR (rapid shallow breathing); also respiratory depressants —> need mech vent

Question 8

molecular basis for action of general anesthetics—both inhaled and IV

Answer 8

(see also general MOA Q)
INHALED
—GABA receptors are believed to be involved (lecture)
—∆s solubility of lipids but also “add’l structural requirements that determine activity in the brain (for amnesia) and in spinal cord (for immobilization)
—may have prot targets, too (luciferase and P450)
**don’t fully understand lipid theory

INTRAVENOUS
—most common inducers now
—lipophilic, paritions into highly perfused lipophilic tissues (brain/spinal cord), thus rapid onset
—great anesthetic, quick on/off, anti-emetic!!

Question 9

molecular basis for action of local anesthetics

Answer 9

block voltage-gated Na+ channels—> no Na+ INflux—> no depol.—> no AP conducted
—non-ionized/lipophil gets thru to receptors faster
—ionized actually inhibits receptor better
—this depends on pH (∆ed in infx)
—can give with NaHCO3 to raise pH

Question 10

discuss pharmacokinetics of locals; particular situations that alter kinetics

Answer 10

i) absorbed into blood quickly so can co-give w/ alpha-agonist (e.g. epi) to vasoconstrict (cocaine doesn’t need this b/c it inhib’s NE uptake thus has sympathomimetic activity)
ii) can bind more easily to open channels: high K+ opens Na+ channels while high Ca2+ decr # open channels
iii) Surface activity: can reach sup. nn. topically e.g. cocaine. benzocaine (both only topical), lidocaine and tetracaine

Question 11

tx for local anesthetic toxicity? tx?

Answer 11

—CNS (present before CV sx): convulsions tx w/ benzos
—Cor: CV depression, worse w/ hyperkalemia
—Metab: acidosis and hypoxia
—Hyperventilate—>ACLS
—best tx is lipid rescue therapy (acts as sink drawing out of tissue, may also reverse inhibition of carnitine acylcarnitine translocase)

Question 12

pharmacology of IV generals, esp propofol

Answer 12

GABAergic MOA
—lipophilic kinetics: preferentially partition into lipophilic compartments (brain, spinal cord)
—three compartment model: blood (immediate), brain/viscera (~30s), fat/muscle (mins/hrs)
—because of this the HALF LIFE CHANGES with dose: the longer your infuse the more you pump into the fat/muscle the longer the half-life becomes

Question 13

explain 3 compartment model and how this affects duration of action of anesthetics

Answer 13

1. blood (immed)
2. brain and viscera (quick as 30 secs)
3. muscle, fat, etc. (20 mins+) —> if it slow exits this 3rd compartment, slower recover time

Question 14

classes of inhaled anesthetics

Answer 14

gas (e.g. nitrous oxide)
volatile liquids (e.g. isoflurane, sevoflurane)

Question 15

classes of IV anesthetics

Answer 15

dissociative (ketamine)
opioids (morphine, fentanyl, remifentanil)
barbiturates (thiopental)
Misc (etomidate, propofol)

Question 16

general anesthesia MOA generally speaking

Answer 16

—either decr excitatory afferents (mostly) or incr inhib efferents
—excitatory targets: AChRs, excitatory AAs (AMPA, kainate, NMDA receptors) or 5-HT(2,3)
—inhibitory ion channels: Cl- channels (GABA*[A] and glycine) and K+
*big thing

Question 17

anesthetic potency

Answer 17

= minimal alv conc (MAC) req’d to prevent resp to surg incision in 50% of cases

generally 1.3 X MAC works for most pts

Question 18

effect of inhaled anesthetics on uterine SMM?

Answer 18

halogenated: potent uterine relaxants

—useful for uterine fetal manipulation or removal of retained placenta, tho incr risk of bleeding

Question 19

Classes of locals

Answer 19

ESTERS*

i) surface action (benzocaine, cocaine)
ii) short-acting (procaine)
iii) long-acting (tetracaine)

AMIDES*

i) medium-acting (lidocaine)
ii) long-acting (bupivacaine, ropivacaine)

*derivatives of benzenes

Question 20

metab of locals?

Answer 20

ESTERS - broken down by plasma pseudocholinesterases; t1/2 1-2 minutes

AMIDES - P450, t1/2 1-4hrs (incr by liver dz)

Question 21

Local anesthetics work more effectively on…

Answer 21

NARROWER nerve fibers vs. thick
HEAVILY MYELINATED vs. light- or non-myelinated
RAPIDLY FIRING vs. slower ones
PERIPHERAL NN vs. ones in core of nerve bundle

Question 22

Horner’s syndrome sx

Answer 22

ptosis, meiosis, and anhydrosis

—stellate ganglion is near brachial plexus and can get hit when doing a nerve block near there

Question 23

Practice Q1 Slide 27

Answer 23

Correct?

Question 24

Practice Q2 Slide 29?

Answer 24

Correct?

Question 25

1. isoflurane
—class?
—PD?
—PK?
—Toxicity?

Answer 25

• *Drug class: pharmacologic class—inhalation anesthetic general, CNS depressant, causes unconsciousness, weakly analgesic, MEDIUM rate of onset & recovery from anesthesia
• *Pharmacodynamics: mech unknown, dose relatively high so likely multiple sites of action. Lipid solubility essential for activity. Potentiates GABA action on GABA(A) receptors and opens K+ channels to reduce neuronal activity.
• *Pharmacokinetics: liver minimally; CYP450: unknown; Excretion: LUNGS (95% unchanged), urine <1%;
• *Toxicity: card/resp depression, dysrhythmias, post-op n/v

Question 26

2. sevoflurane
—class?
—PD?
—PK?
—Toxicity?

Answer 26

similar to isoflurane but faster acting

—rarely can cause kidney damage (not listed for isoflurane)

Question 27

3. nitrous oxide
—class?
—PD?
—PK?
—Toxicity?

Answer 27

**Drug class: pharmacologic class—inhalation anesthetic general, unconsciousness WHEN COMBINED w/ other agents, analgesia, euphoria, very rapid onset & recovery
**Pharmacodynamics: Reduces opening of NMDA receptor channels, increases opening of K+ channels (TREK-1),
**Pharmacokinetics: no metabolism, eliminated rapidly from lungs
**Toxicity: Megaloblastic anemia may occur after prolonged exposure,hypoxia if large amts used, administering pure O2 immediately following anesthesia can reduce this
Interactions: analgesia inhibited by opioid antagonists

Question 28

4. ketorolac (Toradol)
—class?
—PD?
—PK?
—Toxicity?

Answer 28

**Drug class: NSAID (anti-inflam, analgesic, & antipyretic)
**Pharmacodynamics: exact mechanism of action unknown; inhibits cyclooxygenase,
reducing prostaglandin and thromboxane synthesis
**Pharmacokinetics: LIVER primarily; CYP450: unknown; Info: <5 days
—GI: bleed or bowel perf
—CV: thrombotic MI or CVA
—Renal: contraindicated in renal fail
—Heme: contra in bleed d/o
—L/D Risk

Question 29

5. ketamine
—class?
—PD?
—PK?
—Toxicity?

Answer 29

**Drug class: general anesthetic, hallucinogen, drug of abuse ! **Pharmacodynamics: Ketamine has multiple actions including noncompetitive NMDA
receptor (NMDAR) antagonist, inhibits nitric oxide synthase,
**Pharmacokinetics: liver; CYP450: 2B6 (primary), 2C9, 3A4; Info: active metabolite; Excretion: urine primarily (4% unchanged), feces <5%; Half-life: 2.5h
**Toxicity: catatonia, amnesia, analgesia, elevated heart rate, cardiac output & blood pressure, post-op disorientation, sensory & perceptual illusions, vivid dreams
**Interactions: barbiturates, alcohol
**Monitor: ECG, vital signs continuously

EMERGENCY RXN: 12% have psych

Question 29

6. Propofol ("milk of amenesia")
—class?
—PD?
—PK?
—Toxicity?

Answer 29

• *Drug class: short-acting, IV administered hypnotic agent used in general anesthesia; antiemetic actions,
• *Pharmacodynamics: [1]potentiates GABA(A) receptor activity, slowing the channel-closing time and a [2]sodium channel blocker and [3]may impact the endocannabinoid system
• *Pharmacokinetics: duration of action 3-8 minutes, Vd2-10 L/kg, t1/2=3-12 hr., metabolism liver; CYP450: 2B6 substrate
• *Toxicity: injection site pain, apnea, decr CO, hypotension
• *Interactions: emulsion containing 10% soybean oil, 2.25% glycerol, and 1.2% lecithin, the major component of the egg yolk phosphatide fraction (milky) watch for egg allergies
• *Monitor: ECG, oxygen saturation, vital signs continuously; triglycerides if hyperlipidemia risk; urinalysis, urine sediment at baseline and on alternate days if renal impairment risk

Question 30

7. midazolam (Versed)
—class?
—PD?
—PK?
—Toxicity?

Answer 30

**Drug class: benzo sedative; adjunct to general
anesthesia
**PD: enhances the effect of the neurotransmitter GABA on the GABA(A) receptors
**PK: duration of action 15-20 mins, Vd= 1.1-1.7 L/kg, t1/2=1.7-2.6 hr., metabolism liver; CYP450: 3A4 substrate; Info: active metabolite
**Toxicity: respiratory depression, apnea, respiratory failure, cardiac arrest
**Interactions: any drug impacting CYP3A4 activity
**Special considerations: pregnancy D, elderly, children, in alcohol- or drug-dependent individuals or those with comorbid psychiatric disorders. Kidney or liver impairments can slow elimination.
**Monitor: Cr at baseline; ECG, BP, oxygen saturation, respiratory fxn, vital signs continuously

Question 30

8. morphine sulfate
—class?
—PD?
—PK?
—Toxicity?

Answer 30

**Drug class: pharmacologic class—opioid
**PD: opioid receptor agonist, producing analgesia and sedation (opioid agonist)
**PK: urine 85% (9-12% unchanged), bile/feces 7-10%; Half-life: 2-4h
**Toxicity: constipation, addiction, tolerance, CV depression
**Interactions: other CNS depressants
**Special considerations: : pregnancy category C,
Indications and dose/route: PO, Transdermal, Rectal
**Monitor: Cr at baseline; resp. fxn x24h after epidural or intrathecal use

Question 31

9. etomidate
—class?
—PD?
—PK?
—Toxicity?

Answer 31

• *Drug class: pharmacologic class—general anesthetic and adjunct to general anesthesia; hypnotic with no analgesic activity; minimal CV and respiratory depressant effects; short- acting IV drug
• *PD: modulator at GABAA receptors containing !3 subunits
• *PK: liver; CYP450: highly plasma protein bound, metabolized by hepatic and plasma esterases
• *Excretion: URINE primarily; Half-life: 75min **Toxicity: skeletal muscle movements; Laryngospasm; shock

Question 31

10. fentanyl
—class?
—PD?
—PK?
—Toxicity?

Answer 31

**Class: opioid (>lipophilic than morphine, better CNS penetrance)
**PD: opioid receptor agonist, producing analgesia and sedation μ-opioid G-protein-coupled receptors
**PK: hepatic,primarily by CYP3A4
**Toxicity: most common diarrhea, nausea, constipation, dry mouth, somnolence,
confusion, asthenia (weakness), and sweating, severe; respiratory depression respiratory arrest, dependency, abuse Interactions: renal failure, respiratory depression
**Special considerations: AVOID ABRUPT CESSATION-withdrawal sx severe

Question 32

11. remifentanil
—class?
—PD?
—PK?
—Toxicity?

Answer 32

• *Class: Opioids; Anesthesia Adjuncts; ULTRA SHORT-ACTING narcotic analgesic
• *PD: binds to various opioid receptors, producing analgesia and sedation (opioid agonist)
• *PK: metab: ester linkage hydrolyzed by non-specific tissue and plasma ESTERASES, drug does not accumulate and its context-sensitive half-life remains at 4 minutes even after a 4 hour infusion; Excretion: URINE; Half-life: 3-10min
• *Toxicity: hypotension, muscle rigidity, bradycardia, apnea, shivering
• *Interactions: morphine

Question 32

12. bupivicaine
—class?
—PD?
—PK?
—Toxicity?

Answer 32

• *Class: relatively LONGER ACTING LOCAL
• *PD: inhibits Na ion channels, stabilizing neuronal cell membranes and inhibiting nerve impulse initiation and conduction (amide local anesthetic)
• *PK: Metabolism: liver primarily; CYP450: 3A4 substrate; Excretion: urine (5% unchanged); Half-life: 3.5h
• *Toxicity: light-headedness, tinnitus, metallic taste, blurred vision, numbness, twitching, convulsions, hypotension, cardiac arrest/arrhythmias (potentially lethal-LIPID RESCUE)
• *Interactions: MAOIs or ergot alkaloids (when using epinephrine containing solutions) Phenothiazines may reduce the pressor effects of epinephrine