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Anesthesia Pharm > Week 3 - IV Anesthetics > Flashcards

Week 3 - IV Anesthetics Flashcards

1
Q

How does anesthesia work on a macroscopic level?

A

CNS: transmission disrupted throughout CNS

Brain vs Spinal Cord: Decerebration does not alter requirements

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2
Q

How does anesthesia work on a microscopic level?

A

Axon vs Synapse: Axonal disruption needs higher concentration than synaptic disruption

Excitatory vs Inhibitory: Blockage and enhancement of excitatory transmission occurs

Pre vs Post synaptic: Intracellular [Ca] alters pre and other ions alter post

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3
Q

How does anesthesia work on a molecule level?

A

Membrane: they Meyer-Overton rule states that the potency of an anesthetic is proportional to its lipid solubility (this suggests a lipophilic site of action)
Lipid vs Protein: both involved

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4
Q

What receptors do benzodiazepines act on?

A

GAGAa ++
Glycine +
AMPA -
5-HT +

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5
Q

What receptors does Propofol act on?

A 
GABAa ++
NMDA -
Glycine ++
AMPA -
5-HT -
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6
Q

What receptors does Etomidate act on?

A

GABAa ++
2PK -
Glycine +

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7
Q

What receptors does Ketamine act on?

A

GABAa +
NMDA -2
2PK -
5-HT -

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8
Q

What receptors does Sodium Pentathol act on?

A

GABAa ++
Glycine +
AMPA -2
5-HT -

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9
Q

What receptors does Dexmedetomidine act on?

A

GABAa +

NMDA -

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10
Q

What receptors does Isoflurane act on?

A 
GABAa ++
NMDA -
2PK -2
Glycine ++
AMPA -2
5-HT ++
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11
Q

What is included in the central distribution of drug in the body?

A
  • Plasma and the vessel-rich group of tissues
  • Liver, brain, heart, and kidneys
  • Elimination of IV medication occurs through the central compartment (this is the area of action for the sedatives and narcotics)
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12
Q

What is included in the peripheral (vessel-poor group) distribution of drug in the body?

A

includes muscle, bone, skin, and fat

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13
Q

What is the distribution of cardiac output?

A 
VRG = 10% body mass -- 75% CO
Muscle = 50% body mass -- 19% CO
Fat = 30% body mass -- 6% CO
VPG = 20% body mass -- 0.5% CO
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14
Q

How does drug binding affect distribution of drugs?

A

Protein binding decreases available drug

  • Albumin binds acidic drugs - barbiturates
  • A1AG bind basic drugs - local anesthetics)
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15
Q

What affects protein availability?

A

Decreased albumin due to liver, kidney, CHF, Cancer

Increased A1AG due to trauma, infection, MI, chronic pain

Affects bound and free fraction of drug

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16
Q

What affects drug distribution?

A

Protein binding - decreases available drug
Lipid solubility - good for anesthetic agents
Ionization - affects crossing cell membranes

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17
Q

Define Volume of Distribution

A

the theoretical volume in which the amount of drug would need to be uniformly distributed to produce the observed blood concentration

  • quantifies the distribution of a medication between plasma and the rest of the body after dosing
  • initial Vd describes the distribution of a drug throughout the body after dosing and prior to reaching a steady state equilibrium
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18
Q

What is the equation for volume of distribution?

A

Total amount of drug in the body / drug blood concentration

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19
Q

What causes a high Volume of Distribution?

A

Highly lipid soluble drugs and therefore non-polar

Low rate of ionization

Low plasma binding

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20
Q

What is the elimination T1/2, clearance, and Vd for:

  • Propofol -Midazolam -Etomidate -Ketamine -Dexmedetomidine
  • Flumazenil - Lorazepam - Droperidol - Diazepam
  • Thiopental - Methohexital
A

INSERT TABLE

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21
Q

What is the mechanism of action of Propofol?

A
  • Presumed interaction with GABA
  • Delays the dissociation of GABA from receptors (increasing GABA activated opening of chloride ion channels – also acts as Na channel blocker
  • Hyperpolarization of cell membranes
  • No spinal cord depression (as with volatile agents)
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22
Q

What is the pharmacokinetics of Propofol?

A

95-99% protein binding
Elimination half-life 4-7 hours
-Tissue uptake and redistribution are important factors in termination of action (pulmonary uptake is significant)
-Metabolized via glucoronidation in the liver (clearance exceeds hepatic blood flow - must also have an extrahepatic site of metabolism)
-Renal excretion

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23
Q

What is the therapeutic range of Propofol?

A
  • Rapid upstroke of blood levels on induction
  • Rapid decline over 5 mins
  • Below therapeutic window by 7 min (due to redistribution)
  • If no additional agent given patient will likely wake up due to redistribution
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24
Q

What are the CV, pulmonary, and CNS effects of Propofol?

A

CV: decreases SBP, MAP, &SVR; minimal effect on HR

Pulm: dose dependent decrease in RR

CNS: decreases CBF, ICP, & CMRO2 (at really high doses can produce EEG burst suppression)

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25
Q

How is Propofol supplied and what are the doses?

A

Supplied 10mg/mL

Induction of Anesthesia = 1.5 to 2.5 mg/kg IV
-produces unconsciousness in 30-60 sec, minimal if any hangover effect, decreased PONV/PDNV

Continuous Infusion = 25 to 100 mcg/kg/min (sedation) — 100 to 300 mcg/kg/min (anesthesia)

*Beware – allergic reactions, bacteria formation in solution

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26
Q

What are the physiologic effects of Propofol?

A
  • No effect on acute pain, sub-hypnotic doses highly effective in relieving nociceptive responses to neuropathic pain
  • Antiemetic (sub-hypnotic dose 10-15mg)
  • Antipruritic (10mg dose decreases associated pruritus response with neuraxial opioids)
  • Anticonvulsant (via GABA, decreases ECT 35-55%)
  • Attenuation of bronchoconstriction (although newer form has metabisulfite as preservative that can cause bronchoconstriction)
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27
Q

What is Propofol infusion syndrome?

A
  • Associated with Propofol infusion >75 mcg/kg/min for long duration (>24 hours)
  • Acute refractory bradycardia (kids)/Unexpected tachycardia early sign
  • RBBB is an early sign
  • May lead to asystole if one or more – metabolic acidosis, rhabdomyolysis, hyperlipidemia, enlarged or fatty liver
  • Short term infusions have caused acidosis
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28
Q

What is Propofol effect on lipid peroxidation and peroxynitrite?

A

Inhibits lipid peroxidation (propofol phenol ring, reacts with lipid peroxyl radicals to create stable phenoxyl ring)

Scavenges peroxynitrite (most potent reactive metabolite of lipid peroxidation, suppresses phagocytosis)

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29
Q

What effect does Propofol have on intraocular pressure, coags, Cortisol, and PD tremors?

A
  • Decreases intraocular pressure
  • No effect on coags (does affect plt aggregation: thromboxane A & PAF)
  • NO effect on Cortisol (even when long term admin)
  • Temporary effect of PD tremors (don’t use on stereotactic NS)
  • No MH trigger
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30
Q

What are the key points for Propofol?

A
  • Awaken due to redistribution
  • CV depression slightly > than NaP
  • Resp effects similar to NaP but good bronchodilator
  • Doesn’t cause hyperalgesia
  • Reduces PONV and PDNV
  • Good hypnotic
  • Burns upon rapid injection in small vein
  • NOT contraindicated with Egg/Soy allergy
31
Q

How is Fospropofol supplied and what are the doses?

A

Prodrug (multicompartment model needed)

Supplied 35mg/mL
Initial dose 6.5 mg/kg (between 60-90kg)
-Additional 1.6 mg/kg as needed
-<60kg or >90kg use 60 or 90kg
-Reduce dose 25% for >65 years and ASA 3-4
-Perianal dysesthesia in 74%

*not currently at UIHC

32
Q

What is the mechanism of action of barbiturates?

A

Interact with GABAa (alpha subunit) receptor — different from the GABA or the BZD site

  • Directly activate Chloride ion channels, increase their duration of opening (increases efficacy of GABA)
  • Hyperpolarize postsynaptic cell membranes
  • Also block the AMPA receptors
  • Act on adenosine and neuronal nicotinic acetylcholine receptors
33
Q

What are the pharmacokinetics for barbiturates?

A
  • NaP 83% protein bound (Albumin)
  • Highly lipid soluble = rapidly into CNS
  • Achieve CNS uptake in 30 seconds
  • Prompt awakening after a single dose due to redistribution
  • Hepatic metabolism (inactive) and eliminated by kidneys
  • Elimination 1/2 time is faster in kids
34
Q

What are the CV, pulmonary, CNS, renal, and pH effects of barbiturates?

A

CV: decreases SBP, increases HR, decreases SVR
Pulmonary: respiratory depression, APNEA, return w/ slow respers and decreased tidal volumes
CNS: decreases CBF, ICP, CMRO2 (neuroprotective for regional cerebral ischemia)
Renal: modest decrease in blood flow and GFR
pH: metabolic acidosis increases effect of barbiturates, metabolic alkalosis decreases effect, respiratory acidosis has much less effect

35
Q

How are barbiturates supplied and what are the doses?

A

Thiopental supplied 2.5% solution (25 mg/mL)
Methohexital (Brevital) 1% solution (10 mg/mL)

Induction of Anesthesia:

  • 3-5 mg/kg NaP
  • 1-1.5 mg/kg methohexital
  • Rectal methohexital 20-30 mg/kg sedative
36
Q

What do you need to beware of for barbiturates?

A
  • extravasation causes tissue sloughing
  • NaP + SUX = concrete in the IV
  • Intrarterial injection causes severe vasoconstriction
  • Induce the P-450 system
  • Contraindication in patients with Acute Intermittent Porphyria
37
Q

What are the key points for barbiturates?

A
  • Awakening due to redistribution
  • NaP causes dose dependent decreases SBP, SVR, CO due to myocardial depression and increased venous capacitance
  • Potent respiratory depressants
  • Poor analgesics (may cause hyperalgesia)
  • Contraindicated in Acute Intermittent Porphyria
  • Can cause histamine release
  • Avoid SubQ and Intra-arterial injection
38
Q

What is the mechanism of action of Etomidate?

A

Assumed to enhance the effects of GABA (GABAa receptors with beta3 subunits)

  • Rapid onset of sleep 30-60 seconds
  • Rapid awakening
39
Q

What are the pharmacokinetics of Etomidate?

A
  • 75% protein bound
  • Hydrolyzed to inactive metabolites via ester hydrolysis
  • Elimination half life is 3-5 hours
  • Clearance is 5-6x pentothal; equivalent to Propofol
  • Excretion 85% renal, 15% biliary
40
Q

What are the CV, pulmonary, and CNS effects of Etomidate?

A

CV: no effect or decreases SBP, no effect or increases HR, no effect or decreases SVR (very CV stable)

Pulm: minimal respiratory depression, increased with opioids

CNS: decreases CBF, ICP, &CMRO2; similar EEG to NaP (spikes>than with barbs); can elicit focal seizures (caution in sz pts); also has anticonvulsant and used to terminate status epilepticus

41
Q

How is Etomidate supplied and what is the dose?

A

Supplied 2 mg/mL vials

Induction of Anesthesia = 0.2 - 0.4 mg/kg (burns on injection)

42
Q

What do you need to beware of with Etomidate?

A
  • Myoclonus
  • Adrenal Suppression (decreases Cortisol levels – inhibits 11beta-hydroxylase and to a lesser extent 17alpha hydroxylase)
  • Increased PONV vs NaP or Propofol
  • No analgesia
43
Q

What is the mechanism of action of Ketamine?

A

acts on NMDA, Opioid, Monoaminergic, Muscarinic, Voltage gated Ca channels, and Nicotinicneuronal ACh receptors

*only IV anesthetic that doesn’t interact with GABA receptor

44
Q

What are the pharmacokinetics of Ketamine?

A
  • Extremely lipid soluble (5-10x Nap)
  • Metabolized in liver to norketamine (1/3 to 1/5 potency, P450 metabolism leads to tolerance)
  • Norketamine is hydroxylated and conjugated to H2O soluble and excreted
  • Elimination 1/2 life 2-4 hours
  • Excretion >90% renal
45
Q

What are the CV, Pulmonary, and CNS effects of Ketamine?

A

CV: increases SBP, HR, and SVR

Pulm: no respiratory depression (increased with opioids), bronchodilatory

CNS: increases CBF, ICP, and CMRO2 (don’t admin with head injury)

46
Q

How is Ketamine supplied and what are the doses?

A

Supplied 10 mg/mL; 50 mg/mL and 100 mg/mL vials

Induction of Anesthesia = 1-3 mg/kg IV or 4-8 mg/kg IM

Adjunctive Analgesic = 0.2-0.5 mg/kg can provide profound analgesia

47
Q

What do you need to beware of with Ketamine?

A

Emergence Delirium

  • Visual, auditory, proprioceptive, and confusion
  • Premedication with Midazolam seems to help
48
Q

What are key points for Ketamine?

A
  • Reverse opioid tolerance (effect on mu receptor, nitric oxide pathway, NMDA) — 0.3 mg/kg/hr decreases tolerance from hyperalgesia
  • Helps with restless leg syndrome
  • Improves psych disorder (Glutamate implicated in depression)
  • Possibly neuroprotective (studies looking into it)
49
Q

What are benzodiazepines used for?

A
  • Sedation
  • Anxiolysis
  • Anticonvulsant effects
  • Spinal-cord mediated muscle relaxation
  • Anterograde amnesia
  • Unconsciousness/Respiratory Depression (at high doses)
  • NO analgesic properties
  • High Therapeutic Indexes (100s)
  • Benzos + Opiods = TI <10
50
Q

What site does benzodiazepines act on?

A

GABA at the alpha subunit (2alpha & 2beta sites)

  • Enhanced opening on Chloride channels
  • Hyperpolarization of postsynaptic membrane
  • Postsynaptic neurons resistant to excitation
51
Q

What are the pharmacokinetics of Diazepam?

A
  • Very lipid soluble – rapid uptake by the brain, rapid distribution
  • Large Vd (1-1.5 L/kg)
  • Clearance rate = 0.2-0.5
  • Long Elimination 1/2 — 20-50 hours (much longer in elderly)
  • Duration of action is determined by metabolism and elimination
52
Q

How is Diazepam metabolized?

A

Primarily in the liver via oxidative N-demethylation

  • Produces Three Active Metabolites: Desmethyldiazepam, Oxazepam, Temazepam
  • Hepatic clearance doesn’t change as we age (bodily proportion of fatty tissue increases; increases Vd for lipid soluble drugs and takes longer to metabolize)
  • Cimetidine delays hepatic clearance
53
Q

What effect does Diazepam have on anesthetic agents?

A

Reduces the dose of induction agent

Reduces MAC of inhalation agent

  • 0.2 mg/kg IV reduces MAC of Halothane
  • Increasing the dose of diazepam doesn’t further reduce MAC
54
Q

What are the pharmacokinetics of midazolam?

A
  • 2-4x as potent as diazepam
  • Imidazole ring (water soluble at a pH less than 4, closes upon injection and becomes highly lipid soluble)
  • 96-98% protein bound
  • Very Lipid Soluble (rapid uptake by brain, redistribution and re-uptake)
  • Large Vd (1-1.5 L/kg)
  • High rate of clearance (6-8 mL/kg/min
  • Short Elimination 1/2 (1.7-2.6 hr in healthy volunteers)
55
Q

How is midazolam metabolized and cleared?

A
  • Oxidative hydroxylation in the liver: P450
  • Glucoronide conjugation in the kidneys (in renal insufficient, active metabolite may be synergistic with parent compound)
  • Excretion in the urine
  • Metabolites are minimally active
  • Metabolism not affected by H2 receptor antagonists
  • Cardiac responses minimal and similar to NaP
  • Depressed ventilation with 0.15 mg/kg dose
  • Renal failure has minimal effects on T1/2, Vd, and clearance
  • Dose related decrease in CBF and CMRO2
  • Crosses the U-P membrane
56
Q

How does age affect the dose of Midazolam?

A

it takes much less drug to get the same effects in older patients

57
Q

What are the pharmacokinetics of Lorazepam?

A
  • More potent than diazepam or midazolam
  • Elimination T1/2 is 10-20 hours
  • Less lipid soluble than diazepam (slower onset, longer duration)
  • Reliable GI and IM absorption (dissolved in propylene or polyethylene glycol)
  • Clinical effects may outlast diazepam dissociates from the GABAa slower
  • Metabolized to inactive metabolites via glucuronide conjugation in the liver
  • Metabolism is not altered by age, liver dysfunction, or H2 receptor antagonists
58
Q

What are the doses of lorazepam?

A

Excellent PO pre-medication

  • 0.5-2.0 mg at hour of sleep and 0.5-2.0 mg PO at 0600-0700
  • 50 mcg/kg (max 4mg) gives max anterograde amnesia for up to 6 hours
  • Larger doses produce greater sedation without increased amnesia

Elderly pts are sensitive to BZDs
Slow onset limits usefulness as IV pre-med or intra-op sedative

59
Q

Compare the pharmacology of benzodiazepines

A

INSERT TABLE

60
Q

What is the reversal for benzodiazepines?

A

Flumazenil = specific and exclusive BZD competitive antagonist with high affinity for the BZD receptor site

  • Reverses all BZD effects in a dose-dependent manner
  • Not an abrupt reversal of sedative/amnesic effects as with narcotic reversal with nalaxone
  • Onset of action is 30 seconds to 2 minutes
  • Redistribution T1/2 is 7-15 minutes (may necessitate re-dosing, duration of action 30-60min)
61
Q

What is the dose of Flumazenil?

A
  1. 2mg IV over 15 seconds
    - wait 45 seconds, re-dose 0.2 increments over 15 seconds

DO NOT exceed 3.0 mg per hour
If no response after 1 mg flumazenil consider other causes
-Incomplete reversal of muscle relaxation, residual anesthetic agents, narcotic overdose, hypoxemia, hypercarbia, surgical complication

62
Q

What are other option for benzodiazepine reversal besides Flumazenil?

A

Physostigmine - tertiary amine (cholinesterase inhibitor that causes build-up of ACh in brain tissue)

Aminophylline (1mg/kg may antagonize the sedative effects of adenosine in the CNS)

Nonspecific, unpredictable, and inconsistent
Not recommended since Flumazenil

63
Q

What is the mechanism of action of Dexmedetomidine class and what are its effects?

A

Highly selective alpha 2 adrenergic agonist
-alpha2 adrenoreceptors are membrane spanning G proteins (inhibition of adenylate cyclase, modulation of ion channels, alpha2B and 2C receptors in the brain and spinal cord and stimulation leads to sympatholysis, sedation, and antinociception)

  • Sedation – receptors in the locus ceruleus
  • Anxiolysis
  • Hypnosis
  • Analgesia – receptors in LC and spinal cord
  • Sympatholysis
64
Q

What is the T1/2, % protein bound, and metabolism of Dexmedetomidine?

A

Half life 2-3 hours (clonidine 6-10)
90% protein bound
Hepatic metabolism with renal excretion of conjugate
Weakly inhibits P450 (may manifest as increased plasma concentration of opioids)

65
Q

What are the CV, pulmonary, and CNS effects of Dexmedetomidine?

A

CV: decreased HR and SVR (indirectly decreases CO, SBP & contractility)

Pulm: decreases minute ventilation but maintains CO2 response (no curve shift)

CNS: not well defined – some neuroprotection? decrease CBF, CMRO2, no change in ICP, no suppression of EEG spikes, useful in epilepsy surgery

66
Q

What are the anesthetic uses and doses of Dexmedetomidine?

A
  • Premedication: 0.33 - 0.67 mcg/kg 15 min before surgery (used a lot with kids) – decreases induction agent dose, decreases MAC
  • MAC: 1 mcg/kg over 10 min (slower onset/offset than propofol, similar cardiorespiratory effects) — 0.7 mcg/kg/min keeps BIS 70-80
  • Maintenance of GA: reduces MAC of inhaled agent, reduces postoperative opioid requirements, not useful as a solo general anesthetic
67
Q

What is the mechanism of action of Droperidol?

A
  • Acts centrally at sites where dopamine, norepinephrine, and serotonin act (alters normal CNS signal transmission, exerts antiemetic effects at red astrocytes in the Chemoreceptor trigger zone, has moderate alpha-adrenergic blocking ability)
  • May occupy GABA receptors on the postsynaptic membrane causing a buildup of dopamine in the intersynaptic cleft
  • Neuroleptic anesthesia (mimics sleep – more chance of recall)
68
Q

What are the CV, pulmonary, and CNS effects of Droperidol?

A

CV: decreased SVR, MAP, minimal effect on CO and contractility

Pulm: minimal effects

CNS: decreased CBF in dogs (no human data), may worsen extrapyramidal side effects, contraindicated in Parkinson’s

69
Q

What are the doses of Droperidol?

A

Antiemetic: 0.625-1.25 mg IM/IV in adults

Premedication: similar doses

70
Q

What are the pharmacokinetics of Droperidol?

A
  • Onset 5-8 minutes
  • Vd 2.0 L/kg
  • Duration of action 3-6 hr
  • Elimination 1/2 life 1.7-2.2 hr
  • Hepatic transformation – two metabolites
  • Elimination liver and kidneys
71
Q

What are the pharmacokinetics of Scopolamine?

A

Derived from belladonna (nightshade) – aka hyoscine

  • Lipid soluble tertiary amine (crosses BBB and binds muscarinic cholinergic receptors)
  • Elimination 1/2 life 4.5 hours
  • Vd 100L
  • Hepatic clearance 1 L/min, renal 70 mL/min
  • Never given orally, too unpredictable bioavailability
72
Q

What is central anticholinergic syndrome related to Scopolamine?

A
  • Restlessness, hallucinations, somnolence, unconscious
  • Blockade of muscarinic cholinergic receptors and competitive inhibition of acetylcholine in CNS
  • Physostigmine is treament
73
Q

What happens with an overdose of Scopolamine?

A
  • Muscarinic cholinergic receptor blockade
  • Dry mouth, difficulty swallowing, talking, blurred vision, photophobia, tachycardia, dry flushed skin
  • Children vulnerable-even at therapeutic dose (atropine fever: inhibition of sweating by anticholinergic – sweat glands SNS innervation)
74
Q

What is the most common IV anesthetic?

A

Propofol

  • provides rapid onset and offset
  • potentiates GABA induced Chloride channels

Anesthesia Pharm (18 decks)

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