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APEX Study Guide > Unit 4: Pharmacology 1 > Flashcards

Unit 4: Pharmacology 1 Flashcards

1
Q

What is volume of distribution? How is it calculated?

A

Volume of distribution (Vd): relationship between a drug’s plasma concentration following a specific dose
-theoretical measure of how a drug distributes throughout the body

Vd = amount of drug / desired plasma concentration

It assumes two things:

  • drug distributes instantaneously (full equilibration occurs at t = 0)
  • drug is not subjected to biotransformation or elimination before it fully distributes
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2
Q

What are the implications when a drug’s Vd exceeds TBW? What if Vd is less than TBW?

A

If Vd > TBW (>0.6 L/kg or >42 L) – drug is assumed to be lipophilic

  • distributes into TBW + fat
  • requires higher dose to achieve a given plasma concentration
  • ex: propofol, fentanyl

If Vd < TBW (<0.6 L/kg or <42 L) – drug is assumed to be hydrophilic

  • distributes into some or all of the body water, but doesn’t distribute into fat
  • requires a lower dose to achieve a given plasma concentration
  • ex: NMBs (ECF), albumin (plasma)
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3
Q

How do you calculate the loading dose for an IV medication? How about a PO medication?

A

Loading Dose = Vd x Desired Plasma Concentration / Bioavailability

For IV Drug: bioavailability is always 1 (all of the drug enters the bloodstream)

For PO Drug: bioavailability will be less than 1

*any other route than IV may not be absorbed completely and/or may be subject to first-pass metabolism in the liver – reduce bioavailability

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4
Q

What is clearance? What factors increase/decrease it?

A

Clearance = volume of plasma that is cleared of a drug per unit of time

Directly proportional to:

  • blood flow to cleaning organ
  • extraction ratio
  • drug dose

Inversely proportional to:

  • half life
  • drug concentration in the central compartment
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5
Q

What is steady state? How many 1/2-times does it take to occur?

A

Occurs when the amount of drug entering the body is equivalent to the amount of drug eliminated from the body – Stable Plasma Concentration

-each of the compartments has equilibrated

**Achieved after 5 half-times

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6
Q

Describe the alpha- and beta distribution phases on the plasma concentration curve

A

Alpha Distribution Phase:

  • describes drug distribution from the plasma to the tissues

Beta Distribution Phase:

  • begins as plasma concentration falls below tissue concentration
  • concentration gradient reverses, which causes the drug to re-enter the plasma
  • describes drug elimination from the central compartment

**plasma concentration curve graphically depicts the biphasic decrease of a drug’s plasma concentration following a rapid IV bolus

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7
Q

What percentage of initial drug dose REMAINS in the blood after each half-life?

A 
0 half-time = 100%
1 half-time = 50% (50% eliminated)
2 half-time = 25% (75% eliminated)
3 half-time = 12.5% (87.5% eliminated)
4 half-time = 6.25% (93.75% eliminated)
5 half-time = 3.125% (96.875% eliminated)
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8
Q

What is context sensitive half-time?

A

It is the time required for the plasma concentration to decline by 50% after discontinuing the drug

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9
Q

Discuss the context sensitive half-time of fentanyl, alfentanil, sufentanil, and remifentanil. Which has the longest? Which has the shortest, why?

A

Longest = Fentanyl (context sensitive half-time for an infusion increases as a function of how long it was infused)
-also true for alfentanil and sufentanil

Shortest = Remifentanil (it is quickly metabolized by plasma esterases so it has a similar context sensitive half-time regardless of time infused)

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10
Q

What is the difference between a strong and weak acid or base?

A

Difference is the degree of ionization

  • if you put a strong acid or strong base in water it will ionize completely
  • if you put a weak acid or weak base in water a fraction will be ionized and the remaining fraction will be non-ionized

*acid donates a proton – base accepts a proton

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11
Q

What i s ionization? What 2 factors determine how much a molecule will ionize?

A

Ionization describes the process where a molecule gains a positive or negative charge

Amount of ionization is dependent on:

  • pH of the solution
  • pKa of the drug
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12
Q

What occurs when pKa and Ph are the same?

A

50% of the drug is ionized and 50% is non-ionized

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13
Q

How does ionization affect solubility?

A

Ionized = Water Soluble

  • hydrophilic
  • lipophobic

Non-Ionized = Lipid Soluble

  • lipophilic
  • hydrophobic
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14
Q

How does ionization affect a drugs pharmacologic effect?

A

Ionized = Not Active

Non-Ionized = Active

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15
Q

How does ionization affect hepatic biotransformation?

A

Ionized – hepatic biotransformation is LESS likely

Non-Ionized – hepatic biotransformation is MORE likely

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16
Q

How does ionization affect diffusion across lipid bilayer?

A

Ionized: does not cross blood brain barrier, GI tract, or Placenta

Non-Ionized: does cross blood brain barrier, GI tract, and Placenta

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17
Q

What is the basic rule about acids and bases being put in acidic and basic solutions?

A
  • In ACIDIC solution, weak BASES are more IONIZED and water-soluble
  • In BASIC solution, weak BASES are more NON-IONIZED and lipid soluble
  • In ACIDIC solution, weak ACIDS are more NON-IONIZED and lipid soluble
  • In a BASIC solution, weak ACIDS are more IONIZED and water-soluble
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18
Q

How can you tell if a drug is an acid or a base by looking at its name?

A

Most drugs are weak acids or bases and usually prepared as a salt that dissociates in solution

  • Weak acid is paired with a positive ion such as sodium, calcium, or magnesium
  • Weak base is paired with a negative ion such as chloride or sulfate
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19
Q

What are the three key plasma proteins? Does each bind acidic drugs, basic drugs, or both?

A
  • Albumin: primarily binds to acidic drugs (also binds to some neutral and basic drugs)
  • Alpha1-acid Glycoprotein: binds to basic drugs
  • Beta-globulin: binds to basic drugs
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20
Q

What conditions reduce the serum albumin concentration? (5)

A
  • Liver disease
  • Renal disease
  • Old age
  • Malnutrition
  • Pregnancy
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21
Q

What conditions increase alpha1-acid glycoprotein concentration? (5)

A
  • Surgical stress
  • Myocardial infarction
  • Chronic pain
  • Rheumatoid arthritis
  • Advanced age
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22
Q

What conditions decrease alpha1-acid glycoprotein concentration? (2)

A
  • Neonates
  • Pregnancy
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23
Q

How do changes in plasma protein binding affect plasma drug concentration?

A

Decreased PP Binding –> Increased Cp

Increased PP Binding –> Decreased Cp

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24
Q

How do you calculate changes in plasma protein binding?

A

[Free Drug] + [Unbound Protein Binding Sites] [Bound Drug]

  • if a drug is 98% bound and the bound fraction reduces to 96%, the unbound or free fraction has increased by 100% (free fraction went from 2% to 4%)

*Calculate the percent change to complete the calculation
% change = [(New Value - Old Value) / Old Value] x 100

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25
Q

What is first-order kinetics?

A

A constant FRACTION of drug is eliminated per unit of time

  • drug is cleared from the body at a rate proportional to its plasma concentration
  • Most drugs follow this model
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26
Q

What is zero order kinetics? What drugs follow this?

A

A constant AMOUNT of drug is eliminated per unit time

  • describes the situation where there is more drug than enzyme
  • rate of elimination is independent of plasma drug concentration

ex) Aspirin, Phenytoin, Warfarin, Heparin, and Theophylline

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27
Q

What is the function of a phase 1 reaction?

A

Phase 1 reactions result in small molecular changes that increase polarity (water solubility) of a molecule to prepare it for a phase 2 reaction

-most phase 1 biotransformation are carried out by the P450 system

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28
Q

What are the three phase 1 reactions?

A

Oxidation: removes electrons from a compound

Reduction: adds electrons to a compound

Hydrolysis: adds water to a compound to split it apart (usually an ester)

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29
Q

What is the function of a phase 2 reaction? List 5 common substrates

A

Phase 2 reaction conjugates (adds on) an endogenous, highly polar, water soluble substrate to the molecule – results in a water soluble, biologically inactive molecule ready for excretion

Typical Substrates:

  • Glucuronic acid
  • Glycine
  • Acetic acid
  • Sulfuric acid
  • Methyl group
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30
Q

What is enterohepatic circulation?

A

Some conjugated compounds are excreted in the bile, reactivated in the intestine, and then reabsorbed into the systemic circulation

Ex: Diazepam and Warfarin

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31
Q

What is the extraction ratio?

A

A measure of how much drug is delivered to a clearing organ vs how much drug is removed by that organ

  • ER of 1 means that the clearing organ removes 100% of the delivered drug
  • ER of 0.5 means that the clearing organ removes 50% of the delivered drug
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32
Q

How do you calculate the extraction ratio?

A

ER = (Arterial Concentration - Venous Concentration) / Arterial Concentration

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33
Q

Regarding hepatic clearance, what is PERFUSION-dependent elimination?

A

For a drug with a high hepatic extraction ratio (>0.7), clearance is dependent on liver blood flow

  • hepatic blood flow greatly exceeds enzymatic activity, so alterations in hepatic enzyme activity has little effect
  • increased liver blood flow = increased clearance
  • decreased liver blood flow = decreased clearance
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34
Q

Regarding hepatic clearance, what is CAPACITY-dependent elimination?

A

For a drug with a low hepatic extraction ratio (<0.3), clearance is dependent on the ability of the liver to extract the drug from the blood

  • changes in hepatic enzyme activity or protein binding have a profound impact on the clearance of these drugs
  • since only a small amount of drug is removed per unit time, alterations in liver blood flow minimally affect clearance
  • Enzyme induction = Increased clearance
  • Enzyme inhibition = Decreased clearance
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35
Q

Which drugs have a low hepatic extraction ratio? (7)

A
  • Rocuronium
  • Diazepam
  • Lorazepam
  • Methadone
  • Thiopental
  • Theophylline
  • Phenytoin

*affected by CYP activity

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36
Q

Which drugs have a intermediate hepatic extraction ratio? (4)

A
  • Midazolam
  • Vecuronium
  • Alfentanil
  • Methohexital
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37
Q

Which drugs have a high hepatic extraction ratio? (15)

A
  • Fentanyl
  • Sufentanil
  • Morphine
  • Meperidine
  • Naloxone
  • Ketamine
  • Propofol
  • Lidocaine
  • Bupivacaine
  • Metoprolol
  • Propranolol
  • Alprenolol
  • Nifedipine
  • Diltiazem
  • Verapamil
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38
Q

What is the difference between a hepatic enzyme inducer and enzyme inhibitor? List examples of each.

A

Enzyme Inducer: increase clearance, decrease drug plasma level, and dose increase may be requires
- ex: tobacco smoke, barbituates, ethanol, phenytoin, rifampin, carbamazepine

Enzyme Inhibitor: decrease clearance, increase drug plasma level, and dose decrease may be required
- ex: grapefruit juice, cimetidine, omeprazole, isoniazid, SSRIs, erythromycin, ketoconazole

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39
Q

What two drug classes and seven drugs are metabolized by pseudocholinesterase?

A

Some Neuromuscular Blockers:

  • SUX
  • Mivacurium

Ester-Type Local Anesthetics:

  • Chloroprocaine
  • Tetracaine
  • Procaine
  • Benzocaine
  • Cocaine (also metabolized by the liver)
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40
Q

What six drugs are metabolized by non-specific plasma esterases?

A
  • Esmolol
  • Remifentanil
  • Remimazolam
  • Clevidipine
  • Atracurium (and Hofmann elimination)
  • Etomidate (and hepatic)
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41
Q

What drug is biotransformed by alkaline phosphatase hydrolysis?

A

Fospropofol

-propofol prodrug under the trade name Lusedra

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42
Q

What is the definition of pharmacokinetics?

A

“What the body does to the drug”

  • explains the relationship between the dose you administer and the drug’s plasma concentration over time
  • affected by absorption, distribution, metabolism, and elimination
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43
Q

What is the definition of pharmacobiophysics?

A

Considers the drug’s concentration in the plasma and the effect site (biophase)

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44
Q

What is the definition of pharmacodynaamics?

A

“What the drug does to the body”

-explains the relationship between the effect site concentration and the clinical effect

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45
Q

What is potency and how is it measured?

A

Potency = the dose required to achieve a given clinical effect (x-axis of dose-response curve

ED50 and ED90 are measures of potency
-represent the dose required to achieve a given effect in 50% and 90% of the population

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46
Q

How is potency measured on the dose-response curve?

A

Drug A is more potent than Drug B

  • Drug A: curve shifts left with –> increased affinity for receptor –> higher potency –> lower dose required
  • Drug B: curve shifts right with –> decreased affinity for receptor –> lower potency -> higher dose required
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47
Q

What is efficacy, and how is it measured on the dose-response curve?

A

Efficacy = measure of the intrinsic ability of a drug to produce a clinical effect

Height on the plateau on the y-axis represents efficacy

  • higher plateau = greater efficacy
  • lower plateau = lower efficacy
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48
Q

What does the slope of the dose-response curve tell you?

A

How many of the receptors must be occupied to elicit a clinical effect

  • steeper slope = small increase in dose can have profound clinical effect
  • flatter slope = higher doses are required to increase clinical effect
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49
Q

What is the differences between a full agonist, partial agonist, antagonist, and inverse agonist?

A
  • Full Agonist: binds to a receptor and turns on a specific cellular response
  • Partial Agonist: binds to a receptor, but it is only capable of partially turning on a cellular response (less effective than full agonist)
  • Antagonist: occupies the receptor and prevents an agonist from binding to it (has no efficacy)
  • Inverse Agonist: binds to the receptor and causes an opposite effect to that of a full agonist (negative efficacy)
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50
Q

What is competitive antagonism? give an example

A

Competitive antagonism is REVERSIBLE

-increasing the concentration of the agonist can overcome the competitive antagonism

Ex: Atropine, Vecuronium, Rocuronium

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51
Q

What is noncompetitive antagonism? give an example

A

Noncompetitive antagonism is NOT reversible

  • drug binds to a receptor and its effect cannot be overcome by increasing the concentration of an agonist
  • only by creating new receptors can the effect of a noncompetitive agonist be reversed – why DOA is so long

Ex: ASA and Phenoxybenzamine

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52
Q

What is ED50?

A

the dose that produces the expected clinical response in 50% of the population

it is a measure of potency

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53
Q

What is TD50?

A

the dose that will produce toxicity in 50% of the population

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54
Q

What is the therapeutic index?

A

Helps determine the safety margin for a desired clinical effect

TI = TD50 / ED50

  • drug with a narrow TI has narrow margin of safety
  • drug with a wide TI has a wide margin of safety
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55
Q

What is chirality?

A

A division of stereochemistry – deals with molecules that have a center of 3D asymmetry

  • in biologic systems, this type of asymmetry generally stems from the tetrahedral bonding of carbon (carbon binds to 4 different atoms)
  • A molecule with 1 chiral carbon will exist as 2 enantiomers (the more chiral carbons in a molecule, the more enantiomers created)
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56
Q

What is an enantiomer? What is the clinical relevance?

A

Enantiomers are chiral molecules that are non-superimposable mirror images of one another

Different enantiomers can produce other clinical effects – for example the side effect profile of one enantiomer of a drug can be different from another enantiomer of the same drug

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57
Q

What is a racemic mixture? List some commonly used examples

A

Racemic mixture contains 2 enantiomers in equal amounts

1/3 of the drugs we admin are enantiomers (about all of these are racemic mixtures)
-Ex: Bupivacaine, Ketamine, Isoflurane, and Desflurane

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58
Q

What is the mechanism of action of Propofol?

A

Direct GABA-A agonist –> increases Cl- conductance –> Neuronal hyperpolarization –> Prevent action potential

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59
Q

What is the dose, onset, duration, and clearance mechanism for propofol?

A

Dose: induction 1.5 - 2.5 mg/kg IV – infusion 25-100 mcg/kg/min

Onset: 30-60 sec

Duration: 5-10 min

Clearance: Liver (P450) + Extrahepatic metabolism (lungs)

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60
Q

What are the CV and respiratory effects of propofol?

A

CV Effects:

  • decreased BP (due to decreased SNS tone and vasodilation)
  • decreased SVR
  • decreased venous tone –> decreased preload
  • decreased myocardial contractility

Respiratory Effects:

  • shifts CO2 response curve down and to the right (less sensitive to CO2) –> respiratory depression and/or apnea
  • inhibits hypoxic ventilatory drive
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61
Q

What are the CNS effects of propofol?

A
  • Decreased CMRO2
  • Decreased cerebral blood flow
  • Decreased ICP
  • Decreased IOP
  • No analgesia
  • Anticonvulsant properties
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62
Q

What is the formulation of propofol? Is there a pt population where this is a problem?

A

It is prepared as a 1% solution in an emulsion of egg lecithin, soybean oil, and glycerol

-despite concerns that propofol might precipitate anaphylaxis in pts with egg, soy, and/or peanut allergy, there is no evidence to support this

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63
Q

What is propofol infusion syndrome?

A

Propofol contains long chain triglycerides, and is increased LCT load impairs oxidative phosphorylation and fatty acid metabolism

This starves cells of O2, particularly in cardiac and skeletal muscle

*associated with high mortality rate

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64
Q

What are the risk factors for propofol infusion syndrome?

A
  • Propofol dose >4 mg/kg/hr (67 mcg/kg/min)
  • Propofol infusion duration >48 hr
  • Adults > Children
  • Inadequate O2 delivery
  • Sepsis
  • Significant cerebral injury
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65
Q

What is the clinical presentation of propofol infusion syndrome?

A

Clinical presentation includes acute refractory bradycardia –> asystole + at least one of the following:

  • metabolic acidosis (base deficit > 10 mmol/L)
  • rhabdomyolysis
  • enlarged or fatty liver
  • renal failure
  • HLD
  • lipemia (cloudy plasma or blood) may be an early sign
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66
Q

When must a propofol syringe be discarded? How about an infusion?

A

Syringe = within 6 hours

Infusion = within 12 hours

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67
Q

What preservatives are used in brand and generic propofol? what pt population are at risk?

A

Diprivan (brand) contains EDTA as a preservative – not a problem for any pt population

Generic propofol formulation contain different preservatives:

  • metabisulfite can precipitate bronchospasm in asthmatic pts
  • avoid benzyl alcohol in infants
68
Q

How can propofol injection pain be minimized?

A
  • Injecting into a larger more proximal vein
  • Lidocaine (before or mixed)
  • Giving an opioid before
69
Q

What dose of propofol can be used to treat PONV?

A

10 - 20 mg IV or Infusion of 10 mcg/kg/min

70
Q

How is fospropofol converted to its active form?

A

It is a prodrug –> propofol is the active metabolite

Alkaline Phosphatase converts fospropofol to propofol

*explains the slower onset (5-13 min) and longer duration (15-45 min)

71
Q

What is the primary mechanism of action for anesthesia produced by ketamine?

A

NMDA receptor antagonist (antagonizes glutamate)

  • secondary receptor targets include opioid, MAO, serotonin, NE, muscarinic, and Na+ channels
  • ketamine dissociates the thalamus (sensory) from the limbic system (awareness)
72
Q

What are the potential routes of admin for ketamine? Include the doses for each

A

IV: induction 1-2 mg/kg – analgesia 0.1-0.5 mg/kg

IM: 4-8 mg/kg

PO: 10 mg/kg

73
Q

What is the onset, duration, and clearance mechanism for ketamine?

A

Onset: IV 30-60 sec – IM 2-4 min – PO variable

Duration: 10-20 min (may require 60-90 min to return to full orientation)

Clearance: Liver (P450) – produces active metabolite (norketamine: 1/3 -1/5 potency)

74
Q

What are the CV effects of ketamine?

A
  • Increased SNS tone
  • Increased CO
  • Increased HR
  • Increased SVR
  • Increased PVR (caution use in severe RV failure)
  • Sub-hypnotic doses (<0.5 mg/kg) usually don’t activate the SNS

*it is a myocardial depressant – myocardial depressant effects are unmasked in pts with depleted catecholamine stores (sepsis) or sympathectomy

75
Q

What are the respiratory effects of ketamine?

A
  • Bronchodilation
  • Upper airway muscle tone and airway reflexes remain intact
  • Maintains respiratory drive (brief period of apnea may occur following induction)
  • Doesn’t significantly shift CO2 response curve
  • Increased oral and pulmonary secretions –> increased risk of laryngospasm
76
Q

What are the CNS effects of ketamine?

A
  • Increased CMRO2
  • Increased cerebral blood flow
  • Increased ICP
  • Increased IOP
  • Increased EEG activity (caution if hx of seizures)
  • Nystagmus
  • Emergence delirium
77
Q

What is the presentation, treatment, and risk factors for emergence delirium with ketamine use?

A

Presentation: nightmares and hallucinations (risk persists for up to 24 hrs)

Treatment: benzodiazepines are most effective way to prevent (midazolam > diazepam)

Risk Factors: age >15, female, ketamine dose >2 mg/kg, hx of personality disorder

78
Q

Discuss the analgesic properties of ketamine

A
  • Provides good analgesia and opioid sparing effect (only induction agent)
  • Relieves somatic pain > visceral pain
  • Blocks central sensitization and wind-up in the dorsal horn of spinal cord
  • Prevents opioid induced hyperalgesia (after remifentanil infusion)
  • Excellent for burn pts (frequent dressing changes) and those with pre-existing chronic pain syndromes
79
Q

What is the dose, onset, duration, and clearance mechanism for etomidate?

A

Dose: 0.2-0.4 mg/kg IV

Onset: 30-60 sec

Duration: 5-15 min

Clearance: Hepatic P450 + plasma esterases

80
Q

What are the CV and respiratory effects of etomidate?

A

CV Effects:

  • minimal changes in HR, SV, or CO (key benefit is hemodynamic stability)
  • SVR is decreased (accounts for small decrease in BP)
  • doesn’t block SNS response to laryngoscopy

Respiratory Effects:

  • mild respiratory depression
81
Q

What are the CNS effects of etomidate?

A
  • Decreased CMRO2
  • Decreased cerebral blood flow (cerebral vasoconstriction)
  • Decreased ICP
  • CPP remains stable
  • No analgesia
82
Q

What is the relationship between etomidate and myoclonus?

A

Myoclonus is involuntary skeletal muscle contractions, dystonia, or tremor

It is likely due to an imbalance between excitatory and inhibitory pathways in the thalamocortical tract – it is not a seizure

83
Q

What is the relationship between etomidate and seizure activity?

A

If the pt does not have a hx of seizures, etomidate doesn’t increase the risk

If the pt has a hx of seizures, etomidate can increase epileptiform (seizure like) activity and possibly increase risk of seizures

84
Q

What is the relationship between etomidate and adrenocortical suppression?

A

Cortisol and aldosterone synthesis are dependent on enzyme 11-beta-hydroxylase and 17-alpha-hydroxylase

  • etomidate is known inhibitor of these
  • single dose of etomidate suppresses adrenocortical function for 5-8hrs – reason why you should avoid it in pts reliant on the intrinsic stress response (sepsis or acute adrenal failure)
  • mortality may be increased by etomidate (particularly in pts with sepsis)
85
Q

Which induction agent is most likely to cause PONV?

A

Etomidate

86
Q

What are the two sub-classes of barbiturates? List examples

A

Thiobarbiturates: there is a sulfur molecule in the second position (increases lipid solubility and potency)
ex: thiopental, thiamylal

Oxybarbiturates: there is an oxygen molecule in the second position
ex: methohexital, pentobarbital

87
Q

What is the mechanism of action of thiopental?

A

GABA-A agonist –> depresses the reticular activating system in the brainstem

  • Low/Normal Dose: increases affinity of GABA for its binding site
  • High Dose: directly stimulates the GABA-A receptor
88
Q

What is the dose, onset, duration, and clearance mechanism for thiopental?

A

Dose: adult 2.5-5 mg/kg – children 5-6 mg/kg

Onset: 30-60 sec

Duration 5-10 min

Clearance: Liver (P450) – redistribution (not metabolism) determines awakening

*repeated doses –> tissue accumulation –> prolonged wake up time + hangover effect

89
Q

What are the CV and respiratory effects of thiopental?

A

CV Effects:

  • HoTN is primarily the result of venodilation and decreased preload – myocardial depression is a secondary cause
  • causes non-immunogenic histamine release (can contribute to HoTN - short lived)
  • baroreceptor reflex is preserved –> reflex tachycardia helps restore CO
  • less HoTN compared to propofol

Respiratory:

  • respiratory depression (shifts CO2 curve to the right)
  • histamine release can cause bronchoconstriction (caution w/ asthma
90
Q

What are the CNS effects of thiopental?

A
  • Decreased CMRO2
  • Decreased cerebral blood flow (cerebral vasoconstriction)
  • Decreased ICP (used in treatment in intracranial HTN)
  • Decreased EEG activity (can cause burst suppression and/or isoelectric EEG –> neuroprotection)
  • No analgesia
91
Q

In what circumstances can thiopental be used for neuroprotection?

A

Focal ischemia
-ex: carotid endarterectomy, temporary occlusion of cerebral arteries

*Not for global ischemia

92
Q

What is the pathophysiology of acute intermittent porphyria?

A
  • Heme is a key component of Hgb, myoglobin, and cytochrome P450 enzymes
  • Porphyria is caused by a defect in heme synthesis that promotes the accumulation of heme precursors (ALA induction)
  • The porphyrias can be classified as acute or cutaneous – Acute intermittent porphyria is most common and most dangerous type
93
Q

What drugs should be avoided in the pt with acute intermittent porphyria? Why?

A

Any drug or condition that induces ALA synthase will accelerate the production of heme precursors and must be avoided

Drugs to Avoid: barbs, etomidate, ketamine, ketorolac, amiodarone, calcium channel blockers, birth control pills

Conditions to Avoid: emotional stress, prolonged NPO status

94
Q

What is the treatment for acute intermittent porphyria?

A
  • Liberal hydration
  • Glucose supplementation (reduces ALA synthase activity)
  • Heme arginate (reduces ALA activity)
  • Prevention of hypothermia
95
Q

What is the risk of intra-arterial injection of thiopental? What is the treatment?

A

Intra-arterial injection –> intense vasoconstriction + crystal formation (occludes blood flow) + inflammation –> tissue necrosis

Treatment:

  • injection of vasodilator (phentolamine or phenoxybenzamine)
  • sympathectomy (stellate ganglion block or brachial plexus block)
96
Q

What induction agent is the gold standard for ECT therapy? Why?

A

Methohexital

-decreases seizure threshold and produces a better quality seizure

97
Q

What is the mechanism of action for dexmedetomidine?

A

Alpha-2 agonist –> Decreases cAMP –> Inhibits the locus coeruleus in the pons (sedation)

  • analgesia is produced by alpha-2 stimulation in the dorsal horn of the spinal cord (decrease substance P and decrease glutamate release
98
Q

What is the dose, onset, duration, and clearance mechanism for dexmedetomidine?

A

Dose: loading 1 mcg/kg over 10min – maintenance 0.4-0.7 mcg/kg/hr

Onset: 10-20 min

Duration: 10-30 min (after infusion stopped)

Clearance: Liver (P450)

99
Q

What are the CV effects of dexmedetomidine?

A

Most Common = Bradycardia and Hypotension

*rapid admin can cause HTN (alpha-2 stimulation in vasculature -> temporary vasoconstriction –> HTN) – short lived

100
Q

Why is dexmedetomidine attractive for procedural sedation?

A

It doesn’t cause respiratory depression

  • no change in oxygenation
  • no change in blood pH
  • no change in slope of CO2 response curve
101
Q

What are the CNS effects of dexmedetomidine?

A

Produces sedation that resembles natural sleep

  • sedation is result of reduced SNS tone and decreased level of arousal
  • patients arouse easily
  • doesn’t provide reliable amnesia
  • Decreases CBF
  • No change in CMRO2
  • No change in ICP
102
Q

How does dexmedetomidine produce analgesia?

A

By alpha-2 stimulation in the dorsal horn of spinal cord

-decreased substance P and decreased glutamate release

103
Q

Aside from IV, what other routes can dexmedetomidine be administered? What is the dose?

A

Nasal and Buccal Routes

  • 3-4 mcg/kg 1 hr prior to surgery
  • high degree of bioavailability
  • useful for preop sedation in children
104
Q

How does the imidazole ring in Midazolam affect its solubility?

A

Imidazole ring can assume an open or close position depending on the environmental pH

  • Acidic pH –> ring opens –> Increases water solubility
  • Physiologic pH –> ring closes –> Increases lipid solubility

*Midazolam is water soluble inside the vial, it doesn’t require a solvent such as propylene glycol

105
Q

What is the mechanism of action for midazolam?

A

GABA-a agonist: increases frequency of channel opening –> neuronal hyperpolarization

*most GABA-a agonists increase open TIME but benzos increased open FREQUENCY

106
Q

What are the IV and PO doses for midazolam? Why are they different?

A

IV sedation: 0.01-0.1 mg/kg
IV induction: 0.1-0.4 mg/kg
PO sedation in kids: 0.5-1 mg/kg

*PO bioavailability is 50% due to significant 1st pass metabolism

107
Q

Which induction agents produce an active metabolite?

A
  • Midazolam: 1-hydroxymidazolam (1/2 potency)
  • Ketamine: norketamine (1/3 - 1/2 potency)
  • Fospropofol: propofol

*Propofol, Etomidate, and Dexmedetomidine do not produce active metabolites

108
Q

What are the CV and respiratory effects of midazolam?

A

CV Effects:

  • sedation dose = minimal effects
  • induction dose = decrease BP and SVR

Respiratory Effects:

  • sedation dose = minimal effects
  • induction dose = respiratory depression
  • opioids potentiate respiratory depressant effects, even at doses for sedation
  • pts w/ COPD are more sensitive to respiratory depressant effects
109
Q

What are the CNS effects of midazolam?

A

Sedation Dose: minimal effects on CMRO2 and CBF
Induction Dose: decreased CMRO2 and CBF

  • can’t produce isoelectric EEG
  • anterograde amnesia (not retrograde)
  • anticonvulsant
  • anxiolysis
  • spinally mediated skeletal muscle relaxation (antispasmodic)
  • no analgesia
110
Q

What are the unique features of remimazolam?

A
  • It’s ultra-short acting benzo
  • Vial must be protected from light
  • Single use vial must be discarded 8hrs after reconstitution
  • Metabolized by plasma esterases
  • Contraindicated in pts with a history of severe hypersensitivity reaction to Dextran 40
111
Q

What is the reversal agent for benzodiazepines? How does it work?

A

Flumazenil is a competitive antagonist of GABA-a receptor

Initial dose = 0.2 mg IV – titrate in 0.1 mg increments Q1 min

  • very high affinity but has short duration of action (30-60 min)
  • repeat doses may be necessary to prevent re-sedation
112
Q

What are potential side effects of flumazenil?

A

Does NOT increases SNS tone, anxiety, or neuroendocrine evidence of stress like naloxone

Can precipitate signs of withdrawal in benzo-dependent patients (including seizures)

113
Q

How can you tell the difference between the chemical structures of the halogenated agents?

A

Count the halognes:

  • Halothane = 3 fluorine + 1 bromine atom
  • Iso = 5 fluorine + 1 chlorine
  • Des = 6 fluorine
  • Sevo = 7 fluorine
114
Q

How does fluorination affect the physiochemical characteristics of halogenated anesthetics?

A

Adding fluoride ions tends to:

  • decrease potency,
  • increase vapor pressure
  • increase resistance to biotransformation

*even though sevo is heavily fluorinated, its ~3x as potent as des (most likely due to bulky propyl side chain)

115
Q

What is vapor pressure, and how is it affected by the ambient temperature?

A

Vapor Pressure: pressure exerted by a vapor in equilibrium with its liquid or solid phase inside of a closed container

-it is directly proportional to temperature (Increased temp = Increased vapor pressure)

116
Q

How is anesthetic delivery affected by altitude? When does this matter?

A
  • Anesthetic depth is determined by partial pressure of anesthetic agent in the brain (Partial Pressure of a Gas = Vol% x Total Gas Pressure)
  • As atmospheric pressure decreases at higher elevations –> Vol% remains the same but partial pressure of gas decreases (Risk of under dosing anesthetic agent)
  • For Sevo and Iso at elevation under dosing is not a problem – conventional variable bypass vaporizer automatically compensates for elevation change
  • For Des at elevation under dosing IS a problem –the injector design on the Tec 6 vaporizer doesn’t compensate for elevation (18.4% reduction at 1 mile above sea level compared to sea level)
117
Q

What are the vapor pressures of Sevo, Des, Iso, and N2O?

A

Sevo = 157

Des = 669

Iso = 238

N2O = 38,770

118
Q

Which inhalation anesthetics are stable in soda lime? What byproducts can each agent produce in soda lime?

A

Sevo: not stable – compound A (occurs in functional soda lime and worse if soda lime is desiccated)

Des: not stable – carbon monoxide (only if desiccated)

Iso: not stable – carbon monoxide (only is desiccated)

N2O: stable – none

119
Q

What is solubility and how is it measured?

A

Solubility = tendency of a solute to dissolve into a solvent
-in the case of inhalation anesthetics, its the anesthetic agent’s ability to dissolve into the blood/tissues

Blood:Gas partition coefficient = relative solubility of an inhalation anesthetic in the blood vs in the alveolar gas when the partial pressure between the 2 compartments are equal

120
Q

What is the Blood:Gas solubility for Sevo, Des, Iso, and N2O?

A

Des = 0.42

N2O = 0.46

Sevo = 0.65

Iso = 1.45

121
Q

How do we establish an anesthetic concentration inside the alveolus?

A
  1. Turn on vaporizer (creates concentration gradient that pushes anesthetic agent from vaporizer towards the alveoli) – FI
  2. Ventilation washes the anesthetic agent into the alveoli – FA
  3. Buildup of anesthetic partial pressure inside the alveoli is opposed by continuous uptake of agent into the blood – Uptake
  4. CO distributes the anesthetic agent throughout the body – Distribution
122
Q

What does the FA/FI curve tell us? How does anesthetic solubility affect the FA/FI curve for each agent?

(Order the volatile anesthetics from top to bottom on FA/FI curve)

A

FA/FI Curve allows us to predict the speed of induction

  • Low solubility –> Less uptake into the blood –> Increase rate of rise –> Faster equilibration of Fa/Fi –> FASTER onset
  • High solubility –> More uptake into the blood –> Decrease rate of rise –> Slower equilibration of Fa/Fi –> SLOWER onset
123
Q

What factors affect agent delivery to and removal from the alveoli?

A

Determinants of Delivery: setting on vaporizer, time constant of delivery system, anatomic dead space, alveolar ventilation, functional residual capacity

Determinants of Uptake: solubility of anesthetic in the blood (blood:gas coefficient), CO, partial pressure gradient between alveolar gas and mixed venous blood

124
Q

What conditions increase Fa/Fi? Which condition decrease it?

A

For Fa/Fi to INCREASE (faster onset) – must be greater wash in and/or reduce uptake
- increase wash in: high FGF, high alveolar ventilation, low FRC, low time constant, low anatomic dead space
- decrease uptake: low solubility, low CO, low Pa-Pv difference

For Fa/Fi to DECREASE (slower onset) – must be a reduced wash in and/or increased uptake
- decreased wash in: low FGF, low alveolar ventilation, high FRC, high time constant, high anatomic dead space
- increase uptake: high solubility, high CO, high Pa-Pv difference

125
Q

In which pt will the onset of sevo be the fastest? Why?

Patient A: HR 55 bpm w/ SV 100mL/beat
Patient B: HR 60 bpm w. SV 85 mL/beat

A

Patient B

  • anesthetic uptake is directly proportional to CO – high CO removes more anesthetic agent from the alveoli, so it slows rate of rise of Fa/Fi – slowing rate of induction
  • Pt A has CO of 5.5 L/min and Pt B has CO of 5.1 L/min
126
Q

What are the four tissue groups? How much CO does each receive?

A

Vessel-Rich = 75% CO – brain, heart, kidney, liver

Muscle = 20% CO – skeletal muscle, skin

Fat = 5% CO

Vessel-Poor = <1% CO – bone, tendon, cartilage

127
Q

What 3 ways are inhalation anesthetics removed from the body? For each agent, what percent is attributed to hepatic metabolism?

A
  • Elimination from alveoli (most important)
  • Hepatic biotransformation
  • Percutaneous loss (minimal)

Hepatic Biotransformation:

  • N2O = 0.004%
  • Des = 0.02%
  • Iso = 0.2 %
  • Sevo = 2-5%
  • Halotane = 20%
  • rule of 2’s
  • agents spell DISH
128
Q

Discuss the FDA recommendations for the minimal fresh gas flow requirements for Sevo

A

1 L/min for up to 2 MAC hours

2 L/min after 2 MAC hours

*no supporting evidence renal necrosis occurs in humans

129
Q

What is a MAC hour?

A

1% Sevo x 2 hrs
2% Sevo x 1 hr
4% Sevo x 30 min

130
Q

Which volatile agents are metabolized to trifluoroacetic acid? What is a potential consequence of this?

A

Up to 20% of halothane undergoes hepatic biotransformation – high liver concentration may lead to halothane hepatitis

Des and Iso undergo a much smaller degree of hepatic biotransformation

Remote possibility that TFA could precipitate an immune-mediated hepatic dysfunction (especially w/ previous TFA exposure)

131
Q

What are the theoretical consequences of sevo metabolism?

A

its biotransformation results in the liberation of inorganic fluoride ions

  • theoretical concerns of fluoride-induced high output renal failure (no solid evidence of it)
  • signs of high-output renal failure: polyuria, hypernatremia, hyperosmolarity, increased plasma creatinine, and inability to concentrate urine

*compound A occurs inside the circuit – F-ions production occurs from hepatic metabolism

132
Q

What is the concentration effect?

A

Describes an increased rate of alveolar uptake as the concentration of a gas is increased

Function of 2 mechanisms:

  • Concentrating effect - N2O is introduced into the lung, volume of N2O going from alveolus to pulm blood is much higher than amount of N2O moving the opposite direction – causes alveolus to shrink and the reduction in alveolar volume causes relative increase in Fa
  • Augmented gas inflow - on the subsequent breath, the concentrating effect causes increased inflow of tracheal gas containing the anesthetic agent to replace the lost alveolar volume – increases alveolar ventilation and augments Fa – alveolar volume restores quickly, so it is only temporary
133
Q

When compared to N2O, Des has a lower blood-gas partition coefficient. Why does the Fa/Fi ratio for N2O rise faster than Des?

A

Due to the concentration effect

  • despite a slightly higher blood:gas partition coefficient, the alveolar partial pressure of N2O rises faster than Des
  • this is because we can safely deliver a much higher inspiratory concentration, which negates the small difference imposed by the slightly higher blood:gas partition coefficient
134
Q

Anesthetic overpressure results in a more profound effect for agents with a higher OR lower blood solubility?

A

HIGHER blood solubility

  • concentration effect says that the higher the concentration of inhalation anesthetic delivered to the alveolus (Fa), the faster its onset of action – this is also called overpressuring
  • effect is only clinically relevant for N2O, however it may occur with other gases
  • can offset the effects of a higher blood solubility by increasing the inspired concentration on the vaporizer – helps reach Fa/Fi equilibration faster
135
Q

How does N2O affect the uptake of a halogenated anesthetic during induction? What is this called?

A

Use of N2O during anesthetic induction will speed up the onset of a second gas

Called the second gas effect

136
Q

What is diffusion hypoxia? How can it be prevented?

A

N2O moves from the body towards the lungs –> Dilutes alveolar O2 and CO2 –> Decreased respiratory drive and hypoxia

  • it is a risk during emergence
  • administering 100% O2 for 3-5 min after discontinuing N2O prevents it
137
Q

Which inhalation anesthetics are most greatly affected by a right-to-left shunt?

A

The Fa/Fi of an agent with lower solubility (Des) will be more affected than an agent with higher solubility (Iso)

138
Q

Which inhalation anesthetics are most greatly affected by a left-to-right shunt?

A

Left-to-right shunt will not have a meaningful effect on anesthetic uptake or induction time

139
Q

Why does N2O accumulate in closed air spaces?

A

It is 34x more soluble than nitrogen – meaning it will enter a space 34x faster than nitrogen can exit that space

140
Q

What type of spaces does N2O increase volume vs increase pressure?

A

Increases Volume in Compliant Airspaces:

  • fast equilibration between space and blood = pulmonary blebs, air bubbles in the blood, gas bubble in the eye
  • slow equilibration between space and blood = bowel, pneumoperitoneum

Increases Pressure in Fixed Airspaces:

  • fast equilibration between space and blood = middle ear, brain during intracranial procedures
141
Q

How does N2O affect a pt with an ocular gas bubble? When can N2O be used in these patients?

A

N2O can expand the SF6 bubble compromising retinal perfusion – can cause permanent blindness

  • discontinue N2O 15min prior to placing SF6 bubble
  • avoid N2O for 7-10 days post bubble placement
  • if an air bubble is used, avoid N2O for 5 days
  • if perfluoropropane is used, avoid N2O for 30 days
  • if silicone oil is used, there is no contraindication to N2O
142
Q

What is the relationship between N2O and anesthesia equipment?

A

N2O can increase the volume and pressure in:

  • ETT
  • LMA cuff
  • Balloon-tipped pulmonary artery catheter

*attach a manometer to the pilot balloon to check internal pressure

143
Q

How do we quantify anesthetic potency? What is this value for each inhalation agent?

A

Minimum Alveolar Concentration (MAC) = Measure of potency

Iso = 1.2%
Sevo = 2.0%
Des = 6.6%
N2O = 104%

144
Q

What are MAC-bar and MAC-awake?

A

MAC-bar: alveolar concentration required to block the autonomic response following a supramaximal painful stimulus (~1.5 MAC)

MAC-awake: alveolar concentration at which a pt opens his or her eyes - shows hysteresis in that MAC-awake is ~0.4-0.5 during induction but during recovery MAC-awake is as low as 0.15 MAC

145
Q

What factors increase MAC?

A
  • Chronic alcohol consumption
  • Acute amphetamine intoxication
  • Acute cocaine intoxication
  • MAOIs
  • Ephedrine
  • Levodopa
  • Hypernatremia
  • Increased in infants 1-6 months (sevo is same for neonates and infants)
  • Hyperthermia
  • Red hair
146
Q

What factors decrease MAC?

A
  • Acute alcohol intoxication
  • IV anesthetics
  • N2O
  • Opioids (IV & neuraxial)
  • Alpha-2 agonists
  • Lithium
  • Lidocaine
  • Hydroxyzine
  • Hyponatremia
  • Older age (decrease 6% per decade after 40)
  • Prematurity
  • Hypothermia
  • HoTN (MAP < 50)
  • Hypoxia
  • Anemia
  • Cardiopulmonary bypass
  • Metabolic acidosis
  • Hypo-osmolarity
  • Pregnancy –> Postpartum (24-72hr)
  • PaCO2 > 95 mmHg
147
Q

What factors do not affect MAC?

A
  • Hyper or Hypokalemia
  • Hyper or Hypomagnesemia
  • Hyper or Hypothyroidism
  • Gender
  • PaCO2 15-95 mmHg
  • HTN
148
Q

How do hyper- and hypothyroidism affect MAC? Why?

A

they don’t directly affect MAC - but changes in CO associate with these conditions may affect anesthetic uptake and subsequent onset of action

ex: profoundly hypothyroid pts have a reduced CO leading to decreased uptake into the blood and a faster rate of rise of Fa/Fi – making them more susceptible to anesthetic overdose

149
Q

What is the Meyer-Overton rule?

A

States that lipid solubility is directly proportional to the potency of an inhaled anesthetic

-implies the number of anesthetic molecules that are dissolved in the brain determines the depth of anesthesia

150
Q

What is the unitary hypothesis?

A

states that all anesthetics share a similar mechanism of action, although each may work at a different site

151
Q

What is the most important site of halogenated anesthetic action in the brain?

A

Most essential site of volatile anesthetic action is the GABA-A receptor

  • GABA-A receptor = ligand-gated chloride channel
  • Stimulation increases chloride influx and hyperpolarizes neurons (impairs neurotransmission)
  • Volatile anesthetics most likely increase the duration the chloride channel remains open
152
Q

How do halogenated anesthetics produce immobility?

A

Produce immobility in the ventral horn of the spinal cord

153
Q

Which cerebral receptors are stimulated by N2O?

A

NMDA antagonism

Potassium 2P-channel stimulation

*N2O does NOT stimulate the GABA-A receptor

154
Q

In which regions of the brain do halogenated anesthetics produce unconsciousness?

A
  • Cerebral cortex
  • Thalamus
  • Reticular activating system
155
Q

In which regions of the brain do halogenated anesthetics produce amnesia?

A

Amygdala

Hippocampus

156
Q

In which regions of the brain do halogenated anesthetics produce autonomic modulation?

A

Pons

Medulla

157
Q

How do halogenated agents reduce blood pressure?

A

Decrease MAP in a dose dependent fashion – at equivalent doses, there is little difference between agents

  • Primary cause = decrease intracellular Ca2+ in vascular smooth muscle –> systemic vasodilation –> decrease SVR and venous return
  • Secondary cause = decrease intracellular Ca2+ in the myocyte –> myocardial depression –> decrease inotropy
158
Q

How do halogenated anesthetics affect HR?

A

Directly affect cardiac conduction in a dose dependent fashion

  • decrease SA node automaticity
  • decrease conduction velocity through the AV node, His-Purkinje system, and ventricular conduction pathways
  • increase duration of myocardial repolarization by impairing the outward K+ current (prolongs AP duration and QT interval)
  • altered baroreceptor function
159
Q

Why do Des and Iso sometimes have increased HR?

A

they increase HR from baseline by 5-10% – most likely due to SNS activation from respiratory irritation
-pulm irritation –> SNS activation –> increase norepi release –> beta-1 stimulation

rapid increases in Des (Iso to a lesser degree) cause tachycardia
-opioids or beta-1 antagonists can minimize it

160
Q

What is the relationship between Iso and coronary steal?

A

Iso is the most potent coronary artery dilator

  • atherosclerotic vessels can’t dilate, while normal vessels can –> this would preferentially divert blood away from areas of higher resistance, starving those regions of O2

** more of textbook thing than a real-world problem

161
Q

How does N20 (by itself) affect hemodynamics?

A

It activates the SNS – increases MAP as a function of increased SVR (CVP and right atrial pressure may increase)

It is a myocardial depressant, but the increased SNS stimulation outweighs the physiologic consequences of this

162
Q

How do halogenated anesthetics contribute to hypercarbia?

A

Volatile anesthetics cause a dose dependent depression of the central chemoreceptor and the respiratory muscles – contributes to hypercarbia

  • alters respiratory pattern (decreased Vt and compensatory increase in RR –> decrease in Ve and increase in Vd)
  • impairs response to CO2 (slope CO2 response curvee shifts down and right)
  • impairs motor neuron output and muscle tone to the upper airway and thoracic muscles
163
Q

How do halogenated anesthetics affect cerebral metabolic rate?

A

CMRO2 is a function of:

  • electrical activity (60%)
  • cellular homeostasis (40%)

Volatile anesthetics reduce CMRO2 but only to the extent that they reduce electrical activity – once the brain is isoelectric, they can’t reduce CMRO2 any further

*isoelectricity on EEG occurs at 1.5-2 MAC

164
Q

Compare and contrast the effects of halogenated anesthetics and N2O on cerebral blood flow.

A

Brain matches its blood flow with its metabolic requirement –> When metabolic demand increases, blood vessels dilate (cerebrovascular resistance decreases) – When metabolic demand decreases, blood vessels constrict (cerebrovascular resistance increases)

  • Volatile anesthetics uncouple this relationship (CMRO2 decreases and CBF increases – can increase ICP as well)
  • N20 increases CMRO2 and cerebral blood flow appropriately
165
Q

How do halogenated anesthetics affect evoked potentials? How about N2O?

A

Des, Iso, and Sevo produce a dose dependent effect of evoked potentials

  • decrease amplitude (signal not as strong)
  • increase latency (slower signal)

Addition of N2O to halogenated anesthetic agent can lead to a more profound amplitude reduction – do not use during evoked potential monitoring

166
Q

Which type of evoked potential is most sensitive to the effects of volatile anesthetics? Which is the most resistant?

A
  • Visual evoke potentials are the most sensitive to volatile agents
  • Brainstem evoked potentials are the most resistant
  • SSEPs and MEPs are somewhere in between
167
Q

How can N2O cause bone marrow depression?

A

N2O inhibits methionine synthase and folate metabolism – can cause megaloblastic anemia

APEX Study Guide (13 decks)

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