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APEX > Unit 4 - Pharmacokinetics & Pharmacodynamics > Flashcards

Unit 4 - Pharmacokinetics & Pharmacodynamics Flashcards

1
Q

what is volume of distribution

A

relationship between administrated dose and resulting plasmc concentration

theoretical measure of how a drug distributes through the body

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2
Q

Vd =

A

amount of drug / desired plasma concentration

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3
Q

Vd assumes what 2 things

A
  1. drug distributes instantaneously (equilibration at time = 0)
  2. drug isn’t subjected to biotransformation or elimination before full distribution
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4
Q

distribution of body water in 70 kg patient:

A
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5
Q

when is a drug assumed to be lipophilic in regards to Vd

A

Vd > TBW

> 0.6 L/kg or > 42 L

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6
Q

when is a drug assumed to be hydrophilic in regards to Vd

A

Vd < TBW

< 0.6 L/kg or < 42 L

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7
Q

which requires a higher dose to acheive a given plasma concentration - a lipophilic or hydrophilic drug?

A

lipophilic

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8
Q

which requires a lower dose to achieve plasma concentration - lipophilic or hydrophilic drugs?

A

hydrophilic

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9
Q

what is a loading dose

A

amount of drug that must be administered to achieve a therapeutic plasma concentration quickly

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10
Q

loading dose =

A

(Vd x desired Cp) / bioavailability

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11
Q

bioavailability for an IV medication

A

1

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12
Q

what is clearance

A

volume of plasma cleared of drug per unit time

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13
Q

most important clearing organs

A

liver

kidneys

organ independent (Hofmann, esterases)

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14
Q

clearance is directly proportional to:

A
  • blood flow to clearing organ
  • extraction ratio
  • drug dose
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15
Q

clearance is indirectly proportional to:

A
  • half-life
  • drug concentration in central compartment
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16
Q

what is steady state?

A

stable plasma concentration when the amount of drug entering the body is equivalent to the amount of drug eliminated from the body

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17
Q

as a general rule, when is steady state acheived?

A

after 5 half-lives

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18
Q

how to achieve steady state faster in a drug with a long half life

A

give a loading dose

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19
Q

illustrates biphasic decrease of a drug’s plasma concentration after rapid IV bolus

A

2 compartment model

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20
Q

what does the alpha portion of 2 compartment model represent

A

distribution (t ½ a)

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21
Q

what does the beta portion of the 2 compartment model represent

A

elimination (t ½ B)

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22
Q

what does line A represent in 2 compartment model

A

drug distributes to theoretical compartments

follows concentration gradient from central compartment to peripheral compartments

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23
Q

what influences the slope of line A in 2 compartment model

A

Vd

more lipophilic = larger Vd = steeper slope

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24
Q

what does line B in 2 compartment model represent

A

elimination

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25
Q

what determines drug redistribution

A

concentration gradient between plasma and tissues

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26
Q

what is A+B in 2 compartment model

A

plasma concentration over time

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27
Q

what is a rate constant

A

describes the speed at which a reaction occurs or how fast molecules move between compartments

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28
Q

k12

A

rate constant for drug transfer from central to peripheral compartment

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29
Q

k21

A

rate constant for drug transfer from peripheral to central compartment

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30
Q

ke

A

rate constant for drug elimination from the body

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31
Q

what does the 3 compartment model describe

A

different constants going to and from each compartment and central compartment

some compartments may saturate before others

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32
Q

what is elimination half time

A

time it takes for 50% of drug to be removed from plasma during elimination phase

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33
Q

when is a drug considered cleared from the body?

A

when 96.9% of the dose is eliminated from plasma

(~5 half times)

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34
Q

what does half time measure

A

a constant fraction, NOT a constant amount

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35
Q

what is context-sensitive half-time

A

time for plasma concentration to decrease by 50% after gtt stopped

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36
Q

exception to opioid CSHT

A

remifentanil

highly lipophilic but quickly metabolized by plasma esterases = similar CHST regardless of infusion duration

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37
Q

what is an acid

A

substance that donates a proton

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38
Q

what is a base

A

substance that accepts a proton

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39
Q

what happens to a strong acid or strong base in water

A

will dissolve completely

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40
Q

what happens to a weak acid or weak base in water

A

a fraction will ionize

remaining fraction will be non-ionized

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41
Q

is morphine a weak acid or a weak base

A

weak base

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42
Q

how will weak acids and weak bases react in water

A

weak acid will donate a proton to water (pH = 7)

weak base will accept a proton from water (pH = 7)

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43
Q

how will a weak acid act in an acidic solution

A

more non-ionized and lipid soluble

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44
Q

how will a weak acid act in a basic solution

A

more ionized and water soluble

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45
Q

how will a weak base act in an acidic solution

A

more ionized and water soluble

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46
Q

how will a weak base act in a basic solution

A

more non-ionized and lipid-soluble

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47
Q

what has the greatest impact on degree of ionization in a drug with a pKa close to plasma pH

A

small changes in plasma pH

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48
Q

what is ionization

A

process where a molecule gains a positive or negative charge

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49
Q

ionization of weak acids and bases depends on what 2 factors

A
  1. pH of solution
  2. pKa of the drug
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50
Q

what is pKa

A

constant property of a molecule that tells us how much it wants to behave like an acid

equals the pH where 50% of the drug exists as uncharged base & 50% exists as conjugate acid

low pKa = amazing acid

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51
Q

what is the Henderson-Hasselbalch equation

A

pH = pKa + log (base / conjugate acid)

a basic drug placed in a relatively more acidic environment - ionized fraction (conjugate acid) will predominate

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52
Q

drug preparation for weak acids

A

paired with positive ion (Na+, Ca2+, Mg2+)

ex: sodium thiopental

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53
Q

drug preparation for weak bases

A

paried with negative ion (Cl-, sulfur)

ex: lidocaine hydrochloride

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54
Q

which is more likely to undergo hepatic biotransformation - ionized or nonionized

A

nonionized

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55
Q

which is more likely to undergo renal elimination - ionized or nonionized

A

ionized

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56
Q

which diffuses across lipid bilayers into BBB, GI tract, and placenta: ionized or nonionized

A

nonionized

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57
Q

ionized fraction predominates if:

A
  • molecule is a weak base and pH of solution < pKa of drug (base added to acidic solution)
  • molecule is a weak acid and pH > pKa (acid added to basic solution)
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58
Q

non-ionized fraction predominates if:

A
  • molecule is a weak base and pH of solution > pKa (base added to basic solution)
  • molecule is a weak acid and pH of solution < pKa (acid added to acidic solution)
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59
Q

which portion of a drug freely diffuses across a cell membrane

A

only the lipophilic, non-ionized fraction

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60
Q

what causes fetal ion trapping

A
  • fetal pH is a little lower than maternal pH
  • if mom receives a more basic solution, the non-ionized fraction crosses the placenta, a weak base enters a more acidic environment, and there’s a greater degree of ionization inside the fetus
  • ionized drug can’t freely cross placenta back to mother and is trapped in fetus
  • fetal distress increases acidosis and trapping
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61
Q

strongest diffusion gradient for fetal ion trapping

A

maternal alkalosis + fetal acidosis

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62
Q

neuraxial LA most likely to undergo fetal ion trapping

A

lidocaine

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63
Q

neuraxial LA least likely to undergo fetal ion trapping

why

A

chloroprocaine

high pKa, rapid metabolism in mother’s blood

64
Q

for most drugs, rate of metabolism depends on what 2 factors:

A
  1. Concentration of drug at site of metabolism - influenced by blood flow to site
  2. Intrinsic rate of metabolic process - influenced by genetics, enzyme induction/inhibition
65
Q

what is zero order kinetics

A
  • describes situation where there is more drug than enzyme
  • constant amount metabolized per time
66
Q

examples of drugs that follow zero order kinetics

A

aspirin, phenytoin, alcohol, warfarin, heparin, theophylline

67
Q

what is first order kinetics

A
  • Describes situation where there is less drug than enzyme (no saturation)
  • Enzyme will metabolize a constant fraction per unit time
68
Q

nearly all drugs we adminsiter undergo what rate of metabolism

A

first order kinetics

69
Q

what is metabolism

A

enzymatic process of altering a molecule’s chemical structure

70
Q

primary organ of metabolism

A

liver

71
Q

primary role of metabolism

A

change a lipid-soluble, pharmacologically active compound to water-soluble, pharmacologically inactive byproduct

72
Q

how does creating molecules with greater water solubility lead to increased urine elimination

A
  • increasing ionization and decreases Vd
  • increased delivery to kidneys for elimination
73
Q

if the body can’t change a lipid-soluble into a water-soluble drug, what happens?

A
  • it will be continuously reabsorbed by renal tubules into pericapillary fluid - returned to plasma
  • theoretically could remain in the body for a long time
74
Q

what is a prodrug

examples?

A

body converts an inactive molecule into a pharmacologically active molecule

ex- codeine, oxycodone, hydrocodone, fospropofol

75
Q

3 phases of metabolism

A
  1. modification
  2. conjugation
  3. elimination
76
Q

result of phase 1 metabolism: modification

A

Result in small molecular changes that ↑ polarity of a molecule to prepare it for a phase 2 reaction

77
Q

carries out most phase 1 metabolism reactions

A

CYP450 system

78
Q

3 types of phase 1 metabolism reactions

A
  1. oxidation
  2. reduction
  3. hydrolysis
79
Q

what is oxidation

A

removes electrons from a compound

80
Q

what is reduction

A

adds electrons to a compound

81
Q

what is hydrolysis

A

adds water to a compound to split it (usually ester)

82
Q

what happens in phase 2 of metabolism

(conjugation)

A

Conjugates (adds on) an endogenous, highly polar, water-soluble substrate to the molecule

produces water-soluble, biologically inactive molecule ready for excretion

83
Q

common phase 2 metabolism substrates

A

glucuronic acid, glycine, acetic acid, sulfuric acid, methyl group

84
Q

what is enterohepatic circulation

examples?

A

some conjugated compounds excreted in bile, reactivated in intestine, then reabsorbed into systemic circulation (diazepam, warfarin)

85
Q

what happens in phase 3 of metabolism

(elimination)

A

Involves ATP-dependent carrier proteins that transport drugs across cell membranes

Present in kidneys, liver, GI tract

86
Q

hepatic clearance is a product of what 2 things

A
  1. Liver blood flow: how much drug is delivered to liver
  2. Hepatic extraction ratio: how much drug is removed by liver
87
Q

what is an extraction ratio

A

measure of how much drug delivered to clearing organ (Q) vs. how much drug is eliminated by that organ

88
Q

what does an ER of 1.0 mean

A

100% of the drug delivered is removed

89
Q

what does an ER of 0.5 mean

A

50% of drug delivered is removed

90
Q

how is hepatic clearance categorized

A

perfusion-dependent elimination or capacity-dependent elimination

91
Q

hepatic extraction ratio associated with perfusion-dependent clearance

examples

A

high ratio (> 0.7)

fentanyl, lidocaine, propofol, sufentanil, morphine, meperidine, ketamine, metoprolol, nifedpine, diltiazem, verapamil

92
Q

how do alterations in hepatic enzyme activity affect drugs with a high hepatic extraction ratio

A

little effect

93
Q

what increases or decreases clearance in drugs with a high hepatic ER

A

increased or decreased liver blood flow

94
Q

hepatic extraction ratio associated with capacity-dependent clearance

examples

A

low ER (<0.3)

rocuronium, diazepam, lorazepam, methadone, thiopental, theophylline, phenytoin

95
Q

examples of intermediate hepatic ER

A

midazolam

vecuronium

alfentanil

methohexital

96
Q

what affects clearance in drugs with a low hepatic ER

A

alterations in hepatic enzyme activity

induction = increased clearance

inhibition = decreased clearance

97
Q

when are drugs subjected to first-pass metabolism

A

PO drugs with high ER

98
Q

what is first-pass metabolism

A

After drug is absorbed from GI tract, delivered to portal circulation - portion is metabolized before drug reaches biophase

99
Q

what is enterohepatic circulation

A

a process where liver excretes a substance into bile, then that substance is reabsorbed from small intestine and transported back to liver

100
Q

examples of drugs that undergo enterohepatic circulation

A

diazepam, warfarin

101
Q

most important mechanism of drug biotransformation

A

CYP 450 system

102
Q

carries out most of body’s phase 1 biotransformations

A

CYP 450 system

103
Q

unique feature of CYP 450 system

A

exogenous chemicals can influence enzyme expression

104
Q

where are P450 enzymes located

A

smooth ER of hepatocyte

extrahepatic tissue (lungs, kidneys, skin, adrenal gland, GI tract)

105
Q

Most important CYP450 enzyme

A

CYP 3A4

metabolizes 50% of drugs we administer

106
Q

how do enzyme inducers affect drug clerance

A

stimulates enzyme synthesis

increases drug clearance, decreases t ½

107
Q

how does enzyme inhibition affect drug clearance

A

competes for binding sites on enzyme

decreased drug clearance, increased t ½

108
Q

CYP 3A4 inhibitors

A
  • grapefruit juice
  • cimetidine
  • erythromycin
  • azole antifungals
  • SSRIs
109
Q

CYP3A4 inducers

A
  • ethanol
  • rifampin
  • barbiturates
  • tamoxifen
  • carbamazepine
  • St John’s wort
110
Q

CYP 3A4 substrates

A
  • opioids: fentanyl, alfentanil, sufentanil, methadone
  • benzos: midazolam, diazepam
  • LAs: lidocaine, bupivacaine, ropivacaine
111
Q

how does CYP 2D6 inhibition affect codeine

A

codeine is a prodrug metabolized to active metabolite via CYP 2D6

inhibition reduces metabolism to morphine and decreases potency

112
Q

CYP 2D6 substrates

A

codeine

oxycodone

hydrocodone

113
Q

CYP 2D6 inducers

A

disulfiram

114
Q

CYP 2D6 inhibitors

A

isoniazid

SSRIs

quinidine

115
Q

CYP 1A2 substrates, inducers, and inhibitors

A
  • substrate: theophylline
  • inducers: tobacco, cannabis, ethanol
  • inhibitors: erythromycin, cipro
116
Q

what determines renal elimination

A

polarity & pH of glomerular fluid

117
Q

how are most hydrophilic vs. lipophilic drugs excreted

A
  • hydrophilic: excreted unchanged
  • lipophilic: must undergo biotransformation reactions to increase water solubility before excretion by kidneys
118
Q

what happens to lipophilic drugs that don’t undergo biotransformation

A

will be reabsorbed into peritubular fluid by diffusion

119
Q

2 processes to deliver a drug to urine

A

GFR

organic ion transporters

120
Q

how does plasma protein binding affect glomerular filtration of drugs

A
  • drugs not bound to plasma proteins freely filtered by glomerulus
  • Highly protein-bound drugs resistant to glomerular filtration - only free fraction will be filtered
121
Q

what are organic anion and cation transporters

A

transport proteins in proximal tubules actively secrete organic acids & bases into urine

122
Q

examples of OAT (organic anion transporters)

A

furosemide, thiazide diuretics, PCN

123
Q

examples of organic cation transporters (OCT)

A

morphine, meperidine, dopamine

124
Q

what influences whether drugs are excreted into urine or reabsorbed into peritubular capillaries

A

urine pH

125
Q

what does acidic vs. basic urine favor in terms of drug excretion

A
  • Acidic urine favors: reabsorption of acidic drugs, excretion of basic drugs
  • Basic urine favors: reabsorption of basic drugs, excretion of acidic drugs
126
Q

how do ammonium chloride or cranberry juice affect urine drug excretion

A

acidifies - helps eliminate basic drugs

127
Q

how do sodium bicarb or acetazolamide affect urine drug elimination

A

will alkalinize urine - helps eliminate acidic drugs

128
Q

uses water to cleave an ester linkage

A

hydrolysis

129
Q

drugs metabolized by pseudocholinesterases

A
  • Succinylcholine
  • Mivacurium
  • Ester LAs
    • Tetracaine
    • Procaine
    • Chloroprocaine
    • Cocaine (+ hepatic)
130
Q

drugs metabolized by nonspecific esterases

A
  • Remifentanil
  • Remimazolam
  • Esmolol (RBC)
  • Etomidate (+ hepatic)
  • Atracurium
  • Clevidipine
131
Q

drugs metabolized by alkaline phosphatase

A

fospropofol

132
Q

drugs metabolized via Hofmann elimination

A
  • Cisatracurium
  • Atracurium
133
Q

2 factors that affect Hofmann elimination

A

pH

temp

134
Q

pseudocholinesterase deficiency extends duration of what drugs

A

succinylcholine, mivacurium, cocaine, ester LAs

135
Q

which is hydrophilic vs. lipophilic - nonionized vs ionized

A

ionized - hydrophilic

nonionized - lipophilic

136
Q

what percent of CO do these tissues receive:

vessel rich group

fat

muscle

A

VRG = 75%

muscle = 19%

fat = 6%

137
Q

how much drug is eliminated after 2 half lives

A

75%

138
Q

how much drug is eliminated after 3 half lives

A

87.5%

139
Q

how much drug is remaining in the plasma after 5 half lives

A

3.125%

140
Q

where are plasma proteins synthesized

A

liver

141
Q

bond formed by drugs and proteins

A

weak bond (ionic, hydrogen, or van der Waals)

142
Q

extent of plasma binding affects:

A

intensity of drug effects

drug’s duration of action

143
Q

most plentiful plasma protein

A

albumin

144
Q

primary determinant of oncotic pressure

A

albumin

145
Q

T½ of albumin

A

3 weeks

146
Q

which plasma protein primarily binds with acidic drugs

A

albumin

147
Q

what decreases Cp of albumin

A

liver and renal disease, old age, malnutrition, pregnancy

148
Q

plasma protein that primarily binds with basic drugs

A

a1-Acid glycoprotein

149
Q

increases Cp of a1-Acid glycoprotein

A
  • surgical stimulation
  • MI
  • chronic pain
  • RA
  • advanced age
150
Q

decreases Cp of a1-acid glycoprotein

A
  • neonates
  • pregnancy
151
Q

percent change =

A

(new value - old value / old value) * 100

152
Q

causes of decreased plasma proteins

A
  • reduced synthetic function (liver disease, malnutrition)
  • increased protein excretion (renal disease)
  • altered distribution (3rd trimester pregnancy)
153
Q

when can alterations in protein binding be a problem

A
  • CPB: hemodilution & heparinization
  • ECMO circuits: ceftriaxone, fentanyl, midazolam
  • Bilirubin & thyroxine can displace drugs from protein binding
154
Q

how does increased protein binding affect potency

A

increased unbound fraction = increased potency

155
Q

relationship between Vd and degree of protein binding

A

inversely related

156
Q

metabolism and elimination of highly protein bound drugs

A

typically slower

APEX (54 decks)

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