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PHA3112 - pharmacology > pharmacokinetics > Flashcards

pharmacokinetics Flashcards

1
Q

4 Principles of Pharmacokinetics

A

Absorption
Distribution
Metabolism
Elimination

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2
Q

Variable affecting absorption

A

bioavailability

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3
Q

variable affecting distribution

A

volume of distribution

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4
Q

variable affecting metabolism

A

half-life

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5
Q

variable affecting elimination

A

clearance

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6
Q

Bioavailability (F) Definition

A

the fraction of unchanged (still active) drug that reaches the systemic circulation

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7
Q

F = 100% when:

A

the drug is administered directly into a patient’s blood vessels
- IV, IA, PICC

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8
Q

F < 100% when:

A

some of the drug is lost before reaching the heart

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9
Q

How can F < 100%?

A

a. some of the drug is lost before instestinal absorption
b. lost by modification of the drug by intestinal/ hepatic metabolism (enzymes)
c. lost because transporters return the drug to the gastrointestinal tract (into bile, SI)

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10
Q

How is bioavailability calculated?

A

by comparing the amount of drug absorbed over time from the route of administration of interest to the amount of drug absorbed over time when the same dose is giver by the IV route

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11
Q

the Area Under the Curve (AUC) is directly proportional to:

A

the dose administered and the bioavailability of the drug

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12
Q

A large curve (AUC) =

A

a large dose
slow clearance

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13
Q

a large dose =

A

a large area under the curve (AUC)

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14
Q

a small area under the curve (AUC) =

A

a small dose
fast clearance

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15
Q

a small dose =

A

a small area under the curve (AUC)

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16
Q

AUC is inversely proportional to:

A

the clearance of the drug

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17
Q

fast clearance of the drug =

A

small area under the curve (AUC)

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18
Q

slow clearance of the drug =

A

large area under the curve (AUC)

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19
Q

Factors affecting bioavailability: (5)

A
  1. Gastrointestinal System Motility
  2. Gastrointestinal Surface Area
  3. Hepatic Metabolism
  4. pH of liquid surrounding the drug
  5. Drug Interactions
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20
Q

Factors affecting bioavailability: Gastrointestinal System Motility

A

a. rate of gastric (stomach) emptying
b. rate of intestinal emptying (intestinal motility)

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21
Q

Slow gastric emptying =

A

reduced bioavailability of the drug
- reduced SA in stomach for
absorption
- destruction by low pH in
stomach + gastric enzymes

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22
Q

Fast gastric emptying

A

increased bioavailability of the drug
- less time in stomach
subjected to low pH + gastric
enzymes
- moves to an area with
increased SA for absorption

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23
Q

Low intestinal motility (stasis) =

A

increased bioavailability
- more time to interact with SA
and be absorbed
- low pH, not destroyed

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24
Q

Fast intestinal motility (diarrhea) =

A

reduced bioavailability
- less time to interact with SA
and be absorbed
- often discarded in full, no time
to reach therapeutic
minimum

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25
Q

Factors affecting bioavailability: Gastrointestinal SA

A

a. greater SA for absorption in intestines than stomach

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26
Q

Increased gastrointestinal SA =

A

increased bioavailability
- no inflammation
- no resection of the intestines
- intact brush boarder enzymes

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27
Q

Decreased gastrointestinal SA =

A

decreased bioavailability
- inflammation
- resection of the intestines
- decreases brush boarder
enzymes, unable to break
down drug for use

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28
Q

Factors affecting bioavailability: Hepatic Metabolism

A

a. enzymatic activity
b. anatomical or chemicals
inhibiting hepatic function

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29
Q

Increased enzymatic activity (hepatic metabolism) =

A

normal drugs = decreased bioavailability
- body inactivates more drug
pro drugs = increased bioavailability
- body activates more drug

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30
Q

Decreased Enzymatic activity (hepatic metabolism) =

A

normal drugs = increased bioavailability
- body inactivates less = accumulation
pro drugs = decreased bioavailability
- body is unable to activate
drug to exert its effects
occurs in cases of liver failure, liver disease, or chemicals inhibiting hepatic metabolism

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31
Q

Importance of hepatic metabolism

A

some drugs rely on hepatic metabolism working to decrease bioavailability
- ex: nitroglycerine is 90% destroyed by the liver –> if less is destroyed, the risk of overdose increases

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32
Q

Factors affecting bioavailability: pH of liquid surrounding the drug

A

pH can influence the chamical stability of a drug and influence it’s charge
- the drug’s charge will affect its lipid solubility and how readily it can pass through cell membranes to be absorbed (charged drugs cannot be absorped)

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33
Q

Weak acids become HA in:

A

acidic liquids

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34
Q

HA (properties)

A
  • neutrally charged, easily absorbable
  • become neutral in acidic liquids
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35
Q

Weak acids become A in:

A

basic liquids

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36
Q

A +/- (properties)

A
  • charged, not readily absorbable
  • become charged in basic liquids
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37
Q

Weak bases become BH in:

A

acidic liquids

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38
Q

BH (properties)

A
  • charged, not easily absorbed
  • become BH in acidic liquids
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39
Q

Weak bases become B in:

A

basic liquids

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40
Q

B (properties)

A
  • neutral charge, can be absorbed easily
  • become B in basic liquids
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41
Q

Factors affecting bioavailability: Interactions between two drugs

A

can cause the drugs to precipitate and form crystals
* crystals cannot be absorbed
precipitation = decreased bioavailability
no precipitation - increased bioavailability

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42
Q

Factors affecting bioavailability: Interactions between food and drugs

A

the presence of food can affect the pH of the liquid in which the rug is found and change its charge
–> greater when drug is administered during or shortly after ingestion

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43
Q

Distribution Definition

A

following absorption, a drug is distributed via the circulatory system towards the cells in the body

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44
Q

Factors affecting distribution

A

a. lipid solubility of the drug (charge)
b. binding of drug to plasma proteins/ accumulation in tissues
c. blood flow to organs/ relative organ size

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45
Q

Factors affecting distribution: blood flow + organ size

A

more important tissues/ organs have a greater blood supply relative to size –> increased/ faster absorption

less important tissues/ organs have a smaller blood supply relative to size –> decreased/ slower absorption

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46
Q

Organs with rapid distribution:

A

kidney, liver, heart, lungs, brain

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47
Q

Organs with slow distribution:

A

fat, skin, bone, teeth

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48
Q

Volume of Distribution

A

the volume of the pool of bodily liquid required to account for the observed drug concentration initially measured in the body
-> volume of liquid in body that
the dose is being distributed
into

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49
Q

what is Vd directly proportional to?

A

half-life

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50
Q

what is Vd indirectly proportional to?

A

clearancce

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51
Q

an increased Vd =

A

increased half-life
decreased clearance

52
Q

a decreased Vd =

A

decreased half-life
increased clearance

53
Q

Vd equation

A

Vd = amount in body/ plasma concentration

54
Q

dose equation

A

dose (average) = concentration (therapeutic) x Vd

55
Q

If a drug is highly bound to plasma proteins:

A

drug concentration in plasma is high
Vd is small
- plasma proteins cannot leave blood
vessels, so the space in which the
volume is distributed to is low

56
Q

If a drug is NOT highly bound to plasma proteins:

A

drug concentration in plasma is low
Vd is large
- more space to distribute the volume to

57
Q

Interactions of plasma proteins with drugs are:

A

a) high capacity
b) low affinity

58
Q

What kind of drug can leave the blood vessels? (bound or unbound)

A

only unbound drugs can leave the blood vessels

59
Q

Does a drug that is highly bound (99%) to plasma proteins necessarily demonstrate low pharmacological activity?

A

no - even the 1% that is unbound is enough to interact with its target receptor and have an effect

60
Q

Does a drug that is 100% bound to plasma proteins demonstrate low pharmacological activity?

A

yes - there is no unbound drug available to leave the blood vessels to interact with its target receptor and have an effect

61
Q

When are drug-drug interactions affecting the binding of plasma proteins of other drugs clinically relevant (concerning)?

A

a. the initial drug is high bound to plasma proteins (80% +)
b. the therapeutic index of the bound drug is narrow
b. the effectiveness of eliminations is reduced

62
Q

Therapeutic window

A

the ratio comparing the lethal dose in 50% of the population and the effective dose in 50% of the population
- index provides an indication of the
relative margin of safety available when
using the drug

63
Q

Why are drug-drug interactions concerning if the initial drug is highly bound to plasma proteins?

A

the initial drug has to compete for its spot
–> increased risk for excess to be
released into blood stream than
intended

64
Q

Why are drug-drug interactions concerning when the therapeutic index of the bound drug is narrow?

A

the window between the dose that is therapeutic and legal is very small
–> increased risk that too much or
too little drug will become unbound
(less control over effect)

65
Q

Why are drug-drug interactions concerning when the effectiveness of elimination systems is reduced?

A

the body has a reduced ability to excrete excess drug, causing more to accumulate and continue to exert effects
–> increased risk of drug concentration
reaching lethal dose

66
Q

what drug tends to accumulate in bone?

A

tetracycline

67
Q

where does tetracycline tend to accumulate?

A

bone

68
Q

what drug tends to accumulate in the liver?

A

cloroquine

69
Q

where does chloroquine tend to accumulate?

A

liver

70
Q

what drug tends to accumulate in adipose tissue?

A

insecticides

71
Q

where do insecticides tend to accumulate?

A

adipose tissue

72
Q

what are circumventricular organs?

A

areas of the brain that are “leaky”, allowing contact between the blood and specialized neurons

73
Q

what is the blood brain barrier?

A

tight junctions in the blood vessels in the brain that do not permit drugs to filter through gaps in cells (like the rest of the body)

74
Q

what drugs can pass the blood brain barrier

A

lipid-soluble, uncharged –> passive diffusion

non lipid-soluble, charged –> transport proteins (specialized, when present)

75
Q

how can drugs pass through the blood brain barrier?

A

THROUGH cells –> passive diffusion
THROUGH cells –> transport proteins

76
Q

Goal of Metabolism

A

to convert the drug into highly charged, sometimes inactive, mostly water soluble compounds that can be readily excreted by the liver

77
Q

Where are drugs metabolized? (4 organs)

A

Liver, Intestines, Kidneys, Lungs

78
Q

What organ metabolizes the majority of drugs?

A

The Liver

79
Q

Metabolism Phase 1

A

addition of reactive group to drug (-OH, -NH2)
–> drug may be activated, inactivated, or
unchanged

80
Q

Metabolism Phase 2

A

Conjugation (addition) of a reactive group with a highly charged, soluble substrate
–> conjugated is usually inactive

81
Q

what is the most common charged, water soluble substrate attached to reactive group in phase 2 of metablolism?

A

glucuronic acid

82
Q

what is it called when glucuronic acid is conjugated to the reactive group in phase 2 of metabolism?

A

glucuronidation

83
Q

What does metabolism do to normal drugs?

A

Inactivates

84
Q

What does metabolism do to prodrugs?

A

Activates

85
Q

Effect of increased metabolism on normal drugs

A

decreased therapeutic effect/bioavailability –> increased drug inactivation

86
Q

Effect of increased metabolism on prodrugs

A

increased therapeutic effect/bioavailability –> increased drug activation (accumulation)

87
Q

Effect of decreased metabolism on normal drugs

A

increased therapeutic effect/bioavailability –> decreased drug inactivation (accumulation)

88
Q

Effect of decreased metabolism on prodrugs

A

decreased therapeutic effect/bioavailability –> decreased drug activation (cannot exert effect)

89
Q

effect of inducers on metabolism

A

increases the action of CYP

90
Q

effect of inhibitors on metabolism

A

decreases the action of CYP

91
Q

effect of inducers on normal drugs

A

decreases therapeutic effect/bioavailability –> increases inactivation of drug

92
Q

effect of inducers on prodrugs

A

increases therapeutic effect/bioavailability –> increases activation of drugs

93
Q

effect of inhibitors on normal drugs

A

increases therapeutic effect/bioavailability –> inactivates less drugs (accumulation)

94
Q

effect of inhibitors of prodrugs

A

decreases therapeutic effect/bioavailability –> activates less drugs

95
Q

what is the most abundant cytochrome P450?

A

CYP 3A4

96
Q

where is CYP 3A4 found?

A

the liver, intestinal wall

97
Q

what inducer acts on cigarette smoke?

A

CYP 1A2

98
Q

what inducer acts on phenytoin?

A

CYP 3A4

99
Q

what inducer acts on rifampin

A

CYP 2C9

100
Q

what inhibitor acts on ketoconazole

A

CYP 3A4

101
Q

what inhibitor acts on erythromycin

A

CYP 3A4

102
Q

what inhibitor acts of grapefruit juice?

A

CYP 3A4

103
Q

CYP 1A2 acts on:

A

cigarette smoke (inducer)

104
Q

CYP 2C9 acts on:

A

rifampin (inducer)

105
Q

CYP 3A4 acts on:

A

phenytoin (inducer)

ketoconazole (inhibitor)
erythromycin (inhibitor)
grapefruit juice (inhibitor)

106
Q

inducers usually exert effects after ___ exposure

A

chronic (repeated) exposure

107
Q

inhibitors usually exert effects after ___ exposure

A

acute (single) exposure

108
Q

sources of elimination (5)

A
  1. urine
  2. feces
  3. milk
  4. sweat
  5. expired air
109
Q

enterohepatic circulation

A

drug enters the bile from the liver, is secreted into the gut with bile, then is reabsorbed into bile by the liver
–> cycle repeats and drug is stuck in loop,
cannot exert therapeutic effect

110
Q

filtration at the level of the kidney: charged drugs

A

cannot be actively secreted or reabsorbed in the kidney –> eliminated via urine

111
Q

filtration at the level of the kidney: uncharged drugs

A

can be actively secreted and/or reabsorbed in the kidney

112
Q

filtration at the level of the kidney: bound drugs

A

cannot be filtered into the glomerulus –> stay in blood stream

113
Q

filtration at the level of the kidney: free drugs

A

can be freely filtered into the glomerulus –> can leave bloodstream

114
Q

half-life

A

the time required to reduce the drug plasma concentration by 50%
–> independent of dose, fixed value

115
Q

95% of drug plasma concentration is eliminated after ___ half lives

A

4-5 half-lives

116
Q

Concentration Steady State (CSS)

A

if a drug is repeatedly administered before the previous dose is completely eliminated, drug levels will accumulate with time
–> absorption = elimination

117
Q

how many half-lives until concentration steady-state is reached?

A

4-5 half lives

118
Q

magnitude of CSS is directly proportional to:

A

dose/ bioavailability

119
Q

magnitude of CSS is indirectly proportional to:

A

half-life or clearance

120
Q

increased CSS magnitude =

A

decreased half life/ clearance
increased dose/ bioavailability

121
Q

decreased CSS magnitude =

A

increased half-life or clearance
decreased dose/ bioavailability

122
Q

CSS is independent of:

A

dose

123
Q

magnitude of CSS is dependent on

A

dose

124
Q

CSS is dependent on:

A

administration timing

125
Q

loading dose

A

an immediate, large dose of medication to keep plasma drug concentration above therapeutic level until natural CSS is reached
–> will slowly leave the body as plasma concentrations of taken drug rises

126
Q

CSS equation

A

CSS = dose/ clearance

127
Q

what drugs do not have a fixed half-life?

A

some anti-convulsant drugs, phenytoin

PHA3112 - pharmacology (7 decks)

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