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Systemic Pharmacology I > Pharmacokinetics > Flashcards

Pharmacokinetics Flashcards

1
Q

pharmacokinetics

A

the actions of the body on the drug

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2
Q

these properties determine how rapidly and for how long the drug will appear at the target organ

A
  • absorption
  • distribution
  • metabolism
  • excretion
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3
Q

routes of administration determined by:

A 
properties of the drug (solubility, ionization, etc.),
therapeutic objectives (rapid onset, chronic administration, restriction to a local site, setting in which it will be used)
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4
Q

2 major routes of administration

A
  • enteral

- parenteral

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5
Q

enteral administration

A

administration by mouth; simplest and most common method; swallowed or placed under tongue

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6
Q

oral administration advantages

A
  • easily self-administered
  • easier to overcome overdoses
  • large surface area for absorption
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7
Q

oral administration disadvantages

A

-complicated pathway to absorption- harsh environment of stomach, metabolism by liver

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8
Q

oral administration: some drugs are absorbed from ___, major site of absorption and entry into systemic circulation is ___; ____ for absorption

A

stomach;
small intestine;
large surface area

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9
Q

most drugs absorbed in GI tract enter ____ circulation prior to entering ____ circulation; called ____

A

hepatic;
general;
first pass metabolism

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10
Q

sub-lingual administration advantages

A
  • rapid absorption
  • easily administered
  • low incidence of infection
  • avoid stomach and first pass metabolism- preferred route of enteral administration for drugs that undergo extensive first-pass metabolism
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11
Q

parenteral administration

A

introduction of drugs directly across the body’s barrier defenses into the systemic circulation or other vascular tissue (bypass GI tract); any way of administration not by mouth

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12
Q

parenteral administration used for:

A
  • drugs that are poorly absorbed from the GI tract and/or are unstable in the GI tract
  • treatment of unconscious patient
  • when rapid onset of action is required
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13
Q

parenteral administration advantages

A
  • have the highest bioavailability
  • not subject to first-pass metabolism
  • provides the most control over the actual dose delivered
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14
Q

parenteral administration disadvantages

A
  • irreversible

- can cause pain, fear, and/or infection

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15
Q

3 major parenteral routes

A
  • intravascular (IV or IA)
  • intramuscular (IM)
  • subcutaneous (SC)
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16
Q

most common parenteral route

A

intravenous

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17
Q

intravenous characteristics

A
  • rapid effects
  • not easily recalled (greater potential for toxic overdose)
  • potential for infection
  • rate of infusion must be carefully controlled
  • similar concerns apply to IA drugs
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18
Q

intramuscular characteristics

A

-can be aqueous solutions (fast absorption) or depot preparations (slow absorption)

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19
Q

depot preparations

A
  • suspension of drug in a non-aqueous vehicle
  • vehicle diffuses out of muscle leaving the drug to precipitate at site of injection
  • drug dissolves slowly (not fully dissolved)
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20
Q

subcutaneous characteristics

A
  • injection under the skin
  • slower than IV but less risk
  • often combined with epinephrine (acts as a local vasoconstrictor and decreases removal of the drug from the site of administration)
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21
Q

other routes of administration

A
  • inhalation
  • intranasal
  • intrathecal
  • intravitreous
  • topical
  • transdermal
  • rectal
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22
Q

inhalation

A
  • rapid delivery (almost as fast as IV)

- used for gases or aerosol

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23
Q

intrathecal

A

introduction directly into cerebrospinal fluid

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24
Q

transdermal

A
  • through skin, usually a patch
  • used for sustained delivery
  • variation in absorption rate
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25
Q

rectal

A
  • minimizes first pass metabolism- 50% of drainage bypasses liver
  • good for meds that induce vomiting or in a patient that is vomiting
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26
Q

absorption

A

transfer of a drug from its site of administration to the bloodstream

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27
Q

absorption is ___ for IV drug (___ dose reaches circulation); all other routes have ____ absorption and thus lower bioavailability

A

complete;
total;
lower

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28
Q

passive diffusion

A
  • drug moves from area of high concentration to area of low concentration
  • does not involve a carrier molecule, is not saturable, and is not specific; can be through a channel or pore
  • does not require energy
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29
Q

facilitated diffusion

A
  • moves from high concentration to low concentration
  • requires carrier molecule (usually large molecules)
  • does not require energy
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30
Q

active transport

A
  • drugs move from area of low concentration to area of high concentration
  • depends on a carrier protein and is energy dependent
  • requires ATP
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31
Q

endocytosis/pinocytosis

A

large molecules are engulfed by the cell membrane and transported into the cell by a vesicle; exocytosis is the reverse

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32
Q

most drugs are either ____ or ____

A

weak acids; weak bases

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33
Q

pKa is a measure of ____; lower means the drug is more ___; higher means more ___

A

strength of interaction with a proton; acidic; basic

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34
Q

drugs pass through membranes more readily if they are ____

A

uncharged (non-ionized)

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35
Q

weak acids will be non-ionized in environments with ___ pH; absorb better from ___

A

low; stomach

acids like acids!

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36
Q

weak bases will be non-ionized in environments with ___ pH; absorb better from ___

A

high; intestine

bases like bases!

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37
Q

higher blood flow to absorption site= ____;
blood flow to intestine is ____ than that of stomach;
blood flow through deltoid muscle is ____ than through the gluteal muscle

A

greater absorption;
greater;
greater

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38
Q

greater surface area= ____;
surface area of intestine is ____ that of stomach;
gluteal muscle can accommodate a ____ volume of drug

A

greater absorption;
1000-fold;
larger

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39
Q

contact time at the absorption site: if a drug moves through the GI tract very quickly, it is ____

A

not well absorbed

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40
Q

anything that delays movement from stomach to intestine ____ the rate of absorption: sympathetic input (exercise, medications), presence of food

A

delays

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41
Q

____ absorption in areas of high expression of P-glycoprotein

A

reduced

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42
Q

P-glycoprotein is a ____ whose main job is ____

A

membrane transporter protein; to get a foreign molecule and kick it out again

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43
Q

P-glycoprotein is located in many systems

A
  • liver
  • kidneys
  • placenta
  • intestines
  • brain capillaries
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44
Q

bioavailability

A

the fraction of drug that reaches systemic circulation; only a portion of an orally administered drug is free to be used

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45
Q

how is bioavailability determined?

A

determined by comparing plasma levels of a drug after a particular route of administration with levels after IV injection (100% available after IV injection);
can plot plasma levels over time on a graph –> gives “area under the curve” (AUC); curve reflects extent of drug absorption;

bioavailability= AUC oral/AUC injected x 100

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46
Q

factors affecting bioavailability

A
  • first pass metabolism
  • solubility of the drug
  • chemical stability
  • formulation of the drug
  • concentration
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47
Q

first pass metabolism

A

drugs absorbed from the GI tract enter the hepatic circulation before systemic circulation

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48
Q

if rapidly metabolized by the liver, the amount of unchanged drug that gains access to the systemic circulation is ____

A

decreased

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49
Q

even one pass through the liver can ___ many drugs

A

alter

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50
Q

hydrophilic drugs are absorbed ____

A

poorly- cannot cross cell membrane (unless membrane pore or carrier molecule present)

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51
Q

extremely hydrophobic drugs are absorbed ____

A

poorly- cannot dissolve in aqueous body fluids, cannot gain access to cell surface

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52
Q

to be readily absorbed, must be ___ soluble but also have some solubility in ____

A

lipid; aqueous solutions

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53
Q

a drug that is lipophilic will have ___ absorption

A

greater

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54
Q

drugs must be formulated to withstand ____

A

acidity of stomach and actions of enzymes

ex: insulin can not be given orally- susceptible to enzyme degradation, Penicillin G is not acid stable

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55
Q

along with chemistry, absorption can be altered by:

A
  • particle size (smaller is easier)
  • binders or dispersing agents
  • enteric coatings
  • salt form
  • others…
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56
Q

absorption can be increased by ____ the concentration of the drug

A

increasing (up to a certain point)

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57
Q

bioequivalence

A

two drugs that demonstrate comparable bioavailability and similar times to achieve peak blood concentrations; has nothing to do with how well the drugs work, just how much is available for the body to use

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58
Q

therapeutic equivalence

A

two drugs that are comparable in efficacy and safety; bioequivalence does not necessarily equal therapeutic equivalence

59
Q

drug distribution

A

the process by which a drug diffuses from systemic circulation into the extracellular fluid and/or the cells of the tissues

60
Q

drug distribution is dependent on:

A
  • blood flow
  • capillary permeability
  • protein binding
  • lipid solubility of the drug
61
Q

there is a wide variation in rate of _____ to various tissues, resulting in ____ to various organs

A

the rate of blood flow;

an unequal distribution

62
Q

greater blood flow to ____

A

brain, liver, and kidneys

63
Q

____ has the slowest rate of blood flow

A

adipose tissue

64
Q

the ability of a drug to diffuse out of capillaries is determined by:

A
  • the structure of the capillary wall

- the chemical structure of the drug

65
Q

capillary structure is ____ from organ to organ

A

different

66
Q

typical capillary structure

A
  • single layer of endothelial cells resting on a basement membrane; no surrounding smooth muscle or elastic tissue
  • slit junctions and fenestrations; expose the basement membrane and allow for transport out of the capillary
67
Q

in the brain, capillaries have no _____, but rather ____

A

junctions or fenestrations; zonulae occludens (tight junctions)

68
Q

in the liver and spleen, capillaries have ____, which allows ____

A

large slit junctions;

large plasma proteins to pass through

69
Q

blood brain barrier

A
  • tight junctions and zonulae occludens prevent diffusion of many substances from the circulation into the CNS
  • must pass through endothelial cells or be transported in by specific transporters
70
Q

____ molecules readily pass through into the CNS (BBB will not keep them out)

A

lipid-soluble

71
Q

placental barriers

A
  • blood flow is limited from mother to placenta
  • delayed equilibration of a drug between mother and fetus (10-15 mins at least)
  • assume all drugs cross the placental barrier as well as breast milk (unless explicitly stated otherwise)
72
Q

blood aqueous barrier

A
  • capillaries of the choroid and ciliary processes are fenestrated, all others are not
  • selective inhibition of movement of solutes from ocular vasculature into anterior chamber
  • no back flow from Schlemm’s canal
  • capillaries of iris and retina are impermeable
  • most systemic drugs have a difficult time getting into the eye (few exceptions)
73
Q

chemical nature of the drug strongly influences ____

A

ability to cross cell membranes

74
Q

hydrophobic (lipophilic) molecules ____ across most biologic molecules (including BBB); ____ is major factor influencing distribution

A

readily move;

blood flow

75
Q

hydrophilic (lipophobic) molecules _____ across cell membranes; they must ____

A

do not readily move;

go through slit junctions/fenestrations

76
Q

binding of drugs to plasma proteins is usually ____

A

reversible

77
Q

binding of drugs to plasma proteins ____

A

sequesters the drug in a non-diffusable form (too large to pass through any membranes) and thus slows the transfer out of the vascular compartment

78
Q

protein binding to drugs can cause:

A
  • decreased clearance
  • increased half-life
  • drug-drug interactions- displacement of one drug by another
79
Q

____ is main plasma protein that binds drugs

A

albumin

80
Q

bound drugs are ____

A

pharmacologically inactive

81
Q

volume of distribution

A
  • hypothetical volume of fluid into which a drug is dispersed
  • once a drug enters the body, it has the potential to distribute into any one of three functionally distinct compartments of body water or to become sequestered in a cellular site
82
Q

____ are “trapped” within the plasma (vascular) compartment; plasma volume is about ____ of body weight

A

large molecular weight drugs or drugs that bind extensively to plasma proteins; 6%

83
Q

if a drug has a low volume of distribution, it will likely be found in _____

A

circulation in the blood

84
Q

____ can be found in the extracellular fluid;
they move through capillaries into interstitial fluid but can not cross _____;
distribute into ____;
____ of body weight

A

low molecular weight, hydrophilic drugs;
lipid membranes of cells;
plasma water & interstitial fluid;
20%

85
Q

____ can be found in total body water;
can move through ____;
distributes into about ____ of body weight

A

low molecular weight, hydrophobic drugs;
cell membranes and into intracellular fluid;
60%

86
Q

drugs that have a large volume of distribution can be found ____

A

anywhere (plasma, interstitial fluid, and in cells themselves)

87
Q

calculation for volume of distribution

A

V= amount of drug in body (dose)/ plasma concentration

88
Q

in reality, drugs are eliminated and plasma concentrations have 2 phases:

A
  • distribution phase

- elimination phase

89
Q

effect of a large V:

  • drug elimination depends on _____
  • if V is large, most of the drug is in the ____ and ____ to the excretory organs
  • any factor that increases the volume of distribution can lead to ____ half-life and ____ the duration of action of a drug
A 
the amount of drug delivered to the liver or kidney per unit of time;
extra-plasmic space;
is unavailable;
an increased half-life;
extend
90
Q

metabolism

A
  • any chemical that is foreign to our body will be subject to elimination
  • most drugs must be biotransformed (metabolized) before they can be eliminated
91
Q

most drugs must be made more ____ before they can be eliminated

A

polar and/or water soluble (charged and/or hydrophilic)

92
Q

metabolism often results in ____, but some are actually ____

A

inactivation and excretion;

made more active (prodrug)

93
Q

many metabolites ____

A

are either pharmacologically active or cause side effects

94
Q

____ is major site for drug metabolism, although some drugs undergo metabolism in other organs (ex: ____)

A

liver;

kidney, intestines

95
Q

first order kinetics metabolism

A
  • rate of metabolism is proportional to concentration of the free drug
  • rate of metabolism increases as concentration of drug increases
96
Q

zero order kinetics metabolism

A
  • rate of metabolism is constant over time

- dose independent

97
Q

lipophilic drugs are ____ from kidney, making them ____; must be transformed to ____;
2 types of reactions: ____

A

easily reabsorbed;
more difficult to eliminate;
more polar substances;
Phase I, Phase II

98
Q

Phase I reactions convert _____;

most often catalyzed by _____ in the _____

A

lipophilic molecules to more polar molecules;
the Cytochrome P-450 system;
liver

99
Q

Cytochrome P450 system:

  • enzymes are located in most cells but primarily found in ____
  • responsible for metabolism and biotransformation of ____
  • many different ____
  • enzymes are ____ for one particular substrate
A

liver and GI tract;
endogenous compounds and xenobiotics;
enzymes;
not specific

100
Q

the CYP450 system exhibits considerable ____ variability; basis for ____

A

genetic;

differing dosing requirements, therapeutic responsiveness, and risk of adverse events between patients

101
Q

the CYP450 system is one source of ____ interactions, with ____ and _____

A

drug-drug;

inducers; inhibitors

102
Q

inducers

A

increase CYP activity, leading to decreased plasma concentrations of many drugs (being broken down more rapidly)

103
Q

inhibitors

A

decrease CYP activity, leading to increased plasma concentrations of the drug (being broken down less rapidly)

104
Q

other Phase I reactions

A
  • oxidations
  • dehydrogenations (ex: ethanol)
  • deamination
  • hydrolysis

(CYP450 enzymes are most important Phase I reaction)

105
Q

Phase II reactions; most are ____

A

conjugations- attaches an endogenous substrate to molecule to form highly polar conjugate (larger);
glucuronic acid, sulfuric acid, acetic acid, or an amino acid often added

106
Q

_____ is the most common and most important Phase II reaction; it makes ____

A

glucuronidation;

lipophilic molecules more readily excretable in urine

107
Q

not all drugs undergo ____ reactions

A

Phase I and then Phase II

some may skip phase I, some may undergo phase II first

108
Q

individual differences in rates of drug metabolism require ____

A

variations in drug dose

109
Q

factors that influence an individual’s rate of drug metabolism

A
  • genetic factors- enzyme polymorphisms
  • diet and environmental factors- certain foods induce or inhibit CYP enzymes (grapefruit juice, cigarettes, many others…)
  • age and sex
  • drug interactions
  • disease
110
Q

drugs may be removed from the body by a number of routes

A
  • kidney (main organ for drug elimination)
  • liver (either biotransformation or bile)
  • lung
  • “other”
111
Q

glomerular filtration:

  • drugs enter kidney through ___
  • free drug (not bound) flows into ____ as part of glomerular filtrate
  • lipid solubility and pH ____ the passage of drugs into the glomerular filtrate (only ___)
A

renal artery;
Bowman’s space;
do not influence;
molecule size

112
Q

proximal tubular secretion:

  • larger drugs not transferred into the filtrate leave the glomeruli through ____
  • secretion occurs by ____
A 
efferent arterioles;
active transport (requires energy, non-specific- competitive)
113
Q

distal tubular secretion:

  • concentration of drug ____ as it moves towards distal convoluted tubule
  • may diffuse out of nephric lumen, back into systemic circulation if ____
  • can manipulate _____ to increase elimination of certain drugs
A

increases;
unchanged;
pH of urine

114
Q

can manipulate pH of urine to increase elimination of certain drugs, “ion trapping”

A

for weak acids, increase pH;

for weak bases, decrease pH

115
Q

clearance

A

predicts the rate of elimination in relation to drug concentration

116
Q

clearance formula

A

CL= 0.693 x V/half-life

117
Q

rate of drug delivery is constant with ____

A

IV infusion

118
Q

in most cases, the elimination obeys ____ order kinetics

A

first (constant fraction removed per unit time)

119
Q

steady state concentration

A

plasma level increases until elimination rate equals infusion rate

120
Q

steady state is ____ to the rate of infusion

A

directly proportional

121
Q

steady state is ____ to the rate of clearance

A

inversely proportional

122
Q

decrease clearance = ____ steady state concentration

A

increased

123
Q

increase clearance = ____ steady state concentration

A

decreased

124
Q

dosing with continuous infusion can be achieved via:

A
  • IV

- oral fixed-dose/fixed-time intervals (ex: one tablet every 4 hours)

125
Q

steady state is the point at which the amount of drug being administered/absorbed equals ____;
____ with IV;
____ with oral fixed dosage

A

the amount being eliminated;
remain constant;
fluctuate around a mean

126
Q

half-life

A

time required for the drug concentration to change by 50% (usually used as an elimination term)

127
Q

common assumption is that it takes ____ for a drug to reach steady state concentration

A

5 half-lives

128
Q

rate of approach to steady state ____ by the rate of drug infusion

A

is not affected

129
Q

for most drugs, the half-life can help approximate ____

A

how long it will take a drug to reach its full effect after the patient starts treatment

130
Q

any changes in half-life of a drug due to abnormal states may require ____

A

dosage adjustments

131
Q

half-life can be ____;
usually by ____;
anything that effects _____

A

increased or decreased;
disease states;
CL or V

132
Q

when drug infusion is discontinued, the decrease in plasma concentration to zero parallels ____

A

the same time course as that observed with the drug achieving steady state concentration

133
Q

rational dose regimens:

  • based on ____
  • calculation would be easy for ____
A 
assumption of Target Concentration (TC);
continuous infusion (but very inconvenient for patient!)
134
Q

fixed-dose/fixed-time regimens:

  • often more ____
  • result in ____
A

convenient;

time-dependent fluctuations in the circulating level of a drug

135
Q

fixed-dose/fixed-time regimens:

  • using smaller doses at shorter intervals ____
  • SS concentration and rate at which SS is approached ____ by frequency of dosing
A

reduces the amplitude of the swings in drug concentration;

are not affected by

136
Q

maintenance dose:

  • dose of the drug administered to ____
  • drugs administered at ____
  • for drugs not administered via IV, must account for ___
A

establish the desired steady state concentration for therapeutic effectiveness;
intervals;
bioavailability

137
Q

dosing rate formula

A

Dosing Rate= CL x TC (target concentration)

138
Q

maintenance dose formula

A

Maintenance Dose= Dosing Rate/bioavailability x Dosing Interval (bioavailability is usually a known quantity (given))

139
Q

loading dose:

  • a desired plasma concentration level may be delayed due to ____
  • one can administer a loading dose to ____
A

binding to plasma proteins or metabolism;

achieve rapid therapeutic levels (any method of delivery)

140
Q

loading dose formula

A

Loading Dose = V x TC

141
Q

loading dose can be given as ___

A

a single dose or a series of doses

142
Q

if loading dose is given too rapidly, ____ can occur, especially if a drug has ____;
calculated amount does not give rate of administration!

A

toxic reactions; a rapid rate of absorption (like for IV infusion)

143
Q

____ is the most important factor determining drug concentrations

A

clearance

144
Q

clearance is determined by:

A
  • dose
  • organ blood flow
  • kidney and liver function

Systemic Pharmacology I (7 decks)

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