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550 Pharm > Uptake and Distribution of IV Agents > Flashcards

Uptake and Distribution of IV Agents Flashcards

1
Q

Pharmacokinetics consist of?

A 
absorption
distribution
metabolism
excretion
"What the body does to a drug"
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2
Q

Pharmacodynamics consist of?

A

mechanism of effect
sensitivity
responsiveness
“what a drug does to the body”

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3
Q

What are common parameters of pharmacokinetics?

A

elimination of half-time
bioavailability
clearance
volume of distribution

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4
Q

The body is divided into what 2 compartments?

A

Central and Peripheral

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5
Q

The central compartment is made up of what?

A
  • Highly perfused tissues: kidney, liver. heart, brain receive 75% of the CO, represents only 10% of the body mass
  • Rapid uptake of drug
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6
Q

How is the drug distributed?

A

drug first introduced into the central compartment distributes to the 2nd compartment and returns to the central compartment for clearance

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7
Q

The peripheral compartment is made up of what?

A
  • large calculated volume

- extensive uptake of drug

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8
Q

Rate of transfer between compartments…

A

decreases with aging, leading to greater plasma [ ] in certain drugs (thiopental)

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9
Q

What is the volume of distribution?

A

sum of all the volumes of the compartments

Vd = dose of IV drug/plasma [ ] before elimination

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10
Q

Vd is influenced by what physiochemical characteristics of the drug?

A

lipid solubility
binding to plasma proteins
molecular size

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11
Q

What is the elimination of half-time?

A

the time necessary for the plasma [ ] of drug to decline 50% during the elimination phase

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12
Q

E1/2t of a drug is directly proportional to ______ and inversely proportional to its ______.

A

Vd; clearance

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13
Q

T/F: Elimination half-time is independent of the dose of the drug administered.

A

True

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14
Q

How does drug accumulation occur?

A

if the dosing intervals are less than the elimination half times

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15
Q

What is the relationship of half-times to the fractional amount remaining to the amount eliminated, respectively?

A

halftimes—remaining—eliminated

0---1------0
1---1/2----50
2---1/4----75
3---1/8----87.5
4---1/16---93.8
5---1/32---96.9
6---1/64---98.4
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16
Q

As the plasma [ ] of drug decreases below that of highly perfused tissues….

A

drug leaves and is redistributed to less well-perfused sites, i.e. muscle and fat

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17
Q

With continuing elimination of the drug, the plasma [ ] declines below that in the tissues…

A

drug leaves tissues to re-enter the circulation

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18
Q

What happens when tissues accumulate drug?

A

tissues that accumulate drug preferentially act as a reservoir to maintain the plasma [ ] and prolong effect

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19
Q

Large or repeated doses..

A

saturate inactive tissue negating, redistribution, again prolonging duration of action, as now reduction of effect depends on metabolism rather than redistribution

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20
Q

What does absorption depend on?

A

regardless of the route of drug administration, depends on the drug’s solubility

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21
Q

Oral administration

A

most convenient and economic

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22
Q

What are disadvantages of oral administration?

A

emesis, destruction by enzymes or acidic gastric fluid, irregular absorption with food or other drugs

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23
Q

What the is first pass effect?

A

drugs absorbed from the GI system, enter the portal venous blood and pass through the liver before entering the systemic circulation for delivery to tissue receptors. Here they are extensively extracted and metabolized

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24
Q

Sublingual, transmucosal absorption

A

rapid onset; bypasses the liver and prevents first pass effect

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25
Q

Transdermal absorption..

A

provides sustained therapeutic plasma [ ]

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26
Q

Where does the absorption occur with transdermal?

A
  • occurs along sweat ducts and hair follicles that function as diffusion shunts
  • rate limiting step is diffusion across the stratum corneum of the epidermis
  • thickness and blood flow are factors reflected in the skin’s permeability for drugs
  • contact dermatitis can occur at the site
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27
Q

Rectal absorption..

A
  • proximal rectum - transport to the portal system via superior hemorrhoidal veins, thereby first pass effect
  • distal rectum - bypasses portal system
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28
Q

IV absorption..

A

achieve therapeutic plasma levels precisely and rapidly

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29
Q

Lung uptake..

A

lung uptakes basic lipophilic drugs and acts as a reservoir to release drug back into the systemic circulation
(lido, fentanyl, demerol)

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30
Q

T/F: BBB prevents ionized, water soluble drugs from crossing the barrier.

A

True

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31
Q

Under what circumstances can the BBB be overcome?

A

large doses of drug
head injury
hypoxemia

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32
Q

Non-ionized drugs are usually ____ soluble and ____ diffuse across lipid cell membranes.

A

lipid; can

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33
Q

What are some examples of lipid cell membranes?

A

BBB, renal tubules, GI epithelium, hepatocytes

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34
Q

Degree of Ionization

A
  • depends on its dissociation constant (pK) and the pH of the surrounding fluid
  • changes in pH can result in large degree of ionization, i.e. acidic drugs are highly ionized at alkaline pH, and vice versa
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35
Q

Ion trapping

A

[ ] difference of total drug can develop on two sides of a membrane that separates fluids with different pHs, i.e placenta

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36
Q

Protein Binding

A

most drugs bind in various degrees; only free or unbound fraction of drug is readily available to cross cell membranes
-unbound also metabolized and excreted more readily

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37
Q

Drugs that are highly protein bound..

A

are markedly effected by alterations in protein binding

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38
Q

What are examples of drugs that are highly protein bound?

A

warfarin, propranolol, phenytoin, diazepam

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39
Q

What is clearance?

A

volume of plasma cleared of drug by metabolism and excretion

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40
Q

What is First-Order Kinetics?

A

almost all drugs administered in therapeutic dose ranges are cleared at a rate proportional to the amount of drug present in the plasma

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41
Q

What is Zero-Order Kinetics?

A

a few drugs will exceed the metabolic or excretory capacity of the body to clear drugs by first order kinetics even at therapeutic doses

  • constant amount of drug is cleared per unit of time
    i. e. ASA, dilantin, ETOH
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42
Q

Hepatic Clearance

A

determined by hepatic blood flow and hepatic extraction

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43
Q

“Perfusion-dependent elimination”

A

If hepatic extraction for a drug is high (greater than 0.7) the clearance of the drug will depend on hepatic blood flow

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44
Q

“Capacity-dependent elimination”

A

if the hepatic extraction ratio is low (less than 0.3) a decrease in protein binding or an increase in enzyme activity will increase hepatic clearance
-changes in hepatic blood flow will have minimal changes in its clearance

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45
Q

Renal Clearance

A
  • most important organ for elimination of unchanged drugs or their metabolites
  • water-soluble compounds are excreted more efficiently by the kidney’s than lipid soluble
46
Q

Highly lipid soluble drugs are ______ such that little or no unchanged drug is ____ in the urine/

A

reabsorbed; excreted

47
Q

What is metabolism?

A

biotransformation to convert pharmacologically active, lipid soluble drugs into water soluble and often inactive drugs.

48
Q

Increased water solubility _____ the Vd for a drug and ______ its renal excretion.

A

reduces; enhances

49
Q

What are the 4 pathways of metabolism?

A

oxidation
reduction
hydrolysis
conjugation

50
Q

Hepatic Microsomal Enzymes

A

located in hepatic smooth ER

51
Q

Cytochrome P-450

A

large number of different protein enzymes involved in oxidation and reduction and conjugation of a large number of drugs

52
Q

What are the 6 well characterized forms (isozymes) of the cytochrome P-450 system involved in drug metabolism in humans?

A 
CY1A2
CYP2D6
CYP2C19
CYP2E1
CYP2C9
CYP3A
53
Q

Enzyme induction

A

drugs and chemicals stimulate activity of these enzymes (i.e. zero-order kinetics)

54
Q

Nonmicrosomal Enzymes

A
  • metabolize drugs mostly by conjugation and hydrolysis
  • to a lesser degree by oxidation
  • hydrolysis of drugs that contain ester bonds (sux, esmolol)
  • do NOT undergo enzyme induction
  • determined genetically
55
Q

Where are nonmicrosomal enzymes located?

A

liver mostly, plasma, GI tract

56
Q

What is the most common mechanism by which drugs exert pharmacologic effect?

A

by their interaction with specific macromolecules in the lipid bi-layer of cell membranes called receptors

57
Q

Receptors can _____ or ____ in number in response to specific stimuli

A

increase; decrease

58
Q

State of Receptor Activation Theory

A

non-activated receptors are converted to active by the drug

59
Q

Receptor Occupancy Theory

A

The more receptors occupied by drug the more effect

60
Q

Nonreceptor Drug Action

A

mechanisms other than receptor-drug interactions i.e. chelating drugs from bonds with metallic cations that may be found in the body

61
Q

How do antacids neutralize gastric acid?

A

direct action

62
Q

Agonist drugs

A

mimic cell signaling molecules by activating the same receptor sites and causing similar effects

63
Q

Antagonist drugs

A

bind to receptors as well and change the configuration of agonist site or bind to it, preventing effect from cell signaling molecules

64
Q

Structure activity

A

the affinity of a drug for a specific macromolecular component of the cell and its intrinsic activity are intimately related to its chemical structure
-subtle changes as stereochemistry, may result in major changes in pharmacological properties

65
Q

What is elimination half-life?

A

time necessary to eliminate 50% of the drug from the BODY

66
Q

When is elimination half-time and elimination half-life not equal?

A

when the decrease in the drug’s plasma [ ] does not parallel its elimination form the body

67
Q

Most drugs are weak ___ or weak _____;present in both ______ and _______ forms

A

acids;bases;ionized;non-ionized

68
Q

T/F: In the ionized form, the drug can cross membranes.

A

FALSE

in the ionized form it cannot cross

69
Q

Ionized fraction of the drug is excreted by the kidneys _____.

A

unchanged

70
Q

Which fraction of drug is considered active?

A

non-ionized

71
Q

Non-ionized is metabolized by..

A

the liver

72
Q

Phase I metabolism

A

oxidation, reduction, hydrolysis

73
Q

Phase II metabolism

A

parent or metabolite drug reacts with an endogenous substrate to form water-soluble conjugates

74
Q

What are the sites for metabolism?

A

kidneys, lungs, GI tract and

liver- hepatic microsomal enzymes are responsible for metabolism for most drugs

75
Q

Stereochemistry

A
  • enantemerism can be produced by sp3 hybridized carbon atoms
  • free rotation about the chiral carbon is not possible, two stable forms of the molecule exist
  • interaction with biological receptors can differ greatly between two enantomers
  • some isomers may cause entirely different effects
76
Q

Hyper-reactive

A

people in whom unusually low dose of drug produces its expected pharmacologic effect

77
Q

Hypersensitivity

A

immune response, people who are allergic

78
Q

Additive effect

A

second drug acting with the first will produce equla to the sum of both
1+1=2

79
Q

Synergetic effect

A

two drugs interact to produce an effect greater than their sum
1+1=3

80
Q

How is the Vd of a drug related to its lipophilicity, amount bound to plasma proteins, and molecular size?

A

directly proportional to lipophilicity

indirectly proportional to both amount bound to plasma proteins and molecular size

81
Q

Half-time is related to eliminated a drug from the ___________, while half-life is related to eliminating it from the ______________.

A

plasma; body

82
Q

Quick overview:
Acids are proton ___________and bases are proton_________.
The degree of ionization of an agent is determined by its dissociation __________ and the ___________ gradient across the membrane.

A

donors; acceptors

pKa; pH

83
Q

If a medication is a weak base, what happens if:
pH>pKa
pH=pKa or pH is less then pKa

A

pH>pKa= unionized form predominates
pH=pKa=unionized =to ionized
pH is less then pKa=ionized form predominates

84
Q

If a medication is a weak acid, what happens if:
pH>pKa
pH=pKa or pH is less then pKa

A

pH>pKa=ionized form predominates
pH=pKa=unionized form = to ionized
pH is less then pKa=unionized form predominates

85
Q

The ____________ for a specific agent can vary across a membrane that separates fluids w/ different pH values

A

degree of ionization

86
Q

If morphine is a base and in the blood and has a pKa of 7.9, and then enters the stomach, what is likely to happen?

A

ion trapping: stomach has a much lower pH then the blood (1.9 versus 7.4) so when morphine enters the stomach, the morphine (a base) accepts protons and becomes ionized, thus becoming trapped

87
Q

What 2 situations can influence a drug’s clinical effect related to its protein binding capacity?

A
  1. reduction of body proteins (malnourished; liver disease; last trimester of pregnancy)
  2. drug interaction between 2 or more highly protein-bound drugs
88
Q

Albumin generally binds to _________ drugs while alpha1-acid glycoproteins generally bind to ________drugs.

A

acidic, basic

89
Q

Drug that is protein-bound doesn’t have effect on the body but can contribute to _______________

A

duration of effect

90
Q

If a drug that is highly protein bound (more than 90%) i.e. warfarin, is displaced from the plasma protein, what could happen?
Why is this not always seen?

A

intensification of its effect

not always seen because as the amount of unbound drug increases, so does its elimination

91
Q

What types of drugs are best absorbed from the oral route?

A

acidic drugs, i.e. barbituates; they remain unionized and t/f are easily absorbed

92
Q

Three mechanisms cause pre-systemic elimination of oral drugs. What are they?

A

hydrolysis in the stomach
enzymes in GI tract deactivate
first-pass effect

93
Q

What is bioavailability?

A

the extent to which a drug reaches its effect site after its introduction to the circulatory system

94
Q

The rate at which systemic absorption occurs establishes a drug’s ___________ and __________

A

duration of action and intensity

95
Q

What types of drugs will have large Vd and low plasma concentrations?

A

drugs that are free, unbound to proteins, and lipid soluble

96
Q

The Vd is an ____________ variable that allows calculation of a _____________ of a drug if the desired plasma concentration is known

A

independent

loading dose

97
Q

Why is the Vd relevant to a drug’s elimination from the body?

A

b/c drugs can only be eliminated from the body’s organs of elimination (liver, kidneys).
T/f: if a drug has a large Vd but low plasma concentration, very little will be available to the organs of elimination

98
Q

What are the x and y axises of the plasma concentration curve?

A

y axis: plasma concentration

x axis: time after dose is injected

99
Q

Describe the first phase of the plasma conc. curve

A

alpha phase;
distribution phase
represents the initial dispersal of the drug into the tissue compartments from the central compartment

100
Q

When is the slope of the alpha phase steep?

A

when drug is highly lipid soluble: these drugs have the ability to cross membrane lipid bilayers and be distributed to the peripheral compartment rapidly=rapid fall in plasma levels

101
Q

Describe the 2nd phase of the plasma conc. curve

A

Beta phase, or elimination phase
reflects elimination of the drug from the circulation by the hepatic, renal and other systems after equilibrium as been reached
slope is flatter and less steep; plateaus

102
Q

What is the elimination phase of the plasma concentration curve used to determine?

A

elimination half-life of drugs: important for dosing intervals

103
Q

What is steady state?

When does this occur?

A

all body compartments equilibriate w/ circulating agent
tissue concentrations of the drug vary from organ to organ, but they are not changing
elimination = rate at which drug is made available

This occurs w/ chronic administration or continuous IV admin

104
Q

The end result of phase I reactions is typically a ___________ that is easily excreted by the ________.

A

more polar compound

kidneys

105
Q

Phase I reactions enable __________ to occur

A

phase II

106
Q

Products of phase II reactions almost always have ___________ biologic activity?

A

little or no

107
Q

W/ first order kinetics, a constant _____________ of drug leaves the body over time.
W/ zero order kinetics, a constant __________ of drug leaves the body over time.

A

1st order: %, or rate

0 order: amount

108
Q

Clearance is directly proportional to a drug’s _________ and inversely related to its __________ and concentration in the ___________

A

directly related to: dose

inversely related to: half-life and conc in central compartment

109
Q

Drugs w/ extraction ratio of 0.7 or higher rely on __________to be cleared while those w/ extraction ratio of 0.3 or lower rely on ___________ to be cleared

A

perfusion to the liver (pefusion-dependent)

enzymes and degree of protein binding (capacity-dependent)

110
Q

The amount of drug made available to the renal tubule for elimination depends on ____ and _________

A

GFR & amount of free unbound drug

111
Q

The kidneys easily excrete _________ agents, while ____________ agents are usually eliminated by the liver

A

water-soluble

lipid-soluble

550 Pharm (6 decks)

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