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2: Pharmacology > Uptake & Distribution of IV Agents > Flashcards

Uptake & Distribution of IV Agents Flashcards

1
Q

What is pharmacokinetics?

A

what your body does to the drug

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2
Q

What are the four dimensions pharmacokinetics?

A

things you can measure:

absorption
distribution
metabolism
excretion

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3
Q

Absorption is _____.

A

transportation of unmetabolized drug from site of admin to circulation

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4
Q

Distribution is ______.

A

volume distribution - when the drug is brought to the body compartments

mathematical expression of the sum of the volumes of the compartments

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5
Q

Metabolism is _______.

A

convert pharmacologically active lipid soluble drugs into water soluble and inactive metabolites.

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6
Q

Excretion is ______.

A

process of removing drug and metabolites from body via kidneys, liver, GI.

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7
Q

What is Pharmacodynamics?

A

what the drug does to the body

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8
Q

3 dimensions of pharmacodynamics?

A

mechanism of effect
sensitivity
responsiveness

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9
Q

Mechanism of effect is ______.

A

the processes that produce the desired effect of the drug

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10
Q

Sensitivity is ______.

A

the lowest input (smallest dose) required to produce a given degree of output (normal response)

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11
Q

Responsiveness is _______.

A

degree of effect that drug does to body

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12
Q

Measured parameters of injected drugs are (4)

A

elimination half time
bioavailability
clearance
volume of distribution (Vd)

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13
Q

Elimination half time (E1/2t) is ______.

A

time necessary for [PLASMA] of drug to decline 50% during elimination, independent of drug dose

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14
Q

Describe relationship between elimination half time and Volume of distribution.

A

directly proportional,

as Vd increases, elimination increases

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15
Q

Bioavailibility is ______.

A

amount of drug that enters systemic circulation after a given dose, and the ability of the formulation of the drug to deliver it to the site of drug action

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16
Q

Clearance is ______.

A

capacity for drug removal by various organs defined as volume/unit time.

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17
Q

Volume of distribution is ______.

A

volume into which a drug appears to have been dissolved after administration; sum of all volumes of compartments

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18
Q

What are compartment models?

A

division of body into compartments that represent theoretical spaces

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19
Q

What are the two compartments in 2 compartment model?

A

central compartment

peripheral compartment

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20
Q

Describe central compartment.

A

where drugs go first, rapid equilibration
highly perfused tissues: kidney, liver, lungs, heart, brain (vital organs)
receive 75% of CO
only 10% of body mass

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21
Q

What does “arm to brain circulation” mean?

A

drug reaches brain rapidly, 30-60 sec

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22
Q

Describe the pathway of the drug when administered?

A

Drug accumulates in the tissues because the plasma concentration (central) is initially greater than the tissue concentration (peripheral).
However, eventually the plasma concentration falls to such an extent that the net drug movement is from tissues (peripheral) back into blood (central) to be excreted.

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23
Q

What is the peripheral compartment?

A

the tissues that are less perfused: muscle, skin, fat, nails, hair
drug equilibrates slower
no metabolism occurs here
large volume of distribution

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24
Q

What is rate of transfer? In what population is rate of transfer decreased? What’s the significance?

A

distribution of drug between compartments
old people
greater drug plasma concentration, ex thiopental

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25
Q

Describe what a drug reservoir is. Give an example.

A

tissues that accumulate drug
affects drug availability by maintaining plasma concentration when released from storage to bloodstream
permits sustained drug release over time
ex. adipose tissue, bone, transcellular (ion trapping)

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26
Q

What can occur with large, repeated doses of drug?

A

reservoir tissues become saturated after multiple concurrent doses, prolonging the duration of the drug

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27
Q

What are the components of 3 compartment model?

A

vessel rich
vessel poor
muscle

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28
Q

What component of 4 compartment model?

A

vessel rich
muscle
fat
vessel poor

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29
Q

What is the body mass percent for each of the four compartments for a 70kg?

A

vessel rich 10
muscle 50
fat 20
vessel poor 20

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30
Q

What is the blood flow percent of cardiac output in a 70kg person in each of the four compartments?

A

vessel rich 75
muscle 19
fat 6
vessel poor <1

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31
Q

What type of drugs are preferred and why?

A

lipophilic d/t faster action

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32
Q

Describe lung uptake. Give examples of drugs that do this.

A

lung uptakes basic, lipophilic drugs (amines, pKa > 8) and acts as a reservoir to release back into systemic circulation.

lidocaine, fentanyl, demerol

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33
Q

How much of fentanyl goes to lung?

A

70%

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34
Q

What is the blood brain barrier (BBB)?

A

functional and structural protective barrier to prevent ionized, water soluble drugs from crossing into brain circulation

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35
Q

How can the BBB be overcome (3)? Example of type of drug that is deadly if large enough dose crosses BBB?

A

large doses of drug,
hypoxemia,
head injury
lidocaine - seizures, cardiac collapse

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36
Q

What types of drugs have an easier time crossing BBB?

A

lipophillic drugs

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37
Q

Where do drugs exert their biological effect?

A

biophase or effect site (milleau) AKA membrane, receptors, enzymes

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38
Q

What is KE0?

A

The rate constant of drug elimination from effect site. Different for every drug.

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39
Q

What is the formula Vd?

A

Vd = dose of IV drug/ [plasma} BEFORE elimination

aka at time = 0

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40
Q

What 3 factors influence Vd? And their relationships?

A

lipid soluble (highest influence) - direct
binding to plasma proteins - inverse
molecular size - inverse

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41
Q

E1/2t is _______ proportional to its Vd.

A

directly (independent of dose)

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42
Q

Define elimination half life.

A

Time necessary to eliminate 50% of drug from BODY

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43
Q

What occurs if dosing intervals are less than elimination half life?

A

drug accumulation

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44
Q

In anesthesia world, does elimination half time and elimination half life ever be equal? Why?

A

No. Most IV meds/anesthetics are lipophillic so they will be different.

(but PO meds that are water soluble will cause both to be equal to each other sometimes)

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45
Q

How many half lives before most of the drug is eliminated?

A

4-6 half lives

93.8 - 98.4%

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46
Q

Describe graph of half life plasma concentration of drug.

A

x: time
y: log plasma concentration
initial concentration high at time 0
distribution phase (alpha) E1/2t alpha - sharp decline in concentration - peripheral compartment
elimination phase (beta) - more gradual decline in plasma concentration - back in central compartment

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47
Q

When does context sensitive half time apply?

A

refers to discontinuing an infusion

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48
Q

What factors affect context sensitive half time? (3)

A

distribution and excretion, properties of drug, and length of infusion

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49
Q

What is context sensitive half time?

A

time required for 50% of plasma concentration to fall after discontinuing an infusion

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50
Q

Systemic absorption depends on ________ regardless of route of drug.

A

drug solubility AKA lipophillicity

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51
Q

What are advantages of oral route for drugs? (2)

A

most convenient

most economic

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52
Q

What are disadvantages of disadvantages? (3)

A

emesis,
irregular absorption w/ food or other drugs
destruction by enzymes or gastric fluid

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53
Q

What is the first pass effect?

A

drug into GI system
goes to portal venous blood and passes through liver where it is metabolized
before it enters systemic circulation and arrives at tissue receptors

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54
Q

What routes have the first pass effect?

A

oral

proximal (deep) rectum

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55
Q

What is the advantage of sublingual or transmucosal route?

A

rapid onset d/t bypassing liver preventing first pass effect and membrane being so vascular and thin

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56
Q

Describe transdermal route of drug administration.

A

sustained therapeutic [plasma}

absorption through sweat ducts and hair follicles (penetrates several layers of human skin - diffusion shunt)

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57
Q

What are some factors that affect transdermal route? (2)

A

stratum corneum of epidermis - thickness (chest skin thin)
thickness
blood flow to that area of the skin

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58
Q

What is a possible side effect of all transdermal drugs?

A

contact dermatitis

59
Q

Describe the differences in rectal administration of drugs.

A 
proximal rectum (deeper) - drug transported to portal system via hemorrhoidal veins 
distal rectum (shallower) - bypasses portal system
60
Q

What is a disadvantage of rectal administration?

A

unpredictable responses to administration

61
Q

What is an advantage of IV administration?

A

achieve therapeutic plasma level accurately and rapidly

62
Q

Describe ionization’s effect on drugs.

A

drugs are usually weak acids or bases
present in both ionized and non-ionized forms
non-ionized form is more lipid soluble and diffuses readily across membranes
ionized form is poorly lipid soluble, can’t penetrate membranes, excreted from kidneys unchanged

63
Q

The non-ionized form of a drug is _________ active.

A

pharmacologically active

64
Q

What does the degree of ionization of a drug depend on?

A

dissociation constant (pK) -characteristic of a drug and the pH of surrounding fluid

65
Q

A low pKa means a _______ acid that will ______ in solution. A high pKa means a ______ acid. Weak acids exist in _________, AKA have both _______ and ______ forms.

A

strong, dissociate
weak
equilibrium, ionized, unionized

66
Q

What does pKa represent?

A

pKa is defined as the pH at which the ionized and unionized forms exist in equal concentrations

67
Q

When pH = pKa, the drug will exist at ______% ionized and ______% unionized forms.

A

50, 50

68
Q

Ionized drugs are ______ lipophilic. Therefore, _____ likely to cross the lipid bilayer.

A

less

less

69
Q

Physiologic pH is ______.

A

7.4-7.45

70
Q

At alkaline pH, acidic drugs will be more _______ and therefore _______ lipohillic.

A

ionized, less

71
Q

At alkaline pH, basic drugs will be more _______ and therefore _______ lipohillic.

A

unionized

more

72
Q

At acidic pH, acidic drugs will be more ______ and therefore ______ lipophillic.

A

unionized

more

73
Q

At acidic pH, basic drugs will be more ______ and therefore ______ lipophillic.

A

ionized

less

74
Q

Like in like _______ dose because of ______ degree of ionization. Like in unlike _______ dose because of ______ degree of ionization.

A

decrease, high

increase, low

75
Q

What is ion trapping?

A

when a drug changes from unionized form to ionized form as it moves from one body compartment to another

when drugs closer to physiological pH (basic) are in the plasma they exist in lipophillic/unionized form and are able to cross membranes into other compartments, once they cross they become trapped because the pH in these compartments (not plasma) are lower therefore causing more of the drug to exist in ionized/liphobic form and therefore unable to cross membranes.

76
Q

What is plasma protein binding?

A

degree to which drugs bind to proteins in the plasma,

protein-bound drugs will not cross into the peripheral compartment and are pharmacologically inactive

77
Q

Only ________ fraction of drug is able to cross cell membranes and have a pharmacological effect. Therefore it is also ______ and _______ more readily.

A

unbound

metabolized, excreted

78
Q

Drugs that are ______ protein-bound are _______ effected by alterations in protein binding. Examples of drugs like this are:

A

highly, highly

warfarin, propanolol, phenytoin, diazepam

79
Q

Things that affect protein binding are (3):

A

competition at protein-binding site,
alteration of protein that affects affinity for binding
physiological condition that reduces protein binding (kidney or liver issues)

80
Q

What is clearance?

A

volume of plasma cleared of drug via metabolism and excretion

81
Q

Protein-binding can act as a ________ of drug in the body. As unbound drug is _________ and ______ to maintain equilibrium drug will become ______.

A

reservoir
metabolized, excreted
unbound

82
Q

First Order Kinetics is defined as?

A

The amount of drug eliminated is proportional to amount of drug present in plasma. As the concentration drops the rate of elimination rate drops. Curved, non-linear graph. Ex. 2% of drug available is eliminated per minute.

83
Q

Zero Order Kinetics is defined as?

A

The same amount of drug is eliminated per unit time, the rate is independent of plasma concentration, it is constant. B/C plasma concentration of drug exceeding metabolizing capacity of body. Linear graph. Ex. 2mg of drug eliminated per minute.

84
Q

What are examples of drugs that work under Zero Order Kinetics?

A

ASA, dilantin/phenytoin, etOH, fluoxetine, omeprazole

85
Q

What is hepatic clearance?

A

ability of liver to extract and metabolize a drug as it passes through it; it is a range from 0-1, influenced by hepatic blood flow and hepatic extraction ratio.

86
Q

Describe what the hepatic extraction ratio is and how ti affects drug metabolism.

A

0-1.
> 0.7 a large portion of drug is removed per unit of time, clearance depends on hepatic blood flow and enzyme activity has minimal influence AKA perfusion dependent elimination.
< 0.3 only a small portion of drug delivered to liver is removed per unit time, a decrease in protein binding or increase in enzymatic activity greatly affects clearance while changes in blood flow will have minimal effect AKA capacity dependent elimination

87
Q

What is the most important organ for elimination of unchanged drugs or their metabolites? Why?

A

kidneys
water-soluble drugs are excreted more efficiently than compounds that are highly lipid soluble (one of the most important aspects of metabolism is converted lipophillic drugs to water soluble form in order to be excreted)

88
Q

Describe what happens to unchanged/lipid soluble drugs that are in the kidneys.

A

they are reabsorbed in the renal tubules by their epithelial cells

89
Q

What affects the rate of reabsorption of drugs in renal tubules?

A

pH and rate of renal tubule urine flow
highly lipid soluble drugs will be reabsorbed - aka won’t be excreted in urine
urine pH influences the amount of drug in its ionized (easily excreteable form)
ex. weak acid excreted more easily in alkaline urine

90
Q

Define metabolism.

A

Biotransformation of drug from pharmacologically active (lipid soluble, unionized) to pharmacologically inactive (most of the time) (water soluble, ionized) drugs

91
Q

_________ water solubility reduces Vd and _______ renal excretion.

A

Increases

increases

92
Q

True or false: Metabolism always inactivates drugs. Why or why not?

A

False

Some metabolites of drugs are active, ex. ketamine and midazolam

93
Q

What are four pathways of metabolism?

A

oxidation, reduction, hydrolysis, conjugation

94
Q

What is Phase 1? What steps are in Phase 1?

A

it is the polarization of a drug to prepare it for Phase 2

oxidation, reduction, hydrolysis

95
Q

What is Phase 2? What steps are in Phase 2?

A

conjugation reactions that covalently link drugs/metabolites with a highly polar molecule (carbohydrate or amino acid) making it more water soluble and therefore easier to excrete
conjugation

96
Q

Where does drug metabolism occur? (5)

A

plasma, lungs, kidneys, GI tract, liver

97
Q

What enzymes are responsible for metabolism of most drugs?

A

hepatic microsomal enzymes

98
Q

Where are hepatic microsomal enzymes located?

A

primarily: hepatic smooth endoplasmic reticulum
also: small intestine, lungs, kidney, placenta

99
Q

What are the general steps in elimination of a drug from the body? (Ie. metabolism and excretion)

A

drug (unionized, nonpolar) > phase 1 (oxidation, reduction, hydrolysis > drug (ionized, polar) > phase 2 (conjugation) > excretion

100
Q

_______ is the family of enzymes that are responsible for metabolism of most drugs via _______, _______, and _______. There are 6 different forms (also called _______ ) are responsible for metabolizing 90% of drugs.

A

Cytochrome P-450, oxidation, reduction and conjugation

isozymes

101
Q

What are isozymes?

A

molecules with different structures but same function

102
Q

The nomenclature of cytochrome P-450 is:

letters CYP:
first number:
second letter:
second number:

A

letters CYP: cytochrome P-450
first number: genetic family
second letter: genetic subfamily
second number: specific gene/isozyme

103
Q

What is the significance of CYP450? An example?

A

different ethnic backgrounds will have different responses to drugs due to genetic variability (polymorphism)

ex. 1 out of 15 white or black people will have an exaggerated response to beta blockers or no response to tramadol

104
Q

What is the significance of the name of the enzyme cytochrome P450?

A

CYP450 enzymes are named because they are bound to membranes within a cell (cyto) and contain a heme pigment (chrome and P) that absorbs light at a wavelength of 450 nm when exposed to carbon monoxide.

105
Q

What is enzyme induction? What is an example (2) of enzyme induction?

A

It is a feature of hepatic microsomal enzymes. They become stimulated to activate by drugs or chemicals.

The body gets more efficient at processing the drug the more it is exposed to it.

Ex: etOH abusers - liver becomes better at metabolizing etOH, needs to drink more to get same effect, could be harder to anesthetize

smokers - used to processing toxins, will be more effective at processing anesthetics, pt wont experience N/V as often

106
Q

Noncytochrome P450 enzymes (nonmicrosomal enzymes) catalyze reactions responsible for metabolism of drugs via ________ and ________, and to a lesser extent _______ and ________.

A

conjugation and hydrolysis

oxidation and reduction

107
Q

Noncytochrome P450 enzymes (nonmicrosomal enzymes) are generally found in the _______ but also _______ and ________.

A

liver

plasma, GI tract

108
Q

Noncytochrome P450 enzymes (nonmicrosomal enzymes) are responsible for hydrolysis of drugs with ________ bonds, for example ______ and ______.

A

ester

succinylcholine, esmolol (atracurium, mivacurium, ester local anesthetics)

109
Q

Noncytochrome P450 enzymes (nonmicrosomal enzymes) differ from cytochrome P450 enzymes in that they do not undergo _________; they are both similar in that the enzymes are determined _______.

A

enzyme induction

genetically

110
Q

The most common way a drug exerts a pharmacological effect on the body (aka ________) is by interacting with specific ________, which are macromolecules on the lipid bilayer.

A

pharmacodynamics

receptors

111
Q

The concentration of receptors in lipid portion of cell membranes is _______, either increasing ( ________) or decreasing (___________) in response to specific ________.

A

dynamic
up-regulation
down-regulation
stimuli

112
Q

The State of Receptor Activation Theory states:

A

when an agonist binds to receptors it converts the receptor from a nonactivated to an activated state

113
Q

The Receptor Occupancy Theory states:

A

the intensity of effect produced by the binding of drugs to receptors is proportional to the fraction of receptors occupied by the drug.

when all the receptors are occupied maximal drug effects occur.

114
Q

Nonreceptor drug action produces effects via: ________ (example _______) or _________ (example_______).

A

direct chemical action (neutralizing acids - antacids; chelating drugs - binds with metal cations)
or physical action (osmotic diuretics)

115
Q

Describe an agonist drug.

A

bind to receptors and activate them; mimic cell signaling molecules by activating the same receptor sites and causing similar effects.

116
Q

Describe an antagonist drug.

A

drugs that bind to (or alter) receptor sites do not activate them and block receptor activation by agonists; prevents the effect from cell signaling molecules

117
Q

Affinity of a drug for a specific macromolecular component of a cell and its resulting activity are tied heavily to its ________ and _______ so much so that even minor changes in _________ can result in major changes in the drug’s __________.

A

chemical structure and 3D shape, stereochemistry, pharmacological properties

118
Q

An enantiomer is:

A

a chemically identical (same formula, number of atoms) pair of molecules that exist in non-superimposable mirror images of one another (right and left handed)

119
Q

Enantemerism is produced by _________ carbon atoms. Enantiomers are said to be _______ molecules because they are non-superimposable.

A

sp3 hybridized

chiral

120
Q

Superimposable molecules are called _______ molecules.

A

achiral

121
Q

A chiral molecule will have a ________ atom that is surrounded by _______ groups.

A

carbon

4 different

122
Q

Enantiomers can be so different from each other pharmacologically that they can have different ________, ________, and _______. Also, enantiomers can have different ________ for receptor-binding sites. One enantiomer may even be ________ while the other contributes to _______, AKA an ________.

A

rates of absorption, metabolism, excretion
affinities
therapeutically active, side effects, impurity

123
Q

What is an isomer? An _______ is a type of isomer.

A

same number of atoms, different arrangement

enantiomer

124
Q

To determine how many isomers a molecule has:

Give an example.

A

find number of chiral centers (n)
2^n = # of isomers
ephedrine has 2 chiral centers, 2^2 = 4 isomers.

125
Q

Potency is

A

the dose of a drug required to produce a therapeutic effect

126
Q

Efficacy is

A

the ability of a drug to elicit a maximal physiologic response when it interacts with a receptor

127
Q

Describe the graph of potency and efficacy and what it means when the graph moves either left or right and up or down.

A

x axis: log dose of drug
y axis: % response/effect
moving left: increase in potency (less drug required to produce effect)
moving right: decrease in potency (more drug required to produce effect)
moving up: increase in efficacy (higher maximum effect)
moving down: decrease in efficacy (lower maximum effect)

128
Q

Effective dose 50% or ED50 or median effective dose is _______.

A

dose of a medication that produces a desired pharmacologic effect in 50% of the studied patient population that takes the medication.

129
Q

Lethal dose 50% or LD50 or median lethal dose is ______. The lower the LD50 dose is the _______ toxic a substance is.

A

represents the single dose that would kill 50% of a population of test animals
more

130
Q

A ratio between median lethal dose and median effective dose is called the ________ or _______. It is the difference between the dose of a drug that produces a ________ and _________.

A

therapeutic index or margin of safety

desired effect and undesired effect

131
Q

Hyperreactive is used to describe ________.

A

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

132
Q

Hypersensitive is used to describe ________.

A

people who are allergic or sensitized to a drug.

133
Q

The additive effect is when ________.

A

the combined effect of two or more chemicals is equal to the sum of the effect of each agents given alone. drugs don’t interact.

1 + 1 = 2

134
Q

The synergistic effect is when ________.

A

two drugs interacting to produce an effect greater than an algebraic summation

1 + 1 = 3

135
Q

What two drugs are affected by plasma esterase? What is its effect?

A

succinylcholine
adenosine
shortened half life

136
Q

Nonmicrosomal enzymes are determined ________.
__________ is a drug that if the patient is deficient in will have increased sensitivity to _________ drugs, like _________ and _______.

A

genetically
Pseudocholinesterase
anesthetic
succinylcholine and mivacurium

137
Q

Drugs can exert both _______ and ______ effects.

A

direct

indirect

138
Q

Neurotransmitter storage in vesicles at the nerve bulb allow for _______ because they are already made.

A

quick release/activation

139
Q

The number of receptors in the body is _______ and change in number based on _______. Give an example:

A

fluid
signals/stimuli
Beta blockers- chronic use leads the body to make more beta receptors, sudden cessation will cause increased cardio-related effects due to increased Beta receptor activity

140
Q

The cannabinoid system is an example of the State of Receptor Activation Theory, which states that some receptors are ________ until _______ is present, then is _______.

A

State of Receptor Activation Theory
dormant
drug
activated

141
Q

Direct effects of drugs result in an effect produced at the _________, while indirect effects of drugs result __________ from it.

A

receptor

downstream

142
Q

Describe a graph of drug efficacy.

A

x: log dose [drug]
y: effect
relationship: non-linear

143
Q

Why aren’t there as many allergic reactions with anesthetic drugs?

A

because the body does not recognize the drug and therefore can’t react to it - man made

144
Q

Why is there more sensitivity with drugs that are analogs of chemicals found in our bodies?

A

because the body does recognize it and can react to it

2: Pharmacology (2 decks)

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