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APEX > Pharmacology: Pharmacokinetics > Flashcards

Pharmacology: Pharmacokinetics Flashcards

1
Q

What does volume of distribution describe?

A

relationship between a drug dose and the drug’ plasma concentration

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2
Q

Vd assumes two things, what are they?

A
  1. the drug distributes instantaneously (full equilibration occurs at t=0)
  2. The drug is not subjected to biotransformation or elimination before it fully distributes.
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3
Q

Vd is a calculated value, it is not something we can directly measure, what is the formula?

A

Vd = amount of drug / desired plasma concentration

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4
Q

What is the total body water in liters of a 70kg patient?

A

42 L (60%)

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5
Q

If a drug’s Vd exceeds total body water it is known as?

in order to exceed total body water the Vd must be greater than what?

A

lipophilic

> 0.6 L/Kg or > 42 L

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6
Q

If a drug has a very large Vd then will the dose requirement to achieve a given plasma concentration be high or low?

A

higher dose to achieve a given plasm concentration

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7
Q

Having a high Vd means that the drug distributes into what kind of tissues?

A

distributes into the total body water as well as into the fat

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8
Q

What parameter would a drug meet to be considered hydrophilic?

A

a Vd that is less than total body water (less than 0.6L/Kg or < 42L). It distributes into some or all of the body water, but it does NOT distribute into fat.

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9
Q

If a drug has a small Vd and thus is considered hydrophilic, does it require a larger or lower dose to achieve a given plasma concentration?

A

lower dose is required

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10
Q

What are the two components of the ECF?

A

Plasma

interstitial fluid

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11
Q

What is the formula for loading dose?

A

Loading dose = (Vd x desired plasma concentration) / bioavailability

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12
Q

How do you calculate Vd for a loading dose question?

A

The Vd will be given to you, you then multiply it by the patients weight in Kg which will then give you the patient specific Vd in L and you multiply that by the desired Cp and then if it is an IV medication you divide by 1

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13
Q

The dose of a medication that achieves a given plasma concentration is dependent on?

a. timing
b. route of administration
c. gender
d. age

A

b. route of administration

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14
Q

What is clearance?

A

volume of plasma that is cleared of a drug per unit of time

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15
Q

Clearance is directly proportional to? (3)

a. half-life
b. drug dose
c. extraction ratio
d. drug concentration in the central compartment.
e. blood flow to clearing organ

A

blood flow to clearing organ
extraction ratio
drug dose

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16
Q

The most important clearing organs include?

A

liver
kidney
organ independent (Hofmann elimination and ester hydrolysis in the plasma)

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17
Q

rate of administration = rate of elimination describes?

A

steady state

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18
Q

when is steady state achieved?

A

when the amount of drug entering the body is equivalent to the amount of drug being eliminated from the body.
SS is achieved after five half-times

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19
Q

How many half-times must pass for SS to be achieved?

A

five

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20
Q

What is the central compartment?

A

The plasma

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21
Q

What is the peripheral compartments?

A

the tissues

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22
Q

In the two compartment model, what is the alpha phase, what is the beta phase?

A

alpha phase is the steepest portion of the curve which represents redistribution

beta phase is the less steep portion of the curve representing elimination from the plasma

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23
Q

In the two compartment model, what characteristic of a drug would create a steeper slope?

A

the more lipophilic the drug the the larger the Vd and the steeper the slope

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24
Q

True or false:
When a drug distributes from the central compartment to the peripheral compartment the plasma concentration continues to decline, as a result the concentration gradient reverses and the drug then redistributes from the peripheral compartment and re-enters the central compartment?

A

True

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25
Q

What does a rate constant tell you and what symbol is used to represent “rate constant”.

A

rate constant communicates the speed at which a reaction occurs.

k = rate constant

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26
Q

what does k12, k21, and ke mean?

A

k12 - rate constant for drug transfer from the central to peripheral compartment.

k21 - rate constant for drug transfer from the peripheral to central compartment.

ke - rate constant for drug elimination from the body

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27
Q

What is the difference between elimination half-life and elimination half-time?

A

half life is talking about removal of drug (50%) from the body after rapid IV injection.

half time is removal of drug (50%) from the plasma during the elimination phase

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28
Q

We say a drug has been cleared from the body when what % of the dose has been eliminated from the plasma?

A

96.9% or five half-times

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29
Q

Does half-time measure a constant fraction or constant amount?

A

half time measures a constant fraction NOT a constant amount.

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30
Q

What is context sensitive half time?

A

Time required for the plasma concentration to decline by 50% after the infusion has stopped.

It takes the duration of drug administration into account, “time”.

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31
Q

Explain context sensitive half time in relation to fentanyl and remifentanil?

A

The longer fentanyl was infused the longer it will take it to be eliminated by 50% from the plasma concentration, this is because it is highly lipid soluble and has gone out into the tissues and then when the infusion is stopped it goes back into the central compartment.

Remifentanil is an exception to this rule, it is highly lipophilic but it is quickly metabolized by plasma esterase’s and has a similar context -sensitive half time regardless of how long it is infused.

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32
Q

difference between a strong acid or base placed in water vs. a weak acid or base placed in water?

A

strong acids and bases in water will ionize completely

weak acids and bases in water will only partially ionize and the remaining fraction will be unionized

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33
Q

What does ionization mean?

A

ionization is the process where a molecule gains a positive or negative charge.

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34
Q

The amount of ionization is dependent on two things?

A
  1. The pH of the solution

2. The pKa of the drug (pKa = dissociation constant)

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35
Q

When pKa and pH are the same what % of the drug will be ionized and what % of the drug will be unionized?

A

50% ionized

50% unionized

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36
Q

True or false:

small changes in pH do not have much impact on the degree of ionization?

A

False,

small changes in pH can have profound impact on the degree of ionization.

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37
Q

When are the small changes in pH most profound in relation to ionization?

A

when the pKa and pH are very close to each other

less significant when the pKa is very far from the pH

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38
Q

are ionized particles (drugs) soluble in water or lipids?

A

ionized drugs are soluble in water

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39
Q

are unionized particles (drugs) soluble in water or lipids?

A

unionized drugs are soluble in lipids

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40
Q

pharmacologic effect of ionized drugs vs unionized drugs? (which one is active and which one is not active)

A 
ionized = not active 
unionized = active
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41
Q

are ionized or unionized drugs more likely to undergo renal elimination?

A

ionized are more likely to undergo renal elimination

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42
Q

are ionized or unionized drugs more likely to undergo hepatic biotransformation?

A

unionized are more likely to undergo hepatic biotransformation

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43
Q

Is ionized or unionized drugs more likely to diffuse across a lipid bilayer?

A

unionized

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44
Q

acidic and basic drugs, tell me which one in which type of solution (acidic or basic solutions) will give you ionized or unionized drugs?

A

acid with a base = ionized (acid donates protons and base accepts protons)

acid with acid or base with base = unionized (if you place like with like then you will only be wanting to give away or only be wanting to accept the protons)

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45
Q

Weak acids are typically paired with a positive ion preparation, this would include which 3 elements?

A

sodium
calcium
magnesium

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46
Q

Weak bases are typically paired with a negative ion preparation, this would include what 2 elements?

A

chloride or sulfate

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47
Q

If you mix a weak base in what kind of solution will you have predominately unionized fraction of the drug?

A

weak base drug mixed with higher pH solution than the pKa of the drug

(base dissolved in a base)

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48
Q

if you mix a weak base in what kind of solution will you have a predominately ionized fraction of the drug?

A

weak base drug mixed with lower pH solution than the pKa of the drug

(base dissolved in an acid = ionized)

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49
Q

if you mix a weak acid in what kind of solution will you have a predominately unionized fraction of the drug?

A

weak acid drug mixed with lower pH solution than the pKa of the drug

(acid dissolved in an acid)

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50
Q

If you mix a weak acid in what kind of solution will you have a predominately ionized fraction of the drug?

A

weak acid drug mixed with higher pH solution than the pKa of the drug

(acid dissolved in an base = ionized)

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51
Q

are local anesthetics weak acids or bases?

A

LA = weak bases

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52
Q

what are the perfect conditions for fetal ion trapping?

A

basic drug
alkalotic mother
acidotic fetus

The basic drug is given IV to alkalotic mom thus the unionized fraction of the drug is increased and more basic drug is available to diffuse across the placenta and to the fetus. Once in the fetus where it is more acidic than mom or perhaps fetal acidosis is in place the drug becomes ionized (base with acid) and can not cross back over the placenta. This would cause more distress to the fetus and further increase fetal acidosis.

In this scenario usually a LA is being given because it is a weak base drug

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53
Q

in relation to ionized or unionized, which one is lipophilic and which one is hydrophilic?

A

unionized = lipophilic

ionized = hydrophilic

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54
Q

What is the pKa of lidocaine?

A

pKa = 7.9

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55
Q

is fetal pH usually a little lower or higher than maternal pH on average?

A

little lower, thus more acidic than maternal pH

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56
Q

Where do you find plasma proteins?

A

they are synthesized by the liver and remain in the circulation ( to big to pass through cell membranes )

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57
Q

intravascular drug storage compartment describes?

A

plasma proteins

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58
Q

Is the drug bound to a plasma protein active?

A

A drug bound to a plasma protein can not bind to a receptor, so any bound drug can be considered inert. It is only when the drug is released from the protein, is it able to affect the body.

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59
Q

what is the t 1/2 of albumin?

A

3 weeks

60
Q

albumin serves as a measurement of protein synthesis and will reflect acute or chronic changes in nutrition?

A

chronic changes

61
Q

does albumin carry a positive or negative charge?

A

negative

62
Q

acidic, basic, neutral drugs, which kind does albumin primarily bind to?

A

acidic drugs

it will also bind to some neutral and basic drugs

63
Q

primary determinant of plasma oncotic pressure describes?

A

albumin

64
Q

The most plentiful plasma protein is?

A

albumin

65
Q

a1 - acid glycoprotein binds to what pH drugs?

A

Basic drugs (think LA)

66
Q

Beta- globulin binds to what PH drugs?

A

Basic

67
Q

what conditions will increase albumin?

A

n/a

68
Q

What conditions will decrease albumin?

A 
liver dz
renal dz 
old age
malnutrition 
pregnancy
69
Q

a1-acid glycoprotein will be increased in what conditions?

A 
surgical stress
MI
chronic pain
RA
Advanced age
70
Q

a1-acid glycoprotein will be decreased in what conditions?

A

neonates and pregnancy

71
Q

What fraction of a drug is available to cross the lipid membrane?

A

unbound fraction (free fraction)

72
Q

If a drug is highly protein bound but the bound fraction is reduced for some reason then there will be more unbound drug… what does this mean?

A

the unbound portion of the drug is the potion that can exert it’s action, thus the potency or clinical effect of the drug would increase.

73
Q

changes in protein binding can result from what two things?

A

decreased plasma protein content or competition for binding sites on the protein

74
Q

What are the details behind decreased plasma proteins?

A

plasma proteins can reduce due:

reduced synthetic function (liver dz, malnutritoin)

increased protein excretion (renal dz)

altered distribution (3rd trimester of pregnancy)

75
Q

True or false:

highly protein bound drugs typically have a slower rate of metabolism and elimination?

A

True

76
Q

True or false:

Vd is directly proportional to the degree of plasma protein binding?

A

False,
Vd is inversely related to the degree of plasma protein binding.
Thus the more fat loving/soluble a drug the less likely it is to bind to protein’s

77
Q

alterations in plasma protein binding can be a problem during CPB due to what?

A

hemodilution and/or heparin administration as well as ECMO circuits (ceftriaxone, fentanyl, and midazolam)

78
Q

Can bilirubin and thyroxine displace drugs from protein binding sites?

A

yes

79
Q

For the majority of drugs, the rate of metabolism is dependent on 2 factors, what are they?

A
  1. the concentration of drug at the site of metabolism, this is influenced by blood flow to the site of metabolism.
  2. The intrinsic rate of the metabolic process. This is influenced by genetics, enzyme induction, and enzyme inhibition.
80
Q

Which order kinetics has a rate of elimination with a constant amount? Which one eliminates based on a constant fraction?

A

constant amount = zero order

constant fraction = first order

81
Q

which order of kinetics is a straight downs sloping line and which one is a curved down sloping line?

A

zero order is a straight line that slopes down and to the right

first order kinetics is a curved line that slopes down and to the right

82
Q

situation where there is more drug than enzyme describes what order of kinetics?

A

zero order

83
Q

The enzyme will metabolize constant amount per unit of time describes which order of kinetics?
Give me examples of these drugs?

A

zero order kinetics

ASA, warfarin, heparin, alcohol, phenytoin, theophylline

84
Q

less drug than enzyme, no saturation occurs, this describes what order of kinetics?

A

first order kinetics

85
Q

If an enzyme pathway obeys first order kinetics but then becomes saturated what can happen?

A

the kinetics can change from first order to zero order

86
Q

the enzymatic process of altering the chemical structure of a molecule is known as?

A

metabolism (biotransformation)

87
Q

The hepatic microsomal enzymes of the P450 system are generally confined to what? where else can they be?

A

generally confined to the smooth ER (liver), although they also present in the kidney and GI tract

88
Q

Outside of the liver, where is another important site of drug metabolism?

A

Plasma

89
Q

What kind of metabolism occurs in the plasma?

A

Hofmann’s elimination (temperature and pH dependent)

hydrolysis reactions by non-specific plasma esterase’s (esmolol)

pseudocholinesterase

90
Q

What is the primary role of metabolism?

A

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

91
Q

increased ionization will decrease what?

ionization = water soluble

A

volume of distribution (this increases the delivery to the kidneys and elimination)

92
Q

are ionized drugs eliminated in the urine or reabsorbed from the renal tubules?

A

ionized drugs are are eliminated in the urine

93
Q

are lipid soluble drugs eliminated in the urine or reabsorbed?

A

reabsorbed until they can be changed into a water soluble byproduct

94
Q

Tell me about Fospropofol? What kind of drug is it and what is it metabolized by?

A

it is a prodrug that is metabolized by alkaline phosphatases to its active metabolite - Propofol

95
Q

What are the three phases of metabolism?

A

modification, conjugation, elimination

96
Q

Phase 1 of metabolism is known as ?

A

modification

97
Q

What is the purpose of phase 1 metabolism?

A

small molecular changes that increase the polarity (water solubility) of a molecule to prepare it for phase 2 reaction.

98
Q

Most phase 1 biotransformation (metabolism) is carried out by?

A

P450 system

99
Q

What are the 3 phase 1 reactions that you should understand?

A

oxidation - removes an electron
reduction - adds electrons to a compound
hydrolysis - adds water to a compound to split it apart (usually an ester)

100
Q

What is phase II of metabolism?

A

conjugation

101
Q

What does phase II of metabolism of a drug accomplish?

A

conjugates (adds on) an endogenous, highly polar, water soluble substrate to the molecule. This results in a water soluble, biologically inactive molecule ready for excretion.

102
Q

What are common substrates for conjugation reactions include?

A 
glucuronic acid
glycine
acetic acid
sulfuric acid
methyl group
103
Q

explain enterohepatic circulation?

A

some conjugated compounds are excreted in the bile, reactivated in the intestine, and then reabsorbed into the systemic circulation.

104
Q

Example of a drug that undergoes enterohepatic circulation?

A

Diazepam

105
Q

What is phase III of drug metabolism?

A

elimination

106
Q

What does phase III of drug metabolism accomplish?

A

ATP dependent carrier proteins that transport drugs across cell membranes. These are present in the kidney, liver, and GI tract.

107
Q

Hepatic clearance is a product of? (2)

A

liver blood flow - how much is delivered to the liver

hepatic extraction ratio - how much is removed by the liver

108
Q

Explain extraction ratio?

A

a measure of how much drug is delivered to a clearing organ vs. how much drug is removed by that organ.

109
Q

Extraction ratio formula?

A

ER = arterial concentration - venous concentration / arterial concentration

110
Q

Extraction ratio of 1.0 means what?

A

that 100% of the drug delivered to the clearing organ is removed

111
Q

What does an ER of 0.5 mean?

A

That 50% of the drug delivered to the clearing organ is removed.

112
Q

How is hepatic clearance categorized?

A

as flow limited elimination or capacity limited elimination

113
Q

What is the ratio that a drug must exceed to have the clearance of that drug be dependent on liver blood flow?

A

ER > 0.7

114
Q

What is the ratio that a drug must fall under to have clearance be dependence on the ability of the liver to extract the drug from the blood?

A

ER < 0.3

115
Q

If a drug has an ER of 7.2 then what can you tell me about the clearance of this drug?

A

Hepatic blood flow greatly exceeds enzymatic activity, so alterations in hepatic enzyme activity has little effect.

if the liver blood flow increases then clearance increases

if liver blood flow decreases then clearance decreases

116
Q

If a drug has an ER of 2.9 then what can you tell me about the clearance of this drug?

A

Changes in hepatic enzyme activity or protein binding have a profound impact on clearance of this drug.

since only a small amount of drug is removed per unit of time, alterations in liver blood flow minimally effect clearance.

enzyme induction would increase clearance while enzyme inhibition would decrease clearance

117
Q

List the low hepatic ER drugs?

A 
Roc
diazepam
lorazepam
methadone
thiopental
theophylline
phenytoin
118
Q

List the intermediate ER drugs?

A

midazolam
vecuronium
alfentanil
methohexital

119
Q

Name some of the high hepatic ER drugs?

A 
fentanyl
sufentanil
morphine
meperidine
naloxone
ketamine
Propofol
lidocaine
bupivacaine
metoprolol
propranolol
alprenolol
nifedipine
diltiazem
verapamil
120
Q

Is remifentanil affected by liver blood flow or hepatic enzymatic activity?

A

It is not affected by either because it undergoes hydrolysis in the plasma by non specific tissue esterase’s.

121
Q

What system is the most important mechanism of drug biotransformation in the body?

A

P450 system

122
Q

What other names does the P450 system go by?

A

mixed-function oxidase system or the monooxygenases

123
Q

who is responsible for carrying out most of the phase I biotransformation (metabolism)?

A

P450 system

124
Q

Where are P450 enzymes located?

A 
smooth ER of the hepatocytes
lungs
kidneys
skin
adrenal gland 
GI tract
125
Q

What is the most important P450 enzyme?

A

CYP 34A - Metabolizes nearly 50% of the drugs that we administer

126
Q

There are over 20 different P450 enzymes but what are the two you need to know?

A

CYP 3A4

CYP 2D6

127
Q

What is unique about the P450 system in relation to exogenous chemicals?

A

exogenous chemicals can influence the expression of these enzymes, this can be a significant source of drug interaction.

128
Q

If a patient takes a drug that is an enzyme inducer of the P450 system then what happens?

A

enzyme inducers stimulate the synthesis of additional enzyme. This increases drug clearance and reduces t 1/2.

129
Q

If a patient takes a drug that is an enzyme inhibitor of the P450 system then what happens?

A

enzyme inhibitors compete for binding sites on an enzyme. Since there are fewer binding sites available, drug clearance is reduced and t 1/2 is increased.

130
Q

increased drug plasma level, dose decrease may be required, decreased clearance - this describes an enzyme inducer or inhibitor?

A

enzyme inhibitor

131
Q

decreased drug plasma level, dose increase may be required, increased clearance - this describes an enzyme inducer or inhibitor ?

A

enzyme inducer

132
Q

list some substances/drugs that are enzyme inducers?

A 
tobacco smoke
barbiturates
ethanol
phenytoin
rifampin
carbamazepine
St. John's Wart

(cannabis and dexamethasone also)

133
Q

list some substances/drugs that are enzyme inhibitors?

A 
grapefruit juice
cimetidine
omeprazole
isoniazid
SSRI's
erythromycin
ketoconazole

(also quinidine, erythromycin, and ciprofloxacin)

134
Q

is morphine a weak base or acid?

A

morphine is a weak base

135
Q

What determines if a drug is excreted from the urine or not?

A

a drugs polarity and the pH of the glomerular fluid

136
Q

What type of drugs are excreted from the body unchanged?

A

hydrophilic drugs

137
Q

What must occur to lipophilic drugs before they can be excreted by the kidneys?

A

lipophilic drugs must undergo biotransformation reactions to increase their water solubility before they can be excreted

138
Q

What happens to a lipophilic drug that has not undergone biotransformation and it makes it’s way to the kidneys?

A

It will be reabsorbed into the peritubular fluid by diffusion

139
Q

What are the two processes that deliver drug to the urine?

A
  1. glomerular filtration

2. organic anion and cation transporters

140
Q

What influences whether drugs are excreted in the urine or reabsorbed into the peritubular capillaries?

A

Urine pH

141
Q

acidic urine favors reabsorption of acidic or basic drugs?

A

acidic drugs

142
Q

acidic urine favors excretion of acidic or basic drugs?

A

basic drugs

143
Q

Basic urine favors the reabsorption of acidic or basic drugs?

A

basic drugs

144
Q

basic urine favors the excretion of acidic or basic drugs?

A

acidic drugs

145
Q

What two things can you give to a patient to acidify the urine? This will help to eliminate acidic or basic drugs?

A

Ammonium chloride or cranberry juice will acidify the urine and this helps to eliminate basic drugs.

146
Q

What two things can you give to a patient to alkalize the urine? This will help to eliminate acidic or basic drugs?

A

Sodium bicarbonate or acetazolamide will alkalize the urine. This helps eliminate acidic drugs.

APEX (18 decks)

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