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Pharm Block 9 > Metabolism Of Drugs > Flashcards

Metabolism Of Drugs Flashcards

1
Q

Decreased Vd

A

Increased plasma cxn

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2
Q

Decreased Vd

A

Increased plasma concentration

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3
Q

Vd=100

A

Decreased plasma

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4
Q

What is considered normal Vd

A

Anything that sounds physiologic

  • 60% BW water
  • 40L of water in body
  • less than that is low
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5
Q

What is considered a high Vd

A

100, 1000L, higher than physiologic

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6
Q

Vd calculation

A

Amount in body/cxn in plasma

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7
Q

What does Vd refer to

A

Not necessarily to an identifiable physiological bioluminescent, but merely to the volume that would be required to contain all of the. Drug in the body at the same concentration as in the plasma

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8
Q

What is Vd often referred to

A

As the apparent Vd

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9
Q

Two scenarios of distribution

A
  • drugs are distributed throughout the body but not eliminated
  • drugs are distributed throughout the body and are eleiminated

Reality is that drugs are eliminated
-plasma cxn is always going down

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10
Q

What does a classic IV distribution slope look like

A

Starts out high and with a steep slope, and then taping off to a less steep slope, going down. Starts at its highest cxn then falls.

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11
Q

Steep slope in the IV distribution curve

A

Changes plasma cxn fast

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12
Q

Flatter slope in the IV distribution slope

A

Elimination

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13
Q

What does the shape of a distribution curve tell us

A

How the drug was given

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14
Q

When you get a question about Vd, and it asks amount, what should you be careful not to do

A

If it asks amount, looking for mg, not liters. If L are involved, it is a cxn, not amount

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15
Q

What are two ways in which we should know how to calculate Vd

A

Know how much you would give

Know how much MORE you would give to reach a certain amount if there was already some of the drug in the body.
Vd(C2-C1)

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16
Q

What does a large Vd tell us

A

That most of the drug is in the extra plastic space (tissue)

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17
Q

Vd and half life

A

A factor that increases Vd can increase the half life and extend the duration of action of that drug

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18
Q

Drug reservoirs

A

There are a lot of them. Drugs can be in all kinds of tissues

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19
Q

And 80kg person has a Vd of 18L/kg of a drug in his body. Is hemodialysis a good option to rid him of this drug?

A

Vd=18x80=very high Vd!!

Hemodialysis best for low vD, when doing Vd cases, always look at units

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20
Q

Placental transfer of drugs

A
  • not a barrier to drugs, most drugs cross by simple diffusion
  • can cause congenital abnormalities
  • fetus is exposed to some extent to essentially all drugs taken by the mother
  • any drug that can get to the CNS can get to the fetus
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21
Q

3 types of drug metabolism

A
  • mechanism of termination of drug action
  • mechanism of drug activation
  • drug elimination without metabolism
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22
Q

Drug metabolism as a mechanism of termination of drug action

A

Active to inactive. The action of many drugs is terminated before that are excreted because they are metabolized to biologically inactive derivatives

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23
Q

Drug metabolism as a mechanism of drug activation

A

Inactive to active
Prodrugs
Active to more active
Liver metabolizes most drugs, that’s why liver damaged with acetaminophen

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24
Q

Prodrugs

A

Inactive as administered, these drugs must be metabolized in the body to become active

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25
Q

Drug elimination without metabolism

A

Some drugs such as lithium are not modified by the body, act until they are excreted

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26
Q

What are the two types of metabolism

A

Phase I

Phase II

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27
Q

Phase I metabolism

A

Making minor changes to drug to make more water soluble

-accomplished by enzymes (cytochrome P450) found in smooth ER

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28
Q

Phase II metabolism

A

Involve conjugation reactions where an endogenous substrate is conjugated to the drug via the actions of a transferase enzyme
-attach another substance in body to the drug to make it heavy and hard to move in the body

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29
Q

What type of metabolism involves making minor chemical changes to the drug to make more water soluble

A

Phase I

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30
Q

What type of metabolism involves transferase enzymes

A

Phase II

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31
Q

What type of metabolism is lacking in neonate

A

Phase II

-makes them susceptible to drugs metabolized in this manner

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32
Q

For phase I and phase II metabolism, what order do they occur in

A

This is not a sequence and they can occur in any order

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33
Q

Top two sites for metabolism

A

Liver and kidney

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34
Q

What is the most important organ for metabolism

A

Liver

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35
Q

Metabolism occurs via enzymes located in or on:

A
  • smooth ER (phase I)

- cytoplasm (phase II)

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36
Q

What is in the center of a cytochrome P450?

A

Heme complex

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37
Q

How are cytochrome P450 enzymes names

A

With a root CYP followed by a number designating the family, a letter denoting the subfamily, and another number designating the CYP form.
-CYP3A4 is family 3, subfamily A, gene number 4

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38
Q

How many CYPs that metabolize drugs in humans

A

12

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39
Q

The mast active CYPs for drug metabolism re

A

CYP2C, CYP2D, CYP3A

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40
Q

Which CYP does most of the metabolism

A

CYP3A metabolizes 50% of all drugs

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41
Q

What are the phase I reactions (CYP450)

A
  1. Cytochrome P450-dependent oxidation
  2. Reduction
  3. Hydrolysis
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42
Q

Drugs that increase the expression of p450 enzymes

A

CYP inducers

These ultimately increase metabolism, and decrease affect of the drug

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43
Q

Drugs which will reduce the plasma level and therefore the effectiveness of the substrate drug.

A

CYP inducers

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44
Q

What CYP gets most affected from CYP inducers

A

3A, it metabolizes 50% of drugs

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45
Q

List of CYP inducers

A
  • benzopyrenes from cigs
  • ethanol (chronic)
  • carbamazepine
  • rifampin
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46
Q

What is this an example of: in a patient taking oral contraceptives who is later Rxed rifampin for a bacterial infection, she becomes pregnant

A

CYP inducers

Increased enzymes, decreased plasma cxn of BC

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47
Q

Drugs which decrease the expression of p450 enzymes, causing an increase in the plasma level and therefore increase the toxicity risk of the substrate drug

A

CYP inhibitors

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48
Q

List of CYP inhibitors

A
  • cimetidine (ulcer meds)
  • erythromycin
  • Grapefruit juice (NOT GRAPE JUICE)
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49
Q

What is this an example of: in a patient taking warfarin as an anticoagulant who is later Rxed cimetidine for peptic ulcers, he bruises and bleeds easily

A 
CYP inhibitor (cimetidine)
-increased plasma warfarin which increase risk of bleeding
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50
Q

Phase II metabolism reactions

A
  1. Glucuronidation
  2. Sulfate on
  3. Acetlyation
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51
Q

Enzyme associated with glucuronidation

A

Glucuronosyl transferase

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52
Q

Enzyme associated with sulfation

A

Sulfotransferase

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53
Q

Enzyme associated with acetylation

A

Acetyltransferase

54
Q

What is something to take into consideration when talking about acetylation in phase II metabolism reactions

A

Some people are slow or fast acetylators (genetic variation)

  • if fast, you rapidly metabolize drugs by acetyltransferase
  • slow=drug induced lupus
55
Q

Slow acetlators

A

Longer half life, can get lupus if you take certain drugs

56
Q

Difference between drug elimination and drug excretion

A

A drug may be eliminated by metabolism long before the modified molecules are excreted from the body

57
Q

What are the two ways drugs are terminated

A

Metabolism
Renal excretion

(Liver and kidneys!)

58
Q

What are the three steps to renal excretion of drugs

A
  1. Glomerular filtration
  2. Proximal tubular secretion
  3. Distal tubular reabsoprtion
59
Q

Glomerular filtration of drugs

A
  • Only free, unbound drug is filtered

- lipid solubility and pH DO NOT influence passage of drugs into the glomerular filtrate

60
Q

Do lipid solubility and pH influence passage of drugs into the glomerular filtrate?

A

No

61
Q

Proximal tubular secretion in renal exretion of drugs

A

Secretion occurs by active transport

  • OAT
  • OBT

Competition between drugs for certain carriers can occur

62
Q

This part of renal excretion of drugs requires ATP

A

Proximal tubular secretion

63
Q

What are the two energy require transport systems of proximal tubular secretion

A

OAT and OBT

64
Q

Where can there be competition between drugs for carriers within each transport system (OAT and OBT)

A

Proximal tubular secretion

65
Q

What part of the renal excretion of drugs is incomplete in premature infants and neonate

A

Proximal tubular secretion

-may retain certain drugs

66
Q

Distal tubular reabsorption in the renal excretion of drugs

A
  • distal convoluted tubule
  • if uncharged, the drug may diffuse out of the tubular and back into the systemic circulation
  • manipulating the pH of urine increases elimination of drugs
67
Q

What is the exception for charged/uncharged ions and getting across membranes

A

In the glomerulus.

  • it is a poor charge filter but a good size filter
  • lets charged and uncharged in
68
Q

Transporters for weak acids and bases

A

OAT and OBT

69
Q

What part of renal excretion of drugs is affected by manipulating the pH of urine

A

Distal tubular reabsorption (distal convoluted tubules)

70
Q

What is the only type of drug that can get filtered into the glomerulus

A

Free drugs

71
Q

What does adding a weak acid to eliminate the overdose of a weka base have to do with

A

Reabsoprtion

72
Q

Other modes of excretion other than renal

A
  • GI
  • pulmonary
  • milk
73
Q

Relates the rate of elimination to the plasma concentration

A

Clearance

74
Q

high clearance, ____plasma cxn

A

Low

75
Q

Low clearance, _____plasma concentration

A

High

76
Q

Clearance equations

A

CL=(rate of elimination of drug)/(plasma drug concentration [Cp])

Rate of elimination=Cl x Cp

77
Q

What are the two types of elimination kinetics

A

First order

Zero order

78
Q

First order kinetics

A
  • constant fraction of drug eliminated
  • half life is constant
  • non-saturating kinetics (enzymes working at less than Vmax)
79
Q

What kind of kinetics are most drugs

A

Most are eliminated by 1st order kinetics, all drugs are this except PEA, even overdoses

80
Q

Zero order kinetics

A
  • constant amount of drug eliminated
  • half life not constant
  • saturating kinetics (enzymes are at Vmax)
  • HIGH DOSES of aspirin, ethanol, phenytoin (ZERO PEAs)
81
Q

This is the type of elmination seen in very high doses of phenytoin, ethanol, and aspirin

A

Zero order kinetics

82
Q

If the Vd increases, what happens to the half life

A

Increases

83
Q

If the clearance increases, what happens to half life

A

Decreases

84
Q

Time it takes to cut level of drug in half

A

Half life

85
Q

Maintenance dose

A

Drug you are taking every day

Chronic

86
Q

Loading dose

A

Don’t do it often

Acute

87
Q

Proper dosing regimen

A

Achievement of therapeutic window in blood without exceeding minimum toxic concentration of falling below the MEC

88
Q

When do you not need to check a patients plasma levels when they are taking a drug

A

If easily measured, such as in reading blood pressure. You can take their blood pressure and see if it is working as opposed to checking their plasma levels

89
Q

When do you need to check a patients plasma levels when they are taking a drug

A

When you cannot measure the effectiveness by any other means.

  • drugs for prophylaxis
  • must be titrated carefully
  1. Pick desired dose (steady state) plasma level for drug
  2. Compute dose to achieve value
  3. Measure plasma level of drug
  4. Adjust as necessary
90
Q

Maintenance dose

A

MD=Css x CL/F

Css=cxn at stead state (what we want to achieve)
F=bioavailability (F=1 for IV)
CL=clearance

91
Q

What is the maintenance dose for someone with a steady state of 10mg/L, clearance of 1mL/min, and bioavailability of 1 (IV)

A

(10mg/L x 1 mL/min)/1

10mg/min=maintenance dose

92
Q

A patient with an asthma attack was relieved with 40mg/h of theophylline but the clinical wants to maintain the plasma concentration of theophylline at 15mg/L by oral dosing. What would be the calculated oral doses be at 6, 6, and 12 hour intervals?

A

6 hour intervals= 40mg/h x 6hr=240mg

8 hour intervals=40mg/hr x 6hr=320mg

12 hr intervals=40mg/hr x 12h= 480mg

We chose one of these based on the therapeutic window

93
Q

One or series of doses that may be given at the onset of therapy with the aim of achieving the target concentration rapidly

A

Loading dose

94
Q

Equation for loading dosage

A

Loading dose Css x Vd/F

95
Q

If the problem says “Single IV bolts” what kind of dosing is it

A

Loading dose

96
Q

Dose that achieves cxn above MEC immediately, used in life threatening situations

A

Loading dose

97
Q

What is the main difference between maintenance dose and loading dose

A

Maintenance factors in CL, loading dose doesn’t care about that. Loading dose cares about Vd, getting drug to target tissue

98
Q

If the clinician is giving a loading dose to the asthma patient above (15mg/L), how would you calculate the dose given that the volume of distribution of theophylline is 0.5L/kg.

A

15mg/L X (0.5L/kg X 68Kg)

510mg

99
Q

When would you want to give a loading dose

A

-time required too reach steady state is long, such as in ventricular arrhythmias

100
Q

What is the goal of maintenance dose

A

Steady state is the goal

101
Q

Steady state in maintenance dose

A

Curve will plateau, plateau principle. Want to stay at plateau

102
Q

To ensure the appropriate response to a drug given for long term therapy, it is necessary to achieve a ________ of the drug in the plasma

A

Steady state

103
Q

Equation for maintenance dose

A

MD=Css x CL/F

104
Q

The time it takes for reach steady state for a drug is eliminated by _______ kinetics

A

First order

The half life remains constant

105
Q

Half life and steady state

A

Remains constant.

Tells us how long to reach steady state

106
Q

What kind of kinetics must be used for steady state

A

First order kinetics

107
Q

For the graph of steady state (maintenance) and for elimination

A

They are the same, just inverted

  • plasma cxn of drug on the Y axis
  • time on the X axis
108
Q

When looking at a graph with plasma concentration (steady state) on the Y and time on the X, and there is a plateau, what kind of dose is it

A

Maintenance dose

109
Q

Do we care more about clinical steady state or mathematical

A

Clinical

110
Q

Does clinical steady state = mathematical steady state?

A

No

111
Q

It is generally accepted that drugs will reach “clinical” steady state in _______ half lives

A

4-5 half lives

112
Q

Mathematical steady state is approximately ______ half lives

A

10

113
Q

In clinical steady state, do we ever reach 100%

A

No, clinically, 93% and up is considered close enough

114
Q

How do you find the clinical steady state of a drug with a given half life?

A

Since clinical steady state is 4-5 half lives, just multiple the half life times 4 or 5. So a drug with a 2 hour half life would have a steady state of 8-10 hours

115
Q

Theophylline is infused at a rate of 20mg per hour and steady state plasma levels of 7.5 micrograms are reached in 32 hours. If the infusion rate is doubled, how long will it take to reach steady state?

A

32 hours

-depends on half life, infusion rate does not matter, and doesn’t depend on amount of drug

116
Q

What is the steady state level of theophylline at the infusion rate of 40mg/hour? Previously, it was infused at a rate of 20mg per hour at a plasma steady state of 7.5 micrograms/ml

A

20= 7.5xCL/F

40=X x CL/F

If CL and F are constant, then it would have had to have doubled

X=15ug/ml

117
Q

If you have a drug with two different steady states, do they reach the steady state at the same time?

A

Yes, infusion rate doesn’t matter for this, amounts are different but time is the same

118
Q

A single IV injection of 100mg of a drug is given and it takes 8 hours to eliminate 1/2 the drug from the body. How long would it take to eliminate 1/2 the drug if only 50mg were given in a single injection

A

8 hours

  • same drugs, same half life
  • 1/2 life unaffected by amount of drug
119
Q

Half life and amount of drug

A

Half life is unaffected by the amount of drug given either by constant infusion, single injection,or orally, as long as the drug is eliminated by first order kinetics

120
Q

Which of the following dosage regimens would be appropriate for a drug with a half life of 12 hours; a continuous infusion of two units of drug per day, injection of two units of drug once a day, or injection of one unit of drug twice a day?

A

Not enough info

  • need MEC
  • need MTC
  • having these gives us the therapeutic window which is where the steady state needs to stay
  • once a day dosing good with wide window
  • narrow window will work best with 1 unit of drug twice a day, because it doesn’t oscillate as much
121
Q

Where do we want the peaks and troughs of a drugs steady state to stay

A

Within the therapeutic window

122
Q

When it asks for drug concentration after 5 half lives after the dose given

A

Count the peaks over 5

123
Q

When it asks for the drug concentration of a drug before the dose and its asking after a certain number of half lives

A

Count troughs

What is the plasma level before the 3rd dose. Count over 3, including the 0 as your first one

124
Q

The ___________ will usually determine the desired trough levels of a drug given intermittently

A

MEC

125
Q

The _______ determined the permissible peak of a drug given intermittently

A

MTC

126
Q

Drugs you take once a day have a ______ therapeutic window

A

Wide

127
Q

Drugs you take many times a day have a ______ therapeutic window

A

Narrow

128
Q

What is the normal creatinine clearance

A

100mL/min

129
Q

What is the dosage adjustment calculation for patients with renal failure

A

Corrected dose = average dose x (pts creatnine clearance/100mL/min)

130
Q

A dose of 100mg Celebrex is ordered for RA treatment. The patient is found to have a createnine clearance of 50mL/min. What does of Celebrex should be administered to this patient

A

Corrected dose=100mg x (50mL/min/100mL/min)

50mg

If kidney function is half, going to give them half the dose

131
Q

Non renal routes of clearance

A

For example, if a drug is cleared 50% by the kidney, and 50% by the liver, you would have to calculate the dosing according to that

132
Q

What 4 equations WILL be on the test

A

Vd= (amount in body)/(plasma cxn)

Maintenance dose=Css x CL/F

Loading dose= Css x Vd/F

Renal dysfunction= dose x (pts renal/100)

1/2 life = .693 x Vd/Cl (only know relationship)

Pharm Block 9 (7 decks)

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