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E'Pharmacology Test 1 Fall '24 > 09/04 Class 4 > Flashcards

09/04 Class 4 Flashcards

1
Q

Elimination is dependent on

A

which organ is eliminating the drug

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2
Q

Portal Hypertension will affect Extraction ratio and ROE because

A

decrease in blood flow to liver

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3
Q

The organ that is eliminating a drug is dependent on

A
  1. Whether or not the drug is a high-extraction drug
  2. what the blood flow is through that organ
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4
Q

If the blood flow through an elimination organ is normal, we call it

A

high

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5
Q

If the blood flow through an elimination organ is limited, we call it

A

low

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6
Q

Oral morphine doesn’t provide the full effect because

A

After the GI tract morphine goes into the liver and the liver removes a lot of it. It is a high extraction drug

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7
Q

What is the range for a high extraction drug?

A

> 0.7

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8
Q

What is the range for an intermediate extraction drug?

A

0.3-0.7

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9
Q

What is the range for a low extraction drug?

A

<0.3

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10
Q

What is Q in the extraction ratio?

A

The blood flow through an elimination organ.

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11
Q

What is the CLorgan formula?

A

Q x (Cin -Cout/Cin). Drug going in minus drug going out all over Cin

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12
Q

QE (extraction ratio) is

A

in minus out all over in

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13
Q

What is E in the extraction ratio?

A

the percentage of drug that comes out of an elimination organ

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14
Q

If you have a high E and a low Q, what is your CLorgan

A

Low

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15
Q

If you have a low E and a high Q, what is your CLorgan

A

Low

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16
Q

If you have a high E and a high Q, what is your CLorgan

A

high

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17
Q

If you have a low E and a low Q, what is your CLorgan

A

low

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18
Q

Why is the half life important?

A

It helps us determine how we should dose a patient and how much we should dose them

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19
Q

With half life

A

We are essentially giving how much the body is eliminating

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20
Q

Define half life

A

the time it takes the body to get rid of half of the concentration of a drug in the blood

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21
Q

What is the half life formula?

A

T1/2= 0.7 X Vd / CL

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22
Q

What is giving a drug in “steady state” mean?

A

Giving the drug at the same rate that the body is eliminating it.

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23
Q

What do we do to reach target concentration quickly?

A

Give a bolus of a drug

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24
Q

For a drug that has a 4 hour half life, how many half lives would it take for the drug given at steady state to reach target concentration in the blood?

A

16 hours

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25
Q

For a drug that has a 4 hour half life, how many half lives would it take for the drug to be completely eliminated from the blood after the infusion is stopped?

A

16 hours

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26
Q

What effects half life?

A

Many things, including disease state

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27
Q

A true half life will be _____ than the calculated half life

A

greater (drugs have multi compartment pharmacokinetics)

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28
Q

If you don’t wait 4 half lives before taking another dose of the drug, what will happen?

A

The drug will accumulate in the plasma and can become toxic very quickly

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29
Q

How is bioavailability denoted?

A

F

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30
Q

What does bioavailability tell us?

A

How much of the drug reaches systemic circulation (when dosed at steady state)

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31
Q

What is the bioavailability of an IV drug?

A

100%

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32
Q

What factors effect bioavailability?

A
  • Physical properties of the drug (hydrophylicity, PKA, solubility)
  • Route
  • GI- diet, gastric emptying, transporters, health
  • interactions with other drugs
  • disease state
  • circadian rhythm
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33
Q

What is first pass elimination?

A

The first system that the drug goes through that changes the concentration of the drug. (dose not same as concentration)

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34
Q

How many portal systems in body? How made?

A

Pituitary and Hepatic… capillaries from vein and back to capillaries.

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35
Q

T/F High absorption in the gut means high bioavailability in blood? why?

A

False. Can absorb a lot in gut, but liver can eliminate a lot before it reached blood.

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36
Q

What are routes that bypass first pass elimination?

A
  • IV
  • IM
  • SC
  • Inhalation
    *has it’s own first past effect
  • sublingual (blood vessels under tongue - bypasses liver)
  • transdermal (lipid soluble drugs
  • rectal
    *suppositories might move upward, therefore only 50% bypass hepatic circulation (colon goes in to blood)
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37
Q

What is target concentration based on?

A

What we are trying to accomplish in the patient (pain relief, controlling afib)

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38
Q

Target concentration determined by who?

A

Maufacturer (Phase I and Phase II studies)

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39
Q

Maintain steady state by giving _____________

A

just enough to replace drug being eliminated.

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40
Q

What is the most important factor of the dosing rate. DOSING RATEss (steady state)

A

Clearance

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41
Q

Dosing Rate ss = ROE T/F

A

T

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42
Q

How do you solve for dosing RATEss

A

CL X Target concentration. (DRss = ROE) and ROE = CL x TC

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43
Q

For bioavailability that is less than 100%, how is the formula changed?

A

DRoral =DRss/Foral (Foral will be in decimals- 50% will be 0.5)

The CL X Target concentration is divided by the bioavailability.

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44
Q

If your bioavailability is less, your are going to have to give _____ of the drug

A

more

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45
Q

What is an intermittent dose for oral drugs?

A

Giving a pill every few hours instead of constantly.

DRoral X dosing interval (in hours)

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46
Q

If you are given the target concentration, the clearance, and the time interval how do you solve for the intermittent dose?

A
  1. DRss=CL X Target Concentration
  2. DRoral=dosing cate (calc.)/Foral X dosing interval (in hours)
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47
Q

Describe what is happening in this graph.

A

The black line is the drug being given in steady state. It is showing that after 4 half lives, the drug reaches 10mg/L and the patient is receiving the targeted effect of the drug.
The red line shows the drug being given every 8 hours. The patient has peaks and troughs that’s staying right around the target concentration.
The blue line is the drug being given every 24 hours. You can see that at the peaks the patient is receiving a much higher effect than the target concentration, but the troughs are also much lower. In the case of this siezure drug, you can see how the troughs would leave this patient open to having seizures.

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48
Q

How to calculate the loading dose?

A

LD=Vd X TC. (given over 5 mins to give it time to distribute)

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49
Q

Why is rate of administrations critical for potentially toxic drugs?

A

Giving a bolus too fast doesn’t allow time for the drug to distribute into compartments and therefore reaches toxic levels in the plasma very quickly

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50
Q

How do we monitor for therapeutic dosing?

A

Peak and trough tests

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51
Q

When is the peak test taken?

A

5-10 minutes after drug administration

52
Q

When is the trough test taken?

A

30 minutes before the next dose

53
Q

What do the peak and trough tests tell us?

A

Assessment of individual response to standard population pharmacokinetic variables.
To be able to dose the drug to each individual patient based on their disease state, other drugs they’re on etc.

54
Q

If you have a drug that preferentially stays in the fat, which weight do you use?

A

their actual weight

55
Q

If you have a drug that preferentially stays in the blood stream (not in fat), which weight do you use?

A

Their Ideal body weight

56
Q

IBW calculations

A

Men: 52 + (1.9kg x height (in) - 60 inches)
Women: 49 + (1.7kg x Height - 60 inches)

57
Q

What test tells us how well the kidneys are functioning, and how does it work?

A

The creatinine clearance.
The muscles release a steady rate of creatine in the blood as waste which gets down to the kidneys for excretion. If creatinine starts to build up in the body then it is safe to assume that the kidneys are not functioning properly.

58
Q

What is biotransformation?

A

The changing of a drug to either make it work better, or in most cases to decrease or stop the drug from working altogether.

59
Q

Where does most, but not all, biotransformation happen?

A

The liver
Other organs not at same level as liver (lungs, skin , GI, cellular level, etc)

60
Q

What is in the hepatic portal system?

A
  1. oral
  2. gi
  3. local veins
  4. hepatic portal vein
  5. sinusoids very leaky capillaries (drugs cross, interact with hepatocytes, be bio-transformed)
  6. hepatocytes
  7. hepatic vein
  8. vena cava
  9. systemic circulation
61
Q

Where is a drug biotransformed?

A

Hepatocytes

62
Q

What are the 2 different places that biotransformed drugs can go after the hepatocytes?

A

Back into the blood stream to be delivered to the body
Into the Bile duct to be eliminated through bile

63
Q

What is the circulation for a drug given in a central line?

Not first pass. (1st pass if b4 it gets to systemic circulation)

A
  1. Vena cava
  2. systemic circulation
  3. hepatic artery
  4. sinusoids
  5. hepatic vein
  6. vena cava
  7. systemic circulation
64
Q

Why are the sinusoids an area with fairly low oxygen concentration?

A

Because blood from the hepatic portal vein and the hepatic artery both mix here (not as low as Vena Cava)

65
Q

What are the sinusoids in the liver very susceptible to?

A

Heart failure (kills them)

66
Q

Do sinusoids regenerate quickly?

A

yes

67
Q

What are phase 1 reactions?

A

When we take an enzyme and either add or unmask a functional group (-OH, -NH, -SH (sulhydro group) etc.) very small substances.

68
Q

What are phase 2 reactions?

A

We’re tacking on larger molecules

69
Q

In some way, phase 1 and phase 2 help with the ______ of a drug.

A

elimination

70
Q

Is there a specific order phase 1 and phase 2 has to happen?

A

No, and they don’t have to go through both reactions.

71
Q

Phase 1 turns the drug into a more _______ metabolite. Making it harder to cross into the cell and therefore easier to eliminate.

A

polar

72
Q

Phase 2 reactions are ________ reactions.

A

conjugate
meaning to combine 2 things

73
Q

Phase 1 reactions involve ___________,____________,___________

A

oxidation, reduction, hydrolysis

74
Q

After phase 1 most drugs are

A

inactivated

75
Q

Phase 2 results in drugs with a ________

A

higher molecular weight, essentially detoxifying the drug by making it harder to cross into the cell.

76
Q

What are the 4 main groups of phase 1?

A

Oxidation
reduction
dehydrogenation
hydrolysis

77
Q

What is oxidation?

A

Loss of an electron ( some other molecule in liver is reduced)

78
Q

What is reduction?

A

Gaining of an electron

79
Q

What is dehydrogenation?

A

removing an OH group

80
Q

What is hydrolysis?

A

breaking down of water in a reaction and that breaks a bond

81
Q

Why are we focusing on oxidation reactions?

A

Because that is how vast majority of drugs are modified in phase 1 reactions.

82
Q

What is used in the primary oxidation pathway?

A

an enzyme called Cytochrome P450. It’s a molecule

83
Q

P450 cycle

A
  1. drug comes in lipophilic
  2. binds to CYP450
  3. loss of electron
    * Flavoprotein oxidizes and becomes oxidized
    * then goes through the compound NADPH
    * NADPH is reduced turning into NADP+
    * NADPH is recycled somewhere in the liver
    * Now Favoprotein is recycled and is in it’s reduced form
  4. P450 molecule is a holder for the drug
  5. 2 Oxygen molecules and electrons are added to the drug
  6. Oxygen detaches from the drug and attaches to 2 Hydrogen turning into water
  7. The other oxygen stays on the drug and becomes a hydroxyl group
  8. Drug is then more hydrophilic & is released into either the circulation to be excreted by the kidneys or the bile to be excreted through the intestines
84
Q

What takes electrons from P450?

A

Flavoprotein

85
Q

What is the most common flavoprotein?

A

Flavin mononucleotide
FMN

86
Q

By oxidizing P450, Flavoproteins become

A

oxidized themselves

87
Q

CYP3A4 synthesize what percent of oxidation reduction reactions?

A

50%

88
Q

CYP2D6 synthesize what percent of oxidation reduction reactions?

A

20%

89
Q

CYP2B6 synthesize what percent of oxidation reduction reactions?

A

8%

90
Q

What does CYP short for? ; Whats the substrate specificity?

A

Cytochrome P450 ; Low (it combines with a lot of drugs)

91
Q

What is the most important CYP450?

A

CYP3A4 (metabolize 50% of drugs that go through Phase I)

92
Q

Where does the oxidation reaction happen inside of the hepatocyte?

A

Sarcoplasmic reticulum

93
Q

CYP3A4*1 means

A

this is a wild type (most common in population)

94
Q

what does the wild type mean?

A

it is the variant that is most commonly seen in the population.

95
Q

CYP3A4*2

A

is a mutant of the CYP3A41 and may be slower than CYP3A41

96
Q

What is a polymorphic variant?

A

A deviation from the wild type that may have a greater, lesser, or same effect as the wild type.

97
Q

What produces variants?

A

Genetic mutations

98
Q

What is a P450 induction?

A

a drug that increases the number of CYP450 enzymes which increases the CYP3A4 enzyme which effects the drug

99
Q

What is a P450 Inhibition?

A

A drug that decreases the number of CYP450 enzymes which decreases the CYP3A4 enzyme which effects the drug

100
Q

If a drug is inactivated by CYP3A4, and we take an inducer, what will happen?

A

The drug will become inactivated at a much faster rate.

Less drug effect

101
Q

What is a prodrug?

A

A drug that HAS to be activated by CYP3A4

102
Q

Phase II reactions

A

Attach something bigger to molecule (making it larger and hydrophillic) – harder to cross barriers and easily excreted.

103
Q

If a drug is activated by CYP3A4, and we take an inducer, what will happen?

A

The drug will be become active much more quickly and may reach toxic effects quickly.

more drug effect

104
Q

If a drug is inactivated by CYP3A4, and we take an inhibitor, what will happen?

A

Less of the drug is being inactivated, meaning more of the drug is being released into the body and you may reach toxic effects faster.

more drug effect

105
Q

If a drug is activated by CYP3A4, and we take an inhibitor, what will happen?

A

Less of the drug will become activated, meaning that less of the active drug will be available in the plasma.

Less drug effect

106
Q

What is glucuronidation?

A

attaching a glucose

107
Q

What is the acetylation?

A

attaching an Acetyl group

108
Q

What is Glutathione conjugation?

A

attaching a glutathione molecule

109
Q

What is Glycine conjugation?

A

attaching a Glycine

110
Q

What is sulfation?

A

attaching a sulfur group

111
Q

What is Methylation

A

attaching a Methyl group

112
Q

What is water conjugation?

A

attaching a water

113
Q

What is a UGT?

A

Uridine diphosphate glucuronyltransferases
a type of glucuronidation reaction
They attach a glucuronic acid to molecules
A carrier molecule with the Glucuron transferase (which transfers a glucose molecule from UDP to the drug itself)

114
Q

What do UGT’s attach a glucuronic acid to?

A

Phenols, alcohols, carboxyl, and sufhydryl groups

115
Q

Where are UGT’s primarily found?

A

in the liver

116
Q

What is uridine diphosphate?

A

the carrier molecule

117
Q

What do the glucuronyltranferases do? (UGTs)

A

Transfers a glucose molecule from UDP to the drug itself

118
Q

What is the response of a drug undergoing glucuronidation?

A

It becomes more aqueous soluble, and is excreted via the urine more easily

119
Q

What is a Glutathione-S-transferase? GST

A

attach a glutathione

120
Q

Glutathione characteristics

A

ubiquitous
Critically important in detoxification
Increases water solubility to get rid of toxins

121
Q

Where are glutathiones found?

A

Everywhere. Really high in RBC’s because they can build up high amounts of oxidants in them because they carry oxygen.

122
Q

What is a xenobiotic?

A

something that is foreign in the body

123
Q

What happens to xenobiotics when a glutathione binds to it?

A

It forms a glutathione conjugate which makes it more likely to be excreted in the urine

124
Q

What does overdosing do?

A

It overwhelms the normal detox pathways (regular doses- no toxic byproducts)

125
Q

What are extrahepatic metabolism examples?

A

Brain
Lung
Intestine
Plasma (cholinesterase)
Kidney

126
Q

What are things that change the way we metabolize drugs?

A

diet
environment
age and sex
disease state
genetics

DEAD Genetics

127
Q

Tylenol going through phases (pic)

A

E'Pharmacology Test 1 Fall '24 (5 decks)

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