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Intro to Pharmacology > Metabolism and Excretion > Flashcards

Metabolism and Excretion Flashcards

1
Q

Metabolism and excretion together are called?

A

drug elimination

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2
Q

What is biotransformation?

A

metabolism or degradation of a drug from an active form to its inactive form

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3
Q

What is clearance (Cl)?

A

removal of the drug from the body?

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4
Q

What is the first pass effect?

A

oral drug passes through the liver for degradation before distribution into tissues

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5
Q

What is Half-life (t½)?

A

time required for total drug concentration in the body to be reduced by 50%

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6
Q

What is a prodrug?

A

precursor to an active drug

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7
Q

What is pKa?

A

describes how acidic (or not) a given hydrogen atom in a compound is

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8
Q

What is metabolism?

2

A

Change drug into water-soluble form

Promotes excretion

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9
Q

What is excretion?

A

removal of drug from the body

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10
Q

What organs are involved in metabolism?
4
(whats the main one?)

A

Liver
Kidneys
Intestines
Enzymes in blood (e.g., esterases)

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11
Q

What are the funciton of these organs involved in metabolism?
2

A
  1. Detoxify drugs and other foreign substances
    - Active to less active/inactive forms (i.e. metabolites)
  2. Activation of prodrugs
    - Inactive precursor or “parent drug” to active metabolite or “active drug”
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12
Q

What is the primary means of metabolism and where does it occur?

A

enzyme reactions and they occur in the liver

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13
Q

Describe phase I of metabolism?

A

Drugs become more polar and water-soluble. This makes them more prone to renal elimination

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14
Q

What kind of reactions are phase I reactions?

A

Oxidation, hydrolysis, reduction

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15
Q

Describe phase II of metabolism

A

Drugs are conjugated and are usually inactivated or become more water-soluble. This makes them more prone to renal elimination

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16
Q

What kind of reactions are phase II reactions?

A

Formation of glucuronides, acetates, sulfates

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17
Q

What are active metabolites?

Ex?

A

Possess ability to exert effects on body
codeine to morphine
Active forms: Clarinex and prednisolone

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18
Q

What are inactive metabolites?

Ex?

A

No appreciable function

Plavix to carboxylic acid metabolite

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19
Q

What are toxic metabolites?

Two ex?

A

Lead to cell damage or other adverse effects
Demerol can cause a build up of its metabolite normeperidine
which can lead to seizures
Acetaminophen can cause a build up of NAPQI

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20
Q

What enzymes are involved in phase I metabolism?

A

CYP enzymes

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21
Q

What can CYP enzymes do?

A

They can either induce or inhibited by other drugs or substances

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22
Q

What detemines the amount of CYP enzymes you have?

2

A
  1. geneotype variations

2. disease-induced changes can affect CYP enzymes availability

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23
Q

What is induction?

And what does it result in?

A

Drug or substance increases enzyme expression (e.g., caffeine)
Results in faster metabolism

Activates the enzymes itself

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24
Q

What is activation?

And what does it result in?

A

Drug or substance binds to enzyme to increase the activity of the enzyme
Results in faster metabolism

Works on the activated enzyme

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25
Q

What is inhibition? 2

What does this result in?

A
  1. Drug or substance with greater affinity for the enzyme competes with a drug or substance with less affinity

OR

  1. Enzyme expression is reduced (enzymes are not activated e.g., cirrhosis)

Results in slower metabolism

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26
Q

What do plasma esterases do?

3

A
  1. Catalyze the hydrolysis of ester groups
  2. Usually leave drugs inactive
  3. Can activate some prodrugs
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27
Q

How to plasma esterases relate to organ function?

A

They are ubiquitous, independent of organ function

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28
Q

What organs are involved in drug excretion? 5

And what is the main organ?

A 
Kidneys – primary 
Lower gastrointestinal (GI) tract
Lungs
Skin
Glands (sweat, mammary, and salivary)
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29
Q

What is the forcible removal of drugs called?

A

Dialysis

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30
Q

What the most important organ for elimination?

A

kidneys

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31
Q

What are the three things drugs entering the nephron might end up doing?

A
  1. Exert an action (such as diuretics)
  2. Be reabsorbed into the bloodstream
  3. Progress to the collecting duct and be excreted from there
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32
Q

What are the three processes by which a drug can be excreted?

A

Glomerular filtration
Active tubular secretion
Passive tubular reabsorption

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33
Q

What is glomerular filtration and what kind of compounds is it best for?

A

Unbound drug is filtered into tubule

Best for hydrophilic, ionized compounds

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34
Q

Describe active tubular secretion

2

A

Transporters move conjugated metabolites into the tubule

Separate systems for organic acids and bases

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35
Q

Describe passive tubular secretion

A

Some non-ionic drug passively diffuses out of the tubule

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36
Q

Weak acids are excreted faster in what form of urine?

A

alkalized. Because weak acids cannot be reabsorbed in a basic environemt?

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37
Q

Weak bases are excreted faster in what form of urine?

A

acidic. Because weak bases cannot be reabsorbed in an acidic environment

38
Q

Where are weak acids better absorbed?

A

In the stomach where its more acidic/pH is low

39
Q

Where are weak bases better absorbed?

A

In the intestine where its more basic/pH is high

40
Q

The pKa is what in terms of pH?

A

the pH at which concentration of ionized and non-ionised forms is equal.

41
Q

If an acid is in an alkaline environment what will happen in terms of protons?

A

There are few protons in an alkaline environment so it will donate them

42
Q

What will a weak acid dissocaite into?

A

a negatively charged ion (anion)

and a proton (that is donated)

43
Q

So in an alkaline environment weak bases will be what?

2

A

ionized and water soluable!

-not absorbed (need to be neutral and lipid soluble)

44
Q

If an acid is in a acidic environment what will happen in terms of protons?

A

There are many protons so the weak acid will not dissociate, and keep its proton.
This means it will be non-ionized and lipid soluble and will absorb.

45
Q

If a base is in an acidic environment what will happen in terms of protons?

A

The acidic environment is proton rich so the base will accept protons.

46
Q

So in an acidic environment weak bases will be what?

2

A

Ionized and water soluble

-not absorbed (need to be neutral and lipis soluble)

47
Q

If a base is in an alkaline environment what will happen in terms of protons?

A

There are few protons in an alkaline environment so the base will not accept any protons, will not become ionized, and stay lipid soluble so it can be absorbed.

48
Q

if you are trying to prevent reabsorption, how do we want our urine?

A

MAKE THE URINE pH OPPOSITE to the drugs acidity.

49
Q

A base with a high pKa will clear faster or slower into acidic urine than a base with a low pKa?
why?

A

Faster

Gradient is higher to excrete it

50
Q

How are biles excreted?

4

A

From the liver
To the gallbladder
and then empties into the intestines which forms feces and its excreted in that form
Liver>Gall bladder>intestines>feces

51
Q

Other excretion routes you should know?

4

A

Sweat, tears, saliva
Hair, skin
Breast milk
Expiration

52
Q

Factors affecting metabolism and clearance?

6

A 
1. Genetic variance
Presence/absence of enzymes
2. Induction/inhibition of enzymes
3. Competing/complementary pathways
4. Disease factors
5. Age and gender
6. Pregnancy
53
Q

What is a half life?

A

Time required for serum concentration to decrease by ½ after absorption and distribution

One half life=100% to 50%
Two half lives= 50% to 25%

54
Q

What does half life determine?

A

Determines time to reach steady-state

55
Q

How many half lives does it usually take to reach steady state?

A

4-5 elimination half lives

56
Q

What is steady-state?

A

equilibrium between amount of drug entering body and amount of drug leaving the body

57
Q

What is the half life dependent on?

3

A

Volume of distribution
Clearance
Amount of drug

58
Q

Drug X works best with a maximum steady-state concentration of 20 mg/L and a minimum steady-state concentration of 10 mg/L. What would be an ideal dosage interval?

  1. One elimination half-life
  2. One hour
  3. One day
  4. 4-5 elimination half-lives
A
  1. one elimination half life
59
Q

What is the removal of the drug from the body and the final element of the elimination process?

A

clearance

60
Q

What are the three ways drugs can be cleared by?

A

biliary means
renal means
hepatic means

61
Q

What is clearance directly dependant on?

and inversely related to?

A

directly to apparent volume of distribution and inversely related to the elimination half-life

62
Q

Equation for drug clearance?

How is it measured?

A

Clearance (Cl) = 0.693 x Vd/
t½
Measured as volume over time (L/hr)

63
Q

What is creatinine?

A

Byproduct of continual muscle breakdown

64
Q

What is creatinine eliminated by?

A

glomerular filtraiton

65
Q

Is it secreted or reabsorbed in the kidney?

A

no

66
Q

What is creatinine a good indicator of?

2

A

Good surrogate marker for estimating

1. glomerular filtration rate (GFR) 2. renal clearance

67
Q

How is creatinine usually measured and what are the normal lab values?

A

Usually measured through a blood test looking at serum creatinine
Normal value: 0.8 – 1.2 mg/dL

68
Q

What is the cockcroft-gault equation?

A

Creatinine clearance equation

CrCl = [(140-age)X(IBW)] / (SrCrX72) then times all that by 0.85

69
Q

Whats the rule of thumb for creatinine testing?

A

patients 65 or older

patients with a creatinine level of more than 1.5mg/dL

70
Q

What would we do if the creatinine levels was abnormal in the blood test?

A

24 hour urine study

71
Q

What is a loading dose?

A

Large amount given to reach desired serum drug concentrations quickly

72
Q

What is the loading dose based on?

WHAT IS IT NOT BASED ON?

A

Based on volume of distribution (Vd)

Independent of half-life (t½)

73
Q

Why are maintenance doses given?

And what are they based on?

A

Given to replace the amount of drug being eliminated

Based on half-lives

74
Q

What does a steady state graph look like?

A

Goes up fairly quickly at first but will eventually level off

75
Q

What are the two types of pharmacokinetics?

A

linear and non-linear

76
Q

Describe linear pharmacokinetics?

A

1st order pharmacokinetics

These are dose-independent kinetics (non-saturable)

77
Q

Describe non-linear pharmacokinetics.

What are the types?

A

Zero Order Pharmacokinetics
Michaelis-Mentin Kinetics
Non-linear protein binding

Dose-Dependent
Kinetics(saturable)

78
Q

In 1st order pharmacokinetics

if the dose is doubled what happens to the serum drug concentration?

A

it is also doubled

They are proportional

79
Q

In 1st order pharmacokinetics, elimination rate is dependent on drug concentration. What does this result in?
2

A
  1. Constant proportion is eliminated from body
  2. Body is able to keep up with dose increases & prevent accumulation in normal course of therapy

THESE ARE MOST DRUGS IN CLINICAL PRACTICE

80
Q

Describe continuous infusions/dosing with linear pharmacokinetics?

A

Serum concentrations increase until drug infusion rate equals drug elimination rate
Example: Drug X infusing IV at 10 mg/hr would eliminate at 10 mg/hr once the equilibrium or steady-state concentration was achieved

81
Q

Describe intermittent dosing with linear pharmacokinetics?

A

Steady-state occurs when previous dose curve matches next curve

82
Q

How are drugs eliminated in nonlinear zero order pharmacokinetics?

A

eliminated at a constant X mg/hr (amount)

83
Q

In zero order kinetics how is elimination dependant on drug concentration?

A

its not. its independant of it

84
Q

What is the risk with a zero order kinetic drug?

2

A

Can lead to accumulation

Mechanism responsible for metabolism/ excretion is saturated so the drug accumulates in the serum (blood)

85
Q

Example of zero order kinetic drug?

A

ethanol

86
Q

Describe Michaelis-Menten Kinetics?

4

A

Below a given serum concentration, elimination follows 1st order kinetics

Above the given serum concentration, elimination follows zero order kinetics

Steady-state concentrations increase greater than expected with dose increases

Also called saturable metabolism or capacity-limited metabolism

87
Q

Example of Michaelis-Menten Kinetics?

A

phenytoin (dilantin)

88
Q

Describe Nonlinear Protein Binding?

5

A
  1. Binding of drugs to plasma proteins is capacity-limited
    - Plasma proteins become saturated
  2. Steady-state concentrations increase less than expected with dose increases
  3. Unbound drug concentration increases linearly with dose increases
  4. Total drug concentration increases less than proportionally to dose increases
  5. More unbound/free drug results in greater rate of elimination
89
Q

Where does nonlinear protein binding occur more often?

A

Proteins with fewer binding sites

- like α1 acid glycoprotein (Norpace)

90
Q

Why do you monitor drug levels?

2

A
  1. Correlate drug levels with response/efficacy

2. Prevent toxicity

91
Q

What kind of drugs are we wantinng to monitor more closely?

A

drugs with a narrow therapeutic index

92
Q

What is the difference in a normal therapeutic dosing graph compard to one with a loading dose?

A

Shoots immediately up to therapeutic range with the loading dose

Intro to Pharmacology (6 decks)

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