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PHAC3001 > Lecture 4: Pharmacokinetics Part 2 > Flashcards

Lecture 4: Pharmacokinetics Part 2 Flashcards

1
Q

The greatest contributor overall to variances in pharmacokinetics between individuals is

A

Drug elimination

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2
Q

Drugs are eliminated from the body via two processes:

A

Metabolism and excretion.

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3
Q

The major determinants of drug action in the body is

A

Elimination processes (metabolism and excretion)

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4
Q

Major routes for direct drug excretion

A

Urine, bile

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5
Q

Minor routes for direct drug excretion

A

Saliva, sweat, breast milk, other bodily fluids, exhalation

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6
Q

Most drugs require ______ before they can be efficiently excreted from the body

A

Metabolism/biotransformation

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7
Q

(T/F): Most drugs are lipophobic and only partially ionized at physiological pH

A

False. Most drugs are lipoPHILIC and only partially ionized at physiological pH

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8
Q

Why are most drugs lipophilic organic compounds and only partially ionized at physiological pH?

A

Because we design drugs that are optimized for oral absorption. These properties allow the drug to be absorbed efficiently.

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9
Q

Why are lipophilic drugs poorly excreted by the kidney and liver?

A
  • Binding to plasma proteins makes them unavailable for glomerular filtration in the kidneys
  • Reabsorption at renal tubules and biliary epithelium (not excreted)
  • They partition into lipid-rich tissues (e.g. adipose)
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10
Q

The purpose of metabolism in relation to drug excretion is to:

A

Increase polarity, ionization, and water solubility of drugs so that they can be excreted.

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11
Q

Metabolism limits the action of drugs in the body because of

A

Deactivation: Metabolites can have less pharmacological activity

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12
Q

Prodrugs

A

Drugs that have more active or toxic metabolites. The form given is not active; the drug relies on metabolism to activate it. This is aka bioactivation.

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13
Q

Bioactivation

A

Metabolism that activates a prodrug, making metabolites that are more active or toxic.

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14
Q

The major sites for the metabolism of drugs

A

Liver, but the intestine also has significant metabolic capacity for some drugs

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15
Q

Metabolism by __ & __ contribute to the first pass effect, which contributes to the bioavailability of drugs

A

the liver and intestine

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16
Q

Bioavailability

A

The amount of administered drug that reaches systemic circulation in unchange for following administration by any route.

  • IV= 100%
  • Oral < 100%
  • Other routes ≤ 100%
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17
Q

A drug administered orally is subject to metabolism by:

A

The intestine and liver

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18
Q

Once an orally administered drug goes through the first pass, the drug that is left in the systemic circulation is only subject to metabolism by

A

The liver

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19
Q

Drug metabolism can be broken down into

A

Phase I and Phase II Metabolism

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20
Q

Phase I metabolism

A

The creation or unmasking of small polar or reactive functional groups (such as -OH, -SH, -NH2) to create a more polar metabolites

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21
Q

Phase II Metabolism

A

The addition (conjugation) of large polar groups to small reactive functional groups. Goal is to make a more polar metabolite.

E.g. glucuronic acid, sulfate, glutahione, acetate

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22
Q

(T/F) drugs must undergo both phase I and phase II metabolism

A

False. Some drugs only go through one phase, while others go through both sequentially. Phase I groups can be used as attachment groups for groups of phase II.

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23
Q

Hydroxylation in Phase I of a benzene ring

A

Benzene to epoxide (via CYP, cytochrome P450)

Epoxide to alcohol (in the presence of water)

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24
Q

Glucurondation in Phase II metabolism

A

An alcohol (from phase I) can be converted to a glucuronide conjugate via the addition of UDP-GA (catalyzed by UDP-GT). The -OH is used as an attachment point.

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25
Q

The rate at which most drugs are metabolized is generally determined by

A

Phase I metabolism

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26
Q

The most important enzyme group in phase I metabolism

A

Cytochrome P450s

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27
Q

Cytochrome P450 (CYP)

A
  • Refers to a gene superfamily
  • 57 individual genes
  • Multiple physiological roles (make essential steroids, vitamin metabolism, etc.)
  • Families 1, 2, and 3 are most relevant to drug metabolism
  • Most important contributors to Phase I metabolism
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28
Q

How to name Cytochrome P450 genes

A 
CYP34A
-CYP= prefix
-3= Family
-A= Subfamily
4= isoform
29
Q

Why does CYP have an extremely broad substrate range?

A
  • Multiple isoforms
  • Inherent low substrate specificity of individual isoforms

Gives incredibly diversity for drug metabolism

30
Q

How does CYP affect pharmacokinetics?

A

Expression levels of CYP vary among individuals.

31
Q

What can inhibit OR induce enzymatic activity of CYP?

A

Drugs and diet components.

-Can cause decreased or increased rate of metabolism of co-administered drugs

32
Q

What is the most common cause of adverse drug interactions?

A

When drugs are co-administered, enzymatic activity can be inhibited.

33
Q

Cytochrome P450 3A4 (CYP3A4)

A
  • Most abundant CYP in intestine and liver (major contributor to first pass effect)
  • Very broad substrate specificity
  • Metabolizes 50-70% of drugs currently on market
34
Q

Most relevant enzyme to human drug metabolism

A

Cytochrome P450 3A4 (CYP3A4); because it is most abundant CYP in intestine and liver, has a very broad substrate specificity, and metabolizes 50-70% of drugs

35
Q

Inhibitors of CYP34A

A
  • Antifungals (ketoconazole)
  • Antibiotics (erythromycin)
  • Diet (grapefruit juice)
36
Q

Inducers of CYP34A

A
  • Anticonvuslants (phenobarbital)
  • Steroids (dexamethasone)
  • HIV protease inhibitor (saquinavir)
  • Antibiotics (rifampicin)
37
Q

Felodipine

A

A drug that falls in the category of dihydropyridine calcium channel antagonists. It relaxes smooth muscle and is used to treat hypertension. It is also an inhibitor of CYP3A4. It has really bad oral bioavailability

38
Q

Why does felodipine have poor oral bioavailability?

A

It undergoes extensive first-pass metabolism. It is metabolized and deactivated by CYP3A4.

39
Q

What would happen if felodipine was administered with something that inhibits CYP3A4?

A

When consumed with grapfruit juice or other CYP3A4 inhibitors, the bioavailability and plasma concentration of felodipine increases significantly (up to 5 fold)
-This increases the risk for excessive hypotension and cardiac side effects (heart rate increase)

40
Q

Terfenadine

A
  • One of the first non-sedating antihistamines.

- Prodrug extensively metabolized to active drug by CYP3A4

41
Q

CYP3A4 metabolizes terfenadine to:

A

Fexofenadine

42
Q

What happens when terfenadine is taken with CYP3A4 inhibitors?

A

Terfenadine will accumulate in the plasma (won’t be metabolized by fexofenadine), causing loss of therapeutic benefit and serious cardiac side-effects such as inhibition of potassium channels and life-threatening cardiac arrhythmias (cardiac toxicity).

43
Q

Cyclosporine

A

Immunosuppressant drug used to prevent rejection of transplanted organs
-It is metabolized to an inactive metabolite by CYP3A4

44
Q

What happens when cyclosporine and rifampicin are prescribed at the same time?

A

Because rifampicin induces the expression of CYP3A4, you will accelerate the metabolism of cyclosporine to the inactive metabolite, which reduces plasma levels of cyclosporine. This can result in acute rejection episode. If taken at the same time, you would have to increase the cyclosporine dose requirement by 3-fold

45
Q

Rifampicin

A
  • An antibiotic used to treat a variety of infections

- Induces expression of CYP3A4

46
Q

The rate of metabolism of any particular drug can vary up to _____ within the population

A

50-fold.

47
Q

What factors can influence interindividual differences in drug metabolism? (4)

A
  • Diet and environment: Dietary components and co-administered drugs can affect the activity levels of CYPs. Smoking and occupational exposure lead to drug metabolism differences
  • Age: Children exhibit many differences in drug metabolism than adults. In general, drug metabolism is reduced in the elderly.
  • Disease: Drug metabolism is reduced with disease (esp. chronic liver disease)
  • Genetic Factors: Polymorphisms exist for many drug metabolizing enzymes. Genes affect expression level, inherent enzyme activity, and response to inducers.
48
Q

P450 2D6 (CYP2D6) and its role in pharmacogenetics

A
  • Metabolizes 15% of drugs
  • Highly polymorphic (>80 genetic variants in humans)
  • Individuals fall into various phenotypic groups in regards to CYP2D6
49
Q

Four phenotypic groups with respect to the drug metabolism by CYP2D6

A
  • Poor metabolizers: Reduced CYP2D6 expression and/or activity
  • Most common in Caucasians
  • Intermediate metabolizers: Moderately reduces CYP2D6 expression and/or activity. Most common in East Asia and Subsaharan Africa
  • Extensive Metabolizers: Normal CYP2D6 expression and activity. Most common phenotype in all ethnic groups

-Ultrarapid Metabolizers: Elevated CYP2D6 expression and activity.
Most common in Middle East, North Africa, and Oceania

50
Q

Codeine

A

Narcotic analgesic commonly prescribed after surgery. Often prescribed in combination with acetaminophen (e.g. Tylenol 3).

51
Q

The analgesic effect (pain relief) of codeine is largely due to

A

Codeine being converted to morphine metabolites via CYP2D6 metabolism

52
Q

Codeine analgesia for poor metabolizers

A

Reduced analgesia from a normal dose of codeine due to reduces levels of morphine metabolites. Individuals may interpret a patient to be drug-seeking.

53
Q

Codeine analgesia for ultrarapid metabolizers

A

May experience enhanced analgesia and adverse effects (e.g. respiratory depression) as a consequence of a rapid accumulation of morphine metabolites

54
Q

The most important route for parent drug and metabolites is via

A

Urine produced by the kidney

55
Q

Drug excretion by the liver and kidney are promoted by

A

The kidney and liver

56
Q

Drug excretion leaves the liver via

A

Bile

57
Q

Other fluids that take place in drug metabolism

A

Sweat, tears, reproductive fluids, milk, lung

58
Q

Filtering units of the kidney

A

Nephron; functional unit of the kidney

59
Q

Glomerular filtration

A

How things get into the nephron tube

60
Q

Water, metabolic wastes and drugs are filtered from blood at the glomerulus via

A

passive filtration

61
Q

Substances (including some drugs) can be secreted into the nephron from the blood via

A

Active transport from peritubular capillaries

62
Q

Filtrate flows through the nephron to:

A

Collecting duct -> bladder -> external environment via urine

63
Q

Reabsorption

A

The process of water, electrolytes, glucose, and other essential compounds re-entering the blood by active and passive transport into peritubular capillaries surrounding the nephron

64
Q

How are lipophilic compounds (e.g. drugs) reabsorbed into the blood?

A

Via passive diffusion

65
Q

Organic Cation Transporters and Organic Anion Transporters

A

Involved in the sequential movement of drugs from the blood to the urine.

66
Q

How does metabolism promote renal drug secretion?

A

Metabolism changes the nature of the drug structure.

Phase II glucuronidation can convert drugs into organic anions. The drug then becomes a substrate for the organic anion transporters and can be secreted into the urine via active transport.

67
Q

What determines if a drug stays inside of a nephron?(rather than being reabsorbed into the blood stream)

A

The physiochemical properties of the drug.
Highly lipophilic, low polarity, and low ionization states cause reabsorption into the blood.

Drugs that are lipophobic, have high polarity, and have high ionization are more likely to stay in the nephron and be excreted via urine. This is because these drugs move poorly via passive diffusion.

68
Q

How does metabolism promote renal drug excretion?

A

By producing metabolites with greater polarity, ionizability, and reduced lipophilicity.

PHAC3001 (5 decks)

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