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2060B: Pharmacology > Module 4: Metabolism > Flashcards

Module 4: Metabolism Flashcards

1
Q

Why do we need drug metabolism?

A

• Drug metabolism is important in humans to protect us from a number of environmental toxins (exogenous) as well as synthesize essential (endogenous) molecules.

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2
Q

What is drug metabolism?

A

Metabolism is the enzyme mediated alteration of a drug’s structure
- Metabolism is also referred to as biotransformation

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3
Q

Sites of drug metabolism include (4):

A

1) Liver - Primary site of drug metabolism
2) Intestine - Enterocytes that line gut are able to metabolize drugs
3) Stomach - Metabolism of alcohol
4) Kidney - Usually thought of for excretion of drugs but is a metabolic organ too
5) Intestinal Bacteria - Bacterial flora play a role in metabolism

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4
Q

What are types of exogenous toxins? Why?

A
  • Alcohol
  • Red meat
  • Drugs
  • Coffee
  • Vegetables

Note that even things like vegetables considered to be healthy would by toxic if we didn’t have enzymes to process them!

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5
Q

What are types of endogenous toxins?

A
  • Vit D synthesis
  • Bile acid synthesis
  • Cholesterol metabolism
  • Steroid hormones
  • Bilirubin
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6
Q

Drug metabolism can have several different consequences, discuss them (5):

A

1) Increase water solubility of drugs to promote their excretion
- Lipophilic (most drugs) to Hydrophilic

2) Inactivate drugs
- Active to Inactivation

3) Increase drug effectiveness
- Active to More active

4) Activate prodrugs (prodrugs are inactive until metabolized)
- Prodrug (inactive) to Active drug

5) Increase drug toxicity
- Non-toxic to Toxic

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7
Q

Drug Metabolism Kinetics: First Order

  • Describe most clinical situations
  • What is the relationship of drug metabolism to the concentration of the free drug?
  • What does this mean?
  • What are (2) things to note?
A
  • In most clinical situations the concentration of drug is much lower than the metabolic capacity of the body; In these situations drug metabolism displays 1st order kinetics
  • In 1st order kinetics drug metabolism is directly proportional to the concentration of free drug.
  • This means a constant fraction of drug is metabolized per unit time.

1) Notice how the concentration decreases faster when there are higher drug concentrations than at the end when the drug concentrations are low
2) Notice how there is much more enzyme than there is drug

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8
Q

Drug Metabolism Kinetics: Zero Order

  • What is the relationship of drug metabolism to the concentration of the free drug?
  • What does this mean?
  • What are (2) things to note?
A
  • In zero order kinetics, the plasma drug concentration is much higher than the metabolic capacity of the body; In zero order kinetics drug metabolism is constant over time
  • This means a constant amount of drug is metabolized per unit time

1) Notice how a constant amount of drug is eliminated over time
2) Notice this time how there is much more drug than there is enzyme

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9
Q

What is first pass metabolism?

A

Orally administered drugs may undergo significant metabolism prior to entering the systemic circulation
- This is called 1st pass metabolism.

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10
Q

• First pass metabolism can occur via (4):

A
  1. Hepatocytes in the liver
  2. Intestinal enterocytes
  3. Stomach
  4. Intestinal bacteria
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11
Q

What is the net result of first pass metabolism?

A

The result of 1st pass metabolism is a decreased amount of parent drug that enters systemic circulation.

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12
Q

• The amount of metabolism on the first pass through the liver can…

A

… greatly determine a drug’s bioavailability.

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13
Q

Drugs are characterized as having high or low extraction ratio (ER) depending on how much metabolism occurs on the first pass through the liver:
- Describe low vs. high ER

A 
High ER Drugs
- Have low oral bioavailability ( 1- 20%)
- PO doses are usually much higher than 
IV doses (to compensate for high first 
pass metabolism).
- Small changes in hepatic enzyme 
activity produce large changes in 
bioavailability
- Very susceptible to drug-drug 
interactions

Low ER Drugs
- Have high oral bioavailability ( > 80%) PO doses are usually similar to IV doses.
- Small changes in hepatic enzyme
activity have little effect on bioavailability.
- Not very susceptible to drug-drug
interactions.
- Take many passes through the liver via the systemic circulation before they are completely metabolized.

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14
Q

What are the two phases of drug metabolism?

- What is the goal?

A

Drug metabolism is broadly divided into 2 phases, phase I metabolism and phase II metabolism.
- Primary purpose is to make them more hydrophilic to be excreted (i.e. water soluble to be eliminated through urine)

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15
Q

Phase I Metabolism:

  • Converts drugs into?
  • Involves what reactions?
  • Mediated by?
  • Results?
A
  • Convert lipophilic drugs to more polar molecules by introducing or unmasking polar functional groups such as hydroxyl (-OH) or amine (-NH2)
  • Involves oxidation, reduction and hydrolysis reactions
  • Mediated by cytochrome P450 enzymes, esterases and dehydrogenases.
  • Metabolites formed can be more active, less active or equally active as the parent drug.
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16
Q

Phase II Metabolism:

  • Increases polarity of lipophilic drugs via?
  • Conjugates include?
  • Result?
  • Exceptions
A
  • Increase the polarity of lipophilic drugs by conjugation reactions (addition of large water soluble molecule to drug) – more hydrophilic
  • Conjugates include glucuronic acid (a sugar), sulfate (-SO4), acetate or amino acids (i.e. glycine).
  • Metabolites are less active than the parent drug
  • Exception: Morphine 6-glucuronide is a more potent analgesic (pain reliever) than morphine
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17
Q

How do drugs flow through phase I to phase II metabolism?

A

Two Paths:

1) Enter Phase I
- Elimination
- Oxidation/reduction/hydrolysis
- Phase II
- Conjugate products
- Elimination

2) Some enter directly into Phase II
- Conjugation products
- Elimination

18
Q

Where does phase I vs. II drug metabolism occur?

A

Phase I – Phase I drug metabolizing enzymes are localized to the smooth endoplasmic reticulum (ER).
P
hase II – Phase II drug metabolizing enzymes are localized predominantly in the cytosol of the cell with the exception of glucuronidation which is localized to the smooth ER.

19
Q

What does CYP stand for?

  • Drug family?
  • What metabolism phase?
A

Cytochrome P-450

  • CYPs are a large family of drug metabolizing enzymes
  • CYPs are the predominant phase I drug metabolizing enzyme system.
20
Q

The majority of drug metabolism in the body is performed by…

A

… hepatic CYP enzymes.

21
Q

How do CYPs oxidize drugs?

A

By inserting one atom of oxygen into the drug molecule producing water as a by product.

Drug + O2 + NADPH + H+ → Drug(oxidized) + H20 + NADP+

22
Q

How many families of CYPs?

- How many accounting for majority of drug metabolism?

A

There are 12 families of CYPs

- with 3 accounting for the majority of drug metabolism.

23
Q

What can decrease CYP activity?

- Why?

A

Malnutrition can decrease CYP activity

- as these enzymes require dietary protein, iron, folic acid and zinc for full activity.

24
Q

What metabolizes the largest fraction of currently marketed drugs?

A

CYP3A4

25
Q

Nomenclature of CYP?

A

CYP3A4

3 = Family
A= Sub-family
I = Isozyme
26
Q

Phase II drug metabolizing enzymes include:

A
  1. UDP-glucuronosyltransferases (UGTs)
  2. Sulfotransferases (SULTs)
  3. Glutathione S Transferases (GSTs)
  4. N-acetyltransferases (NATs)
  5. Thiopurine Methyltransferase (TPMT)
27
Q

How are drugs metabolized by phase II split in comparison to CYPs?

A

Unlike CYPs, the fraction of drugs metabolized by phase II enzymes is relatively equally split between UGTs, SULTs, GSTs and NATs.

28
Q

UDP-glucuronosyltransferases (UGTs):

  • Localized?
  • Catalyze?
  • Polarity?
  • How many human UGT enzymes?
  • Equation
A
  • Are localized in the smooth endoplasmic reticulum and are part of phase II drug metabolism.
  • Catalyze the transfer of a glucuronic acid (sugar) to a drug.
  • Glucuronidated drugs are more polar and therefore more easily excreted.
  • There are 19 human UGT enzymes.

Drug + UDP-glucuronic acid → drug-glucuronide + UDP

29
Q

Sulfotransferases (SULTs):

  • Localized?
  • Catalyze?
  • Polarity
  • How many human UGT enzymes?
  • Equation
A
  • Are cytosolic phase II drug metabolizing enzymes.
  • Catalyze the transfer of a sulfate group to a hydroxyl group of drugs.
  • Sulfated drugs are more polar and therefore more easily excreted.
  • There are 11 human SULT enzymes.

Drug + sulfate → drug-sulfate

30
Q

Glutathione S Transferases (GSTs):

  • Localized?
  • Catalyze?
  • What is GSH?
  • What makes the metabolite less toxic?
  • How many human UGT enzymes?
  • Equation
A
  • Are phase II drug metabolizing enzymes that may be cytosolic or microsomal.
  • Catalyze the transfer of a glutathione molecule to a drug.
  • Glutathione (GSH) is an intracellular anti-oxidant.
  • Transfer of a glutathione onto a reactive (i.e. toxic) drug renders the metabolite less toxic.
  • There are over 20 human GST enzymes.

Reactive Drug + GSH → drug-GSH

31
Q

N-acetyltransferases (NATs):

  • Localized?
  • Catalyze?
  • Major cause of variability to drug response?
  • How many human UGT enzymes?
  • Equation
A
  • Are cytosolic phase II drug metabolizing enzymes.
  • Catalyze the transfer of an acetyl group from acetyl CoA to a drug.
  • Subject to genetic polymorphisms which is a major cause in variability to drug response.
  • There are 2 human NAT enzymes, NAT 1 and NAT2.

Drug + Acetyl CoA → Acetylated Drug + CoA

32
Q

Thiopurine Methyltransferase (TPMT):

  • Localized?
  • Catalyze?
  • Subject to?
  • Equation
A
  • Are cytosolic phase II drug metabolizing enzymes.
  • Catalyze the transfer of a methyl group from S-adenosylmethionine to a drug.
  • Subject to genetic polymorphisms - Although rare, these polymorphisms have dramatic effect on drug safety (more later).

Drug + S-adenosylmethionine → Drug-CH3 + Methionine

33
Q

W• There are a number of factors that affect drug metabolism. These include:

A
  1. Age
  2. Drug interactions (enzyme inducers and enzyme inhibitors).
  3. Disease state
  4. Genetic Polymorphisms
34
Q

Describe how age affects drug metabolism and give an example.

A

The expression and activity of drug metabolizing enzymes changes as we age.

For example, infants have almost no CYP activity. It takes babies approximately 1 year after birth until they have a reasonable level of drug metabolizing enzymes.
- By age 2, babies have the same amount of drug metabolizing enzymes as adults do.

35
Q

Describe how drug interaction affects drug metabolism:

1) Enzyme inducers
- Define induction
- What is susceptible?
- Consequences of CYP induction?
- Important roles?
- Consequences of increased drug metabolism

2) Enzyme inhibitors
- What can they inhibit?
- Consequence of CUP inhibition ?
- Consequence of decreased drug metabolism?

A
  • Induction is a process where a cell synthesizes an enzyme in response to a drug or other chemical.
  • Certain CYP isozymes are susceptible to induction by drugs.
  • The consequence of CYP induction is increased drug metabolism.
  • Enzyme induction plays an important role in drug interactions (more later).
  • Consequences of increased drug metabolism may include:
    a) Decreased plasma drug concentration.
    b) Decreased drug activity (if metabolite is inactive).
    c) Increased drug activity (if metabolite is active).

Ex. Smokers

2) Enzyme Inhibitors
- Some drugs and natural compounds can inhibit CYPs
- The consequence of CYP inhibition is decreased drug metabolism
- Decreased drug metabolism may result in:
a) Higher plasma drug concentration.
b) Increased therapeutic effect of drugs.
c) Increased drug toxicity.

36
Q

Describe how disease state affects drug metabolism:

- Examples

A

Disease can play a critical role in determining CYP activity

Diseases that decrease CYP activity include:

1) Liver disease
2) Kidney Disease
3) Inflammatory diseases
4) Infection

37
Q

Describe how genetic polymorphisms affects drug metabolism:

  • What is an SNP?
  • What does it affect?
  • What do they cause?
A

Genes for some drug metabolizing enzymes have genetic polymorphisms also known as single nucleotide polymorphisms (SNPs).

  • A SNP is a change of a single nucleotide (A, T, G or C) in our DNA.
  • SNPs often affect the protein (i.e. drug metabolizing enzyme) that is produced.
  • There are a number of SNPs in drug metabolizing enzymes that cause pronounced differences to the response of drugs.
38
Q

Phase I SNPs:

1) CYP2C9
- Metabolizes?
- Polymorphism results in?
- PT’s require a lower dose of?
- Why?

2) CYP2D6
- Metabolizes?
- Polymorphism results in? (4) - State their type of activity.

A

1) CYP2C9
- Metabolizes the anticoagulant drug warfarin.
- Polymorphism of CYP2C9 results in an enzyme with decreased activity.
- Patients with a polymorphism in CYP2C9 require a lower dose of warfarin.
- If the dose is not lowered, patients may experience extensive bleeding, a side effect of warfarin.

2) CYP2D6
- Metabolizes codeine to morphine (morphine is a more potent analgesic than codeine)
- CYP2D6 has many genetic polymorphisms that can result in 4 distinct phenotypes:
a) Ultra-rapid metabolizer (UM),
b) Extensive metabolizer (EM),
- Normal enzymatic activity
c) Intermediate metabolizer (IM)
- Reduced metabolic activity
d) poor metabolizer (PM)
- Almost no metabolic activity

39
Q

What is true about ultra-rapid metabolizers? (2)

A

1) Ultra-rapid metabolizers have significantly increased CYP2D6 activity.
2) Ultra-rapid metabolizers possess multiple copies of the CYP2D6 gene.

40
Q

Phase II SNPs

1) UGT1A1
- Part of what family?
- What is glucuronidates?
- What decreases activity?
- What are PT’s at an increase risk for?

2) NAT2
- What does it do?
- How many types of SNPs in that NAT2 gene?
- PT’s are classified by?
- Slow acetylators (2)?

A

1) UGT1A1
- Is part of the UGT family of enzymes.
- Glucuronidates the anti-cancer compound SN-38 (the active metabolite of irinotecan)
- Polymorphisms in UGT1A1 decrease its activity.
- Patients with UGT1A1 polymorphisms are at increased risk of diarrhea and dose limiting bone marrow suppression (potentially fatal)

2) NAT2
- Acetylates the drug isoniazid (used to treat tuberculosis), caffeine and various cancer causing chemicals
- There are over 23 different SNPs in the NAT2 gene
- Patients are classified as either rapid or slow acetylators based on their genotype.
- Slow acetylators are more susceptible to isoniazid toxicity (neuropathy, hepatotoxicity) than rapid acetylators; Slow acetylators have a higher risk for developing certain types of cancer.

2060B: Pharmacology (18 decks)

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