Pharmacology Exam 2

What is the ultimate purpose of drug metabolism (biotransformation)?

To make drugs/xenobiotics more water-soluble so they can be eliminated more easily from the body, typically through the urine

How does metabolism usually affect a drug’s physiochemical properties?

a. Increases lipophilicity

b. Increases water solubility

c. Decreases polarity

d. Enhances bioavailability

b. Increases water solubility

T/F: Drug metabolism always leads to drug inactivation or detoxification.

False

Name two outcomes of drug metabolism besides detoxification

• Bioactivation (producing an active metabolite)

• Conversion of a prodrug into its active form

What is a prodrug?

A pharmacologically inactive compound that becomes active after being metabolized in the body

Which property of a drug facilitates its excretion?

a. Lipophilicity

b. Hydrophilicity

c. Having a neutral pH

d. Large molecular weight

b. Hydrophilicity

Why does hydrophilicity facilitate a drug’s excretion?

Water-soluble substances are more easily eliminated via the kidneys in urine, which is primarily water.

What is the major organ responsible for drug metabolism?

Liver

What is the main cell type in the liver, which is involved in drug metabolism?

Hepatocytes

Can drug metabolism occur outside the liver?

a. No

b. Yes, in the kidney and intestines

c. Yes, but only in the lungs

d. Yes, in the bones

b. Yes, in the kidney and intestines

Which cytochrome P450 isozyme is responsible for metabolizing nearly 50% of drugs on the market?

a. CYP1A2

b. CYP2C9

c. CYP2D6

d. CYP3A4

d. CYP3A4

Do conjugation reactions belong to phase I or phase II metabolism?

Phase II

Does functionalization (oxidation, etc.) belong to phase I or phase II metabolism?

Phase I

Does the process of greatly increasing hydrophilicity of a drug belong to phase I or phase II metabolism?

Phase II

Does exposing or adding polar groups to a drug belong to phase I or phase II metabolism?

Phase I

What is the most common phase I reaction?

Oxidation

What are common groups that are added/exposed during phase I metabolism?

• Hydroxyl (-OH)

• Amine (-NH₂)

• Sulfhydryl (-SH)

What are “conjugates” in phase II metabolism?

Molecules that are added to drugs or their metabolites to increase water solubility (e.g., glucuronic acid, sulfate, glutathione)

What is the First Pass Effect?

Significant metabolism of a drug in the liver before it reaches systemic circulation, reducing its bioavailability

Which route of administration is most affected by the first pass effect?

a. IV

b. Oral

c. Sublingual

d. Transdermal

b. Oral

Name one method that avoids the ‘first pass effect’

Administering the drug via a route that bypasses the liver, such as IV, sublingual, or rectal

What is bioactivation in the context of drug metabolism?

Metabolic conversion of an inactive or less active compound into a more active or toxic metabolite

Which enzyme is responsible for metabolizing acetaminophen (Tylenol) into the toxic metabolite NAPQI?

a. CYP2C9

b. CYP3A4

c. CYP2E1

d. CYP1A2

c. CYP2E1

Why is NAPQI toxic?

It binds to cellular proteins and depletes glutathione, leading to oxidative stress and liver cell damage

How does alcohol influence Tylenol bioactivation?

Alcohol induces CYP2E1, enhancing the formation of NAPQI and thus increases the risk of liver toxicity

What are the clinical consequences of Tylenol overdose or combining Tylenol with alcohol?

Severe liver damage or liver failure due to increased production of toxic metabolites and depletion of protective glutathione

How does grapefruit juice affect CYP3A4 activity?

It inhibits CYP3A4 in the intestinal wall, decreasing metabolism of some drugs and increasing their plasma levels

What is the effect of rifampin on cytochrome P450 enzymes?

Rifampin induces (increases expression of) several CYP enzymes, enhancing drug metabolism

A patient takes a drug that is metabolized by CYP3A4. They also drink large amounts of grapefruit juice daily.

• What will happen to the plasma levels of the drug?

Plasma levels of the active drug would increase due to CYP3A4 inhibition

A patient takes a drug that is metabolized by CYP3A4. They also drink large amounts of grapefruit juice daily.

• Why might this be a problem?

This may lead to toxicity due to higher systemic exposure

A patient takes a drug that is metabolized by CYP3A4. They also drink large amounts of grapefruit juice daily.

• What would happen if the drug was a prodrug?

The reduction of drug metabolism could lead to lower active drug levels, reducing therapeutic effect

Pharmacogenomics refers to:

a. The study of how diseases alter gene expression.

b. The study of how genetic variation affects drug response.

c. The genetic manipulation of drugs to improve efficacy.

d. The metabolism of xenobiotics by the liver.

b. The study of how genetic variation affects drug response.

Phase I metabolic reactions involve which of the following?

a. Conjugation with glucuronic acid or sulfate.

b. Oxidation, reduction, or hydrolysis reactions.

c. Direct excretion of the drug unchanged.

d. Transport across cell membranes.

b. Oxidation, reduction, or hydrolysis reactions.

Phase II metabolic enzymes include which of the following?

a. CYP450s and esterases

b. UGTs, SULTs, and NATs

c. MAOs and FMOs

d. ABC and SLC transporters

b. UGTs, SULTs, and NATs

What is the main function of drug transporters?

a. Metabolize drugs through oxidation

b. Facilitate movement of drugs across membranes

c. Catalyze conjugation reactions

d. Increase plasma protein binding of drugs

b. Facilitate movement of drugs across membranes

The two main classes of drug transporters are?

ABC and SLC

ABC (ATP-Binding Cassette) Transporters

Efflux transporters (e.g., P-gp, BCRP)

• Out of the cell only

SLC (Solute Carrier) Transporters

Uptake transporters (e.g., OATP, OCT)

• In and out of the cell

Which of the following factors can significantly affect ADME?

a. Food intake

b. Genetic variation

c. Age and Sex

d. All of the above

d. All of the above

Mirabegron inhibits which metabolic enzyme?

a. CYP3A4

b. CYP2D6

c. CYP2C19

d. UGT1A1

b. CYP2D6

According to CPIC guidelines, which patients should not receive codeine?

a. Normal metabolizers (NM)

b. Ultrarapid metabolizers (UM)

c. Intermediate metabolizers (IM)

d. Poor metabolizers (PM)

b. Ultrarapid metabolizers (UM)

How does pharmacogenomics differ from pharmacogenetics?

Pharmacogenomics: broad study of how genes influence drug response across the genome.

• Genome-wide

Pharmacogenetics: focused on specific gene-drug interactions (e.g., CYP2D6 and codeine).

• Single-gene focus

Explain the purpose of phase I and phase II metabolism.

Phase I: Introduces or exposes functional groups via oxidation, reduction, or hydrolysis.

Phase II: Conjugates drug/metabolite with polar molecules (glucuronic acid, sulfate, etc.), enhancing excretion.

• Both aim to increase water solubility and facilitate elimination/excretion of the drug

Name two ABC transporters and two SLC transporters.

ABC: P-gp (ABCB1), BCRP (ABCG2)

• Uses ATP to efflux drugs; energy driven

SLC: OATP1B1, OCT2

• Relies on ion gradients for uptake; facilitated

How does age affect ADME?

Elderly have reduced hepatic metabolism → slower clearance (e.g., diazepam).

• Example: Newborns have immature UGT enzymes, resulting in chloramphenicol toxicity (‘grey baby syndrome’)

How do age and disease alter drug metabolism/excretion?

Age:

• Elderly = ↓ CYP activity, ↓ renal clearance

Disease:

• Liver failure = ↓ drug metabolism

• Kidney disease = ↓ drug excretion

Name one online pharmacogenomic tool

PharmGKB (or ClinPGx) → database linking genes, variants, and drug responses

How can PGx affect drug transport / metabolism / PD?

Transport: SLCO1B1 variants ↓ statin uptake, leading to an increased risk of myopathy.

Metabolism: CYP2D6 PMs have poor codeine activation, resulting in ineffective pain control.

PD: EGFR mutations affect Osimertinib response in cancer (disease is controlled/uncontrolled)

Phenoconversion

When environmental factors (e.g., inhibitors, inducers) change enzyme activity to mimic a different genotype

An example of phenoconversion

CYP2D6 normal metabolizer taking fluoxetine (CYP2D6 inhibitor) becomes a functional poor metabolizer

If metabolism inactivates a drug:

↓ enzyme activity; ↑ active drug concentration

• Risk of toxicity

If metabolism activates a prodrug:

↓ enzyme activity; ↓ active drug concentration

• Treatment failure

Example: Codeine needs CYP2D6 to produce its active metabolite, morphine

When are PGx responses most pronounced?

When the drug is primarily cleared by a single pathway and has a narrow therapeutic window

For a patient that has CYP2D6 *1/*4:

a) what is the activity score?

b) what is the phenotype?

*1 → score 1

*4 → score 0

a) 1 + 0 = 1.0

b) Intermediate metabolizer (IM)

What happens when a CYP2D6 poor metabolizer takes codeine?

Minimal conversion to morphine, resulting in poor analgesia effect

• Explanation: Codeine is a prodrug activated by CYP2D6

What PGx gene is known to interact with Codeine?

CYP2D6

What PGx gene is known to interact with Irinotecan?

UGT1A1

What PGx gene is known to interact with Simvastatin?

SLCO1B1

What PGx gene is known to interact with Warfarin?

CYP2C9 & VKORC1

What PGx gene is known to interact with Osimertinib?

EGFR

How do somatic mutations in EGFR gene affect pharmacodynamics of Osimertinib?

EGFR mutations increase receptor activation, resulting in tumors responding to Osimertinib

• Resistance mutation specifically predicts Osimertinib sensitivity

How does Carbamazepine and PGx affect adverse drug reactions?

• HLA-B *15:02 (common in Asians) → severe skin reactions (e.g., SJS / TEN)

• HLA-A *31:01 → risk of hypersensitivity 

Testing prevents life-threatening adverse reactions

What is the affect of CYP2D6 phenoconversion on Mirabegron?

• Phenoconversion: Normal → IM or PM

• Decreased metabolism of CYP2D6 substrates = ↑ plasma levels, leading to potential toxicity (e.g., metoprolol bradycardia)

Clinically relevant PGx example: Warfarin

Patients with CYP2C9 & VKORC1 variants require a dose adjustment.

Clinically relevant PGx example: Irinotecan

Patients with UGT1A1 *28 homozygotes are at risk of severe neutropenia

Clinically relevant PGx example: Simvastatin

Patients with SLCO1B1 variant are at risk of statin-induced myopathy

The acronym SERM stands for:

a. Selective Estrogen Receptor Modifier

b. Selective Estrogen Receptor Modulator

c. Specific Estrogen Response Molecule

d. Steroid Estrogen Regulatory Mechanism

b. Selective Estrogen Receptor Modulator

Why are SERMs termed this way?

They’re compounds that bind to estrogen receptors (ERs) and act as agonists in some tissues and antagonists in others. They’re “selective” because their effect depends on the tissue type and which co-activators/co-repressors are present.

Which of the following promotes breast cancer growth?

a. Estrogen

b. Tamoxifen

c. Raloxifene

d. Both tamoxifen and raloxifene

a. Estrogen

What is the effect of (1) estrogen, (2) tamoxifen, and (3) raloxifene on growth of (a) breast, (b) bone, and (c) uterus?

Estrogen

• Breast / Bone / Uterus: promotes growth

Tamoxifen

• Breast: Inhibits growth

• Bone: Promotes bone density

• Uterus: Promotes growth (partial-agonist)

Raloxifene

• Breast: Inhibits growth

• Bone: Promotes bone density

• Uterus: No effect/inhibits (antagonist)

The tamoxifen-ER complex in breast lacks:

a. Co-activators

b. Co-repressors

c. DNA binding ability

d. Estrogen response elements

a. Co-activators

The major risk of long-term tamoxifen therapy is:

a. Osteoporosis

b. Endometrial (uterine) cancer

c. Breast cancer recurrence

d. Hypocalcemia

b. Endometrial (uterine) cancer

Raloxifene, compared to tamoxifen, has which advantage?

a. Stronger estrogenic effect on the uterus

b. Decreased risk of uterine cancer

c. No action in bone

d. Stronger breast agonist activity

b. Decreased risk of uterine cancer

CYP induction can be defined as which of the following?

a. Drug inhibits CYP enzyme activity

b. Drug increases CYP gene expression and enzyme levels

c. Drug increases enzyme inhibition potency

d. Drug causes genetic mutation in CYP genes

b. Drug increases CYP gene expression and enzyme levels

When a drug induces CYP3A4, what happens?

a. CYP3A4 protein decreases

b. Drug metabolism slows

c. CYP3A4 expression and activity increase

d. Liver toxicity 

c. CYP3A4 expression and activity increase

What is PXR and what does it do?

PXR is a nuclear receptor that detects lipophilic xenobiotics and induces CYP3A4 & transporters

The Pregnane X Receptor (PXR) is activated by which of the following?

a. Steroid hormones

b. Various xenobiotics including rifampin and St. John’s wort

c. Heavy metals only

d. Endogenous estrogens only

b. Various xenobiotics including rifampin and St. John’s wort

Activation of PXR leads to:

a. Increased transcription of CYP3A enzymes

b. Decreased metabolic enzyme activity

c. DNA degradation

d. Reduced drug clearance

a. Increased transcription of CYP3A enzymes

The Aryl hydrocarbon Receptor (AhR) is primarily activated by:

a. Polycyclic aromatic carbons (PAHs) and dioxins (TCDD)

b. Amino acids

c. Monosaccharides

d. Fatty acids

a. Polycyclic aromatic carbons (PAHs) and dioxins (TCDD)

AhR activation leads to the induction of what?

a. CYP1 enzymes (e.g., CYP1A1)

b. CYP2 enzymes

c. CYP3 enzymes

d. Transporter proteins only

a. CYP1 enzymes (e.g., CYP1A1)

PXR-mediated induction is “turned off” when which of the following occurs?

a. Ligand concentration decreases and receptor dissociates from DNA

b. CYP enzymes are saturated

c. The liver reaches steady-state metabolism

d. The drug is permanently bound to PXR

a. Ligand concentration decreases and receptor dissociates from DNA

Regulation of metabolic gene expression is necessary because:

a. Constant enzyme expression wastes energy and resources

b. All genes must stay on all the time

c. Gene regulation has no physiological relevance

d. Drugs cannot affect enzyme synthesis

a. Constant enzyme expression wastes energy and resources

Ligands for PXR

Rifampin, St. John’s Wort

Physiological effect of PXR

↑ Drug clearance

Ligands for AhR

Dioxin, PAHs

Physiological effect of AhR

↑ Detoxification of aromatic compounds

What is the overarching principle of toxicology?

“The dose makes the poison”

• any substance can be toxic at a high enough dose

Can drugs be poisons? If so, what’s an example?

Yes, drugs can be poisons

• Example: Acetaminophen → liver failure with overdose

Can poisons be drugs? If so, what’s an example?

Yes, poisons can be drugs

• Example: Botulinum toxin → used as Botox for therapeutic purposes

Are all FDA-approved drugs and “natural” products “safe”?

No, safety depends on dose and use; natural products can also be toxic

What are 3 different types of adverse drug reactions based on the lecture slides?

• “Side Effect” (effect on nontarget tissues)

• “Toxic Reaction” (exaggerated effect on target tissues)

• “Allergic Reaction” (hypersensitivity)

“Toxic Reaction”

An exaggerated effect on target tissues that’s predictable and dose-dependent

• e.g., Acetaminophen toxicity

“Allergic Reaction” 

Hypersensitivity reaction that’s unpredictable and immune-mediated (not dose-dependent)

• e.g., penicillin allergy (rash, hives)

What does “sensitization” mean?

Initial immune exposure that primes the immune system; subsequent exposure triggers allergic reaction

What biological molecules and cell types are involved in mediating hypersensitivity responses?

IgE, mast cells, basophils, and histamine

Drugs that are contraindicated during pregnancy

Tetracycline, NSAIDs, Benzodiazepines (sedatives), and Metronidazole

Drugs that are “safe” to use during pregnancy

Penicillin, Erythromycin, and Acetaminophen

Why is type I hypersensitivity (anaphylaxis) considered the most dangerous hypersensitivity reaction?

It causes systemic vasodilation, bronchoconstriction, edema, and shock; results in death if left untreated

• Hives, swelling of lips/tongue/throat/face, airway* and CV system* (* = life threatening)

What teratogenic effect did thalidomide cause when introduced during gestation in the 1950-60s?

Congenital malformations and fetal developmental abnormalities

When are fetuses most susceptible to teratogenic effects of drugs and why?

During first trimester, because this is when major organs/body systems are being developed and are more sensitive to the harmful effects of teratogens