Equations and Enzymes

Question 1

• made up of many different enzymes
• enzymes can be inhibited or induced
• genetic variations can alter activity
• Part of Liver Metabolism: Phase I Enzymes

Answer 1

P - 450 System

Question 2

• METABOLIZES 50% of MEDICATIONS
• basis for many drug interactions
• Most important enzyme of P-450 system

Answer 2

CYP3A4

Question 3

What type of metabolism occurs when a prodrug becomes an active compound?

Answer 3

Inactive Drug to Active Metabolite

Question 4

What type of metabolism occurs when a metabolite is further metabolized?
(Heroin –> Morphine)

Answer 4

Active Drug to Active Metabolite

Question 5

What type of metabolism occurs when the drug is ready for excretion and is the most common form of drug deactivation?

Answer 5

Active Drug to Inactive Metabolite

Question 6

What type of metabolism occurs when a metabolite is then further metabolized into a toxic metabolite?
(one of the metabolites of acetaminophen is toxic)

Answer 6

Active Drug to Toxic Metabolite

Question 7

Volume of Distribution (Vd) Equation

Answer 7

Vd = (Dose) / (plasma concentration)

Question 8

Bioavailability Equation

Answer 8

AUCₒᵣₐₗ / AUCᵢᵥ = f

Question 9

Amount of drug that is absorbed after oral administration vs. the amount of drug that is absorbed after IV administration

Answer 9

Bioavailability

Question 10

Bioavailability of drugs given IV

Answer 10

f = 1 (100%) because they do not undergo first pass.

Question 11

Rate at which a drug is cleared from the body

Answer 11

Clearance

Question 12

Clearance Equation

Answer 12

Clearance = (Rate of Drug Elimination) / (Plasma Concentration)

Question 13

A CONSTANT % of the DRUG IS LOST PER UNIT of TIME
90% OF DRUGS FOLLOW THIS

Answer 13

First-Order Kinetics

Question 14

Time it takes for the blood level (concentration) of a drug to fall exactly half (50%)

Answer 14

Half-life
increased concentration = increased half life

Question 15

Point where drug accumulation equals drug elimination

Answer 15

Steady State Concentration

Question 16

How many half lives are needed to reach Steady State Concentration?

Answer 16

5 Half-lives

Question 17

Single large dose of a drug used to raise the plasma concentration to a therapeutic level more quickly than would occur through repeated smaller doses

Answer 17

Loading Dose

Question 18

CONSTANT AMOUNT OF DRUG IS LOST PER UNIT OF TIME

Answer 18

Zero-Order Kinetics

Question 19

Up to 25% of all drugs are metabolized via this enzyme.
- Beta Blockers
- Opioids
- Antipsychotics

Answer 19

CYP2D6

Question 20

Preference for acidic drugs
- PPI
- Antidepressants
- Antiplatelets
- Polymorphism in Asian populations

Answer 20

CYP2C19

Question 21

Clinical significance in cancer and immunological treatments
- UGT1A1 & TMPT

Answer 21

Phase II Enzymes

Question 22

• Rate limiting step in Pentos Phosphate Pathway
• Significant source of NADPH in body
• African and Mediterranean Populations
  Leads to Hemolysis

Answer 22

G6PD

Question 23

Drug Induced Hypersensitivity Reaction

Answer 23

Rash due to severe skin toxicity
- Steven Johnson Syndrome (SJS)
- Toxic Epidermal Necrosis (TEN)

Question 24

Genetic component determines if sustained virology response of anti-viral medication is likely
- European populations

Answer 24

IFNL3

Question 25

Indication: HIV Tested: All patients Test: HLA-B*5701 gene Result: if (+) do NOT use Clinical: ↑risk of serious hypersensitivity reactions - beware of combination products that contain the drug

Answer 25

Abacavir (Ziagen)

Question 26

Indication: Epilepsy, neuralgias, BPD Tested: Asian patients Test: HLA-B*1502 gene Result: if (+) do NOT use Clinical: ↑risk of SJS and TEN

Answer 26

Carbamazepine (Tegretol)

Question 27

Indication: HIV Tested: All patients Test: HIV Tropism with Trofile Result: Must be CCR5 (+) to use Clinical: Patients with only CCR5 can use this drug

Answer 27

Maraviroc (Selzentry)

Question 28

Indication: Gout Tested: Chinese, Thai, or Korean with Renal impairment Test: HLA-B*5801 gene Result: If (+) not recommended Clinical: ↑Risk of serous dermatologic reaction - Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome

Answer 28

Allopurinol

Question 29

Indication: Acute Coronary Syndrome Tested: Patients at initial treatment Test: CYP2C19 gene Poor Metabolizers = 2C19*2 or *3 Fully Functional = 2C19*1 Clinical: ↑risk of cardiovascular events

Answer 29

Clopidogrel (Plavix)

Question 30

Indication: Pain or Cough Tested: Not typically tested Test: CYP2D6 gene Ultra-rapid metabolizers = 2D6*2 allele Clinical: ↑Respiratory depression

Answer 30

Codeine

Question 31

Clot prevention & treatment Tested: Not typically tested Test: CYP2C9 and VKORC1 gene 2C9*2 or 2C9*3 or VKORC1 G = USE LOWER STARTING DOSE Clinical: ↑Risk of bleeding due to decreased metabolism

Answer 31

Warfarin (Coumadin)

Question 32

Clinical testing is carried out in human volunteers in three formal phases of clinical trials - Institutional Review Board must approve the study - Volunteers are informed of possible risks - Chronic safety testing in animals goes on concurrently

Answer 32

Clinical Trials

Question 33

20-100 healthy volunteers (do not target disease) Evaluates safety Determines dosage range Identifies adverse effects or toxicities

Answer 33

Phase 1

Question 34

Studies 100-300 patients (with target disease) Determines efficacy and dose Evaluates short-term effects and risks Only 25% of drugs make it here

Answer 34

Phase 2

Question 35

Tested in formulation for market Establishes and confirms safety and efficacy 2-10 years If good results --> application to FDA - Review may take months to years

Answer 35

Phase 3

Question 36

Important phase that relies on you as a provider Drug has been approved to market Adverse effects reported to FDA through MedWatch program

Answer 36

Phase 4