Equations and Enzymes Flashcards
- made up of many different enzymes
- enzymes can be inhibited or induced
- genetic variations can alter activity
- Part of Liver Metabolism: Phase I Enzymes
P - 450 System
- METABOLIZES 50% of MEDICATIONS
- basis for many drug interactions
- Most important enzyme of P-450 system
CYP3A4
What type of metabolism occurs when a prodrug becomes an active compound?
Inactive Drug to Active Metabolite
What type of metabolism occurs when a metabolite is further metabolized?
(Heroin –> Morphine)
Active Drug to Active Metabolite
What type of metabolism occurs when the drug is ready for excretion and is the most common form of drug deactivation?
Active Drug to Inactive Metabolite
What type of metabolism occurs when a metabolite is then further metabolized into a toxic metabolite?
(one of the metabolites of acetaminophen is toxic)
Active Drug to Toxic Metabolite
Volume of Distribution (Vd) Equation
Vd = (Dose) / (plasma concentration)
Bioavailability Equation
AUCₒᵣₐₗ / AUCᵢᵥ = f
Amount of drug that is absorbed after oral administration vs. the amount of drug that is absorbed after IV administration
Bioavailability
Bioavailability of drugs given IV
f = 1 (100%) because they do not undergo first pass.
Rate at which a drug is cleared from the body
Clearance
Clearance Equation
Clearance = (Rate of Drug Elimination) / (Plasma Concentration)
A CONSTANT % of the DRUG IS LOST PER UNIT of TIME
90% OF DRUGS FOLLOW THIS
First-Order Kinetics
Time it takes for the blood level (concentration) of a drug to fall exactly half (50%)
Half-life
increased concentration = increased half life
Point where drug accumulation equals drug elimination
Steady State Concentration
How many half lives are needed to reach Steady State Concentration?
5 Half-lives
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
Loading Dose
CONSTANT AMOUNT OF DRUG IS LOST PER UNIT OF TIME
Zero-Order Kinetics
Up to 25% of all drugs are metabolized via this enzyme.
- Beta Blockers
- Opioids
- Antipsychotics
CYP2D6
Preference for acidic drugs
- PPI
- Antidepressants
- Antiplatelets
- Polymorphism in Asian populations
CYP2C19
Clinical significance in cancer and immunological treatments
- UGT1A1 & TMPT
Phase II Enzymes
- Rate limiting step in Pentos Phosphate Pathway
- Significant source of NADPH in body
- African and Mediterranean Populations
Leads to Hemolysis
G6PD
Drug Induced Hypersensitivity Reaction
Rash due to severe skin toxicity
- Steven Johnson Syndrome (SJS)
- Toxic Epidermal Necrosis (TEN)
Genetic component determines if sustained virology response of anti-viral medication is likely
- European populations
IFNL3
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
Abacavir (Ziagen)
Indication: Epilepsy, neuralgias, BPD
Tested: Asian patients
Test: HLA-B*1502 gene
Result: if (+) do NOT use
Clinical: ↑risk of SJS and TEN
Carbamazepine (Tegretol)
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
Maraviroc (Selzentry)
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
Allopurinol
Indication: Acute Coronary Syndrome
Tested: Patients at initial treatment
Test: CYP2C19 gene
Poor Metabolizers = 2C19*2 or 3
Fully Functional = 2C191
Clinical: ↑risk of cardiovascular events
Clopidogrel (Plavix)
Indication: Pain or Cough
Tested: Not typically tested
Test: CYP2D6 gene
Ultra-rapid metabolizers = 2D6*2 allele
Clinical: ↑Respiratory depression
Codeine
Clot prevention & treatment
Tested: Not typically tested
Test: CYP2C9 and VKORC1 gene
2C92 or 2C93 or VKORC1 G = USE LOWER STARTING DOSE
Clinical: ↑Risk of bleeding due to decreased metabolism
Warfarin (Coumadin)
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
Clinical Trials
20-100 healthy volunteers
(do not target disease)
Evaluates safety
Determines dosage range
Identifies adverse effects or toxicities
Phase 1
Studies 100-300 patients
(with target disease)
Determines efficacy and dose
Evaluates short-term effects and risks
Only 25% of drugs make it here
Phase 2
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
Phase 3
Important phase that relies on you as a provider
Drug has been approved to market
Adverse effects reported to FDA through MedWatch program
Phase 4
