Pharmacology lecture 4

define parent drug

initial compound inserted to the body which turns into biotransformation

define active metabolite

active compound produced from the body metabolising the drug

define toxic metabolite

toxic compound produced from the body metabolising the a drug, results in harmful effects to the body

deine inactive metabolite

inactive compound produced when body metabolizes a drug. has no effect. it’s water soluble

define pro drug

when an inactive form of the med is converted to an active metabolite

compare phase 1 and phase 2

phase 1:

• increases water solubility

• introduces polar groups

• can be eliminated here or undergo phase 2

phase 2:

• increases water solubility

• conjugation

• leads to elimination via bile or urine

what are major enzymes in phase 1? In phase 2?

phase 1:

• CYP3A4/5

Phase 2:

• UGT

Conjugation can occur w an enzyme called?

Transferace

define xenobiotics

foreign substances

define substrate

substance on which an enzyme acts

define inducer

substance that results in the production of gene expression causing an increase in enzyme activity

define inhibitor

substance that interacts w the enzyme leading to a loss in function

what is biotransformation?

drug metabolism

(chemical modification of molecules within a cell)

where does drug metabolism occur?

in the liver

Where are non polar (hydrophobic) molecules most likely to be reabsorbed

from urine or bile

what is CYP450

responsible for majority or drug metabolism (46%)

Factors affecting metabolism? (5)

1. sex

2. age

3. disease status

4. generics

5. other drugs

how does age play a role

• babys have no fully functioning drug metabolism enzyme

• young adults have increased metabolism

• older people have decreased metabolism

how does sex play a role

testosterone increases metabolism

how does disease state play a role

infection, cardiac disease, liver disease

more hydrophilic =

better marked for elimination by urine or bile

Some phase 2 enzymes include (2)

UGT and SULT

Phase 1 enzymes include (2)

CYP3A4/5 and CYP2D6

Major phase 2 metabolism enzyme?

UGT major enzymes

What is tacrolimus used for

used to prevent organ rejection such as a lung, heart, or kidney transplant

What activity does a inducer and a prodrug create

increase activity

What activity does a inducer and a active drug create

Decrease activity

What activity does a inhibitor and a prodrug create

decrease activity

What activity does a inhibitor and a active drug create

increase activity

Our body does one of the two pathways. What are the pathways?

1. glucuronidation

2. sulfation

AM is a 45 year old female who has a past medical history of pulmonary edema, HTN and heart failure. AM was diagnosed with a UTI and was prescribed Bactrim on 10/18  at discharge .

¨Current medication: Metoprolol, Warfarin 2mg daily, Furosemide

¨New Medication: Sulfamethoxazole / Trimethoprim (Bactrim) x 7 days

¨INR 2.6 (goal 2-3, normal 1)


¨Three days into treatment she returns to the emergency department with INR of

4.5 and melena.

¨What does this mean?

¨Warfarin is anticoagulation effects are measured in effects in INR most goals are

2.5 (2-3). The patient is now above the therapeutic target (supratheraputic) range and is at an increased risk for bleeding.

¨What could have caused this?

🞑 Let investigate how each drug is metabolized.

🞑 Metoprolol CYP2D6

🞑 Warfarin CYP2C9

🞑 Bactrim CYP2C9

🞑 Furosemide minimally hepatic

1. INR has increased, her blood is too thin, and she is more prone to bleeding

2. There is an overlap between metoprolol and warfarin

3. Bactrim inhibits warfarin metabolism

   1. Warfarin is an active drug and now added an enzyme inhibitor

      1. slowing down clearance and clearing exposure to active drug

4. higher exposure to warfarin because INR went up

OVERALL: all due to inhibition of bactrim

¨What should be done?

🞑 Change the antibiotic depending on susceptibility and other information needed like allergy.

¨What could have been done to prevent this?

🞑 When selecting the antibiotic remembering the patient is on warfarin a substrate of CYP2C9

🞑 When choosing the antibiotic remembering that Bactrim is a CYP2C9 inhibitor and could increase the level warfarin.

🞑 This could increase the risk of bleeding

Pick another one that does not inhibit warfarin metabolism

IF need to use bactrim, reduce amount given, so lower dose while on bactrim