Drug Metabolism

Question 1

What is the primary source of drug metabolism

Answer 1

Liver

Question 2

What is first pass metabolism?

Answer 2

Orally→SI→liver

If rapidly metabolized in liver it never reaches circulation

Question 3

What drugs are never given orally?

Answer 3

Nitroglycerin

Morphine

Question 4

Describe metabolism in the liver

Answer 4

• Metabolism via cytochrome system
• Smooth ER of liver cells contain complex of enzyme referred to as cytochrome P450
  
  • Most significant is CYP3A4–metabolizes about 50% of drugs we will talk about
• CYP catalyze oxidation rxns→make molecule more polar→more water soluble→easily excreted by kidney
• CYP can be affected by environment

Question 5

Inhibitors of CYP and the effect

Answer 5

• Grapefruit juice
• Some antibacterials and anti fungals
• Some antihistamines

Cause increase conc. of drug

Question 6

Activators of CYP and the effect

Answer 6

• Phenytoin
• St Johns
• Rifampin
• Phenobarbital

Cause decreased conc. of drug

Question 7

Phase 1 rxn

Answer 7

• CYP450 responsible for 75% of phase 1 rxns
• Form polar group or remove NP
  
  • ​Hydroxylation rxns (add OH)
    
    • Ibuprofen
  • N-oxidation rxns (add OH to N)
    
    • Acetaminophen
  • S-oxidation rxns (add OH to S)
    
    • Antihistamine
  • N-dealkylation (remove CH3 from N)
    
    • Caffeine
  • O-dealkylation (remove CH3 from O)
    
    • Codeine

Non CYP450 phase 1 rxns=25%

• Deamination (amphetamine)
• Hydrolysis-estarase (cocaine)
• Peptidases
• Phosphatases

Question 8

Phase 2 rxn

Answer 8

• Add a moeity to make it more polar
• Sometimes phase 2 occurs alone, but typically after phase 1
• Moeity examples
  
  • Acetyl group
  • Gluconic acid (morphine)
  • Methyl group (histamine)
  • Sulfate group (acetaminophen
  • AA

Question 9

Basis of drug excretion

Answer 9

Altering pH

• Ammonium Cl acidifies urine
• Bicarbonate alkalizes urine

Question 10

Where do we excrete drugs

Answer 10

Urine, feces, sweat, lungs, breast milk

Question 11

Factors that alter absorption

Answer 11

• When you give (when eating, etc)
• Age-don’t metabolize as well as we age
• GI dysfunction-affects absorption
• Environment-if taking other drugs too

Question 12

Factors that alter distribution

Answer 12

• Body weight
• Gender
• Environmental (other drugs)

Question 13

Factors that alter metabolism and excretion

Answer 13

Genetic factors:

• P450 differences
• Plasmacholinesterase differences (breaks down esters)
• G6DPH deficiency
  
  • Maintains RBC integrity so w/o it, drugs cause hemolysis of RBCs
• Slow and fast acetylators
  
  • Phase II
  • If slow metabolism due to slow acetylators then lupus like syndrome

Gender

Age

Route of admin

Disease and pregnancy (impact CYP450)

Question 14

Intro of new drugs

Answer 14

1. Animal testing (2-3 yrs)
2. Phase I-dose dependent in normal human volunteers
3. Phase II-small # of pts w/ target disease (1-2 yrs)
4. Phase III-larger # of pts. If passes apply for NDA

Only 10% make it through

Question 15

Pregnancy ratings

Answer 15

• Category A-no risk
• Category B-no risk in animals, humans have not been tested
  
  • Benefit>>risk
• Category C-humans not tested, risk can’t be ruled out
  
  • Benefit>risk
• Category D-there is risk
  
  • Benefit=risk
• Category X-severe risk. Drug is contraindicated