Drug metabolism and excretion

Question 1

What is drugs in circulation determined by?

Answer 1

Determined by supply rate and removal from the body

Question 2

Process of elimination(metabolism)

Answer 2

• Metabolism
○ Removal of lipid soluble drug molecules to prevent reabsorption by kidneys
○ Achieved by converting drugs into water soluble molecules
○ Mostly in liver but also in plasma, lung and intestinal epithelium

Question 3

Process of elimination(Excretion)

Answer 3

• Excretion
○ Removal of drug/metabolites from the body
○ Mostly in urine but also via bile, sweat, tears, saliva, nce for drugs following 1st order kinetics

Question 4

What is the plasma CL for a drug which is removed by liver metabolism and kidney excretion?

Answer 4

Plasma CL=hepatic CL+ renal CL

Question 5

Importance of drug metabolism and excretion(Dosing issues)

Answer 5

• Dosing issues:
○ Metabolism/clearance determine the amount of drug available at site of action

Time taken for a drug to reach steady state levels

Question 6

Importance of drug metabolism and excretion(Safety issues)

Answer 6

○ Metabolism produces new chemical entities that may have their own effects
○ Components of racemic molecules handled differently

Question 7

When does drug removal begin?

Answer 7

• Drug removal begins immediately

Question 8

what do most drugs undergo?

Answer 8

• Most undergo metabolism prior to removal to increase excretion
○ Loss of biological activity by
§ Increase in polarity
§ Less receptor binding

Question 9

How are some drugs activated?

Answer 9

Some drugs activated by metabolism(prodrug)

Question 10

How are some drugs eliminated?

Answer 10

• Some drugs are eliminated unchanged

Question 11

2 phases of drug metabolism

Answer 11

• Phase 1:
○ Main process is oxidation within the liver
○ Addition of oxygen molecules to carbon, nitrogen, sulphur molecules in drug structure
○ Carried out by cytochrome P450 enzymes
§ Bind drug and molecule of oxygen
§ Oxidation of drug occurs through one oxygen atom, the other oxygen atom is reduced to water
○ Other reactions are hydrolysis and hydration etc.
○ Mainly by CYP isoforms
• Phase 2:
○ Increases water solubility of drug for excretion
○ The product of phase one is conjugated with an endogenous substance through production of stable covalent bonds

Question 12

Excretion via the kidneys(Glomerulus filtration)

Answer 12

○ Filters <20kDa molecules

○ Amount excreted depends on levels of drug bound to plasma proteins

Question 13

Excretion via the kidneys(Reabsorption)

Answer 13

○ As molecules pass through tubules, they are concentrated
§ Creates large concentration gradient for reabsoprtion

Hence need to make drugs water soluble

Question 14

Excretion via the kidneys(Tubular secretion)

Answer 14

○ Acid/base molecule carriers transport molecules into tubular fluid
○ Lower levels of unbound drug in plasma, pushing reaction for plasma protein to release more free drug for secretion by carriers
○ Excretion=filtration-reabsorption+secretion

Question 15

What is renal clearance?

Answer 15

Volume of plasma cleared of drug per unit time in one pass through kidney

Question 16

What happens in renal clearance as drug is cleared in renal clearance?

Answer 16

• Drug is cleared from blood and appears in urine

Question 17

What happens as renal elimination decreases?

Answer 17

As renal elimination decreases, plasma half life increases

Question 18

Factors affecting drug metabolism and excretion(Age)

Answer 18

• Age
○ Cyto p450 activity reduced in elderly
○ GFR reduced greatly in elderly
○ Increased % fat content in elderly

Question 19

Factors affecting drug metabolism(Genetics)

Answer 19

• Genetics
○ 45% in west and 80-90% in east have fast acetylators
○ 1/3000 slow metabolism by pseudocholinesterase

Question 20

Factors affecting drug metabolism(Drug metabolising enzymes)

Answer 20

• Drug metabolising enzymes:
○ Can be induced by other drugs or lifestyle factors
○ Can be inhibited by some drugs

Question 21

Factors affecting drug metabolism(Disease)

Answer 21

• Disease:
○ Liver disease impairs drug metabolism-drug toxicity
○ Renal disease may alter pharmacokinetics

Question 22

Why is drug concentration monitored?

Answer 22

• For drugs that have a narrow therapeutic index
• For drugs concentrations that relate well to either therapeutic effect or toxic effect
• To individualise therapy
• To confirm adherence of therapy
• To diagnose toxicity
• To determine presence of other drugs before starting therapy
  
  • Post marketing surveillance to detect drug-drug interactions