Drug Metabolism + Excretion

Question 1

What is metabolism related to drugs?

Answer 1

Removal of lipid soluble drug molecules to prevent reabsorption by kidney
It is achieved by converting drugs into water soluble molecules

Question 2

What is excretion?

Answer 2

Removal of drug/metabolites from body

Question 3

What contributes to clearance?

Answer 3

Both metabolism + excretion

Question 4

What are prodrugs?

Answer 4

They are drugs which are activated by metabolism
Used as it usually avoids first pass metabolism or issues with absorption
For prodrugs, metabolism is important activation step

Question 5

What does drug metabolism lead to?

Answer 5

Loss of biological activity

Increase polarity/ less receptor binding

Question 6

What are 2 phases of drug metabolism?

Answer 6

Phase 1 introduces chemically reactive groups via mainly oxidation in liver but also other reactions like hydrolysis+ hydration
Phase 2 increases water solubility of drug for excretion. Conjugated phase 1 product with endogenous substance through production of stable covalent bonds e.g. glucuronidation (reaction of glucose)

Question 7

What enzymes carry out phase 1 drug metabolism?

Answer 7

Cytochrome P450 enzymes
They bind drug and molecule oxygen and oxidation of drug occurs through one oxygen atom, the other oxygen atom is reduced to water

Question 8

What drug breaks the rule of drug metabolism of first undergoing phase 1 metabolism then phase 2?

Answer 8

Paracetamol metabolism usually relies on just phase 2 reactions
Conjugation with glucose and sulphate
Due to paracetamol structure, oxidation of cytochrome p450 leads to production of toxic intermediate
Glutathione conjugation leads to non toxic water soluble metabolite to be formed which can be removed from body

Question 9

What happens when an alcoholic takes too much paracetamol?

Answer 9

There is an increase in cytochrome P450 therefore more likely to undergo the toxic pathway.
In alcoholics, one or two isomers of CYP is upregulated so they are more susceptible to liver toxicity

Question 10

What are 3 stages of excretion via the kidney?

Answer 10

Glomerulus filtration- filters <20kDa molecules. Smaller the molecule, the more readily it is filtered into tubules
Reabsorption- as molecules pass through tubules, they are concentrated creating large concentration gradient for reabsorption. Hence need to make drugs water soluble. Lipophilic molecules are reabsorbed more readily in kidney so doesn’t promote excretion
Tubular secretion- acid/base molecule carriers transporting molecules into tubular fluid. Lower levels of unbound drug in plasma, pushing reaction for plasma proteins to release more free drug for secretion by carriers

Question 11

What is definition of renal clearance?

Answer 11

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

Question 12

What are some factors affecting drug metabolism and excretion?

Answer 12

Age= CYP450 activity reduced in neonates/elderly, GFR reduced greatly in neonates/elderly. Increased % fat content in elderly
Genetics
Drug metabolising enzymes= can be induced by other drugs or lifestyle factors, can be inhibited by some drugs or lifestyle factors
Disease= liver disease impairs drug metabolism-drug toxicity, renal disease may alter pharmacokinetics

Question 13

Why monitor drug concentrations?

Answer 13

For drugs that have narrow therapeutic index
For drug concentration that relate well to either therapeutic effect or toxic effect or both
To individualise therapy
To confirm adherence of therapy
To diagnose toxicity
To determine presence of other drugs before starting therapy
As part of post marketing surveillance to detect drug-drug interactions