Concepts in Drug Elimination

Question 1

What is the driving force of glomerular filtration?

Answer 1

The hydrostatic pressure of blood flowing in capillaries

Question 2

What is used to estimate GFR?

Answer 2

Serum Creatinine

Question 3

What is the GFR (ml/min) often used as a threshold to diagnose first stage chronic kidney disease?

Answer 3

60ml/min

Question 4

What 3 things do we assume when using GFR as a measure of renal clearance for a drug?

Answer 4

1. ) That no drug is reabsorbed back from the nephron (proximal tubule) into the blood
2. ) That no drug is actively secreted into the nephron from the blood
3. ) We know the Fu

Question 5

Why do we use Creatinine to estimate GFR?

Answer 5

1. ) IT is removed unchanged from the blood primarily by GFR (only a small amount by proximal tubule secretion)
2. ) Little or no tubular reabsorption occurs

Question 6

If filtration in the kidney is deficient, do serum creatinine levels rise or fall?

Answer 6

Rise

Question 7

Why is GFR important?

Answer 7

It is a measure of renal function

Question 8

Why would creatinine clearance be different in males and females?

Answer 8

Because creatinine is a byproduct of muscle metabolism and so would expect to see higher muscle mass in males.

Question 9

Name two ways that a drug administered IV would enter the liver.

Answer 9

1. ) from circulation via hepatic artery

2. ) perfuse into small intestine and drain into liver via portal vein

Question 10

Name the two components of hepatic elimination

Answer 10

1. ) Metabolism within hepatocytes

2. ) Secretion into bile

Question 11

How is bile recycled?

Answer 11

via the enterohepatic circulation i.e. the bile in the small intestines is returned to the liver via the hepatic portal vein.

Question 12

Where are cytochrome p450 enzymes expressed?

Answer 12

In the endoplasmic reticulum of cells that undertake a vast array of oxidation reactions. The liver has the highest conc and broadest range of CYP450 enzymes.

Question 13

What is the aim of metabolism?

Answer 13

To make xenobiotics (substances that weren’t produced in the body) more polar so that they can be easily excreted by the body.

Question 14

Name 2 phase one CYP reactions

Answer 14

Epoxidation, Hydroxylation, oxidation (N,S), deamination, dealkylation (N,O,S)

Question 15

Name 2 phase one non-CYP reactions

Answer 15

Oxidation

Hydrolysis

Question 16

Name two conjugations

Answer 16

Amino acids
Glucuronidation
sulphation
acetylation
methylation
Fatty acids

Question 17

What is the name of the amino acid that conjugates with the toxic metabolite NAPQI in paracetamol metabolism?

Answer 17

Glutathione

Question 18

What happens in paracetamol overdose?

Answer 18

More paracetamol is shunted to the phase 1 (CYP450) pathway to produce NAPQI. The liver’s supply of glutathione becomes depleted and so NAPQI isn’t converted into its non-toxic form. It reacts with cellular membrane molecules of hepatocytes and causes liver damage (necrosis) or even death by acute liver failure.

Question 19

How is paracetamol overdose treated?

Answer 19

N-acetyl cysteine = substitute for glutathione which replenishes the livers glutathione reserves.