BP 7 - Pharmacokinetics: Metabolism and Excretion

Question 1

What is enterohepatic recirculation?

Answer 1

Drugs eliminated in bile is reabsorbed in the GIT

Question 2

Name some drugs that undergo enterohepatic recirculation.

Answer 2

morphine, erythromycin, oral contraceptives, lorazepam

Question 3

What major systems are involved in elimination of drugs from the body?

Answer 3

Kidneys, hepatobilary system and lungs

Question 4

What is drug metabolism?

Answer 4

Enzymatic modification of the drug

Question 5

Where is the major site of metabolism of drugs in the body?

Answer 5

Liver

Question 6

What are the phases of drug metabolism?

Answer 6

Phase 1 - mainly oxidation, reduction/hydrolysis - converting drug into derivative
Phase 2 - conjugation - converting derivative into conjugate

Question 7

What is the function of the cytochromes P450 in metabolism?

Answer 7

They drive phase 1, used to expose the functional group (e.g. OH)

Question 8

If the drug decreases lipid solubility in phase 1 metabolism reactions, what occurs?

Answer 8

Increases pharmacological or toxological activity

Question 9

What are cytochrome P450’s?

Answer 9

Heme cofactor-containing enzymes

Question 10

What are the location of CYPs?

Answer 10

In the endoplasmic reticulum of all cells

Liver hepatocytes (high CYP in the body)
Intestine enterocytes 
Kidney, nasal passages, WBCs

Question 11

Describe the CYP reaction.

Answer 11

Redox reaction - adding and removing electrons - heme group catalyses process

Question 12

Where is ethanol completely metabolised?

Answer 12

Liver

Question 13

Describe the ethanols metabolism.

Answer 13

Ethanol to acetaldehyde catalysed 2/3 by alcohol dehydrogenase and 1/3 by CYP2E1 (more with chronic administration)

Acetaldehyde to acetic acid catalysed by aldehyde dehydrogenase

Question 14

What enzyme in ethanol metabolism does metronidazole inhibit?

Answer 14

Aldehyde dehydrogenase

Question 15

Where are groups conjugated in phase 2 metabolism?

Answer 15

The exposed functional group

Question 16

Where is the conjugate in phase 2 metabolism excreted?

Answer 16

Urine or bile

Question 17

What is the most common conjugation reaction?

Answer 17

Glucuronidation

Question 18

How is glucuronidation mediated?

Answer 18

UDP-glucuronyl transferases

Question 19

Why is glucuronidation rapidly excreted?

Answer 19

Due to polar planes making them inactive

Question 20

What is conjugated with paracetemol usually?

Answer 20

Mainly sulfate and glucuronic acid

Minor by CYP450 to a toxic metabolite which is usually detoxified by glutathione

Question 21

What occurs in the overdose of paracetamol?

Answer 21

Conjunction pathways are saturated and co-factors lower as more is being metabolised via CYP450
Toxic metabolite reacts with liver proteins instead of glutathione (depleted)
Tissue damage occurs leading to hepatic necrosis

Question 22

What drug is rapidly cleared from the blood in renal excretion?

Answer 22

Penicillin

Question 23

What drug is slowly cleared from the blood in renal excretion?

Answer 23

Diazepam

Question 24

What are in the processes in renal excretion

Answer 24

Glomerular filtration
Tubular reabsorption
Tubular secretion

Question 25

What drugs go unchanged through the kidneys?

Answer 25

Water soluble drugs

Question 26

What is the process of lipid soluble drugs within the kidney?

Answer 26

Filtered into glomeruli, then reabsorbed on the distal portion of the nephron, then metabolism to more polar compounds and excreted in urine

Question 27

What molecular weight and plasma albumin can not enter the glomerular filtrate?

Answer 27

(MW) <20000

68000

Question 28

What is the ppb of warfarin?

Answer 28

98%, therefore 2% of drug is in the plasma

Question 29

Where does renal blood flow pass?

Answer 29

20% in through the glomerulus

80% on the peritubular capillaries of the proximal tubule

Question 30

What is tubular reabsorption dependent on?

Answer 30

Drug lipid solubility

pH of the tubular fluid

Question 31

What is the result of pH partition?

Answer 31

Rate at which drugs permeate membs and distribution of drug between aq compartments

Question 32

What drugs will be exerted in urinary acidification?

Answer 32

Weak bases

Question 33

What drugs will be exerted in urinary alkalisation?

Answer 33

Weak acids

Question 34

What does the clearance parameter measure?

Answer 34

Ability of the eliminating organs to remove a compound from the body

Question 35

How do your work out the clearance of a drug?

Answer 35

Vol of plasma/(blood) cleared of the compound per unit time

Question 36

What is the half life of a drug?

Answer 36

Time for conc of compound to reach 50% of its current value

Question 37

How many half lives does it take for a drug to leave the body?

Answer 37

6

Question 38

What is the induction of drug metabolising enzymes?

Answer 38

Increased synthesis of enzymes (phase I and II)

Question 39

What are the drawbacks of induction?

Answer 39

Decreased drug effectiveness on chronic exposure
Need to increase drug dose
May be problems when inducer is removed
Basis of many drug-drug interactions, e.g. rifampicin and oral contraceptives

Question 40

What 2 factors act as drug inducers?

Answer 40

Smoking and ethanol

Question 41

What occurs with the inhibition of metabolising enzymes?

Answer 41

Inhibition of the CYP system caused by many drugs

Reduced rate of metabolism and increased pharmacological effect

Question 42

What is commonly consumed and acts as an acute drug metabolism inhibitor?

Answer 42

Ethanol