Pharmacology 4 - Elementary drug metabolism

Question 1

What most drugs leave the body in?Where else are drugs excreted via? (3)

Answer 1

Urine (excretion via the bile is occasionally significant + minor contributions via exertion via the sweat or milk)

Question 2

What kind of molecule must drugs be to be excreted by the body? Why?

Answer 2

PolarSo that they can be regularly reabsorbed by the kidney facilitating excretion

Question 3

What is a xenobiotic?

Answer 3

A foreign chemical substance that is found within an organism that is not naturally produced by or expected to be present within that organism

Question 4

What does metabolism usually do in terms of rendering the activity of the drug?What are 3 other things that metabolism less rarely does to drug activity?

Answer 4

Usually make the drug less pharmacologically activeConverts them from inactive to active compounds or gain activityHave unchanged activityPossess a different type, or spectrum of action

Question 5

What is an example of a drug that gains activity during metabolism?

Answer 5

Codeine to morphine

Question 6

What is an example of a drug that has unchanged activity after metabolism?

Answer 6

Diazepam to nordiazepam

Question 7

What is an example of a drug that possess a different type, or spectrum, of action after metabolism?

Answer 7

Aspirin (anti-inflammatory and andti-platelet) to salicylic acid (anti-inflammatory with no anti-playlet activity)

Question 8

What is the main organ of drug metabolism?What other places have metabolism activity? (3)

Answer 8

LiverGI tracyLungsPlasma

Question 9

How many steps does drug metabolism usually have?

Answer 9

2 sequential steps

Question 10

What is the purpose of phase 1 drug metabolism?

Answer 10

To make the drug more polar and also to add a chemical “handle” permitting conjugation during phase 2

Question 11

What are the 3 things involved in phase 1 drug metabolism?

Answer 11

OxidationReductionHydrolysis

Question 12

What is the purpose of phase 2 drug metabolism?

Answer 12

To add an endogenous compound increasing polarity for excretion

Question 13

What is the 1 thing involved in phase 2 drug metabolism?

Answer 13

Conjugation(some drugs skip straight to phase 2 whilst some drugs are excreted unchanged)

Question 14

What are examples of the chemicals that are drugs are conjugated with during phase 2 drug metabolism?

Answer 14

GlucuronylSulphateMethylAcetyl

Question 15

What are the 2 phases of drug metabolism of aspirin (acetylsalicylic acid)?

Answer 15

Aspirin is converted to salicylic acid (OH added) before being converted to the conjugate (glucuronide) during phase 2

Question 16

What are the cytochrome P450 (CYP) family of monooxygenases?

Answer 16

Haem porteins located in the endoplasmic reticulum of liver hepatocytes (and elsewhere) mediating oxidation reaction (phase 1) of many lipid soluble drugs

Question 17

How many gene families is the Cytochrome P450 family of monooxygenases made up of?

Answer 17

74 gene families - it is a superfamily

Question 18

what are the main 3 gene families in the liver?

Answer 18

CYP1CYP2CYP3

Question 19

What are 3 examples of common cytochrome P450s?

Answer 19

CYP3A4 - accounts for 50% of metabolism of all presciription drugsCYP2D6CYP2C

Question 20

What are the basics of what happens in the monooxygenase P450 cycle?

Answer 20

Drug enter the cycle as a drug substrate, RHMolecular oxygen (O2) provides 2 atoms of oxygenOne atom of oxygen is added to the drug to yield the hydroxyl product (ROH) which leaves the cycle The second oxygen combines with protons to form H2Othis is mediated by monooxygenases

Question 21

In phase 2 reactions, what type of groups on the drugs are the endogenous molecules commonly added to?

Answer 21

Chemical reactive groups e.g. hydroxyl (OH), thiol (SH) or amino (NH2)

Question 22

What is a common reaction in phase 2 that tends to detoxify most drugs?

Answer 22

Glucuronidation

Question 23

What does glucuronidation commonly involve?

Answer 23

The transfer of glucuronic acid to electron-rich atoms on the drug (such as N, O or S ) forming amide, ester or thiol bonds

Question 24

what enzyme mediates glucuronidation?

Answer 24

UDP-glucuonyl transferase

Question 25

what are 2 endogenous substances that are subject to glucuronidaiton?

Answer 25

BilirubinAdrenal corticosteroids

Question 26

Give an example of a drug that is excreted by the kidneys very fast and drugs that are excreted by the kidneys very slowly?

Answer 26

Penicillin = extremely fastDiazepam = extremely slow

Question 27

What are the 3 basic processes by which the kidney filters?

Answer 27

Glomerular filtrationActive tubular secretionPassive reabsorption by diffusion across the tubular epithelium

Question 28

What drugs are freely filtered during glomerular filtration?

Answer 28

Drugs with a MW less than 20000 (most) provided they are not bound to large plasma proteins (which are not filtered)*drug charge is unimportant

Question 29

How do many drugs exist in the blood?

Answer 29

In an equilibrium between unbound and protein-bund forms e.g. albumin (only unbound drugs can enter the filtrate via glomerular filtration)

Question 30

What is the equation for clearance by filtration?

Answer 30

CL(fil) = GFR x fraction of drug unbound in plasma (fup)

Question 31

What is GFR?

Answer 31

The glomerularfiltration rate (normally 120ml min-1)

Question 32

What are the names of the 2 independent transporter systems that are present in the epithelial cells of the proximal tubule that actively secrete drugs into the lumen of the nephron?

Answer 32

Organ anion transport (OAT)Organic cation transporter (OCT)

Question 33

What does the organic anion transporter handle? (3)

Answer 33

Acidic drugs (e.g. penicillins)Endogenous acids (e.g. uric acid)The marker for renal plasma flow (i.e. para-aminohippuric acid)

Question 34

What does the organic cation transporter handle?

Answer 34

Basic drugs e.g. morphine

Question 35

What of the 3 mechanisms for drug elimination by the kidney is the most effective?

Answer 35

Excretion by tubular secretion e.g. benxylpenicillin and PAH

Question 36

How is the rate at which a drug is secreted from the body related to the concentration of the drug?

Answer 36

They are linearly related (as plasma concentration of drug increases, the rate of excretion also increases)

Question 37

Are the transporters across the epithelial cells of the proximal tubule able to become saturated?

Answer 37

Yes - each carrier has a transport maximum (Tm) for a particular drug

Question 38

How can drugs that are highly protein-bound be secreted?

Answer 38

By tubular secretion

Question 39

How can frusemide and thiazides lead to gout?

Answer 39

They are both excreted by the same tubular transporter system as uric acid meaning they can compete with the transport system leading to a build up of uric acid

Question 40

Why are drugs passively reabssrobed across the distal tubule by diffusion?

Answer 40

Concentration of the urine favours this

Question 41

What are the factors that influence drug reabsorption? (4)

Answer 41

Lipid solubility (drugs with high lipid solubility will be extensively reabsorbed and excreted slowly)Polarity (highly polar drugs will be excreted without reabsorption)Urine flow rate (diuresis decreases reabsorption)Urinary pH

Question 42

How does alkaline and acidic pH affect the excretion of acidic and alkaline drugs?

Answer 42

Alkaline pH = increases excretion of acidsAcidic pH = increases excretion of bases

Question 43

What can be used to accelerate the excretion of aspirin (weak acid) in the case of an overdose?

Answer 43

Can be used to accelerate the excretion of aspirin (weak acid)