Lecture 13 - enzymes and alcohol

Question 1

Why are enzymes important in pharmacology?

Answer 1

• Drug metabolism
- Enzymes remove drugs and other substances from the body
- Changes in their activity can change individual drug responses
• Drug targets
- Enzymes can be inhibited to change disease pathology`

Question 2

What do we need to know about enzymes in order to develop specific treatments?

Answer 2

Targets and the effects of the enzyme

Question 3

What two enzymes are involved in alcohol/ethanol metabolism?

Answer 3

Alcohol dehydrogenase

Aldehyde dehydrogenase

Question 4

Drug metabolism of alcohol

Answer 4

Ethanol (alcohol) to Acetaldehyde (aldehyde) to Acetic acid (made into this so it can be excreted)

Alcohol dehydrogenase turns alcohol into aldehyde

Aldehyde dehydrogenase turns aldehyde into acetic acid

Question 5

Alcohol dehydrogenase

Answer 5

ADH processes all alcohols
Hard to clear if intake greatly exceeds metabolism i.e. binge drinking
Produces NADH and acetaldehyde (is toxic and therefore must be cleared quickly)
It will preferentially clear substrates with a lower Km - lower km means higher affinity which means that it will bind more easily
Redox reaction

Question 6

Bad hangover is a result of …

Answer 6

Build up of acetaldehyde

Question 7

Substrate preferences of ADH

Answer 7

Kinetic parameters can help you

Lower Km can be metabolised quicker to prevent toxicity for example

Question 8

Ethylene Glycol metabolism and toxicity

Answer 8

Also known as antifreeze

Ethylene glycol (alcohol) —> (using alcohol dehydrogenase) Glycoaldehyde —> (using aldehyde dehydrogenase) Glycolic acid (glycolate, toxic effects) —> Glyoxylic acid —> Oxalic acid and Glycine to …..

Glycolic acid, ethylene glycol and oxalic acid all have toxic effects

Question 9

How do drugs act?

Answer 9

“Drug molecules must exert some chemical influence on one or more chemical constituents of cells in order to produce a pharmacological response.”

Drugs bind to things in cell and change stuff (to do this they often interact with cellular proteins)

Question 10

Receptors

Answer 10

Traditionally drugs bind receptors which come in lots of shapes and sizes
Some receptors form a channel across the membrane 
Some receptors transmit a signal across the membrane 
Some receptors are membrane bound enzymes 
Some receptors are intracellular and won’t be covered in these lectures

Question 11

Enzyme vs receptor

Answer 11

Enzyme
Generally one active site 
Binds substrates 
Changes substrate into product 
Can be membrane bound or free in cytosol 

Receptor
Several binding sites 
Binds ligands 
Releases ligand unchanged 
Can be membrane bound or free in cytosol 

Both can be used as drug targets but the language is different

Question 12

Receptor

Answer 12

a protein molecule that receives chemical signals from outside a cell

Question 13

Ligand

Answer 13

A molecule, or drug, that binds to a receptor. Includes both agonists and antagonists

Question 14

Agonist

Answer 14

A chemical capable of activating a receptor to induce a response

Increases the action of the receptor

Question 15

Antagonist

Answer 15

A drug that blocks the receptor and stops the effects of another drug or molecule

Blocks the action of the receptor

Question 16

Alcohol is an …

Answer 16

Agonist at the GABAa receptor

Receptor in the brain, binds to receipt and causes (inhibitory) response

Question 17

GABAa receptor

Answer 17

The GABAA receptor is a membrane bound ligand gated chloride channel 

It’s main effects are inhibitory (i.e. it damps down responses to other stimuli) 

It has many ligands including benzodiazepines (sedatives), barbiturates (sedatives) and alcohol (ethanol) 

5 subunits with multiple binding sites, with a ligand bound it will cause the gate to open and let through Cl-

GABA is a ligand gated ion channel

Question 18

Alcohol and GABAa

Answer 18

Agonist binding opens the channel and allows chloride ions (Cl-) into the cell 

This decreases the general activity in the nervous system (brain) 
• Causes loss of co- ordination, memory loss, slurred speech etc. 

Effects are dose dependant
Lower doses are associated with loss of inhibitions and relaxation. 
Too much alcohol results in a coma or death.

Question 19

Mechanism of alcohol and GABAa receptors

Answer 19

Alchohol binds - conformational change - channel opens - Cl- into cell - hyper polarisation - INHIBITORY effects

Question 20

Ethylene glycol and GABAa

Answer 20

Ethylene glycol is also an agonist for the GABAa receptor and therefore inhibits activity in the brain causing symptoms of drunkenness

Question 21

Beer and paracetamol

Answer 21

They interact and form a toxic relationship

Question 22

How does specifically inhibiting certain enzymes lead to a therapeutic effect?

Answer 22

The binding of an inhibitor can stop a substrate from entering the enzyme’s active site and/or hinder the enzyme from catalyzing its reaction.