Molecular aspects of drug action

Question 1

List the four main targets of drug action

Answer 1

All the major targets for drug action are proteins. There are four main categories of protein that drugs act on:
- Transporters
- Ion channels
- Receptors (Type 1-4)
- Enzymes ^[(And exceptions)]
or “TIRE”

Question 2

List the four types of receptors targeted by drugs

Answer 2

1. Ligand-gated ion channels
2. GPCRs
3. Kinase linked and related receptors
4. Nuclear receptors

All are examples of transmembrane signalling mechanisms

Question 3

Describe transporters

Answer 3

Transporters are required to allow passage across cell membranes when passive diffusion is not possible

Transporters factilitate transport across cell membranes.

Passive transport (diffusion) can occur with carrier-mediated transporters.

But, the most common form of transport is active transporters

Hydrolysis of ATP (adenosine triphosphate) creates energy to actively pump a substance across a membrane against an electrochemical gradient

Secondary Active Transporters:

Transporter uses the energy created by transporting an ion down it’s electrochmical gradient to transport another molecule simultaneously against it’s electrochemical gradient.

Symporter:  A transporter that moves both molecules across the membrane in the same direction
Antiporter:  Molecules move across the membrane in opposite directions

Examples of drugs:
e.g. Omeprazole - proton pump inhibitor
Suppresses acid secretion in the stomach by 80-95%
(can be useful in gastro-esophageal reflux disease, and to aid healing of gastric ulcers); on H/K ATPase; prodrugs, irrev comp antag–need to resynthesise pumps beforeacid secretion can resume, takes longer than drug re-converts to original form

e.g. furosemide - loop ascending limb - inhibitor of na k 2 cl smymporter- HT, congestive heart failure (Chronic) and acute pulmonary oedema

e.g digoxin, cardiac glycoside – potent, selective NA/K/ATPase

Question 4

Describe ion channels

Answer 4

Proteins embedded in cell membrane that control the flow of ions into and out of the cell

Ions can only pass through an ion channel down their electrochemical gradient from a compartment of higher ion concentration to a compartment containing lower ion concentration

The rate of flow through the channel is very high

*Drugs target ion channels (eg)

Amiloride (weak diuretic - blocks sodium channels)
Verapamil (Calcium channel blocker)

Question 5

Describe enzymes

Answer 5

Biological catalysts that control biochemical reactions within the cell

Drugs can either ACTIVATE or INHIBIT enzyme activity to alter a physiological response

Eg Warfarin inhibits the enzyme Vitamin K epoxide reductase --> prevents activation of vitamin K1--> blocks the production of vitamin K1-dependent clotting factors

Drugs that interact with enzymes often resemble substrate structure of the enzyme

Question 6

Describe ligand gated ion channels

Answer 6

Type 1 - Ligand gated ion channel (Membrane bound channels)

Activated when a ligand binds to a specific site on the protein. May be induced to open or close.

Rapid response (milliseconds)

Responsible for functions such as:

Central and peripheral synaptic transmission mediated by neurotransmitters

Example: Nicotinic (acetylcholine) receptors; GABA receptors

Question 7

Describe GPCRs

Answer 7

At least 800 different types

Mediate response of hormones and neurotransmitters

Stimulate GTP binding protein which modulate intracellular second messenger

Takes seconds to respond

Effector can be a channel or enzyme

Example: Muscarinic (acetylcholine); beta (adreno); opioid

Question 8

Describe kinase linked transmembrane recpeors

Answer 8

Response takes hours

Receptors are linked to processes that alter gene transcription and protein synthesis

Example:

Tyrosine kinase receptor
Insulin
Growth factors
Cytokine receptors

Question 9

Describe nuclear receptors

Answer 9

Regulate gene transcription

Require binding of various other molecules prior to translocation to the nucleus (interact with specific response elements on genes)

Response time is hours (new proteins are synthesised)

Example:

Steroid hormone receptors

Question 10

Describe the changes that receptors can undergo

Answer 10

Tachyphylaxis:

Diminished response of receptor after repeated exposure to the same concentration of drug

Desensitisation:

Decreased response of the receptor-second messenger system

Downregulation:

A decrease in the number of receptors
Can contribute to desensitisation and loss of response

Upregulation:

An increase in receptor number
Can cause receptor hypersensitivity
Often occurs after chronic use of drugs that block receptors à drug removed à patient experiences ↑ response to stimuli