Targets of Drug Action 1

Question 1

What is meant by a drug ?

Answer 1

• a chemical substance of known structure, other than a nutrient or an essential dietary ingredient, which when administered to a living organism, produces a biological effect
• may be synthetic chemicals, chemical obtained from plants or animals, or the products of genetic engineering
• substance must be administered rather than released by physiological mechanisms

Question 2

What is meant by a medicine ?

Answer 2

• a chemical preparation containing one or more drugs administered to produce a therapeutic effect
• usually contains other substances (eg. excipients, stabilisers etc)

Question 3

What is meant by Specificity ?

Answer 3

• reciprocal: drugs bind to certain targets……individual targets recognise only certain drugs
• No drugs are completely specific

Question 4

A receptor is ?

Answer 4

A recognition molecule which relays signals from extracellular mediators to intracellular signalling pathways and enzymes

Question 5

Define an agonist ?

Answer 5

An agonist is a ligand which binds to a receptor and triggers its activation

Question 6

Define an antagonist ?

Answer 6

An antagonist is a ligand which binds but does not activate the receptor

Question 7

A drug that is an antagonist will inhibit ?

Answer 7

The effects of agonists

Question 8

Example of water soluble mediators and explain ?

Answer 8

Mediators:
- hormones
- neurotransmitters
- growth factors
Mediators are amino acids or derivatives of them, or peptides – they are water soluble; cannot cross hydrophilic plasma membrane so require a plasma membrane cell surface receptor with a mechanism to transduce their signal intracellularly

Question 9

Example of hydrophobic mediators and explain ?

Answer 9

Mediators:
- steroid hormones
- thyroid hormones
Some mediators are hydrophobic so can cross the plasma membrane to interact directly with intracellular receptors

Question 10

What are the 4 different types of receptors ?

Answer 10

Type 1: Ligand-gated ion channels allowing movement of ions across the membrane (ionotropic receptors)
Type 2: G-protein-coupled receptors responsive to extracellular hydrophilic signalling molecules
Type 3: Kinase-linked and related receptors responsive to extracellular hydrophilic signalling molecules
Type 4: Nuclear “intracellular” receptors

Question 11

Within each family there is commonly several ?

Answer 11

Molecular varieties termed subtypes:

- similar structure, differing molecular sequences, often differing pharmacological profiles

Question 12

Give an example of this for Adrenaline ?

Answer 12

β1 - Maintain/stimulate heart rate
β2 - Mediate bronchodilation
β3 - Mediate lipolysis in fat cells

Question 13

Give examples of G-protein couple receptors (GPCRs) ?

Answer 13

7TM, heptahelical, ‘metabotropic’ receptors

Question 14

What does IP3 trigger and how ?

Answer 14

IP3 triggers an increase in Ca2+ in the cytosol by activating Ca2+ channels in the membrane of the ER and allowing Ca2+ to flow out of the ER into the cytosol

Question 15

What is an IP3 receptor ?

Answer 15

The Ca2+ channel in the ER membrane activated by IP3

Question 16

Explain Asthma – β2 receptor agonists ?

Answer 16

1. Reversible obstructive airway disease
2. Attacks can be life threatening
3. Wheezing, coughing, difficulty in breathing
   ~300M patients worldwide
   Mortality - ~250,000 patients per annum
4. Two characteristic features:
   - Inflammatory changes to the airway
   - Abnormal sensitivity to stimuli (hyper-reactivity)

Question 17

Adrenaline and noradrenaline will ?

Answer 17

Dilate bronchioles - occurs physiologically; not great as drugs as effects are shortlived due to short half life of adr and nadr

Question 18

Bronchodilators – mainstay of asthma management (Synthetic β2 agonists) ?

Answer 18

1. Short acting agonists eg. salbutamol, terbutaline
   - Usually delivered by inhalation
   - Duration of action: 4 – 6 hours
   - Prevents or treats wheezing in patient (rescue)
2. Long acting agonists (LABAs) eg. salmeterol
   - Taken by inhalation
   - Duration of action: 12 hours
   - Prevents bronchospasm (eg. at night or after exercise) in patients requiring long term bronchodilator therapy
   - May be combined with anti-inflammatories (steroids) and muscarinic antagonists (LAMAs)
3. Longer duration drugs in clinical testing (24 hours) eg. indicaterol

Question 19

Describe Type 3 receptors: Kinase linked and related ?

Answer 19

• Large group of receptors on the plasma membrane with single transmembrane spanning helix
• Receptor on outside and an inactive enzyme on inside - most often a kinase
• Most are receptor tyrosine kinases (RTK)
  eg. receptors for growth factors such as EGF & NGF

Question 20

Describe Type 4 receptors:

Nuclear receptors ?

Answer 20

1. Target of hydrophobic hormones
   - steroid and thyroid hormones
2. Unique characteristics
   - Receptor can interact directly with DNA - separate ligand receptor and DNA-binding domains
   - Monomeric structure, not embedded in membranes
3. Type 1: Cytosolic
   - normally in an ‘inactive’ state in association with an inhibitory protein (e.g. HSP90)
   - Following interaction with ligand, the inhibitory protein is released & complex migrates into the nucleus
4. Type 2: Nuclear
   - Function as heterodimer with RXR
   - bound to co-repressor, dissociates on ligand binding

Question 21

What is meant by receptor desensitisation ?

Answer 21

When the drugs don’t work (as well as they used to)

Question 22

What is meant when a receptor is said to be dynamic?

Answer 22

Respond in response to stimulation and can change rapidly

Question 23

Define desensitisation or tachyphylaxis ?

Answer 23

Effect of drug or hormone diminishes suddenly/rapidly

Question 24

Define Tolerance ?

Answer 24

Gradual decrease in response to drug

Question 25

Define Refractoriness ?

Answer 25

Complete loss of therapeutic efficacy

Question 26

Define Resistance ?

Answer 26

Loss of effectiveness of anti-microbial or anti-tumour drugs