Mechanism of drug action

Question 1

What are the 4 drug target sites?

Answer 1

receptors
ion channels
transport systems
enzymes

Question 2

Discuss about receptors as target sites.
where...
activated by...
defined by...
how many types... grouped according to...
drug examples

Answer 2

• within cell membranes - except steroid intracellular receptor
• activated by neurotransmitters and hormones
• defined by agonists and antagonists - the term is specific to the receptor
• 4 types - grouped by molecular structure and transduction system
• ACh(agonist) and atropine(muscarinic cholinoceptor antagonist)

Question 3

Discuss about ion channels as target sites.
types
drug examples

Answer 3

• selective pores down conc gradient

- 2 types: voltage sensitive (VGSCs)
                receptor linked (nicotinic acetylcholine receptor)

• local anaesthetics: VGSCs blocks -> slows propagation -> reduce perception of pain
  Ca2+ channel blocker: reduce Ca2+ influx in smooth muscle cell - antihypertensive

Question 4

Discuss about transport systems as target sites.

drug examples

Answer 4

• against conc gradient
• tricyclic antidepressants: slow down NA uptake -> prolonged NA effects (depression = NA transmission not optimal)
  cardiac glysocides: slow down Na/K ATPase -> increase intracellular Ca2+ conc -> increase heart contractility - cardiac stimulant

Question 5

Discuss about enzymes as target sites.
3 drug interactions
unwanted effects

Answer 5

1. enzyme inhibitors: eg. anticholinesterases
   - slows down ACh metabolism
2. false substrates: eg. methyldopa - antihypertensive
   - takes place of DOPA in NA synthesis pathway -> methyl NA produced -> is a less effective NA(vasoconstrictor) -> TPR reduce -> BP reduce
3. prodrugs: eg. chlorate hydrate - insomnia treatment
   - activated after interaction with enzymes in the body
   - chlorate hydrate -> trichloroethanol in liver

• paracetamol: metabolised in the liver
  - overdosed -> liver enzymes saturated -> metabolised by different enzyme -> harmful metabolites released -> liver and kidney damage
  - irreversible, delayed onset

Question 6

Give 3 non-specific drug actions.

Describe.

Answer 6

1. general anaesthetics
   - dampen synaptic transmission
   - no specific receptors or transport system
2. antacids - dyspepsia and indigestion treatment
   - reduce acidity of stomach contents
   - Al/Mg hydroxides
3. osmotic purgatives - laxatives, stimulate voiding
   - draws water into the stomach -> soften stools and increase gut volume

Question 7

What is protein plasma binding. What is the significance?

Examples.

Answer 7

• drugs binding to plasma albumin
• reservoir of inactive drug - not produce physiological response
• determines distribution of drug
• Warfarin, Aspirin

Question 8

What is...?
agonist - examples
antagonist - examples
potency - depends on...
full agonist
partial agonist
selectivity
structure-activity relationship

Answer 8

agonist: binds to receptor and stimulates it - change receptor conformational shape (eg. ACh, nicotine)
antagonist: interacts with receptors but not generate a response (eg. atropine, hexamethonium)
potency: depends on affinity(ability to bind to receptor) and efficacy(ability to induce change of receptor conformational shape)

partial agonist: cannot generate maximal tissue response (not enough efficacy)
- full agonist + partial agonist => partial agonist act as antagonist

selectivity: interacts with few other receptors, preference rather than specificity

structure-activity relationship: small change of drug structure can change agonist to antagonist

Question 9

Describe log dose-response curve.

Answer 9

• full agonist with lower affinity requires higher dose to reach maximal tissue response
• partial agonist will never reach maximal tissue response - peaks before reaching maximal tissue response

Question 10

Describe antagonist referring to affinity and efficacy.

What are the 2 types of antagonist? Give examples.

Answer 10

affinity but no efficacy

competitive: - act on the same site as agonist
- surmountable (agonist still able to reach maximal tissue response if given in enough dose)
- shift D-R curve to the right
- atropine (competitive muscarinic cholinoceptor antagonist)
propranolol (non-selective beta blocker)

irreversible: - act on a different site or binds tightly (covalently)
- insurmountable
- hexamethonium (irreversible nicotinic cholinoceptor antagonist)