L3- antagonists and dose repsonse curves

Antagonist

A drug which blocks the response to an agonist

How do agonists cause an action

Cannot cause an action by themselves- must work in the presence of an agonist

Stages of atangonist action (3)

• antagonist binds to recptor

• Form antagonist receptor complex

• Causes effect

Example of an antagonist (3)

• propanolol binds to b-adrenoreceptro

• Forms propanolol b-adrenoreceptor complex

• Blood pressure decreases

General classes of antagonists (3)

• chemical

• Physiological

• Pharmacological

Chemical antagonists (Method, common name, example) (3)

• is the binding of two agents to render active drug inaction

• Commonly called chelating agents

• Eg Protamine binds and sequesters heparin

Physiological antagonists (effect and exmapel) (2)

• when 2 agents with opposite effects cancel each other out

• Glucocorticoids and insulin

Pharmacological antagonist (action)

Binds to receptor and blocks the normal action of an agonist on receptor responses

Types of non receptor antagonists

Chemical and physiological antagonists

Types of receptor antagonists

Active site binding and allosteric binding

Active site binding antagonists

Antagonists binds to the same site as the agonist blocking it

Types of active site binding

Reversible and irreversible

What are reversible active site binding agonists called and what can they be overcome by

Competitive → overcome by increasing concentration of agonist

What are irreversible active site binding antagonists called and what cn they be overcome by

non competitive → cannot be overcome as they bind to the same site as the agonist but irreversibly

What happens in non competitive antagonist allosteric binding g

Antagonist bins to allosteric site so agonist can no longer bin to active site

Efficacy of antagonist

Has no efficacy as cannot cause effect on its own

What happens to EC50 if the agonist response curve shifts to the right

EC50 increases and potency decreases

Types of pharmacological antagonism (3)

• competitive

• Irreversible (non comp active site)

• Non competitive (allosteric site)

How does competitive pharmacological antagonism work and what effect on teh agonist response curve does it have

• Binds and prevents agonist action but can be overcome with increased agonist concentration

• causes parallel shift to the right on the agonist response curve

How does irreversible pharmacological antagonism work and what effect on teh agonist response curve does it have

• binds and forms irreversible covalent bonds woth the receptor

• Causes parallel shift to the right of the agonist response curve and a reduced maximal asymptote

How does non competitive pharmacological antagonism work and what effect on teh dose response curve does it have

• Is signal rasnduction rather than recepotr effects

• The downstream responses ae blocked

• Reduces the slope and max of dose response curve

What does the pA2 value describe

Teh activity of a receptor antagonist in simple numbers- is the neg log of the molar conc of antagonist required to produce an agonist dose ration equal to 2

How to calculate pA2 value

pA2= -log Kb

When can pA2 values be calculated

Only is teh relationship is linear nad the slop of the Schild plot =1 eg only if it is a comp antagonist

What does the extent of antagonist inhibition depend on

The concentration o the cmoeteing agonist

How does teh concentration of competing agonist vary

Varies in response to physical activity, disease and person to person → not everyone has the same resonse to the same drug

What does the extent of agonist inhibition depend on

The antagonists concentration → inter individual difference in metabolism of clearance influence plasma concentrations

Effect of irreversible antagonist on the agonist curve and why (3)

• do not have same form

• Have reducedmaximal response and shift slightly to right because of this

• Because the antagonist binds irreversible to gives rise to antagonism that cant be overcome by an increased conc of agonist

What is teh effect of irreversible antagonism on EC50 And max response and why (3)

• increases EC50, decreases max repsonse

• The duration of the effect is related to receptor turnover

• Receptor reserves allwo teh parallel shift to the right but max effect is still decreased

Whic is the more common type of antagonist comp or Ii reversible

Competitive

Examples of competitive antagonists (2)

• Cimetidine at H2 recptor

• tamoxifen at oestrogen recptor

How can tamoxifen be both a comp antagonist and a partial agonist

Depends on the setting int he body

• can be used in breat cancer treatment

• Can also be used to prevent osteoporosis in post menopausal women

Example of irrverble antagonist

Phenoxybenzamine at the alpha 1 adrenoceptor

How does the non comp antagonist work and what effect on slop, max effect and ec50 does it have

• blocks signal transduction events

• Reduces the slop and maximal effect

• Increases EC50

Why cant non comp antagonism be overcome by increases the concentration of agonist

they aren’t working a the same site

Therapeutic window

the dose range between therapeutic and toxic effects

Equation for therapeutic window/index

TD50/ ED50 or LD50/ED50

Where:

• TD50/LD50 is the toxic dose that causes unwanted effects

What doe s a low herpeuti index suggest

Narrow therapeutic window

What drug has a small TI

Warfarin

Which drugs have wide TI (3)

• penicillin

• Ibuprofen

• Paracetamol