Pharmacodynamics 2 - Partial Agonists & Antagonists Flashcards

1
Q

What is the difference between full and partial agonists?

A

Full agonist

  • EC50 < or = to Kd
  • +/- spare receptors
  • higher intrinsic activity

Partial agonist

  • EC50 about Kd
  • no spare receptors (all receptors occupied but insufficient intrinsic activity for maximal response)
  • lower intrinsic activity
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2
Q

What is intrinsic activity?

A

Measure of maximal response.

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3
Q

Why do partial agonists have a lower intrinsic activity than full agonists?

A

They have lower efficacy - usually lower intrinsic efficacy (don’t quite stimulate correct conformational change).
May still have high potency due to high affinity.

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4
Q

How can a partial agonist be changed into a full agonist?

A
  • By increasing receptor number - still has low intrinsic efficacy at each receptor but sufficient receptors to generate a full response.
  • Partial agonism is compound and system dependent.
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5
Q

What are the different types of antagonism?

A
  1. Reversible competitive antagonism (most common)
  2. Reversible non-competitive antagonism
  3. Irreversible antagonism
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6
Q

What is reversible competitive antagonism?

A
  • Antagonist competes with agonist for binding site.
  • Greater [antagonist] = greater inhibition.
  • Inhibition is surmountable by increasing [agonist].
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7
Q

What is IC50?

A
  • Concentration of antagonist giving 50% inhibition (50% agonist response).
  • Index of antagonist potency.
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8
Q

What is the effect of a reversible competitive antagonist on [agonist]-response curve?

A

Parallel shift to the right

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9
Q

Give a clinical example of a reversible competitive antagonist.

A
  • Naloxone = high affinity, competitive antagonist at u-opioid receptors.
  • Can be used clinically in reversal of opioid-mediated respiratory depression (e.g. In heroin overdose).
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10
Q

What is irreversible competitive antagonism?

A
  • When the antagonist dissociates slowly or not at all from the receptor.
  • Non-surmountable
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11
Q

What is the effect of a irreversible competitive antagonist on [agonist]-response curve?

A
  • Causes a parallel shift to the right

- At higher concentrations, suppresses the maximal response (as insufficient receptors)

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12
Q

Give a clinical example of an irreversible competitive antagonist.

A
  • Phenoxybenzamine = non-selective irreversible alpha1-adrenoreceptor blocker used in hypertension episodes in pheochromocytoma (tumour of adrenal chromaffin cells).
  • Inhibits the vasoconstriction stimulated by excessive adrenaline/NA binding to alpha1 adrenoRs.
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13
Q

What is non-competitive antagonism?

A
  • Generally allosteric, sometimes post-receptor.

- Binding to allosteric site reduces orthosteric ligand affinity and/or efficacy.

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14
Q

Give a clinical example of a non-competitive antagonist.

A

Maraviroc used in AIDS: negative allosteric modulator of chemokine receptor 5 (CCR5) - blocks HIV entry into cells.

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15
Q

What is the effect of opioids?

A

Act primarily through u-opioid receptor (GPCR) in:

  • pain relief
  • euphoria
  • BUT respiratory depression - can lead to death
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16
Q

Name an example of an agonist and a partial agonist of u-opioid receptors. Which has the higher affinity and efficacy?

A
  • Agonist = morphine
  • Partial agonist = buprenorphine

Buprenorphine has lower Kd so higher affinity, but lower efficacy (inability to produce full response).

17
Q

Why can buprenorphine be used in the treatment of opioid addiction?

A
  • Enables gradual withdrawal.
  • Prevents use of other illicit opioids as can provide antagonism: has higher affinity than heroin so occupies receptors and limits response.
18
Q

Which receptors are targeted by agonists used in asthma treatment?

A
  • Stimulation of beta2-adrenoreceptors in lungs to promote bronchodilation (smooth muscle relaxation).
  • But may also act on other beta-receptors, e.g. Beta1 in heart - increases inotropy and chronotropy.
19
Q

Name 2 drugs used in the treatment of asthma.

A
  • Salbutamol

- Salmeterol

20
Q

Which problems are associated with the use of salbutamol?

A
  • Has a Kd of 20uM for Beta1 Rs, and of 1uM for Beta2 = only 20-fold more beta2 selective.
21
Q

How is the utility of salbutamol enhanced despite poor beta2 selectivity?

A
  • Has beta2-selective efficacy (less drug required to activate beta2 than beta1).
  • Route of administration (preferentially target airways).
22
Q

Describe the selectivity of salmeterol for beta adrenoRs. What is it based on?

A
  • Has Kd of 1900 nM for Beta1, and of 0.55 nm for Beta2 - 3455-fold more Beta2-selective.
  • Has no selective efficacy (once bound will bind to anything) - selectivity is based on affinity.