S9-10) Pharmacodynamics Flashcards

1
Q

How do drugs exert their effects?

A

Drugs exert their effects by binding to a target (mainly proteins)

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2
Q

The concentration of drug molecules around receptors is critical in determining drug action.

Account for the measure of concentration

A

Concentration is measured in terms of molarity

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3
Q

What are the prefixes for the following:

100

10-3

10-6

10-9

10-12

A
  • Molar (M): 100
  • Millimolar (mM): 10-3
  • Micromolar (μM): 10-6
  • Nanomolar (nM): 10-9
  • Picomolar (pM): 10-12
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4
Q

Why do most drugs bind reversibly to receptors?

A

Binding is governed by association and dissociation

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5
Q

What are the two effects of most drugs?

A
  • Agonist: activate a receptor
  • Antagonist: block the binding of an endogenous agonist
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6
Q

How do drugs act on receptors?

A
  • They must bind to the receptor
  • They must have an affinity for the receptor in order to bind
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7
Q

After the receptor is activated, things must occur to evoke a response.

What is the concept that governs this?

A
  • Efficacy is the ability of a ligand to evoke a response
  • Activation is governed by intrinsic efficacy (agonists only)
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8
Q

Compare and contrast efficacy in agonists and antagonists

A
  • Agonists have affinity, intrinsic efficacy and efficacy
  • Antagonists have affinity only (no efficacy)
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9
Q

Binding is how we quantify drug-receptor interaction.

In light of this, what is Kd?

A
  • Kd = dissociation constant
  • Kd is the concentration of ligand (drug) required to occupy 50% of available receptors
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10
Q

Which of the following drugs have a higher affinity?

  • Drug A: Kd = 10-9
  • Drug B: Kd = 10-3
A
  • Drug A as a lower concentration is required to occupy 50% of receptors
  • For Kd, the lower the value, the higher the affinity (reciprocal)
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11
Q

Why is affinity important for ligands?

A

High affinity allows binding at low concentrations of hormones, neurotransmitters and drugs

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12
Q

What form of regression does drug concentration follow?

A

Logarithmic

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13
Q

The terms concentration and dose are often used interchangeably.

Distinguish between them

A
  • Concentration is the known amount of drug at site of action
  • Dose is the amount of drug at site of action is unknown
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14
Q

What is potency?

A
  • Potency (EC50) is the effective concentration giving 50% of the maximal response
  • It depends on both affinity and intrinsic efficacy plus cell/tissue specific components
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15
Q

How do cell/tissue dependent factors such as receptor number influence agonist potency?

A
  • ‘The greater the receptors = the greater the response’ is not always true
  • Response is often controlled/limited by other factors
  • E.g. a muscle can only contract so much, a gland can only secrete so much*

This revolves around the concept of spare receptors

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16
Q

What does the presence of spare receptors indicate?

A

Spare receptors means < 100% occupancy = 100% response

17
Q

Spare receptors allow for amplification is a signal transduction pathway.

In terms of GPCRs, illustrate this.

A

A few adrenaline molecules can cause a massive cellular response:

  • The β-adrenoceptor → Gs protein → adenylyl cyclase part of the cascade causes relatively little amplification
  • Nevertheless, activation of adenylyl cyclase generates many molecules of cyclic AMP which then activate the enzyme PKA
18
Q

Why are there spare receptors?

A
  • Spare receptors increase sensitvity
  • It allows responses at low concentrations of agonist
19
Q

What is the effect of changing receptor number?

A

Changing receptor number changes agonist potency and can affect the maximal response

20
Q

Discuss the relevance of altered receptor number

A

Receptor numbers are not fixed:

  • Tend to increase with low activity (up-regulation)
  • Tend to decrease with high activity (down-regulation)
21
Q

What are full and partial agonists?

A

Partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist

22
Q

In terms of EC50, compare and contrast partial and full agonists

A
  • Full agonist: EC50 < Kd

- Partial agonist: EC50 = Kd

23
Q

Describe the properties of a partial agonist

A
  • Lower intrinsic activity
  • Lower efficacy
  • Insufficient intrinsic efficacy for maximal response
24
Q

What is the clinical relevance of partial agonists?

A
  • Allows for a more controlled response e.g. adequate pain control
  • Works in the absence/low levels of endogenous ligand
  • Acts as antagonist if high levels of full agonist
25
Q

How can a partial agonist become a full agonist?

A

Increasing receptor number – there is still low intrinsic efficacy at each receptor, but enough receptors to produce a full response

26
Q

Antagonists block the effects of agonists.

What are the three types of antagonism?

A
  • Reversible competitive antagonism
  • Irreversible competitive antagonism
  • Non-competitive antagonism
27
Q

Outline reversible competitive antagonism

A

In reversible competitive antagonism, antagonists compete with agonists for binding:

  • Inhibition is surmountable
  • Greater [antagonist] = greater inhibition
28
Q

What is IC50?

A

- IC50 is the concentration of antagonist giving 50% inhibition

  • It is the index of antagonist potency and is determined by [agonist]
29
Q

Outline irreversible competitive antagonism

A

In irreversible competitive antagonism, the antagonist dissociates slowly or not at all:

  • Parallel shift to the right as spare receptors are filled by antagonist
  • Maximal response suppressed at [higher] due to insufficient receptors for full response
  • Non-surmountable
30
Q

Outline non-competitive antagonism

A

In non-competitive antagonism, the antagonist binds to allosteric site:

  • No competition for binding site
  • Thus, negative allosteric modulation