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ICPP > ICPP S9 Pharmacodynamics > Flashcards

ICPP S9 Pharmacodynamics Flashcards

1
Q

What is pharmacodynamics?

A

Branch of pharmacology concerned with the effects of drugs and the mechanism of their action.
Is the study of how a drug affects the body.

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2
Q

What is a ligand?

A

A substance that binds to a receptor to cause a measurable biological response.

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3
Q

What are ligand concentrations at receptors usually?

A

In the nanomolar range.

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4
Q

What is ligand binding governed by?

A

Association and dissociation.

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5
Q

What laws do ligands obey in terms of binding?

A

Le Chateliers Principle

Law of mass action.

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6
Q

What is an antagonist?

A

A ligand that blocks the binding of an endogenous ligand.

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7
Q

What is an agonist?

A

A ligand that binds to the receptor, activating it.

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8
Q

What is receptor activation governed by?

A

Intrinsic efficacy

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9
Q

What is intrinsic efficacy?

A

How well a ligand can activate a receptor?

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10
Q

What is efficacy?

A

How well the drug/ ligand causes a measurable response.

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11
Q

What is affinity?

A

How well a ligand/ drug binds to the receptor.

A measure of attraction between the ligand and receptor.

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12
Q

What do agonists have that antagonists don’t have?

A

Agonists have intrinsic efficacy and efficacy, whereas antagonists only have affinity.

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13
Q

What is clinical efficacy?

A

A measure of how well a treatment succeeds in achieve in its aim.

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14
Q

What is pharmacological efficacy a combination of?

A

Affinity, intrinsic efficacy and efficacy.

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15
Q

How can we measure binding of ligand to a receptor?

A

Incubate radioligands with receptors (either on cell or membranes prepared from cells) and then separate bound and free receptors and measure the amount of bound radioligand.

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16
Q

On what graph can we plot Bmax and Kd?

A

Receptor occupancy - concentration.

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17
Q

What is Bmax?

A

The maximum number of receptors.

Maximum possible binding capacity of the drug.

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18
Q

What is Kd?

A

Concentration of drug at which 50% of the receptors are occupied.

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19
Q

What does Kd indicate?

A

Kd is a measure of the affinity of the drug aka the strength of interaction.

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20
Q

What does a low Kd value indicate?

A

A lower Kd indicates increased affinity, because a lower concentration of drug is needed to occupy 50% of the receptors.

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21
Q

Is concentration of a drug usually fall into a linear or logarithmic pattern?

A

Logarithmic.

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22
Q

What shape does a response/occupancy-concentration graph take if X axis is logarithmic?

A

Sigmoidal

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23
Q

Response graphs can be drawn for agonists and antagonists, true or false?

Explain your answer.

A

False, response requires drug efficacy which antagonists can not achieve.

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24
Q

What could a biological response be?

A
  • Change in a signalling pathway.

- Change in cell or tissue behaviour.

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25
Q

What can we see/ plot onto a response - concentration graph?

A

Emax, EC50.

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26
Q

What is Emax?

A

The maximal response/ effect possible.

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27
Q

What is EC50?

A

The concentration of drug needed to create 50% of the maximal response.

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28
Q

What is EC50 a measure of?

A

Agonist potency.

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29
Q

What does EC50 depend on?

A

Affinity and intrinsic efficacy.

Depends on cell/ tissue specific components that allow for a response to occur.

30
Q

Distinguish between concentration and dose.

A

Concentration is the known concentration of drug at site of action, whereas dose is the amount administered to the patient without knowledge of the specific concentration of the drug at the site of action.

31
Q

What are 2 main pathological components of asthma?

A

Airflow obstruction

Bronchospasm

32
Q

What does agonist action of B2 adrenoceptors in smooth muscle airways result in?

Why is this antagonism relevant in asthma treatment?

A

Relaxation of smooth muscle in airways.

Provides functional antagonism / reverses airflow obstruction.

33
Q

If non-selective B adrenoceptor agonists are used in asthma treatment what are the possible side effects?

A

The agonist would act on B1 adrenoceptor in the heart.

Causing positive chronotropy and positive inotropy.

34
Q

What are the advantages of using salbutamol in asthma treatment?

A
  • Utility - can be directly administered to lungs via inhaler. Increasing concentration at B1 adrenoceptors.
  • Soluble - can be administered intravenously.
  • Good intrinsic efficacy.
35
Q

What are the disadvantages of salbutamol in asthma treatment?

A

Poor selectivity - results in side effects - increased heart rate, especially in angina patients.

36
Q

What are the advantages of salmeterol in asthma treatment?

A
  • Very good selective - reducing side effects.

- Long acting

37
Q

What is the disadvantage of using salmeterol in asthma treatment?

A

Is insoluble therefore can not be administered intravenously.

38
Q

What is a spare receptor?

A

A receptor that even if bound to would not increase the response, as it is already at maximal.

39
Q

Spare receptors are often seen when they activate what kinds of receptor?

A
  • Tyrosine kinase

- GPCR

40
Q

Why do spare receptors exist?

A
  • Signal amplification in signal transduction pathway.

- Due to response being limited by a post-receptor event.

41
Q

What does agonist action (ACh from parasympathetic nerves) of M3 receptors in the airway lead to?

A

Contraction of smooth muscle.

42
Q

What does increasing the receptor number do to agonist potency?

A

Increases agonist potency.

43
Q

Why do spare receptors increase sensitivity?

A

They allow for responses at low concentration of agonist.

44
Q

Increasing receptor number above number of receptors needed for full response has what effect on the a response - concentration curve?

Why is this effect seen?

A

Curve shifts to the left due to decreased concentration being required to achieve Emax.

Increased potency of agonist.

45
Q

If receptor number decreased below the receptors needed for a full response what is the effect on the concentration - response curve?

Why is this effect seen?

A

Curve will shift to the right and Emax won’t be achieved.

Curve shifts to right due to reduced potency and Emax not attained due to insufficient occupancy.

46
Q

What causes change in receptor number?

A

Low activity - leads to up-regulation.

High activity - leads to down-regulation.

47
Q

What is the difference between partial agonists and full agonists?

A

Full agonists elicit a response equal to Emax whereas partial agonists do not.

48
Q

Compare EC50 and Kd of full agonists and partial agonists.

A

Full agonists have EC50 equal to or less than their Kd due to spare receptors.

Partial agonists have ED50 is around equal to their Kd due to no spare receptors.

49
Q

What can be said about a partial agonists occupancy and response curve?

A

They have matching occupancy response curves.

50
Q

What can be said about partial agonists efficacy and intrinsic efficacy?

A

Both are lower.

51
Q

Why are partial agonists used as drugs?

A
  • More controlled response
  • Work in absence or at low concentration of the endogenous ligand
  • Act as competitive antagonists in the present of full agonists.
52
Q

What receptors do opiods act on?

A
  • u-opioid receptors

Types of GPCRs

53
Q

What are opioids used for?

A

Pain relief

Recreationally - euphoria eg heroin.

54
Q

What is a side effect of opioid use?

A

Respiratory depression.

55
Q

What is respiratory depression?

A

Respiratory depression aka hypoventilation is inadequate ventilation to perform gas exchange.

56
Q

What can result from respiratory depression?

A

Respiratory acidosis due to hypercapnia.

57
Q

In terms of pain relief, why is buprenorphine used instead of morphine?

A

Buprenorphine is a partial agonist.
Has higher affinity than morphine and lower efficacy.
Higher affinity means it can outcompete morphine and allow for adequate pain control.

Lower efficacy reduces chances of respiratory depression.

58
Q

In terms of opioid addiction why is buprenorphine used?

A

Binds with higher affinity to the opioid receptors than for example heroin.

Provides some antagonism - displacement of heroin from receptor.

Limits response and therefore reduces chances of respiratory depression.

Enables gradual withdrawal and prevents use of other illicit opioids.

59
Q

How does continued drug taking lead to tolerance?

A

Reduced receptor number

Reduced post-receptor signalling.

60
Q

What are the 3 types of antagonism and which one is most commonly used in therapeutics?

A

Reversible competitive - most common in therapeutics
Irreversible competitive
Non-competitive

61
Q

What is IC50 on a antagonist-concentration response graph?

A

Concentration of antagonist giving 50% Inhibition.

62
Q

Kd can be used to define antagonist affinity, true or false?

A

True.

63
Q

What is meant by “reversible competitive inhibition is surmountable”?

A

Increasing agonist concentration can overcome the affect of the agonist.
Emax can be achieved provided enough agonist is present.

64
Q

What is naloxone?

A

High-affinity reversible competitive agonist.

Reverse effects of opioid-mediated respiratory depression by competing with other opioids at u-opioid receptors.

65
Q

What does an irreversible competitive antagonist do to a receptor?

A

Strongly associates to a receptor by covalent bonds.

66
Q

Are the effects of irreversible competitive antagonism surmountable?

Explain you answer.

A

No, because as antagonist concentration increases more and more receptors become blocked.

67
Q

What are the effects of an irreversible competitive antagonist on a response-[agonist] curve?

A

Curve will shift to the right - decreased potency of the drug as fewer receptors present.

As all spare receptors fill up Emax will not be attained as there will be insufficient receptors for full response.

68
Q

What is pheochromocytoma?

A

Rare tumour of adrenal gland.

69
Q

What results from pheochromocytoma?

A

Increased release of adrenaline and noradrenaline.

70
Q

What is phenoxybenxamine?

A

Non-selective irreversible alpha1-blocker used in paroxysmal or sustained episodes of hypertension resulting from pheochromocytoma.

Provides antagonism of alpha1 receptors - Inhibition of vasoconstriction.

71
Q

How does a non-competitive antagonist act?

A

Binds to allosteric site

Reducing orthosteric ligand affinity and efficacy.

72
Q

What is maraviroc?

A

Allosteric modulator of chemokine receptor 5r which is used by HIV to enter cells.

ICPP (17 decks)

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