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Semester 1 Introduction to Cell Physiology and Pharmacology > L17&18: Pharmacodynamics: Receptor Theory > Flashcards

L17&18: Pharmacodynamics: Receptor Theory Flashcards

1
Q

What is pharmacodynamics?

A

Action of the drug on the body

Influence of drug concentration on magnitude of response

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2
Q

What is the difference between endogenous and exogenous ligands?

A

Endogenous–> from within the body

Exogenous–> from outside the body

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3
Q

What are the different targets for drugs?

A

RITE

  • Receptor (KING)- (kinase linked receptor, ion channel (ligand gated), nuclear/intracellular, GPCR)
  • Ion channel
  • Transporter
  • Enzyme
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4
Q

What is an orphan receptor?

A

Protein–> similar structure to other receptors

Potential drug targets

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5
Q

What does Molarity mean?

A

1 mole of substance contains 6 x 10^23 particles

1 molar solution contains 1 mole of substance, in 1 Litre of solvent

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6
Q

Why is concentration important?

A

Determine the number of drug molecules around the receptor at the site of action

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7
Q

What equations are useful for comparing drugs and concentrations?

A

Moles= mass/ Mr (molecular weight)

Molarity or Concentration= moles/ volume

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8
Q

What is significant about drug-receptor interactions?

A

Reversible (usually)
Association-dissociation rate important
–> more reactant reaction goes forward
–> more products reaction goes backwards

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9
Q

What are the two main classification of drugs on receptors?

A

Agonist–> compete for the receptor site, activate the receptor
Antagonist–> block the binding of endogenous agonists, bind elsewhere to the receptor

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10
Q

What determines whether a agonist binds to the receptor?

A

Affinity

Receptor must have affinity to bind ligand

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11
Q

What has to happen for a response to occur at a receptor?

A

Affinity–> ligand must bind
Intrinsic efficacy–> must be able to produce a conformational change to activate receptor
Coupled with other changes in a cell to produce a measurable response

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12
Q

Define intrinsic efficacy?

A

The ability of a agonist to produce a conformational change activating the receptor
Results in a fully or partially activated receptor state

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13
Q

Define efficacy?

A

The intrinsic efficacy and other things that influence the response (things within the cell/tissue)
Causes a measurable response

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14
Q

What is the difference between agonists and antagonists?

A

Agonists have affinity, intrinsic efficacy and efficacy

Antagonists have affinity but no intrinsic efficacy or efficacy

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15
Q

What is the difference between pharmacological efficacy and clinical efficacy?

A

Pharmacological–> what happens within the body e.g. blood vessels dilate
Clinical–> indication of how well a treatment succeeds in achieving its aim, what changes can be seen e.g. lower blood pressure

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16
Q

How can the binding of a ligand be measured?

A

Radioligands–> radioactively labelled ligands
Measure the radioactive levels in a cell or tissue
More binding = larger radioactive signal

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17
Q

How is ligand binding quantified?

A

Plot bound vs ligand concentration graph

Usually use logarithmic graphs

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18
Q

What is the Bmax?

A

The maximum binding capacity

Information on receptor number

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19
Q

What is the Kd?

A

The dissociation constant

Concentration when 50% of available receptors in a define tissue or cell expressing the target protein are occupied

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20
Q

What does the Kd tell you?

A

Affinity of ligand
Low concentration= high affinity
High concentration= low affinity

21
Q

Why is it important to know the affinity of a ligand?

A

Given two drugs can determine which will bind better to a receptor–> out compete a drug
Useful in drug overdose

22
Q

How is response to a drug measured?

A

Concentration response curves
Response require efficacy
Usually plotted on logarithmic scale

23
Q

What is the Emax?

A

The concentration of drug required to produce 100% response

24
Q

What is the EC50?

A

Effective concentration that results in 50% of the maximal response

25
Q

What is the EC50 a measure of?

A 
The potency of a drug 
It includes all the sequential stages leading up to a therapeutic response including the-
- affinity
- intrinsic efficacy 
- cell/tissue dependent effects
26
Q

What is the difference between concentration and dose?

A

Used interchangable HOWEVER

  • concentration–> used in vitro when precise concentration of drug around receptor can be manipulation
  • dose–> used when measuring response in whole animal/human when precise concentration around a receptor is unknown
27
Q

What is important about the potency of a drug?

A

Variable –> cell/tissue dependent factor affect overall efficacy
Affinity and intrinsic efficacy are fixed

28
Q

What can affect the potency of a drug?

A

Receptor number

cell/tissue dependent factors

29
Q

How does the receptor number affect the potency?

A

No receptors–> no binding–> no response

More receptors–> more binding–> bigger response

30
Q

Why do you get spare receptors?

A

Other cell/tissue factors affect the response to ligands
e.g. muscle can only contract so much, gland can only secrete so quickly
Eventually an increase in the number of receptors doesn’t affect the response level

31
Q

What is the point of spare receptors?

A

Increases the sensitivity

Allows the maximal response at a lower concentration of drug

32
Q

How do you get a full response if you have spare receptors?

A

Exists because of amplification in the signal transduction pathway e.g. GPCR and tyrosine kinase
Cascade of events after receptor binding

33
Q

Is receptor number fixed?

A

NO
Varies with cell type
Low activity–> up regulation of receptors
High activity–> down regulation of receptors (linked to negative feedback–> leads to tolerance to drugs and withdrawal symptoms)

34
Q

What is the difference between full and partial agonists?

A

Partial agonists are unable to produce a maximal response even with full receptor occupancy
They have a decreased intrinsic efficacy (relationship between the Kd (binding affinity) and EC50 (response))
Unable to produce a fully activated receptor so gave lower intrinsic efficacy

35
Q

Give an emaple of how partial agonist can be used clinically?

A 
Treatment of opioid addiction (heroin)
Herion is a full agonist
Buprenophine is a partial agonist
Both work on the opioid receptor
Buprenophine has a higher affinity and inhibit the effect of heroin--> doesn't produce a full response because it is a partial agonist
36
Q

What are the effects of buprenophine in heroin addiction?

A

Buprenophine doesn’t produce a full response only partial so patient becomes ill–> withdrawal symptoms

37
Q

What is withdrawal or abstinence syndrome?

A

Sustained drug taking leads to tolerance–> reduced receptor number
When drug is withdrawn the endogenous ligands are less effective and can’t produce same full response

38
Q

How do antagonists work?

A

Block the affect of agonists

Prevent receptor activation

39
Q

What are the three main methods of action of antagonists?

A

1- Reversible competitive antagonism
2- Irreversible competitive antagonism
3- Non-competitive antagonism

40
Q

How do reversible competitive antagonists work?

A

Dynamic equilibrium between the agonist and antagonist
Both associate and dissociate continuously
In competition with each other
Increase conc of the antagonist will inhibit the effect of the agonist as more antagonist will bind e.g.

41
Q

How do irreversible competitive antagonists work?

A

Dissociate from the binding site slowly or not at all
e.g. covalent bond formed- effectively non-surmountable once bound
However agonist and antagonists compete for the free binding sites

42
Q

How do non-competitive antagonist work?

A

Antagonist doesn’t bind to the orthosteric site (natural binding site for ligand)
Non competition for binding site

43
Q

What is the Ki?

A

The Kd but for an antagonist

Binding affinity of an antagonist

44
Q

What is the IC50?

A

The concentration of antagonist that will produce a 50% reduction from the Emax

45
Q

What is the effect of adding a reversible competitive antagonist to a concentration response curve?

A

(Note: Effects of antagonists cannot be measured without agonist present)
Shift in the agonist response curve to the right
Higher concentration of agonist will be required to produce a response
Emax can still be achieved

46
Q

What is the effect of irreversible and non-competitive antagonists?

A

Both cause a right shift
Depression in Emax
Irreversible binding so agonist unable to occupy sufficient binding sites to cause a full response

47
Q

What are some clinical examples of where antagonists are used?

A

NSAIDs such as Iburprofen–> competitive antagonist of enzymes that synthesis prostaglandins

Hypertension treatment–> ACE inhibitors prevent ACE converting angiotensin I to angiotensin II

Hypertension treatment–> block VOCC in arteriolar smooth muscles –> limit opening of channels after depolarisation resulting in vasodilation

48
Q

How is herion overdose treated?

A

Naloxone–> high affinity competitive antagonist at the opioid receptors
Competes with agonist (herion)
Reverses respiratory depression
Also used after surgery where fentanyl (powerful pain relief) is used

Semester 1 Introduction to Cell Physiology and Pharmacology (5 decks)

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