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Pharmacology > SN4 - Pharmacodynamics > Flashcards

SN4 - Pharmacodynamics Flashcards

1
Q

Define pharmacodynamics

A

What the drug does to the body - the mechanism of action,

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2
Q

Mechanisms of actions of drugs - name 2

A

Specific: Specific molecular targets - low doses (most drugs)
Non specific: most drugs at high doses. (not binding to specific targets) eg bicarb

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3
Q

Name some drugs that don’t bind to specific targets

A
  • Osmotic drugs laxatives, diuretics
  • Buffers
  • Oxidants
  • reducing agents
  • chelating agents
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4
Q

What is the pharmacological dogma

A

Most drugs interact with specific molecular targets to induce biological response - mutual recognition

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5
Q

Name 6 receptor properties

A
  1. sensitivity
  2. selectivity
  3. specificity - depends on the cell where it is
  4. saturability
  5. pharmacological profile
  6. correlation between receptor binding and biological activity
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6
Q

Receptor sensitivity

A
  • High binding affinity (often pico molar). if micro molar it’s not to a receptor
  • signal amplification is needed
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7
Q

Slope of a curve with higher affinity will be?

A

Steeper

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8
Q

To get affinity you use?

A

Km which is half the Kmax

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9
Q

Lower Km means?

A

Higher affinity (need less of it to bind)

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10
Q

What are the two parameters you can measure from dose response curve?

A

Potency - sensitivity of organ or tissue to drug - dose dependent
Efficacy - maximal effect induced by a certain drug - dose independent

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11
Q

2 kinds of dose-effect response curves

A

Gradual - usual curve - one person - correlates dose to effect intensity
Cumulative - population . group - correlates to effect frequency

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12
Q

How do we assess potency on a dose response curve

A

Look at ED50 - dose that gives 50% of the effect

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13
Q

3 features that makes log scale dose response curve more convenient

A

1 - much wider dose interval

  1. ED50 and potency is at inflection point so immediately you realise potency value
  2. central portion is a straight line - easier to understand
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14
Q

Agonist define

A

drug that act on binding a receptor induces a cellular / biological response effect

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15
Q

Antagonist define

A

drug that on interacting with receptor does not induce any response, but reduces the response induced by co-existing agonist. Indirect effect by interfering with agonist.

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16
Q

Law of mass action

A

the rate of a reaction is directly proportional to the concentration of the substance

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17
Q

The higher the equilibrium constant K is, the …. the affinity?

A

Lower

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18
Q

Occupational therapy

A

Effect is proportional to the concentration of agonist-receptor complexes

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19
Q

Full agonist - define

A

Every drug that when binding to the receptor produces a maximal effect - intrinsic activity is equal to 1

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20
Q

Partial agonist

A

every drug that when binding to the same receptor produce less effect than a full agonist, intrinsic activity is between 0 and 1

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21
Q

Why do we need partial agonists clinically

A

Full agonist may go over the max limit of therapeutic window

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22
Q

Partial agonists differ from FULL agonists in terms of?

A

EFFICACY (thus in terms of potency they can be opposite - partial agonist can be more potent than full agonist!)

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23
Q

ON a graph, if you don’t see any response, what does this mean?

A

It is an antagonist!

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24
Q

3 Types of antagonists

A
  1. Pharmacological: same receptor! competitive / non competitive (mostly used in Pharma)
  2. Chemical - no receptor, blocks the ion
  3. Physiological antagonist (work on different receptors but antagonise each other eg Act vs Adrenaline)
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25
Q

Discuss efficacy and potency of a agonist in the presence of a competitive antagonist. What does it do the the curve?

A

Less potent but efficacy is the same - meaning you can still achieve the max response but you will need a higher dose.
Shifts the curve to the right

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26
Q

If you use a agonist with a NON competitive antagonist - what happens to curve, efficacy and potency

A

The curve will lower indicating reduced efficacy - potency we would need to calculate

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27
Q

Competitive inhibition:
Where does the antagonist bind on receptor?
Discuss affinity and concentration here

A

Ortosteric - meaning same site as agonist
The drug with the highest affinity for the site will win, also the concentration is important. You can displace antagonist with higher concentration of agonist

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28
Q

Non competitive inhibition:

Where does it bind, can you overcome it?

A

allo = different site
Changes the active site, so agonist binds less
Here to get a full response you have to wait until antagonist goes way.

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29
Q

Reversible (surmountable) antagonist - what does it do to the dose response curve?

A

To the right (decreasing agonist potency) - but does not normally affect maximal effect

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30
Q

Irreversible antagonist - what does it do to the dose response curve?

A

Shift the curve to the right in non parallel manner (potency is not modified), but DECREASES EFFICACY /maximal effect

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31
Q

Partial agonist in presence of a full agonist can act like a?

A

Competitive antagonist

32
Q

What is an inverse agonist

A

For example with GABA A - binding causes inhibition - so we use Benzodiazepines (agonist which binds allosterically to receptor increasing effect of GABA). But some substances binding to the same site can cause the OPPOSITE EFFECTS = Beta-carbolines = convulsions
Flumazenil = binds to the same site = competitive antagonist (its an antidote to benzodiazepines intoxication). Inverse agonists are found only for CONSTITUTIVE activity.

33
Q

What is constitutive receptor activity and what helped us discover it?

A

it means the receptor signals in the absence of an agonist (spontaneous activity). Thus the binding to receptor can either increase or decrease the spontaneous activity. (because remember if activity is zero it can only go up). Efficacy is vectorial, it can go up and down.

34
Q

How can a receptor signal by itself

A

Protein structure is dynamic, eventually it can find an active confirmation in the absence of agonist. Mutations also occur

35
Q

Spare receptors:

A

the receptor ocupancy curve is to the right of the response curve - the organ is more sensitive (common in hormones)

36
Q

Post receptor elements

A

Shifts the curve to the LEFT

37
Q

Therapeutic index of a drug

A

DT50 (toxic) / DE50 (therapeutic)
A good index is necessary for a general drug. Say penicillin is 100, you can increase dose 100 fold before toxic effect is seen.

38
Q

2 locations of receptor

A

Cytosol

Nucleus

39
Q

4 types of receptors

A 
inotropic
metabotropic
enzymatic - tyrosine kinase
all above are membrane bound
intracellular - function is always to control gene transcription
40
Q

All intracellular receptors are mediated by

A

gene transcription

41
Q

Muscular nicotinic -channel components

A

2 alpha, beta gamma

42
Q

Neuronal nicotinic - channel components

A

2 x Alpha 3 x beta

43
Q

nicotine acts by stimulating mostly

A

NEURONAL NICOTINIC receptors (so NOT nicotinic muscular!)

44
Q

The stimulus to poop after smoking is due to:

A

nicotinic receptors in periphery response, does not act on the muscle, acts on the neurons - stimulates peristalsis.

45
Q

GABA A receptor - describe

A

ionotropic - pentamer of 5 proteins, 5 subunits,
2 alpha, 2 beta, 1 gamma - but many different forms of each of these subunits.
controls the flux of CHLORIDE ions, negative charge = hyperpolarisation = inhibition.
(ethanol, anaesthetic, benzo)

46
Q

Benzodiazepine and Phenobarbitals effect on GABA receptor

A

Benzo: channels open more frequently
Pheno (barbituate): increases the time not frequency that the channel is open
Explains why barbiturates are so dangerous, response depends on concentration. BUT benzodiazepines have an upper limit, when GABA is at max, benzo won’t do more.

47
Q

2 kinds of metabotropic receptors

A

1 regulating activity of enzyme

2. ion channel - regulate the opening and closing

48
Q

G protein coupled receptors -discuss similarity between all of them and difference

A

ALL OF THEM: ALWAYS a single protein = always 7TMD Carboxy inside, N outside.
Difference between them:
is in the loops and terminal domains.

49
Q

What are the functions of 7TM receptors?

A

Mediate sense perceptions :

sight, smell taste

50
Q

Discuss G proteins structure

A

G protein is not a single protein - it is a trimer consisting of 3 subunits:
Alpha, Beta, Gamma. Activated by binding of GDP / GTP. The G-protein is much bigger than its receptor.

51
Q

Which subunits changes GTP to GDP?

A

Alpha subunit. Beta gamma unit stays together. cos their loops are intertwined.
Beta is very small - has a propeller structure = stability

52
Q

Most metabotropic receptors are?

A

dimeric - 2 receptors on one G protein.

53
Q

Discuss dual regulation of adenyl cyclase?

A

enzyme can be stimulated by receptors coupled to both Gi and Gs - amount of cAMP is dictated by the amount of inhibition / stimulation

54
Q

Discuss the conformation of Protein Kinase PKA

A

cAMP dependent kinase, 4 proteins, 2 regulatory, 2 catalytic. Camp binding causes catalytic sites to dissociate and they can then phosphorylate proteins.

55
Q

What breaks down camp

A

phosphodiesterase

56
Q

3 families of protein kinases stimulated by

A

cAMP
Ca++ and DAG
Ca=Calmodulin complex

57
Q

base vasodilation and contraction on 2nd messengers

A

vasodilation (camp)

Contraction - Phospholipase c

58
Q

2 ways you can regulate a response

A
  1. Increase function of receptor - sensitisation / upregulation
  2. decrease response - desensitisation / down regulation
59
Q

Discuss difference between desensitisation and downregulation.

A

desensitisation - repeated stimulation causes decreased response - seconds to minutes
downregulation - over hours

60
Q

Ways to downregulate:

A

Inducer of metabolic enzymes - reduce effect of drug quicker. Pharmacokinetic tolerance

61
Q

What is pharmacological / receptor mediated tolerance

A

Downregulation caused by giving drug multiple times

62
Q

Name 2 kinds of receptor desensitisation (ologous)

A
  1. Homologous - only the receptor stimulated is desensitised (phosphorylated) - once phosphorylated ARRESTINS can bind - endocytosis.
  2. Heterologous - when other receptors are phosphorylated and desensitised too
63
Q

Discuss the Arrestin pathway in desensitisation

A

Once receptor is desensitised via phosphorylation, arrestins bind, endocytosed

  • receptor can dephophorylate and go to membrane and be restored = RECEPTOR RECYCLING
  • alternative pathway - lysosome fusion and degradation
64
Q

What is pleuridimensional efficacy?

A

different responses due to different elements. We can have biased ligands.

65
Q

What is a biased ligand -

A

ligands that selectively activate or block only certain signalling pathways coupled by GPCR

66
Q

2 responses can happen when agonist binds a receptor

A
  1. cascade and cell response

2. beta arrestin - desensitisation

67
Q

3 things that the beta arrestin does once bound

A
  • desensitisation (steric hindrance due to binding)
  • scaffold formed for many different proteins and cascades.
  • internalising
68
Q

Describe the beta arrestin protein

A

cytosolic protein that binds to phosphorylated receptors. When not bound normally has a buried C terminus, but when bound exposes C terminus so other proteins can bind

69
Q

Biased ligand binds in which manner

A

Allosterically

70
Q

Acute heart failure is characterised by

A

low cardiac output
normal or elevated BP
elevated RAAS system
Vicious cycle.

71
Q

Which of the opiod receptors are responsible for respiratory depression

A

mu

72
Q

Discuss GPCR oligomerisation

A

can form dimers or oligomers:

  • homooligomers - all the same
  • heterooligomers - all different
73
Q

Gaba B receptor - discuss the type and 2 forms, and how it functions

A

GABA B receptor 1 is METABOTROPIC (GABA A is ionotrophic):
GBR1 - stays in ER
GBR2 - reaches membrane but doesn’t respond
2 brings 1 to membrane, can function only as a dimer.
Heteroreceptor as it has 2 different receptors.

74
Q

How do GABA B1/2 form dimers? 3 ways

A
  1. disulphide bond formation
  2. coiled coil interaction
  3. transmembrane interaction
75
Q

What is the point of GPCR dimerisation

A
  1. essential to bring to surface of cell (receptor maturation
  2. response
  3. pharmacological diversity - different drugs can act on both receptors or a drug can activate both
76
Q

What is a Janus molecule

A

Bivalent ligand:

  • peptide - long enough to bind both at same time
  • 2 headed drug with a chain - spacer needs to be precise.
77
Q

Discuss a enzymatic receptor - name, what they work on and mechanism

A

Tyrosine-kinase receptors - for growth factors and insulin, dimers that only form once ligands bind = activated.
tyrosine kinase autophosphorylate (opposite tails) serving then as a scaffold for a host of other signalling proteins - final response is GENE TRANSCRIPTION.

Pharmacology (10 decks)

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