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LIFE > Part I: Pharmacodynamic Principles > Flashcards

Part I: Pharmacodynamic Principles Flashcards

1
Q

Define the term ‘drug‘

A

Chemical with a selective therapeutic effect

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2
Q

List the main receptor superfamilies from fastest (ms) to slowest (day)

A

Ligand gated ion channels, G Protein Coupled Receptors, catalytic and nuclear receptors

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3
Q

Most common type of catalytic receptor

A

Receptor tyrosine kinases

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4
Q

Catalytic receptor meaning

A

Have a binding site and enzyme activity associated directly within the receptor

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5
Q

Define substrate

A

Molecule acted upon by an enzyme

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6
Q

Define inhibitor

A

Substance blocking enzyme activity

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7
Q

Define agonist

A

It reproduces the effects of the endogenous messenger. (Activator of a receptors response)

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8
Q

Define antagonist

A

It blocks the effects of the endogenous messenger (Blocker of receptor activation)

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9
Q

Define receptor

A

Proteins which respond to to an endogenous messenger by initiating a signal

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10
Q

Affinity def

A

Ability of the drug to bind to its target

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11
Q

Efficacy def

A

Ability of drug to activate receptor by a conformational change

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12
Q

Example of a nuclear receptor

A

Steroid hormones

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13
Q

Why are drugs selective but not specific?

A

Higher affinity for certain receptors, but at high enough concentration they will interact with additional binding sites - side effecs

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14
Q

Examples of an agonist + antagonist for the sympathetic nervous system

A

Adrenaline -> increase heart rate. <beta blocker like bisoprolol -> decrease rate, blood pressure

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15
Q

What is Law of Mass action in D+R<->DR

A

Where KD = Koff/Kon =[D][R]/[DR]

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16
Q

Equation for receptor occupancy (α)

A

α = [D] / ( [D] + KD )

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17
Q

KD def in terms of receptor occupancy

A

Concentration of drug needed to occupy 50% of receptors (measure of its affinity)

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18
Q

What is dissociation rate constant. WRITE MROE WHEN WATCHED LECTURE (ADVANCED ONE)

A

Koff = rate that drug unbinds from receptor

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19
Q

Steps of radioligand binding studies

A

1) Make radiolabelled drug (eg swap hydrogen with titrium). 2) Make preparation containing drug target (membranes, cells, brain). 3) Mix drug + receptors in assay buffer. 4) Equilibrium reached to measure KD. 5) Separate bound from free drug (using filter) and count radioactivity.

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20
Q

How to separate specific binding from total binding in radioligand binding

A

Use excess non-radioactive drug. Competes for target binding site - displaces them. Radioactive left = non-specific. Total - non-specific = Specific binding

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21
Q

What is saturation analysis in radioligands and how to find Bmax and KD

A

Vary concentration of radioligand to get a graph of bound ligands (count) against conc of radioligand. Bmax is the amount of bound ligands where it plateaus. KD is the radio conc at 1/2 of the bound ligands of Bmax.

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22
Q

What is competition analysis in radioligands. How to find IC50

A

Same conc of radiolig but change unlabelled ligand conc. As it increases, bound radioligands decrease. Graph of count against unlabelled conc. The middle between the 2 plateaus is the IC50.

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23
Q

Find dissociation constant (Ki) using IC50 from competing ligand and the name of the equation.

A

Cheng-Prusoff correction:
Ki = IC50 / (1 + [radio]/KD(radio))

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24
Q

Use of bioassay

A

To quantify drug action as a functional response

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25
Q

Different types of bioessays and some disadvantages

A

Callular, Tissue, Organ, System. Cellular may not behave same in actual organ. For the rest: response composed of many effects, drug could be working on other receptors too

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26
Q

Describe agonist conc-response curve. What is Rmax and EC50?

A

Muscle respons compared to reference (in %) against conc of agonist. Rmax is max response where it plateaus. EC50 is Effective Conc of agonist at 50% response.

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27
Q

What does EC50 tell you about the agonist

A

Its potency

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28
Q

Sigmoid equation to find R from con-response curve

A

R = Rmax * [D] / ([D] + EC50)

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29
Q

Difference between full and partial agonist

A

Full has the same Rmax, partial has less compared to the other agonist therefore it has lower efficacy (ability to activate receptors)

30
Q

What is equipotent vs a drug that is more potent than another

A

Equipotent has the same EC50 value, more potent has a LOWER EC50

31
Q

What is receptor reserve

A

Spare receptors bc not all needed due to signal amplification as 1 active receptor can cause a cascade of responses

32
Q

What factors do EC50 (50% response) and Rmax depend on

A

EC50: Affinity, efficacy, amplification. Rmax: Efficacy, amplification

33
Q

3 types of antagonists and examples

A

Receptor. Physiological antag: 2 drugs that counteract by separate molecular mechanism eg noradrenaline and acetycholine on heart. Antag of the stimulating messenger: Antibody therapy that inactivate the protein growth factors which stops them from stimulating receptors.

34
Q

Competitive vs non-competitive antagonist def

A

Comp: Antag binds at orthosteric (same) site as agonist. Non-comp: Antag binds at an allosteric (different) site

35
Q

Reversible vs irreversible antag

A

Irreversible is covalent bond, other is not

36
Q

What is use-dependence

A

In non-comp antagonists, agonist must open channel before antagonist can block

37
Q

What is surmountable antagonism and what does it do to conc-response curve

A

For reversible antags: If agonist conc is sufficiently high, it can reoccupy enough receptors to reach original Rmax before antagonists

38
Q

When does non-surmountable antagonism happen + conc-response curve effect

A

If antag is irreversible OR if antag is non-competitive as it binds at allosteric (different) site, Rmax is decreased

39
Q

How is concentration ratio (CR) measured for antagonists

A

Agonist EC50 in presence of antag/Original EC50 of agonist

40
Q

What is the Gaddum equation

A

KD (or Kb for Gaddum) = [Antagonist] / (CR - 1) to show affinity of antagonist

41
Q

What is Schild plot

A

KD is worked out using many different [antagonist]. Then plotted on log(CR-1) against log(antag) for a straight line. x-intercept is - logKD (pA2)

42
Q

What is pA2

A

-log(KD) found from Schild plot (x-intercept)

43
Q

What type of antagonist must it be for Gaddum and Schild to work?

A

Competitive reversible and surmountable

44
Q

2 types of enzyme drug action

A
  1. Communication via cellular messengers. 2. Chemotherapy
45
Q

Neurotransmission pathway

A
  1. Synthesis of NT in presynaptic 2. Storage 3. Release from presynaptic neuron in response to an Action Potential. Then calcium entry. Then presynaptic inhibitory receptors which inhibits further NT release. 4. Postsynaptic receptors lead to signalling. 5. Metabolism (removing NT from synapse) by enzyme. 6. Uptake of post NT back into presynap unchanged
46
Q

3 ways drugs csn be used

A

As substrates, inhibitors, false substrates

47
Q

Explain drugs as substrates

A

Boosts conversion to a desired product. Eg A–enzyme–>B so add A which produced desired B.

48
Q

Explain drugs as inhibitors

A

Molecule that competes with original molecule of rate limiting step -> prevents synthesis

49
Q

Explain drugs as false subtrates

A

Are substrates for target enzyme BUT produces slightly different product - reduced biological activity

50
Q

How do NSAIDs work

A

Cyclooxygenase (COX) synthesises prostaglandins (inflammatory lipid mediators) but NSAIDS inhibits synthesis

51
Q

Explain chemotherapy as enzyme drug action

A

Agents that are selectively toxic to the target cells compared to normal human cells using biochemical differences. Several of these targets are enzymes

52
Q

Examples of chemotherapy

A

Treatment of infectious disease (fungal, bacterial, viruses).
Cancer chemotherapy - targeting rapidly dividing tumour cells

53
Q

What is a suicide substrate

A

Antibiotics that target final enzymes in BACTERIAL cell wall synthesis (cell walls don’t exist in human cells)

54
Q

What are 2 cancer chemotherapies where enzymes are involved in mitosis

A

Inhibitors of purine nucleotide synthesis (methotrexate) and inhibitors of DNA/RNA synthesis (doxorubicin)

55
Q

What is on a Michaelis-Menten graph

A

Enzyme acticity (% to control) vs [substrate]. It was Vmax and half is Km

56
Q

Michaelis menten equation

A

V = Vmax * [S] / ([S] + Km)

57
Q

Definition of Michaelis-Menten constant, Km

A

The concentration of substrate at which 50% of the maximal enzyme velocity (V) is obtained

58
Q

What is the steady state approximation and why is it useful

A

That [ES] (enzyme + substrate) does not change. Can derive an expression for Km based on it

59
Q

What is kcat

A

Catalytic rate constant. Between ES comples -> E + P

60
Q

Km equation

A

(koff + kcat)/kon

61
Q

KD equation and what does it represent

A

koff/kon. The affinity of the substrate for the enzyme - 50% enzyme occupancy

62
Q

What does it mean if Km > KD

A

The concentration of substrate required for 50% velocity is greater than for 50% enzyme occupancy

63
Q

How does competitive reversible inhibitor change Michaelis-Menten plot

A

Same Vmax, higher Km. Shows it is surmountable inhibition.

64
Q

If binding equilibrium is reached fast aka koff&raquo_space; kcat then what happens to KD and Km

A

They are almost equal to each other

65
Q

Equation to work out dissociation constant Ki (inhibitor affinity) from Km

A

Km(obs) = Km(control) * (1 + [inhibitor]/Ki)

66
Q

What is on a competition curve for comp reversible inhibitors

A

Enzyme activity % against Log[inhibitor] at constant [substrate]. Can compare different inhibitors. At 50% of acitivity -> IC50 of inhibitor!

67
Q

Work out Ki using Cheng-Prusoff eq:

A

Ki = IC50 / (1 + [substrate]/Km )

68
Q

How does irreversible inhibitor change Michaelis-Menten plot

A

Decreased Vmax (not surmountable) but no change in Km

69
Q

How does non-competitive reversible inhibitor change Michaelis-Menten plot

A

Vmax decreased and Km unchanged

70
Q

What does a non-competitive inhibitor bind to

A

Both enzyme and ES complex at an allosteric site

71
Q

How to calculate Ki from non-comp reversible inhibs

A

Vmax(obs) = Vmax(control) / (1 + [inhib]/Ki )

72
Q
A

LIFE (4 decks)

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