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FPP > Fundamental Principles of Pharmacology > Flashcards

Fundamental Principles of Pharmacology Flashcards

1
Q

What is a drug?

A

A drug can be defined as; a chemical substance of known structure, other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect.

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2
Q

drugs that are used theraputically have how many names? what are they?

A
  • chemical name –
    e.g. (RS)-2-(4-(2-methylpropyl)phenyl)propanoic acid
  • common name – ibuprofen
  • Proprietary (trade) names – e.g. “Nurofen”;
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3
Q

by what 2 things are drugs grouped

A
  • Usually grouped according to therapeutic use e.g. analgesics, antihypertensives, antibiotics
  • Or sometimes by mechanism of action e.g. cyclooxygenase inhibitor, beta- blocker

IE Ibuprofen is a cyclooxygenase inhibitor that acts as an analgesic

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4
Q

what kind of molecules are drugs?

A

Drugs are exogenous molecules that mimic or block the actions of endogenous molecules

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5
Q

what are 4 target proteins for drugs

A
  • Receptors for neurotransmitters or hormones
  • Enzymes
  • Ion channels
  • Carrier or transporter molecules
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6
Q

What are ligands?

A

The small drug molecules that bind to large target proteins are called “ligands”

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7
Q

What do modern computer modelling techniques allow for?

A

Modern computer modelling techniques allow drugs to be designed in silico.

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8
Q

how well a drug fits into its binding site is governed by 2 things, what are they?

A

the size and flexibility of the drug (steric factors)

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9
Q

how well a drug bind to its target protein is determined by what?

A

the nature of the chemical bonds that form between the molecule and binding site

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10
Q

what type of bonds do most drugs form with their target proteins?

(reversible)

A

hydrophobic & hydrogen bonds plus weaker van der Waals interaction

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11
Q

what type of bonds do most drugs form with their target proteins?

(irreversible)

A

covalent interactions

this leads to the formation of a ligand-protein complex which will alter the activity of the protein in some way

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12
Q

what are the two “S’s” essential in therapeutic drug use?

A

selectivity and specificity

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13
Q

what is one way we can achieve selectivity in drugs?

A

design drugs that bind with a high degree of specificity to their target protein.

Ideally they will bind ONLY to their target protein and no others

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14
Q

What is pharmacodynamics?

A

= what the drug does to the body

drugs actions at a molecular level on physiology of an organism

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15
Q

What is pharmacokinetics?

A

= what the body does to the drug

how its handles, how does it get to site of action, how. is it metabolised

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16
Q

What are PK/PD studies?

A

When drugs are being developed for therapeutic use, a true understanding of the drug’s effectiveness only comes when pharmacodynamics and pharmacokinetics are considered together, so-called PK/PD studies

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17
Q

What are the 4 critical elements of pharmacokinetics?

A

ADME;

  • Absorption
  • Distribution
  • Metabolism
  • Excretion
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18
Q

how long does the preclinical stage last?

A

5-10 years

only one or two drug candidates taken forward to human clinical trials

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19
Q

how long does a patent for a new drug last?

A

20 years

after which time anyone can copy the drug

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20
Q

what is Phase I of clinical trials known as?

A

Exploratory; first in human.

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21
Q

how is the chronic toxicity of the drug assessed in Phase I of clinical trials?

A

Chronic toxicity of the drug will have been assessed in at least 2 mammalian species (1 non rodent)

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22
Q

how long does phase I of the clinical trial last and what is its purpose?

A

6 months to a year

  • SAFETY (check for side effects)
  • TOLERABILITY (unpleasant symptoms e.g. headaches, nausea)
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23
Q

what do we look for in phase II of clinical trials?

A

Efficacy, proof of concept and safety

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24
Q

what is the primary purpose of Phase II of clinical trials?

A

to determine how clinically effective the drug is in patients

to confirm safety and tolerability

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25
Q

Describe Phase IIa of clinical trials.

A
  • Exploratory
    • 50-200 patients; lasts approximately 1 year
    • Dose and treatment regimen based on Phase 1 results
    • Usually placebo-controlled, randomised, double-blind
26
Q

describe phase 11b

A

Phase IIb
- Confirmatory
- 200-500 patients; lasts approximately 2 years

- Safety and efficacy compared to placebo or current treatment in randomised, double-blind design
27
Q

what happens during phase III of clinical trials?

A
  • Full scale evaluation of how EFFECTIVE and SAFE the treatment is compared to current standard treatment (or placebo)
28
Q

how many patients is the drug tested in during phase III?

A

2000-10 000

29
Q

how long does phase III last?

A

several years

30
Q

what is the ultimate purpose of phase III of clinical trials?

A

Provides data to support registration;

once completed can apply for registration for use in specified condition

31
Q

what is the point of phase IV of clinical trials?

A

post-market surveilance, monitors consequences of increasing exposure in tens of thousands of patients

Also yield information on the drug’s efficacy in sub-groups of the population (elderly, young)

ongoing

32
Q

the relationship between drug concentration (or dose) and the response produced by the drug. is called what?

A

concentration-response curves.

33
Q

what concentration-response curve do you get when looking at ‘drug concentration’

A

rectangular hyperbola

34
Q

what concentration-response curve do you get when looking at ‘log drug concentration’

A

symmetrical sigmoid

35
Q

What is the Emax of the log concentration-response curve?

A

Emax is the maximum effect (response) that a drug can produce e.g. an increase in heart rate of 70 beats per minute

36
Q

Where is the EC50 on the log concentration-response curve?

A

The EC50 is the concentration of a drug that produces 50% of the maximum response

37
Q

what does the EC50 indicate?

A

indicates the position of the curve on the concentration axis, used to quantify the potency of a drug

38
Q

What is a receptor

A

Receptors are protein macromolecules usually inserted across the lipid bilayer of the cell

39
Q

what are 2 main functions of a receptor

A
  • Recognition or detection of extracellular molecules
  • Transduction; having detected the presence of an extracellular molecule they then bring about changes in cell activity
40
Q

Describe the binding of a drug to a receptor (and what it looks like graphically when receptors occupied (p) vs drug concentration [D]).

A

D+R ⇌ DR
Binding is reversible (in most cases

41
Q

Describe the binding of a drug to a receptor (and what it looks like graphically when p vs log[D]).

A

D + R ⇌ DR

42
Q

What is KD in terms of affinity?

A

The affinity of a drug for its receptor is quantified as “the MOLAR concentration of drug required to occupy 50% of the receptors at equilibrium”

43
Q

what does the symbol KD stand for?

A

This concentration of drug is given the symbol KD

44
Q

whats the relationship of KD and a drugs affinity?

A

Drugs with HIGH affinity have a LOW KD

45
Q

What is KD in terms of equilibrium?

A

KD is the equilibrium dissociation constant

  • k+1 and k-1 are rate constants that tell us something about the likelihood of the forward and backward reactions occurring
  • Rate of FORWARD reaction = k+1[D][R]
  • Rate of BACKWARD reaction = k-1[DR]
  • At equilibrium, backward rate = forward rate, so k-1[DR] = k+1[D][R]
    KD = k-1/ k+1 = [D][R]/ [DR]
46
Q

What is KD a measure of?

A

The KD is a measure of how tightly the receptor holds on to the drug once they come together

47
Q

What do agonists do which differs to other drugs?

A
  • Many drugs bind to the receptor (i.e. have affinity), occupy it, and do little else
  • AGONISTS however bind and then activate the receptor i.e. the agonist has efficacy
  • After binding, agonists produce a change in the shape of the receptor - a conformational change - that will ultimately lead to a response in a cell or tissue
  • Activation of receptor (R) by an agonist (A) produces a biological response
48
Q

What are agonists?

A
  • So agonists bind to the receptor (have affinity) and activate it (have efficacy)
  • All naturally occurring neurotransmitters and hormones are agonists e.g. adrenaline, acetylcholine, insulin, dopamine + many more
  • Agonists can be either partial agonists or full agonists
49
Q

whats the efficacy of full agonists and how effective it is at producing a biological response

A

Full agonists have high efficacy and as a result are very effective at activating receptors and producing a biological response

50
Q

whats the efficacy of partial agonists and how effective it is at producing a biological response

A

Partial agonists have low efficacy and are therefore less effective at activating receptors and less able to produce a biological response

51
Q

what kind of response do full agonists make

A

Full agonists often produce maximal response whilst activating only a fraction of the available receptors (p) i.e. there are lots of spare receptors

52
Q

what kind of response do partial agonists make

A

Partial agonists often fail to produce a full response despite occupying all the available receptors

53
Q

Why as an agonist is EC50 = KD not possible?

A

the overall response to an agonist is determined by both its affinity and its efficacy; receptor occupancy is determined only on affinity

54
Q

What are antagonists?

A

They act to inhibit the effects of a neurotransmitter or another drug

55
Q

What is the most common type of drugs used?

A
  • Reversible competitive antagonists

e.g. pancuronium, cetirizine, propranolol

56
Q

What effect do reversible competitive antagonists produce on a log concentration vs response curve?

A

Reversible competitive antagonists produce a parallel shift to the right of the AGONIST log concentration vs response curve.

57
Q

The extent of the shift in the position of the agonist curve produced by the antagonist can be measured using what

A

the “dose-ratio” i.e. the ratio of the concentration of agonist producing the same response in the presence and absence of the antagonist

58
Q

What is the ‘extent of the shift’ a measure of?

A

The ‘extent of the shift’ is a measure of the affinity of the ANTAGONIST for the receptor

59
Q

what is the affinity of an antagonist quantified by

A

pA2

60
Q

what does a bigger pA2 mean?

A

bigger the pA2, higher the affinity of the antagonist for the receptor

61
Q

how can you overcome the inhibitory effects of an antagonist?

A

increasing the concentration of the AGONIST

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