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PBL SEM 1 > pharmacology (case 6) > Flashcards

pharmacology (case 6) Flashcards

1
Q

what do most drugs target?

A

proteins

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2
Q

what are a few exceptions of drugs that don’t target proteins?

A
  • antacids (bases, neutralise stomach acid)
  • osmotic diuretics (reduce intracranial pressure)
  • DNA modifying drugs (cancer therapy)
  • drugs that target membrane lipids (some antibiotics)

these interactions tend to be non-saturable (lots of binding sites), with little specificity

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3
Q

a successful drug has a molecular weight less than what?

A

less than 500 Da

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4
Q

what is a binding domain?

A

= drug only interacts with a small part of the protein called the binding domain — can form a relatively limited number of interactions with the drug

  • the binding domain has a distinct arrangement of amino acids which determines whether a drug can bind or not
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5
Q

do most drugs form a reversible or irreversible bond and why is this useful?

A

reversible which is useful as we want drugs to have an effect for a defined length of time

irreversible — have to wait for the body to synthesise new copies of the target protein before the drug’s effects wear off

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6
Q

name 3 drugs which modify their targets covalently

A
  • aspirin
  • clopidogrel
  • omeprazole
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7
Q

drugs often form numerous weak bonds. name the types of bonds made

A
  • hydrogen bonds
  • Van der Waals forces
  • hydrophobic bonds
  • dipole-dipole interactions
  • dipole-ion interactions
  • ionic bonds
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8
Q

what is a protein superfamily?

A

= a collection of families of proteins
= a group of more distally related proteins that share structural and functional features
= probably evolved from a common ancestor

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9
Q

what is a protein family?

A

a group of closely related proteins

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10
Q

how does diversity arise and what does it give rise to?

A

arises by gene replication and mutation, gives rise to families

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11
Q

what do hydrocortisone and corticosterone (corticosteroids) bind to? what about synthetic steroids?

A

bind to both mineralocorticoid and glucocorticoid receptors (closely related). synthetic steroids (dexamethasone) can select for the GR vs MR, reducing side effects

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12
Q

what is a receptor?

A

= a protein that binds an information carrying molecule
= passes on the information in a different form
= causes changes in cell behaviour

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13
Q

what is transduction?

A

passing on a signal in a different form

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14
Q

what are the 4 main types of receptor? which is the most common?

A

1) ligand-gated ion channel
2) G protein-coupled receptor (metabotropic) = most common
3) Receptor tyrosine kinase
4) Nuclear hormone receptor

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15
Q

classes of molecule that interact with receptors: full agonist

A

bind to a site on the receptor and activate it fully eg. natural ligand

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16
Q

classes of molecule that interact with receptors: partial agonist

A

bind to the receptor and activate it, but doesn’t do this as well as a full agonist part way between an agonist and a full agonist

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17
Q

classes of molecule that interact with receptors: antagonist

A

competitive antagonist bind to the agonist site and block activation

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18
Q

classes of molecule that interact with receptors: allosteric modulator

A

binds to a site distinct from the agonist site and changes receptor behaviour. can be either positive (increase receptor activity) or negative (decrease receptor activity)

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19
Q

what is a ligand?

A

any class of drug, neurotransmitter or hormone that binds to a receptor

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20
Q

describe Cys Loop Receptors

A
  • have at least 2 binding sites for their natural agonist
  • they are transmembrane proteins
  • pentameric proteins
  • all ligand-gated ion channels

eg. GABAA receptors and nicotinic acetylcholine receptors (have 17 different subunits)

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21
Q

describe receptor tyrosine kinase receptors and give an example

A
  • transmembrane proteins (58 in human genome)
  • can exist as monomers or dimers, but always act as dimers
  • bind peptide hormones, growth factors, cytokines
  • recognise specific sequences in target proteins
  • phosphorylate target protein tyrosines

eg. insulin receptor

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22
Q

describe G protein-coupled receptor (GPCR)

A
  • biggest receptor family (831 human genome)
  • 7 transmembrane proteins
  • important in nervous system, vision and olfaction
  • act via accessory proteins (G proteins) = trimeric proteins
  • Gs, Gi, Gq = 3 main receptors

eg. B2 - adrenoreceptor

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23
Q

describe ligand-gated ion channel receptors

A
  • multi subunit transmembrane proteins
  • all have at least 2 agonist sites
  • ion channel is part of receptor
    — activation opens channel
    — changes cell membrane potential
    — can trigger action potential
  • can allow for very fast signalling eg. nerve to muscle
  • several structurally different types
    — cys-loop receptors
    — iGlutamate receptors
    — P2X receptors (nucleotide gated channels)
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24
Q

describe nuclear hormone receptors

A
  • 48 NHRs in man
  • intracellular location — therefore bind lipid soluble ligand eg. steroids
  • when activated bind to DNA
    — increase transcription of specific genes
    — decrease transcription of specific genes
  • effects tend to be slower than other receptor types — hours to days
  • eg. glucocorticoid receptor
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25
Q

what assumptions are made about drug binding for mathematic reasons?

A

1) drug is binding to a protein — therefore limited number of binding sites
2) drug binds reversibly to its target
3) conc of drug can be changed

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26
Q

what equation links D, R and DR?

A

D + R —>/

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27
Q

what do D, R and DR represent?

A 
D = drug conc
R = free receptor conc 
DR = bound drug
28
Q

what is Kd?

A
  • eqm dissociation constant (K +1/ K - 1)
    = a parameter which describes the affinity of a drug for a receptor
    = conc giving 50% max binding (how well size and shape of drug matches receptor — measurement of affinity)
29
Q

what is ED50?

A

ED50 = the parameter that best describes the potency of a drug in a clinical trail

30
Q

what is Bmax?

A

= R + DR

= the total number of receptor molecules (max number of binding)

31
Q

what equation links B, Bmax, [D], and Kd?

A

B = Bmax. [D] / Kd + [D]

32
Q

what would a low Kd imply?

A

high affinity

33
Q

how do you calculate how much higher the affinity is in one thing compared to another?

A

low affinity value / high affinity value

34
Q

what does the Hill-Langmuir Equation describe?

A

describes how drug binding with a receptor varies with drug concentration

35
Q

what is EC50?

A

a measure of potency — ECx format means the conc required to give X% of the max response

36
Q

what is potency in terms of EC50 and ED50?

A

potency is the concentration (EC50) or dose (ED50) of a drug required to produce 50% of that drug’s maximal effect

37
Q

what is the Hill-Langmuir Equation?

A

E (effect) = Emax.[D] / EC50 + [D]

38
Q

what are the advantages of a log scale?

A
  • data less cramped — easier to see what is going on at a lower conc — easier to read off EC50 value
39
Q

describe the beta1 - adrenoceptor

A

= coupled to the cAMP pathway via the G protein Gs
- when these receptors are activated by agonist, Gs stimulates adenylyl cyclase resulting in the production of cyclic AMP (cAMP) from ATP

40
Q

what can you measure to measure the activation of the beta1-adrenoceptor?

A

conc of cAMP in our cells

41
Q

describe nuclear hormone receptors

A

= a superfamily of receptors of lipophilic substances (steroid hormones)
- all have similar structure and same basic mechanism (bind agonist and regulate transcription of DNA — changes protein expression)

42
Q

give some examples of nuclear hormone receptors

A
  • progesterone, oestrogen, androgen receptors
  • thyroid hormone receptors
  • glucocorticoid, mineralocorticoid receptors
  • vitamin D receptor
  • retinoic acid receptor
43
Q

what is transactivation?

A

increasing transcription of a gene

44
Q

what is transrepression?

A

repressing/decreasing transcription

45
Q

what can an excess of glucocorticoids lead to?

A

cushing’s syndrome

46
Q

via what 2 mechanisms can an excess of glucocorticoids arise?

A
  1. given a high dose of a glucocorticoid drug eg. prednisolone
  2. tumour which results in excess glucocorticoid production by the adrenal cortex

pituitary tumour can arise in a form of Cushing’s syndrome

47
Q

describe the 2 glucocorticoid receptors and what they control

A
  1. glucocorticoid receptor — has metabolic effects, anti-inflammatory effects (most important), immunosuppressive effects
  2. mineralocorticoid receptors — water and electrolyte balance
48
Q

what natural steroids are there and what receptors are they selective for?

A
  • cortisol (hydrocortisone) / corticosterone = show both activities. non-selective GCR ad MCR
  • aldosterone = MCR only
49
Q

what are the effects of a high dose of hydrocortisone?

A

anti-inflammatory effects (DESIRABLE), immunosuppression (sometimes desirable), metabolic effects (usually undesirable), mineralocorticoid effects (dose may be high enough to overcome effect of enzyme protected MCR), depression

50
Q

what are symptoms of Cushing syndrome?

A
  • moon face
  • thinning of skin
  • poor wound healing
  • osteoporosis
  • muscle wasting
  • increased abdominal fat
  • buffalo hump
  • hypertension
51
Q

what removes undesirable effects of mineralocorticoid effects?

A

dexamethasone

52
Q

duration of action of hydrocortisone, fludorocortisone, prednisolone, dexamethasone

A

hydrocortisone and fludrocortisone = short duration
prednisolone = medium duration
dexamethasone = long duration

53
Q

transactivation vs. transrepression effects

A

transactivation = some anti-inflammatory effects, metabolic effects, skin thinning

transrepression = some anti-inflammatory effects

54
Q

to remove undesirable side effects, what do you want a drug to favour?

A

want a drug to favour transrepression — mono form instead of dimeric form

55
Q

what are SEGRAMS?

A

= Selective Glucocorticoid Receptor Agonist/Modulator

  • designed to favour transrepression pathway
  • should have a more favourable side effect profile
  • bind to receptor, changing its structure subtly —receptor no longer dimerises (stays in monomeric form)
  • none on the market, some currently in clinical trials
  • BIASED AGONISM
  • act via trans-repression of glucocorticoid receptor responsive genes
56
Q

what are CRF and ACTH?

A 
CRF = corticotropin releasing hormone 
ACTH = adrenocorticotropic hormone
57
Q

how does dexamethasone stop the production of CRF and ACTH??

A

negative feedback

58
Q

why doesn’t the stop in the production fo CRF and ACTH by dexamethasone cause too many problems?

A

because dexamethasone can take over the physiological roles of hydrocortisone and corticosterone

59
Q

if a patient suddenly stops taking dexamethasone, what happens?

A

suddenly there are no glucocorticoids produced by the adrenal cortex and there are none in circulation — ADRENAL INSUFFICIENCY

60
Q

how should you stop taking dexamethasone?

A
  • don’t stop treatment unless under medical supervision
  • when stopping, do so in a stepped fashion
  • carry a steroid treatment card — provide medical personnel with useful information in an emergency
61
Q

what happens to hydrocortisone levels under stress and what is its effect?

A

levels increase (it is a stress hormone) — increases availability of glucose

62
Q

what happens to hydrocortisone in major depression?

A

in people with major depression, they have an impaired negative feedback mechanism — high levels of hydrocortisone in their system due to stress, but this doesn’t dampen down the production of CRF and ACTH sufficiently — hydrocortisone levels become very high

63
Q

what regions of the brain do corticosteroids have negative effects on? what effect do they have?

A

particularly the hippocampus and the prefrontal cortex — increased apoptosis in depression in these regions and decreased neurogenesis — thought to be an affect of the high levels of glucocorticoids

64
Q

in depression, what is thought to cause high plasma concentrations of glucocorticoids?

A

prolonged stress leading to failure of negative feedback signalling in the hypothalamus and anterior pituitary

65
Q

what is the likely immediate consequence of immediately stopping steroid treatment?

A

acute adrenal insufficiency, leading to life-threatening symptoms

PBL SEM 1 (9 decks)

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