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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
what assumptions are made about drug binding for mathematic reasons?
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
26
what equation links D, R and DR?
D + R —>/
27
what do D, R and DR represent?
``` D = drug conc R = free receptor conc DR = bound drug ```
28
what is Kd?
- 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
what is ED50?
ED50 = the parameter that best describes the potency of a drug in a clinical trail
30
what is Bmax?
= R + DR | = the total number of receptor molecules (max number of binding)
31
what equation links B, Bmax, [D], and Kd?
B = Bmax. [D] / Kd + [D]
32
what would a low Kd imply?
high affinity
33
how do you calculate how much higher the affinity is in one thing compared to another?
low affinity value / high affinity value
34
what does the Hill-Langmuir Equation describe?
describes how drug binding with a receptor varies with drug concentration
35
what is EC50?
a measure of potency — ECx format means the conc required to give X% of the max response
36
what is potency in terms of EC50 and ED50?
potency is the concentration (EC50) or dose (ED50) of a drug required to produce 50% of that drug’s maximal effect
37
what is the Hill-Langmuir Equation?
E (effect) = Emax.[D] / EC50 + [D]
38
what are the advantages of a log scale?
- data less cramped — easier to see what is going on at a lower conc — easier to read off EC50 value
39
describe the beta1 - adrenoceptor
= 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
what can you measure to measure the activation of the beta1-adrenoceptor?
conc of cAMP in our cells
41
describe nuclear hormone receptors
= 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
give some examples of nuclear hormone receptors
- progesterone, oestrogen, androgen receptors - thyroid hormone receptors - glucocorticoid, mineralocorticoid receptors - vitamin D receptor - retinoic acid receptor
43
what is transactivation?
increasing transcription of a gene
44
what is transrepression?
repressing/decreasing transcription
45
what can an excess of glucocorticoids lead to?
cushing’s syndrome
46
via what 2 mechanisms can an excess of glucocorticoids arise?
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
describe the 2 glucocorticoid receptors and what they control
1. glucocorticoid receptor — has metabolic effects, anti-inflammatory effects (most important), immunosuppressive effects 2. mineralocorticoid receptors — water and electrolyte balance
48
what natural steroids are there and what receptors are they selective for?
- cortisol (hydrocortisone) / corticosterone = show both activities. non-selective GCR ad MCR - aldosterone = MCR only
49
what are the effects of a high dose of hydrocortisone?
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
what are symptoms of Cushing syndrome?
- moon face - thinning of skin - poor wound healing - osteoporosis - muscle wasting - increased abdominal fat - buffalo hump - hypertension
51
what removes undesirable effects of mineralocorticoid effects?
dexamethasone
52
duration of action of hydrocortisone, fludorocortisone, prednisolone, dexamethasone
hydrocortisone and fludrocortisone = short duration prednisolone = medium duration dexamethasone = long duration
53
transactivation vs. transrepression effects
transactivation = some anti-inflammatory effects, metabolic effects, skin thinning transrepression = some anti-inflammatory effects
54
to remove undesirable side effects, what do you want a drug to favour?
want a drug to favour transrepression — mono form instead of dimeric form
55
what are SEGRAMS?
= 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
what are CRF and ACTH?
``` CRF = corticotropin releasing hormone ACTH = adrenocorticotropic hormone ```
57
how does dexamethasone stop the production of CRF and ACTH??
negative feedback
58
why doesn’t the stop in the production fo CRF and ACTH by dexamethasone cause too many problems?
because dexamethasone can take over the physiological roles of hydrocortisone and corticosterone
59
if a patient suddenly stops taking dexamethasone, what happens?
suddenly there are no glucocorticoids produced by the adrenal cortex and there are none in circulation — ADRENAL INSUFFICIENCY
60
how should you stop taking dexamethasone?
- 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
what happens to hydrocortisone levels under stress and what is its effect?
levels increase (it is a stress hormone) — increases availability of glucose
62
what happens to hydrocortisone in major depression?
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
what regions of the brain do corticosteroids have negative effects on? what effect do they have?
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
in depression, what is thought to cause high plasma concentrations of glucocorticoids?
prolonged stress leading to failure of negative feedback signalling in the hypothalamus and anterior pituitary
65
what is the likely immediate consequence of immediately stopping steroid treatment?
acute adrenal insufficiency, leading to life-threatening symptoms

PBL SEM 1 (9 decks)

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