Treatment Flashcards
what type of receptor is a nicotinic acetylcholine receptor
receptor-operated ion channel
name the two competitive antagonists to the nicotinic acetylcholine receptor and state which one is reversible/irreversible
reversible:
tubocurarine and vecuronium
irreversible:
(a) bungarotoxin
name two examples of non-competitive antagonists in a nicotinic acetylcholine receptor
lidocaine and tetrodotoxin
what type of receptor is a GABAA receptor
receptor-operated ion channel
to which superfamily of receptors do the adrenoceptor family and the muscarinic acetylcholine receptor family belong
superfamily 2
G-protein coupled receptors
what enzyme is responsible for the turning on and off of a G protein coupled receptor
GTPase
is it GTP or GDP when the G protein is switched on
GTP = on GDP= off
describe the Role of G-proteins and second messengers in Superfamily 2 receptor-effector coupling (how G protein coupled receptors work)
- first messenger
- receptor
- transducer (G protein)
- effector (enzyme or ion channel)
- second messenger (regulate an internal target)
- cellular response
how are second messengers generated within cells
- synthesis inside cell catalysed by enzymes whose activity is regulated by cell surface receptors
or
- influx of ions via channels whose activity is regulated (indirectly) by cell surface receptors
what are the two key protperties of G proteins
Amplification:
- receptor remains active long enough to active several G-proteins (or the same one several times)
- effector remains activated by Ga subunit long enough to generate many molecules of second messenger
Specificity- different Ga subunits (>28):
- each encoded by a different gene or splice variant
what are these effectors regulated by:
- adenylate cyclase (makes cyclic AMP)
- phospholipase C-b (makes IP3 and DAG)
- voltage-gated potassium channels
- voltage-gated calcium channels
effectors regulated by G - proteins
how do allosteric modulators work
allosteric modulators cause shape change in channel protein on binding elsewhere on the protein
This affects properties of gate and influences time for which channel is open (and ions can move)
what do inhibitor modulators do
↓amount of time channel open, ↓ion flux
what do Facilitator Modulator (+ve) do
↑amount of time channel open, ↑ion flux
what are the 5 factors that affect size of response to a receptor agonist
- concentration of drug in vicinity of receptor at a given time - influenced by dose given, route of administration,
distribution throughout the body, rate of elimination
(metabolism, excretion) - affinity - tendency to bind, strength of attraction between agonist and receptor
- ‘intrinsic efficacy’ - ability to activate a shape change leading to response
- nature of receptor-response coupling ‘signal transduction mechanism’
- total number of receptors present
briefly describe receptor occupancy
-Theoretically, size of overall response varies with proportion of receptors occupied by agonist (occupancy)
- maximum response to agonist occurs when all receptors for that
agonist that are present in that tissue are occupied by agonist - proportion of total receptors available which are occupied depends on:
- agonist concentration
- strength of bonds formed
what is the equation of occupancy
Occupancy = [XA]
__________________
[XA] + KA
KA = equilibrium constant* for agonist drug A
what happens when KA = XA in the occupancy equation
occupancy = 50%
KA is numerically equal to the concentration of agonist when half of the total receptors present are occupied
what does an increase and decrease in Ka mean in terms of occupancy
If KA is a very small value (e.g. picomolar, <10-9 M), the bonds formed between an agonist and its receptor are very strong
and it is easier to form complexes but more difficult to reverse or dissociate binding (↑affinity)
If KA is a very large value (e.g. micromolar, >10-6 M), the bonds formed between an agonist and its receptor are very weak and
it is more difficult to form complexes but much easier to reverse or dissociate binding ↓affinity
what is the definition of EC50
EC50 : effective concentration
to produce 50% of maximum response
how is EC50 used
EC50 is a practical, indirect, measure of Drug A’s potency, measured downstream of receptor – relates agonist drug A’s concentration to biological effect produced as a consequence of occupancy
what is intrinsic efficacy
ability of an agonist on binding to a receptor to activate a change in shape or folding of that receptor
what would the typical intrinsic efficacy values be of a full agonist and a partial agonist
full: +1 (or 100%)
- Evoke the maximum shape change/activation response of
which the receptor protein is capable
partial: between 0 and +1
- Evoke less than the maximum shape change/activation
response of which the receptor is capable
briefly describe inverse agonists stating their possible efficacy value
- [-1 < efficacy <0]
- cause –ve shape change which stabilises inactive state of receptor and attenuates coupling/basal activity
- Make receptor less likely to activate signal transduction – negative efficacy value – make it even harder for receptor to be activated
state the equation of the size of response (R) to an agonist
see slide 30
lecture 31 - treatment 2
what may cause a reduction in size of response during chronic exposure to an agonist drug (desensitisation)
- ↑ removal/metabolism of drug - ↑synthesis/activation of enzymes/transport proteins
- altered characteristics of agonist receptor complex - e.g. phosphorylation of amino acids in receptor proteins - influence affinity and/or efficacy (i.e. binding/activation)
- exhaustion, down-regulation of signal transduction mechanisms downstream from receptor
- ↓number of receptors - ↓synthesis and/or ↑ internalisation, degradation
what is an antagonist drug
‘any drug which reduces the response to another drug’
what would the intrinsic efficacy value be of a competitive antagonist
0
describe the action of competitive antagonists
compete with chemical mediator or agonist drug for binding
to similar or overlapping binding site on the same receptor but
without initiating a cellular response; reduce probability that
receptors will be occupied by chemical mediator or agonist drug
give an example of a competitive antagonist at B1 adrenoreceptors
atenolol
give an example of a reversible competitive antagonist
atenolol
describe reversible competitive antagonists
associate but can then dissociate again so effects can be overcome by adding more agonist (as this increases chance that receptor will be occupied by an agonist rather than antagonist molecule when antagonist dissociates to leave a free receptor)
what is the effect of a competitive reversible antagonist on the agonist log concentration response relationship
rightward parallel shift without reduction in maximum response to agonist
see treatment 3 slide 7
what is the equation fir the dose ratio
see treatment 3 slide 7
give an example of an irreversible competitive antagonist
phenoxybenzamine
describe irreversible competitive antagonists
associate and remain associated with receptor indefinitely;
receptors are permanently blocked and increasing agonist
concentration will have no effect since the receptors remain
blocked and agonist molecules cannot get in to the binding site
to replace antagonist molecules
what is the effect of competitive irreversible antagonists
on agonist log concentration-response curve
progressive reduction in maximum response to agonist without rightward parallel shift in agonist log concentration response curve
describe non-competitive antagonist
- affects action of agonist at some point in chain leading to response but does not compete with agonist for binding to same site on receptor
- can be reversible or irreversible
- normally ↓ maximum response
give an example of a non-competitive antagonist
palonosetron
or lidocaine:
Ion channel blocker lidocaine antagonises the action of acetylcholine
at a point downstream in the chain leading to response
describe the two methods of action of non-competitive antagonists
- can involve binding to an allosteric site on an unoccupied receptor to cause conformational change which alters agonist binding elsewhere and/or initiation of signal transduction
- or can involve interference with a component of signal transduction pathway downstream from receptor
describe and give an example of Physiological (Functional) antagonist
has an opposite effect to the agonist but achieves its result by acting
as an agonist on separate cells or tissues or on different population of receptors/signal pathway in the same cell i.e. two systems are involved
e.g. parasympathetic and sympathetic nerves supplying heart - see T3 - slide 14
describe pharmacokinetic antagonist
one drug ↓ concentration of another drug by interfering with its absorption, distribution, metabolism or excretion (and hence concentration in vicinity of its molecular target)
give an example of a Pharmacokinetic Antagonist and describe how it works
antibiotic rifampicin induces expression of liver enzymes which metabolise anti-coagulant drug warfarin
anticoagulant protection is reduced
what is the difference between an alpha and beta adrenoreceptor
alpha: noradrenaline > adrenaline
beta:
adrenaline> noradrenaline
what receptor does diazepam work on
GABAA receptor /chloride channel
what are the two Pharmacological classification of cholinoceptors
nicotinic (NMJ)
Muscarinic (PNS)
what’s the difference between stimulatory and inhibitory G-proteins
stimulatory G-proteins induce conformational change in effector protein (channel or enzyme) to more active state (enhanced activity)
inhibitory G-proteins induce conformational change in effector protein (channel or enzyme) to less active state (reduced activity)
name 5 processes regulated by cyclic AMP-dependent protein kinase
- smooth muscle relaxation
- cardiac muscle contraction
- ion transport via voltage-operated channels:
altered gating, neuronal excitability etc - cell growth and differentiation:
↑ transcription factor activation (phosphorylation of cyclic AMP response element binding protein, CREB) - cellular metabolism:
enzymes controlling lipolysis, glycogen synthesis and degradation
what is the function of theophylline
- ↓ metabolism of cyclic AMP;
prolongs/enhances cyclic AMP-dependent signalling events
Main actions:
- relaxes bronchial smooth muscle
- some anti-inflammatory effects
- stimulates respiratory centre in brain
Therapy for asthma and COPD
- now rarely used clinically due to numerous side-effects
- narrow therapeutic index
what is IP3
IP3 is a second messenger which causes release of pre-stored
calcium from intracellular organelles into the cytoplasm
what does elevated cytoplasmic calcium ion concentration regulate
- activity of contractile proteins in smooth and cardiac muscle
- secretion from exocrine and endocrine glands
- release of neurotransmitters
- activity of many enzymes and ion channels
Processes regulated by phosphorylation of cellular proteins by PKC include:
- contraction of smooth muscle
- neurotransmitter release
- release of hormones from endocrine glands
- receptor desensitization (reduced activity)
- ion transport across membranes
- inflammation
what is DAG
DAG is a second messenger which activates a phosphorylating
enzyme called Protein Kinase C
give two examples or receptors that are coupled to Phospholipase C-b by G-proteins
a1 adrenoceptors (blood vessels)
M3 muscarinic cholinoceptors (airway smooth muscle)
what are the agonists and antagonists for a1 adrenoreceptors
agonists are vasoconstrictors (noradrenaline, phenylephrine)
antagonists are vasodilators (prazosin, doxazosin)
what are the agonists and antagonists for M3 muscarinic cholinoceptors
agonists are bronchoconstrictors (acetylcholine)
antagonists are bronchodilators (ipratropium bromide, tiotropium)
describe the phospholipase C-b signalling pathway: termination of response
- cytoplasmic calcium leaves cell or is returned to organelle stores
- dephosphorylation of proteins that were phosphorylated by PKC is undertaken by phosphoprotein phosphatases
give two examples of SH-2 domain-containing proteins
glucose transporter proteins (GLUT4) responsible for glucose uptake across cell membrane
MAPK enzyme involved in cell proliferation, differentiation and survival pathways
describe the JAK/STAT pathway
when agonist (cytokine) binds, receptor dimerizes and associates with cytosolic tyrosine kinase (Jak)
Jak phosphorylates receptor dimer
phosphorylated receptor dimer is a binding site for transcription factor, STAT (SH-2 domain containing protein)
STAT is phosphorylated, travels to nucleus and alters gene expression
give two examples of drugs that target tyrosine kinase-linked receptors
renal cancer drug - sunitinib
breast cancer drug - trastuzumab (herceptin)
what are the main types of receptors linked to tyrosine kinase
- insulin receptor - insulin-like growth factor receptor - epidermal growth factor receptor - (cytokine receptors)
