Drug targets - receptors, ion channels, enzymes, transporters Flashcards
combination of 2 lectures: drugs and enzymes & drugs and receptors
what is an enzyme inhibitor?
a molecule that binds to an enzyme and decreases its activity.
It prevents the substrate from entering the enzyme’s active site and prevents it from catalysing its reaction.
what are the 2 types of enzyme inhibitor?
- Irreversible inhibitors – react with the enzyme and change it chemically
- Reversible inhibitors – bind non-covalently and different types of inhibition are produced depending on whether these inhibitors bind to the enzyme, the enzyme-substrate complex, or both.
name a VERY COMMON drug that uses enzyme inhibition in its pathway
what enzyme does it inhibit and why
statin
statins inhibit the enzyme HMG-CoA reductase in the formation of cholesterol pathway
therefore lower lipids
example of enzyme inhibition: what does inhibiting ACE in the RAAS pathway cause?
inhibiting of Angiotensin converting enzyme
reduces angiotensin I from becoming angiotensin II
leads to reduction in blood pressure
what disease is commonly treated with enzyme inhibitor drugs?
parkinsons
inhibit dopamine degradation
what is the difference between passive and active transporters?
no energy required for a passive transporter
energy required for an active transporter
what are the 2 main types of passive transporter?
Symporter (cotransporter protein)
Channels
what is the main type of passive transporter?
ATP-ases
what are the 3 main types of cell membrane proteins transporters?
uniporter
symporter
antiporter
(symporter and anti porter are cotransporters)
does a uniporter use ATP?
yes - use energy from ATP to pull molecules in
does a symporter use ATP? give an example of a symporter
No
uses the movement of one molecule to pull in another molecule against a concentration gradient.
Both substances go in same direction
E.g the Na-K-Cl cotransporter (NKCC) in kidney
does a antiporter use ATP? give an example of a antiporter
No
one substance moves against its gradient, using energy from the second substance (mostly Na+, K+ or H+) moving down its gradient.
Substances go in opposite directions
how does a voltage gated ion channel work ?
Closed normally, then activated when exposed to depolarisation (action potential)
Calcium enters the cell at depolarisation, which activates Ca-sensitive K channels, which causes muscle contraction, and excitation of neurons etc.
what drug inhibits a voltage gated calcium channel in order to lower blood pressure?
amlodipine
(inhibits muscle contraction)
stopping Ca influx across cell membranes. This causes vasodilation, reduced peripheral vascular resistance and lowers BP
which channels are important in regulation of insulin secretion ?
voltage gates potassium channel
in the islets of langerhans in pancreas
(drugs blocking them triggers insulin secretion and therefore these are used in type 2 DM treatment)
how does the sodium pump work in the heart?
(Na/K ATP-ase)
Pumps 3 Na out of cell, 2 K into cell,
against both their concentration gradients therefore needs ATP
how does the sodium pump work in the heart?
(Na/K ATP-ase)
Pumps 3 Na out of cell, 2 K into cell,
against both their concentration gradients therefore needs ATP
what drug inhibits the Na/K ATP-ase pump in the heart, why is it useful?
Digoxin inhibits it
causes an increase in intracellular Na and then an increase in intravceullar Ca
this lengthens CO and a decrease in heart rate is seen
so it is used Ito treat AF and heart failure
what is a proton pump and where is it used?
K/H ATP-ase in the stomach
exchanges K I the intestinal lumen with H+ (aq)
responsible for acidification of the stomach because its activates pepsin
inhibit the pump to inhibit acid secretion
name the major enzyme family involved in drug metabolism
CYPs
cytochrome P450
these deactivate drugs so they can be excreted
examples of drug targets
these are all proteins –>
receptors
enzymes
transporters
ion channels
what is a receptor?
a component of a cell that interacts with a specific ligand and initiates a change of biochemical events leading to the ligands observed effects.
what are examples of exogenous and endogenous ligands?
Exogenous (extrinsic) - drugs
endogenous (intrinsic) - hormones, neurotransmitters
what is a ligand
a molecule that binds to another (usually larger) molecule
what are the types of receptors?
ligand gated ion channels
G protein coupled receptors
kinase linked receptors
what are 4 types of receptors?
ligand gated ion channels
G protein coupled receptors
kinase linked receptors
nuclear receptors
how do ligand gated ion channels act as receptors?
Ion channels form pores in the membrane that allow ions to pass through and cause a shift on electric charge distribution
how do G protein coupled receptors act as receptors?
GPCRs elicit a conformational change that causes an intracellular signal cascade
when a ligand binds, they catalyse the exchange of GDP to GTP (using G proteins?)
how do G protein coupled receptors act as receptors?
GPCRs elicit a conformational change that causes an intracellular signal cascade
when a ligand binds, they catalyse the exchange of GDP to GTP (using G proteins?)
how do kinase-linked receptors act as receptors?
what are they specifically receptors for?
kinases catalyse the transfer of phosphate groups (substrate gains a phosphate, donated from ATP
they are receptors for growth factors
how do nuclear receptors act as receptors?
what are they specifically receptors for?
they are steroid hormone receptors
they are intracellular molecules that modify gene transcription
they have zinc fingers (to bind to DNA) and a ligand binding site
how do drugs activate receptors ?
(2 state model of receptor activation)
drugs activate receptors by inducing or supporting a conformational change in the receptor from off to on
what are Log concentration response curves used for?
plot drugs against their dose response.
It shows how a response is mediated by an increasing amount of the drug
useful in deciding dosages
what is the normal shape of a log concentration response curve?
sigmoidal
eventually increasing the dose doesn’t make an increased response, saturated
what is EC50?
half maximal effective concentration’ ie. the concentration of a drug needed to cause half of the maximum possible effect/response
what is a partial agonist?
Agonist that never reaches stage where it can elicit a 100% response
what is the intrinsic activity of a drug?
a measure of the ability of a drug that is bound to the receptor to generate an activating stimulus and produce a change in cellular activity.
ie. eficiicay
ie. its ability to produce a maximum response
what is the maximum response shown as on theog concentration response curve?
Emax
what is allosteric modulation?
When an allosteric ligand binds to a different site on the molecule to the agonist, and also causes conformational change in the protein
can have the same or different effect
A non-competitive antagonist binds to an allosteric binding site on the receptor and here it does not completely block the effect of the agonist
allosteric site is just ‘the other’ binding site
do antagonists have a high or low efficacy?
ZERO efficacy
(because they block receptors, dont activate receptors at all )
is the following true:
the more receptors a cell has, the easier it is to reach maximum response
higher dose does cause more activation of more receptors
however some agonists only need to activate a small fraction of the existing receptors to produce maximal response. there is a receptor reserve seen
what is inverse agonism?
When a drug that binds to the same receptor as an agonist, but induces an opposite response to that agonist! This is an inverse agonist
what is the difference between tolerance and desensitisation to a drug?
both see a reduction in drug effect,
tolerance is a slow process building up over time
desensitisation is rapid
