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Flashcards in How do drugs work Deck (25):

What are the four main drug targets in the body

Most drugs produce their effect by binding to a protein and causing a conformational change to the protein. The four main proteins targeted are:
- Ion channels
- Enzymes
- Carrier molecules
- Receptors (60% of drugs will act on receptors)

The only none protein drug target that sometimes occurs is DNA.


Drugs can act on all steps of neurotransmission. Describe the main steps in neurotransmission.

1. Neurotransmitter synthesis - once the neurotransmitter has been made it is then stored in vesicles in the axon terminal of a neuron.

2. Neurotransmitter release - stimulated by the arrival of an action potential at the axon terminal of a neuron. Vesicles are held in the cytoskeleton of the pre synaptic neuron by Ca2+ sensitive proteins. When an action potential arrives it opens calcium channels and the influx of Ca2+ ions triggerrs fusion of the vesicle with the cell membrane.

3. Neurotransmitter acts on target cell - the neurotransmitter travels across synaptic cleft and binds to receptors at the post synaptic membrane which causes depolarisation and therefore triggers an AP there.

4. Neurotransmitter inactivation/removal - once bound to the post synaptic receptor the neurotransmitter must then be removed. This can be by an enzyme which degrades/breaks down the neurotransmitter or it can be recycling of the neurotransmitter back into the pre synaptic neuron.


What parts of the cholinergic system (where Ach acts as a neurotransmitter) can be targeted to prevent neurotransmission?

1. ACh synthesis - we can block the chAT enzyme which is essential in producing ACh or we can block the choline transporter which is responsible for transporting choline into the cell and is essential in the production of ACh.
This would stop neurotransmission but only after some time as we have stores of ACh in our neurons.

2. ACh vesicle fusion with pres synaptic membrane - we could block the Ca2+ ion channel to prevent the influx of Ca2+ into the neuron when an AP arrives or we could block the fusion of the vesicle to the pres synaptic membrane.


4. ACh removal/reuptake - Acetylcholine esterase is an important enzyme that breaks down ACh. Acetylcholine inhibitors prevent the enzyme acetyl choline esterase from being able to degrade ACh and so the ACh stays bound. Reversible AChi's are very useful in treatment of conditions such as alzheimers and myasthenia gravis but irreversible AChEi's are very toxic and can cause death (eg nerve gases).


What are the four main families of receptors that drugs may act on

1. Ligand gated ion channels
2. G protein coupled receptors
3. Tyrosine kinase/cytokine receptors
4. Nuclear/steroid receptors


Describe the location, structure and effect of ligand gated ion channels. What is the difference between an inhibitory ligand gated ion channel and an excitatory ligand gated ion channel.

remember a ligand is just an ion or molecule.

Found in the membrane these receptors are made up of multiple sub units and are only activated in response to specific ligands. Once a ligand is bound they are very fast acting (fast signal transduction) and allow for flow of ions into a cell.

An excitatory ligand gated ion channel is one that allows the flow of positive ions into the channel and an inhibitory ligand gated ion channel is one that allows negative ions into the channel.


How does binding of ACh to the receptor pore allow for an influx of ions into the cell

Binding of ACh to the receptor pore causes a "snap" opening of the kink in the centre of the channel which allows a select type of ion to flow through. Most excitatory neurotransmitters such as ACh and glutamte allow for increased permeability of Na+ and K+ through the channel which causes the inside of the cell to become more positive (depolarised) so greater chance of an action potential.


Describe the process of G protein coupled receptor signalling from the moment a agonists binds to the receptor to deactivation of the G protein

At rest, the G protein is bound to ADP and is in the inactive state. Upon binding of an agonists to the extracellular side of the receptor the recpetor undergoes a conformational change which results in the activation of the G protein by causing GTP to replace GDP.

This activated G protein will then dissociate from the receptor and diffuse across to an enzyme which will then cause activation or inhibition of an enzyme depending on the type of G protein.

Gs protein:
will cause the activation of adenyly cyclase, which converts ATP to cAMP. This increases the level of cAMP in the cell. cAMP serves as a second messenger that causes the activation of other signalling pathways.

Gi protein:
will cause the inactivation of adenyly cyclase, decreasing the level of cAMP in the cell

Gq protein:
will cause the activation of phopholipase C that convert PIP2 to DAG and IP3. IP3 then serves as a second messenger that activates other signalling cascades.

Once they have elicited a cellular response, G proteins undergo authophosphorylation to inactivate the G protein and return it to its unactivated state. (it functions as a GTPase enzyme, where it hydrolyses GTP to GDP, inactiving the G protein).
The inactive G protein then dissociates from the enzyme, which returns to its orginial state. The G protein is then available for reuse.


What are the 5 main subtypes of GPCR's.

M1, M2, M3, M4, M5


Describe the negative feedback loop that the M2 GPCR is involved in on pre synaptic membranes in the cholinergic system

M2 receptors are found on the pre synaptic membrane. These recpetors have Gi proteins. When ACh from the synpatic cleft binds to the GPCR is results in activation of the Gi protein which therefore goes on to inhibit the release of adenylate cyclase. This inhibits the Ca2+ channels in the presynaptic membrane so ultimately prevents further ACh release as the vesicles cant fuse with the pre synpatic membrane.


What is the result of blocking the M2 GPCR's on the pre synaptic membrane of neurons?

It increases neurotransmitter release by up to 10 fold. These receptors are therefore often the target of drugs that impair cognitive ability .


Describe the process of Tyrosine kinase receptor signalling from the moment a ligand/agonist binds

After binding of a ligand to the extracellular portion of a tyrosine kinase receptor, it stimulates dimerization of adjacent tyrosine kinase receptors. This then allows for auto-crossphosphorylation of tyrosine residues on each of the intracellular portions of the TKR's. This phosphorylation leads to a signally pathway in the cell which will elicit a cellular response.

Tyrosine kinase receptors usually bind to growth factors, cytokines and certain hormones such as insulin.


What type of receptor are vascular endothelial growth factor receptors and what might drugs target them for?

They are a type of tyrosine kinase receptor. Drugs will often target these receptors in order to prevent angiogenesis (eg in cancer therapy) and also to increase angiogenesis to stimulate wound healing.


How do drugs bind to receptors both reversibly and irreversibly? (with what differing strengths do they bind to receptors)

Covalent binding - essential irreverisble. Drug action is maintained for a much longer duration.

This means the drugs will dissciate after sometime - they are trasnsient in their binding.
Van der Waal forces - weak force or attraction
Hydrogen binding - stronger binding
Ionic interaction - between atoms/ions of opposite charges. This is stronger than hydrogen binding but weaker than covalent.


What is the potency of a drug?

Describes the activity of a drug in terms of how much of a drug is required to produce an effect of given intensity.

A drug that is very potent will cause a given effect at low concentrations whereas a drug of low potency will require much higher concentrations to produce the same desired effect.

Potency is determined by affinity and efficacy of a drug.


What is the affinity of a drug?

Affinity of a drug is a measure of the ability of a drug to bind to a receptor.

A low affinity drug will mean it will not bind to the receptor for as long and the chance of binding will also be less.

Affinity is decribed by the Kd (dissosciation constant). A high Kd means a low affinity.
Kd can be defined as the concentration of the drug at which 50% of the target receptors become occupied.


What is the efficacy of the drug?
And what is the difference between positive efficacy, negative efficacy and no efficacy.

The ability of a drug to elicit a cellular response. (the ability of a drug to bind to a receptor and cause a change in the receptors action).

Positive efficacy = agonists. Drugs that bind to receptors and cause a conformational change that will increase/promote a cellular response.

Negative efficacy = inverse agonists. Drugs that bind to receptors and decrease receptor activity/decrease cellular response.

No efficacy = anatgonists. Drugs that bind to a receptor but cause no conformational change/cellular response. They just occupy the binding site so that the normla biological angonist cant bind.


What is Emax a measure of and what is EC50 a measure of?

Emax is a measure of the concentration of a drug at which maximal effect is reached. This is a measure of the efficacy of a drug.

EC50 is a measure of the concentration of a drug at which 50% of the maximal effect is achieved. This is a measure of the potency of a drug.


What is the biological response of a drug?

The biological response of a drug is the effect a drug has on desired target tissue. Eg the effect blood pressure lowering drugs have on blood pressure


What is the difference between a full and a partial agonist?

A full agonist is a drug that can elicit a maximal response. Partial agonists are drugs that can only elicit a proportion of the maximal response - even with 100% receptor occupancy.

Note: The same drug may be a full agonist in one tissue of the body whereas a partial agonist in another tissue. This is due to the difference in tissue properties in the body.


What are antagonists and what is the difference between reversible competitive antagonism and irreversible antagonism?

Antagonists are drugs which bind to receptors but do not cause a cellular response (they have affinity but no efficacy). Reversible competitive antagonists are drugs which bind to receptors to block the normal agonists from binding but will dissociate after some time. This will mean higher concentrations of agonist are required in order to compete for these binding sites and produce the desired effect. On the other hand, irreversible antagonists will covalently bind to receptors which reduces the number of receptors available for binding. Therefore even if you increase the concentration of the agonists, you wont be able to increase the effect. Soemtime an irreversible antagonist may look like a reversible antagonist at low concentrations because there is still enough binding sites open to allow for a maximal response/effect.


Drugs that act on receptors can either activate or inactivate the receptors whereas drugs that act on enzymes tend only to inhibit, why is this?

Drugs acting on receptors are just binding to a protein that then influences the opening or closing of channels etc so they are not directly binding to a substrate whereas drugs that act on proteins can only really bind to the binding site which will only inhibit the binding of a agonists or even if binding to a site that isnt where an agonist binds it will most likely cause a conformational change in the enzyme and as binding is shape specific this will mean the agonist will be unable to bind. Therefore developing a drug that can bind to an increase the activity of an enzyme is very difficult.


In contrast to the way ACh is removed from the post synaptic membrane (enzyme degradation), how is serotonin removed and what are inhibitors of this process used to treat?

Serotonin is a neurotransmitter that is thought to effect sleep, appetite, memory and mood. Instead of being broken down by an enzyme, serotonin is removed from the synaptic cleft by the transporter 5HT.

SSRI's (selective serotonin receptor inhibitors) are drugs called antidepressants as they prevent serotonin being removed from the synaptic cleft and therefore it improves mood.


Ecstasy causes a massive dumping of serotonin from the neuron - what effect does this have?

Initially this will improve mood quite substantially but it depletes all of the neurons stored of serotonin and so later on you get a rebound depression.


What is Emax?

The maximal effect a drug can produce.


Name 5 drugs and describe how they act on various components of the neurotransmission

Pyridogstigmine - an ACh esterase inhibitor

Atropine - binds to M2 receptor on presynaptic membrane this inhibiting the negative feedback loop which normally stops neurotransmitter release

Floxitine (Prozac) - inhibits the SSR (selective serotonin receptor) which is prevents the reuptake of serotonin from the synaptic cleft.

Benzodiazapine - binds to GABAa receptor (ligand-gated ion channel) on the post synaptic membrane to prevent neurotransmitter from binding

Gabapentin - binds to voltage-gated calcium ion channels in the pre synaptic membrane and inhibits the influx of Ca2+ required for to initiate the fusion of vesicles carrying neurotransmitter with the pre synaptic membrane