Pharmacodynamics Flashcards
What are the 4 types of 3 types extracellular and one intracellular drug receptors
A drug can work at the receptor and produce a cellular response
Ligand Gated Ion Channels
G- protein Coupled Receptors
Tyrosine Kinase Receptors
The first three are for hydrophilic large drugs
Why they are large will not be able to act on different types of receptors plus they are polarized- charged ions that aren’t allowed to pass through the phospholipid bilayer.
Intracellular receptors
Hydrophobic small drugs
What is ligand gated ion channel’s
A drug can work at the ligand gated ion channels receptor, produce a cellular response by binding onto a ligand gated ion channels either to open or closed the channel depending upon what kind of channels it they bind onto will determine which kind of ion flows in or out that is associated with the cellular response.
Chemical signal binds as a ligand to a G protein-linked receptor
G protein linked receptor changes shape and interacts
with a G protein
Interaction causes GDP to be displaced and GTP to be bound to the G protein
The active G protein binds to another protein, usualvan
enzyme
The enzyme is activated
G protein hydrolyzes to GDP
G protein releases from the enzyme and the reaction
stops
On a neurone there is a particular channel suppose to allow particular ions to flow in and out.
There is a gate on the neurone controlling the entry of drugs thus blocking these ions from moving in or out the cell.
But if a particular drug is given to bind to a pocket that is part of the ligand gated ion channels and once it binds onto the pocket it then lifts the gate open ( the gate that was closed is now open) giving an opportunity for the particular ion to flow in or out of the neurone eg of a drug such as Lorazepam which acts on a GABA receptor (which is a ligand gated ion channel) if GABA binds to the receptor, it will open the channels and allow negative chloride ions to flow in easily into the neurone making the cell negatively charged. It becomes hyperpolarized - given to situations where u want to decrease the activity of the neurones such as seizures- able to work by inhibiting or decreasing seizure activity.
what is Adenyly Cyclase activity
Activation and inhibition of adenylyl cyclase by agonists that bind to catecholamine receptors. Binding to B adrenoceptors stimulates adenylyl cyclase by activating the stimulatory G protein, G., which leads to the dissociation of its alpha subunit charged with GTP. This alpha, subunit directly activates adenylyl cyclase, resulting in an increased rate of synthesis of CAMP. Alpha, adrenocaptor ligands inhibit adenyl/l cyclase by causing dissociation of the inhibitory G protein, G, into its subunits; ie, an alpha, subunit charged with GP and a beta-gamma unit. The mechanism by which these subunits inhibit adenylyl cyclase is uncertain. CAMP binds to the regulatory subunit (R) of CAMP-dependent protein kinase, leading to the liberation of active catalytic subunits (C) that phosphorylate specific protein substrates and modify their activity. These catalytic units also phosphorylate the cAMP response element binding protein (CREB), which modifies gene expression.
first the signaling molecule adrenaline
will migrate to the cell surface and
bind to the g-protein coupled receptor
the g-protein coupled receptor will
undergo a conformational change which
encourages the alpha subunit of the
g-protein to release its bound GDP and
buy new gtp binding of new gtp will
activate the alpha subunit the alpha
subunit will then activate the membrane
bound enzyme adenylyl cyclase adenylyl
cyclase will turn ATP in the cytosol
into cyclic a MP or camp camp will then
bind to the inhibitor proteins on
protein kinase a and release them this
activates protein kinase a and a
phosphorylation cascade protein kinase a
activates phosphorylase kinase using ATP
phosphorylase kinase then activates
glycogen phosphorylase in the same
manner glycogen phosphorylase will lead
to the breakdown of glycogen to be used
as energy by the skeletal muscles during
the fight-or-flight response
what is selectivity of a drug
Selectivity refers to a drug’s ability to preferentially produce a particular effect and is related to the structural specificity of drug binding to receptors.
The drugs then interact with cells or tissues where they produce their intended effects (target sites). This interaction is called selectivity. Selectivity is the degree to which a drug acts on a given site relative to other sites.
What is drug receptor selectivity
Receptor selectivity refers to the extent to which a receptor binds with a particular drug rather than other molecules. Selectivity depends both on the receptor and on the size, shape, and bioelectrical charge of the drug molecule.
the cellular response (also called receptor-effector coupling)
the cellular response (also called receptor-effector coupling). Among the most important ones are the following: (1) direct control of ion channels in the cell membrane, (2) regulation of cellular activity by way of intracellular chemical signals, such as cyclic adenosine 3′,5′-monophosphate (cAMP), inositol phosphates, or calcium ions, and (3) regulation…
What is G protein Coupled Receptors
Also known as as Seven pass receptors or Serpentine receptors
Has a receptor domain where the drug combines to the pocket
It changes the shape of the actual receptor of the intracellular domain that is connected to a G protein called GQ protein that is now stimulated.
The G protein is bound to a GDP that is now pop out. ( the GDP will now bind to a GTP- this is what stimulates the GQ protein that will move along the cell membrane to stimulate the enzyme called phospholipase C(mechanism- breaks down different components of the cell membrane such as a molecule called pip2 further broken down into 2 components called diacylglycerol and ionocytotriphosphate) both will act on a protein kinase particularly a protein kinase C thus increasing the Ca2+ ions inside of the cell- why are they important ( protein kinase- they phosphorylates things for eg channels on a cell that are inactivated currently, but a drug bind unto the receptor and then activates this enzyme- then activates the second messengers like diacylglycerol and ionocytotriphosphate) thus increasing the Ca2+ now why they are cool? The protein kinase c can then phoshosphorylates all the channels if they add a phosphate group all the channels either being activated or inactivated if open the positive ions will flow in this stimulating the cell.
Norepinephrine acting on Serpentine receptors
Norepinephrine to act on the heart cells on the heart muscles
What norepinephrine will do?
It will bind onto to the receptor ( the serpentine receptor) and activate the GQ protein, that will activate the enzyme protein kinase C to active the second messages called diacylglycerol and ionocytotriphosphate to phosphorylates the channels to increase the Ca2+ ions or Na+ ions influx. The anesthetic triphosphate will activate the smooth ER to activate the sarcoplasmic reticulum to release the Calcium into the actual muscle cell: basically the main concept is to increase the ions particularly Calcium ions inside the muscle cell to increase the contraction of the heart.
Thus, the clinical response of the norepinephrine working on the heart muscle to increase the amount of ions to rush into the cell to stimulate its ability to contract.
The concept of cellular response of the heart muscle is to increases contraction.
Two other G proteins known as G stimulatory proteins
Inhibitory proteins
Stimulatory proteins, a drug binds to its receptors and changes its shape and activates the G stimulatory proteins ( for it to be fully activated it needs to get rid of the GDP and bind onto the GTP) once activated it move along the cell membrane and stimulates the adenylate cyclase enzyme ( once activated- its ATP and converts it into Cyclic AMP, it will then activate a molecule called protein kinase A ( it phosphorylate thus either it will open or close the channels to increase or decrease the intake of ions)
Thus potentially produce a cellular response eg norepinephrine as well acting on the heart muscle cells.
Both stimulatory and inhibitory proteins once activated can cause a cellular response. But the inhibitory protein is the opposite…
Inhibitory protein
A drug binds to the G protein coupled receptors- changes its shape and activates the G inhibitory proteins- that will then release a GDP and bind to a GTP. The G inhibitory protein wil then then go and inhibit this enzyme called adenyly Cyclase( that suppose to convert ATP i to Cyclic AMP- that also supposed to activate protein kinase A which supposed to phosphorylate a specific type of proteins (such as structural proteins, enzymatic proteins, functional proteins- ) that can go phosphorylate which could either inactivate or activate a particular protein.
In this situation the G inhibitory protein will inhibit the adenylate cyclase thus inhibiting the ability to convert ATP into cyclic AMP, protein kinase A is decreased and lastly decreasing the phosphorylation
Tyrosine Kinase Receptors
Same concept a receptor is on the outside (of the extracellular membrane) A drug called insulin that will bind to this receptor ( what will happen if it does?)
Because the insulin will bind to this receptor- the G protein is changed ( morphology) activates these enzymes ( tyrosine kinase) that are part of the receptor. On the tyrosine kinase receptor there are residues called amino acids . When insulin binds to the receptor kinases and becomes activated. The tyrosine kinase on either side of the receptor will cross phosphorylate. Once phosphorylation occurs, it causes a change in their structure thus making easier for the receptors to bind to specific proteins/ second massagers , that will further be activated and produce a cell response.
