Sesh 6- Pharmacodynamics Flashcards
What 3 general factors affect potency?
- Affinity-strength of binding
- Intrinsic efficacy- ability wto activate the receptor
- Cell/tissue-dependant factors
2+3= efficacy
Do G proteins bind GDP or GTP in their inactive state?
GDP
Do most drugs bind reversibly or irreversibly to receptors?
Reversibly
The affinity of a ligand for a receptor describes the ________ of binding.
Strength
What is the intrinsic efficacy of a ligand?
The ability of a ligand to activate the receptor.
*Applies to agonists only
What is meant by a ligand’s efficacy?
The ability of a ligand to produce a measurable biological response. This is governed by the intrinsic efficacy plus cell/tissue-dependant factors.
Do antagonists have intrinsic efficacy?
No, only affinity, as they bind to block the receptor.
How are drug-receptor interactions by binding measured?
By using a radioligand, you can calculate Bmax and Kd.
What does Bmax give information about?
The maximum binding capacity i.e. Number of receptors
Kd is an index of________ of a _________ for a __________.
- Affinity
- Ligand
- Receptor
Define Kd.
Kd is the dissociation constant. It is the concentration of ligand required to occupy 50% of the available receptors.
A drug binding curve plotted on a logarithmic scale produces a ________ shape plot.
Sigmoidal.
Define EC50.
The ligand concentration required to produce 50% of the maximal response (Emax).
The EC50 value of an agonist gives a measure of its _____________.
Potency.
What is functional antagonism?
Opposing a response in a way that is independent of the mechanism causing that response.
Give an example of a cell or tissue-specific factor that can influence drug potency.
The number of receptors in that cell or tissue.
Spare receptors increase the _______ of cells to a ligand, and increases the agonist ________.
- Sensitivity
- Potency
*ligand doesn’t need to occupy all receptors for max response.
Increasing the activation of a receptor pharmacologically, e.g. By dosing successively, will ___________ the receptor number.
Decrease/down regulate. This can lead to tolerance or tachyphylaxis.
Buprenorphine is a _____________ at the mu opioid receptor.
Partial agonist.
Why are partial agonists sometimes referred to as mixed agonist/antagonists?
Because if they have higher affinity for a receptor than another ligand, but lower efficacy, they can antagonise that ligand, and limit the response produced.
Partial agonism is dependent on the _______and _________.
- Compound
2. System-e.g. Receptor number can change a partial agonist into a full agonist
What is the IC50?
The concentration of antagonist needed to inhibit 50% of the max response. It is an index of antagonist potency.
Why is competitive inhibition surmountable?
If you increase the agonist concentration, it can compete with the antagonist for binding sites and eventually elicit the maximal response.
What type of antagonism is non-surmountable?
Irreversible competitive antagonism.
How do irreversible competitive antagonists work?
They block the receptor binding site and dissociate slowly or not at all e.g. covalently bind.
That receptor site that the endogenous ligand binds is termed the __________ site.
Orthosteric.
What is intrinsic activity?
A measure of the level of response produced.
What do RGS proteins do?
They regulate the rate that the G-alpha intrinsic GTPase hydrolyses GTP to GDP, thereby affecting the length of the response.
How does cAMP activate pKA?
It binds the cAMP binding sites on the regulatory subunits of pKA, causing a conformational change. This shape change releases the catalytic subunits of pKA, which are then free to phosphorylate target proteins.
For signal amplification to occur, downstream target molecules need to be very _________.
Specific. Prevents amplification of many unwanted processes within the cell.
What effect does adrenaline have on cardiac muscle at the cellular level?
- Binds to beta 1 adrenoceptors (Gs coupled)
- shape change recruits Gs G protein
- GDP displaced for GTP on Gs-alpha
- Gs alpha dissociates from beta-gamma to stimulate adenylyl cyclase
- ad cyc converts ATP to cAMP
- cAMP activates pKA
- pKA phosphorylates voltage-gated calcium channels, so they are more likely to open upon depolarisation
- therefore get increased calcium influx, and inotropic effect.
Outline the steps of the cascade that occurs when morphine binds a mu opioid receptor.
- changes receptor shape
- Gi recruited
- Gi-alpha binds GTP, displacing GDP
- beta gamma subunit dissociates and directly binds to the voltage gated calcium channels to inhibit them
- get less pre-synaptic calcium influx
- reduced pre-synaptic neurotransmitter release
