Lecture 2 - Pharmacodynamics (Receptors) Flashcards
what is the Law of Mass Action?
the rate of a reaction is dependent on the concentration of the reagents and how well they mix together
how fast a drug and receptor bind
rate of association
how fast the drug and receptor unbind
rate of dissociation
in pharmacology, the “reagents” of a reaction are:
the drug and the receptor
at equilibrium, the rates of association and dissociation are equal so:
the amount of drug bound to the receptor is stable
what is the equilibrium dissociation constant (Kd)?
the ratio of the dissociation constant (Koff) and association constant (Kon) at equilibrium
what does it mean for a drug to have low Kd?
the drug binds to the receptor very well (very little dissociation)
what is the Hill-Langmuir equation?
[AR] = ([A][Rt]) / ([A]+[Kd])
*A = drug
*R = receptor
the law of mass action equation forms what type of curve?
a sigmoidal curve
when [A]=Kd, the concentration of the drug is just enough to:
occupy half the receptors (Kd = [Rt]/2)
what two characteristics the law of mass action can be determined using the Hill-Langmuir equation (but more specifically the graph)?
the maximum system capability (Rt) and the system sensitivity (Kd)
most drugs interact with receptors in a _____ manner to produce change in the state of the receptor
reversible
the binding of a drug and receptor determines the quantitative relationship between:
dose and effect
most drugs influence a cellular process, either by interacting with a ____, ____, ____, or _____
receptor, channel, transporter, or enzyme
proteins that respond to an external stimulus, and induces a change inside the cell
receptors
proteins which form pores in the cell membrane that allow passive movement of ions into or out of the cell
channels
movement of ions across the cell membrane through channels is driven by:
passive diffusion, and do not require energy
proteins which actively transport molecules across the membrane using ATP or other high energy molecules
transporters
types of receptors which are located inside the cell
intracellular receptors
in order for drugs to act on an intracellular receptor, they must:
cross the plasma membrane
in order for drugs to cross the plasma membrane, they must be:
lipid soluble
what is an example of drugs which act on intracellular receptors?
steroid hormones
a steroid binds to the _____ of a steroid hormone receptor, leading to displacement of _____ or other chaperones, which exposes a DNA recognition domain and leads to _____
ligand binding domain (LBD), heat shock protein (HSP), transcription of target genes (receptor enters nucleus and binds DNA)
how quickly do steroid hormones act?
effects typically have a slow-onset and are long-lasting
the largest group of membrane receptors in eukaryotes
G-protein-coupled-receptors (GPCRs)
how many marketed drugs act at GPCRs?
1/3 to 1/2
in GPCRs, ligands bind to the extracellular side, and trigger a conformational change that:
activates a signalling cascade mediated by intracellular G-proteins
GPCRs are made of a single polypeptide that is folded into a globular shape embedded in the plasma membrane called a:
7 transmembrane receptor
what is the purpose of the extracellular loops of GPCRs?
form a pocket where signalling molecules can bind
specialized proteins that bind nucleotides guanosine triphosphate (GTP) and guanosine diphosphate (GDP)
G-proteins
GPCR G-proteins are _____, meaning they have three different subunits (alpha, beta, gamma)
heterotrimeric
what does the alpha subunit do when the GPCR is activated?
the alpha subunit swaps a GDP nucleotide (resting form) for a GTP nucleotide (active form)
when GDP is swapped for a GTP on a GPCR, this causes the protein to:
dissociate into two parts (alpha and beta-gamma)
true or false: when the G-protein dissociates, both subunits remain tethered to the membrane and can interact with other signalling molecules
true
has GTPase activity that acts like a molecular ‘timer’ to terminate the signal
the alpha subunit
what happens to the G-protein after GTP is hydrolyzed back to GDP?
the inactive G-protein complex reassembles and the system can reset
GPCRs can be categorized based on:
the type of alpha subunit that is associated
what are the three types of alpha subunits?
Gs, Gi, and Gq
different alpha subunits influence different signalling cascades via effects on _____ or _____
adenylate cyclase (AC), phospholipase C (PLC)
can influence the activity of a variety of protein types including ion channels
beta-gamma subunits
one of the most common G-protein mediated signalling cascades is via:
adenylate cyclase (AC)
list the mechanism of action when a drug binds to a receptor coupled to the Gs signalling cascade
1) increased activity of AC
2) production of cAMP
3) activation of cAMP dependent protein kinases (ex: PKA)
4) phosphorylation of targets
list the mechanism of action when a drug binds to a receptor coupled to the Gi signalling cascade
1) suppressed activity of AC
2) decreased production of cAMP
3) inactivation of cAMP dependent protein kinases
4) no phosphorylation of targets
list the mechanism of action when a drug binds to a receptor coupled to the Gq signalling cascade
1) increased activity of PLC
2) production of inositol triphosphate (IP3) and diacyl glycerol (DAG) from the breakdown of PIP2
3) IP3 triggers the release of intracellular Ca++ (influences a variety of signalling pathways)
4) DAG activates protein kinase C (PKC) and target substrates
activation of tyrosine kinase receptors is driven by _____ in the presence of a ligand, causing the receptors to _____ and become activated
dimerization of receptors, autophosphorylate
drugs that inhibit or stimulate the activation of tyrosine kinase receptors will influence:
downstream signalling molecules
the fastest mechanism of signalling in the body depends on:
electrical signals generated by ion channel proteins
allow ions to cross the membrane rapidly, leading to changes in membrane voltage
ion channels
different ion channels are controlled by distinct stimuli, such as _____ or changes in _____
ligand binding, membrane voltage
proteins which open or close in response to the binding of a small signalling molecule (like amino acids or neurotransmitters)
ligand-gated channels
proteins which response very rapidly to changes in membrane voltage
voltage-gated ion channels
specialized proteins that assist in the movement of ions, peptides, small molecules, lipids, and macromolecules across a biological membrane, moving the substrate against their concentration gradient (uses energy)
active transporters
what is an example of an active transporter?
the dopamine transporter: which clears dopamine from the synapse
cocaine blocks the dopamine transporter, leading to an accumulation of dopamine in the synapse
