Pharmacodynamics II, lect 3 Flashcards
when spare receptors exist, the concentration-response curve (EC50) is shifted to the right or left?
Left; smaller dose concentrations
what is the relationship between EC50 and Kd when there are spare receptors
EC50 is lower than Kd
identify 1 and 2
- agonist alone
- agonist + allosteric activator
identify 3 and 4
- agonist + competitive antagonist
- agonist + non-competitive antagonist
what effect does a non-competitive antagonist have on an agonist
reduces the magnitude of the maximal response that can be attained by any amount of agonist
what effect does a competitive antagonist have on a agonist
affect the amount of agonist necessary to achieve a maximal response (does not affect the magnitude of the maximal response)
competitive antagonist bind to the same receptor as agonist. What effect does this have on the agonist’s Kd? Does the curve shift to the right or left?
- competitive antagonist decreases affinity (increases Kd) of an agonist for its receptor
- curves of agonist shift to the right
As the concentration of antagonist increases, what happens to the potency of agonist
- potency of agonist decreases (increases EC50)
non-competitive antagonist act either allosterically or covalently. Describe both
- allosteric: inhibit agonist binding at active site by binding to a secondary site on the receptor
- covalent: irreversibly bind to the same site as agonist
What effect does adding non-competitive antagonist have on the affinity (Kd) and potency (EC50) of agonist?
affinity (Kd) and potency (EC50) do not change
* E max decreases
what is functional (physiological) antagonism
- counteracts effects of agonist
- generally not as specific or as easy to control
- ex: reversing a fall in BP produced by histamine with epinephrine
what is chemical antagonism
- directly interacts with agonist and inactivates it
- ex: inactivation heparin with protamine sulfate; neutralizing stomach acid with antacids
partial agonist have what level of efficacy (alpha) compared to full agonist
- lower efficacy
- cannot produce the same maximal response as full agonist
what is Bmax
the maximum amount of drug that can bind speficially to the receptors; used to measure density of receptor site
efficacy
describes the way that agonists vary in the response they produce when they occupy the same number of receptors. High efficacy agonists produce maximal response while occupying a relatively low proportion of total receptor population
dose response curve for a partial agonist will have what Emax and Bmax compared to agonist
- LOWER Bmax and Emax
if you have a single concentration of full agonist and increasingly add concentrations of a partial agonist,
- what happens to the response cause by the full agonist?
- What happens to the response caused by partial agonist?
- What happens to the total response?
- response caused by full agonist decreases
- response caused by partial agonist increases
- total response gradually decreases
when partial agonist is added to a full agonist, why does the response caused by full agonist decrease ? Why does the total response gradually decrease?
- partial agonist can act as competitive antagonist
- bind to receptor, displacing the agonist and the overall effect is lower
what is the primary function of intracellular receptors
- modifies gene transcription and protein synthesis in the nucleus
- effect in not immediate
- effects are long lasting
what type of ligans are able to stimulate intracellular receptors
lipid soluble ligands (hormones; steroid) : cross plasma membrane
receptor tyrosine receptors are what type of receptors? How do they activate substrates when a ligand binds to them?
- transmembrane proteins
- ligand binding to receptor causes 2 receptors to dimerize and activate the kinase causing phosphorylation of the receptor and several down-stream substrates
What is the mechanism of Imatinib (Gleevec)
anti-cancer agent: signal transduction inhibitor (STI)
In cytokine receptors, where is the kinase activity?
in a seperate protein JAKs
how do cytokine receptors work
- ligand binding causes receptors to dimerize
- JAKs phosphorylate tyrosine residues on recptor and activate STATs via phosphorylation
- STATs dissociate from receptor and regulate gene expression
ions channels come into 2 forms: name them
- ligand:ex: acetylcholine binds to nicotinic receptors which open Na+ channels and excites the cell
- Voltage: ex: local anesthetics and anticonvulsants
What is the effect of GABA on GABA receptors
- the binding of GABA to GABA receptors open Cl- channels
- hyperpolarizes (inhibits) the cell
benzodiazepines, barbituates, and ethanol all act on what receptor to increase Cl- flow in the cell
GABA
G protein coupled receptors come as Gs and Gi: what are the action of these
- Gs: stimulatory; activate cAMP
- Gi: inhibitory; inhibit cAMP
List the steps associated with activation of G-protein receptor
- GTP binds and GDP is releases
- alpha unit of G-protein binds to adenylate cyclase to generate intracellular signal
- the signal is terminated by hydrolysis of GTP
B1 and B2 are stimulate Gs or Gi
stimulate Gs and activate cAMP
alpha2 stimulate Gs or Gi
stimulate Gi and inhibit cAMP
what affect does G-protein receptor kinases (GRK) have on G-protein couples receptors
- increases binding of B-arrestin and decreases the ability of the receptor to interact with G-protein
- reduces response and “desensitizes” the receptor
binding of B-arrestin has what effect on G-protein coupled receptors
increases endocytosis of the receptor
In receptor-effector coupling, what is the function of coupling
the transduction process that links the drug-induced change in receptor conformation to the biological effect
In receptor-effector coupling, what are the effectors
the mechanisms coupled to the receptor (Adenylate cyclase; phospholipase C (PLC), etc)
in receptor-effector coupling, the biological effect is either what?
- linear: (signal is 1-1)
- amplified: biological response is greater than the degree of receptor occupancy
adenylate cyclase has what effect on cAMP production
- Gs proteins activate AC which results in the conversion of ATP to cAMP
What are the major intracellular targets for cAMP? What function does cAMP have on the targets?
- protein kinases (PKA; PKC)
- kinases are composed of 2 regulatory (R) and 2 catalytic (C) subunits; binding of cAMP releases C unites that phosphorylate substrates
Gq proteins activate what?
PLC
After Gq activates PLC; what is the action of PLC
PLC hydolyzes PIP2 to form IP3 and DAG
what is the function of IP3 and DAG
- IP3 diffuses through the cytoplasm and releases Ca2+ from intracellular stores
- DAG activates protein kinase C (PKC)
how does nitric oxide elicit relaxation of vascular smooth muscle
- NO is a diffusable ligand that activates guanyl cyclase
- activated guanyl cyclase converts GTP to cGMP
- cGMP activates protein kinase G (PKG)
- PKG -> vasodilation
