Podgorski - Dose Response Curves Flashcards
Pharmacokinetics
How factors affect the conc. of drug at active site as a function of time
Pharmacokinetic processes
ADME - absorption, distribution, metabolism, excretion
Pharmacodynamics
How target cells respond to delivered conc. of drug
Majority of drug receptors:
Drugs:
Cell-surface signaling protein. Bind NT/hormones
Proteins
Basic mechs of transmembrane signalling
- Lipid-soluble ligand
- Transmembrane receptor protein
- Transmembrane receptor
- Ligand-gated ion channel
- G-protein coupled receptor – production of intracellular second messengers
Transmembrane receptor protein
Its activity regulated allosterically by a
ligand binding to extracellular domain
Lipid-soluble ligand
Acts on intracellular receptor
Transmembrane receptor
Binds and stimulates protein tyrosine kinase
Ligand-gated ion channel
Opening and closing regulated by ligand binding
G-protein coupled receptor
Production of intracellular second messengers
Receptor Properties (3)
- Determine the quantitative relations between dose or
concentration of drug and pharmacologic effects - Determine drug selectivity of action (depending on
molecular size, shape, and electrical charge of a drug) - Mediate the actions of pharmacologic agonists and
antagonists.
Drug receptor vs. target
Phospholipids, gangliosides, channel proteins, intracellular enzymes, DNA = Targets
Lipid Soluble Drugs:
Enzymes
Transcription factors
Structural proteins
Enzymes: alter production of metabolic molecule (vit k and coagulase cascade)
TFs: steroids and thyroid hormone
SPs: antimitotic vinca alkaloids
Glucocorticoid receptor action
Act by:
Lag period:
Persists:
Act by regulating gene expression
Lag period of 30 min to several hours
persisting effects – hours or days
Transmembrane enzyme receptors:
Extracellular vs intracellular
extracellular hormone-binding domain
intracellular enzyme domain
Transmembrane enzyme receptors:
Mediate first steps in:
insulin, EGF, PDGF, ANP, and TGFb signaling
Transmembrane enzyme receptors intensity and duration regulated by:
receptor downregulation
Transmembrane enzyme receptors:
examples:
monoclonal antibodies (trastuzumab, cetuximab); small molecule inhibitors (gefitinib, erlotinib)
Source of protein kinase activity in cytokine receptors:
Jak kinases (not intrinsic)
Cytokine receptors examples:
Ligands include growth hormone, erythropoietin, several kinds of interferon; mechanism closely related to RTKs
LIGAND-GATED CHANNELS Mimic action of:
endogenous ligands (acetylcholine, serotonin, GABA, glutamate)
LIGAND-GATED CHANNELS Transmit signal across plasma membrane by:
Transmit signal across plasma membrane by increasing transmembrane conductance and changing membrane potential
LIGAND-GATED CHANNELS regulated by:
multiple mechanisms (e.g. phosphorylation and endocytosis)
LIGAND-GATED CHANNELS response time:
rapid (milliseconds)
Voltage gated channels are controlled by:
membrane potential
Voltage gated channels ex:
verapamil (voltage-gated calcium channel). anti arrhytmic effects through actions on voltage-gated calcium channels.
remember, both ligand and voltage-gated channels have very fast response times (millliseconds)
Examples of ligand-gated receptor:
Nicotinic acetylcholine (ACh) R
G-protein coupled receptors,
mech
second messengers
G-protein coupled receptors,
examples
Biggest group
beta-adrenoreceptors, glucagon receptors, thyrotropin receptors, subtypes of DA and 5HT Rs
2nd messenger activation: adenylyl cyclase
type of response:
acts via:
response
Hormonal responses
Acts via stimulation of cAMP-dependent
neurotransmitters, growth factors
protein kinases
Response: increase or decrease in cAMP
2nd messenger activation: Phospholipase C
triggered by:
acts via:
response:
Triggered by hormones, neurotransmitters,
growth factors
- Acts via binding to GPCR (G Protein-Coupled Receptors) or RTKs (receptor tyrosine kinase)
- Response: increase in IP3, DAG
Mass action
increasing ligand conc. produces more binding
controls binding of ligands to receptor
Kd =
Equilibrium dissociation constant
conc. at which 50% of receptors or occupied
Kd = [D][R]/ [DR] = Koff/Kon
D= free drug R= free receptor DR= drug-receptor complex
Kd at equilibrium =
[D][R] Kon = [DR] Koff
Why do the binding and response curves look identical?
assume response is directly proportional to the amount of drug-receptor complex that is formed.
How is drug-receptor binding like enzyme kinetics?
Response ~ velocity
Kd ~ km
Response/response max =
[DR]/[R]t = [D]/[D] + Kd
Agonist definition
binds to a receptor and stabilizes
it in a particular conformation
Efficacy def:
measure of max response (height on curve)
EC50 def:
conc. req. for 50% of the max response
Potency def:
comparison of EC50s.
More potency = less conc. needed for response
(The one closer to the left has higher potency)
Antagonist def:
An agent that binds to a receptor but cannot produce the conformational change
necessary to trigger the downstream events.
Response when antagonist binds by itself:
None; binds but can’t produce the conformational change necessary to trigger downstream events
Competitive vs noncompetitive antagonists
competitive: reversible
non: irreversible
effects of competitive antagonists on chart:
Apparent Kd for the agonist increases
Shifts to the right (higher conc. needed for same response)
No effect on efficacy
NC antagonist binds:
effect on efficacy
binds to active or allosteric site of the receptor (downstream effects)
This cannot be overcome by increasing agonist
concentrations
reduces efficacy
Non competitive antagonist summary
effect on affinity and potency
As the noncompetitive inhibitor conc.increases, the apparent efficacy decreases since the inhibitor inactivates receptors or downstream effectors.
no effect on apparent affinity (Kd) for pure noncompetitive antagonists
potency is not affected
Physiological antagonism:
Exs:
Caused by agonist and antagonist acting at two independent sites and inducing independent, but opposite effects
Exs: glucocorticoid hormones and insulin)
Chemical antagonism:
Exs:
Caused by combination of agonist with antagonist, with resulting inactivation of the agonist
(e.g., dimercaprol and mercuric ion; heparin and protamine)
Inverse agonist
Inverse agonist produces effect opposite to the effect of agonist
Which of the following terms best describes a drug that blocks the action of epi at its vascular alpha receptors by occupying the epi receptor binding sites without activating them?
Non-competitive antagonists
What best describes an antagonist that interacts directly with the agonist and not at all, or only incidentally with the receptor?
Chemical antagonist
“Spare receptors”
What pathway?
Effects?
common for:
linked to:
alpha 1 adrenergic pathway
full response with less than 100%
receptor occupancy
common for hormone receptors and
neurotransmiiters
true for receptors linked to enzymatic
signal transduction cascades
Mechanism of spare receptor:
Results:
receptor remains activated after the agonist departs, allowing one agonist molecule to activate several receptors
cell signaling pathways allow for significant amplification of relatively small
signal, and activation of only few receptors produces maximal response
result: high sensitivity with fast turn-off
Receptor regulation:
Rapid desensitization
Resensitization
Downregulation
congeners of ACh
Analog of ACh
congeners of ACh: propionylcholine and butyrylcholine
Analog of ACh: acetylthiocholine
