2.1 Flashcards
What is a receptor?
Specialized target macromolecule that binds drug or ligand and mediates its pharmacologic action
What is drug specificity? How are receptors specific?
Have structural features that permit drug specificity
Specificity selectivity of response
Must have both a drug-binding domain and an effector (active) domain
What are some examples of drugs that don’t have to bind to a receptor?
Antacids Osmotic Diuretics manitol Heavy Metal Chelating Agents EDTA(Ethylenediaminetetraacetate) – lead poisoning Barrier Ointments and Cream A&D ointment, Zinc oxide ointment Disinfectants Chlorhexidine (hibiclens) Alkylating anticancer agents Cyclophosphamide
What are soluble receptors?
Lipid soluble ligand crosses cell membrane act on intracellular receptor in nucleus for transcription/translation
What are examples of lipid-soluble receptors?
Ex: steroids, vitamin D, and thyroid hormone stimulate the transcription of genes
Consequences:
What are the consequences of lipid-soluble receptors?
Take time (at least 30min) Transcribe genes and synthesize new proteins Not immediately relieve sx The effects can persist for hours or days after the drug has long been eliminated (need to wait for the proteins these drugs encode for to be used)
What are transmembrane receptors? How do they work? Example?
Drug binds to a receptor on a protein that spans the cellular membrane which starts a cascade of effects within the cell. Ex: tyrosine kinase
How does tyrosine kinase work? Broadly? With a specific example?
Broadly- add a phosphate group to tyrosine
More specifically: EGF(epidermal growth factor) binds to receptor convert from monomeric to dimeric state initiates phosphorylation of tyrosine promote cell growth
What are the consequences of using tyrosine kinase?
Target site for drug therapy
Ex: gefitinib (Iressa), erlotinib (Tarceva) – NSCLC
Inhibit receptor’s kinase activity in the cytoplasm
Inhibit cell growth
How do ligand-gates transmembrane channels function? Common example?
Channel that opens when a messenger (ligand) binds to it.
Nicotinic acetylcholine (Ach) receptor Ach binds to the receptor Open Na+ channel Na+ to rush into cell skeletal muscle contraction
What are the consequences of ligand-gated channels?
Time to response is fast; can be in milliseconds
Create important drug target (i.e. Verapamil inhibits voltage-gated calcium channels in heart and smooth muscle antiarrhythmic effects and reducing BP
How does a G-membrane channel work?
Transmembrane receptor stimulates GTP-binding signal transducer G protein increase intracellular second messenger signal amplified
What is an example of a g-membane receptor?
Norepi stimulates receptor stimulates production of GTP amplify the original signal produce effects
Which classes of receptors require gene transcription?
Tyrosine Kinase
Transmembrane diffusing nuclear receptors
What are full and partial agonists?
Full Agonist – trigger a full response
Partial Agonist – trigger a “partial” response (i.e. not as pronounce as the full agonist regardless of concentration)
What is an allosteric agonist?
Uses a separate active site to magnify response of agonist
What is an inverse agonist? What needs to be present for this response to occur?
Receptor needs basal activity; that is, without a ligand bound it does something, so when the inverse agonist binds the signal is suppressed and theres an opposite effect
What is a non-competitive antagonist?
bind to receptor equally well whether or not receptors already bound the substrate
Binding to same active site
What is an allosteric non-competetive antagonist?
binding to a separate site
antagonist that doesn’t need to compete. Just turns off fxn.
What is an un-competetive antagonist?
ligand binds to a receptor, THEN a new site opens up, that allows an antagonist to bind
What is a neutral antagonist?
blocks the docking of the agonist but does not trigger an effect
Like a hat- blocks the receptor but doesn’t do anything
What is efficacy?
Percent of maximum effect that can be achieved?
What is potency?
How much is needed to trigger a given effect
What is EC50? Why is it used?
The concentration of drug that produce 50% of response – use to compare potency
What is affinity? What influences it?
The tendency of a drug to bind to a receptor
Directly proportional to efficacy and potency
Mostly influenced by the rate of dissociation (KD)
i.e. the lower KD, the higher affinity
Allow us to measure the fraction of receptors occupied to reach a full biological response
What is a graded response curve?
Continuous data points needed
What is a quantal response curve?
Response is discrete: yes/no; impossible to make a graded curve; eg with toxicity alive or dead
What is ED50?
50% Effective Dose
The dose at which 50% of maximum effect is achieved.
What is LD50?
50% Lethal Dose
the dose at which 50% of the animals die.
What is TD50?
50% Toxic Dose
the dose at which 50% of the humans developed toxicity.
What is the therapeutic index? How is it measured?
A measure of drug safety
Therapeutic index = LD50 / ED50 (animal)
Therapeutic index = TD50 / ED50 (human)
What is tachyphylaxis?
Responsiveness drop rapidly after administration of a drug (i.e. tolerance)
Diminished response with subsequent doses
What affects tachyphylaxis in pts?
Age, gender, body size
Dz state, genetics
Co-administration with other drugs
At a cellular level, why does tachyphylaxis occur?
Drug conc. change at receptors site
Soluble receptor conc. Change
Change in number or function of transmembrane receptors
When agonist induces decrease # of receptors down regulation of receptors or desensitization
Change in components different from receptor (i.e. disease compensatory mechanism)
What are the 2 types of desensitization?
Homologous desensitization
Heterologous desensitization
What is homologous desensitization?
Decreased response at a single type of receptor (i.e. only the activated receptors are “turn off”)
Loss of response to one single subtype of receptor
agonist-dependent
Rapid (seconds~minutes)
receptor stays in the plasma membrane (usually)
Ex: Continuous administration of Nitrates reduce in drug response must allow nitrate free period
What is heterologous desensitization?
Decreased response at two or more types of receptor (i.e. activation of one receptor resulted in the inhibition of another)
= “Cross desensitization” – unresponsiveness to a variety of other agonists after prolonged stimulation by one agonist
agonist-independent
Slow (min~hrs)
receptor is internalized (usually)
Ex: Morphine inducing desensitization of opioid-receptors leading to desensitization to other opioid agonists
What is drug inactivation?
The loss of ability of a receptor to respond to stimulation by a drug or ligand.
Complete turning off the receptor may result from phosphorylation of the receptor completely block the signaling activity lead to the removal of the receptor from the cell surface.
What is the refractory period/
The time lapse between the first and the next interaction of a drug that can produce an effect on a receptor
Voltage-gated Sodium channel mediate firing of the neuronal action potentials are subject to refractory periods.
