Pharmacodynamics II Flashcards
Define Saturability
Receptors exist in finite numbers and can be saturated by high concentrations (doses) of drugs
Increasing dose will increase response - only up to some maximal effect
What does the pharmacological response depend upon?
There is some quantitative relationship bt the magnitude of the response and the total number of receptors occupied, which relies on:
The amount of drug reaching its site of action
The specific drug-receptor interacts at that site (coupling efficiency)
The functional status of the receptor and/or target cell (desensitization/supersensitivity)
What is Bmax?
receptor density in a sample of tissue - the cellular steady state levels
intracellular receptors can only be activated by what?
lipid soluble drugs that can cross the plasma membrane
What is an example of a gene active receptor?
glucocorticoid receptor
ligand binding releases hsp90 which uncovers DNA binding and transcription activation domains
What are the therapeutic consequences of gene active receptors?
lag period (30 min - few hours) before effects will be observed
The effects of gene active receptors may persist for hours or days after the agonist is gone (therapeutic or toxic effects will decrease slowly)
Thus there is NO simple relationship between plasma drug levels and the magnitude of the effect
What is the correlation between a gene active drug and the presence of the drug in the body?
the activation of the gene, and its effects, may long outlast the presence of the drug in the body
What are three types of plasma membrane receptors?
Ligand-regulated transmembrane enzymes (protein tyrosine kinase and cytokine receptors)
Ligand-gated channel receptors
G-protein family of transmembrane enzymes
Discuss some general features of the ligand regulated transmembrane enzymes receptors (eg protein tyrosine kinase)
TM proteins that bind EC ligands and can phosphorylate tyrosines or serines
autophosphorylation of tyrosines can intensify or prolong the duration of receptor activation
subject to down regulation via endocytosis (can be accelerated by ligand binding)
What are some endogenous substances that use tyrosine kinase receptors?
insulin, epidermal growth factor (EGF), atrial naturitic factor (ANF)
Discuss the general features of the cytokine receptor mechanism
closely resemble the tyrosine kinase receptors but utilize a separate protein tyrosine kinase that binds non-covalently and is not intrinsic to the receptor
-kinase activity not inherent to the tm protein
describe the mechanism of cytokine receptor signaling
ligand binding/dimerization
activation of JAKS which phosphorylate tyrosines on the receptor
tyrosine residues bind STAT
STATs phosphorylated by JAKS
STATs dimerize and regulate gene transcription
What is an example of a ligand gated channel receptor, and what are some neurotransmitters that use them?
nicotinic cholinergic receptor
others: excitatory amino acids (glutamate, aspartate), GABA
discuss the mechanism of ligand gated channel receptors
ACh binding to alpha subunits opens the channel allowing sodium ions to pass into the cell
What is the time range of the ligand gated channel receptors?
time between binding and response is milliseconds
provides for rapid info transfer
What are some neurotransmitters that utilize G-protein linked receptors?
DA, NE, 5-HT, ACh
Discuss the key aspects of g-protein linked receptors
polypeptide transverses membrane 7 times
amino terminus is EC, carboxy terminus IC
the third intracellular loop regulates ability to interact with specific G proteins
carboxy terminus contains serine residues that are subject to phosphorylation and regulation of receptor function
What does Gs activate?
AC
What does Gq activate?
PLC
What does Gz activate?
neuroendocrine secondary messingers
What does activation of adenylyl cyclase produce?
a single cAMP
What does activation of the phosphoinositide hydrolysis pathway produce?
activation of phospholipase C produces IP3 and DAG
This system has a greater amplification that AC pathway
What does Gi inhibit?
AC
What is an idiosyncratic drug response?
an unusual response that is not frequently observed in the majority of patients
What is a quantitative variation in drug response?
intensity of a given dose may be higher or lower depending on the individual, or the intensity may vary during the course of therapy
How does the body counter the effects of a drug imposed on the system?
receptor desensitization (in response to over stimulation)
receptor supersensitivity (in response to under stimulation)
What is tachyphalaxis?
rapid development of diminished responsiveness to a drug (as ocmpared to the slow development of pharmacodynamic tolerance (desensitization))
What are some of the mechanisms involved in desensitization?
agonist induced P of the activated receptor and subsequent binding of B-arrestin (reversible)
receptor down regulation
post-receptor adaptations – receptors becoming functionally uncoupled from post-receptor components due to modifications of G proteins or 2nd messenger enzymes
What is the resulting DR curve for desensitization?
shift to the right and generally no change in Emax… unless receptor reserve is exceeded
What is homologous desensitization of the beta-adrenergic receptor?
beta-adrenergic receptors P by kinases (GRK2, GRK3)
These only P sites on the agonist occupied receptor (is specific for the receptor, no others)
THus, desensitization is restricted to only the receptor population that was activated by the drug
What is heterologous desensitization
agonist activation of one receptor subtype results in a decreased responsiveness of one or more different receptor subtypes
Thus, this type of desensitization is not restricted to only the receptor population activated by the drug
What are some kinases that can desensitize in a heterologous manner?
PKA, PKC
What is supersensitivity?
a compensatory receptor mechanism in which the loss of activity on receptors leads to an increase in receptor density and/or an enhanced receptor-effector coupling
What will happen to the DR curve in supersensitivity?
This results in an increased responsiveness to subsequent receptor activation and a shift to the left in the dose response curve
