1: Pharmacodynamics 2 Flashcards
description of intracellular receptors
- lipid-soluble ligand crosses the cell membrane and acts on an intracellular receptor
ex: corticosteroids, mineralocorticoids, sex steroids, vitamin D, thyroid hormone
-stimulate the transcription of genes in the nucleus by binding to specific DNA sequences near the gene whose expression is to be regulated
therapeutic significance of intracellular receptor binding
- drugs produce their effects after a characteristic lag period
- cannot be expected to alter a pathologic state w/i minutes
- effects of these agents can persist after the [agonist] has been reduced to zero due primarily to the relatively slow turnover of most enzymes and proteins (or due to high affinity of receptors for the hormone)
- no simple temporal correlation b/w plasma levels of the hormone and its effects
protein tyrosine kinases: what type of enzymes are they, what is their mechanism of action, examples
- ligand-regulated transmembrane enzymes
- adds a phosphate group to substrate
- ex: insulin, EGF, PDGR
protein tyrosine kinases: describe the receptor
- extracellular hormone-binding domain
- cytoplasmic enzyme domain with protein tyrosine kinase activity
- spans lipid bilayer once
protein tyrosine kinases: how do they work
- usually act as dimers
- hormoen binds to extracellular domain -> conformational change
- receptor molecules associate -> brings together protein tyrosine kinase domains
- kinase becomes capable of autophosphorylation
- tyrosine residues in both cytoplasmic domains are phosphorylated -> activates enzymatic activity -> phosphorylation of substrate proteins
- P-substrate proteins become signal for the effects of the ligand
how is the process initiated by protein tyrosine kinases turned off/regulated?
- duration and intensity of the action is limited by receptor down regulation
- upon ligand binding, endocytosis of the receptor is stimulated
how can ligand-gated channels be utilized by drugs?
drugs can mimic or block the actions of endogenous ligands that regulate the flow of ions through plasma membrane channels -> transmits signal across by increasing transmembrane conductance of the relevant ion -> alters electric potential across membrane
speed of ligand-gated channel interactions
-often milliseconds -> rapidity is crucially important for extremely rapid transfer of signals across synapses
calcium and phosphoinositides
- effector enzyme = PLC
- releases phosphoinositides and diacylglycerol
- results in release of Ca2+ –> increase cytoplasmic [Ca2+]
- diacylglycerol can activate PKC
speed of ligand-gated channel interactions
-often milliseconds -> rapidity is crucially important for extremely rapid transfer of signals across synapses
GPCRs action
-ligands acts by increasing intracellular concentrations of second messengers
-generally signaling system has 3 components:
-extracellular ligand is detected by cell-surface receptor
-receptor triggers activation of G protein on cytoplasmic
face of plasma membrane
-changes activity of an effector element
-effector changes [second messenger] –> effect
cAMP
- effector enzyme = adenylyl cyclase (ATP –> cAMP)
- stimulates cAMP-dependent protein kinases (also EPAC)
- specificity due to distinct substrates of the kinases that are expressed in different cells
definition of therapeutic index/ratio
- relative safety of a drug expressed as LD50/ED50 or TD50/ED50
- larger the ratio –> greater the relative safety
cGMP
- effector enzyme = guanyl cyclase
- activates cGMP-dependent protein kinase
- much more specific than other messenger systems
quantal drug responses vs. graded drug responses
- quantal is all or none (binary response)
- threshold: minimum effective dose of the drug which evokes an all-or-none response
- normal frequency distribution
