Pharmacodynamics I: Receptors and Receptor Mechanisms Flashcards
drugs that dont depend on receptors to produce their effects
antacids
mannitol
bile acid binding resins e.g. colestyramine and colestipol
metal chelators
bulk and lubricating laxatives
purine/pyramidine or folic acid structural analogues
receptor response to drug: Direct
agonist:
drug binds at same site of receptor and mimics endogenous ligament
competitive antagonist:
competes for binding site on receptor
competitive inhibitor:
binds elsewhere on the substrate obstructing its access to the enzyme
receptor response to drug: Indirect
allosteric regulation:
indirect agonism
non competitive antagonism
drugs acting at ion channels
NAChR = suxamethonium, tubocurarine, pancuronium
GABA A receptor = benzodiazepines
glutamate receptor = ketamine
GPCR second messengers
adenyl cyclase
phospholipase C
ion channels (K+ in particular)
drugs acting at GPCR channels
MAChR = atropine, hyoscine
adrenoceptors = propanolol
opiate R = morphine
G protein subtypes
activate:
Gs = adenylate cyclase producing intracellular cAMP
Gq = phospholipase C = PIP2 liberating diacylglyceride and IP3 to activate protein kinase C which phosphorylates target proteins.
inactivate:
Gi = inhibits adenylate cyclase reducing cAMP levels
G0= coupled to potassium channels to hyperpolarise the cell membrane
protein kinases
PKA responds to cAMP (adenylate cyclase pathway)
PKG responds to cGMP (guanylate cyclase pathway)
PKC responds to Ca2+ and DAG (Phospholipase C and PIP3 pathway)
DAG and IP3
formed from PIP3 by phospholipase C
IP3 releases calcium from intracellular stores
DAG in the presence of calcium can activate PKC
NOTE: calcium doesnt get broken down but rather is re - sequestered into ER
receptors with direct kinase activity
change in expression of specific genes
receptors for a variety of hormones:
insulin, epidermal growth factor (EGF) receptor, nerve growth factor receptor, toll like receptors
these receptors are monomers comprising a single polypeptide chain with 3 distinct parts/domains
1. extracellular domain = ligand binding site where conformation undergoes a change
- single alpha helix crossing the membrane once
- intracellular domain carries out the catalytic activity
and phosphorylates target proteins on serine/threonine and tyrosine kinase residues
receptors phosphorylating on tyrosine kinase residues
regulate growth, differentiation, development
includes receptors for:
insulin
epidermal growth factor
platelet derived growth factor
receptors phosphorylating on serine/threonine kinase residues
tumour growth factor beta receptor (TGF beta)
receptor with direct kinase activity MOA
extracellular domain undergoes a change in conformation and interacts with another extracellular domain to dimerise and cross phosphorylate with one another.
now there is an activated receptor dimer.
this is recognised by a GRB2 intracellular protein which binds onto the receptor and becomes phosphorylated.
membrane protein RAS will recognise GRB2 complex and bind to it.
RAS becomes activated to Raf and binds GTP.
sequence of events to activate intracellular enzymes culminating in the phosphorylation of various transcription factors (in the nucleus or translocate to the nucleus)
RESULT: change in expression of specific genes
intracellular receptors
intracellular receptors are located in the cytosol and in the resting state they are complexed with a variety of other proteins.
entry of lipid soluble ligand will bind to intracellular receptor causing a conformational change and liberating it.
this then exposes a w shaped structure known as the zinc finger. This a common structure which interacts with DNA helix causing a change in the transcription of specific genes.
examples of intracellular receptors
steroids e.g. glucocorticoids, mineralocorticoids, sex steroids and vit D
thyroid hormones
lipids e.g. fatty acids, cholesterol
inducers of drug metabolism e.g. barbiturates which act on CYP enzymes
