Pharmacodynamics Flashcards
Efficacy
Ability of drug to drive a reactions response to full effect. Measured by Emax.
Potency
EC50 - concentration of drug required to produce a response
Affinity
Kd - strength of drug binding to receptor (action is longer plus higher chance of binding)
Orthosteric site
Where agonist binds
Endogenous ligand
what the ligand normally binds to
Agonist
has affinity and efficacy. Drug binds to receptor and produces a response (like endogenous ligand)
Partial agonist
binds (has affinity) but doesn’t fully activate to maximal efficacy, even at 100% occupancy (acts as antagonist)
Full agonist
Will produce full effect (at lower capacity)
Receptor reserve
irreversible antagonist act as a reversible due to not 100% binding having 100% efficacy
Inverse agonist
has negative efficacy, reduces basal activity “turns receptor off”
Constitutive activity
basal activity
Antagonist
binds to ligand but has no effect (efficacy)
Competitive orthosteric antagonist
binds reversible to orthosteric site but has no efficacy
Irreversible antagonist
reduces the maximal response of agonist by covalent bonds
Allosteric modulator
binds to a different place on receptor to the endogenous ligand and modifies response to orthosteric ligand (affinity or efficacy)
Allosteric vs orthosteric
selective, natural signalling pattern, no ceiling effect
Surmountable
action of agonist can be restored
Two state model
RR, agonist (towards R), inverse (towards R), antagonist (no change)
Therapeutic index
lethal dose 50/ED50
cAMP
PKA, ATP->ADP, Ca2+, fat and glycogen metabolism, release energy, lipolysis, decrease synthesis
G protein receptor kinase (GPRK) -> phosphorylation
= desensitisation, Arestin - binds to c terminal, blocks binding lead to invagination = tolerance
Nerve terminal drug targets (10)
Precursor transporter, neurotransmitter formation enzyme, vesicle storage, Na+ (action potential) ion channel, Ca2+ ion channel, vesicular fusion (enzymes), post synaptic receptor, pre synaptic receptor, off signal enzyme, neurotransmitter uptake transporter
Ion channel
protein creates pore across cell membrane. Can be blocked or modulated.
Ligand gated ion channel
receptor/protein that drug binds to. Receptor pore increases permeability.
Voltage gated ion channel
response to change in membrane potential
Carrier molecules/transporters
move ions/molecules across membranes. Can be normal transport, inhibited, false substrate.
Enzymes
biological catalysts. inhibitor, false substrate or prodrug. (non-competitive/competitive)
GPCR
G protein coupled receptors. (guanine nucleotide binding protein). 7 transmembrane domains, single polypeptide. intracellular c terminal. alpha, beta and gamma. binding -> GTP (alpha) -> dissociates
Family A GPCR
ligand binds in transmembrane bundle (small molecule/peptide)
Family B GPCR
binding in exterior N terminal (peptide hormones)
Family C GPCR
large N terminals, folding pocket
Adhesion family GPCR
chops off N terminal and binds ligand
Frizzled family GPCR
extracellular N terminal, intracellular C terminal
Gs
activates adenylate cyclase, increase cAMP
Gi
inhibits adenylate cyclase, decreases cAMP
Gq
activates PLC -> PIP2 -> DAG (->PKC) and IP3 (->Ca2+)
Kinase linked/cytokine receptor
extracellular domain, intracellular transmembrane domain, tyrosine kinase domain. dimerisation -> autophosphorylation -> phosphorylate SH2 domains -> signalling cascade (growth hormones, cytokines, hormones)
Kinase linked categories
tyrosine kinase, serine/threonine, cytokine
Nuclear/steroid hormone receptor
N terminal, AF1, DNA BD, HR, LBD, C terminal, AF2. regulate CYP.
Type one nuclear receptor
Steroid nuclear receptor. cytoplasm, homodimers, endocrine. Binding -> conformation change -> nucleus.
Type two nuclear receptor
metabolite receptor. nucleus, heterodimers, lipids. nucleus -> binding ->conformation -> gene transcription
Allosteric binding example
Benzodiazepine binding to GABAa to increase efficacy (Cl transport)
Antagonists example
Propranolol (beta blocker), antihistamine
Irreversible antagonist example
Novichok (Poison) - irreversible AChE inhibitor, parasympathetic then sympathetic
Partial agonist example
Buprenorphine, replacement therapy for opioids
Na+ channel inhibitor example
Lignocaine = local anaesthetic
Nicotinic ion channel antagonist
Nicotine, pancuronium - muscle relaxant
Prodrug
L-dopa - prodrug for dopamine = alzheimers (+carbidopa to inhibit metabolism in body)
False substrate example
Methyl dopa - creates methyl noradrenaline a2 agonist
Inhibits p-gp (p-glycoprotein)
Verapamil = increase bioavailability of drug/xenobiotics
activates insulin receptor orthosteric site as Kinase linked receptor drug
Insulin
RTK inhibition of multiple kinase linked receptors
Lapatinib
Class one nuclear receptor drugs
Cortisol (glucocorticoid receptor), estrogen
Class two nuclear receptor drugs
PPAR, cholesterol
