Week 1 Pharmacology - Pharmacodynamics and Kinetics Flashcards
What is potency?
Concentration (EC50) or dose (ED 50) of a drug required to produce 50% of drugs maximal effect
What does potency depend upon?
Affinity for receptor
Efficiency of drug-receptor interaction coupled to response
What is maximal efficacy?
Limit of dose-response relationship (i.e. increasing dose fails to exert greater effect)
What is an agonist?
Drug that binds and ACTIVATES receptor, directly or indirectly bringing about an effect
What is a full agonist?
Drug that causes shift of almost all receptors within a pool to active state (i.e. when binding, producing high response when all receptors occupied)
What is a partial agonist?
Drugs that produce small/low response at full receptor occupancy
What is an inverse agonist?
Drugs which bind in the same way as agonist, but reduce levels of activity below basal levels observed in absence of drug
What is an antagonist?
Drug that binds to and inhibits receptors and downstream pharmacological effect
What is a competitive antagonist, and give example?
In presence of fixed concentration of agonist, increasing concentration of competitive antagonist progressively inhibit agonist response (and vice versa)
Noradrenaline and propranolol
What happens to the Emax of an agonist if adding a competitive antagonist?
Emax remains the same, but the dose response curve is shifted to the right. (I.e. you can ‘outcompete’ the antagonist if you increase the dose of the agonist, and eventually you will reach the maximal effect)
What is a non-competitive antagonist?
Often binds in covalent way, preventing future occupation by an agonist and reducing total number of receptors available for binding
What happens to Emax in setting of a non-competitive antagonist?
Bind receptors and prevents agonist from activating, no matter the concentration of the agonist (i.e. you cannot outcompete this antagonist by increasing dose)
Therefore, Emax is reduced (i.e. you cannot reach the same maximal effect as before, unless you have enough spare receptors or antagonist concentration is low enough)
What is a chemical antagonist?
When one drug ionically binds another, making agonist unable to interact with receptor
What are the respective axises on a dose/response curve?
Y axis = ‘percentage of maximum’ and x axis = ‘agonist dose’
How does a partial agonist effect the dose response curve?
Will effectively reduce total drug response by occupying potential receptors sites of the agonist, and eliciting a partial activation/response when compared to a full agonist. i.e. doesn’t shift curve per se, but does reduce the Emax
What types of receptors are located intracellularly? What properties allow the agonists/molecules to reach them?
Steroid, lipid soluble molecules allow passage across plasma cell membrane
What is the usual effect of binding an intracellular receptor?
Change in regulation of gene transcription, i.e. up or down regulating protein synthesis to bring about a particular action (i.e. thyroid hormone causing increased synthesis of thyroglobulin)
What is a ligand-regulated transmembrane receptor, and common example?
Polypeptide with extracellular hormone binding domain, and cytoplasmic enzyme domain, connected by hydrophobic component that spans lipid bilayer.
Insulin = common example, (tyrosine kinase)
What are examples of ligand gated ion channels?
Nicotinic/Muscarinic receptors
GABA receptors
What is the underlying mechanism by which G-protein-coupled receptors exert their effect?
Up-regulate intracellular concentrations of 2nd messengers - i.e. cAMP, Ca2+, IP3)
What are the steps involved in activation of GPCR?
- Activation by binding extracellular component of receptor
- This causes activation of G-protein on cytoplasmic side of GPCR
- G protein then changes activity of effector element, usually enzyme or ion channel
What is the mechanism of cAMP?
Binding of extracellular component of GPCR causes activation of Adenylyl cyclase (enzyme) –> formation of cAMP from ATP, and main enzymatic target is protein kinase A –> downstream effects
What are some common examples of cAMP mediated activity?
Effects of catecholamines
Glycogenolysis
Vision
What is the mechanism of phospholipase C?
GPCR binding that causes activation of phospholipase C enzyme, which splits PIP2 (component of plasma membrane) into 2 second messengers (IP3 and DAG). DAG activates PKC and IP3 diffuses through cytosol to bind to ligand gated calcium channels to cause release from intracellular vesicles –> downstream effects