Pharmacodynamics Flashcards
What determines the upper and lower bounds of sizes of a drug?
Lower bound - needs to be large enough to have some specificity for the target receptor
Upper bound - needs to be small enough to be able to move through the body
Most drugs are between 100 and 1000 molecular weight units in size
What are the three types of drug-receptor interactions and which is most common?
- Covalent - i.e. irreversible
- Electrostatic - most common, varying strength
- Hydrophobic - mostly lipid soluble drugs
What is hydrophobicity important for drugs?
The greater the hydrophobicity, the greater ability to cross biological membranes
What are the three types of intracellular receptors? What is the general length of action?
- Enzymes - alter production of a metabolic molecule
- Transcription factors - i.e. steroids and thyroid hormones
- Structural proteins
Generally have a lag-time of about 30 minutes, and then persist for hours or days
What are the four types of non-intracellular receptors?
- Receptor Tyrosine kinases
- Cytokine receptors
- Ligand / Voltage-gated ion channels
- G-protein coupled receptors
How is the activity of a transmembrane receptor regulated? What is the structure of these receptors?
Via downregulation -> endocytosis from cell surface and degradation
They work via extracellular hormone-binding domain and a cytoplasmic tyrosine kinase, serine kinase, or guanylyl cyclase
How does a cytokine receptor differ from a receptor tyrosine kinase?
They still dimerize upon ligand binding, however, the protein kinase activity is not intrinsic and comes from a JAK kinase which is bound non-covalently to the receptor.
What is the mechanism by which a Jak kinase carries signal downstream and give one receptor example?
Jak kinases will bind and phosphorylate STAT receptors, which dimerize and regulate transcription of target genes
I.e. growth hormone
What is the relative response time of ligand and voltage-gated channels?
Very fast - milliseconds
What are the three elements of the G-protein coupled receptor?
- Cell surface receptor
- G-protein on cytoplasmic face of membrane
- Effector element
What are the mechanisms of inactivation of Gq GPCR’s?
- Dephosphorylation of IP3
- Phosphorylation or acetylation of DAG
- Ca+2 efflux via pumps
What is desensitization and resensitization? What could prevent this from happening?
Desensitization - cAMP response via a ligand is diminished after a few minutes with continued presence of an agonist
Resensitization - cells recover to full response of a stimulus following agonist removal
Can not happen if cells are exposed to agonist repeatedly or over a more prolonged time period
What are the molecular mechanisms underlying desensitization and resensitization?
Desensitization - phosphorylation of GPCR via GPCR kinases when activated allows binding of Beta-arrestin, which diminishes the receptor’s ability to interact with Gs subunit, terminating the response.
Resensitization - GPCR activation is terminated, disallowing further GPCR kinase activation, and phosphatases will subsequently cause removal of Beta-arrestin
What are the functions of Beta-arrestin?
- Blocks Gs binding
- Accelerated endocytosis of receptors, which allows quicker resensitization via phosphatases. However, endocytosis also means that cells may be degraded by the lysosome more readily.
In what situation is there not a 1:1 correspondence between ligand binding and response?
Signalling systems where downstream effectors are enzymes that can provide biological amplification of the signal - i.e. spare receptors
What do Kd and Response in in drug-receptor complex formation correspond to in enzyme kinetics?
Kd - corresponds to Km (concentration of ligand at which 50% of the receptors are occupied)
Response - Velocity / Vmax - the maximal response via the receptor
What is the definition of an agonist?
A ligand (drug or endogenous) that binds to a receptor to directly activate a signalling pathway and produce a response
What is efficacy vs potency?
Efficacy - maximum response obtained with the highest concentrations of the agonist
Potency (EC50) - concentration of agonist required to achieve 50% of the maximum response (Usually equal to Kd, except will be lower whenever spare receptors are in place)
EC = Effective concentration
What is a partial agonist? How does this happen moleculary?
A drug that produces a lower efficacy than a full agonist
This is not well understood -> partial agonist is thought to trigger a conformational change in receptor, but not large enough to create a full response
How can partial agonists sometimes work as antagonists?
If they are competing for receptor binding with the full agonist, there will be an overall decrease in receptor response even with the partial agonist bound
What are the two types of non-receptor antagonism? Define them.
- Physiological antagonist - Agonist and antagonist act and two independent sites and produce two independent but contradicting effects (i.e. glucocorticoid activation + insulin secretion)
- Chemical antagonist - chemical directly interacts with the agonist to inactivate it
What is needed in order to see an antagonist’s effect?
The presence of an agonist (in order to be blocked). Addition of antagonist without agonist present does nothing. This is why they are called “blockers”?
What are the two types of receptor antagonists? How does each work?
- Competitive - bind to the main receptor site but do not trigger downstream effects
- Non-competitive - bind allosteric site or irreversibly to agonist site, but do not produce conformational change necessary to trigger downstream effects
How does a competitive antagonist change the dose response curve for the agonist?
Shifts the curve to the right.
Efficacy remains unchanged because the antagonist binding is reversible and can become oversatured with agonist.
Potency will be decreased -> need higher concentrations of agonist for the same effect
