Flashcards in Pharmacodynamics Deck (44):
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?
1. Covalent - i.e. irreversible
2. Electrostatic - most common, varying strength
3. 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?
1. Enzymes - alter production of a metabolic molecule
2. Transcription factors - i.e. steroids and thyroid hormones
3. 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?
1. Receptor Tyrosine kinases
2. Cytokine receptors
3. Ligand / Voltage-gated ion channels
4. 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?
1. Cell surface receptor
2. G-protein on cytoplasmic face of membrane
3. Effector element
What are the mechanisms of inactivation of Gq GPCR's?
1. Dephosphorylation of IP3
2. Phosphorylation or acetylation of DAG
3. 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?
1. Blocks Gs binding
2. 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.
1. Physiological antagonist - Agonist and antagonist act and two independent sites and produce two independent but contradicting effects (i.e. glucocorticoid activation + insulin secretion)
2. 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?
1. Competitive - bind to the main receptor site but do not trigger downstream effects
2. 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
What is the primary functional difference between a non-competitive and competitive antagonist?
Non-competitive agonists are irreversible ->, increasing agonist concentrations will not overcome the blocking effect
Can be an issue if overdose occurs -> need to unblock via an alternate pathway
What is the big advantage to using non-competitive antagonists?
Competitive antagonists must be kept at relatively constant blood concentrations and are subject to varying clearance and excretion.
Non-competitive antagonists must simply bind the receptor and do not need to remain in blood -> activity is just dependent on rate of turnover of receptor molecules rather than rate of elimination
What is an inverse agonist and what are they active against? Give an example?
They are chemicals which produce effects opposite to an agonist. They act on receptors that are constitutively active to reduce the basal firing (antagonist would leave it unchanged).
They stabilize the receptor in its inactive form
Example: GABA-A inverse agonist will cause anxiogenic effect
What is the definition of spare receptors?
When a maximal biological response can be achieved without a full occupancy of all receptors, the extra receptors are "spare"
How does a spare receptor modify the dose-response curve for non-competitive antagonists?
Until all spare receptors have been neutralized, the dose response curve will appear to simply shift to the right (agonist becomes less potent)
Once the spare receptors are gone, the maximum efficacy will begin shifting downward (typical effect of a non-competitive antagonist)
What is the typical response to a non-competitive antagonist on the dose-response curve?
Efficacy will shift downward, but potency will not be affected because receptor affinity has not been changed (receptors have simply been suicide-inactivated)
What systems typically utilize spare receptors?
Neurotransmitters and signal transduction pathways.
What is a quantal dose response curve?
Plots based on the dose response of a drug for a large number of individuals or experimental animals. It is called "Quantal" because it is discrete and measures an "all-or-nothing" response to a drug -> i.e. relief of headache, sleep, etc
What is the typical distribution of a quantal dose response curve? What is it distributed around?
Lognormally distributed - few individuals will be affected at low doses, followed by large numbers in the middle, and few need the highest doses to get a quantal response
It is distributed around the ED50 or effective dose 50 -> dose required to make 50% of individuals respond
"median effective dose"
What is the median toxic dose?
TD50 - the dose required to produce a particular toxic effect in 50% of animals
What is the median lethal dose?
LD50 - dose at which toxic effect is death of animal in 50% of cases
What is the therapeutic index?
TI = LD50/ED50, where a higher number is better (proportion of lethal to effective dose is much higher)
Where are the problems with therapeutic index?
Data is collected in animals, so meaning is uncertain. Lethal dose in mice does not necessarily mean toxic dose in humans which we care about, and also we want the ED99.
What is the certain safety factor?
The greater the ratio, the less toxic the drug. TD1 = dose which is toxic in 1% of population. ED99 = dose which is therapeutic in 99%. If the ratio is greater than 1 that's pretty good
What factors contribute to drug response?
Sex, age, percent body fat, genetics
What is an idiosyncratic drug response?
Drug response rarely observed in most patients, usually caused by genetic differences in metabolism or immunologic mechanisms
What is tachyphylaxis?
When responsiveness diminishes rapidly after administration of a drug -> rapid tolerization
What is typically rate limiting clearance by the liver?
Drug delivery via hepatic blood flow, rather than P450 enzymes
What accounts for the majority of drug toxicities in clinical practice?
A direct pharmacological extension of the therapeutic effects of the drug -> i.e. bleeding caused by anticoagulant therapy (this is where drug monitoring is important).
Also for instance when beneficial and toxic effects are mediated by different types of receptors (adrenergic receptors which are nonselective)