Pharmacology Flashcards
How Drugs act
Mostly through a receptor
Receptors
Recognizes then turns on effector pathway
Normally amplifies signal
Can be modulated at any step
Enhance
Inhibit
Turn off
Structure:
Ligand binding domain
Effector domain
Drug to response
Dose should be: absorbable Not destroyed Delivered to receptor target Concentration at target --> Response
Pharmacodynamics
Concentration of drug at target leading to response
Problems can occur if the receptor is mutated –> doesn’t elicit desired result
Pharmacokinetic
Dose to concentration at the target
drug is absorbed but the effective dose is not reached at the target
Important considerations of drug chemistry and receptors
Size (MW 7-50000 da)
Lipophilicity/Hydrophilicity
Source – natural, synthetic
Drug-Receptor Interactions
Covalent, electrostatic, hydrophobic (van derWaals): important for getting great specificity
Often multiple involved
May need to displace water
Implications of chirality
Enantiomers (one will bind better to the receptor than the others and the metabolism will differ between them) vs. Racemic Mixtures
Implications – efficacy, toxicity (R vs. S one produces result and the other doesn’t then we would have to give a double dose of a racemic mixture or 1/2 of enantiomer)
Examples
Prilosec/Nexium (one is the R and the other S, S is the active but the R can be converted to S in our bodies)
Albuterol (Racemic)/Xopenex (R, active)
Properties of the drug
Must bind specifically to receptor Must get to receptor Must not be destroyed/eliminated too quickly Must be safe Must be stable on the shelf
Drug Discovery/Development
Make slight changes to molecule to:
Improve potency –> Improve pharmacokinetics –> decrease toxicity –> make it possible to be in pill form
Success rate is very low, those that make it must balance potency vs. toxicity
First in class normally have a high toxicity or have a lot of drug interactions (b/c there aren’t any alternatives)
Second in class: must be better than first (better pKa, less toxicity, less interactions)
Nuclear receptor: overview
Ligands are lipid-soluble (like corticosteroids, thyroid hormone, mineralcorticoids, sex steroids) that bind to their intracellular receptor –>
Stimulate the transcription of genes by binding to DNA regions near the gene to be regulated
Nuclear receptor: mechanism
In the absence of ligand, the receptor is bound to hsp90(inhibits proper folding of receptor structural domains)
Ligand binds to receptor –> hsp90 is released –> receptor dimerizes & enters the nucleus –> DNA-binding & transcription-activating domains fold into an active form –> alteration of specific gene expression
Nuclear receptor: therapeutic consequences
Characteristic lag time: seen b/c it requires time to synthesize new proteins (could take minutes to hours)
Effect of the agent lingers for days/hours after the drug has been stopped, results from slow turnover of enzymes or proteins
Nuclear receptors: possible pharmaceutical modulation
Something that binds to the binding site (prednisone)
Something that removes hsp90 (although it is not specific enough)
Something that binds to the DNA-binding domain (also not specific enough)
Tyrosine kinase: possible pharmaceutical interventions
Target drugs that prevent dimerization
Kinase inhibitor
Something that acts as the ligand
Tyrosine kinase: mechanism
Transmembrane enzyme whose ligand is a polypeptide hormone or growth factor
Ligand binds –> receptor dimerizes & transphosphorylation of tyrosines –> phosphorylated tyrosine can then bind to specific proteins
Tyrosine kinase: therapeutic consequences
Effects gene expression –> responses will be delayed
Intensity & duration of response are impacted by down-regulation
Once ligand binds –> induces rapid endocytosis of receptor
Cytokine receptors: overview
Respond to peptide ligands (growth hormone, erythropoietin, & other regulators of growth & development)
Response mediated by JAK/STAT pathway to impact gene expression
Cytokine receptors: mechanism
Ligand binds –> receptor dimerizes & transphosphorylation of JAK & phosphorylation of tyrosines at receptor tail –> phosphorylated tyrosine recruits STAT –> STAT is phosphorylated by Jak –> STATs dissociate and dimerize (by interaction w/ phosphotyrosine) –> can enter nucleus to regulate transcription of target genes
Voltage & Ligand Gated Channels
Function to change the transmembrane conductance of the specific ion –> altering electrical potential across membrane
G Proteins: Sensitization & destruction
Agonist binds –> G protein coupling (activation) –> go to effector
Sensitization (in seconds) occurs once agonist binds –> GFK phosphorylates the serine residues –> beta-arrestin binds causing the receptor to not respond to agonist
Destruction (in weeks): the receptor is internalized into an endosome where it can be recycled or degraded by lysosome
Phospholipase C: pathway
Production of PIP2 (increase Ca intracellular) & DAG (activation –> phosphorylation of proteins)
This pathway can also be activated by tyrosine kinase
Antagonist
Binds to receptor w/out activation and inhibits effects of agonist (in the absence of agonist, it WILL NOT DO ANYTHING)
Can be reversible or irreversible
Competitive, non-competitive, allosteric
Occupancy Theory
k-1/k1
Different than a Km (when enzyme is at 50% of Vmax)
Kd is when 50% of receptors that are present are OCCUPIED
High affinity –> low Kd
Low affinity drugs –> High Kd
EC50
Concentration of drug that produces 50% effect
It is not normally the Kd
Spare receptors
In most case, the relationship between receptor occupancy and response is not linear but some function of receptor occupancy.
Fraction of receptors are spares in excess of those required for a full response
i. e. we get 100% effect at 25% receptor occupancy
- -> therefore we need less of the ligand to have the same effect)
If the cell has a 50x more receptors than needed –> you will get a 50% effect at with a 1% occupancy
Upregulatation of receptors by 5 fold –> 10 fold decrease in % occupancy needed (this type of control only possible if there are spare receptors)
Potency
Amount of drug needed to produce a certain effect
Calculated based on EC50s (Emax x C)/(C + EC50)
Efficacy
Which drug produces the higher effect at maximal saturation (100% maximal effect vs. 50% maximal effect)
Agonist
Occupies receptor & activates downstream effector mechanism in a response
Functional antagonism
a drug that produces the same effect but not through the same receptor system
Competitive antagonists
The potency is effected, the efficacy is not impacted
The %effect vs Log[A] is shifted to the right
Can be combated by adding more ligand
Noncompetitive antagonism
Diminishes efficacy and may or may not effect EC50
Ligand cannot overcome effect
Pseudo-irreverisble: may have similar graph, antagonist binds more tightly and dissociates slower
Allosteric antagonist
Not binding at the same site, no chance for competition
Reduce the maximal response, cannot overcome by adding more ligand
Role of spare receptors in antagonism
Since there are spare receptors, the antagonist will not effect the curve b/c the excess receptors allow for maximal response; once there are no extra receptors –> effect will be reduced
Full agonist
Binds to the active state and forces the receptor to stay in the active state
No affinity for the inactive state –> able to reach maximal response
Partial agonist
Has some affinity for the active state but also some for the inactive state
When it binds, it holds some of the receptors in the inactive state which prevents full receptor activation, no matter the concentration of the drug –> never get full response
Inverse agonist
Drug has high affinity for the inactive form of the receptor –> keeping the receptors in inactive form
If you have a receptor system that is constitutively active (in the absence of ligand), this would inactive this system
Common adverse effects
GI (nausea, vomiting) CNS (nausea, vomiting, headache) Immune (allergic reactions) Hepatic (receives highest level of drug) Cardiac (worried about arrhythmias) Developmental (fetal, neonatal, pediatric)
Allergic reactions to drugs
Type I: IgE (anaphylactic, immediate hypersensitivity reaction)
Type II: IgG, IgM (autoimmune)
Type III: IgG (arthus, serum sickness)
Type IV: T-cells, macrophages (Delayed responses)
General Toxicology Concept
Off target effects of the drug
Can cause oxidative stress or covalently bind to protein and/or DNA
Differential organ toxicity b/c different tissues have different Cyp profiles –> varying toxicities in different organs
