Pharmacology

Question 1

How Drugs act

Answer 1

Mostly through a receptor

Question 2

Receptors

Answer 2

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

Question 3

Drug to response

Answer 3

Dose should be:
absorbable
Not destroyed 
Delivered to receptor target
Concentration at target --> Response

Question 4

Pharmacodynamics

Answer 4

Concentration of drug at target leading to response

Problems can occur if the receptor is mutated –> doesn’t elicit desired result

Question 5

Pharmacokinetic

Answer 5

Dose to concentration at the target

drug is absorbed but the effective dose is not reached at the target

Question 6

Important considerations of drug chemistry and receptors

Answer 6

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

Question 7

Implications of chirality

Answer 7

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)

Question 8

Properties of the drug

Answer 8

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

Question 9

Drug Discovery/Development

Answer 9

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)

Question 10

Nuclear receptor: overview

Answer 10

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

Question 11

Nuclear receptor: mechanism

Answer 11

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

Question 12

Nuclear receptor: therapeutic consequences

Answer 12

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

Question 13

Nuclear receptors: possible pharmaceutical modulation

Answer 13

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)

Question 14

Tyrosine kinase: possible pharmaceutical interventions

Answer 14

Target drugs that prevent dimerization

Kinase inhibitor

Something that acts as the ligand

Question 15

Tyrosine kinase: mechanism

Answer 15

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

Question 16

Tyrosine kinase: therapeutic consequences

Answer 16

Effects gene expression –> responses will be delayed

Intensity & duration of response are impacted by down-regulation
Once ligand binds –> induces rapid endocytosis of receptor

Question 17

Cytokine receptors: overview

Answer 17

Respond to peptide ligands (growth hormone, erythropoietin, & other regulators of growth & development)

Response mediated by JAK/STAT pathway to impact gene expression

Question 18

Cytokine receptors: mechanism

Answer 18

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

Question 19

Voltage & Ligand Gated Channels

Answer 19

Function to change the transmembrane conductance of the specific ion –> altering electrical potential across membrane

Question 20

G Proteins: Sensitization & destruction

Answer 20

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

Question 21

Phospholipase C: pathway

Answer 21

Production of PIP2 (increase Ca intracellular) & DAG (activation –> phosphorylation of proteins)

This pathway can also be activated by tyrosine kinase

Question 22

Antagonist

Answer 22

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

Question 23

Occupancy Theory

Answer 23

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

Question 24

EC50

Answer 24

Concentration of drug that produces 50% effect

It is not normally the Kd

Question 25

Spare receptors

Answer 25

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)

Question 26

Potency

Answer 26

Amount of drug needed to produce a certain effect | Calculated based on EC50s (Emax x C)/(C + EC50)

Question 27

Efficacy

Answer 27

Which drug produces the higher effect at maximal saturation (100% maximal effect vs. 50% maximal effect)

Question 28

Agonist

Answer 28

Occupies receptor & activates downstream effector mechanism in a response

Question 29

Functional antagonism

Answer 29

a drug that produces the same effect but not through the same receptor system

Question 30

Competitive antagonists

Answer 30

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

Question 31

Noncompetitive antagonism

Answer 31

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

Question 32

Allosteric antagonist

Answer 32

Not binding at the same site, no chance for competition Reduce the maximal response, cannot overcome by adding more ligand

Question 33

Role of spare receptors in antagonism

Answer 33

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

Question 34

Full agonist

Answer 34

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

Question 35

Partial agonist

Answer 35

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

Question 36

Inverse agonist

Answer 36

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

Question 37

Common adverse effects

Answer 37

``` GI (nausea, vomiting) CNS (nausea, vomiting, headache) Immune (allergic reactions) Hepatic (receives highest level of drug) Cardiac (worried about arrhythmias) Developmental (fetal, neonatal, pediatric) ```

Question 38

Allergic reactions to drugs

Answer 38

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)

Question 39

General Toxicology Concept

Answer 39

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