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MOD1 > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

How Drugs act

A

Mostly through a receptor

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2
Q

Receptors

A

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

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3
Q

Drug to response

A 
Dose should be:
absorbable
Not destroyed 
Delivered to receptor target
Concentration at target --> Response
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4
Q

Pharmacodynamics

A

Concentration of drug at target leading to response

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

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5
Q

Pharmacokinetic

A

Dose to concentration at the target

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

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6
Q

Important considerations of drug chemistry and receptors

A

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

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7
Q

Implications of chirality

A

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)
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8
Q

Properties of the drug

A 
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
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9
Q

Drug Discovery/Development

A

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)

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10
Q

Nuclear receptor: overview

A

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

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11
Q

Nuclear receptor: mechanism

A

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

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12
Q

Nuclear receptor: therapeutic consequences

A

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

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13
Q

Nuclear receptors: possible pharmaceutical modulation

A

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)

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14
Q

Tyrosine kinase: possible pharmaceutical interventions

A

Target drugs that prevent dimerization

Kinase inhibitor

Something that acts as the ligand

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15
Q

Tyrosine kinase: mechanism

A

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

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16
Q

Tyrosine kinase: therapeutic consequences

A

Effects gene expression –> responses will be delayed

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

17
Q

Cytokine receptors: overview

A

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

Response mediated by JAK/STAT pathway to impact gene expression

18
Q

Cytokine receptors: mechanism

A

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

19
Q

Voltage & Ligand Gated Channels

A

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

20
Q

G Proteins: Sensitization & destruction

A

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

21
Q

Phospholipase C: pathway

A

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

This pathway can also be activated by tyrosine kinase

22
Q

Antagonist

A

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

23
Q

Occupancy Theory

A

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

24
Q

EC50

A

Concentration of drug that produces 50% effect

It is not normally the Kd

25
Q

Spare receptors

A

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)

26
Q

Potency

A

Amount of drug needed to produce a certain effect

Calculated based on EC50s (Emax x C)/(C + EC50)

27
Q

Efficacy

A

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

28
Q

Agonist

A

Occupies receptor & activates downstream effector mechanism in a response

29
Q

Functional antagonism

A

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

30
Q

Competitive antagonists

A

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

31
Q

Noncompetitive antagonism

A

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

32
Q

Allosteric antagonist

A

Not binding at the same site, no chance for competition

Reduce the maximal response, cannot overcome by adding more ligand

33
Q

Role of spare receptors in antagonism

A

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

34
Q

Full agonist

A

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

35
Q

Partial agonist

A

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

36
Q

Inverse agonist

A

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

37
Q

Common adverse effects

A 
GI (nausea, vomiting)
CNS (nausea, vomiting, headache) 
Immune (allergic reactions)
Hepatic (receives highest level of drug)
Cardiac (worried about arrhythmias) 
Developmental (fetal, neonatal, pediatric)
38
Q

Allergic reactions to drugs

A

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)

39
Q

General Toxicology Concept

A

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

MOD1 (3 decks)

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