Pcol Exam 1 Flashcards

Pharmacology

The study of how drugs affect physiological function

Drugs

exogenous chemicals administered to affect biological functions substances used to diagnose, prevent, treat or cure disease

Ligand

something that binds to something else

• has affinity (how well something binds to something else, usually via number of chemical bonds or strength of the bonds)

Target

what drug binds to → mostly proteins, enzymes, transporters, ion channels

• drug are usually designed to have high affinity for this to elicit a biological response.

Draggability

refers to the target itself

• how easy it is to design a drug that does what is wanted at target

agonist

substances that activates receptors (many drug mimics this)

Antagonist

ligand that binds to receptor and prevents activation

voltage acitvated, ligand gated

Channels can be ____ or ____

into, depolarize, positive

Na+ moves ___ cell and _______ cell, making it more ____

into, depolarize, positive

Ca+ moves ____ cell and ____ cell, making it more ____

out of, hyperpolarize, negative

K+ moves ____ cell and ____ cell making it more ______

into, hyperpolarize, negative

Cl- moves ____ cell and ____ cell making it more ______

Enzyme

coverts substrate to product

inhibit

____ enzyme will lead to increase substrate amount and decreased product amount

activate

_____ enzymes will lead to decrease substrate and increased product amount

into or out of

a transporter or a pump moves substances _____ cell

inhibit

inhibiting a transporter or pump will ____ movement across membrane

increase

activating a transporter or pump will ____ movement across membrane

agonist + receptor → autophosphorylation → activation of cellular signaling

List the tyrosine kinase receptor pathway

agonist + receptor (inside cell) → transport to nucleus → activation of gene transcription and translation

List the nuclear hormone receptor pathway

agonist + receptor (7-TM) → G-protein activation → generation of second messenger → activation of cellular signaling

List the G-protein coupled receptor

allow cell to cell communication

what is role of receptor

adenyl cyclase → cAMP → Protein kinase A → increase protein phosphorylation

Gs binds to b-adrenergic receptor. List rest of pathway

phospholipase C → diaglycerole → protein kinase C

phospholipase C → IP3 → Ca2+ release

Gq binds to mGluR receptor and leads to an increase protein phosphorylation and activate calcium binding proteins. List rest of pathway

adenyl cyclase → cAMP → protein kinase A → decreased protein phosphorylation

Gi binds to Dopamine D2. List rest of inhibition pathway

decrease protein phosphorylation and open K+ channels

Gi does 2 important things

hyperpolarize

Gi opens K+ channels

• because K+ is higher in cell → K+ dumps out of cell and cell becomes _____ (cell more negative and less active)

IP3 and DAG, enzymes

____ are second messangers are produced by _____

basal state

when no agonist are present

inactive

____ receptors are more energetically favorable

active

G-proteins binds to ____ receptors ONLY

more ligand + active receptor complexes are formed

More agonist = more [R*L] complexes are formed, what does [R*L] mean

they will shift into active receptors

As more [R*L] forms, what happens to inactive receptors

inverse agonist

____ binds preferably to inactive receptors

agonist

preferential affinity

• if ligand has 100-300x higher affinity for active receptor

inverse agonist

preferential affinity

• if ligand has 100-150x higher affinity for inactive receptor

partial affinity, 100x

10x affinity for active is not selective enough → ____

• ____x affinity is the cutoff

partial agonist

_______ binds to both active and inactive receptors with reduced efficacy compared to a full agonist

• can have a higher affinity for an active receptor but a lower efficacy than a full agonist.

neutral antagonist, inverse agonists

Antagonists: used to reduce response of endogenous agonists

graded response

numerical value such as (HR= beats/min, BP=millimeters of mercury, glucose level = mg/dL)

quantal response

yes or no (did this drug kill an animal, did drug prevent pregnancies?)

potency

efficacy is “how effective” a drug is

• unrelated to ____

Emax, y -axis

Efficacy is determined by

• the maximum efficacy

• the plateau

EC50 or ED50, x-axis

____ or ____ represents potency

• the concentration/dose that produces 50% of maximal response

Kd

equilibirum dissociation constant

• describes affinity of ligand for receptor

high

low KD = _____ affinity

low

high KD = ___ affinity

additivity

1+1=2

synergy

1+1=3

potentiation

1+0=2

additive

agonist with 2nd substance increases response

synergistic

2 agonist combined = GREATER than additive effect

potentiation

agonist + inactive leads to a response MORE than agonist on its own

competitive antagonist

dose response curve shift to right and Emax is not reduced

• effect can be overcome with higher dose of agonist

• higher dose of antagonist = needs even higher dose of agonist for a response

reversible competitive antagonism

irreversible noncompetitive antagonism

Competitive antagonists, reversible

______ are usually ________ because they bind to the exact same site on a receptor that the natural molecule (the agonist) would. This is the active site. The binding is typically non-covalent, meaning it's a temporary interaction, like a magnet.

• Competition for the Active Site: The antagonist and the agonist are like two people trying to sit in the same chair. Whichever one is present in a higher concentration, and has a higher affinity (stronger attraction) for the chair, will win the spot.

• Overcoming the Antagonist: Because the binding is reversible, you can overcome the antagonist's effect by simply increasing the concentration of the agonist. If you flood the area with enough agonists, they will eventually outcompete the antagonists and activate the receptors.

• Analogy: Think of a key (agonist) and a master key (competitive antagonist) trying to get into the same lock (receptor). The master key doesn't open the lock, but it occupies the keyhole. However, if you have enough regular keys, you can eventually displace the master key and open the lock.

Noncompetitive antagonists, irreversible

________ are often ________ because they don't compete for the active site. Instead, they bind to a different location on the receptor, called an allosteric site.

• Change in Shape: When the noncompetitive antagonist binds to the allosteric site, it causes a change in the overall shape of the receptor. This conformational change is often permanent or long-lasting due to the formation of strong, sometimes covalent (irreversible) bonds.

• No Competition: The key difference is that they are not competing with the agonist. The agonist can still bind to its active site, but because the receptor's shape has been altered, it can no longer be activated.

• Overcoming is Not Possible: You cannot overcome the effect of a noncompetitive antagonist by increasing the agonist's concentration. The receptor is effectively "broken" or deactivated, and no amount of agonist will fix it. The only way for the receptor to become functional again is for the cell to create a new receptor.

• Analogy: This is like someone gluing a piece of wood to the inside of the lock's mechanism. The key (agonist) can still go into the keyhole (active site), but no matter how many keys you try, you can't turn the lock because the internal mechanism is permanently blocked.

are non-therapeutically favored because

• too high dose, too high response

• cant administer agonist to reduct effect

selectivity

the relative affinity for a ligand + target in comparison to some other protein

high affinity

drug is designed to bind to target

low selectivity

drug has high affinity to other proteins in the body as well

high selectivity

drug has low affinity to other proteins but high affinity to target

specific

A ____ drug would ideally have an effect on only a single, unique target. Specificity is a theoretical ideal that is rarely, if ever, achieved in practice. A truly specific drug would bind to its target and nothing else, regardless of the dose. It's a binary concept: a drug is either specific or it's not. Since all drugs have the potential for some level of off-target binding, the term "specificity" is generally avoided in favor of "selectivity”

LD50/ED50 or ED50 (adverse effect)/ED50 (therapeutic effect)

therapeutic index

high affinity, high selectivity

drugs prefer ____ and ____

20nM because low # means higher affinity

a drug with 400 nM and 20 nM affinity, which one has higher affinity?

mechanism of action

how drug works

therapeutic effects

reason why give drug

indications

disease state to give drug

side effects

an effect other than therapeutic effects

adverse effect

an effect other than therapeutic effect that causes a bad/undesirable response

contraindications

reason why NOT to give drug

toxic

what happens with high level of drug

• usually an exacerbation of what drug does

  • too much drug is administered or too little drug is leaving the body

allergic

involves immune system → it recognizes drug as harmful

idiosyncratic

we dont know why patient responses a certain way to drug → reason usually has to do with patient’s genetics

fetopathic

kills fetus in uterus

teratogenic

leads to deformity in fetus when born m

mechanism based side effects

due to drug binding to targets its designed to bind but target is in many different parts of the body

ex; drug may bind to different target (position wise)

off target side effect

caused by drug binding to something else (selectivity problem)

potent

a drug with high affinity for its target would be more _____ than a drug with low affinity for same target

dissociation (activation) of Gs - activation of adenylate cyclase- activation of PKA

what is the correct order for following activation of Gs-coupled receptor

off-target adverse effect

an _____ is due to poor selectivity of a drug

affinity

the KD is a measure of a drug’s ____

hydrophilic

How does a metabolite differ from a parent drug?

• metabolite is made more ______ and is usually less active than the parent drug.

  - stays in nephron to be eliminated via urine

• biotransformation (same as Metabolism): body's ability to convert lipophilic drug to metabolite

  Substrate → product is same as drug → metabolite

cytochrome p450, hydrophilic

Phase I metabolism involves ______ family enzymes → metabolize endogenous substances, synthesize some molecules or breakdown exogenous substances

• simple reactions to make phase I metabolism more _____

transferases

Phase II Metabolism involves the enzyme ____ (enzyme that transfer or attach hydrophilic endogenous and large substances onto phase I metabolites

• so they can be eliminated from the body b/c theyre so hydrophilic so little chance of being reabsorbed

first pass metabolism

how much metabolism occur on first pass through liver

• drug is given orally = absorbed from GI to travel to liver (where phase I metabolism occurs before entering systemic circulation)

high first pass metabolism

drug is good substrate for enzyme so very little parent drug is going to come out into bloodstream

low first pass metabolism

drug is NOT good substrate for enzyme so most parent drug is going to come out into bloodstream after it first pass through liver

decrease

increase bioavailability, ____ first pass metabolism

increase

decrease bioavailability, ____ first pass metabolism

very little gets into bloodstream

drug with high first pass metabolism means _____

• drug cannot be given orally or give super high oral dose

oral bioavailability, Fpo

% of parent drug that reaches circulation (as parent drug, NOT metabolite) following oral administration

oral absorption and first pass metabolism

what are the two factors that oral bioavailability depends on

48

if 100 mg of a drug is given and 80% absorbed, 40% first pass metabolism, what is Fpo

TOXICITY

Why can metabolism differ between patients or within the same patient?

• disease status: liver disease (liver is site to drug metabolism and status means reduced metabolism)

• age: newborns (will have undeveloped complements of enzymes and will not metabolize well) vs elderly (above age of 65 loses 1 of hepatocytes yearly = less or metabolism = increased drug level and metabolites = _____

prodrugs

low drug level, increase metabolites

inhibition of metabolic enzymes

how does metabolism contribute to drug-drug interactions?

enzyme inducers

leads to sub-therapeutic responses

enzyme inhibitors

leads to increase in drug level and toxicity