Exam 2- Drug Target Interactions Flashcards
Agonist
activator
- May be direct or indirect
- Any activity usually begins with a conformational change of receptor
Anatgonist
inhibitor
- Usually competes for binding with other/ endogenous ligands (prevents receptor activation)
- If its tight/covalent, then its non-competable with agonists
Competitive
binds to the same site
Allosteric
binds to a different site
Histamine H2 receptor
- present significantly only in the GI tract ( stomach and small intestine)
- Its endogenous ligand is histamine
Histamine does what
stimulates gastric acid production
Pepcid - Famotidine is what
H2 receptor antagonist
- Its a competitive antagonist for histamine
- It blocks histamine from binding, hence less acid is produced
Used to treat GERD
The more interactions of a drug with its receptor
the greater the affinity
The greater the affinity of the receptor for a drug
the more of that drug will be bound at a given drug concentration
Affinity is expressed as
Kd
Kd =
[D][R] / {DR]
- expressed in molar units, uM, nM, pM
- concentration of drug at which half of the receptor is bound
D
concentration of free drug
R
concentration of free receptor
DR
Concentration fo bound drug-receptors
A small Kd indicates
high affinity
Adding drug shifts the equilibrium
to the left which forms more drug-bound receptors
More drug bound receptors equals
greater biological effect
As we increase drug concentration
we increase the amount of receptor binding
At drug conc. = Kd
theres an equal amount of bound/ free receptors
It takes a lower conc. of a drug with a small Kd
to reach the same level of receptor binding
The weaker a drug- receptor is
the more it wants to dissociate into its free drug
- The Kd will be high
The stronger a drug-receptor interaction is
the more it wants to remain in its undissociated for
- The Kd will be low
If it takes a long time to form [DR], then
[D] may diffuse or be transported away from target organ by blood flow
Pharmakon
poison/ drug
Pharmacology
study of substances that interact with living systems through chemical processes, especially binding to regulatory molecules and activating or inhibiting normal body processes
Toxicology
branch of pharmacology dealing with the undesirable effects of chemicals on living systems, from cells to humans, to environments and ecosystems
Drug
any substance that changes biological function through chemical (covalent/ non-covalent) interactions
- Have a beneficial effect in an addition to any deleterious effects
Receptor
The biological target of the agonist or antagonist. Its function changes when bound to an endogenous ( anything that originates internally) ligand or drug
Osmotic agents
move water
Antacids
neutralize acid
Posion
almost exclusively toxic effects (although anything can cause harm in a dose-dependent manner, including manner)
Toxins
Biological poisons (made by a biological system
Properties of drugs
- Physical properties
- Molecular size
- Reactivity and bond formation
- Shape
Physical properties of drugs
Solid, liquid or gas at RT- determines best route of administration
- Solubility
- Ionization state
- Hydrophobicity
Size
MW can vary greatly
- most often 200-500 Da
- Has to fit well in receptor, with level of specificity, be absorbed and move throughout the boy
- very large drugs often require direct compartment administration
- Size and MW are usually but not always proportional
Reactivity and bond formation
Drugs interact with receptors via chemical bonds
Strongest to weakeast bonds
- Covalent- rare, strong and virtually irreversible
- Ionic
- Hydrogen bonds
- Hydrophobic bonds
Shape
determines receptor binding
- Lock and key model
- Effected by chirality/ stereoisomerism
Racemic mixture
a solution in which there is an equal amount of two enantiomers
Racemic drugs
A single enantiomer is more susceptible to metabolizing enzymes
- one enantiomers duration of action, or elimination half-life may vary dramatically from the other
Which of the following is a TRUE statement?
A.Enantiomeric drugs are usually equipotent or equi‐effective
B.All drugs are poisons at high enough doses
C.Antagonists inhibit receptor function
D.Most clinically efficacious drugs are<100MW
C. Antagonists inhibit receptor function
Which is an example of a pharmacokinetic effect?
- An increase in BP upon drug dosing
- An amount of drug released into urine
- An immune reaction to a drug
- The decomposition of a drug during storage
- An amount of drug released into urine
Receptor
What a drug binds to
- The component of a cell or organism that interacts with a drug and starts the events leading to drug effect
- Mediators of Mechanism of Action
If the drug binds to site on receptor other than original ligand/agonist binding site, it is called
Allosteric interactor
Allosteric antagonist cannot
be overcome with increased agonist
Orthosteric site
site at which the agonist binds to
Competitive agonist
blocks activity of natural agonist. It competes with the agonist to bind to that site
Allosteric site
Site other than the normal binding site of the agonist
-Not competitive
Drug generally binds to receptors ->
some effect
Drug +Receptor ->
D+R complex -> effect
Simple
D+R ->
D+R complex -> effector molecule -> effect
More complex
D+R ->
D+R complex -> activation of coupling mechanism -> effector molecule -> effect
Most complex
Receptors can be
in the active form (Ra) or inactive for (Ri)
Basal tone/ constitutes activity
a pool of receptors will exist in each form (Ra and Ri)
What do agonist do to equilibrium
it shifts the equilibrium
Ra->Ri and vice versa but more is going to the active form Ra
An Full agonist will
shift all receptors into active form
A partial agonist will
shift only some receptors into active form
- Even if you add more drug, you cant get anymore Ra activation
- produces a lower effect at full receptor occupancy than full agonists
Partial agonists have
low intrinsic(natural) activity which is independent of receptor activity - can competitively inhibit full agonist activity
An antagonist will
block the activity of the natural agonist
A inverse agonist will
block the original activity of the receptor.
In the graph the curve goes down
- shuts down 100% of activity
Treatment of a receptor with an allosteric inhibitor
A. Overall response would be diminished, compared to agonist alone
B. More agonist would be required to reach the same response
C. Response would be enhance, as compared to agonist alone
A. Overall response would be diminished, compared to agonist alone
Inverse antagonist
no such thing
A receptor is stimulated with a full competitive agonist. A non-competitive (allosteric) agonist is added. What happens to the response
- Response is increased
- Adding a non-competitive agonist to an agonist, it will increase the response
A receptor is stimulated with a partial agonist. An antagonist is added. What happens to the response?
Response is diminished
- Adding an antagonist will inhibit the activity of the agonist
A drug was administered that lowered Peripheral Vascular Resistance (PVR) below basal tone
Inverse agonist
If a drug was administered that maintained PVR at basal tone, even in the presence of endogenous ligand. You would predict the drug to be an
Neutral antagonist
Orphan receptors
Receptors that have no known agonists, activities or related drugs
Regulatory proteins
- mediate action of endogenous chemical signals
- Ex: GABA-R
Enzymes are proteins that
Mediate chemical reactions/ structural conversions (EX: DHFR)
Transporters proteins
Move things often across membranes
Ex: Na+/ K+
Structural proteins
provides tissue or cellular structure ( Ex: actin, microtubules/tubulin
Important aspects of drug
- Receptors as the link between drugs and their effects
- Receptors regulate/ mediate chemical signaling and provide good drug targets
- determine therapeutic and toxic drug effects
Emax
the maximal effect for a given agonist or partial agonist
EC50
the concentration of agonist ( or partial agonist) needed to give 50% Emax (maximal effect)
Antagonism
The antagonist does not activate the receptor, but it block its activation by the endogenous agonist by
- competing for binding with agonist
- irreversibly binding
- binding at the allosteric site (allosteric antagonist)
For a noncompetitive antagonist, increasing agonist will
recover some E but NEVER reach Emax
For a competitive antagonist, increasing agonist
will recover E and will eventually reach Emax
EC50 increases as
the affinity of the antagonist increases
- agonist becomes weaker as EC50 increases
How does Emax change when the affinity of the antagonist increases
It stays the same
Low Kd means
high affinity
IC50 or Ki
Drug inhibitory activity
If Kd»_space; IC50 this suggests that
there are lots of spare receptors
- You do not need to stimulate all of the receptors to get the full effect
Irreversible antagonist
- can be caused by covalent or exceptionally tight binding (picomolar)
- receptor is unavailable for agonist binding
- Good bc it can better control naturally fluctuating agonist, such as hormones and catecholamines
- Bad bc if overdosed, it cannot pharmacologically agonize. They also tend to be less specific
- kills the receptor
- In the diagram this would be represented by a straight line
IC50
concentration of antagonist that blocks 50% of activity
Potency
requires lowest amount of drug to have full effect
- lowest conc of drug to reach highest Emax
- smaller E50 -> more potent
Efficacy
Drug with the highest maximal response is more efficacious
The orthosteric site is
where the ligand bind, aka the active site
With fixed agonist, increasing antagonist will
diminish E
