Module 8 - Drug Receptor Interactions Flashcards
what are the 2 receptor theories that we use to describe drug-receptor interactions
- simple occupancy theory
- modified occupancy theory
simple occupancy theory states what?
- intensity of a drug’s response is proportional to the number of receptors occupied
- the maximal response occurs when all the receptors are occupied
- This implies that two drugs that act at the same receptor should produce the same effect. This is not true! We know this because there are many drugs that act at the same receptor yet have different efficacies.
Modified occupancy theory states?
1) The intensity of a drug’s response is proportional to the number of receptors occupied.
2) Two drugs occupying the same receptor can have different binding strengths (i.e. affinity).
3) Two drugs occupying the same receptor can have different abilities to activate the receptor (i.e. intrinsic activity).
- modified occupancy theory takes into account the affinity of the drug for the receptor and the ability of the drug to activate the receptor.
Modified Occupancy Theory – Affinity
- affinity is the attraction that a drug has for it’s receptor
Drugs with High affinity
- Drugs with a high affinity are highly attracted to their receptor and therefore bind to the receptor effectively even at low concentration.
Drugs with high affinity for their receptor have high potency
Drugs with Low affinity
- Drugs with low affinity are weakly attracted to their receptor and therefore bind ineffectively to the receptor even at high concentration.
drugs with low affinity for their receptor have low potency.
Modified Occupancy Theory – Intrinsic Activity
- Intrinsic activity is the ability of a drug to activate the receptor.
Drugs with high intrinsic activity
Cause intense receptor activation
- drugs with high intrinsic activity have high maximal efficacy
Drugs with low intrinsic activity
only minimally activate the receptor.
drugs with low intrinsic activity have low maximal efficacy.
Agonist definition
a molecule that binds to a receptor and activates it. Agonists mimic the action of endogenous ligands
Antagonist definition
Molecules that bind to a receptor but do not activate it.
Partial Agonists definition
Molecules that bind to the receptor but have minimal ability to activate it.
What do agonists do?
Drugs that we design as agonists are often targeted to mimic the action of the body’s endogenous molecules.
- both affinity AND intrinsic activity since they are able to bind and activate a receptor
- Some agonists can bind to different receptors (remember specificity) and therefore may cause different effects depending on the dose.
- A good example of this is dopamine, an endogenous neurotransmitter that we also give as a drug
Physiological response of an agonist
does not always increase a physiological response (i.e. heart rate). Agonists may cause either increased or decreased physiological response depending on which receptor is activated
what do antagonists do
- bind to receptors but do NOT activate them
- have affinity BUT NO intrinsic activity
- profound pharmacological effects
- generate their effect by preventing the binding of endogenous molecules and other agonist drugs
Would an antagonist do anything if there was no agonist present?
NO, the pharmacological effect of an antagonist is dependent on the presence of agonist
Examples of Antagonist drugs
Beta blockers - block binding of endogenous epinephrine to beta 1 receptors in the heart = slows heart
Antihistamines - block binding of histamine to H1 receptors in nasal mucosa = prevents allergy symptoms
Gastric Acid Reducers - block binding of histamine H2 receptors in the gut = decreased gastric acid secretion
Opioid Receptor Blockers - block binding of opioids to opiate receptors - treats overdose
What treats overdose?
antagonist
types of antagonists
1) Competitive Antagonists – Binding occurs at the same site as the agonist and is reversible.
2) Irreversible Antagonists – Binding occurs at the same site as the agonist but is irreversible.
3) Allosteric Antagonists – Binding occurs at a different site than the agonist.
competitive antagonist
- compete for binding with agonist at the same binding site
- is reversible
- If the antagonist and agonist have equal affinity, the one with the highest concentration will occupy the binding site.
- Because the binding is reversible, the effect of a competitive antagonist can be overcome by increasing the concentration of the agonist.
irreversible antagonist
- bind to the same receptor site as the agonist
- binding is irreversible (non-competitive)
- The effects of irreversible antagonists cannot be overcome by increasing the dose of agonist.
- Because the agents are irreversible in nature they are very seldom used in therapeutics
the intensity of response depends on the agonist binding to the receptor. If the antagonist permanently blocks receptor sites, it effectively decreases the maximal response the agonist may have.
Do the effects of irreversible antagonists last forever?
NO! Our body is constantly degrading old receptors and making new ones. The effect of irreversible antagonists lasts until the receptor is replaced.
Allosteric Antagonists
- bind to a different site on the receptor than the agonist does.
- Binding of the allosteric antagonist changes the conformation of the receptor, so the agonist is no longer able to bind.
- The binding of an allosteric antagonist is reversible but not competitive.
- The binding is non-competitive because the agonist and allosteric inhibitor bind to different sites on the receptor.
- Similar to irreversible antagonists, the effects of allosteric antagonists cannot be overcome by increasing the dose of agonist.
- Allosteric antagonists effectively decrease the maximal response that the agonist may elicit.
Partial Agonist
- are agonists that have only minimal or moderate intrinsic activity.
- The maximal efficacy that a partial agonist can produce is less than that of a full agonist.
- Partial agonists are also able to act as antagonists
How can partial agonists also act as antagonists
Remember that a partial agonist has only minimal or moderate activity to activate a receptor. Therefore binding of a partial agonist will cause minimal or moderate activation of the receptor but will also block the binding of a full agonist.
Regulation of cell surface receptor expression
- The number of receptors on the cell surface is not constant and can change with exposure to drugs.
- For most drugs, their action depends on the receptor being present on the cell surface (exception: intracellular receptors/transcription factors, which are normally found inside the cell).
drug tolerance
when patients are continually exposed to agonists, the response to the agonist may decrease. this is known as tolerance
3 types of drug tolerance
- desensitization
- metabolic tolerance
- tachyphylaxis
Desensitization
Continuous exposure to an agonist can cause receptor desensitization. In receptor desensitization, the receptor is internalized into the cell or destroyed. The net effect is a decrease in cell surface receptor expression and decreased drug effects.
Metabolic tolerance
Continuous exposure to some drugs results in the induction of drug metabolizing enzymes. Induction of drug metabolizing enzymes may cause a decrease in the plasma concentration of the drug.
Tachyphylaxis
A rapid decrease in the response to a drug. Some drugs require a drug free period between administrations to prevent rapidly developing tolerance
what is receptor upregulation
- continuous exposure to an antagonist has the opposite effect of tolerance.
- In this case, the cell is said to become hypersensitive or super sensitive.
- This occurs because the cell synthesizes more receptors.
- Therefore, there are a greater number of receptors at the cell surface and the response increases
