Drug Receptor Interactions II Flashcards
Drug+Receptor= Cellular effect
A drug can activate or prevent the activation of a cascade of intracellular processes
*Drug has its particular effects according to which receptors it interacts with and what the receptors do
Receptor mediated actions of drugs
- Act on ion channels
- Receptor with enzymatic activity
- Activating protein complex that generate 2a messenger (alters metabolism, change expression of proteins, cell division, etc)
- Receptor with intracellular enzyme component (tyrosine kinase activity)
- Receptor drug complex goes to Nucleus–> directly stimulate DNA transcription/translation
Drugs that act at ion channels
Benzodiazepines
Local anesthetics
Drugs that act at tyrosine kinases
Insulin
Drugs that act by blocking enzymes
Acetylcholinesterase inhibitors
Drugs that bind intracellular receptors
Steroids
Drugs that act at G protein receptors
Muscarinics Adrenergics Histaminergics Serotonergics Angiotensin II inhibitors
G-protein receptors
General set of receptors w/three subunits that initiate production of intracellular substances
Intracellular substances
Secondary messengers
- Agonist binds to Alpha subunit of G (which binds GDP)
- GDP exchanged for GTP (alpha subunit breaks off from beta and gamma subunits)
- Alpha subunit activates enzyme system to create 2a messenger (or have a direct effect)
Gq Protein
Gq stimulates phospholipase C==> DAG and IP3
These open internal calcium stores, activate protein kinase C (can turn off or on 50 other proteins) resulting in smooth mm contraction, hormone production or inflammation
Gs Proteins
Stimulate adenylyl cyclase==> cAMP
This activates cellular energy production by phosphorylation of enzymes and K+ channel opening
Gi proteins
Inhibit adenylyl cyclase
Major secondary effectors (review)
DAG IP3 cAMP cGMP Calcium
Some drugs work by directly altering concentration of 2a messengers
Caffeine
Sildenafil (Viagra)
Steps three and four
Cellular actions combine to have a physiological effect
Collection of activated cells will have a tissue effect which= a physiological effect
Cellular actions and physiological effects of agonist on skeletal mm channel
Opening up sk mm Na channels will cause contraction (myasthenia gravis meds)
Cellular actions and physiological effects of antagonists
Prevents sk mm from contracting (neuromuscular paralysis for surgery)
Physiological effects of epinephrine
Will increase HR, BP, etc: useful for anaphylactic shock
Antagonist of this given to pt with high BP (prevents action of endogenous epi)
Drugs do not act unilaterally
Body reacts
Compensatory mechanisms kick in to readjust heart rate and BP (in the case of epinephrine or antagonist)
Physiological effect of Histamine in:
Veins
Mast Cells
Skin
**Block histamine and you block these effects (anti-histamines)
It binds histamine receptors, these receptors in the veins cause vasodilation which causes:
- A significant drop in BP.
- Increased capillary permeability.
- Body reacts to drop in BP by increasing HR.
Histamine from mast cells (nasal membranes, eyes, mouth, bronchioles) cause:
- Tissue swelling and fluid leakage
- Runny nose, difficulty breathing
Histamine in dermis promotes itching
Direct and indirect effectors of ACh action
- Cholinergics (compounds that mimic ACh): muscarinics and nicotics, have an effect of intracellular actions
- Acetylcholinesterase inhibitors are used to enhance ACh action at neuromuscular junctions and in CNS (by preventing breakdown of ACh)
- Anticholinergics (block ACh by binding its receptors at the neuromuscular junction): Antimuscarinics, neuromuscular blockers, ganglionic blockers
ACh effect on pupillary constriction
Causes dilation
Effect of epinephrine during anaphylaxis:
Histamine has flooded the system causing vasodilation (BP drops), bronchoconstriction, bronchospasm, and swelling of mucous tissue
Epinephrine: Vasoconstricts (reverses drop in BP), reduces swelling around pharynx and larynx, open up bronchioles, stimulates heart.
***Doesn’t block histamine, but acts as an agonist at same tissues to reverse effects of histamine.
Glucocorticoids and Antihistamines are given for maintenance.
Effect of local concentration of a drug:
follows the law of mass action
More drug=more effect
Basically, how many receptors it triggers/blocks is dependent on local concentration of the drug
Law of mass action
E=Emax* C/C + ED50 meaning:
Need some drug to get effect
For a little while, more drug=linear effect (increasing effect)
Then reach near max effect, and you can add more and more drug but it will only give you a small effect
(law of diminishing return, like more and more caffeine when you’re already tired)
Log drug concentration vs receptor occupied
Again, more drug more receptors
X axis is the log of drug concentration
Y is % of receptors occupied
Log dose response curve (LDR):
Measures degree of response
X axis still log of drug concentration
Y axis is the %max effect of drug (Emax)
Spare receptors
Non-active receptors on outside of cell (ACh in smooth mm)
Meaning that the receptor occupied curve won’t match drug response
***An agonist can have its action with few receptors activated
How is drug efficacy measured?
By how great an effect it can produce (Emax)
Drug w/higher Emax is more effective
**Efficacy is very important
What is a partial agonist?
A drug that achieves an effect less than Emax
How does a partial agonist bind to same receptors as a full agonist but still produce less of an effect?
Receptors exist in equilibrium of two forms: active and inactive.
- Full agonists bind tightly to active form.
- The inactive form is recruited to become an active form=restores equilibrium=increase active receptors=increasing max effect.
- Partial agonists bind inactive form, preventing it from becoming active=total number of possible active receptors are fewer.
Intrinsic activity as a measure of the effect of an agonist:
Is measured by the ability/effect of an agonist by activating a receptor
- A full agonist has intrinsic activity of 1
- Partial agonist w/half the effect of a full agonist has an intrinsic activity of 0.5
- Antagonists have intrinsic activity of 0
ED50
Drug concentration in blood that delivers 50% of max effect
Eg. If the max effect of lower MBP is 40mmHg then Emax is a drug that lowers it 20mmHg
ED90
Drug concentration in blood that delivers 90% max effect.
Using the MBP Emax example (40mmHg), the ED90 lowers MBP by 36mmHG
Drug Potency: drug that is effective at a lower concentration is more potent
How strongly a drug binds to its receptor can be measured by its affinity constant or dissociation constant.
**Defined by what concentration half of receptors are bound.
Drug with high affinity is highly potent.
Graphs comparing drug potencies: Which line would indicate the most potent drug?
The line that is furthest to the left is more potent b/c lesser ED50 means that its effect happens requiring less concentration of the drug than the other drug.
Efficacy vs. potency: graphs
The more efficacious drug will usually have a higher flat line, whereas the most potent drug will be the line that is further to the left
Definition of down-regulation
When a receptor is regularly activated a cell may produce less of these receptors.
***Causes tolerance
Tolerance
When more drug is required to achieve the same effect
Desensitization
Number or receptors stay the same, but the cell deactivates them.
Reduced action.
Tachyphylaxis
Same as desensitization.
Reduced action of receptors.
Downregulation and desensitization in terms of potency and efficacy:
Can reduce potency and maximal efficacy of drug.
Ex:Oxymetaazoline (decongestant, afrin); after a few days, receptors downregulate, drug is less effective and pt experiences a rebound.
Other causes of tachyphylaxis
Reduced production of neurotransmitters or through other pathways
Tachyphylaxis and morphine:
Morphine’s 3 effects are analgesia, respiratory depression and constipation
Prolonged use of morphine causes less pain-relief over time, so you up the dosage and pain relief returns to original level but increased constipation and respi depression.
**B/c CNS opioid receptors downregulate but not the GI or respi receptors
Tolerance in graphs
Emax lowers, looks like a partial agonist.
Basically, tolerance to a drug is akin to converting it to a partial agonist.
Up regulation
When a receptor is regularly blocked by an antagonist, cell increases the number of receptors.
Can cause SUPERsensitivity
Supersensitivity example
Chronically blocking Beta adrenergic receptors increase their numbers. Stop taking med, pt become super-responsive (sensitive) to a B-adrenergic agonist (or own production of epinephrine)
Constant exposure to an antagonist increases number of working receptors:
Emax is elevated in a graph (flat line higher)
Upregulation or supersensitivity
Reversible antagonists:
Competitive antagonists
Only blocks the receptor while the drug is present.
Irreversible antagonists:
modifies the receptor to irreversibly shut it off.
non-competitive antagonist
As if a key breaks off in a lock
Physiological antagonist
A drug that counteracts the effect of another drug but through different mechanisms or receptors
Rise in HR caused by a stimulant (epi) can be countered by a CNS depressant (benzo)
Competitive antagonists (Reversible) on the LDR
Blocks agonists action, but can be overwhelmed by more agonist.
Makes the agonist less potent.
**Drug curve shifts to the RIGHT
Non-competitive/irreversible antagonists effect on LDR
Alters and deactivates the receptor.
Turns a full agonist into a partial one, lowering flat line of the drug curve.
**Recovery depends on the production of new receptors.
Real life irreversible antagonists:
aspirin, omeprazole
More powerful than reversible inhibitors.
May have an effect for days after the drug is discontinued.
Quantal dose-response curve
Measured by % of people for whom the drug worked. All or nothing.
Ed50 is concentration where 50% of ppl are cured/affected; ED90 is where 90% are affected.
Quantal LDR and drug effectiveness
Y axis is % of patients showing desired effect.
X axis is the log drug concentration
