Drug-receptor interactions and mechanisms of drug action Flashcards
What is pharmacokinetics?
The effect of the body on the drug
E.g. ADME
What is pharmacodynamics?
The effect of the drug on the body (responses produced, mechanism of action)
What is a drug?
A chemical substance that interacts with a biological system to produce a physiological effect
What are the 4 main drug target sites?
Receptors
Ion channels
Transport systems
Enzymes
What is a receptor?
Protein molecules whose function it is to recognise and respond to endogenous chemical signals
What is an ion channel?
Selective pore within membrane of lipid bilayer
Allows passage of ions depending on EC gradient
What are the 2 types of ion channel?
Voltage-sensitive
Receptor-linked
What are some drugs that interact with ion channels rather than with the receptors themselves?
Local anaesthetics - block VGSCs in sensory axons; fewer APs propagated; reduced perception of pain
Calcium channel blockers
- Usually end in -dipine
- Block VSCCs
What is a transport system?
System of carriers that transport substances against their CG, e.g. glucose, ions, NTs
Show specificity for certain species
E.g. Na/K pump, NA uptake 1
Why are transport systems not receptors?
Don’t mediate a response
Just allow NT to bind to protein and then move it somewhere else
What are the 3 ways in which drugs interact with enzymes?
- Enzyme inhibitors
- False substrates
- Prodrugs
What are the exceptions to the 4 target site rule?
Some drugs produce responses due to the physiochemical properties
- General anaesthetics dampen synaptic transmission but don’t interact with specific transport system or receptor
- Antacids - reduces acidity of stomach contents - basic
- Osmotic purgatives (laxatives) - stimulate voiding of gut contents - draw water into stomach contents - softens stool
What is an agonist?
A molecule that binds to a receptor and stimulates it to generate a response
E.g. nicotine
What is an antagonist?
A substance that interacts with and binds to a receptor but does NOT produce a response
Gets in the way of agonist
E.g. atropine
Define potency
How powerful a drug is
What does potency depend on?
Affinity
Efficacy
What is affinity?
How willingly a drug binds to its receptor
What is efficacy?
AKA intrinsic activity
Ability of a drug to generate a response once bound to receptor
Usually involves some sort of conformational change
What is a full agonist?
An agonist that generates the maximal response
What is a partial agonist?
An agonist that generates less than the maximal response
What is selectivity?
When a drug prefers interacting with a particular receptor type
Explain the log dose-response curve
Tissue response Y
Log [A] X
Full agonists with lower affinity with still generate a maximal response but needs much higher concentration
Partial agonist curve peaks before it gets anywhere near maximal tissue response
Do antagonists have:
a) affinity?
b) efficacy?
Have affinity
No efficacy
What are the 2 main types of antagonists?
- Competitive
2. Irreversible
How does a competitive antagonist work?
Binds to same site as agonist on receptor
Need higher agonist conc to generate maximal response
Why are the responses of competitive antagonists surmountable?
They bind to same site as agonist on R
By increasing agonist concentration, you can overcome the effect of competitive antagonist
How do competitive antagonists affect the log dose-response curve?
Shifts it RIGHT
Need higher [A] for same tissue response
How do irreversible antagonists work?
Bind to same site as agonist but more tightly with covalent forces - can’t be shifted
OR
Bind to different site –> insurmountable antagonism bc not competing
What is receptor reserve? Advantages?
‘Spare receptors’
In some tissues, you don’t have to occupy 100% of Rs to generate maximal response
May be as low as 1%
Advantage = increased sensitivity of tissue to agonist and increased speed of response
How do irreversible antagonists affect the log dose-response curve?
Curve falls away and won’t be able to generate maximal response regardless of [A]
What are the 4 types of drug antagonism?
Receptor blockade
Physiological antagonism
Chemical antagonism
Pharmacokinetic antagonism
Explain receptor blockade
Antagonist binds to receptor and prevents binding of agonist
What is use dependency? Give an example
- Refers to ion channel blockers
- The more active the target tissue, the more effective the blocker
E.g. normal neurones fire at a relatively low rate
Put local anaesthetic on them –> relatively low blockage
Nociceptor neurones fire rapidly and bc APs are generated rapidly, ion channels are open more often
LAs work by binding to inside of ion channels after they open – channels open more often –> more chance for blockage
Gives LAs a selective action on nociceptor neurones - act on pain conducting fibres more specifically than normal neurones
Explain physiological antagonism and give an example
2 drugs act at different receptors to have opposite effects in same tissue
E.g. NA on vasculature binds to adrenoceptors –> vasoconstriction
Coadminister histamine - acts on different Rs to cause vasodilation
Explain chemical antagonism and give an example
Interaction of drugs in solution
E.g. dimercaprol is a chelating agent - forms heavy metal complexes which are more rapidly excreted by kidneys - reverses lead poisoning
Explain pharmacokinetic antagonsim and give an example
One drug reduces concentration of another drug at the site of its action
by reducing absorption, increasing metabolism or increasing excretion of the other drug
Must be aware of this so you don’t administer two drugs that interfere with each other
E.g. repeatedly administering barbiturates increases production of microsomal enzymes
Administering another drug metabolised by same enzymes –> metabolised more quickly –> reduced effect
What is drug tolerance?
Gradual decrease in responsiveness to a drug with repeated administration
What can cause drug tolerance?
Pharmacokinetic factors Loss of receptors Change in receptors Exhaustion of mediator stores Physiological adaptation
How can pharmacokinetic factors cause drug tolerance?
Metabolism of drug increases when given repeatedly over time
E.g. barbiturates and alcohol
How can loss of receptors cause drug tolerance?
If cell is repeatedly stimulated by an agonist, cell will endocytose some receptors so there are fewer available on cell surface = receptor downregulation
Beta adrenoceptors are susceptible to this
How can change in receptors cause drug tolerance?
No. of receptors on cell surface stays same but Rs themselves undergo desensitisation
Trigger = continued stimulation over long period of time
Involves conformational change
Proportion of Rs are no longer effective
How can exhaustion of mediator stores cause drug tolerance?
Happens with amphetamines
Amphetamine = CNS stimulant - gets into BS, crosses BBB into brain and acts on noradrenergic neurones
Amphetamine binds to uptake 1 protein - taken into central NA synthesis system - replaces NA in vesicles - big increase in NA production
2nd dose - less severe response due to exhausted NA stores - no more NA unless de novo synthesis
How can physiological adaptation cause drug tolerance?
Like a homeostatic response
Body attempts to maintain a stable internal environment
What are the 4 receptor families?
Type 1 - ionotropic
Type 2 - G-protein coupled
Type 3 - tyrosine kinase-linked
Type 4 - intracellular steroid type
Describe type 1 ionotropic receptors and give 2 examples
Ion channel linked
Mediate very fast responses - milliseconds
4 or 5 subunits
Defining feature: transmembrane alpha helices
External binding domain - stimulates and opens ion channel
E.g. nicotinic ACh R and GABA
Describe type 2 G-protein coupled receptors and give an example
Must first link to a G protein before it can mediate a response Much slower - seconds 1 subunit 7 transmembrane alpha helices E.g. b1 adrenoceptors in heart
Describe type 3 tyrosine kinase linked receptors and give 2 examples
Single protein 1 transmembrane domain When agonist stimulates R, activates catalyst inside cell and stimulates kinase activity of R --> phosphorylation of IC proteins --> response E.g. insulin receptor, GF receptor Minutes
Describe type 4 intracellular steroid type receptors
Activated by steroids and thyroid hormones
Regulate DNA transcription
Drug must pass through cell membrane and into nucleus before effect
R stimulates –> zinc fingers uncovered –> DNA binding –> increased transcription
Hours
What is a drug target site?
Anything to which a drug is directed and/or binds, resulting in a change in its behaviour or function
