Lecture 3 - Mechanisms of Drug Action Flashcards
What are the four types of drug antagonism?
Receptor blockade
Physiological antagonism
Chemical antagonism
Pharmacokinetic antagonism
Explain how receptor blockade is a form of drug antagonism.
An antagonist molecule binds to the receptor and prevents the binding of the agonist
What is the concept of “use dependency”?
Refers to ion channel blockers
Means that the more active the tissue is that the drug is acting on, the more effective that drug will be. (at blocking the channel)
What is an example of a type of drug that utilises “use dependency” and how does it do so?
Local anaesthetics
Nociceptors (pain receptors) fire rapidly when there is pain and because the action potentials are generated rapidly then the ion channels will be open much more frequently.
Explain how physiological antagonism works.
Two drugs act at DIFFERENT receptors to have OPPOSITE effects in the SAME tissue
What is an example of physiological antagonism in the body?
Noradrenaline on the vasculature binds to adrenoreceptors and causes VASOCONSTRICTION. If histamine co-administered, it acts on DIFFERENT receptors also on the vasculature and causes VASODILATION.
Explain how chemical antagonism works.
Interaction of drugs in solution.
What is an example of chemical antagonism?
Dimercaprol - this is a chelating agent, it forms heavy metal complexes which are more rapidly excreted by the kidneys. Useful for things like lead poisoning.
Explain how pharmacokinetic antagonism works.
When one drug reduces the concentration of the other drug at the site of its action. This can be done by reducing the absorption, increasing the metabolism, or increasing the excretion of the other drug.
What is an example of pharmacokinetic antagonism?
Repeatedly administering barbiturates increases the production of microsomal enzymes. If another drug is administered that is metabolised by these enzymes then this drug will be metabolised more quickly and its effect will be reduced.
What is the concept of drug tolerance?
Gradual decrease in the responsiveness to a drug with repeated administration. e.g. benzodiazepines
What are the 5 causes of drug tolerance?
Pharmacokinetic factors Loss of receptors Change in receptors Exhaustion of mediator stores Physiological adaptation
How are pharmacokinetic factors involved in drug tolerance?
The metabolism of the drug increases when it is given repeatedly over a period of time.
E.g. alcohol, barbiturates
How is loss of receptors involved in drug tolerance and what is it also known as?
The cell takes receptors off its membrane via membrane endocytosis, the more the cell is repeatedly stimulated by an agonist, the more the cell moves receptors for that agonist inside the cell. This results in fewer available receptors on the cell surface.
This is also known as RECEPTOR DOWNREGULATION. e.g. Beta Adrenoceptors
What happens when changes in the receptors themselves influence drug tolerance?
Conformational change in some of the receptors after continued stimulation over time. Leads to a proportion of receptors being unavailable.
What happens when exhaustion of mediator stores influences drug tolerance and what is an example?
Example is amphetamines.
Amphetamine binds to uptake 1 protein and gets taken into the central noradrenaline synthesis system and replaces the noradrenaline in the vesicles. This results in a big increase in the production of noradrenaline. If you take a second dose of amphetamine shortly after the first, you’ll get a less severe response because the NA stores have been exhausted and the same reaction will not be acquired until the stores are replenished.
How does physiological adaptation influence drug tolerance?
Homeostatic response
The body attempts to maintain a stable internal environment so if you take a lot of a drug that is usually not present in the body, the body tries to get back to the state it was in where there was no drug present.
What are the four receptor families?
Type 1 - ionotropic receptor
Type 2 - G-protein Coupled receptor
Type 3 - Tyrosine Kinase-linked receptor
Type 4 - Intracellular Steroid Type receptors
What are the features of the type 1 or ionotropic receptor family and give an example?
Ion channel-linked
Mediate very very fast responses
E.g. Nicotinic Acetylcholine receptor and GABA
Works in milliseconds
What are the features of the type 2 or G-protein coupled receptor family and give an example?
When the receptor is stimulated, it has to first link to a G protein before it can mediate response
Responses are much slower than ionotropic.
Example, beta-1 adrenoceptors in the heart
Works in seconds
What are the features of the type 3 or Tyrosine Kinase-linked receptor family and give an example?
Result in the phosphorylation of intracellular proteins
E.g. insulin receptor and growth factor receptors
Works in minutes
What are the features of the type 4 or Intracellular Steroid Type receptor family and give an example?
Regulates DNA transcription
Drug has to pass through cell membrane first and access the nucleus before it can have an effect
Works in hours
E.g. steroid and thyroid hormone receptors
What are the structurally defining features of Type 1 or ionotropic receptors?
- 4/5 subunits (forms a pore)
- Transmembrane sections (alpha helices)
- External binding domain which will stimulate and open the ion channel
What are the structurally defining features of Type 2 or G Protein coupled receptors?
- Metabotropic (g-protein linked)
- 1 subunit
- 7 transmembrane domains (7 alpha helices)
What are the structurally defining features of Type 3 or Tyrosine Kinase-linked receptors?
- Kinase linked
- Single protein
- 1 transmembrane domain
- Inside the cell there is an intracellular domain
- Agonist stimulates the receptor and activates the catalyst inside the cell and stimulates the kinase activity of the receptor leading to phosphorylation or proteins that leads to a response.
What are the structurally defining features of Type 4 or Intracellular Steroid Type receptors?
- Found in the nucleus
- DNA binding domain is called ZINC FINGERS
- When receptor gets stimulated the zinc fingers get uncovered leading to DNA binding and an increase in transcription.
