Mechanisms of Drug Action Flashcards
State the 4 types of drug antagonism.
Receptor blockade
Physiological antagonism
Chemical antagonism
Pharmacokinetic antagonism
What is meant by ‘use dependency’ in terms of receptor blockade?
The more the tissue on which a drug is acting is being used (more active), the more effective the channel blocker will be.
What is physiological antagonism?
When 2 drugs act on different receptors in the same tissue and have opposite effects
E.g. NA will bind to alpha-1 receptors and cause vasoconstriction, histamine will bind to histamine receptors and cause vasodilation
What is chemical antagonism?
Interactions of drugs in solution. 1 negates the action of another
E.g. dimercaprol is a chelating agent that forms heavy metal complexes that are more easily excreted by the kidneys
What is pharmacokinetic antagonism?
When 1 drug reduces the concentration of another drug at the site of its action
A drug may reduce the absorption, increase the metabolism or increase the excretion of the other drug
Define drug tolerance.
Gradual decrease in responsiveness to a drug due to repeated administration of the drug
What are the 5 main mechanisms of drug tolerance?
Loss of receptors Change in receptors Pharmacokinetic factors Physiological adaptation Exhaustion of mediator stores
Describe how exhaustion of mediator stores leads to drug tolerance
Occurs with amphetamines –they locate central NA neurones and bind to uptake transporters. Bind to vesicles, causing release of NA, increase NA in synaptic transmission.
Response diminishes with time as endogenous stores run out
What are the 4 receptor families? Describe how their transmission varies.
Type 1 – ion channel linked receptors Type 2 – G protein coupled receptors Type 3 – tyrosine kinase linked Type 4 – intracellular steroid type They increase in transmission time from 1-4
Describe the structure of type 1 receptors and give an example
Consists of 4 or 5 subunits, each with transmembrane alpha helices
e.g. nAChR, GABA A
Describe the structure of type 2 receptors and give an example
Consists of 1 subunit with 7 transmembrane domains.
e.g. B1 adrenoceptors (heart)
Describe the structure of type 3 receptors and give an example
Single protein with 1 transmembrane domain
Inside the cell there is an intracellular domain
When the agonist stimulates the receptor it activates the catalyst
e.g. insulin, growth factors
Describe the structure of type 4 receptors and give an example
Steroid receptors that are found in the nucleus, change DNA transcription
e.g. steroids, thyroid hormones
What is another name for the DNA binding domain of the steroid-receptor complex?
Zinc fingers
How can we take advantage of use dependency?
Normal neurons fire at a quite low rate so LA’s have fairly limited effects.
Nociceptor neurons fire rapidly so their channels are open more, thus the LA can get inside the ion channel and block it more easily.
Give an example of a drug that works by pharmacokinetic antagonism. How do these become an issue if given long term?
Barbiturates.
They are enzyme inducers- liver enzymes that metabolise barbiturates become upregulated, becomes an issue if we need to give them another drug that is metabolised by the same set of enzymes- need to increase dose
Describe how loss of receptors leads to drug tolerance
Overstimulation can lead to endocytosis of receptors so there are fewer receptors available on the cell membrane
Describe how change in receptors leads to drug tolerance
Conformational change in the receptors, they become desensitized, so a proportion of the receptors are no longer stimulated by the agonist
Describe how pharmacokinetic factors lead to drug tolerance
Metabolism of the drug is increased after repeated use (e.g. alcohol, barbiturates)
Describe how physiological adaptation leads to drug tolerance
Homeostatic responses to maintain a stable internal environment e.g. Antihypertensives reduce BP, homeostatic response slightly increases BP
How can physiological adaptation causing drug tolerance be beneficial?
Contributes to tolerance of drug side effects
