Mechanisms of Drug Action Flashcards
State the four types of drug antagonism.
Receptor blockade
Physiological antagonism
Chemical antagonism
Pharmacokinetic antagonism
What is meant by ‘use dependency’ in terms of receptor blockade?
This refers to ion channel blockers
The more the tissue on which a drug is acting is being used (i.e. the more active they are), the more effective the blocker will be E.g. normal neurons fire at a relatively low rate so if you put local anaesthetic on them there’ll be fairly limited effects. Nociceptor neurons fire rapidly so their iron channels are open more often meaning that the local anaesthetic can get inside the iron channel and block it more easily.
What is physiological antagonism?
When two drugs act on different receptors in the same tissue and have opposite effects
E.g. noradrenaline will bind to alpha-1 receptors and cause vasoconstriction, histamine will bind to histamine receptors and cause vasodilation
What is chemical antagonism? Eg of drug
Interactions of drugs in solution
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 one 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
- Eg barbituates increase conc of microsomal enzymes, so wouldnt co-administer with a drug broken down by microsomal enzymes
Define drug tolerance.
Gradual decrease in responsiveness to a drug due to repeated administration of the drug
What are the five main mechanisms of drug tolerance?
Loss of receptors Change in receptors Pharmacokinetic factors Physiological adaptation Exhaustion of mediator stores
Describe each of these mechanisms of drug tolerance briefly.
Loss of receptors – overstimulation can lead to endocytosis of receptors so there are fewer receptors available on the cell membrane
Change in receptors – conformational change in the receptors so that they are desensitized, so a proportion of the receptors are no longer effective
Pharmacokinetic factors – metabolism of the drug is increased after repeated use (e.g. alcohol)
Physiological adaptation – sort of like a homeostatic response to maintain a stable internal environment
Exhaustion of mediator stores – this happens with amphetamines –they get into the central noradrenaline synthesis system and replaces noradrenaline in the vesicles so you get a big increase in the production of noradrenaline
What are the four receptor families? Describe how their transmission varies.
Type 1 – ionotropic
Type 2 – metabotropic (G protein coupled)
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 examples
Consists of 4 or 5 subunits with transmembrane alpha helices.
- GABA (inhib, cl- channel) and Nicotinic Ach (excitatory)
- milliseconds mediate rapid responses
- external binding domain
Describe the structure of type 2 receptors.
- GPCR
- Consists of 1 subunit but with 7 transmembrane domains
- Seconds (slower than T1 as need to link protiens)
- eg B1 adrenoceptors in heart
Describe the structure of type 3 receptors.
Tyrosine kinase linked
Single protein with 1 transmembrane domain
Inside the cell there is an intracellular domain
When the agonist stimulates the receptor it activates the catalyst, this catalyst activates kinase activity and causes phosphorylation of intracellular protein and response
- minutes
- eg insulin rec and GH rec
Describe the structure of type 4 receptors. And desc/examples
These are steroid receptors that are found in the nucleus
- respond to steroid or thyroid hormones
- slow acting (hours)
- responsible for regulating dna transcription
- have zinc fingers that are dna binding domain
- when receptor is stimulated zinc fingers are uncovered and allows for transcription of DNA
What is another name for the DNA binding domain of the steroid-receptor complex?
Zinc fingers
How do local anaesthetics work?
Receptor blockade antagonism. Nociceptors fire rapidly so use dependancy is high and therefore ion channel blocking LA is very effective. They have selective action as more likely to be taken up by nociceptor neurones as they’re firing more/channels opening more. Therefore act on pain conducting fibres more than other fibres.
