2. Mechanisms of Drug Action Flashcards
What are the 4 types of drug antagonism?
- Receptor blockade
- Physiological antagonism
- Chemical antagonism
- Pharmacokinetic antagonism
What is a receptor blockade?
Simply an antagonist binding to a receptor and preventing the binding of an agonist
What is ‘Use Dependency’ and how does this relate to anaesthetic selectivity?
• Refers to ion channel blockers
• Blocker is more effective on more active tissues
• e.g. anaesthetic blocks normal neurones less than nociceptors which fire more rapidly
- due to ion channels being open more often in nociceptors
- anaesthetic can bind inside the channel more easily
What is physiological antagonism?
- Describes the behaviour of a substances that produces opposite effects of another substance
- Does not involve binding to the same receptor
- e.g. NA causes vasoconstriction but histamine causes vasodilation, acting on different receptors
What is chemical antagonism?
- Drug reduces the concentration of an agonist by forming a chemical complex
- e.g. dimercaprol is a chelating agent - forms heavy metal complexes which are more rapidly excreted by kidneys (for lead poisoning)
What is pharmacokinetic antagonism?
• When one drug reduces the concentration of the other drug at the site of its action, by:
- reducing absorption
- increasing metabolism
- increasing excretion
Why do we need to be aware of pharmacokinetic antagonism?
- Avoid administration of interfering drugs
- e.g. repeated administration of barbiturates increases the production of microsomal enzymes - if another drug is metabolised by the same enzymes, it will be metabolised more quickly and its effect will be reduced
What is drug tolerance?
Gradual decrease in the responsiveness to a drug with repeated administration e.g. benzodiazepines
What are 5 causes of drug tolerance?
- Pharmacokinetic factors
- Loss of receptors
- Change in receptors
- Exhaustion of mediator stores
- Physiological adaptation
What does drug tolerance by pharmacokinetic factors mean?
- Metabolism of drug when given repeatedly over a period of time
- e.g. alcohol and barbiturates
Why do drugs cause a loss of receptors?
- Repeated stimulation by an agonist causes removal (membrane endocytosis) of receptors
- Fewer receptors on surface
- Called receptor downregulation
- e.g. beta adrenoceptors are susceptible
How do drugs cause a change in receptors?
- Continued stimulation over a long period of time
- Conformational change
- Desensitisation
- Proportion of the receptors are no longer effective
What does drug tolerance by ‘exhaustion of mediator stores’ mean?
- Happens with amphetamines - CNS stimulant
- Crosses blood-brain barrier and acts of noradrenergic neurones in the brain
- Binds to uptake protein 1 and is taken into central NA synthesis system
- Replaces NA in vesicles - big increase in production of NA => NA exhausted
Why does a second dose of amphetamine have a different effect than the first?
- NA stores exhausted after first dose
* Less severe response after second dose
What is a physiological adaptation, with reference to drug tolerance?
- Like a homeostatic response
* Body attempts to maintain a stable internal environment
What are the 4 receptor families?
- Type 1 - Ionotropic receptor
- Type 2 - G-protein Coupled (metabotropic) receptor
- Type 3 - Tyrosine Kinase-linked receptor
- Type 4 - Intratracellular Steroid type receptors
Summarise the Type 1 receptors
(Ionotropic)
• Ion channel linked
• Mediate very fast responses (milliseconds)
• e.g. GABA and Nicotinic ACh receptors
- 4 or 5 subunits
- Has transmembrane sections (alpha helices)
- External binding domain stimulates and opens the ion channel
Summarise the Type 2 receptors
- Type 2 has to first link to a G protein before mediating a response
- Much slower response (seconds)
- e.g. beta-1 adrenoceptors in the heart
- 1 subunit
- 7 transmembrane domains (7 alpha helices)
Summarise the Type 3 receptors
(Tyrosine Kinase-linked)
• Phosphorylation of intracellular proteins
• e.g. insulin receptors and growth factor receptors
• acts in minutes
- Single protein
- 1 transmembrane domain
- Intracellular domain in cell
- Agonist stimulates the receptor => activates the catalyst inside the cell (stimulates kinase activity) => phosphorylation of proteins => response
Summarise the Type 4 receptors
(Intracellular Steroid Type)
• Activated by steroids and thyroid hormones
• Regulates DNA transcription
• Drug has to pass through cell membrane and access the nucleus first
• acts in hours
- DNA binding domain is called ‘zinc fingers’
- receptor stimulation => zinc fingers uncovered => DNA binding => increased transcription
What form of antagonism is utilised by anti-venom (harvested antibodies)?
Chemical antagonism
