Pharm 2 - Mechanisms of Drug Action Flashcards
What are the 4 types of Drug antagonism?
- Receptor blockade
- Physiological antagonism
- Chemical antagonism
- Pharmacokinetic antagonism
Explain how receptor blockade works
Antagonist binds to the receptor and prevents agonist from binding
Receptor blockade involves “use dependency”. What is this
Receptor blockade is more effective against more active tissues. This applies to ion channel blockers
What form of drug antagonism does local anaesthetic use?
Receptor blockade (nociceptor neurones fire at a faster rate than normal neurones)
How does local anaesthetic work?
Binds on the inside of ion channels after they open
Explain how physiological antagonism works
When 2 drugs act on different receptors to bring about opposing effects on the same tissue
e.g. NA acts on vasculature and causes vasoconstriction. If histamine is coadminstered, it acts on different receptors and causes vasodilation. Net effect = antagonistic effects on BP
Explain how chemical antagonism works.
When drugs interact in solution.
e.g. giving dimercaprol (chelating agent) - this forms heavy metal complexes, which are rapidly excreted by the kidney. Very useful for things like lead poisoning
Describe how pharmacokinetic antagonism works
When one drug decreases the concentration of another drug at its site of action.
i.e. drug A decreases absorption / increases metabolism / increases excretion of drug B
What must you be careful of with pharmacokinetic antagonism?
Not to administer a drug that interferes with another drug
e.g. barbiturates increase the concentration of microsomal enzymes –> must ensure that the administered drug isn’t metabolised by microsomal enzymes
Define drug tolerance
Gradual decrease in responsiveness to a drug with repeated administration
Give 5 causes of drug tolerance
- Pharmacokinetic factors
- Loss of receptors
- Change in receptors
- Exhaustion of mediator stores
- Physiological adaptation
Explain how pharmacokinetic factors can cause drug tolerance
Drug metabolism increases over repeated administration
Give examples of drugs that induce tolerance due to pharmacokinetic factors
Alcohol and barbiturates
Explain how loss of receptors can cause drug tolerance
Receptor downregulation occurs.
Repeated stimulation by agonist –> cell endocytoses receptors —> cell loses receptors
Give an example of a type of receptor susceptible to receptor downregulation
B-adrenoreceptors
How can a change in the receptors induce drug tolerance
Receptor desensitisation occurs due to a conformational change in receptors - renders a proportion of receptors ineffective.
Occurs when there is continued stimulation of receptors
Give an example of a receptor that can change due to repeated stimulation
NAChR at NMJ
Explain how exhaustion of mediator stores can cause drug tolerance
e.g. amphetamines –> taken up into brain, and acts on noradrenergic neurones in the brain.
Amphetamines taken up into presynaptic terminals via uptake 1, causes NA efflux from vesicles into cytoplasm and then into synaptic cleft. Lots of NA in synaptic cleft which causes the euphoria. Second dose of amphetamines shortly after first dose won’t work because NA stores exhausted, no more NA is present in the presynaptic nerve terminals to be released.
Describe how physiological adaptation can cause drug tolerance
Physiological adaptation is a homeostatic-esque response, whereby the body is trying to maintain a stable internal environment
Name the 4 receptor type families
- Ionotropic receptor
- G-protein coupled
- Tyrosine-Kinase ined receptor
- Intracellular steroid type receptor
Rank the receptors in terms of how fast they are
- Ionotropic receptor (ms)
- G protein coupled receptor (seconds)
- Tyrosine-kinase linked receptor (minutes)
- Intracellular steroid type receptor (hours)
Give an example of a type 1 receptor (ionotropic receptor)
NAChR or GABA
Give an example of a type 2 receptor (G protein coupled)
MAChR / B-1 receptors in the heart
Give an example of a tyrosine kinase linked receptor
Insulin receptors & GF receptors
Through what mechanism do tyrosine-kinase linked receptors work?
Via intracellular protein phosphorylation
How are intracellular steroid type receptors activated?
Via steroids and thyroid hormones - used in DNA transcription
Why do intracellular steroid type receptors take the longest time to work?
The drug must pass the cell membrane and enter the nucleus
How many subunits does the ionotropic receptor have?
4/5 subunits - consisting of transmembrane sections that have an external binding domain
How many subunits does the G protein coupled receptor have?
1 subunit
7 TM domains (alpha helices)
How many TM domains does the tyrosine kinase linked receptor have?
1
How is protein phosphorylation achieved in tyrosine kinase linked receptors?
The tyrosine kinase linked receptor has an intracellular catalytic domain which is activated when the agonist stimulates the receptor
Which type receptor has DNA binding domain of “zinc fingers”
Intracellular steroid receptor
What do the Zn fingers do?
When the intracellular steroid receptor is stimulated, the Zn fingers are uncovered which enables DNA binding and transcription
