Cholinoceptor antagonists Flashcards
What is affinity in terms of receptors?
The strength with which an agonist binds to a receptor
What is efficacy in terms of receptors?
Once the drug has bound, the ability to transduce a response and activate intracellular signalling pathways
In terms of efficacy and affinity, what do agonists show?
High efficacy and affinity
In terms of efficacy and affinity what do antagonists show?
High affinity but no efficacy
What is the normal series of events when an agonist binds to a receptor?
It binds for mere milliseconds to produce a response and then unbinds and this is continuous until the drug is cleared by enzymes
What are the two groups of cholinoceptors?
Nicotinic- present at all autonomic ganglia
Muscarinic- present at effector organs of parasympathetic system and sweat gland innervated by sympathetic
What are the two ways that you can interfere with nicotinic receptors?
Blocking the receptor
Blocking the ion channel
Which drugs are clinically more useful than nicotinic receptor antagonists?
Ganglion blocking drugs- they block ion channel so block ions from moving through it
What are some clinical examples of ganglion blocking drugs?
Hexamethonium and trimetaphan
What does use-dependent block mean?
These drugs work most effectively when the ion channels are open so the more agonist present at the receptor, the more opportunity for the antagonist to block the channel and thus more useful and effective these drugs can be
Do these drugs completely block the ganglia?
No it is only an incomplete block- they don’t completely switch off function but slow it down and so reduce it considerably
Why are the effects of these drugs tissue specific?
It depends on which branch of the autonomic nervous system predominates in a particular tissue
Which tissues are sympathetically dominated?
Kidneys (increase renin secretion, sodium and water retention) and blood vessels (particularly vasoconstriction in the gut)
What will be the effect of administering a nicotinic cholinoceptor antagonist due to the sympathetically dominated tissues?
Hypotensive effect- sympathetically driven responses in the kidneys and blood vessels to increase blood pressure are reduced
What branch of the autonomic nervous system dominates the eye and how?
Parasympathetic- it acts to maintain a level of partial pupil constriction at rest. This allows them to dilate or constrict further when necessary.
What will be the effect of a ganglion blocking drug on the eye?
Pupil dilation
How is the parasympathetic the predominating control in the lungs?
In a similar way to the eyes, relating to smooth muscle control- bronchioles are always partially constricted under parasympathetic control so that further dilation or constriction can occur when required (Drugs cause bronchodilation)
Where else is the same effect of partial smooth muscle control also seen due to parasympathetic predominance?
Bladder, ureters and GI tract- can cause bladder dysfunction, loss of GI motility, tone and secretions
Why is hexamethonium historically important?
It was the first anti-hypertensive
Why was hexamethonium superseded?
It had very generalised action therefore a large side effect profile- loss of bladder control, pupil dilation and loss of GI motility
Why is trimetaphan not used often?
It is very potent- it is used during surgery when controlled hypotension is needed but is very short acting
What sort of antagonists are found widely in the world of toxins and venoms?
Receptor blockade antagonists
How does alpha-bungarotoxin (common krait snake venom) work?
Receptor blockade antagonist- targets skeletal muscle of the somatic nervous system causing paralysis of the skeletal muscle and diaphragm- suffocation and death
Why are muscarinic receptor antagonists more therapeutically useful?
They are more specific and only target parasympathetic effector organs and sweat glands
What are two common examples of muscarinic receptor antagonists?
Atropine and hyoscine
Why is atropine poisoning sometimes seen in children?
Atropine comes from deadly nightshade and children will be poisoned if they eat the berries
What are the basic effects of muscarinic receptor antagonists?
They will affect pupil constriction, bronchoconstriction, bladder function, salivary production, sweating, heart parasympathetic inflow and gut secretions
What is the PNS important for in the CNS?
Attention, memory and also certain sleep pathways
What are the effects of atropine and hyoscine in low doses on CNS?
Atropine- Restlessness
Hyoscine- Sedative
Tropicamide is a muscarinic receptor antagonist, what does it do?
It acts on receptors with the iris of the eye to cause pupil dilation. This is used in eye exams to examine the retina
Why can muscarinic receptor antagonists be used for anaesthetic premedication?
They will cause the airways to dilate and dry the throat a bit which will reduce risk of aspiration
What is hyoscine commonly used to treat in the form of patches?
Motion sickness
How does hyoscine treat motion sickness?
Muscarinic receptors are important in relaying information from the labyrinth of the inner ear to the vomiting centres- a lot of motion sickness is mediated by labyrinth of inner ear but antagonists reduce the flow of information thus reducing nausea
What common CNS disorder can muscarinic antagonists be used to treat?
Parkinson’s
How does Parkinson’s develop?
In the brain, nigrostrial dopamine neurones are important in fine control of movement- these neurones are lost in Parkinson’s and obvious signs start to show
How do muscarinic receptor antagonists help treat Parkinson’s?
Muscarinic receptors have a negative effect on dopamine signalling from these neurones by decreasing receptor interactions- in a healthy person this is a level of control but in someone with Parkinson’s they’ve lost 60-70% of the producing neurones so negative effect of muscarinic receptors is unwanted
What is ipratropium bromide used to treat?
Asthma and COPD (lung stuff)
What is the difference between ipratropium bromide and atropine?
A large quaternary amine structure- localises the response
How is ipratropium bromide administered?
As an aerosol
Why is ipratropium bromide positively charged?
So it can’t can’t get out of the lungs very well so it is localised
What is the effect of the ipratropium bromide?
It removes the effect of bronchoconstriction so helps in obstructive airways disease
What are the unwanted side effects of muscarinic receptor antagonists?
Hot as hell (decreased sweating interferes with thermoregulation)
Dry as a bone (Reduced secretions)
Blind as a bat (effects of accommodation ability of ciliary muscles)
Mad as a hatter (high dose effect CNS-agitation, restlessness, confusion)
Poisoning
What is considered the deadliest and most potent toxin in the world?
Botulinum toxin
Why is botulinum so toxic?
It interferes with exocytosis (ACh release from the nerve terminals)- it binds to the SNARE complex which would usually allow vesicles to fuse with the membrane and release ACh
What is botulinum commonly used clinically as?
Botox- injected into the face to remove wrinkles- it goes back to the effect of ACh on skeletal muscle as it locally paralyses skeletal muscle
