7. Cholinoceptor Antagonists Flashcards
What is the difference between affinity and efficacy?
Affinity • ability to bind to receptor • rapid and reversible • agonists and antagonists • not antagonists blocking a channel pore
Efficacy
• ability to stimulate an effect
• only agonists
Where can nicotinic ACh receptors be found?
All autonomic ganglia
What are nicotinic receptor antagonists also known as?
Ganglion-blocking drugs
What are the 2 actions of nicotinic receptor antagonists?
- Block the nicotinic receptor (ion-channel linked receptor)
* Block the channel itself
What is Hexamethonium?
- Nicotinic-receptor antagonist
- Blocks both the receptor and channel pore
- Anti-hypertensive
- Vasodilation - blocked sympathetic tone in vessels
- Decreased renin - less aldosterone released
Which nicotinic antagonists is used clinically?
- Trimetaphan
- IV during surgery to induce hypotension
- Reduces chance of blood loss
- Short acting
- Selective - only blocks the receptor
What does use-dependent block describe?
- Degree of block is proportional to opposing stimulation
- Any drug that blocks an ion channel tends to present with this
- More agonist => more open channel => more effective block (as it’s more accessible to the antagonist)
- However, it is nearly always incomplete - can never get complete block
How can you overcome antagonisms of a nicotinic receptor (not channel)?
- Add more ACh
* Competitive
Do ganglion-blocking drugs produce sympathetic or parasympathetic effects at rest?
• Sympathetic
- parasympathetic is dominant at rest, and this is blocked
What are the side effects of ganglion-blocking drugs?
- Pupil constriction interference (dilation)
- Bladder dysfunction
- Decreased GI tone
- Decreased saliva production
- Impaired sweating capacity
- Decreased exocrine secretions
What poison comes from the krait snake and how does it act?
- Alpha-bungarotoxin
- Most potent toxin at the nicotinic receptor
- Irreversible (covalent forces)
- Targets both the autonomic and somatic (skeletal) nervous system receptors
- Paralysis
How are muscarinic receptor antagonist different to the nicotinic receptor antagonists?
- More selective
- Only influence (block) parasympathetic function
- Muscarinic receptors only found at end of parasympathetic nerves (end sympathetic innervating sweat glands)
What are the effects of 2 muscarinic receptor antagonists (normal + toxic dose)?
Atropine
• Normal dose: little effect
• Toxic dose: mild restlessness
• Less M1 selective
Hyoscine
• Normal dose: sedative, amnesia
• Toxic dose: CNS depression or paradoxical CNS excitation
• Greater permeation into CNS due to lipid solubility
What happens if you add a muscarinic receptor antagonist into the eye (and which one is used)?
- Tropicamide is an opthalmic drug
- Causes pupil dilation
- Parasympathetic usually constricts the pupil and this is blocked
How can muscarinic receptor antagonists be used in surgery?
- Anaesthetic premedication
- Reverses constriction in lungs => bronchodilation => assists inhalation of anaesthetic for surgery
- Dries up salivary secretions - reduced risk of aspiration
- Counteracts slowing effects (e.g. HR) by anaesthetic
- Hyoscine is sedative - calms patient
What causes motion sickness and how do muscarinic antagonists affect this?
- Sensory mismatch between visual system and labyrinth (balance + posture)
- Make activate vomiting centre if it doesn’t match - cholinergic
- Hyoscine can prevent the cholinergic system from activating the vomiting centre
How can muscarinic receptor antagonists be used in Parkinson’s disease?
- Dopaminergic neurones originate from the substantia nigra and project down to the striatum
- Modulation of fine control of movement
- Dopamine is released in the striatum and binds to D1 receptors on striatal neurones
- Muscarinic receptors (M4) impair D1 receptor function
- Parkinson’s - loss of dopaminergic neurones, reduced D1 activation
- M4 not down-regulated
- Muscarinic antagonists block this inhibitory effect
How can muscarinic receptor antagonists be used in respiratory diseases?
• Parasympathetic constricts the airways
• Local administration of MRAs can act as bronchodilators
• Ipratropium bromide is a derivative of atropine
- positive charge, can’t enter systemic circulation
How can muscarinic receptor antagonists be used in GI diseases?
- In IBS, parasympathetic NS activates gut motility and secretions
- Symptoms are due to hyperactive gut - diarrhoea
- MRAs slow down the gut and decrease motility and secretions
- M3 receptor antagonists used
What are the unwanted side effects of muscarinic receptor antagonists?
- Inability to sweat - impaired thermoregulation
- Decreased salivary/exocrine secretions
- Cycloplegia - decreased ability to adjust visual focus
- CNS disturbance
Where is atropine mainly seen and how is it treated?
- Children who accidentally eat atropa belladonna berries
- Bethanechol (agonist) or physostigmine for treatment
- Physostigmine blocks acetylcholinesterase - increasing ACh in synapse
- More abundant drug will produce the greater effect if competing
How does Botulinum toxin work?
- Diffuses into parasympathetic nerves
- Prevents ACh vesicles from fusing with membrane - blocks SNARE complex proteins
- ACh exocytosis prevented
How can botox be used clincally?
- Paralyse skeletal muscle in diluted, less potent form to remove wrinkles locally
- Injection into sweat and salivary glands to control secretions
