Drugs affecting neurotransmitters Flashcards
What is the action of BoTox (Botulinum toxin A)?
- modulates release of ACh by blocking vesicular exocytosis
- Tx: wrinkles, dystonia (e.g. blepharospasm/abnormal eye contraction), hyperhydrosis
How does BoTox function?
- taken up selectively into cholinergic fibres
- light chain acts as a protease to cleave SNARE proteins
- SNARE proteins on the outer synaptic vesicle interact with the neuronal membrane to trigger exocytosis
- tf blocks exocytosis of NT into the synaptic cleft
How is AChE modulated?
- AChE inhibitors
- false substrates that mimick ACh
- bind to AChE active site, blocking degradation of ACh
- tf ACh acts in synaptic cleft for longer
What are the differentiating properties of anticholinesterases?
- variable selectivity
- NMJ (somatic) versus parasympathetic junctions
- variable CNS access (many cannot permeate BBB)
- variable duration of action
- short, medium, irreversible
Edrophonium
- short acting AChE
- used in Dx of myasthenia gravis
Neostigmine/Pyridostigmine
- reverse effect of neuromuscular blockers
- used in Tx of myasthenia gravis
Donepezil
- enters CNS
- used in Tx of Alzheimer’s (one of the few)
What is myasthenia gravis?
- autoimmune disorder
- formation of Abs to own nicotinic receptors
- causes immune response and complement activation at NicRs and their site
- flattens architecture of the NMJ (normally cilia-like)
- cross-linking of 2 AChRs causing them to internalize on the postsynaptic membrane
- [rare] autoAbs prevent ACh binding to NicRs
How do anticholinesterases help in myasthenia gravis?
- blocks degradation of ACh so there is more in the synaptic cleft to activate the remaining ACh NicRs
- early stage compensation
- long-term lose more receptors and this method is ineffective
- plasmaphoresis to try to remove Ab or immunosuppressive drugs to target underlying cause
What is the Tensilon test?
- administration of edrophonium, short-acting AChE inhibitor to test myasthenia gravis as a cause of muscle weakness
- if edrophonium relieves weakness, MG is likely cause
What are Nm receptors?
- peripheral somatic nicotinic receptors
- cause contraction of skeletal muscle
What are Nn receptors?
- peripheral neuronal nicotinic receptors of the ANS ganglia
- stimulate both ANS branches
Nicotinic agonists are not typically used for
- peripheral disorders
- can be used for smoking cessation (e.g. patches)
What are the clinical uses of nicotinic receptor antagonists?
- presurgical skeletal muscle relaxants (Nm selective)
- e.g. non-depolarising forms tubocurarine/vecuronium
- ANS ganglion blockers (Nn selective) - rare and limited use
- e.g. hexamethonium
Agonist stimulation of ANS muscarinic receptors yields
-
SLUD:
- Salivation, Lacrimation, Urination, Defecation
- sweating
- bradycardia
- bronchoconstriction
- vasodilation (non-neural)
What is an example of the clinical use of ANS muscarinic receptor agonists?
Pilocarpine for glaucoma Tx; reduces intra-occular pressure
Antagonistic stimulation of ANS muscarinic receptors yields
dependent on level of PS tone
- reduced SLUD (Salivation, Lacrimation, Urination, Defecation)
- reduced sweating
- tachycardia - if fit, high PS dependence; if unfit, high SNS dependance tf no change
- bronchodilation
What are some clinical uses of muscarinic antagonists?
- Atropine
- reduce secretions triggered by anaesthesia (irritant) and produce bronchodilation pre-anaesthesia
- bradycardia if driven by increased PS tone (unfit)
- pupil dilation for retinal examination
- AChE-inhibitor poisoning
- Hyoscine
- motion sickness (CNS action)
- Ipratropium
- COPD (inhaled)
How can NA reuptake at the neuronal membrane be impeded?
- Cocaine and tricyclic antidepressents block mechanism (high-affinity uptake 1)
- can increase HR and BP
- this increases NA in the synaptic cleft and stimulation of receptors downstream
- effect is mediated by CNS
- similar mechanisms for uptake of dopamine and serotonin
How can metabolism of NA inside the neuron be impeded?
- in sympathetic neurons monoamine oxidase (MAO) normally degrades NA released and re-uptaken by neuron
- MAO inhibitors lead to increased NA leak and +NA in the synaptic cleft
- commonly used as anti-depressents in the past
What is the mechanism of indirectly actin sympathomimetics?
- taken up by the high-affinity Uptake 1 transporter on the sympathetic neuronal membrane similar to NA
- displace NA from synaptic vesicle storage
- NA degraded by MAO or
- released into cleft via transporter in reverse
- acting indirectly by displacing endogenous agonists, driving NA into the cleft
What are examples of indirectly acting sympathomimetics?
- amphetamine
- ephedrine (pseudoephedrine)
- tyramine
Ephedrine (pseudoephedrine)
- indirectly acting sympathomimetic
- used as nasal decongestant
- displaces NA in leaky, swollen nasal blood vessels
- NA stimulates alpha-adrenoceptors on BV to constrict, reducing leakiness and swelling
Tyramine
- indirectly acting sympathomimetic
- used as a dietary product (cheese, salami, vegemite)
- substrates for MAO
- abundant in GIT, tf little reaches systemic circulation
- if on MAO-inhibitors (depression), can cause unwanted cardio effects like tachycardia, hypertension
Why is use of isoprenaline limited in asthma?
- Isoprenaline causes bronchodilation via beta-2 aRs, but also tachycardia via beta-1 aRs
- tf selective beta-2 aR agonist salbutamol is better, causes only the bronchodilation
