Lecture 8 part 2 Flashcards
Recap - basic steps in neurotransmission
What are the most common site of drug action?
Roughly what proportion of the synapsis in ANS are cholinergic?
3/4
Therefore, if we interfer with cholinergic function, we can cause a very large, widespread effect
How is ACh synthesised? How is ACh degraded?
Acetylcholine synthesis:
acetyl CoA + choline -> acetylcholine + coenzyme A
(enzyme - choline acetyltransferase CAT)
Acetylcholine degradation:
acetylcholine -> acetate + choline
(enzyme - (acetyl)cholinesterase AChE)
Cholinergic transmission -
How can cholinergic transmission be intervened therapeutically? Give an example of a drug that does this.
- nAChR: Blocking nAChR’s at autonomic ganglia, e.g.: trimethaphan used in hypertensive emergencies (nAChR at autonomic ganglia and at the neuromuscular junction differ in structure, therefore can make drugs more selective)
- Blocking ACh breakdown via AChE inhibitors, e.g.: pyridostigmine in myasthenia gravis
- mAChr: At present, there are few sub-type selective mAChR agonists or antagonists (some are now being developed)
Why is it important that we use selective mAChR agonists rather than non-selective?
As non-selective agonists will have significant side effects on various body systems, e.g. for mAChR:
- Heart: Decreased HR and decreased cardiac output
- Smooth muscle: Increased bronchoconstriction
- Glands: Increased sweating + increased salivation
What is “Sludge” syndrome? When does it occur? What is it treated with?
- The pneumonic for pathological effective due to prolonged over-stimulation of mAChR’s innervated by the parasympathetic NS.
- Occurs in drug overdose, ingestion of magic mushrooms, exposure to insecticides and nerve agents (latter two - these bind irreversibily with acetylcholinesterase, to irreversibly deactivate the enzyme and raise ACh levels)
- Treated with anti-cholinergic agents such as atropine or pralidoxime.
- Salivation,
- Lacrimation,
- Urination,
- Defecation,
- GI upset,
- Emesis
Sympathetic neuroeffector junction
- Depolarisation of the axon
- Invades each varicosity causing their depolarisation
- This causes a localised release of neurotransmitter
The vast majority of postganglionic sympathetic neurons are (nor)adrenergic – that is, they utilize noradrenaline as the chemical transmitter.
Post-ganglionic sympathetic neurons possess a highly branching axonal network with numerous varicosities, each of which is a specialized site for Ca2+ -dependent vesicular noradrenaline release.
Noradrenergic varicosity
- Depolarisation across the varicosity
2, Activates voltage gated Ca2+ channels - This influx of Ca2+ is sufficient to cause the fusion of the vesicle with the outer membrane
4, Noradrenaline is released. It then has the capacity to interact with the different receptors in the system. The receptors may be on the effector or the varicosities itself - Lifetime of NA outside of the varicosity is very limited because their is a high affinity NA reuptake mechanism returning NA into the varicosity. This NA is largely repackaged and reused but there is also some metabolism of NA
- There is some metabolism going on, so there is a requirement for NA synthesis
How is noradrenaline synthesised and adrenaline synthesised?
In the cytoplasm:
- Tyrosine (diet)
–> Tyrosine to DOPA via tyrosine hydroxylase
–> DOPA to dopamine via decarboxylase
–> Dopamine packaged into vesicle
In the vesicle:
–> Dopamine to noradrenaline via dopamine β-hydroxylase
Noradrenaline -> adrenaline
Within the adrenal medulla noradrenaline is converted to adrenaline by the enzyme phenylethanolamine N-methyltransferase, chromaffin cells release the adrenaline. This is why adrenaline (rather than nor-adrenaline builds up)
NA (noradrenaline) transmission across the synapse?
- NA released by Ca2+-dependent exocytosis
- NA diffuses across the synaptic cleft and interacts with adrenoceptors in the post-synaptic membrane to initiate signalling in the effector tissue
- NA interacts with pre-synaptic adrenoceptors to regulate processes within the nerve terminal – e.g. NA release
- NA has only a very limited time in which to influence preand post-synaptic adrenoceptors as it rapidly removed from the synaptic cleft by noradrenaline transporter proteins
How is NA transmission terminated?
Termination:
Uptake 1) By re-uptake into pre-synaptic terminal by Na+ dependent transporter (NET).
Uptake 2) Not all re-uptaken so required further re-uptake by a lower affinity, non neuronal mechanism
Metabolism:
2) Within pre-synaptic terminal, the NA not taken up into vesicles is susceptible to metabolism by two enzymes:
- monoamine oxidase (MAO)
- catechol-O-methyltransferase (COMT)
Name a couple adrenoreceptor agonist and antagonists used clinically.
β2 -adrenoceptor-selective agonists: Salbutamol, causes bronchodilation to improve asthma symptoms (β2-adrenoceptor-selectivity is important as it limits possible cardiovascular side-effects, e.g. positive iontrophic and chronotropic actions)
α1 -adrenoceptor-selective antagonists: e.g. doxazosin (used to treat a number of cardiovascular disorders, including hypertension)
β1 -adrenoceptor-selective antagonists: e.g. atenolol (used to treat a number of cardiovascular disorders, including hypertension)
Graph showing non-selective β-agonist and a selective β-agonist
Non-slelective β agonist: (acts on both β1 and β2 adrenoreceptors) Using a non-selective β-agonist agent, we can see that as a dose reponse occurs, it is paralleled with a change in the cardiovascular index. This shows that a non-selective agent doesn’t seperate respiratory with cardiovascular (this puts a cardiovascular strain on the patient for a respiratory benefit).
Selective β agonist: In contrast, if we use a selective β2-agonist, get the respiratory effect but see much less of the cardiovascular effect.
Working out if it is an adrenoreceptor or muscarinic receptor
- What is actually happening e.g. slowing heart rate
- Is this fight or flight? If yes, it is sympatehtic response, if no, it is a parasympathetic response
- Parasympathetic: muscarinic receptors
- Sympathetic: Adrenoreceptors
