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| Question | Answer |
| Subdivisions of the nervous system | |
| Pre- and post- junctional events at a cholinergic synapse summary | 1. Synthesis 2. Storage 3. Release 4. Receptor stimulation 5. Inactivation |
| 1. Synthesis and 2. storage of Ach | 1. Synthesis: Acetate + choline= acetylcholine (therough the enzyme CAT; cholineacetyltransferase). 2. Storage: acetylcholine taken up into the vesicles via a carrier mediated process, ready for exocytosis. |
| Drugs that effect synthesis and storage of Ach | 1. Synthesis: hemicholinium- toxin with no clinical use (but experimentally useful) that inhibits choline uptake mechanism. Very selective for this mechanism. 2. Storage: vesamicol- inhibits carrier processes that involve Ach being packaged into vesicles (again, more experimental uses) Botulinium toxin- selectively inhibits release of Ach from cholinergic nerves. Can be used to treat blepherospasm- spasms of the face. |
| 3. Release of Ach and 4. Ach/receptor interaction | 3. Release from vesicles by exocytosis 4. Synapses of the ANS have no post-junctional specialisation. Ach-sensitive receptors are: - Muscarinic; if it prefers and activates m receptors - Nicotinic; if it has higher affinity to and is an agonist at the NAchR - Presynaptic receptors can modulate neurotransmitter release. |
| Structure-activity relationships | the structure of neurotransmitters affect their specificity and activity |
| Muscarinic receptors | - muscarinic receptors are g-protein coupled receptors; Gq linked - Effects of muscarinic agonists inc: Cardiovascular effects, effects on smooth muscle, sweating etc, effects on the eye. |
| Clinical uses of muscarinic agonists | - Pilocarpine- eyedrops to treat glaucoma, half life longer than that of Ach - Bethanechol- stimulates gut motility and bladder emptying |
| Antagonists that block Ach receptors: clinical uses | Atropine- taken from deadly nightshade, non-selective muscarinic antagonist that blocks secretions and causes mild tachycardia, dilates pupils. Treats urinary problems. Hyoscrine- passes blood brain barrier, blocks mucous secretions. effective antimotion sickness drug. Tolterdine- antimuscarinic used to treat urinary incontinence |
| Side effects of muscarinic antagonists | -Blurred vision -Dry mouth -Reduced bronchodilation -Constipation -Palpitations/arrythmias |
| Nicotine receptors | - Pentameric ligand-gated ion channels; 5 subunits making up a non-selective ion channel - 2 Ach molecules bind to 2 alpha-subunits, depolarising the postsynaptic cell bodies, resulting in excitory neurotransmission. - (different NachRs) At the neuromuscular junction they depolarise the motor end plate, triggering muscle contraction if threshold is reached. - The 2 different types of NAchrs are structurally and pharmacologically different, revealled by antagonists. |
| Nicotinic agonists and antagonists | Agonists: Nicotine Labeline. Neither have therapeutic use but have important CNS effects. Antagonists: On receptors in ganglia: Hexamethonium and tripnephan In the neuromuscular junction: Tubocurarine, pancuronium, atracurium |
| 5. Inactivation (of released Ach) | - Cholinestherases: anticholinesterase is tethered to basement membrane at the NMJ/neuronal membranes at synapse. - BchE and AchE exist in soluble forms - Bothe AchE and BchE are serine hydrolases that catalyse Ach to form choline and acetate - The active site of AchE has 2 regions: -esteratic site -Anionic site - AchE activity is very high |
| Anticholinestherases; block AchE activity by different mechanisms | Different mechanisms: Short acting- lasts minutes. Eg edrophonium, binds reversibly & breifly to anionic site Medium acting- lasts hours EG neostigmine/pyridostigmine, binds to the carbymylate esteric site of Ach, slowing activity and leading to longer lasting chE inhibition. Irreversible; organophosphates eg dyflos, parathion. Phosphorylates esteratic site, new enzyme has to be synthesised to overcome. |
| Therapeutic uses of anticholinestherases | Edrophonium- can be used as a test for myasthenia gravis (autoimmune condition that leads to muscle weakness). Neostigmine/pyridostigmine- medium duration treatments for myasthenia gravis Ecothiopate- glaucoma; contracts atiary muscles to increase outflow of aqueous fluid, reducing intra-ocular pressure. |
| Side effects of anticholinestherases that act at the ganglia in the ANS | - Increased parasympathetic activity eg bradycardia, hypertension. - |
| Side effects of anticholinestherases at the neuromuscular junction | - Prolongue end plate potentials and restore Ach transmission in the presence of competitive NachR antagonist |
| Side effects of anticholinestherases at the CNS | - Can pass the blood brain barrier which causes initial excitation, then depression, which leads to respiratory failure. |
| Side effects of the anticholinestherases organophosphates | - posioning: bradycardia or hypotension ORGANOPHOSPHATE ANTAGONIST- Pralidoxime: - can reactivate phosphorylated BchE (butyrylcholinestherase) |
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