LS2- Peripheral Neural Transmission Flashcards
Hemicholinium
Choline Co-Transporter Blocker. Prevents ACh synthesis by blocking the Na+ dependent choline co-transporter (SLC5A7).
Tetanus Toxin
Binds to synaptobrevin (V-SNARE), preventing vesicular NT release. Doesn’t act directly on the motor neuron, instead is retrogradely transported to the cell body, then transfers to inhibitory interneuron, which is unable to release NT and inhibit the motor neuron, which becomes more excitable as a result. Results in characteristic tetanus posture
Triethylcholine.
Competitive substrate that is acetylated to acetyltriethylcholone and released in place of ACh.
Vesamicol
Non Competitive Reversible ACh transporter blocker. Prevents newly synthesized ACh being loaded into storage vesicles by blocking vesicular ACh Transporter (VAChT)
Botulinum
Blocks ACh release. Exotoxin that enzymatically cleaves proteins required for ACh vesicle docking.
Beta-Bungarotoxin
Blocks ACh release. Has 2 functional chains that are linked by a S-S bond. 1 chain acts through phospholipase A2 activity, which is localised to the membrane through the K+ channel binding moiety found in the other chain. ? Apparently decreases release in the short term but then increases it long term?
Alpha-Latrotoxin
Causes massive ACh release. Tetramers form a Ca2+ permeable membrane pore. Also targets neurexins, latrophilin receptors (GPCRs) and other transmembrane proteins. Inhibits K+ channels and may lead to repiratory failure.
Alpha-Bungarotoxin
Irreversible NAChR blocker at the nmj. Does not affect (α3)2(β4)3 type (ganglionic) or (α4)2(β2)3 type (brain). It will block (α1)2β1δε type at the nmj and (α7)5 type also in the brain.
Trimetaphan
Competitive Anatagonist for ganglionic NAChRs, the (α3)2(β4)3 type. It is not active at the nmj, selective for the ganglionic isotope only.
Nicotine
NAChR agonist with a higher potency at the ganglion than the nmj. When “painted” on, causes stimulation then block of the ganglion (depolarising block with two phases)
Mecamylamine
Non-competitive NAChR antagonist- acts through channel blocking.
Hexamethonium
Use-dependent NAChR channel pore blocker: non-competitive antagonist. First drug to be used clinically for hypertension, but complicated effects due to action on ANS- the hexamethonium man.Changing chain length affects selectivity between ganglion and nmj, 6C methylene chain is the optimum length for ganglionic block.
D-Tubocurarine
Competitive antagonist of NAChR, causing a non-depolarising block. Relatively non-selective between the nmj and the ganglion at clinical doses, however 70-80% occupancy must be achieved to result in transmission failure.
Pancuronium
Competitive antagonist of the NAChR at the nmj. As a quaternary ammonium compound it is not orally active. It blocks the EPP in response to nerve stimulation and directly application of ACh externally.it is used for longer operations as it is not easily hydrolysed, so has a sustained effect.
Atracurium
Competitive antagonist of the NAChR at the nmj. As a quaternary ammonium compound it is not orally active. It blocks the EPP in response to nerve stimulation and directly application of ACh externally. It is an ester that is broken down by spontaneous hydrolysis so it has a short lives effect in most patients.
Decamethonium and Suxamethonium
Depolarising neuromuscular blocking agent, selective for NAChRs at the nmj. They block transmission by causing a prolonged depolarization. During phase 1, their effects are potentiated by anti-ChEs and countered by non-depolarising blockers. In phase 2, anti-ChEs reverse the blockade. Suxamethonium is in clinical use do very short procedures (e.g. Intubation) as normally it is rapidly broken down NB- in 0.1-0.2% of the population they have a deficiency in enzyme activity which can prolong its action.
ACh and Carbachol
Non-selective agonists of the AChR, acting on both nicotinic and muscarinic types
Muscarine
Selective MAChR agonist
Methacholine
Non-selective AChR agonist that has two isomers. Neither can be broken down by BuChE but (+) Methacholine can bee hydrolysed by AChE and is 200x more potent than the (-) isomer at the MAChR.
Bethanechol
Non-selective muscarinic AChR agonist, poorly absorbed from the GI tract and it’s polar nature means it is rapidly excreted from the kidneys, so of limited clinical use. Used systematically to treat bladder dysfunction.
Pilocarpine
Also a non-selective MAChR that is poorly absorbed from the GI Tract. Used in the treatment of glaucoma- ciliary muscle contraction produces traction in trabecular meshwork that facilitates the drainage of aqueous humour.
Cevimeline
M3 selective agonist that can increase salivation and lacrimal ion in conditions such as Sjögren’s syndrome- an autoimmune disease of fluid secreting glands.
Atropine
Non-selective MAChR antagonist used to produce pupillary dilation- however long duration of action makes adrenoreceptor agonists more suitable
Benzilylcholine Mustard
Non-selective irreversible MAChR antagonist.
Pirenzipine
Selective M1 antagonist, acting on receptors of intramural nerves in local ganglia rather than the oxytocin cells themselves. Used as an antosecretory agent in the treatment of gastroduodenal ulcers.
Darifenacin
Selective M3AChR antagonist used to mediate bladder contraction in the treatment of incontinence.
Edrophonium
Non-covalent, truly reversible inhibitor of AChE. Quaternary ammonium compound that binds only to the ionic site of the enzyme through electrostatic interactions. A useful diagnostic of myasthenia gravis- it’s effects last only a few minutes, causing a temporary increase in the muscle tension that can be acheived by an affected patient
Neostigmine
Moderately reversible inhibitor that binds to the ester of site (present on BuChE and AChE) via a weak covalent interaction. The cholinesterase is inhibited for several minutes. Used intravenously to reverse neuromuscular blockade after surgery, also taken orally as a treatment for myesthenia gravis
Sugammadex
Cyclic dextrin that forms an inactive complex in the plasma with steroidal nmj blocking drugs which can be excreted in the kidneys, thus relieving the block
Dyflos
Irreversible ACh inhibitor. An organophosphorus compound that can produce a strong covalent bond between the phosphorus atom and serine residue at the esteric site. Used in the treatment of glaucoma.
Malathon
Irreversible ACh inhibitor. An organophosphorus compound that can produce a strong covalent bond between the phosphorus atom and serine residue at the esteric site. Used as an insecticide to kill lice as it can paralyze the insect without causing long lasting damage to the host.
Pralidoxome
Can reverse inhibition by organophosphorus agents in the first few hours after inhibition, before aging can occur. It has a strongly nucleophilic oxime group which is brought into close proximity with the phosphorylated serine of inhibited enzyme, leading to phosphate group transfer.
α-methyltyrosine
Competitive inhibitor of TOH, the enzyme that catalysts the rate limiting tyrosine to DOPA step of catecholamine synthesis. Used experimentally to reduce NA production.
Carbidopa
Peripheral DOPA decarboxylase inhibitor that reduces peripheral side effects of giving L-DOPA (a dopamine substitute that can cross the BBB) to treat Parkinson’s.
L-DOPS
Converted to NA by DDC, used in clinical trial for the treatment of neurogenic orthostatic hypotension- a condition associated with low levels of catecholamines in the periphery. It is lipophilic so can cross the blood brain barrier, and may have therapeutic or detrimental effects.
Disulfiram
DBH inhibitor. Used experimentally, chelates the Ca2+ ion essential for enzyme function. It also inhibits alcohol dehydrogenase so can be used to treat alcohol addiction- acetylaldehyde can’t be broken down. However it may produce vomiting and thus has an associated risk of asphyxiation.
α-methyldopa
A false transmitter of the noradrenergic system. It is taken up and converted into α-methyldopamine then to α-noradrenaline. It is less active at α1 but more active at α2 so there is decreased vasoconstriction following sympathetic stimulation as negative feedback via α2 is greatly enhanced. It’s primary site of action as an anti hypertensive is in the CNS.
Reserpine
Tightly binds to VMAT2, preventing the loading of mono amines into vesicles. It results in 5-HT depletion. It acts in the periphery and brain and was discontinued as an antihypertensive due to the severe psychological depression it could cause
Tyramine
Indirectly-acting sympathomimetic amine. It is transported into the nerve terminal+vesicles and displaces the NA. Some NA escapes metabolism by MAO and enters the extracellular space to activate local adrenoreceptors. Tyramine-rich foods should be avoided by patients taking MAO inhibitors to avoid widespread vasoconstriction and increased blood pressure.
Dexamfetamine
Indirectly acting sympathomimetic amine that cannot be metabolised by MAO due to the α-methyl group, so acts as a weak inhibitor. It is also a weak base, so upon uptake into the vesicle it decreased pH and amine packaging. Displaced NA leaves the nerve terminal and stimulates receptors.
Guanethidine
Blocks the release of NA. It also competes with NA to be taken into the presynaptic terminal by uptake 1 so can potentiate the effects of exogenously applied NA.
Cocaine
NET (Norepinephrine transport protein) blocker, stopping high affinity, low capacity uptake 1 into the presynaptic neuron.
Imipramine & Amitryptaline
Tricyclics antidepressants that act by blocking uptake 1 and block both NA and 5-HT transport
Clorgiline
A selective MAO-A inhibitor. It is used to treat depression
Selegiline
A selective MAO-B inhibitor that is used to treat Parkinson’s disease.
Tranylcypromine
Non-selective irreversible MAO inhibitor used in the treatment of refractory depression.
Entacapone
Inhibitor of COMT (associated with uptake 2) used in the treatment of Parkinson’s.
Mirabegron
β3 receptor agonist. Relaxes the bladder detrusor muscle. Used to treat over active bladder.
Phenylephrine
Selective α1 receptor agonist that can be used to raise blood pressure in acute hypotension.
Clonidine
α-adrenoreceptor agonist, with a slight selectivity for α2Rs. Can be used as an antihypertensive agent (through its action on receptors in the hindbrain) however it is not widely used in the uk.
Xylazine
Selective α2 adrenoreceptor agonist used in veterinary medicine for its sedative effect via acting on α2Rs in the CNS. Both Xylazine and dexmedetomidine (another α2R agonist) have an advantage over other anaesthesia methods in that they don’t cause respiratory depression.
Isoprenaline
Non-selective β- adrenoreceptor agonist. Previously used for asthma due to its bronchodilator effects, however it has been replaced by more selective agonists due to its unwanted effects effects on heart rate.
Salbutamol
Selective β2 adrenoreceptor agonist used to relax bronchi in asthma.
Dobutamine
Selective β1 adrenoreceptor agonist used in acute cardiogenic shock
Prazosin
Selective α1 adrenoreceptor antagonist to treat hypertension. Risk of postural hypotension
Phentolamine
Non-selective α adrenoreceptor antagonist. Use is largely obsolete as an antihypertensive agent as they bring about a large reflex increase in heart rate (reflex tachycardia)
Tamsulosin
Selective α1Α antagonist used to treat benign prostatic hyperplasia. It relaxes the smooth muscle in the prostate and neck of the bladder. Allowing better emptying.
Idazoxin
α2 antagonist
Dutasteride
Inhibits all 3 isoforms of 5α reductase, the enzyme that catalyses the rate-limiting step in the synthetic pathway for testosterone. It’s anti-androgenic effects are used in co-therapy with transmission to treat benign prostatic hyperplasia.
Atenolol
β1 selective antagonist. 2nd generation hypertensive agent, also used to treat cardiac dysthymias and angina. Can be used in combination with phenoxybenzamine to prevent the effects of large catecholamine release that occurs during surgical tumour removal.
Phenoxybenzamine
Irreversible α adrenoreceptor antagonist (it is a 2-chloro-ethylamine like Benzilylcholine mustard). It will block uptake 2 and (at 10x higher concentrations) uptake 1.
Yohimbine
α adrenoreceptor antagonist. Slightly more sensitive for α2.
Labetolol
Combined α and β receptor blocking agent. The four isomers each have different actions and receptor affinities. Used to treat hypertension in pregnancy.
Propranolol
Non-selective β antagonist. Used to be widely used to treat hypertension, however it has been superceded by selective β1 blockers.
Butuxamine
β2 antagonist
Ergotamine
Partial α adrenoreceptor agonist. It’s use in treating migraines is probably due to its action on 5-HT receptors. When ingested it can cause intense peripheral vasoconstriction that can lead to gangrene “St Anthony’s Fire”
Adenosine
Produced extracellularly by the hydrolysis of ATP. May act as a retaliatory metabolite as it slows the rate and force of myocardial contraction, saving energy in hypoxia
Caffeine
A1 receptor antagonist with waking action. Acts as a PDE inhibitor, potentiates cAMP signaling and can increase rate and force of contraction.
Dipyridamole
Blocks adenosine transport into cells, potentiating responses mediated by endogenous adenosine. This has universal vasodilatory effects which is detrimental during ischaemia due to the phenomenon of coronary steal, where bloods is diverted from the ischaemic region.
Nitric Oxide
Unconventional neurotransmitter. Gaseous inorganic free radical synthesized in a Ca2+ dependent manner, principally in endothelial cells and neurons. 3 types of NOS produce NO. It interacts with the haem moiety of GC, increasing cGMP levels. PKG activation leads to smooth muscle relaxation.
Glyceryl Trinitrate (Nitroglycerin) + Isosorbide Dinitrate
Agents that generate NO sometimes called NO donors. “Nitrovasodilators”. Used to treat angina.
Ricociguat
Allosteric activator of GC, used in some forms of pulmonary hypertension, improving ventilation perfusion ratio by synergistically augmenting selective intrapulmonary vasodilation of NO.
Sildenafil
Selective inhibitor of PDEs, an enzyme that breaks down cGMP. Used to treat impotence (also pulmonary hypertension?)
L-NMMA
Analogue of L-Arginine, non-selective NOS inhibitor.
7-NI (7-Nitroindazole)
Selective inhibitor of any NOS form in neurons (acting selectively on cell type rather than the isoform)
L-NIO
Potent + Irreversible inhibitor of iNOS in activated macrophages.
Asymmetric Dimethylarginine (ADMA)
Endogenous inhibitor of NOS, its concentration is increased in hypercholesterolaemia and renal failure- in the latter, its concentration can be used as a marker of disease selectivity and prognosis.
