Synaptic pharm Flashcards
Preganglionic parasympathetic NT?
ACh nicotinic
Postganglionic sympathetic NT?
NA and ACh muscarinic
Postganglionic parasympathetic NT?
ACh muscarinic
What NT does the adrenal medulla release?
Adrenaline and noradrenaline
What effect does atropine have on heart rate and why?
Blocks parasympathetic innervation and causes a massive increase in heart rate
What effect does propranolol have on the heart rate and why?
Non selective beta blocker, mild decrease in heart rate as it blocks sympathetic innervation.
What are synaptobrevin, SNAP-25 and syntaxin?
SNARE proteins - v-SNARE and t-SNAREs
What does Munc-18 do?
Stabilise closed syntaxin conformation
What does munc-13 do?
Open syntaxin conformation
What are synapsins and how are they regulated?
Proteins on the vesicle surface that link the vesicle to the cytoskeleton. Regulated by phosphorylation by PKA or CaMKII. In phosphorylated form allow dissociation from cytoskeleton and vesicle movement.
What are complexins?
Small cytoplasmic proteins that bind at the interface of syntaxin and synaptobrevin. Promote zippering and act as a partial clamp.
What are botulinum neurotoxins?
Neurotoxins released by gram positive bacteria. There are 7 known forms, each targeting specific SNARE proteins. Composed of a 50kDa light chain linked to a heavy chain via a disulphide bond.
What do BoNT A and E target?
Cleave SNAP-25 (t-SNARE)
What do BoNT B, D, G and F target?
Cleave synaptobrevin.
What does BoNT C target?
Syntaxin and SNAP-25
How does BoNT gain access to synapses?
Bind to ganglioside expressed on cholinergic neurons and N-termini allows translocation via channel formation in the endosome membrane.
How does TeNT enter the host?
Enters through puncture wounds in the skin.
How does TeNT disinhibition motor neurons and cause muscle tetanus?
Cleaves synaptobrevin in the cytoplasm of the pre synaptic terminal.
What are the two types of NT interaction sigh the pre synaptic membrane?
Homotropic and heterotropic
What is a homotropic pre synaptic NT interaction?
Action at its own pre synaptic terminal at auto receptors.
What is a heterotropic interaction at a presynaptic terminal?
NT release from one terminal acting on another Presynaptic terminal to modulate NT release.
What are the 5 points of pharmacological intervention for synaptic pharmacology?
Synthesis Interaction at pre and post receptors Release Reuptake/degradation Storage
What does hemicholinium do?
Block Na+/choline co-transporter.
What is the effect of triethylcholine and how does it work?
Competitive substrate for choline acetyltransferase (CAT). Is released in replace of ACh but is less potent at ACh receptors.
What does vesamichol do?
Blocks ACh/H+ vesicular transporter
Beta-bungarotoxin
Binds to presynaptic K+ channels. Has PLA2 activity - breaks down lipids in the active zone preventing vesicle release inhibiting neurotransmission.
Taipoxin
Binds to presynaptic K+ channels. Has PLA2 activity - breaks down lipids in the active zone preventing vesicle release inhibiting neurotransmission.
Alpha-latrotoxin
Binds to neurexins - forms calcium permeable channels causing massive ACh release.
What are the two acetylcholinesterase types?
AChE found in presynaptic nerve and synaptic cleft. Relatively selective for ACh.
Butyrlcholinesterase. Synthesised in liver and found in plasma.
How does AChE achieve such rapid hydrolysis?
12 catalytic sites.
What neurotransmitter is present at preganglionic synapses in the sympathetic nervous system?
ACh acting on nicotinic receptors
What does alpha-bungarotoxin do?
Irreversible antagonist of adult NMJ receptors. No inhibitory action on ganglionic receptors.
What does trimetaphan do?
Antagonist at ganglionic nicotinic receptors but not at NMJ receptors.
What does hexamethonium do?
Selective ganglionic nicotinic receptor blocker.
What does decamethonium do?
Selective for NMJ nicotinic receptors over ganglionic nicotinic receptors.
What is D-tubocurarine?
Non selective nicotinic receptor competitive antagonist (between NMJ and ganglionic).
Give an example of a non-depolarising neuromuscular blocking agent.
Pancuronium, rocuronium, atracurium, mivacurium.
How do selective non-depolarising neuromuscular blocking agents also inhibit ACh release?
Block presynaptic nicotinic receptors.
Why do atracurium and mevacurium have shorter periods of action?
Atracurium is unstable at physiological pH. Mevacurium is hydrolysed by BuChE.
What does sugammadex do?
Speeds up reversal of non-depolarising blockade. Fewer side effects than AChE inhibitors.
Name 3 depolarising neuromuscular blocking agents.
Nicotine
Suxamethonium
Decamethonium
What does suxamethonium do?
Depolarising nicotinic receptor blocker. Hydrolysed by BuChE.
What are the side effects of suxamethonium?
Bradycardia, hyperkinesia, initial transient muscle twitching.
What is the difference between the two isomers of methacholine?
+ isomer - substrate for AChE, 200x more potent at muscarinic receptors than - isomer.
What is carbachol?
Non-selective ACh receptor antagonist. (Both nicotinic and muscarinic).
How is the M1 receptor coupled?
Gq
How does activation of M1 receptors affect neurons?
Inhibit the “M current” which is K+ conductance mediated by VGKC family
How is the M2 receptor coupled?
Gi - decreases NT release.
What does the beta gamma subunit of the M2 receptor do?
Opens GIRKs causing hyper polarisation in the pacemaker cells of the heart. Also inhibits presynaptic N-type CaVs, inhibiting NT release.
How is the M3 receptor coupled?
Gq - stimulates glandular secretion.
What is the effect of activation of M3 receptors in endothelial and smooth muscle cells?
Endothelial. - activation of NOS.
SM cells - contraction due to increase in Ca
Bethanechol
Muscarinic receptor agonist. Poorly absorbed by GI tract. Administered in urinary retention due to M3 receptor activation that causes contraction of the detrusor muscle.
Pilocarpine
Activates M2 and M3 muscarinic receptors (agonist) in ciliary muscle causing contraction. Used to treat glaucoma.
Cevimeline
Muscarinic receptor agonist. Activates M3 receptors. Used to treat Sjögren’s syndrome, an autoimmune condition that leads to destruction of glands that secrete fluids.
What is tropicamide used for?
Dilate the pupil for ophthalmic examination. Causes contraction of iris dilator muscle. Adrenoceptor antagonist.
Ipratropium
Muscarinic receptor antagonist. Used to cause bronchodilation in asthma and COPD.
Darifenacin
Muscarinic receptor antagonist. Used to treat urinary incontinence as it inhibits M3 receptors so prevents contraction of the detrusor muscle in the bladder.
Edrophonium
Short acting anticholinesterase. Binds to anionic site of AChE. Short duration of action due to non-covalent interaction.
Tacrine
Short acting anticholinesterase. Binds to anionic site, can penetrate BBB. Used to treat Alzheimer’s disease but withdrawn - frequent hepatotoxicity.
Donepezil
Short acting anticholinesterase. Selective for AChE over BuChE. Non-charged. Currently used to treat Alzheimer’s.
Neostigmine and pyridostigmine
Medium acting reversible anticholinesterases. Used to treat myasthenia gravis. Pyridostigmine preferred due to longer duration of action
Physostigmine
Medium lasting reversible anticholinesterase. Used to treat glaucoma. Does not cross the BBB.
Rivastigmine
Medium lasting reversible anticholinesterase. Used to treat Alzheimer’s disease. Can cross BBB.
Neostygmine, physostigmine, pyridostigmine.
Medium acting reversible anticholinesterases. Carbamyl esters. Carbaryl group is transferred to Ser hydroxyl of esteratic site. Carbamylated AChE takes much longer to hydrolyse.
What is myasthenia gravis?
Autoimmune condition where autoantibodies attack the nicotinic NMJ receptors. Results in muscle weakness and inability to maintain muscle tension.
What are dyflos, ecothiophate and malathion?
Long acting irreversible anticholinesterases.
Dyflos
Long acting irreversible anticholinesterase. Cannot interact with anionic site.
Ecothiophate
Long acting irreversible anticholinesterase. Can interact with anionic site.
How is anticholinesterase poisoning treated?
Atropine and pralidoxime.
How is tyrosine hydroxylase regulated?
End product inhibition by catecholamines.
Activation of transcription factors.
Phosphorylation of Ser40 increases Ki for end product inhibition and increases Km for BH4 binding.
What converts DA to NA and where?
DBH - dopamine beta hydroxylase in the vesicle
How is DA taken up into vesicles?
Vesicular monoamine transporter
What is L-DOPA used to treat? What is it often given alongside?
Parkinson’s disease. Given alongside peripheral DDC inhibitors such as carbidopa
Alpha-methyl tyrosine
Competitive substrate for TOH
Disulfram
DBH inhibitor. Also inhibitor of aldehyde dehydrogenase. Used in alcohol aversion therapy to give flushing and tachycardia if alcohol is consumed.
Methyl dopa
Given as an anti hypertensive. Causes less vasoconstriction as alpha methyl noradrenaline is less potent at alpha1 receptors (less SM contraction) but more potent at alpha2 receptors (negative effect on NA release)
6-hydroxydopamine
Taken up by noradrenergic nerve terminals. Converted to reactive quinine that destroys nerve terminal. Used experimentally.
Guanethidine
Blockade of NA release. Taken up by NET and concentrated in vesicles.
Which adrenoceptors appear presynaptically to modulate NA release?
Alpha2 - activation decreases NA release (Gi coupled). Beta - activation increases NA release (Gs coupled).
What are the 3 main pharmacological intervention points for catecholamine storage and release?
Evoke NA release in the absence of depolarisation.
Blockade of release.
Presynaptic modulation of release.
How is NA removed from the synapse?
Uptake into neuronal and non-neuronal cells.
Desiprimine
Inhibits NET - antidepressant.
Amitriptyline
Inhibits NET/SERT. Antidepressant.
Cocaine
Non-selective inhibitor of NET/SERT/DAT.
What does the EMT transport?
Extra neuronal monoamine transporter. NA and Adr.
Normetanephrine
Inhibitor of EMT
Phenoxybenzamine
Inhibits NET and EMT. Also irreversible alpha2 antagonist
How is alpha1 adrenoceptor coupled?
Gq
How is alpha2 adrenoceptor coupled?
Gi
Role of alpha2 receptor?
Inhibit NA release, vasoconstriction, platelet aggregation.
Role of alpha1 receptor?
Vasoconstriction, contraction of uterine smooth muscle, salivary secretion.
Role of beta1 receptor?
Increase heart rate and force of contraction, relaxation of GI smooth muscle.
Role of beta2 receptor?
Bronchodilation, coronary and skeletal muscle vasodilation, relaxation of uterine and smooth muscle in the bladder.
Phenylephrine
Alpha1 selective agonist. Nasal decongestant.
Methoxamine
Non-selective alpha agonist. Nasal decongestant.
Clonidine
Alpha2 selective agonist. Anti hypertensive.
Dexmedetomidine
Alpha2 agonist. Sedative in humans and animals.
Dobutamine
Beta1 agonist. Cardiogenic shock.
Salbutamol
Beta2 agonist. Taken by inhalation.
Salmeterol and formoterol
B2 agonists, long acting. Side effects are tremor (b2 in skeletal muscle) and tachycardia (b2 in cardiac muscle).
Indacaterol
Long acting b2 agonist. Used to treat COPD.
Mirabegron
B3 agonist. Used to treat overactive bladder due to relaxation of detrusor muscle.
Labetalol
Mixed a/b adrenoceptor antagonist. Used to treat hypertension in pregnancy.
Phentolamine
Non-selective alpha-adrenoceptor antagonist. Cannot be used to treat hypertension due to postural hypotension and tachycardia.
Phenoxybenzamine
Non-selective alpha-antagonist. Long lasting effects due to covalent binding. Used to prepare patients for phaeochromocytoma surgery.
Prazosin
Selective alpha1 antagonist. Used to treat hypertension. Less tachycardia.
Doxazosin
Alpha1 selective antagonist. Longer half life so can be given in daily dosing. Side effects: postural hypotension and incontinence.
Tamsulosin
Selective alpha1A antagonist. Fewer side effects of postural hypotension and urinary retention.
Yohimbine
Selective alpha2 antagonist. No clinical use.
Propranolol
Non-selective beta antagonist. Used as anti hypertensive. Decreases cardiac output and renin release. But can produce bronchoconstriction in asthmatics.
Atenolol
Beta1 selective antagonist. Anti hypertensive without bronchoconstriction risk.
Nebivolol
Beta1 selective antagonist. Anti hypertensive. Metabolite also has beta3 agonist action increasing NO production and causing vasodilatation.
What are Dales criteria for a neurotransmitter?
- Transmitter must mimic stimulation.
- Drugs modifying transmitter response must modify stimulation.
- Transmitter or precursor must be in terminal.
- Storage and synthesis systems.
- Release upon stimulation.
- Mechanisms for termination.
What are the 3 types of purinoceptor?
Adenosine receptors. P2X - ionotropic. P2Y - metabotropic.
How is ATP taken up into cells?
VNUT - vesicular nucleotide transporter
How is ATP released?
Exocytosis or through NtT (nucleotide transporter).
How is adenosine metabolised?
Changed to I nosing by adenosine deaminase.
How is adenosine taken up into the cell?
NsT - nucleoside transporter.
How can ATP act at a synapse?
Bind to P2X or P2Y receptors. Be converted to ADP by ectonucleotideases and act at P2Y. Be converted to adenosine by ectonucleotideases and act at adenosine receptors.
Suramin
A2X antagonist
How are A2A and A2B adenosine receptors coupled?
Gs
How are A1 and A3 adenosine receptors coupled?
Gi
Caffeine
A1 antagonist and phosphodiesterase inhibitor.
Dipyridamole
Blocks NsT. Potentiates the effects of adenosine.
Where are neuropeptide receptors expressed?
NPYR1 expressed in postganglionic cells of SNS. NPYR2 expressed presynaptically as auto receptor. Both Gi coupled.
Where is VIP expressed?
Neurons of PNS innervating salivary glands and airway smooth muscle. Gs coupled.
Where is gonadotropin-releasing hormone expressed? How is it coupled?
SNS ganglia. Gq coupled.
Where is substance P expressed? How are the receptors coupled?
SNS ganglia and enters nervous system. Gq coupled.
Where are enkephalins present? How are the receptors coupled?
In neurons innervating the bladder neck. Opioid receptors are Gi coupled.
Desmopressin
Replaced vasopressin as treatment for diabetes insipidus. (Reduced or lack of vasopressin secretion)
Oxytocin
Peptide used to induce labour.
What are the 3 NOS isoforms?
Neuronal (nNOS/NOS1). Inducible (iNOS/NOS2). Endothelial (eNOS/NOS3).
How are nNOS and eNOS activated?
Via Ca calmodulin. Regulated by phosphorylation.
How is normal blood pressure maintained by NO?
Tonic eNOS production of NO. Activates PKG in adjacent cells. Phosphorylation of MLCK which inactivates it, relaxing smooth muscle, and of SERCA pumps decreasing Ca2+.
How is NO terminated?
Oxidation to nitrite/nitrate and excretion in urine or combination to haem of haemoglobin.
Glyceryl trinitrate.
Induces vasodilatation to treat angina. Administered using sublingual spray.
What is oesophageal achalasia?
Failure of lower oesophageal sphincter to fully relax and therefore inability to move food through the oesophagus. Associated with loss of nitrergic neurons.
What is hypertrophic pyloric stenosis?
Failure of pyloric sphincter to relax to allow food to pass from stomach to duodenum. Associated with loss of nNOS.
How does sexual stimulation create an erection?
Activation of nitrergic nerves. nNOS activation. NO release. sGC activation in smooth muscle cells. PKG activation via increased cGMP and therefore vasodilatation. Dilated arteries and arterioles compress venules limiting venous outflow.
Sildenafil
First selective PDE V inhibitor. Enhances erectile response to sexual stimulation. Can cause visual disturbances due to PDE VI inhibition in the retina.
Alprostadil
Prostaglandin E1 analogue. Taken by intracavernosal injection. Dilates blood vessels directly. Erection lasts about 30-60 minutes.
How does NO contribute to cerebral damage in a stroke?
Cerebral hypoxia. Insufficient ATP, neuronal depolarisation, Glut release, AMPA activation, further depol, NMDA activation, massive Ca entry, nNOS activation, NO release, cell death due to peroxynitrate formation.
L-NAME
L-arginine analogue, inhibits all NOS isoforms. No clinical use
7-NI
Neuronal NOS inhibitor. Selectively targets neurones rather than nNOS.
L-NIO
Irreversible inhibitor of iNOS.
