Receptors and peripheral nerves Flashcards
Cholera toxin
ADP-ribosylates the a-subunit of Gs preventing its GTPase activating and therefore sustaining activation of adenyl cyclase
Pertussis toxin
ADP-ribosylates the a-subunit of Gi preventing it’s activation and hence preventing the inhibition of Adenyl cyclase leading to sustained activation
Whooping cough
AIF4-
Mimics the Y phosphate of GTP and can causes consistent activation of the G-protein
Lithium
Inhibits the recycling of IP3 into Inostol in GQ/11 coupled receptors
Carvedilol
Third generation B-blocker, activates the B-arrestin pathway
Tyrophostins
Act to inhibit receptor tyrosine kinases, used to control neoplastic growth
Procaine
Local anaesthetic (ester)
Acts by inhibiting NaV by binding to IFY motif on 6th segment of 4th domain
Preference to pain fibres (Ad+c) and rapidly firing, must block 3 node of Ranvier to inhibit conduction
Weak base - inhibits channel in charged form but must pass through the membrane uncharged
Voltage dependence - inhibition increased with hyperpolarising pre-pulse
Lindocaine
Local anaesthetic (amide)
Acts by inhibiting NaV by binding to IFY motif on 6th segment of 4th domain
Preference to pain fibres (Ad+c) and rapidly firing, must block 3 node of Ranvier to inhibit conduction
Shifts inactivation value which results in a greater number of channels being inactivated at membrane potential
Preferentially binds to the channel in its inactive state therefore shows use dependence
Weak base - inhibits channel in charged form but must pass through the membrane uncharged
Voltage dependence - inhibition increased with hyperpolarising pre-pulse
Most effective in ischemic tissue, used in the treatment of ventricular arrhythmia’s
Benzocaine
Local anaesthetic (ester)
Acts by inhibiting NaV by binding to IFY motif on 6th segment of 4th domain
Preference to pain fibres (Ad+c) and rapidly firing, must block 3 node of Ranvier to inhibit conduction
Voltage dependence - inhibition increased with hyperpolarising pre-pulse
Quinidine
Local anaesthetic, inhibits NaV channel, rate of inhibition and dissociated slow, use dependence, used in the treatment of suproventricular tachycardia
Tetrodatoxin
Natural inhibitor of the NaV channel
Bind to outer ring of charged glutamate residues and promotes sodium to leave the cell
NaV channels in the heart glutamate is replaced with cystine therefore toxins have reduced action
Saxitoxin
Natural inhibitor of the NaV channel
Bind to outer ring of charged glutamate residues and promotes sodium to leave the cell
NaV channels in the heart glutamate is replaced with cystine therefore toxins have reduced action
Batrachatoxin
Poison from the tree frog
Activated the NaV channel at more negative potentials resulting in increased excitability of the cells
Risk of arrhythmia’s
Cd2+ and Mn2+
Can cause non-selective block of Voltage gated calcium channels
Nifedipine
Dihydropyridine
L-Type selective CaV channel inhibitor
Very lipid soluble
Action seen on cardiac and smooth muscle cells
Preferentially block CaV channels in the heart therefore used was anti-dysrhytmics
Can cause peripheral and coronary vasodilation - used in the treatment of hypertension ??
Verapamil
Phenylalkyamine L-type selective CaV channel inhibitor Reduces affinity for dihydropyridines Use dependence Preferentially block CaV channels in the heart therefore used was anti-dysrhytmics
Diltiazem
Benzothiazepine L-Type selective CaV channel inhibitor increases affinity for dihydropyridines Use dependence Preferentially block CaV channels in the heart therefore used was anti-dysrhytmics
Mibefradil
Benzimidazolt tetraline
Inhibits both L and T-type calcium channels
Diazoxide
K+(ATP) channel opener
Inhibits ATP binding therefore causes channel to open leading to hyperpolaristion of the cells therefore smooth muscle relaxation
Hypertension, Asthma, IBS
Minoxidil
K+(ATP) channel opener
Inhibits ATP binding therefore causes channel to open leading to hyperpolaristion of the cells therefore smooth muscle relaxation
Hypertension, Asthma, IBS
Nicorandil
K+(ATP) channel opener
Inhibits ATP binding therefore causes channel to open leading to hyperpolaristion of the cells therefore smooth muscle relaxation
Hypertension, Asthma, IBS
Tolbutamide
Hypoglycemic agent Closes K(ATP) channel by action on sulphonylurea receptors - causes depolarisation Acts in pancreatic B-cells, firing CaV channels stimulating insulin release
Glibencalamide
Hypoglycemic agent Closes K(ATP) channel by action on sulphonylurea receptors - causes depolarisation Acts in pancreatic B-cells, firing CaV channels stimulating insulin release
Botulinium toxin
Preferentially targets Cholinergic neurones - C terminus binds to ganglioside receptor on neurone surface, endocytosed and N-terminus punctures endosome releasing toxin into cytoplasm
Somatic muscle weakness, constipation, blurred vision, urinary retention and dry skin
A+E = SNAP-25
C = SYTAXIN + SNAP-25
B, D, F+G = SYNAPTOBREVIN
Tetanus toxin
Retrograde transport to motor neurone cell body and transferred to inhibitory interneuron inhibiting inhibition through the inactivation of SYNAPTOBREVIN
Locked jaw and arched body
Hemicholinium
Inhibits choline uptake into the nerve terminal, binds to the outface of the receptor
Triethylcholine
ACh false transmitter - Competitive substrate, acetylated within the nerve into acetyltriethycholine and released instead of ACh
Vesamicol
Non-comeptitive, reversible inhibitor of VACht (transports ACh into vesicle with ATP, ratio of 10:1)
B-Bungarotoxin
Inhibits the release of ACh - 2 chain toxin linked with a disulphide bond, binds to the synaptic K+ channels and through the action of phospholipase A2 acts to break down nerve terminal
Respiratory failure and paralysis of respiratory muscles
A-Ladrotoxin
Causes massive release of ACh - bind to neurexins, transmembrane receptors on the pre-synaptic terminal, causes the formation of a divalent cation pore which allow Ca2+ influx and consequent transmitter release, also inhibits K+ channels
Respiratory failure and paralysis of respiratory muscles
Trimetaphan
Selective ganglionic nicotinic competitive antagonist, used during surgery to lower blood pressure
A-Bungarotoxin
Irrreversible Inhibitor of the NMJ nicotinic receptor, also inhibits the A(7) nicotinic receptor in the brain
Mecamylamine
Non-competitive selective inhibitor for the ganglionic nicotinic receptor
Hexamethonium
Non-competitive selective inhibitor for the ganglionic nicotinic receptor, causes use dependence block, used to used in the treatment of hypotension, blocks the ganglionic receptor of both parasympathetic and sympathetic pre-ganglionic however - caused decrease in cardiovascular tone, cause dry mouth and skin, and constipation
Has a 2+ charge therefore administered IV
D-Tubocurarine
Non-selective, non-depolarising nicotinic receptor antagonist, charged therefore administered IV, leads to flaccid paralysis - action requires 70-80% of receptors to be blocked however
Atracurium
Non-depolarising selective antagonist for the NMJ nicotinic receptor, quaternary amide therefore IV, inhibits the production of tetanus following sustained stimulation = tetanic fade achieved by blocking auto transmitters required for +ve feedback on transmitter release
Ester therefore broken down through spontaneous hydrolysis
Panacuronium
Non-depolarising selective antagonist for the NMJ nicotinic receptor, quaternary amide therefore IV, inhibits the production of tetanus following sustained stimulation = tetanic fade achieved by blocking auto transmitters required for +ve feedback on transmitter release
Secreted by the kidney, longer acting that atracurium
Decamethonium
Depolarising blocker for the nicotinic NMJ
Suxamethonium
Depolarising blocker selective for the nicotinic NMJ, short lived ester, can be broken down via BuAChE, used during intubation
1-2% of population mutation in enzyme required for breakdown, can lead to increase in plasma K+ an hence arrhythmia
Carbachol
Non-selective cholinergic receptor agonist (muscarinic and nicotinic)
Methacholine
Non-selective cholinergic receptor agonist (muscarinic and nicotinic) + isomer broken down by AChE
Cevimeline
Muscarinic ACh M3 Selective agonist, used to increase salivation in Sjogren’s syndrome
McN-A-343
Muscarinic ACh M1 selective agonist, tissue selective stimulator at ganglionic neurones
Pilocarpine
Non-selective muscarinic agonist, used in the treatment of glaucoma, administered via eye drops, causes contraction of colliery muscles and hence opening of clean of schelem
Ipratropium
Non-selective muscarinic antagonist, quaternary compound, used in the treatment of asthma
Atroprine
Non-selective muscarinic antagonist, dilates pupils, decreases glandular secretions, decreases GI motility, and increases heart rate
Benzilylcholine (mustard)
(Irreversible) Non-selectove muscarinic antagonist
Pirenzepine
M1 Muscarinic selective antagonist, antisecretory agent in the treatment of gastroduodenal ulcers, acts on the intramural nerves rather than the oxyntic cells directly
Tripitramine
M2 Muscarinic selective antagonist
Gallamine
M2 Muscarinic selective antagonist
Darifenacin
M3 Muscarinic selective antagonist, used in bladder incontinance
Bethanochol
Non-selective muscarinic agonist, used in badder dysfunction acts to reduce urinary retention
Hyoscine
Non-selective muscarinic antagonist, dilates pupils, decreases glandular secretions, decreases GI motility, and increases heart rate
Endrophonium
Anti-Cholinesterase - short length of action, forms reversible ionic interactions, quaternary ammonium, binds to the anionic site of the enzyme therefore selective for ACeE
Used to diagnose myasthenia gravis and causes a slight increase in muscle tension generation
Neostigmine
Anti-cholinesterase - Medium length of action, acts as a suicide inhibitor by forming weak covalent bonds, carbomic acid ester, binds to the esteratic site and carbomoylates the enzyme, the enzyme is regenerated slowly
Used IV to reduce neuromuscular blockade after surgery and orally to treat myasthenia gravis
Physotigmine
Anti-cholinesterase - Medium length of action, acts as a suicide inhibitor by forming weak covalent bonds, carbonic acid ester, binds to the esteratic site and carbomoylates the enzyme, the enzyme is regenerated slowly, used in the treatment of glaucoma - seen to make the ciliary muscles contract
Pyridostigmine
Anti-cholinesterase - Medium length of action, acts as a suicide inhibitor by forming weak covalent bonds, carbonic acid ester, binds to the esteratic site and carbomoylates the enzyme, the enzyme is regenerated slowly, used in the treatment of mysathenia gravis
Dyflos
Anti-cholinesterase - Long length on action, forms irreversible strong covalent bonds with the serine residues in the esteratic site
Organophosphorus compound, used in the treatment of glaucoma, long term exposure can lead to demyelination as inhibit an ester in the myelination process,short term exposure can also lead to death through cholinergic overdose - convulsions and respiratory depression
Malathion
Anti-cholinesterase - Long length on action, forms irreversible strong covalent bonds with the serine residues in the esteratic site
Organophosphorus compound, used as an insecticide to kill lice, long term exposure can lead to demyelination inhibit an ester in the myelination process, short term exposure can also lead to death through cholinergic overdose - convulsions and respiratory depression
Tacrine
Anti-Cholinesterase - Short length of action, reversible covalent bonds, non-selective between AChE and BuAChE, used in the treatment of Alzhimers disease, uncharged therefore can cross the blood brain barrier
Donezepil
Anti-cholinesterase - short length of action, forms non-covalent bonds to enzyme, selective for AChE, similar action to tacrine but has fewer peripheral side effects
Sugammadex
Steroidal cyclodextrin, acts to remove neuromuscular blockage following surgery, binds to blocker forming and inactive complex on the plasma and is the excreted in the urine
Praildoxime
Can reverse the inhibition of organophosphorus compounds, contains an oxide group which is a strong nucleophile into close proximity to the phosphorylated serine causing the phosphate group to be transferred, only works a few hours following inhibition as the complex becomes ages
A-Methyltyrosine
Competitive inhibitor of tyrosine hydroxylase therefore reduced all catecholamine production
L-DOPA
Used as a Dopamine replacement in the treatment of Parkinson’s disease - a substrate that avoids the rate limiting TOH step
Carbidopa
Inhibitor of DOPA decarboxylase, often used in conjunction with L-DOPA to prevent catecholamine production in the periphery as cannot cross BBB
Droxidopa
Under clinical trials for the treatment of Neurogenic Arthrostatic hypotentsion - a condition associated with reduced peripheral Na and Adrenaline
Can be converted into catecholamines via DOPA decarboxylase
Disulfiram
Inhibitor of Dopamine B-Hydroxylase (also inhibits aldehyde dehydrogenase) used in the treatment of alcohol abuse, functions through chelating the essential Cu ion in the enzyme, induces vomiting
Methyldopa
False transmitter for catecholamine production, taken up into the nerve terminal in the place of tyrosine and converted into a-methylnoradrenaline
Less responsive at A1 but more response at A2 receptors
Reserpine
Inhibits the vesicular monoamine transporter (VMAT2) responsible for the packaging of NA into synaptic vesicles, almost irreversibly binds to amine binding site, also causes long lasting depletion of NA stores and causes vesicular leak - recovery requires synthesis of new vesicles
Used to have clinical use as anti-hypertensive but causes physiological depression
Tyramine
Indirectly acting sympathomimetic amine - taken up into the nerve terminal where it acts to displace NA from the vesicles into the cytoplasm where it is either broken down via MAO of transported into the synaptic clef via NET stimulating post synaptic membrane…
Found in wine, cheese and marmite - causes the ‘cheese effect’ can cause temporary increase in blood pressure
Can also be converted via Dopamine B-Hydroxylase into Octopamine which acts as a false transmitter
Tachyphylaxis
Ephendrine
Indirectly acting sympathomimetic amine - used as a nasal decongestant
Tachyphylaxis
Dexamphetamine
Indirectly acting sympathomimetic amine, weak inhibitor of MAO (a-methyl group prevents its breakdown), is itself taken up into the synaptic vesicles where it acts as a weak base reducing the pH and therefore reducing NA storage
Tachyphylaxis
Ritalin
Indirectly acting sympathomimetic amine
Tachyphylaxis
MDMA (Ecstasy)
Indirectly acting sympathomimetic amine, also acts upon 5-HT2 receptors
Tachyphylaxis
Guanethidine
Inhibits NA release from pre-synaptic terminal when stimulated by AP, it odes not inhibit spontaneous release, thought to be as a result of action on the K+ or VGCC causing hyperpolarisation
High doses can act as indirectly acting sympathomimetic amine
Taken up into nerve terminal via uptake 1
Bretylium
Inhibits NA release from pre-synaptic terminal when stimulated by AP, it odes not inhibit spontaneous release, thought to be as a result of action on the K+ or VGCC causing hyperpolarisation
High doses can act as indirectly acting sympathomimetic amine
Taken up into nerve terminal via uptake 1
Cocaine
Inhibits the action of NET - transporter for uptake 1 into presynaptic cells
Imipramine
Tricyclic antidepressant, inhibits the action of NET - transporter for uptake 1 into presynaptic cells, also blocks serotonin and adrenaline uptake
Amitryptyline
Tricyclic antidepressant, inhibits the action of NET - transporter for uptake 1 into presynaptic cells, also blocks serotonin and adrenaline uptake
Fluoxetine
Inhibits the serotonin 5-HT2 transporter, new generation of antidepressants
Normetanephrine
Inhibits ENT or OCT3 Uptake 2 transporters into the postsynaptic cell
Phenoxybenzamine
Irreversibly inhibits ENT or OCT3 involved in uptake 2
Clogiline
Selectively inhibits MAO-A, used in the treatment of depression
Selegiline
Selectively inhibits MAO-B used in the treatment of Parkinson’s disease
Tranylcypromine
Irreversibly inhibits MAO (non-selective) used in the treatment of refractory depression
Encatapone
Inhibits COMT, used in the treatment of Parkinson’s
Mirabegron
Selective B3 adrenoceptor agonist
Bupranolol
Selective B3 adrenoceptor antagonist
Phenylepherine
Selective A1 adrenoceptor agonist, used to raise blood pressure in acute hypotension
MethlyINA
Selective A2 adrenoceptor agonist
Clonidine
Slightly selective A2 adrenoceptor agonist, acts on the hindbrain as an anti-hypertensive
Xylazine
Selective A2 adrenoceptor agonist, used as a sedative in veterinary medicine
Salbutamol
Selective B2 adrenoceptor agonist, asthma
Dobutamine
Selective B1 adrenoceptor agonist, used in cariogenic shock
Phentolamaine
Non-selective A-adrenoceptor antagonist
Phenoxybenzamine
Non-selective A-adrenoceptor antagonist
Prazosin
Selective A1-adrenoceptor antagonist
Yohimbin
Selective A2-adrenoceptor antagonist
Idazoxan
Selective A2-adrenoceptor antagonist
Propanolol
Non-selective B-adrenoceptor antagonist
Atenolol
Selective B1-adrenoceptor antagonist, used during the removal of a phaeochromacytoma
Butaxamine
Selective B2 adrenoceptor antagonist
Labetalol
Non-selective adrenoceptor (A+B) antagonist, 4 different isomers, used to treat hypertension in pregnancy, third-generation beta-blocker
Xylometazoline
Non-selective A-adrenoceptor agonist, used to relive nasal congestion
Tamsulosin
Selective A1-adrenoceptor antagonist, used in begin prostatic hyperplasia - relaxes smooth muscle in prostrate
Carvedilol
Third generation beta-blocker, combines antagonism with vasodilation
Nebivolol
Third generation beta-blocker, combines antagonism with vasodilation
Ergotamine
Ergot Alkaloid derived from fungus, used in the treatment of migraines due to action on 5-HT2 receptors, when ingested causes St-Anthony’s fire = intense peripheral vasoconstriction ca lead to gangrene
Suramin
P2X ATP receptor inhibitor
Caffeine
A1 Adrenoreceptor antagonist, prevents the induction of sleep, also inhibits phosphodiesterase’s increasing rate and force of contraction
Dipyramidamole
Inhibits Adenosine uptake (and therefore inactivation) into cells, potentiates its response
glycerol Trinitrate
NO donor, used to cause vasodilation and relaxation of smooth muscle
Isorbide Dinitrate
NO donor, used in the treatment of angina
Sidenafil
Selective inhibitor for Phosphodiesterase - 5 which selectively breaks down C-GMP, used in the treatment of impotence
Amyl Nitrate
Used in the treatment of angina, administered through inhilation, acts to lower cardiac oxygen demand, causes relaxation of anal sphincter however
L-NMMA
Non-selective NOS inhibitor
L-NAME
Non-selective NOS inhibitor
7-NI
Selective nNOS inhibitor
L-NIO
Selective iNOS inhibitor
Assymetic dimethylamine
Endogenous inhibitor of NOS, synthesised during post-translational methylation, elevated in renal failure, feedback regulator for NOS production
