2 - Pharmacology Of Peripheral Neurotransmission Flashcards
Tetanus toxin
Retrogradely transported to motor cell body
Transfers to inhibitory inter neutron, blocking it
Motor neuron more excitable
Targets SNARE synaptobrevin
Botulinum toxins
Preferentially effects cholinergic neurons
C terminus of heavy chain binds ganglioside receptor
N terminus translocation light chain into the cell through a channel
Light chain has peptidase activity, and once inside, cleaves the snare
Blocks ACh release
Botulinum toxin C1
Target
Syntaxin and SNAP25
Botulinum toxins A&E
Target
SNAP25
Botulinum toxins B,D,F,G
Target
Synaptobrevin
Hemicholinium
Blocks transporter that takes up choline into nerve cell
Vesamicol
Blocks transporter that carries ACh into storage vesicles
Non-Competitive and reversible inhibition
B-bungarotoxin
Blocks ACh release
Acts through phospholipase A2
a-latrotoxin
Binds neurexins
Cause massive release if ACh
Trimetaphan
Blocks ganglionic nicotinic receptors
Competitive antagonist
a-bungarotoxin
Irreversible antagonist at nmj
Doesn’t affect ganglionic receptors
Nicotine
Stimulates post synaptic cell
Long-lasting
Phase I block - VGNa channels inactivated
Phase II block - nicotinic receptors become desensitised
In phase II can be directly stimulated by electrical means
Hexamethonium
Use dependent blockade of ganglionic transmission
Double positive charge - had to be administered frequently by injection
Causes loss of sympathetic and parasympathetic control
D-tubocurarine
Nicotinic receptor antagonist
Non selective between ganglion and nmj
Quaternary ammonium compounds so not orally active
Atracurium
Competitive antagonist at the nicotinic receptor of the nmj
Quaternary ammonium compound
Not orally active
Block end plate potential in response to nerve stimulation
Antagonise affects directly applied by ACh etc
Tetanic fade (tetanus is not maintained) due to block of nicotinic receptors on nerve endings auto receptors , positive feedback to maintain transmitter release
Ester - spontaneous hydrolysis and plasma esterases
Pancuronium
Competitive antagonist at the nicotinic receptor of the nmj
Quaternary ammonium compound
Not orally active
Block end plate potential in response to nerve stimulation
Antagonise affects directly applied by ACh etc
Tetanic fade (tetanus is not maintained) due to block of nicotinic receptors on nerve endings auto receptors , positive feedback to maintain transmitter release
Long action, not hydrolysed
Decemethonium
Block nicotinic receptor at nmj by causing prolonged depolarisation
Depolarisation of phase I- anticholinesterases deepen the blockade
Effects can be opposed by non-depolarising blockers
Phase II - repolarisation, anticholinesterases reverse the blockade
Suxamethonium
Block nicotinic receptor at nmj by causing prolonged depolarisation
Depolarisation of phase I- anticholinesterases deepen the blockade
Effects can be opposed by non-depolarising blockers
Phase II - repolarisation, anticholinesterases reverse the blockade
Only depolarising blocker in clinical use
Short duration - ester broken down by plasma BuCHE
Carbachol
Non selective agonist at muscarinic acetyl choline receptors
Not selective between nicotinic and muscarinic receptors
Muscarine
Muscarinic receptor (agonist)
Methacholine
Agonist for muscarinic receptors
2 isomers
Neither hydrolysed by BuCHE
(+) is a substrate for AChE. More potent than at muscarinic receptors (-)
Acetylcholine
Non selective agonist at muscarinic acetyl choline receptors
Bethanechol
Non selective agonist at muscarinic acetyl choline receptors
Poorly absorbed in GI tract
Systemic use in bladder dysfunction
Pilocarpine
Non selective agonist at muscarinic acetyl choline receptors
Poorly absorbed from GI tract
Treatment of glaucoma, contracts ciliary muscle
Atropine
Non selective antagonist of muscarinic acetylcholine receptor Dilate pupils (mydriasis) Long duration
Benzilylcholine mustard
Non selective antagonist of muscarinic acetylcholine receptor
Pirenzepine
Antagonist of m1 muscarinic acetylcholine receptor
Anti secretory agent, gastro duodenal ulcers
Darifenacin
Antagonist m3 muscarinic acetylcholine receptor
Mediate bladder constriction
Edrophonium
Short acting, reversible ionic interaction with AChE
Used for diagnosis of myasthenia gravis
Neostigmine
Medium acting reversible weak covalent bond with AChE
Orally treats myasthenia gravis
Bind esteratic site and carbomylate enzyme
Intravenously to reverse neuromuscular blockade
Dyflos
Long acting, irreversible strong covalent bond with AChE
Glaucoma
Malathion
Long acting, irreversible string covalent bond with AChE
Insecticide to kill lice
Pralidoxime
Reverse inhibition of AchE by organophosphorous agents
Brings oxime (nucleophile) close to phosphorylated serine
Only occur a few hours after inhibition - before ageing occurs
a-methyltyrosine
Competitive inhibitor of TOH (Tyrosine Hydroxylase)
Reduces NA production
Carbidopa
Inhibit peripheral dopadecarboxylase
Reduce peripheral side effects of increased NA and DA
Disulfiram
Inhibits DBH (dopa-B-Hydroxylase)
Methyldopa
a-methyldopa
Converted by DDC to alphamethyldopamine Then by DBH to alphamethylnoradrenaline Stored and released with NA False transmitter Anti hypertensive agent in CNS
Reserpine
Binds amine binding site Blocks uptake Long lasting depletion of stored NA Anti hypertensive Side effects of psychological depression from serotonin depletion
Tyramine
In cheese, red wine and marmite
Transported into nerve endings and storage vesicles
Displaces NA from vesicle, NA reaches extra cellular space and activates local adrenoceptors
= indirectly acting sympathomimetic amine
Uptake 1 substrate
Dexamfetamine
D-amphetamine
Alpha methyl group so not metabolised by MAO
Weak inhibitor of MAO
Taken up into vesicles, reduces pH gradient and packing of amines
Displaced NA leaves nerve and stimulates receptors
Uptake 1 substrate
Guanethidine
Blocks release of NA Taken up into nerve by uptake 1 Low doses - block release of NA High doses - act as indirectly acting sympathomimetic amines Uptake 1 substrate
Cocaine
Blocks NET (norepinephrine transport protein), blocks uptake 1
Imipramine
Tricyclic antidepressant
Blocks NET (norepinephrine transporter protein), blocks uptake 1
Block NA and 5HT transport
Amitryptyline
Tricyclic antidepressant
Blocks NET (norepinephrine transporter protein), blocks uptake 1
Block NA and 5HT transport
Clorgiline
Selectively inhibits MAO-A
Used in depression
Selegiline
Selectively inhibits MAO-B
Treats Parkinson’s
(MAO-B metabolises DA)
Tranylcypromine
Non selective irreversible inhibitor MAO
Treatment of refractory depression
Entacapone
Inhibitor of COMT (catechol-I-methyltransferase)
Treat parkinsons
Noradrenaline
Adrenoreceptor agonist
a1
a2 B1
B2
Adrenaline
Adrenoreceptor agonist
a2
a1
B
Isoprenaline
Adrenoreceptor agonist B Asthma - relax bronchi But increase in heart rate Replaced by salbutamol
Phenylephrine
Adrenoreceptor agonist
a1
B1
Raise blood pressure in acute hypotension
Methyl INA
Adrenoreceptor agonist
a2
a1
Clonidine
Adrenoceptor agonist
a2
a1
Anti hypertensive agent
Xylazine
Adrenoreceptor agonist
a2
a1
Veterinary sedative
Salbutamol
Adrenoreceptor agonist
B2
B1
Dobutamine
Adrenoreceptor agonist
B1
B2
Acute cardiogenic shock
Phentolamine
Adrenoreceptor antagonist
a1 a2
Anti hypertensive - but bring about large heart rate increase
Phenoxybenzamine
Adrenoreceptor antagonist (irreversible)
a2
a1
With atenolol prevent effects of large releases of catecholamines after tumour displacement
Prazosin
Adrenoreceptor antagonist
a1
a2
Used in hypertension
Yohimbine
Adrenoreceptor antagonist
a2
a1
Idazoxan
Adrenoreceptor antagonist
a2
a1
Propranolol
Adrenoreceptor antagonist
B1 B2
Used to treat hypertension - but risk of brunch constriction
Replaced by atenolol
Atenolol
Adrenoreceptor antagonist
B1
B2
Hypertension, cardiac dysrhythmia, angina
With phenoxybenzamine, prevent effects of large releases of catecholamines after tumour displacement
Butaxamine
Adrenoreceptor antagonist
B2
B1
Labetalol
Adrenoreceptor antagonist a1 B1 B2 3rd generation B blocker Treat hypertension in pregnancy 4 isomers -RR B blocker, weak a blocker -RS a blocker, weak B blocker -SR no activity -SS a1 blocker
Ergotamine
Partial agonist at a adrenoreceptors
-used in migraine, but acts on 5HT receptors
Ingested - st Anthony’s fire, peripheral vasoconstriction, (a1) gangrene
Caffeine
A1 receptor antagonist
Non-selective, also inhibits phosphodiesterase (breaks down cyclic nucleotides) increase rate and force of cardiac contraction
Potentiation of cAMP mediated signalling
Dipyramidole
Blocks transport of adenosine back into cells
Potentiation responses mediated by adenosine
Glyceryl trinitrate
Nitroglycerin
Nitric oxide donor
Nitrovasodilator
(Produce NO2)
Treat angina
Isosorbide dinitrate
Nitric oxide donor
Nitrovasodilator
(Produce NO2)
Treat angina
L-NMMA
NOS inhibitor
Analogue of L-arginine
Not very selective
D-isomers are inactive
7-NI
7-nitroindazole
Selectively inhibits neuronal NOS
L-NIO
Potent and irreversible inhibitor of iNOS (inducible NOS in macrophages)
ATP
Released from sympathetic neurons
Rapid responses
***Mecamylamine
Inversine
Non selective,non competitive antagonist of nicotinic acetylcholine receptors
Orally active Anti hypertensive drug
***Octopamine
Similar to norepinephrine
Acts on adrenergic and dopaminergic receptors
Sympathomimetic agent
