Lecture Course 2: Peripheral Neural Transmission Flashcards
* Botulinum toxin (general) *
- Prevents neurotransmitter release
- Preferential for cholinergic neurones
- Heavy chain C terminus -> ganglioside receptor
- N terminus translocates peptidase light chain into cell/vesicle
- Peptidase cleaves target snare
- Symptoms
- Somatic muscle weakness
- Loss of autonomic cholinergic activity
- (constipation, blurred vision, dry skin)
* Botulinum toxins B, D, F and G *
- Prevent neurotransmitter release
- Preferential for cholinergic neurones
- Cleaves v-SNARE Synaptobrevin
- Symptoms
- Somatic muscle weakness
- Loss of autonomic cholinergic activity
*Botulinum toxins A and E*
- Prevent neurotransmitter release
- Preferential for cholinergic neurones
- Cleaves t-SNARE SNAP-25
- Symptoms
- Somatic muscle weakness
- Loss of autonomic cholinergic activity
* Botulinum toxin C1 *
- Prevent neurotransmitter release
- Preferential for cholinergic neurones
- Cleaves v-SNARE **Synaptobrevin **and t-snare SNAP-25
- Symptoms
- Somatic muscle weakness
- Loss of autonomic cholinergic activity
* Tetanus toxin *
- Blocks vesicle release in inhibitory interneurones
- Retrogradedly transported to cell body, then transferred to inhibitory interneurone
- Targets t-snare synaptobrevin whichprevents inhibitory neurotransmitter release
- Motor neurones become more excitable
- => tetanus
* Hemicholinium *
- Blocks sodium-choline cotransporter, responsible for reuptake of choline into the cell to form Ach
Triethylcholine
Competitive substrate for Ach at transporters.
Released in place of Ach- a false transmitter.
Vesamicol
Non competitive reversible blocker of the vesicular ACh transporter.
This prevents vesicles from being filled with ACh.
* Beta Bungarotoxin *
- Blocks ACh release.
- Potassium channel binding region
- Phospholipase A2 activity
* Alpha latrotoxin *
- Binds to neurexins on plasma membrane and causes mass release of ACh by forming calcium permeable channels.
- Can also inhibit potassium channels.
- Black widow spider toxin
Alpha bungarotoxin
- Irreversibly blocks n.m.j.
- Does not block ganglions.
Trimetaphan
- Competitive antagonist for ganglionic nAChR
- Used for controlled lowering of blood pressure during surgery.
* Nicotine *
- nAChR agonist
- Selective for ganglionic nAChR
- Phase I- depolarising block. Neuron cannot be stimulated further.
- Phase II - desensitisation of nicotinic receptor - sodium channel inactivation. Neuron can be stimulated electrically directly but not via presynaptic neurone.
* Hexamethonium *
- Non competitive ganglion blocker.
- Use dependent blockade.
- Causes loss of sympathetic and parasympathetic systems - ‘hexamethonium man’.
* D-tubocurarine *
- Nicotinic receptor antagonist.
- Non selective between ganglionic and nmj.
- Leads to flaccid paralysis.
- Cannot cross intestinal epithelium or placenta.
* Atracurium *
- Competitive nAChR antagonist.
- Also may block nicotinic autoreceptors => tetanic fade
- Not orally active
- Used in anaesthesia
- Selective for white muscle
- Short half life.
- Ester - Broken down by plasma esterases.
* Pancuronium *
- Competitive nAChR antagonist.
- Also may block nicotinic autoreceptors => tetanic fade
- Not orally active
- Used in anaesthesia
- Selective for white muscle
- Long half life
- Not broken down by plasma esterases.
Decamethonium
- Depolarising nmj blockade.
- Phase I - spastic paralysis.
- Prolonged in multiply innervated muscles.
- Deepened by anticholinesterases, reversible with non depolarising blockers
- Prolonged in multiply innervated muscles.
- Phase II- flaccid paralysis.
- Desensitisation block.
- Reversed by anticholinesterases, deepened by curare like drugs.
- Phase I - spastic paralysis.
Suxamethonium
- Depolarising nmj blockade.
- Used for short term muscle relaxation
- eg. Intubation.
- Can cause dangerous increases in plasma K+.
- Phase I - spastic paralysis.
- Prolonged in multiply innervated muscles.
- Deepened by anticholinesterases, reversible with non depolarising blockers
- Phase II- flaccid paralysis.
- Desensitisation block.
- Reversed by anticholinesterases, deepened by curare like drugs.
Acetylcholine
- Non selective agonist for muscarinic and nicotinic receptors.
- Broken down by AChE and BuChE
Carbachol
- Non selective agonist for nicotinic and muscarinic receptors.
** * Muscarine ***
Muscarinic receptor agonist
Methacholine
- Non selective muscarinic agonist.
- Two isomers:
- +-Methacholine is broken down by AChE and 200x more potent than - isomer
Cevimeline
- Selective agonist for M3 muscarinic receptors (on glands and smooth muscle).
- Used to treat dry mouth in Sjögren’s syndrome.
* Atropine *
- Non selective antagonist for muscarinic receptors.
- Used to dilate eye (opthalmic examination) - although too long lasting
- Decrease bronchial and salivary secretions, bronchodilatation, increase heart rate, decrease GI motility
Pirenzepine
- Selective antagonist for muscarinic M1 receptors (on the PNS and CNS).
- Used to decrease gastric acid secretion.
* Darifenacin *
- Selective antagonist for muscarinic M3 receptors (on glands and smooth muscle and oxytinic cells).
- Used in cases of urinary incontinence.
M1 and M3 muscarinic receptors
Mechanism:
- couple through Gq/11 - generation of IP3 and DAG through cleavage of PIP2
- M1 only also inhibits potassium channels
- M3 only also increases intracellular calcium concentration
M2 muscarinic receptors
Mechanism:
- Couple to Gai
- inhibits adenylyl cyclase.
- cAMP decrease.
- decreased VG calcium channel activation, lower heart excitability and less neurotransmitter release
- beta gamma subunit opens potassium channel in SAN, decreasing heart rate
* Bethanechol *
- Non selective agonist for muscarinic receptors.
- Poorly absorbed from GI tract.
- Used for systemic treatment for urinary retention.
* Pilocarpine *
- Non selective agonist for muscarinic receptors.
- Poorly absorbed across GI tract.
- Used topically for glaucoma - absorbed through cornea and contracts cillary muscle.
* Edrophonium *
- Short acting Anticholinesterase.
- Reversible ionic interaction with AChE.
- Used to diagnose myasthenia gravis.
* Neostigmine *
- Medium length Anticholinesterase.
- Forms weak covalent bonds with AChE.
- Carbamylates active site
- Reverses surgical block and used to treat myasthenia gravis.
Sugammadex
- Forms inactive complex in the plasma with non-depolarising n.m.j agents (eg. Atracurium)
- Excreted in the urine.
* Pralidoxime *
- Reverses organophosphoric agent inhibition at n.m.j
- Binds to phosphoric group and removes it
Noradrenaline
- Catecholamine.
- Main sympathetic neurotransmitter, also involved in CNS.
- Acts on:
- a1 > a2 = B1 > B2
Adrenaline
- Catecholamine.
- Synthesised in adrenal gland - hormone in periphery.
- Acts on:
- a2 > a1 > B
- Used in treatment of extreme conditions eg. Anaphylatic shock, acute cardiac failure.
Dopamine
- Catecholamine.
- Precursor for noradrenaline.
Alpha-Methyltyrosine
- Competitively Inhibits Tyrosine hydroxylase (TOH)
- Catalyses Tyrosine -> DOPA
- The rate limiting step for dopamine/noradrenaline/adrenaline production.
- Catalyses Tyrosine -> DOPA
* Carbidopa *
- Inhibits DOPA decarboxylase
- Catalyses the conversion of DOPA -> dopamine.
- Only works peripherally
- Administered alongside L-DOPA in treatment of parkinsons to reduce peripheral side effects
Disulphiram
- Inhibits dopamine Beta-hydroxylase (DBH)
- catalyses dopamine -> noradrenaline.
- Used in the treatment of alcohol abuse by a different mechanism.
* Methyldopa *
- False transmitter
- acts on alpha 1 and alpha 2 adrenergic receptors
- Less active than noradrenaline on alpha 1
- More active on alpha 2
- Used as an antihypertensive.
* Reserpine *
- Binds tightly to vesicular monoamine transporter.
- This blocks uptake of NA and DA into vesicles.
- Vesicular leakage of stored NA and DA into the cytoplasm causes long lasting depletion.
- Use as an antihypertensive discontinued due to depression.
* Tyramine *
- Indirect sympathomimetic amine.
- Displaces NA from vesicles.
- Some displaced NA reaches synaptic cleft and activates adrenoreceptors.
- Found in cheese, wine, marmite, soya beans.
- May cause widespread vasoconstriction if too much ingested -‘cheese effect’.
- In normal amounts converted to octopamine, a false transmitter.
- Repeated use produces lower response due to less NA in vesicles - tachyphylaxis.
Dexamfetamine
- Indirectly acting sympathomimetic amine.
- Evades monoamine oxidase and is taken up into vesicle.
- Displaces noradrenaline, which may leave nerve and activate adrenoreceptors.
- MDMA has similar effects, but also acts on 5HT2 receptors.
- Repeated use produces lower response due to less NA in vesicles - tachyphylaxis.
* Guanethidine *
- Adrenergic neurone blocker.
- Taken up into nerve by uptake 1 - compete with NA.
- Block NA release in low repeated doses.
- Unknown mechanism.
- Act as indirect sympathomimetic amines in large doses.
* Imapramine *
- Tricyclic antidepressant which blocks NET (uptake 1).
- Blocks catecholamine reuptake - sustains action
* Cocaine *
- Catecholamine uptake 1 blocker.
- Blocks NET (presynaptic)
- Sustains action of catelcholamines
* Amitryptyline *
- Catecholamine reuptake blocker.
- Tricyclic antidepressant which blocks NET (uptake one on presynaptic terminal)
* Clorgiline *
- Monoamine oxidase (MAO) A inhibitor - blocks Catecholamine metabolism.
- Used as antidepressant.
* Selegiline *
- Monoamine oxidase (MAO) B inhibitor - blocks Catecholamine metabolism.
- Used in parkinsons treatment.
* Tranylcypromine *
- Non selective Irreversible inhibitor of monoamine oxidase (MAO).
- Used in treatment of refractory (treatment resistant) depression.
* Entacapone *
- Catechol O-methyltransferase (COMT) inhibitor.
- Blocks catecholamine metabolism, especially that associated with uptake 2.
- Used in treatment of parkinsons disease.
Mirabegron
- Selective B3 adrenoreceptor agonist. -> Negative ionotropic effect.
- Used in treatment of overactive bladder.
- Relaxes bladder detrusor muscle.
* Isoprenaline *
- Beta-Adrenoreceptor agonist. P
- reviously used in asthma to relax bronchial - but led to increase in heart rate.
* Phenylephrine *
- Alpha1 adrenoreceptor agonist.
- Some action at B1
- Used to raise blood pressure in acute hypotension
MethylNA
- Alpha adrenoreceptor agonist.
- a2>>a1
* Clonidine *
- Alpha adrenoreceptor agonist.
- a2>a1
- Used as an antihypertensive.
* Xylazine *
- Selective a2 adrenoreceptor agonist.
- Used as a sedative in veterinary medicine due to actions in CNS.
- Advantage over other anaesthetics as no respiratory depression
* Salbutamol *
- Beta 2 adrenoreceptor agonist.
- Some action at B1.
- B2 selectivity allows use as a bronchial dilate in asthma without increasing heart rate
* Dobutamine *
- Beta adrenoreceptor agonist.
- B1>> B2
- Used in acute cardiogenic shock.
* Phentolamine *
- Alpha adrenoreceptor antagonist.
- Obsolete antihypertensive due to reflex tachycardia.
- Slight blocking action on toxic effects of noradrenaline in cardiac failure
Phenoxybenzamine
- Irreversible antagonist for alpha adrenoreceptors.
- Similar to benzocholine mustard.
- Used in combination with atenolol to prevent effects from catecholamine release during tumour removal surgery
* Prazosin *
- Alpha adrenoreceptor antagonist.
- Selective for a1
- Used as an antihypertensive
Yohimbine
- Alpha adrenoreceptor antagonist.
- Strongly selective for a2
* Idazoxan *
- Alpha adrenoreceptor antagonist.
- Strongly selective for a2
* Propranolol *
- Beta adrenoreceptor antagonist.
- Ex antihypertensive agent - non selectivity gave rise to bronchiconstriction
- Attenuation of toxic noradrenaline effects in heart failure.
- Class II antidysrythmic. Sympathetic innervation can lead to dysrhythmia
** Atenolol *
- Beta adrenoreceptor antagonist.
- Selective for B1
- Used in combination with Irreversible inhibitor phenoxybenzamine to prevent effects from catecholamine release during tumour removal surgery
- Used as an antihypertensive
- Class II antidysrythmic. Sympathetic innervation can produce dysrhytmia
* Butaxamine *
- Beta-Adrenoreceptor antagonist.
- Strongly selective for B2
* Labetalol *
- Adrenoreceptor antagonist.
- Selective for a1, B1, B2
- Four isomers with different actions.
- Used as an antihypertensive during pregnancy.
Tamsulosin
- Selective a-1a adrenoreceptor antagonist.
- Used in benign prostatic hyperplasia - relaxes smooth muscle of prostate and neck of bladder.
Dutasteride
- Used in conjunction with tamsulosin in treatment of benign prostatic hyperplasia.
- Antiadrogenic effects - blocks testosterone synthesis.
* Caffiene *
- A1 receptor antagonist => wakefulness
- Also non selectively inhibits phosphodiesterases.
* Dipyridamole *
- Blocks adenosine inactivation
- Potent vasodilator PDE V inhibitor - raises cAMP
- Used in treatment of congestive heart failure
Glyceryl trinitrate
- Nitric oxide donor.
- Nitrovasodilator.
Isosorbide dinitrate
- Nitric oxide donor.
- Nitrovasodilator.
- Used in angina treatment.
* Sildenafil *
- Selective inhibitor of PDE 5 (selectively breaks down cGMP)
- Used to treat impotence
- Also in pulmonary arterial hypertension
7-NI
- NOS inhibitor.
- Selective for NOS in neurones.
- Does not effect eNOS or iNOS
L-NMMA
- Non selective inhibitor of NOS
- D isomer not reactive
L-NIO
- Irreversible inhibitor of iNOS
- Activated in macrophages
* Asymmetric Dimethylargenine (ADMA) *
- endogenous NOS inhibitor
- Synthesised during post translational protein methylation
- Increased in hypercholesterolaemia and renal failure