Pharmacology of the Peripheral Neural Transmission (Drugs) Flashcards
What are the major processes that can be affected by drugs during cholinergic transmission?
- ACh synthesis
- ACh release
- ACh receptor binding
- ACh break-down
Which drugs affect ACh systhesis?
Triethylcholine: Competitive antagonist for choline acetyltransferase (CAT)
Which drugs affect ACh vesicular transport?
Vesamicol: Reversibly (but non-competitively) inhibits VAChT and prevents ACh loading into vesicles. Inhibits ACh release.
Which drugs affect ACh release?
- Aminoglycoside antibiotics (e.g. streptomycin, neomycin): Inhibits P-type Ca2+ channels that mediate Ca2+ entry into the pre-synaptic terminal. Inhibits ACh release.
- Botulinum toxin: Several isoforms all cut SNARE complex at different sites. Inhibits ACh release.
- Tetanus toxin: Degrades synpatobrevin. Inhibits ACh release.
- α-Latrotoxin: Causes massive uncontrolled discharge of ACh from nerve terminals and depletes ACh. Inhibits ACh release.
- β-bungarotoxin: Causes activation of phospholipase A2, leading to destruction of pre-synaptic nerve terminal. Inhibits ACh release.
Which drugs affect ACh re-uptake?
Hemicholinium: Inhibits Na+-dependent choline transporters (ChT) and thus inhibits choline re-uptake. This decreases amount of choline available for ACh synthesis and thus decreases ACh availability. Inhibits ACh release.
Which types of drugs affect ACh receptors?
- Neuromuscular-blocking drugs (nicotinic receptor antagonists)
- Ganglion stimulating/blocking drugs
- Muscarinic receptor agonists/antagonists
What are the types of neuromusclular-blocking drugs?
- Depolarising blocking agents
- Non-depolarising blocking agents
What are the depolarising blocking drugs?
Suxamethonium: nAChR agonist that causes sustained depolarisation of the post-synaptic terminal and thus induces blocking of ACh action (phase I and II)
What are the non-depolarising blocking drugs?
All non-depolarising drugs are competitive antagonists of nAChRs (but more selective for N1). Clinically significant compounds include:
- Pancuronium
- Vecuronium
- Atracurium
- Mivacurium
What is a non-reversible NMJ blocker?
- α-bungarotoxin: Blocks nAChRs irreversibly in NMJ
- Decamethonium
What are the ganglion stimulating drugs?
nAChR agonists that bind selectively to N2 receptors in parasympathetic ganglia. Non-clinically used compounds include:
- Nicotine
- Lobeline
Clinically used compounds include:
- Epibatidine
- Varenicline
What are the gangion blocking drugs?
All ganglion bocking drugs are nAChR antagonists specific for N2 ACh receptors.
Non-clinically used: Hexamethonium
Few are in clinical use due to widespread side effects. Clinically used: Trimethapan (lowers BP to minimise bleeding during surgery)
What are the muscarinic agonists?
- Choline esters:
- Acetylcholine
- Methacholine
- Carbachol
- Bethanechol - Cholinomimetic alkaloids:
- Muscarine
- Arecoline
- Pilocarpine
- Cevimeline
What are the clinically used muscarinic agonists?
- Bethanechol: Treatment of bladder/gastrointestinal hypotonia
- Pilocarpine: Treatment of glaucoma
- Cevimeline: Treatment of Sjögren’s syndrome
What are the muscarinic antagonists?
- M1 selective:
- Pirenzepine: Treatment of peptic ulcers (reduces gastric acid secretion) - M2 selective:
- Tripitramine - M3 selective (treatment of over-reactive bladder):
- Oxybutynin
- Tolterodine
- Darifenacin
- Solifenacin - Non-selective:
- Atropine: Used to reduce secretions in airways during surgery and reduces GI and bladder spasms.
- Hyoscine butylbromide: Anti-spasmodic
- Benzilylcholine
- Tropicamide
- Ipratropium
Which drugs affect acetylcholine breakdown?
- Short-acting (non-covalent):
- Edrophonium: Diagnosis of myasthenia gravis
- Tacrine: Treatment of Alzheimer’s disease
- Donepezil: Treatment of Alzheimer’s disease - Intermediate-acting (covalent):
- Neostigmine:
Intravenous → Reverses neuromuscular block
Oral → Treatment of myasthenia gravis - Pyriostigmine: Treatment of myasthenia gravis
3. Irreversible (covalent): - Echothiophate: Treatment of glaucoma
- Dyflos: Treatment of glaucoma
- Malathion: Treatment of headlice
What are antidotes for organophosphate poisoning?
- Atropine: Counteracts systemic effects
- Pralidoxime (2-PAM): Reactivates AChE by dephosphorylating Ser203
Which drugs affect noradrenaline synthesis?
- α-methyltyrosine (phaeochromocytoma): inhibits tyrosine hydroxylase
- Carbidopa (Parkinson’s): Inhibits DOPA decarboxylase (DDC)
- Disulfiram (Chronic alcoholism): Inhibits dopamin β-hydroxylase (DBH)
- α-Methyldopa (Hypertension): False transmitter and inhibits action of NA is several ways:
- Inhibits DDC and DBH
- Displaces NA from vesicles and causing MAO breakdown
- Binds to pre-synpatic α2 receptors and inhibits NA release via feedback inhibition
Which drugs block noradrenaline storage and release?
- Reserpine: Inhibits VMAT and thus NA uptake into vesicles
- Guanethidine: Possibly inhibits exocytosis of NA and displaces NA from vesicles
What are the indirect sympathomimetics?
- Tyramine (found in foods)
- Ephedrine (nasal congestion)
- Dextroamphetamine (narcolepsy & ADHD)
Which drugs affect noradrenaline uptake?
- Tricyclic antidepressants (e.g. imipramine): Inhibits NET (uptake 1)
- Cocaine: Inhibits NET (uptake 1)
- Steroid hormones (e.g. hydrocortisone): Inhibits EMT (uptake 2)
- Normetnephrine: Inhibits EMT (uptake 2)
- Phenoxybenzamine: Inhibits NET & EMT
Which drugs selectively act on α1 adrenreceptors?
Agonists:
- Phenylephrine
- Oxymetazoline
Antagonists:
- Prazosin
Which drugs selectively act on α2 adrenoreceptors?
Agonists:
- Clonidine
- Xylazine
Antagonists:
- Yohimbine
Which drugs non-selectively act on α adrenoreceptors?
Agonists:
- Topical decongestants
Antagonists:
- Phenozybenzamine
- Phentolamine
Which drugs selectively act on β1 adrenoreceptors?
Agonists:
- Dobutamine
Antagonists:
- Metoprolol
- Nebivolol
Which drugs selectively act on β2 adrenoreceptors?
Agonists:
- Salbutamol
- Salmeterol
- Terbutaline
- Clenbuterol
Antagonists:
- Butoxamine
Which drugs act selectively on β3 adrenoreceptors?
Agonists:
- Mirabegron
Which drugs act non-selectively on β adrenoreceptors?
Agonists:
- Isopraline
Antagonists:
- Propanolol
- Alprenolol
Which drugs act non-selectively on adrenoreceptors in general?
Agonists:
- Adrenaline
- Noradrenaline
Antagonists:
- Labetalol
- Carvedilol
