Cholinergic Transmission and Depolarizing Block

Cholinergic Transmission

• Acetylcholine (ACh) acts on nicotinic (neuromuscular or ganglionic) synapses
• ACh causes influx of cations, particularly sodium (Na+) and potassium (K+), and calcium (Ca2+) to a lesser extent leading to depolarization of the postsynaptic membrane
• Depolarization of the postsynaptic membrane: leads to the endplate potential (epp) in a skeletal muscle fiber
• epp spreads along adjacent excitable parts of the muscle fiber
• Amplitude of the epp reaching the threshold for excitation initiates action potential, propagating contraction throughout the muscle
• Depolarization also causes a fast excitatory postsynaptic potential (fast epsp) at ganglionic synapses
• epsp's cause localized current flows, which may reach the axon hillock and trigger an action potential

Depolarizing Block

• Occurs when nicotinic acetylcholine receptors (nAChRs) are persistently activated
• Results in decreased electrical excitability of the postsynaptic cell
• Persistent activation of receptors by nicotine leads to initial depolarization and action potential firing, but eventually leads to cessation of firing and blockade of transmission
• Main reason for loss of electrical excitability is inactivation of voltage-sensitive sodium channels, preventing their opening upon stimulation
• Following prolonged nicotine exposure, the cell partially repolarizes, but transmission remains blocked, likely due to receptor desensitization.

Non Depolarizing Neuromuscular Blockers

• Examples include: Tubocurarine, Rocuronium, Pancuronium, Vecuronium, Cisatracurium, Atracurium
• Competitively antagonize nAChRs, blocking ACh binding and preventing muscle contraction
• Competitive nature allows for reversal of block with increased ACh concentrations at the neuromuscular junction
• This is why acetylcholinesterase inhibitors (AChEIs) are used to reverse neuromuscular blockade following surgery
• At high doses, non-depolarizing neuromuscular blockers cause physical blocking of the ion channel pore, leading to more intense motor blockade that is difficult to reverse with AChEIs

Acetylcholinesterase Inhibitors

• Increase ACh levels in the synapse and enhance cholinergic activity
• Ocular effects: can cause pupillary constriction (miosis) and contraction of the ciliary muscle
• Can enhance outflow of aqueous humor, making them potentially useful for treating glaucoma
• Organophosphates are examples of AChEIs, widely used as pesticides and insecticides
• Some organophosphates are chemical warfare agents
• Widely absorbed from skin, mucous membranes, and gut
• Lipophilicity leads to distribution throughout the body, including the CNS
• Organophosphate toxicity can occur after dermal, ocular, or oral exposure

Organophosphate Toxicity: Signs and Symptoms

• Increased ACh in the body activates both muscarinic and nicotinic receptors leading to a range of symptoms:
  • Muscarinic Effects: Salivation, Lacrimation, Miosis, Accommodative spasm, Bronchoconstriction, Bradycardia, Hypotension, Emesis, Intestinal cramps, Diarrhoea, Urinary incontinence
  • Nicotinic Effects: Depolarizing neuromuscular blockade, Muscle weakness, Respiratory muscle weakness, Fasciculations
  • CNS Effects: Anxiety, Restlessness, Headaches, Seizures, Respiratory depression, Coma

Management of Organophosphate Toxicity

• Remove contaminated clothing and wash patient with soap and water
• Administer activated charcoal if within 1-2 hours of exposure
• Ensure adequate airway and intubate if necessary
• Administer Atropine: Antimuscarinic drug that binds to muscarinic receptors, acting as an antagonist
• Administer a cholinesterase reactivator: to restore cholinesterase enzyme activity

Nicotinic Receptors

• There are three types of Nicotinic receptors: muscle type, ganglion type, and CNS type
• The location for the muscle type is the skeletal neuromuscular junction, mainly postsynaptic
• The location for the ganglion type receptor is autonomic ganglia: mainly postsynaptic
• The location for the CNS type receptor is many brain regions: pre- and postsynaptic
• The membrane response for the muscle type is excitatory, increased cation permeability (mainly Na+, K+)
• The membrane response for the ganglion type is excitatory, increased cation permeability (mainly Na+, K+)
• The membrane response for the CNS type is pre- and postsynaptic excitation, increased cation permeability (mainly Na+, K+)
• Agonists for the Muscle type receptor are Acetylcholine, Carbachol, Succinylcholine
• Agonists for the Ganglion type receptor are Acetylcholine, Carbachol, Nicotine
• Agonists for the CNS type receptor are Nicotine, Epibatidine, Acetylcholine, Varenicline
• Antagonists for the Muscle type receptor are Tubocurarine, Pancuronium, Atracurium, Vecuronium
• Antagonists for the Ganglion type receptor are Mecamylamine, Trimetaphan, Hexamethonium
• Antagonists for the CNS type receptor are Mecamylamine, Methylaconitine

Acetylcholinesterase inhibitors

• AChE inhibitors are drugs that result in the activation of cholinergic receptors by not binding directly to muscarinic or nicotinic receptors
• These drugs increase acetylcholine (ACh) levels by inhibiting the breakdown of ACh by the enzyme acetylcholinesterase (AChE)
• These drugs increase the effects of ACh on both nicotinic and muscarinic receptors
• AChE inhibitors can be classified as reversible or irreversible depending on how strongly they bind to the enzyme
• Reversible cholinesterase inhibitors bind to the anionic site of AChE but do not form a covalent bond, allowing for easy reversibility
• Examples of reversible AChE inhibitors: Edrophonium, Neostigmine, Physostigmine, Pyridostigmine
• Irreversible cholinesterase inhibitors form a strong covalent bond with the catalytic site of AChE, making the bond very difficult to break
• Examples of irreversible AChE inhibitors: Ecothiophate, Parathion, Malathion, Isoflurophate

Clinical Uses of AChE inhibitors

• Edrophonium is mainly used to diagnose myasthenia gravis and can also be used to differentiate between a myasthenic crisis and a cholinergic crisis
• Neostigmine and Pyridostigmine are used to treat myasthenia gravis
• Neostigmine and Pyridostigmine can also be used to reverse the effects of neuromuscular blocking agents, which are used to cause paralysis during surgery
• Ecothiophate is used topically to treat glaucoma
• Parathion is an insecticide that can cause toxicity in humans
• Malathion is used topically to treat head lice

Explore the intricate mechanisms of cholinergic transmission involving acetylcholine and nicotinic receptors. Understand how depolarization affects postsynaptic membranes and the implications of persistent receptor activation leading to depolarizing block. This quiz covers key concepts essential for grasping neuromuscular and ganglionic synapse functions.