ANS Pharm – ANS drugs

Master answer

Background

• Acetylcholinesterase (AChE) is an enzyme that hydrolyse acetylcholine (ACh) into choline & acetate
• AChE is found in synaptic clefts and is responsible for the termination of synaptic transmission
• Common action of anti-cholinesterases = allow build up of Ach and prevent it from being destroyed.

Naturally Occuring Cholinesterases

Two types of naturally occurring cholinesterases:

1. Achesterase – nerve endings & in RBCs
2. Non-specific or pseudocholinesterases – destroy other esters – tissues & plasma

Anticholinesterase drugs

AntiAchE drugs are administered in anaesthesia when spontaneous recovery from NDNMB is occurring to accelerate it.

Classification:

Drugs are classified by the way in which they inhibit the activity of AchE.
3 main types of anticholinesterase:

1. Reversible antagonist via electrostatic binding
   • ie. edrophonium
   • causes electrostatic attachment to the anionic site of the enzyme -> stabilising the H+ bond at the esteratic site -> edrophonium-AchE complex prevents Ach from binding
2. Reversible antagonist via covalent bonding [Formation of carbamyl esters (carbamates)]
   • ie. neostigmine, physostigmine & pyridostigmine
   • antagonise AchE enzyme by being competitive substrate for Ach -> forms a carbamyl-ester complex at the esteratic site of enzyme.
   • longer lasting bond (15-30min)
3. Irreversible antagonist via covalent bonding
   • ie. organophosphate anticholinesterase drugs (echothiopate), insecticides & nerve gases
   • combine with Ach at the esteraic site to form a stable covalent bond -> does not undergo hydrolysis.
   • synthesis of a new AchE is required.

Pharmacodynamic effects

Anticholinesterase drugs inhibit AChE, thereby increase the concentration of ACh at both nicotinic and muscarinic ACh receptors
Muscarinic effects occur at lower doses than nicotinic effects

Muscarinic effects

• CVS – bradycardia ± hypotension
• RESP – bronchoconstriction ± bronchospasm
• CNS – miosis, cholinergic syndrome – confusion, agitation, nausea/vomiting
• GIT – hypersalivation, ↑GIT motility, nausea/vomiting, diarrhoea
• GUT – urination, incontinence
• OTHER – lacrimation, diaphoresis

Mnemonic: SLUDGE-BM: Salivation/Sweating, Lacrimation, Urination, Diaphoresis/Diarrhoea, GI upset, Emesis, Bradycardia/bronchospasm, Miosis

Nicotinic effects

• Reversal of non-depolarising neuromuscular blockers
• Prolongs effect of suxamethonium (depolarising NMB)
• Anticholinesterase overdose → excess synaptic ACh → depolarisation block ± fasciculation

Clinical uses

1. Reversal of non-depolarising neuromuscular blocker
   • Mechanism – anticholinesterase drugs ↑ synaptic ACh → competes with ND-NMB in synapse for nAChR → reversal of neuromuscular block
   • Drugs – usu. neostigmine, administered together with glycopyrrolate or atropine
2. Diagnosis and treatment of myasthenia gravis
   • Mechanism – anticholinesterase drugs ↑ synaptic ACh → competes with myasthenia auto-antibodies for post-synaptic nAChR → ↑muscle strength
   • Drugs – e.g. edrophonium for diagnosis, pyridostigmine for maintenance
3. Treatment of cognitive impairment in neurodegenerative diseases (e.g. Alzheimer’s disease, Lewy body dementia, etc)
   • Mechanism – ↑ synaptic ACh in CNS → ↑ cholinergic transmission
   • Drugs – e.g. rivastigmine, galantamine, donepezil
4. Treatment of glaucoma
   • Mechanism – constriction of sphincter pupillae and ciliary muscles → miosis → facilitate outflow of aqueous humor → IOP decreases
   • Drugs – e.g. echothiophate eye drops, physostigmine
5. Treatment of anticholinergic syndrome
   • Anticholinergic syndrome caused by: anti-histamines, anti-parkinsonians, atropine, anti-spasmodics, mydriatics, skeletal muscle relaxants, plants
   • CLINICAL FEATURES: delirium, tachycardia, dry and flushed skin, dilated pupils, myoclonus, hyperthermia, urinary retention, bowel sounds, seizures, dysrhythmias(tachy)
   • Mechanism – increase synaptic ACh
   • Drugs – e.g. physostigmine (tertiary amine + lipophilic → readily crosses BBB)

JC 2019

Answer by JC