Ch.10 Cholinesterase Inhibitors

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Ch.10 Cholinesterase Inhibitors

• R1 ???

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Cholinesterase Inhibitors

• Primary Clinical use to reverse nondepolarizing
  muscle blockade
• Commonly used
• Neostigmine
• Edrophonium
• Pyridostigmine
• Physostigmine

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Cholinergic Pharmacology

• Cholinergic the effects of the neurotransmitter
  Acetylcholine
• Ach is the neurotransmitter for
• The entire parasympathetic nervous system
  (parasympathetic ganglions effector cells)
• Parts of the sympathetic nervous system
  (sympathetic ganglions, adrenal medulla, sweat
  gl)
• Some neurons in the CNS
• Somatic nerves innervating skeletal m.

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Cholinergic Pharmacology
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Cholinergic Pharmacology

• Cholinergic Receptors Two major groups
• Nicotinic receptor
• -gt autonomic ganglia skeletal m
• -gt blocked by neuromuscular blockers
• Muscarinic receptor
• -gt end-organ effector cells in
• bronchial smooth m, salivary gl,
• SA node
• -gt blocked by anticholinergic drugs

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Mechanism of Action

• Normal Neuromuscular Transmission
• Ach binds to Nicotinic Rc on motor end plate
• Nondepolarizing muscle relaxants
• Act by competing with Ach Competitive
  Antagonist
• Reversing neuromuscular blockade-to maximize
  nicotinic transmission-to minimize Muscarinic
  side effects

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Mechanism of Action

• Reversal of blockade
• Spontaneous reversal
• Diffusion
• Redistribution
• Metabolism
• Excretion
• Pharmacologic reversal
• Cholinesterase Inhibitors increase the amount of
  Ach available

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Mechanism of Action

• In excessive doses - Cholinesterase inhibitors
  paradoxically potentiate a nondepolarizing
  neuromuscular blockade
• Cholinesterase Inhibitors prolong the blockade of
  succinylcholine (Depolarizing NMB) by
• An increase in Ach
• Inhibition of pseudocholinesterase activity

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Clinical Pharmacology

• An increase in Ach affect Nicotinic receptors of
  skeletal muscle but also
• Cardiovascular Rc vagal-like bradycardia,
  bradyarrhythmias
• Pulmonary Rc bronchospasm
• Cerebral Rc Physostigmine can cross BBB
  Diffuse excitation
• GI Rc increase peristaltic activity and
  glandular secretion

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Clinical Pharmacology

• These unwanted Muscarinic side effects can be
  minimized by the administration of
  anticholinergic medication
• Atropine sulfate
• Glycopyrrolate

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Clinical Pharmacology

• Dosage depend on the degree of neuromuscular
  block
• Estimated by the response to peripheral nerve
  stimulation
• Some evidence of spontaneous recovery (i.e.. The
  1st twitch of the TOF) must be present before
  reversal is attempted!

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Clinical Pharmacology

• Time required for full reversal depend on
• The choice and dose of the Cholinesterase
  Inhibitor
• (e.g.. Edrophonium reversal is faster than with
  Neostigmine// Large doses lead to faster
  reversal)
• The choice and dose of the muscle relaxant
• (e.g.. Intermediate-acting relaxants reverse
  sooner than long acting)
• The extent of blockade
• (e.g.. A shallow block is easier to reverse than
  deep blocks)

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Clinical Pharmacology

• Unless full reversal can be demonstrated or
  postop. plans include continued ventilation A
  reversal agent should be routinely given to
  patients who have received nondepolarizing muscle
  relaxants

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Clinical Pharmacology

• Peripheral nerve stimulators should also be used
  (to monitor the progress and confirm the adequacy
  of reversal)
• Suggested end points of recovery
• In anesthetized pts sustained tetanus for 5s in
  response to a 100-Hz stimulus
• In awake pts sustained head lift (gt inspiratory
  force gt vital capacity gt tidal volume)

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Specific Cholinesterase Inhibitors
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Neostigmine

• Physical Structure
• Lipid insoluble, cannot pass BBB

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Neostigmine

• Dosage Packaging
• 0.04-0.08 mg/kg (up to 5mg in adults)
• 10mL of a 1mg/mL solution
• Clinical Considerations
• Effects apparent in 5-10 min
• peak at 10 min
• lasts more than an hour
• Pediatric and elderly pts are more sensitive
  ? require a smaller dose

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Neostigmine

• Anticholinergics minimize Muscarinic side effects
• Glycopyrrolate has similar onset of action
  
  (0.2mg per 1ml of Neostigmine)
• Atropine is better choice in pregnant pts
  
  (b/c Neostigmine crosses placenta resulting in
  fetal bradycardia)
• Side effects
• N/V, incontinence, delayed recovery room
  discharge, atropine-resistant bradycardia (higher
  dose, 200ug)

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Pyridostigmine

• Physical structure
• Lipid insoluble, cannot pass BBB

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Pyridostigmine

• Dosage Packaging
• 0.1- 0.4mg/kg (up to total 20mg in adults)
• Solution of 5mg/mL
• Clinical Consideration
• onset is slower (10-15 min)
• duration is longer (gt2h)
• Glycopyrrolate (0.05mg per 1mg of Pyridostigmine)
  or atropine (0.1mg per 1mg of Pyridostigmine)
• Glycopyrrolate is preferred

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Edrophonium

• Dosage Packaging
• Less than 10 as potent as Neostigmine
• 0.5-1mg/kg
• Solution of 10mg/mL
• Clinical Consideration
• Most rapid onset 12mins
• Shortest duration of effect
• Higher doses prolongs duration (more than 1h)
• Not as effective in reversing intense blockade
• Atropine(0.014mg per 1mg of Edrophonium)

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Physostigmine

• Physical structure
• lipid soluble, freely passes the BBB

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Physostigmine

• Dosage Packaging
• 0.01-0.03mg/kg
• Solution of 1mg/mL
• Clinical Consideration
• Limited as reversal agent
• Effective in treatment of central anticholinergic
  toxicity
• Reverses CNS depression and delirium associated
  with use of benzodiazepine and volatile
  anesthetics
• Preventing postoperative shivering(0.04mg/kg)
• Partially antagonizes morphine induced
  respiratory depression

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Physostigmine

• Side Effects
• excessive salivation, vomiting, convulsion