Anticholinesterases, Anticholinergics, and the Autonomic Nervous System Flashcards
somatic (voluntary)
skeletal muscle
autonomic (visceral)
cardiac muscle, smooth muscle, glandular tissue
parasympathetic cranial nerves
3, 7, 9, 10
- III oculomotor nerve
- VII facial nerve
- IX glossopharyngeal nerve
- X vagus nerve
cholinergic nerves
release AHc (muscarinic and nicotinic)
adrenergic nerves
NE and Epi (alpha 1+2, beta 1+2, dopaminergic 1-5)
preganglionic nerves
arise in CNS and synapse in ganglia
postganglionic nerves
from ganglia to effector sites
cholinergic nerves include…
– All motor nerves that innervate skeletal muscle (somatic)
– All preganglionic parasymp and pregang symp neurons
– All postganglionic parasymp neurons
– Some post ganglionic symp neurons (sweat glands and certain bld vess)
– Preganglionic symp neurons that originate from the grtrsplanchnic nerve and innervate the Adrenal Medulla
– Central cholinergic neurons
dual innervation
symp and parasymp innervation
cholinergic function
• The parasympathetic NS is localized in its effects
– Conservation of energy and maintain organ function
– Massive parasympathetic response (i.e., after anticholinesterase administration)
• Salivating
• Wheezing
• Urinating
• Seizing
• Weeping
• Vomiting
• Defacating
– Necessary for maintenance of life in contrast to SNS
effects of Ach
• The Muscarinic effects of ACh are similar to vagal stimulation
- Generalized vasodilation (incl cor/pulm circ)
- Negative chrono/dromotropic effects
- Inhibition of NE release from adrenergic nerves
- Smooth musc contraction (bronch, int, gu)
- Relaxation of sphincters
- Contraction of the iris
- Lacrimal, trach/bronch, salivary, dig, exocrine secretion
anticholinesterases =
cholinesterase inhibitors
cholinesterase inhibitors (use)
• Primarily used for reversal of residual NMB by NDMRs
– Goal is inhibition of AChE (“true cholinesterase”) •
– “Reversal” is only appropriate (SAFE) after evidence of spontaneous recovery from NDMRs
• A single twitch on the TOF MUST be present – 2/4 on TOF is better.
cholinesterase inhibitors (specificity)
• Are not specific to the nAChRs of the NMJ
– By inhibiting the hydrolysis of ACh, the neurotransmitter is available in greater concentrations at all sites of action
• Ganglionic nAChRs (both parasympathetic and sympathetic) • However, mAChRs produce the most important effects
cholinergic crisis/ anti cholinesterase overdose
• Often by organophosphate insecticides manifest as
– Bradycardia – Miosis – Abdominal cramps – Loss of bowel and bladder control – Weakness – Confusion – Ataxia – Coma seizures – Ventilatory depression SLUDGE syndrome: Salivation, Lacrimation, Urination, Defacation, GI upset, Emesis
cholinergic crisis treatment
• Treatment
– Supportive measures
• Intubation and mechanical ventilation
– Administration of an anticholinergic
– Also, administration of the AChE reactivator
• Pralidoxime
– “Antagonizes” the CNS effects of excessive ACh
anticholinergic poisoning
- Mad as a hatter.
- Blind as a bat.
- Dry as a bone.
- Red as a beet.
- Hot as a pistol.
Reversible Inhibition
– Reversible Inhibition
– Edrophonium
• Formation of Carbamyl Esters
– Neostigmine, pyridostigmine, physostigmine
Irreversible Inactivation
– Irreversible Inactivation
• Echothiophate, other organophosphates
Edrophonium
• Electrostatic attachment to the anionic site on
the enzyme
– Further stabilization by hydrogen bonding at the
esteratic site
• Brief DOA
• Predominant site of action appears to be
presynaptic nAChE
• Milder muscarinic effects than the longer acting anticholinesterases
Neostigmine, pyridostigmine, physostigmine
• Carbamyl ester complex formed at the
esteratic site of the enzyme – Produces reversible inhibition
• These drugs compete with Ach for binding sites on the AChE enzyme
Echothiophate
• Organophosphates combine with AChE at the esteratic site to form a stable inactive complex that does not undergo hydrolysis
– Synthesis of new enzyme is required for return of normal function (can take hours)
(Echothiophate is available as eye drops but is not used clinically in anesthetic practice)
Pharmacologic Effects‐ Anticholinesterases
• Primarily reflect muscarinic effects – Bradycardia and decreased SVR
– Salivation and Hyperperistalsis
– Bronchial secretions and bronchoconstriction – Miosis
• Antimuscarinic (also anticholinergic or antiparasympathetic) drugs block the effects of anticholinesterases at muscarinic sites but not at the NMJ
– Atropine, glycopyrrolate, scopolamine
Neostigmine Structure
• Carbamate moiety
– Provides covalent bonding of the drug to AChE
• Quaternary ammonium group
– Limits diffusion across plasma membranes
Neostigmine Clinical Considerations
• Peak: ~10 minutes
- Glycopyrrolate is preferred as the antimuscarinic due to its slower time to onset (for co-administration)
- Less resultant tachycardia than atropine
-• DOA:>1hour
– Prolonged with CRI/CRF
Neostigmine (peds and elderly)
• Peds and Elderly: – more sensitive to effects – more rapid onset – require smaller dose • Elderly: – prolonged DOA • Muscarinic effects are attenuated by prior or concomitant administration of an anticholinesterase (glycopyrrolate)
Neostigmine (pregnancy)
Fetal bradycardia has been reported indicating crosses placenta
Neostigmine (nausea)
• Neostigmine causes N/V at doses exceeding 2 ‐2.5 mg
Pyridostigmine (structure)
• Structurally similar to neostigmine – Except NH4+ group is incorporated into phenol ring – Carbamate moiety • Covalent bonding to AChE An ester linkage is a covalent bond – Poorly lipid soluble • 20% as potent as neostigmine
Pyridostigmine (onset, DOA)
• Time to onset: 10‐15 min
Glyco is preferred as the antimuscarinic due to its slower time to onset (for co-administration)
• DOA: > 2 hours
– Prolonged with CRI/CRF
Edrophonium (structure)
• Lacks carbamate group
– bonding to AChE is noncovalent • Quaternary ammonium group
– limits lipid solubility
• Less than 10% as potent as neostigmine
Edrophonium (onset, DOA)
• Onset: 1‐2 min
– Fastest in the class
Clinical Considerations
– Atropine may be co‐administered d/t fasteronset time
– Glycopyrrolate should be administered several minutes prior to
edrophonium
• DOA: > 1 hour in large doses
– Smaller doses have much shorter DOA – Prolonged with CRI/CRF
Edrophonium vs Neostigmine
• Less effective than neostigmine when residual NMB is significant
• Less muscarinic effects compared with neostigmine and pyridostigmine
– May use smaller doses of antimuscarinic
Edrophonium (age)
• Patients at extremes of age are not more sensitive to edrophonium
Physostigmine (structure)
• Carbamate group
– Covalent bonding to the AChE
• Tertiary amine group (unique for the class)
– Confers lipid solubility
– The only available anticholinesterase that can reliably access the CNS
Physostigmine (uses)
– The only available anticholinesterase that can reliably access the CNS
• Useful in the treatment of anticholinergic toxicity caused by atropine & scopolamine, but not NMBD
• Also may reverse CNS depression and delirium and MSO4‐induced apnea
– 0.04 mg/kg may prevent post op shivering
– Large doses may cause central cholinergic crisis
• glycopyrrolate is not effective in the tx of CCC because of its limited lipid solubility.
Physostigmine (onset, DOA)
• Anticholinergic agent not generally necessary…
• Bradycardia is infrequent, but atropine and glyco should be immediately available
• Onset: 5 min
• DOA: 30‐300 min
– Not prolonged with CRI/CRF
• Metabolism: plasma esterases (unique for the class)
Physostigmine (other effects)
– Salivation, vomiting, convulsions…
Echothiophate (eye gtts)
• Organophosphate
• Combines irreversibly with AChE at the esteratic
site
– A stable inactive complex is formed
• Hydrolysis does not occur
– Synthesis of new enzyme is required for termination
of effects
• Inhibits plasma cholinesterase and may prolong
duration of action of SCh
Anticholinergic Drugs and Muscarinic Receptors
• Combine reversibly with muscarinic receptors to compete with ACh
– Presynaptic cholinoreceptors may inhibit the release of NE
• Antimuscarinic drugs may enhance sympathetic activity • Block all muscarinic effects
– Drugs are in development to act on specific muscarinic receptor subtypes (heart, bronchial smooth musc)
Anticholinergic Drugs Clinical Uses
– Treatment of reflex bradycardia
• Atropine is the drug of choice (use with care)
-Reversal of NMB
• In combination with anticholinesterases to prevent deleterious parasympathetic effects, concomitant or prior to anticholinesterase
– Biliary sm musc relaxation
• Decreases biliary and ureter smooth muscle contraction
– Bronchodilation
• Ipratropium MDI used in asthma
– Few extrapulmonary effects
• Prevention of motion sickness / PONV – Scopolamine transdermal patch
Anticholinergic/Antimuscarinic
• Comptetively block acetylcholine
• Antimuscarinic is a more appropriate term for these drugs as their actions are most selective for muscarinic receptors
– Subclasses of muscarinic receptors have varying affinity for the antimuscarinic agents
Central Anticholinergic Drugs
• Central Anticholinergic Syndrome – Scopolamine and atropine can cause unwanted CNS effects • Restlessness • hallucinations • Somnolence • unconsciousness
Treatment Central Anticholinergic Symptoms
– Treat with physostigmine (15‐60 mcg/kg IV)
Atropine (uses)
- premedicate antisialogogue
- minimize the muscarinic effects of anticholinesterases (potent effects of heart and bronchial smooth muscle, most efficious for tx brady)
Atropine (caution)
- caution is patients with glaucoma, prost hypertrophy, bladder and neck obstruction
- lipid solubility, risk for central anticholinergic toxicity
Scopolamine (uses)
• More potent antisialogogue and greater CNS effects than atropine
• Sedation and amnesia as well as restlessness and delirium may
occur
• Prevention of motion sickness / PONV
– To minimize the muscarinic effects of anticholinesterases
Scopolamine (caution)
- Caution in patients with narrow (closed) angle glaucoma, prost hypertrophy, bladder neck obstruction
- Lipid solublityrisk for Central Anticholinergic toxicity – Amenable to transdermal administration
Glycopyrrolate (uses)
• Potent antisialogogue
• ↑HR after IV—but less so with IM—administration • DOA: 2‐4 hours after IV adm
– To minimize the muscarinic effects of anticholinesterases
