Anticholinesterases, Anticholinergics, and the Autonomic Nervous System

Question 1

somatic (voluntary)

Answer 1

skeletal muscle

Question 2

autonomic (visceral)

Answer 2

cardiac muscle, smooth muscle, glandular tissue

Question 3

parasympathetic cranial nerves

Answer 3

3, 7, 9, 10

• III oculomotor nerve
• VII facial nerve
• IX glossopharyngeal nerve
• X vagus nerve

Question 4

cholinergic nerves

Answer 4

release AHc (muscarinic and nicotinic)

Question 5

adrenergic nerves

Answer 5

NE and Epi (alpha 1+2, beta 1+2, dopaminergic 1-5)

Question 6

preganglionic nerves

Answer 6

arise in CNS and synapse in ganglia

Question 7

postganglionic nerves

Answer 7

from ganglia to effector sites

Question 8

cholinergic nerves include…

Answer 8

– 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

Question 9

dual innervation

Answer 9

symp and parasymp innervation

Question 10

cholinergic function

Answer 10

• 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

Question 11

effects of Ach

Answer 11

• 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

Question 12

anticholinesterases =

Answer 12

cholinesterase inhibitors

Question 13

cholinesterase inhibitors (use)

Answer 13

• 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.

Question 14

cholinesterase inhibitors (specificity)

Answer 14

• 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

Question 15

cholinergic crisis/ anti cholinesterase overdose

Answer 15

• 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

Question 16

cholinergic crisis treatment

Answer 16

• 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

Question 17

anticholinergic poisoning

Answer 17

• Mad as a hatter.
• Blind as a bat.
• Dry as a bone.
• Red as a beet.
• Hot as a pistol.

Question 18

Reversible Inhibition

Answer 18

– Reversible Inhibition
– Edrophonium
• Formation of Carbamyl Esters
– Neostigmine, pyridostigmine, physostigmine

Question 19

Irreversible Inactivation

Answer 19

– Irreversible Inactivation

• Echothiophate, other organophosphates

Question 20

Edrophonium

Answer 20

• 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

Question 21

Neostigmine, pyridostigmine, physostigmine

Answer 21

• 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

Question 22

Echothiophate

Answer 22

• 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)

Question 23

Pharmacologic Effects‐ Anticholinesterases

Answer 23

• 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

Question 24

Neostigmine Structure

Answer 24

• Carbamate moiety
– Provides covalent bonding of the drug to AChE
• Quaternary ammonium group
– Limits diffusion across plasma membranes

Question 25

Neostigmine Clinical Considerations

Answer 25

• 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

Question 26

Neostigmine (peds and elderly)

Answer 26

``` • 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) ```

Question 27

Neostigmine (pregnancy)

Answer 27

Fetal bradycardia has been reported indicating crosses placenta

Question 28

Neostigmine (nausea)

Answer 28

• Neostigmine causes N/V at doses exceeding 2 ‐2.5 mg

Question 29

Pyridostigmine (structure)

Answer 29

``` • 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 ```

Question 30

Pyridostigmine (onset, DOA)

Answer 30

• 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

Question 31

Edrophonium (structure)

Answer 31

• Lacks carbamate group – bonding to AChE is noncovalent • Quaternary ammonium group – limits lipid solubility • Less than 10% as potent as neostigmine

Question 32

Edrophonium (onset, DOA)

Answer 32

• 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

Question 33

Edrophonium vs Neostigmine

Answer 33

• Less effective than neostigmine when residual NMB is significant • Less muscarinic effects compared with neostigmine and pyridostigmine – May use smaller doses of antimuscarinic

Question 34

Edrophonium (age)

Answer 34

• Patients at extremes of age are not more sensitive to edrophonium

Question 35

Physostigmine (structure)

Answer 35

• 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

Question 36

Physostigmine (uses)

Answer 36

– 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.

Question 37

Physostigmine (onset, DOA)

Answer 37

• 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)

Question 38

Physostigmine (other effects)

Answer 38

– Salivation, vomiting, convulsions...

Question 39

Echothiophate (eye gtts)

Answer 39

• 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

Question 40

Anticholinergic Drugs and Muscarinic Receptors

Answer 40

• 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)

Question 41

Anticholinergic Drugs Clinical Uses

Answer 41

– 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

Question 42

Anticholinergic/Antimuscarinic

Answer 42

• 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

Question 43

Central Anticholinergic Drugs

Answer 43

``` • Central Anticholinergic Syndrome – Scopolamine and atropine can cause unwanted CNS effects • Restlessness • hallucinations • Somnolence • unconsciousness ```

Question 44

Treatment Central Anticholinergic Symptoms

Answer 44

– Treat with physostigmine (15‐60 mcg/kg IV)

Question 45

Atropine (uses)

Answer 45

- premedicate antisialogogue - minimize the muscarinic effects of anticholinesterases (potent effects of heart and bronchial smooth muscle, most efficious for tx brady)

Question 46

Atropine (caution)

Answer 46

- caution is patients with glaucoma, prost hypertrophy, bladder and neck obstruction - lipid solubility, risk for central anticholinergic toxicity

Question 47

Scopolamine (uses)

Answer 47

• 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

Question 48

Scopolamine (caution)

Answer 48

* Caution in patients with narrow (closed) angle glaucoma, prost hypertrophy, bladder neck obstruction * Lipid solublityrisk for Central Anticholinergic toxicity – Amenable to transdermal administration

Question 49

Glycopyrrolate (uses)

Answer 49

• 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