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Pharmacology > Anticholinesterases, Anticholinergics, and the Autonomic Nervous System > Flashcards

Anticholinesterases, Anticholinergics, and the Autonomic Nervous System Flashcards

1
Q

somatic (voluntary)

A

skeletal muscle

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2
Q

autonomic (visceral)

A

cardiac muscle, smooth muscle, glandular tissue

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3
Q

parasympathetic cranial nerves

A

3, 7, 9, 10

  • III oculomotor nerve
  • VII facial nerve
  • IX glossopharyngeal nerve
  • X vagus nerve
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4
Q

cholinergic nerves

A

release AHc (muscarinic and nicotinic)

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5
Q

adrenergic nerves

A

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

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6
Q

preganglionic nerves

A

arise in CNS and synapse in ganglia

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7
Q

postganglionic nerves

A

from ganglia to effector sites

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8
Q

cholinergic nerves include…

A

– 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

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9
Q

dual innervation

A

symp and parasymp innervation

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10
Q

cholinergic function

A

• 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

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11
Q

effects of Ach

A

• 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
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12
Q

anticholinesterases =

A

cholinesterase inhibitors

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13
Q

cholinesterase inhibitors (use)

A

• 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.

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14
Q

cholinesterase inhibitors (specificity)

A

• 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

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15
Q

cholinergic crisis/ anti cholinesterase overdose

A

• 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
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16
Q

cholinergic crisis treatment

A

• 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

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17
Q

anticholinergic poisoning

A
  • Mad as a hatter.
  • Blind as a bat.
  • Dry as a bone.
  • Red as a beet.
  • Hot as a pistol.
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18
Q

Reversible Inhibition

A

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

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19
Q

Irreversible Inactivation

A

– Irreversible Inactivation

• Echothiophate, other organophosphates

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20
Q

Edrophonium

A

• 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

21
Q

Neostigmine, pyridostigmine, physostigmine

A

• 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

22
Q

Echothiophate

A

• 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)

23
Q

Pharmacologic Effects‐ Anticholinesterases

A

• 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

24
Q

Neostigmine Structure

A

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

25
Q

Neostigmine Clinical Considerations

A

• 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

26
Q

Neostigmine (peds and elderly)

A 
• 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)
27
Q

Neostigmine (pregnancy)

A

Fetal bradycardia has been reported indicating crosses placenta

28
Q

Neostigmine (nausea)

A

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

29
Q

Pyridostigmine (structure)

A 
• 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
30
Q

Pyridostigmine (onset, DOA)

A

• 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

31
Q

Edrophonium (structure)

A

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

32
Q

Edrophonium (onset, DOA)

A

• 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

33
Q

Edrophonium vs Neostigmine

A

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

34
Q

Edrophonium (age)

A

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

35
Q

Physostigmine (structure)

A

• 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

36
Q

Physostigmine (uses)

A

– 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.

37
Q

Physostigmine (onset, DOA)

A

• 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)

38
Q

Physostigmine (other effects)

A

– Salivation, vomiting, convulsions…

39
Q

Echothiophate (eye gtts)

A

• 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

40
Q

Anticholinergic Drugs and Muscarinic Receptors

A

• 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)

41
Q

Anticholinergic Drugs Clinical Uses

A

– 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

42
Q

Anticholinergic/Antimuscarinic

A

• 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

43
Q

Central Anticholinergic Drugs

A 
• Central Anticholinergic Syndrome
– Scopolamine and atropine can cause unwanted CNS effects
• Restlessness 
• hallucinations
• Somnolence 
• unconsciousness
44
Q

Treatment Central Anticholinergic Symptoms

A

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

45
Q

Atropine (uses)

A
  • premedicate antisialogogue
  • minimize the muscarinic effects of anticholinesterases (potent effects of heart and bronchial smooth muscle, most efficious for tx brady)
46
Q

Atropine (caution)

A
  • caution is patients with glaucoma, prost hypertrophy, bladder and neck obstruction
  • lipid solubility, risk for central anticholinergic toxicity
47
Q

Scopolamine (uses)

A

• 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

48
Q

Scopolamine (caution)

A
  • Caution in patients with narrow (closed) angle glaucoma, prost hypertrophy, bladder neck obstruction
  • Lipid solublityrisk for Central Anticholinergic toxicity – Amenable to transdermal administration
49
Q

Glycopyrrolate (uses)

A

• 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

Pharmacology (9 decks)

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