by Dr N Shava (SHO Anaesthesia) United Bulawayo Hospitals

1. CHOLINESTERASE INHIBITORS
AND ANTICHOLINERGIC DRUGS

2. ROLE OF ACETYLCHOLINE IN THE NERVOUS
SYSTEM

4. • Acetylcholine is one of the major neurotransmitters in the nervous system
• In the CNS: Found in the basal forebrain, diencephalon, hippocampus
• In the PNS:
• All parasympathetic neurons- both pre and postganglionic
• All preganglionic sympathetic neurons
• Postganglionic sympathetic neurones in sweat glands and skeletal muscle
blood vessels
• All somatic motor neurons (at the NMJ – mediates muscle contraction)
• Action of Ach at these sites (whether excitatory or inhibitory), depends on
the receptor type

5. CHOLINERGIC RECEPTORS
• Receptors that respond to acetylcholine
• Two types: Nicotinic and Muscarinic
• Whereas muscarine will only bind muscarinic receptors and nicotine only
nicotinic, acetylcholine binds both
• The effect of acetylcholine is determined by the type of receptor it binds
NICOTINIC MUSCARINIC

6. NICOTINIC RECEPTORS
• Ligand-gated Sodium Na⁺/ K⁺ channels
• Excitatory receptors
• Mediate fast synaptic transmission of nerve impulses
• Two subtypes:
• Nₘ (N1) - Located only on skeletal muscle( NMJ) – mediate muscle
contraction
• Nₙ (N2) - postganglionic neuronal cells
- Adrenal medulla ( chromaffin cells)
- Central nervous system ( memory, arousal, analgesia)

7. MUSCARINIC RECEPTORS
• Transmembrane proteins
• G-protein coupled receptors
• Can be excitatory (M1, M3, M5) , or inhibitory (M2, M4)
• Mediate a slow metabolic response via second messenger cascades

8. M1 CNS
GIT
Cognitive function
Stimulates gastric glands
M2 Heart - SA Node
-AV Node
-Presynaptic nerve terminals
Decreases heart rate
Decreases conduction velocity, heart block
Inhibits release of acetylcholine
M3 Exocrine glands - Sweat glands
Respiratory system -Naso-palatal glands
-Bronchial glands
-Bronchial smooth muscle
GI Tract -Salivary glands
-Motility/ tone
-Sphincters
-Secretion
- GB and ducts
Urinary -Detrusor muscle
-Internal urethral sphincter
Eye -Sphincter pupillae muscle
-Ciliary muscle
-Lacrimal gland
Increased sweating
Secretion (↑mucus production)
Stimulation (↑mucus production)
Bronchoconstriction
Increased saliva production
Increased ( ↑peristalsis)
Relaxation of internal anal-defecation
↑ HCL , Pepsinogen, Intestinal secretions
Contraction (bile secretion)
Bladder contraction – voiding
Relaxation – voiding
Contraction (pupil constriction)
Contraction (accommodation for near vision)
Secretory (produces tears)
M4/ M5 CNS functions Memory, arousal, analgesia

9. SYNTHESIS OF ACETYLCHOLINE
• Acetylcholine is synthesised in the cholinergic nerve terminals
• The precursors are Acetyl CoA from the mitochondria and choline which is
transported into the cytoplasm of the neurone from the extracellular space
by the choline/Na transporter, it has its highest concentration in nerve
terminals and its presence is a marker that a neurone is cholinergic
• The enzyme Choline acetyltransferase catalyses this reaction
• After synthesis Ach is transported into vesicles by the vesicular Ach
transporter where it is stores until it’s needed
• 1000-50000 Ach molecules per vesicle, 300 000 vesicles per neurone
• Release from vesicles occurs when calcium interacts with the vesicles
causing them to fuse with the presynaptic membrane via SNARE proteins

11. • After Ach is released from the nerve terminals, one of three things may
happen
1. May bind to post synaptic receptors and elicit a cellular response
2. May bind to the Ach autoreceptor on the pre-synaptic membrane
thereby shutting down its further release
3. May be immediately degraded by the Acetylcholinesterase (AchE)
enzyme
- this is the primary way of inactivating Ach
-Acetylcholinesterase is found mostly bound to the post-synaptic
membrane adjacent to cholinergic receptors
-AchE is very efficient – cleaves Ach molecules at a rate of 1000/second

12. ACETYLCHOLINESTERASE
• Two main physiologic types of AchE TRUE AchE (1st AchE/ AchE)
PSEUDO AchE (plasma/s-type/butyryl)
TRUE ACETYLCHOLINESTERASE
• Highly specific for Ach and a few closely related esters
• Has a very high affinity for Ach, has a high turnover rate and is
inhibited by high concentrations of Ach
• Found in all excitable tissue: nerve, muscle, most erythrocytes,
placental tissue ; soluble form is found in the CSF
• It is not found in serum

13. PLASMA/PSEUDOCHOLINESTERASE
• More widely distributed: found in tissues like Brain, liver, skin, smooth
muscle
• Soluble form is found in plasma
• Physiologic function is not known
• Hydrolyses synthetic Butyrylcholine, Suxamethonium, Mivacurium,
Procaine
• Not inhibited by excess acetylcholine

14. AChE has 2 active sites, an
anionic site and an esteric site
- the anionic site is
responsible for binding of Ach
to the enzyme
-the esteric site is the site of
hydrolysis
• Catalytic hydrolysis of Ach
results in transfer of its
acetyl group to the esteric
site, releasing a free choline
molecule and acetate
• The enzyme is
spontaneously hydrolysed
during the process, thus
reactivated
• Any drug that acts as an
AchE inhibitor should inhibit
the activity of the esteric
site

15. ACETYLCHOLINESTERASE INHIBITORS
• Drugs that prolong the existence of Ach by inhibiting AchE and PseudoAchE
• They can be classified as – Short acting
- Medium acting
- Long acting
• Short and medium acting inhibitors exhibit reversible inhibition
• Long acting inhibitors are irreversible
• Duration of action varies according to the stability of the bond formed
between the enzyme and the drug
• There are three important chemical groups: Carbamates
- Organophosphates
- Quaternary ammonium cmpds

16. SHORT ACTING AChE INHIBITORS - EDROPHONIUM
• The only short acting AchE inhibitor available for reversal of
neuromuscular blockade
• It contains a quaternary amine group that binds AchE at the anionic
site
• It has an OH grp that interacts with the enzyme at the esteric site-
forming a hydrogen bond
• The weak hydrogen bond accounts for its short duration of action
• It is also rapidly eliminated by the kidneys
• It exhibits competitive inhibition – when Ach levels are increased, the
action of Edrophonium decreases

17. • Recommended dose for reversal of neuromuscular blockade is 0.5 –
1mg/kg
• When administered IV, peak effect is within 0.8-5.0 minutes and duration
of action is about 10 minutes
• Potency is 12-16 X less than that of Neostigmine and effects are less
predictable
• Significant spontaneous recovery should be present for it to be effective
• Unsuitable for antagonizing long-acting neuromuscular blockers as their
duration of action may outlast it, especially if given at less than
recommended doses

18. • It has less pronounced muscarinic side effects – requires half the amount of
anticholinergic as neostigmine
• Short onset of action is similar to that of atropine hence they can be used
together (0.014mg Atropine per 1mg Edrophonium)
• If Glycopyrrolate ( 0.007mg/1mg) is used it has to be given several minutes
before the Edrophonium to avoid the possibility of bradycardia
• Edrophonium contains a tertiary ammonium group which renders it lipid
insoluble – it does not cross the Blood-brain-barrier(BBB)
• An important role is its use in the diagnosis of Myasthenia Gravis (tensillon
test)

19. MEDIUM ACTING ACETYLCHOLINESTERASE INHIBITORS -
STIGMINES
• Stigmines have an ammonium group that binds to the anionic site of
the enzyme
• They have a carbamate group on the other side that interacts with
the esteric site of the enzyme, forming a covalent bond
• The carbamate group is ultimately transferred to the serine moiety of
the esteric site (carbamylation), thereby inhibiting its activity
• Carbamylation forms a strong bond that cannot be easily hydrolysed
therefore increasing duration of action

20. NEOSTIGMINE
• A synthetic acetylcholinesterase inhibitor
• Contains a quaternary ammonium group- cannot cross the BBB, only
has peripheral actions
• Recommended dose is 0.04 – 0.08mg/kg ( up to 5mg in adults)
• Onset of action is about 1 minute but effects are apparent after about
5 minutes with a peak at 10 minutes and last 20-30 minutes
• Duration of action is increased in geriatrics
• It is metabolised by plasma esterases to a quaternary alcohol, 60% is
excreted in urine – in the presence of renal impairment plasma
clearance is reduced and ½ life prolonged

21. • Neostigmine causes bradycardia which may progress to cardiac arrest
with high doses
• It also increases the incidence of PONV
• Muscarinic side effects are best prevented by coadministration with
Glycopyrrolate (0.2mg/1mg) which is better matched to the time
course of action of neostigmine than atropine (0.4mg/1mg) and is
associated with less tachycardia
• Neostigmine crosses the placenta and may cause fetal bradycardia
• Other clinical uses include treatment of Myasthenia gravis, Urinary
bladder atony and paralytic ileus

22. PYRIDOSTIGMINE
• A synthetic AchE inhibitor
• Has a quaternary ammonium group – cannot cross the BBB
• It is an analogue of neostigmine with about a quarter of its potency
• Not used for reversal of neuromuscular blockade due to its long onset
of action ( >16 minutes), and long duration of action (2-6 hours)
• It is the drug of choice for the treatment of myasthenia gravis
• Administered in doses up to 25mg/kg
• It must be given together with Glycopyrrolate or atropine to prevent
bradycardia

23. PHYSOSTIGMINE
• A naturally occurring compound
• Has a methylcarbamate group responsible for its actions on AchE
• It contains a tertiary amine group rendering it lipid soluble – the only
clinically available AchE inhibitor that crosses the BBB, this limits its
usefulness as a reversal agent for non-depolarizing blockade
• It can be used in the treatment of atropine overdose where it can
inhibit the central side effects
• It also reverses some of the CNS depression and delirium associated
with the use of benzodiazepine and volatile anaesthetics

24. • It is also effective in preventing post-op shivering (0.04mg/kg)
• Partially antagonises morphine induced respiratory depression
• Bradycardia is infrequent at recommended doses
• Glycopyrrolate does not cross the BBB so will not reverse effects
• At high doses it may cause convulsions due to CNS excitation
• It is metabolised by plasma esterases

25. ORGANOPHOSPHATES
• Most clinically important long acting AchE inhibitors
• The phosphorus group interferes with the serine residue and causes its
phosphorylation
• This results in a very strong bond which cannot be reversed
• Organophosphates produce long lasting effects that persist beyond the presence
of the drug in circulation
• High lipid solubility, low molecular weight and volatility are features of this group
of drugs facilitating rapid and effective absorption via inhalation and the
transdermal route. They also readily penetrate the central nervous system
• Recovery of anticholinesterase activity depends mainly on synthesis of new
enzyme
• Death occurs due to overstimulation of both nicotinic and muscarinic receptors –
usual due to asphyxia caused by diaphragmatic spasm

26. ECOTHIOPATE
• An irreversible organophosphate used clinically as topical drops for
the treatment of glaucoma
• Also inactivates plasma AchE- may therefore prolong the action of
suxamethonium
• Advice is to discontinue echothiophate for a week before surgery for
elective cases

27. REVERSAL OF NEUROMUSCULAR BLOCKADE
• AChE inhibitors increase residence time of acetylcholine at the neuromuscular junction,
thereby allowing rebinding of the neurotransmitter with the nicotinic receptors
• This gives Ach a competitive advantage over the neuromuscular blocking agent
• They also increase the amount of Ach released by their action on presynaptic receptors
• The result is re-establishment of normal neuromuscular transmission – increased muscle
contraction and strength
• In overdose, depolarization of the endplate caused by excess acetylcholine predominates
and leads to depolarization block.
• The excess acetylcholine at the synapse also causes repeated stimulation of the
receptors resulting in the decay time of the endplate potential being prolonged.
• This destroys the synchrony between endplate depolarization and the development of
action potentials, leading to asynchronous excitation, and fibrillation and fasciculation of
the muscle.

28. The time required to fully reverse a non-depolarizing block depends on
several factors
• The choice and dose of AchE inhibitor
• The muscle relaxant being antagonized
• The extent of blockade before reversal

29. The choice and dose of AchE Inhibitor
• We have already looked at pharmacological factors that affect duration of
action of AchE inhibitors
• Clinical duration of action is also influenced by the rate of drug
disappearance from the plasma
• Clearance is due to both hepatic (25 -50%) and renal excretion (50-75%)
• In the presence of hepatic or renal insufficiency the duration action of
inhibitors is prolonged
• Differences in duration of action can also be altered by dosage adjustments
Thus the normally short duration of action of Edrophonium can be partially
overcome by increasing the dose
• Increasing the dose of inhibitor can also speed up reversal

30. The Muscle Relaxant being antagonized
• Spontaneous reversal of blockade must begin before administration of
reversal agent for it to be effective
• Spontaneous reversal depends on the diffusion, redistribution, metabolism
and excretion from the body of the muscle relaxant
• Concurrent excretion of metabolites provides a proportionately faster
reversal of the short and intermediate acting agents
• Intermediate acting muscle relaxants therefore require a lower dose of
reversal agent (for the same degree of block) than long acting relaxants
• These advantages can be lost in conditions associated with severe end
organ disease, e.g., the use of Vecuronium in a patient with homozygous
atypical pseudocholinesterase

31. The extent of blockade before reversal
• A shallow block is easier to reverse than a deep block
• Antagonism of residual block should not be attempted unless the
twitch height has recovered to more than 20% of control, or two
twitches are detectable on train-of-four stimulation.
• The deeper the block on antagonism, the longer the time required for
a standard dose of anticholinesterase to restore the twitch height or
train-of-four response to control values.
• Spontaneous recovery to a level adequate for pharmacological
reversal may take longer than 1 hour with long acting muscle
relaxants because of insignificant metabolism and slow excretion

32. • Factors associated with faster reversal are also associated with lower
incidence of residual paralysis in the recovery room and a decreased
risk of post-op respiratory complications
• A reversal agent should be routinely given to patients who have
received non-depolarizing muscle relaxants, unless full reversal can be
demonstrated or the post-op plan includes continued intubation and
ventilation
• Clinical signs of adequate reversal vary in sensitivity:
Sustained head lift > inspiratory force > vital capacity > tidal volume

33. MUSCARINIC SIDE EFFECTS
• Raised Ach levels caused by administration of AchE inhibitors act on
both nicotinic and muscarinic receptors (affect muscarinic more than
nicotinic)
• When reversing neuromuscular blockade, the goal is to maximize
nicotinic transmission with a minimum of muscarinic side effects
• It is advisable to co-administer muscarinic antagonists such as
Atropine or Glycopyrrolate to counter the accumulation in the
muscarinic synapses of the GIT, bronchi and CVS

34. Cardiovascular system
• Vagal influences on the heart are augmented by anticholinesterases. The
effective refractory period of atrial muscle is shortened and the refractory
period and conduction time at the sino-atrial (SA) and atrio-ventricular (AV)
nodes are prolonged. The predominant effect on the heart is bradycardia
caused by the accumulation of acetylcholine. This can result in a decrease
in cardiac output and blood pressure. Centrally-acting agents may cause
these effects by action on the vasomotor centre.
Respiratory system
• Anticholinesterases cause bronchial smooth muscle contraction leading to
bronchospasm and hypoxia, which is aggravated by an increase in
secretions.

35. Gastrointestinal system
• Oesophageal motility, gastric motility and production of gastric secretions are
enhanced. Also, anticholinesterases augment the motor activity of the small and
large bowel. In high doses, they can lead to vomiting, diarrhea and incontinence.
Eye
• On local application, anticholinesterases cause constriction of the sphincter
pupillae and ciliary muscles leading to miosis and blocking of the accommodation
reflex. Intraocular pressure, if elevated, usually decreases as a result of facilitation
of the outflow of aqueous humor.
Secretory glands
• Anticholinesterases increase the activity of all secretory glands innervated by
postganglionic cholinergic fibres, i.e. bronchial, salivary, sweat, lacrimal, gastric,
intestinal and pancreatic glands

36. ANTICHOLINERGIC DRUGS
• This term is commonly applied to drugs that block muscarinic
receptors
• Anticholinergics compete with Ach for a common binding site on the
muscarinic receptor
• The binding site is in a cleft formed by the muscarinic receptor’s
transmembrane helices
• Anticholinergics have an ester linkage that helps bind to the receptor
causing conformational change

38. ATROPINE
• Atropine is a synthetically derived form of the endogenous alkaloid
isolated from the plant Atropa belladona
• A non -selective competitive, reversible muscarinic antagonist
(M1,M2, M3, M4, M5)
• It has a role as a muscarinic antagonist, an anaesthesia adjuvant, an
anti-arrhythmia drug, a mydriatic agent, a parasympatholytic, a
bronchodilator agent, an antidote to organophosphate
and sarin poisoning
• It is typically given intravenously or by IM injection and is also
available as eye drops

39. ATROPINE – PHARMACOLOGICAL PROPERTIES
CARDIOVASCULAR SYSTEM
• Blocks M2 receptors in the sinoatrial node thereby blocking vagal influence and leading to
tachycardia
• There may initially be a transient bradycardia due to blockade of presynaptic M2 receptors on
parasympathetic (vagus) fibres, transiently increasing the amount of Ach in the synapse
• Atropine is particularly useful in reversing bradycardia due to vagal reflexes (baroreceptor,
peritoneal traction, oculomotor)
• There is decreased AV node conduction time – this may lead to increased ventricular rate in
patients with AF or Afib
• The effect on resting heart rate is less pronounced in infants and the elderly
• Patients with coronary artery disease may not tolerate the increased myocardial oxygen demand
and decreased oxygen supply associated with the tachycardia caused by atropine
• High doses may cause dilatation of cutaneous blood vessels causing flushing

40. • RESPIRATORY SYSTEM
• Atropine causes bronchodilatation and reduces bronchial secretions
• This may be useful in surgical procedures such as airway endoscopy
and in reducing excess secretions induced by anaesthetic agents like
ketamine
• It may increase respiratory rate and inhibit mucociliary clearance

41. EYE
• Atropine relaxes the ciliary muscle leading to pupil dilatation – this
manifests as photophobia
• Paralysis of accommodation – cycloplegia
• Loss of normal pupillary light reflex
• May increase intra-ocular pressure in patients with narrow angle
glaucoma

42. GASTROINTESTINAL SYSTEM
• Decreased salivary secretions –dry mouth
• Decreased gastric secretions with larger doses
• Decreased intestinal motility and peristalsis – increased gastric
emptying time
• Reduced lower oesophageal sphincter tone

43. GENITOURINARY SYSTEM
• Decreased ureter and bladder tone through blockade of M3 receptors
• Urinary retention (increased risk in elderly men with prostatic
hypertrophy)
THERMOREGULATION
• Inhibition of sweating and increased basal metabolic rate increases
body temperature
• Administration in infants and children with febrile illness may lead to
life threatening hyperthermia

44. CENTRAL NERVOUS SYSTEM
• Atropine does not easily cross the BBB in clinical doses
• High doses (5 -10mg)may cause restlessness, hallucinations and
delirium – progressing to CNS depression and coma
• Elderly patients are more vulnerable to CNS effects
• Large topical ophthalmic doses may also cause CNS effects

45. ATROPINE – CLINICAL USES AND DOSING
• The IV dose of atropine ranges from 5 to 20mcg/kg
• Peak effect is reached 1 min after i.v. administration and effects last up to
1 hr
• Atropine is absorbed from the gastrointestinal tract and metabolized in the
liver to tropine and tropic acid. Over 90% of the drug and its metabolites
are excreted in the urine within 24 h
Premedication
• Dose is 0.01 -0.02mg/kg (0.4 -0.6 in adults) IV or IM
• No longer routinely given due to the danger of masking physiologic
changes associated with arousal, pain, raised ICP, hypovolemia

46. Treatment of bradycardia
• for sinus bradycardia the dose is 0.04mg/kg (0.5-1mg)
• Larger IV doses of up to 3mg needed for severe bradycardia
• Contraindicated in hypothermic bradycardia and bradycardia with
acute haemorrhage causing myocardial ischaemia/ acute MI
• No longer indicated in PEA and asystole unless the cardiac arrest is
due to vasovagal response
• Ineffective in high degree A-V blocks

47. Antisialogogue:
• Dose is 0.01- 0.02 mg/kg IM
Organophosphate poisoning
• Given IV in high doses repeatedly/ infusion
• Do not give IM
• Also available as a mixture with Pralidoxime –recommended
• Reverses the effects of muscarinic stimulation but not the muscle
weakness resulting from nicotinic stimulation

48. Ophthalmology
• Ophthalmic preparations are available for eye examinations and
treatment of inflammatory conditions
Bronchospasm
• 0.025mg/kg in 2,5mls saline can be given 6-8hrly as a nebulizer
Reversal of neuromuscular blockade

49. ATROPINE -CONTRAINDICATIONS
• Narrow angle glaucoma
• Prostatic hypertrophy
• Bladder neck obstruction
• Pyloric stenosis

50. Glycopyrrolate
• Glycopyrrolate is a quaternary ammonium derivative, which is more
potent than atropine at most muscarinic and nicotinic receptors.
• It lacks central anticholinergic effects because of poor penetration
through the blood–brain barrier- also has no ophthalmic activity
• The i.v. dose is 3–10 mg kg1 .
• Although onset of action is within 1 min of i.v. administration, peak
effect is at 3 min
• Oral absorption is very poor. The drug is metabolized in the liver by
hydroxylation and oxidation, and excreted in urine and bile

51. • Cardiovascular responses to glycopyrrolate are similar to those of atropine. Bradycardia
may occur at lower doses, but tachycardia is usually less prominent and of shorter
duration
• Impairment of autonomic and baroreceptor reflexes is about half the duration of that
with atropine
• Main indication is for premedication due to potent inhibition of salivary gland and
respiratory tract secretions
• The antisialogogue effect of glycopyrrolate is pronounced and lasts up to 8 hours, which
is 2–5 times longer than that of atropine
• The usual dose of glycopyrrolate is 0.004 mg kg–1 as an antisialogogue or for reversal of
intraoperative bradycardia.
• For reversal of neuromuscular blockade the recommended dose of glycopyrrolate is 0.2
mg for each 1 mg of neostigmine or 5 mg of pyridostigmine.
• Also used to treat peptic ulcers in the oral form

52. SCOPOLAMINE
• It is a tertiary amine- therefore more readily penetrates the CNS
• In the usual clinical doses of 0.3–0.6 mg causes drowsiness, fatigue,
amnesia, dreamless sleep, and occasionally euphoria , making it a popular
choice for premedication prior to surgery.
• Sedative effects may interfere with awakening following short procedures
• Restlessness, vertigo, hallucinations, and delirium may occur in the elderly,
or in the presence of pain, even with the usual clinical doses.
• The most effective single drug to prevent and treat motion sickness ,
• It is less effective in preventing and treating perioperative nausea and
vomiting

53. • It has less effect on the cardiovascular system than atropine, but a
greater effect on the sweat glands and on the eye
• Because of its pronounced mydriatic effects, scopolamine is best
avoided in patients with closed-angle glaucoma
• Scopolamine inhibits bowel and bladder tone and should be avoided
in patients with intestinal obstruction and obstructive uropathy.
• Like atropine, scopolamine readily crosses the placenta , but it is not
considered to be teratogenic. It is safe in nursing mothers.

54. References
• Morgan & Mikhail's Clinical Anesthesiology, 6e. John F.
Butterworth IV, David C. Mackey, John D. Wasnick
• Miller's Anesthesia, 8th Edition
• Anesthetic Pharmacology. Basic Principles and Clinical
Practice, 2nd edition. Bovill, James G. MD, PhD.
• Online sources: YouTube, Wikipedia, BJA