ANTICHOLINESTERASE DRUGS

ANTICHOLINESTERASE DRUGS- NEOSTIGMINE
PHYSO, PYRIDO, EDROPHONIUM

1. ANTICHOLINESTERASE
DRUGS
DR. ZIKRULLAH
1

2. WHAT ARE
ANTICHOLINESTERASES?
Drugs that enhance cholinergic
transmission either by inhibiting
cholinesterase (the main group) or by
increasing acetylcholine release.
2

3. CHOLINERGIC PHARMACOLOGY
a)Main neurotransmitter: acetylcholine
b)Sites of action: parasympathetic ganglions
and effector cells,sympathetic
ganglia,adrenal medulla,sweat
glands,CNS neurons,somatic nerves
innervating skeletal muscles
c)Receptors: nicotinic and muscarinic
3

4. 4

5. 5

6. NICOTINIC MUSCARINIC
LOCATION Autonomic
ganglia(s,p)
Skeletal muscle
Glands(lacrimal,
salivary,gastric);
smooth
ms(bronchial,gi,
bladder,blood
vessels);heart(S
A/AV node)
AGONISTS Acetylcholine
Nicotine
Acetylcholine
Muscarine
ANTAGONISTS Nondepolarising
relaxants
Antimuscarinics
6

7. STRUCTURE-ACTIVITY
RELATIONSHIP
-chromosome 7q22(single gene)
a)Anionicsite:binds to quaternary ‘N’ of Ach
b)Esteraticsite:binds to ester linkage
-nerve growth promotiong activity &
modulation of nicotinic receptors
-single molecule is able to hydrolyse approx.
300,000 molecules of Ach
7

8. CLASSIFICATION
a)Reversible inhibition
Edrophonium
b)Carbamyl ester formation
Neostigmine,Pyridostigmine,Physostigmine
c)Irreversible inhibition
Organophosphorous insecticides,Nerve gases
8

9. MECHANISMS OF ACTION
a)Enzyme inhibition
Neostigmine,pyridostigmine,physostigmineact as
competitive substrate substitutes for Ach.
Acetylcholinesterase is carbamylated and it’s
ability to hydrolyse Ach is decreased
Edrophoniuminhibits enzyme by forming
electrostatic attachment to anionic site and
hydrogen bonding to esteratic site
This complex prevents Ach from approximating
correctly with the enzyme
9

10. b)Presynaptic effects
edrophoniumacts prejunctionally to enhance Ach
mobilisation and release
c)Direct effects at neromuscular junctions
neostigminehas an agonist action at nicotinic
receptors
*at very high doses,neuromuscular blockade may
occur due to excess Ach at neuromuscular
junction causing end-plate desensitisation
10

11. NEOSTIGMINE
-physical structure
carbamate moiety(covalent bonding)
quaternary ammonium group(lipid insoluble)
-onset ofaction:5-10 minutes
-duration of action: >1 hour
-50% dose actively secreted in renal tubules
-50% dose metabolised in the liver
-dose:0.04-0.08 mg/kg
-available as ampoules of 1ml(0.5 mg/ml or 0.25mg/ml)
and10ml(1 mg/ml) [prostigmin,tilstigmin]
11

12. -uses
i)antagonist-assisted reversal of nm blockade
0.2mg glycopyrrolate per 1mg neostigmine
0.4mg atropine per 1 mg neostigmine
ii)T/t of myasthenia gravis
oral dose 30 times more than i/v dose
iii)post-operative analgesia
intrathecal(50-100mcg) or epidural(1-4mcg/kg)
iv)T/t of paralytic ileus or urinary bladder atony
0.5-1.0mg s/c dose
12

13. *large volume of distribution(0.7-1.4L/kg) reflects extensive tissue storage in
liver and kidneys
*an increase in potency & duration of action occurs by linking 2 quaternary
ammonium nuclei by a chain of appropriate structure and length
DEMECARIUM=2 molecules of neostigmine connected at carbamate ‘N’
atoms by a series of 10 methylene groups
*dose requirement is decreased in infants & children
*duration of maximum response is increased in elderly
*as elimination t1/2 is increased in renal failure pts.,plasma clearance of these
drugs is prolonged to a greater extent than that of nondepolarising nm
blockers thus making occurrence of recurarization unlikely
13

14. PYRIDOSTIGMINE
-Physical structure
carbamate moiety
quaternary ammonium group incorporated into phenol ring
-onset ofaction:10-15 minutes
-duration of action: >2 hours
-75% dose actively secreted in renal tubules
-25% dose metabolised in the liver
-dose:0.1-0.4mg/kg(20% as potent as neostigmine)
-available as ampoules of 5 mg/ml [mestinon,regonol]
14

15. -uses
i)antagonist-assisted reversal of nm blockade
0.05 mg glycopyrrolate per 1 mg pyridostigmine
0.1 mg atropine per 1 mg pyridosigmine
ii)T/t of myasthenia gravis
iii)T/t of glaucoma
decrese intraocular pressure in both narrow and wide angle
glaucoma(reduce resistence to aqeous humor outflow)
*Pyridostigmine bromide has been FDA approved for military use during combat
situations as an agent to be given prior to exposure to the nerve agent Soman
in order to increase survival. Used in particular during the first Gulf War,
pyridostigmine bromide has been implicated as a causal factor in Gulf War
syndrome[2].
15

16. EDROPHONIUM
-Physical structure
lacks a carbamate group(non covalent binding to
acetylcholinesterase)
-onset ofaction:1-2 minutes(most rapid)
-duration ofaction:15-20 minutes(shortest)
-75% dose actively secreted in renal tubules
-glucuronide conjugation occurs in liver
-dose:0.5-1.0 mg/kg(<10% as potent as neostigmine)
-available as 10mg/ml ampoules [tensilon,reversol]
*ENLON-PLUS:10mg edrophonium + 0.14 mg atropine per
ml
16

17. -uses
i)Antagonist assisted reversal of nm blockade
more effective in reversing mivacurium blockade
0.014 mg atropine per 1 mg edrophonium
0.007 mg glycopyrrolate per 1mg edrophonium
ii)assesment of drug therapy of myasthenia gravis{TENSILON TEST}
1.0mg i/v every 1-2 minutes
decrease in symptoms points to inadequate drug therapy
increase in skeletal ms. weakness points to cholinergic crisis
iii)Diagnosis & management of cardiac dysarrhythmias
5-10mg i/v(25-30mg over 30 min.) in PSVT
17

18. PHYSOSTIGMINE
-Physical structure
tertiary amine with a carbamate group
no quaternary ammonium group(lipid
soluble)
-completely metabolised by plasma
esterases
-dose:0.01-0.03mg/kg
-available as 1 mg/ml ampoules [eserine]
18

19. -uses
I)T/t of CNS effects of certain drugs
i)central anticholinergic syndrome
overdose of atropine or scopolamine
15-60mcg/kg i/v decreases restlessness and confusion
ii)opiods
2mg i/v abolishes somnolent effects,reverses
depression of ventilatory response to CO2 and produces
analgesia comparable to that by 50 mg meperidine
19

20. iii)Volatile anaesthetics
2 mg i/v decreases post operative somnolence and delerium
iv)Ketamine,benzodiazepines,morphine
reverses adverse CNS effects and respiratory depression
II)Post operative shivering
0.04mg/kg i/v
similar efficacy as compared to meperidine or clonidine
III)Poisoning
antidote of choice in datura stramonium & atropa belladona
intoxication
20

21. PHARMACOLOGIC EFFECTS
-therapeutic or undesirable depending upon
the reason for anticholinesterase drug
administration
I)CVS
bradycardia
nodal and ventricular escape beats
asystole
decrease in systemic blood pressure
21

22. II)GIT
increased peristaltic
activity(esophageal,gastric,intestinal)
increased glandular secretions(salivary,parietal)
*perioperative bowel anastomotic
leak,nausea,vomiting,fecal incontinence
III)Respiratory
inceased bronchial secretions
bronchospasm
22

23. IV)CNS
diffuse activation on EEG
V)Urinary
increased tone of urinary bladder
VI)Eye
miosis
inability to focus for near vision
reduction in intraocular pressure
23

24. 24

25. CONTRAINDICATIONS
myotonia
muscular dystrophies
spinal cord transection
extensive burns
*increased occurrence of fasciculations and an augmented
twitch response
intestinal obstruction
urinary tract obstruction
25

26. DRUG INTERACTIONS
Echothiophate
Demecarium
Isofluropohote
Malathion: combination of these medicines with
anticholinesterase agents may result in SERIOUS side effects.
Guanadrel
Guanethidine
Mecamylamine
Procainamide
Trimethaphan: the effects of these medicines may interfere with
the actions of the anticholinesterase agents.
26

27. OTHER USEFUL
ANTICHOLINESTERASES
I)Tacrine
9-amino-1,2,3,4-tetrahydroacridine
penetrates blood-brain barrier
used in T/t of alzheimer’s disease
proposed as a disinfectant and in case of
morphine induced respiratory depression
high incidence of hepatotoxicity(reversible)
27

28. II)Donepezil
piperidine analogue
selective reversible inhibiitor of acetylcholinesterase
penetrates blood brain barrier
once daily dosing(elimination t1/2-70 hrs)
used in T/t of alzheimer’s disease
no hepatotoxicity
high incidence of nausea,vomiting,diarrhoea,abdominal
pain,dizziness,bradycardia
28

29. III)Rivastigmine
carbamate
well absorbed orally
penetrates blood brain barrier
twice daily dosing
used in T/t of alzheimer’s disease
no hepatotoxicity
IV)Ambenonium
carbamate
long acting anticholinesterase
used in the T/t of myasthenia gravis
29

30. V)Galantamine
phenanthrene derivative
selective,reversible inhibitor of cholinesterase
active both peripherally and in the CNS
used in the T/t of alzheimer’s disease
used in patients with chronic fatigue syndrome on antidepressive
drug therapy
VI)Huperazine
alkaloid of vegetable origin
inhibits cholinesterase reversibly
penetrates blood brain barrier
proposed as a dietary supplement intended to reduce memory
disorders
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31. OVERDOSEOF
ANTICHOLINESTERASE DRUGS
Effects of an acute overdose manifest as muscarinic
&nicotinic symptoms on peripheral & CNS sites
-muscarinic symptoms
miosis,difficulty in focussing
salivation
bronchoconstriction
bradycardia
abdominal cramps
loss of bladder and rectal control
31

32. -nicotinic symptoms
skeletal muscle weakness to overt paralysis resulting in
apnoea
-CNS symptoms
confusion
ataxia
seizures
depression of ventilation
coma
32

33. Diagnosisis made by history of exposure and
characteristic signs & symptoms
Organophosphorous anticholinesterases are
present in insecticides
-absorbed rapidly across alveoli,skin,gut
-accidental poisoning most often by inhalation or
dermal absorption
-high lipid solubility ensures passage across
blood-brain barrier
33

34. -management
atropine
35-70mcg/kg i/v every 3-10 min. until muscarinic symptoms disappear
no impact on nicotinic actions at neuromuscular junction
pralidoxime
15mg/kg i/v over 2 min.,repeated after 20 min. if nicotinic symptoms do not disappear
ineffective unless given within minutes
more effective in counteracting effects of drugs that phosphorylate cholinesterase than
against drugs that carbamylate it
Supportive measures
endotracheal intubation & mechanical ventilation
diazepam or thiopental to supress seizures
34

35. SUGAMMADEX
-first selective relaxant binding agent
-3-D structure resembles a hollow truncated cone
or doughnut
-hydrophobic cavity and hydrophilic exterior
-Addition of side chains for better acccomodation
of 4 hydrophobic steroidal rings of rocuronium
-addition of negatively charged carboxyl group to
side chains for enhancing electrostatic binding to
positively charged quaternary ammonium of
rocuronium
35

36. 36

37. Mechanism of action
-tight complexes in 1:1ratio
-doughnuthole:hydrophobic interactions trap drug
in cyclodextrin cavity resulting in formation of
water soluble guest-host complexes
-rapid removal of free rocuronium from plasma
creates a concentration gradient favouring
movement of remaining relaxant from NMJ back
to plasma where it is encapsulated by free
sugammmadex molecules
37

38. 38

39. -sugammadex also enters tissues to form
complexes with rocuronium
-thus,neuromuscular blockade is terminated
by diffusion of relaxant away from nm
junction back into plasma
*no effect on acetylcholinesterase or any
receptor system in body thus eliminating
the need for anticholinergic drugs during
reversal
39

40. Pharmacokinetics
-clearance:120ml/min
-elimination t1/2:100 min.
-volume of distribution:18 L
-75% dose eliminated in urine
*>75% dose of rocuronium undergoes biliary
excretion,but R-S complexes once formed
undergo excretion mainly by renal route
40

41. Pharmacodynamics
-dose: 4-8 mg/kg i/v (upto 16 mg/kg)
-onset of action: 1-2 minutes
-effect more quickly and reliably than either
neostigmine or edrophonium
-more complete recovery of neuromuscular
function
-choice of anaesthetic agent does not influence
it’s ability to antagonise nm blockade
41

42. -rapid and effective reversal of even profound nm
blockade(post-tetanic count<10)
-ineffective against
Sch,mivacurium,atracurium,cisatracurium(as inclusion
complexes cannot be formed)
*administration of 1.2mg/kg rocuronium followed 3 min.later
by 16 mg/kg sugammadex has a better onset-offset
profile(1-3 min.) than that seen with 1mg/kg
Sch(approx.10 min)
Thus,combinations of rocuronium & sugammadex could
replace Sch for rapid sequence intubation and also
completely eliminate risk of residual paralysis in post-
anaesthetic recovery room
42

43. Side-effects
hypotension
coughing
movement
nausea,vomiting,dry mouth
parosmia
sensation of changed temperature
abnormal levels of N-acetyl glucosaminidase in urine
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44. THANK YOU
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