L2ii / 18A14 / 15A21 : Classify Anticholinesterase drugs according to chemical interaction with an example of each (30). Outline the PD effects of anticholinesterase drugs and their clinical indications (70)

18A14: Exam Report

Classify anticholinesterase drugs according to chemical interaction with an example of each (30% of marks). Outline the pharmacodynamic effects of anticholinesterase drugs and their clinical indications (70% of marks).

32% of candidates passed this question.

Many candidates who scored poorly confused anticholinesterase drugs with anticholinergic drugs. Some described pharmacokinetics when it was not asked. Similarly, treatment of organophosphate poisoning and/or cholinergic crisis was not asked for in the question.

15A21: Exam Report

Describe the pharmacodynamic effects and indications for the use of anticholinesterase drugs.

25% of candidates passed this question.

It was expected the answer would provide a structured approach to describing the pharmacodynamics (what the drug does to the body) of this discreet class of drugs. A brief acknowledgement of the drugs in this class followed by a catalogue of the various clinical uses of this class of drugs would be a good start. If this was followed up with a description of the effects of these drugs on the CVS, GIT, Salivary glands, eye, NMJ and the lungs a good mark would have been awarded.
A number of candidates described the actions at the receptors in detail which did not attract marks. The extensive range of clinical uses for this class of drugs was poorly appreciated.
Few answers demonstrated any understanding of the PD effects of the drug class. There was generally a good knowledge of representative drugs within this class. Failing to achieve a pass mark reflected scant/brief answers that just did not cover enough of the expected material.

L2i / 18A14 / 15A21: Classify Anticholinesterase drugs according to chemical interaction with an example of each (30). Outline the PD effects of anticholinesterase drugs and their clinical indications (70)

Definition

Anticholinesterase Drug = drug that increases duration of action  of ACh by binding to and inhibiting the Aceytlcholinesterase enzyme (AChE)

Mechanism of Action AChE

AChE has two binding site; anionic & esteratic

Anionic site binds Quaternary amine group of Ach

Esteratic site binds ester group of Ach

AChE

Binding → hydrolysis → breaks down to Choline + AcetylCoA and regenerates original enzyme

Classification

Length of Action

Short

Edrophonium

Medium

Neostigmine

Long

Organophosphate

Binding

Reversible

Edrophonium

Neostigmine

Irreversible

Organophosphate

(technically takes 100hrs to hydrolyse this so it is classified as irreversible)

Physiochecmical

Edrophonium (Tensilon)

Neostigmine

Organophosphate

Group

Edrophonium (Tensilon)

Quaternary amine

Neostigmine

Quaternary amine

Organophosphate

Organophosphates

Presentation

Edrophonium (Tensilon)

Clear soln

10mg/ml

Neostigmine

Clear soln

2.5mg/ml

Tablet 15-30mg

Organophosphate

Multiple

ie Sarin

Use

Edrophonium (Tensilon)

Reversal NDMR

Diagnose MG (Tensilon test)

Assess MG crisis

Neostigmine

Reversal NDMR

Tx MG

Urinary retention

Paralytic Ileus

Organophosphate

Insectisides

Nerve gas

Onset

Edrophonium (Tensilon)

1-2min

Neostigmine

7-10min

Organophosphate

Fatal in minutes

X500 more toxic than cyanide

Duration

Edrophonium (Tensilon)

10min

Neostigmine

50min

Organophosphate

Long – requires new AChE synthesis

Dose

Edrophonium (Tensilon)

2-10mg for Tensilon test

0.1mg/kg for reversal NDMR

Neostigmine

0.05mg/kg

Low dose = muscarinic effects

High dose = nicotinic effects

Organophosphate

Pharmacodynamic

Edrophonium (Tensilon)

Neostigmine

Organophosphate

MoA

Edrophonium (Tensilon)

Reversibly binds AChE

Weak electrostatic bond

Quaternary prevents crossing BBB

↑­[ACh]

Neostigmine

Reversible binds AChE

Covalent bond

Hydrolses enzyme at slow rate

­↑[ACh]

Hydrolysis regenerates enzyme

Organophosphate

Irreversible

Covalent bond with AChE

Recovery requires new AChE synthesis

NMJ

Edrophonium (Tensilon)

Neostigmine

­↑[ACh] @NMJ

overcomes NDMR

ACh can bind nAChR and allow muscle contraction

Organophosphate

Muscle weakness

Fasciculations

CVS

Edrophonium (Tensilon)

Neostigmine

Organophosphate

Bradycardia

↓CO

­↑conduction time

RESP

Edrophonium (Tensilon)

Neostigmine

Organophosphate

Bronchospasm,↑ ­secretions

CNS

Edrophonium (Tensilon)

Neostigmine

Nil cannot cross BBB

Organophosphate

Excitation, seizures → then CNS, CVS, RESP depression

GI

Edrophonium (Tensilon)

Neostigmine

Organophosphate

Diarrhoea, ↑­secretions

Renal

Edrophonium (Tensilon)

Neostigmine

Organophosphate

Incontinence

ANS

Edrophonium (Tensilon)

Neostigmine

Organophosphate

DUMB BELLS

Diarrhoea, Urinarytion, Myosis, ‘deadly Bs’ Bronchoconstriction & Bradycardia, Emesis, Lacrimation, Lethargy, Salivation

Mx SE

Edrophonium (Tensilon)

Neostigmine

Atropine,

Glycopyrrolate

Organophosphate

Pralidoxime – releases ACh by promoting hydrolysis

Anticonvulsants

Atropine

Pharmacokinetic

Edrophonium (Tensilon)

Neostigmine

Organophosphate

A

Edrophonium (Tensilon)

Neostigmine

Poor, 1% OBA

Organophosphate

V lipid soluble

transcutaneous

D

Edrophonium (Tensilon)

VD 1L/kg

Neostigmine

10% PPB

Highly ionised

0.5L/kg

Organophosphate

Large

M

Edrophonium (Tensilon)

Liver: glucuronidation

Neostigmine

Plasma esterases

Organophosphate

E

Edrophonium (Tensilon)

35% biliary metabolites

65% renally unchanged

Neostigmine

65% urine

renal unchanged

Renal failure = prolonged DoA

Organophosphate

Long

NB Pyridostigmine

  • Analogue of Neostigmine
  • ¼ potency
  • MoA Neostigmine
  • Slower onset 16mins (so not used to reverse NDMR)
  • DoA 6hrs (used for MG)