ACE inhibitors

Question 1

Edrophonium

Answer 1

Anticholinesterase
Short action - Reversible ionic interaction with AChE
Quartenary ammonium compound

Used to diagnose myasthenia gravis: causes a temporary increase in the muscle tension that can be developed by the patient.

Only ‘true’ inhibitor. Particular affinity for ionic site, does not inhibit BuChE.

Question 2

Neostigmine

Answer 2

Anticholinesterase
Medium ‘reversible’ action. Relatively weak covalent bond interaction with AChE

Carbamic acid ester of choline.
Binds to esteratic site & carbamoylates the enzyme.
Hydrolysis of carbamoylated serine proceeds at much slower rate than acetylated serine- thus enzyme is inactivated for many minutes.

Used intravenously to reverse neuromuscular blockade after surgery, orally to treat myasthenia gravis.

Question 3

Dyflos

Answer 3

Anticholinesterase
Long ‘irreversible’ action. Strong covalent bond (irreversible) interaction with AChE

Used in glaucoma

Question 4

Malathion

Answer 4

Anticholinesterase
Long ‘irreversible’ action
Strong covalent bond (irreversible) interaction with AChE.

Used as an insecticide e.g to eliminate live infestations.

• activated by replacement of its sulphur atom by oxygen, a process carried out more efficiently by insect than mammalian cytochrome P450s
• can be detoxified by plasma carboxylesterases, which are more active in mammals & birds than insects.

Question 5

Organophosphorous compounds

Mechanism?
Examples?
Nerve gases- effects of long term and short term exposure. Treatment?

Answer 5

Produce a strong covalent bond between their phosphorous atom and the serine residue at the esteratic site.
E.g dyflos, malathion, ‘nerve gases’: sarin, tabun, soman.

‘Nerve gases’ readily penetrate the skin, cause acute & chronic toxic effects.
Long term exposure (e.g sheep dips) -> demyelination (though inhibition of an esterase, not Che, involved in myelin processing)
Short term exposure to high doses: can cause death as a result of widespread cholinergic activity:
- convulsions (excessive activation of brain muscarinic receptors)
- respiratory distress.
Primary form of treatment= atropine.
Pralidoxime can reverse inhibition by organophosphorous agents in first few hours.

Question 6

Pralidoxime

Answer 6

Structure of drug brings oxime group (a strong nucleophile) in close proximity with the phosphorylated serine of the inhibited enzyme. Phosphate group then transferred to NOH of pralidoxime. AChE is regenerated.

Can reverse inhibition by organophosphorous agents- but only for a few hours after inhibition has occured. Otherwise ‘ageing’ occurs: enzyme/inhibitor complex undergoes a chemical rearrangement, bond is no longer susceptible to nucleophillic attack.
Patient must then be kept alive until can produce more AChE.

Question 7

Sugammedex

Answer 7

A cyclodextrin
Alternative approach to AChE for reversing blockade by steroidal n.m.j blocking drugs.
Forms inactive complex in the plasma with the blocker- this is excreted into the urine unchanged.

Question 8

Anticholinesterases

General effects?

Evidence that mechanism is indirect?

Answer 8

3 classes.
Prolong the life of ACh in the region of the receptors - thus effects resemble those of cholinergic stimulation at nicotinic & muscarinic receptors.
At nicotinic receptors, may have effect of leading to a depolarising blockade.

• onset of action is slow relative to v rapid effect seen with ACh and other receptor agonists
• effect is reduced/ absent in denervated preparations or systems in which ACh release has been blocked by e.g botulinum toxin or β-bungaratoxin.

Question 9

Effects of AChE at NMJ

Answer 9

Prolong end plate potential, can lead to single stimulus causing repetitive firing in muscle fibre.
At high [ ], can cause spontaneous twitching (spontaneous release of ACh, which normally causes MEPPS, becomes sufficient to evoke APs in muscle)

Can restore transmission after blockade by non-depolarising agents e.g atracurium.
Deepen blockade by depolarising blockers

Question 10

Myasthenia gravis

Symptoms/ causes?
Effects of AChEs?

Answer 10

Autoimmune, affects ~1/2000
Fatigue, muscle weakness resulting from destruction of neuromuscular nicotinic receptors, which may reach 70%.
In a series of stimuli to a nerve, tension developed in a muscle declines sharply (thus can develop tone but cant maintain it): antiChE prevent this effect & enhance developed tension.

Question 11

Effects of AChEs (via augmentation of parasympathetic actions) on:

• Heart
• Blood vessels
• Bronchi
• GI tract
• Bladder
• Eye

Answer 11

Heart: bradycardia, hypotension

Blood vessels: no effect (PNS has generally no effect)

Bronchi: bronchoconstriction, excessive secretions (NB particularly life-threatening)

GI tract: hypermotility, excessive secretions.

Bladder: urination (PNS promotes contraction)

Eye: increased constriction of pupil -> impression of darkness. Increased constriction of ciliary muscle -> reduced intraocular pressure.