03.01.3.1 Inhibition of Acetylcholinesterase

The first example is the drug neostigmine, which inhibits the enzyme acetylcholinesterase and is used in the treatment of myaesthenia gravis, an autoimmune disease.

To understand how the drug works, it is necessary to understand the physiology and pathophysiology at the neuromuscular junction. Every time I contract the muscles in my arm, I am activating my somatic (or voluntary) nervous system to release the neurotransmitter acetylcholine, Ach (Figure 3.7).

Figure 3.7 Neuromuscular junction – physiological (Copyright QUT, Sheila Doggrell)

The released acetylcholine activates receptors for acetylcholine on the muscle. Like noradrenaline, acetylcholine has receptor sub-types, and the ones on the muscle are called nicotinic, as they can be stimulated by nicotine. Stimulation of the nicotinic receptors leads to muscle activity, the contraction of the muscles. However, it is difficult to keep the muscles contracted, as the action of acetylcholine is very short lived. This is because, there is an enzyme, acetylcholinesterase, lurking, which breaks the acetylcholine down to acetate and choline. Thus, it is difficult to maintain a flexed arm.

In myasthenia gravis, there is a loss of nicotinic receptors (Figure 3.8).

Figure 3.8 Neuromuscular junction – myasthenia gravis (Copyright QUT, Sheila Doggrell)

In myasthenia gravis, the nerves is working fine; it is still releasing acetylcholine, and the acetylcholine is still being broken down. However, as there are reduced nicotinic receptors, there is reduced muscle activity. The drug used to treat myasthenia gravis is neostigmine, which inhibits acetylcholinesterase to prevent the breakdown of acetylcholine (Figure 3.9).

Figure 3.9 Neostigmine in myasthenia gravis (Copyright QUT, Sheila Doggrell)

Inhibiting the breakdown of acetylcholine, leads to a build up in the concentration of acetylcholine in the synapse, and this causes more stimulation of the existing nicotinic receptors. The build up of acetylcholine, in the absence of acetylcholinesterase, means that the acetylcholine can diffuse further without breakdown to reach other nicotinic receptors. This restores muscular activity in myasthenia gravis. Myasthenia gravis is a rare disease, but drugs that act as enzyme inhibitors are also used in common disorders.