Cholinomimetics: Indirect agonists (anticholinesterases)

The nervous system is divided into the central nervous system, that is the brain and spinal cord, and the peripheral nervous system, which includes all the nerves that connect the central nervous system to the muscles and organs.

The peripheral nervous system can be divided into the somatic nervous system, which controls voluntary movement of our skeletal muscles; and the autonomic nervous system, which controls the involuntary activity of the smooth muscles and glands of our organs, and is further divided into the sympathetic and parasympathetic nervous systems.

Parasympathetic neurons in the central nervous system project preganglionic fibers towards parasympathetic ganglia, which are collections of neurons near the organ they are supposed to affect.

From there, postganglionic fibers project towards the target cell.

Both the preganglionic and postganglionic neurons release the neurotransmitter acetylcholine.

Acetylcholine released from preganglionic fibers acts on nicotinic receptors on the postganglionic neurons.

And acetylcholine released from postganglionic neurons acts on muscarinic and nicotinic receptors on target organs.

Nicotinic receptors are coupled to ion channels that let sodium in and potassium out, causing depolarization.

Muscarinic receptors are G-protein coupled receptors, which means they trigger secondary messenger proteins that activating a cascade of enzymes inside the cell.

The physiologic effects of the muscarinic and nicotinic stimulation can be remembered with the mnemonic: DUMB HAVES, so defecation; urination; muscle excitation; bronchospasm; heart bradycardia; autonomic ganglia stimulation; vasodilation; eye miosis, which is constriction of the pupil, and eye accommodation, which is contraction of the ciliary muscles of the iris to facilitate looking at near objects; and secretions from the lacrimal, salivary, and sweat glands, as well as the glands in the GI tract.

Now, medications that act on muscarinic or nicotinic receptors are called direct cholinomimetics.

On the other hand, indirect cholinomimetics, also called anti-cholinesterases, don’t bind to the receptor directly.

Instead, they inhibit the enzyme acetylcholinesterase that normally degrades acetylcholine in the synaptic cleft.

As a result, more acetylcholine molecules remain, causing increased and prolonged acetylcholine-mediated muscarinic and nicotinic effects.

Examples of anticholinesterases include edrophonium, neostigmine, physostigmine, pyridostigmine, rivastigmine, galantamine, and donepezil.

Anticholinesterases are either organophosphates or carbamates.

Organophosphates like parathion are often used as pesticides.

The chemical weapon sarin gas also belongs to this group.

The most clinically used anticholinesterases are carbamates, and they are either tertiary or quaternary amines.

This is important because only the anticholinesterases with a tertiary structure can cross the blood brain barrier, or BBB, and enter the brain.

An easy way to remember this is that tertiary, or 3rd in order, crosses the three-lettered BBB.

Now, let’s take a look at some of these medications! Edrophonium, neostigmine, and pyridostigmine all have quaternary structures so they don’t cross the blood brain barrier, and can only act in the peripheral nervous system.

Edrophonium is the shortest acting anticholinesterase so it’s used for diagnosing myasthenia gravis, a disease where antibodies bind to nicotinic receptors on skeletal muscle cells, preventing acetylcholine from binding and therefore causing muscle weakness.

This is termed competitive inhibition, meaning if we increase the concentration of acetylcholine, it can displace the antibodies off of the nicotinic receptors.

So, if someone is suspected to have myasthenia gravis, we give edrophonium, which increases acetylcholine concentration in the synaptic cleft, causing a visible improvement in that person’s muscle strength for a brief period of time.