Cholinomimetics: Indirect agonists (anticholinesterases)

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Introduction0:00–0:37

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.

Physiology0:37–2:11

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.

Mechanism of Action2:11–3:39

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!

Quaternary Structure Cholinomimetics3:39–5:22

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.
For treating this disorder, pyridostigmine, the longest acting medication of the three, is the treatment of choice. Although neostigmine can also be used for myasthenia gravis, it’s usually reserved for another reason; when someone goes under anesthesia for surgery, a neuromuscular blocker is often given to paralyze that person so that they don’t move during the operation.
These drugs bind to and inhibit the nicotinic receptors in the muscles. When the operation is complete, this paralysis can be reversed by giving neostigmine, which increases acetylcholine concentration in the synaptic cleft, and displaces the neuromuscular blocker off of the receptor, reversing the paralysis.
Next, we have donepezil, galantamine, rivastigmine, and physostigmine, all of which have a tertiary structure, meaning they can cross the BBB.

Tertiary Structure Cholinomimetics5:22–6:30

Physostigmine is often used as an antidote for people who overdose on an anti-cholinergic, such as atropine. This is because if someone takes too much atropine, they’ll develop peripheral effects, such as constipation and urinary retention, as well as central nervous system effects, such confusion or tremors.
Donepezil, galantamine, and rivastigmine are specifically indicated for Alzheimer’ disease. That’s because in Alzheimer’s disease, the levels of acetylcholine are decreased, especially in the front of the brain at a location called the basal nucleus of Meynert.
Because these drugs can cross the BBB, they’re capable of increasing acetylcholine levels in the brain, resulting in some improvement in symptoms.
It’s important to note that these drugs do not prolong survival, instead they mainly improve the quality of life in patients with Alzheimer’s disease.

Side Effects6:30–7:34

Now the side effects caused by all anticholinesterases are similar, but they are usually longer lasting and more severe for organophosphates.
These include increased smooth muscle contraction causing miosis, diarrhea, urination, and bronchospasms; and increased secretions leading to salivation, lacrimation, and sweating.
They can also cause life-threatening emergencies by stimulating the central nervous system leading to convulsions and coma, and they also depress the cardiovascular system, causing bradycardia.
To reverse the effects of anticholinesterases, an antimuscarinic like atropine is the medication of choice for emergency treatment.
Next, pralidoxime can be given to promotes the regeneration of acetylcholinesterase enzymes but it’s slow acting. Now, we want to make a simple and fun mnemonic that’ll help you efficiently memorize and retain all these pharm facts!
Okay, so let’s have a river to represent the blood brain barrier. On the right side will be the medications that can cross this barrier and the ones that can’t will be on the left side.

Memory Palace7:34–9:38

On the left side, there’s a grave for myasthenia gravis, which is the main indication for these medications. Let’s have a businessman drop his phone, cutting his call short, for the short acting edrophonium.
Next, is a pirate stag with an eye patch and peg legs for pyridostigmine. It’s licking off the moss on the headstone with its super long tongue to help you remember it’s the longest acting drug, and the treatment of choice for myasthenia gravis.
Finally, we got a stag with neon glow sticks tied to its antlers for neostigmine. It’s standing by the grave, but it’s also licking a sleeping surgeon to help you remember it’s used to reverse paralysis after surgeries.
Now let’s look at the drugs that can cross the blood brain barrier. So we have a wet stag that’s stuck in the river for rivastigmine.
Trying to pull it out of the river is a gallant knight for galantamine, and a mafia don holding a pretzel for donepezil.
Standing by them is a confused and lost old man with alzheimer's disease, which is the primary indication for these 3. Finally, we have a stag with broken legs that needs physical therapy for physostigmine.
It’s leaning on a tropical palm tree since it’s mainly used to reverse the effects of atropine overdose. Okay, for the side effects, let’s put a brain on fire on the right side of the river, for CNS stimulation.
On the left side we have the peripheral side effects, so there’s a woman with a frozen heart for bradycardia. And her dejected lover is crying and slobbering into a bucket, for increased secretions.
He’s sitting on a toilet next to a urinal for diarrhea and increased urination. In the urinal is a large asthma inhaler for bronchospasms.
Alright, as a quick recap. Indirect cholinomimetics, or anticholinesterases, exert their effect by inhibiting acetylcholinesterases, therefore increasing the concentration and duration of action of acetylcholine on the muscarinic and nicotinic receptors.

Review9:38–10:19

Anticholinesterases can either have a tertiary or a quaternary structure, and it’s the medications with tertiary structures that’s capable of crossing the BBB.
Anticholinesterases are used for the diagnosis and treatment of myasthenia gravis, and the treatment of anticholinergic toxicity, as well as improving the quality of life of people with Alzheimer disease.
But wait, there’s more: Here’s a mind map with all of the mnemonics. Go ahead and pause the video so you can test yourself to see what you remember.

Mind Map10:19–10:30

Stay tuned for the answers after the credits.