Autonomic Pharmacology | Cholinergic Agonists

Introduction to Cholinergic Agonists

In this video, the speaker introduces cholinergic agonists and their pharmacology. The cholinergic system is briefly explained, and the speaker encourages viewers to check out their website for more information.

Understanding the Cholinergic System

• The cholinergic system is where neurons release acetylcholine.

• Cranial nerves with parasympathetic fibers innervate target organs, such as cranial nerve three supplying the eye.

• Parasympathetic fibers cause pupillary constriction (meiosis) and play a role in accommodation.

• Cranial nerve seven supplies lacrimal and salivary glands, playing a role in lacrimation and salivation.

• Cranial nerve nine plays a role in salivation via the parotid gland.

• The vagus nerve has cholinergic fibers that work on viscera like the heart, slowing down conduction and potentially causing bradycardia.

Pharmacology of Cholinergic Agonists

• Cholinergic agonists are also known as parasymapthomimetics.

• Pupillary constriction caused by parasympathetic fibers is an example of a normal function of cholinergic agonists.

• The vagus nerve's negative chronotropic effect can lead to decreased cardiac output.

Parasympathetic Nervous System

This section discusses the parasympathetic nervous system and its effects on various organs in the body.

Bronchoconstriction

• The parasympathetic nervous system induces bronchoconstriction, which narrows the airways and reduces airflow during rest and digestion.

GIT Secretion and Motility

• The vagus nerve innervates parts of the gastrointestinal tract (GIT), promoting secretion of hydrochloric acid by the stomach and other molecules within the intestines.

• The parasympathetic fibers from the sacral part of our spinal cord increase GIT motility, peristalsis, and defecation.

Urinary Tract Function

• Parasympathetic fibers from S2 to S4 increase motility and contraction of the bladder causing urination.

Sympathetic Nervous System

This section discusses cholinergic pathways in the sympathetic nervous system that act on specific organs in the body.

Sweating

• Postganglionic and preganglionic fibers release acetylcholine in sympathetic outflow to act on skin inducing sweating.

Cholinergic Pathways in Cerebrum

This section discusses cholinergic pathways within cerebrum that play a role in cognitive function.

Cognitive Function

• Cholinergic pathways within cerebrum play a role in cognitive function, and their decrease may lead to cognitive decline in older patients or those with specific diseases.

The Role of the Vagus Nerve in Digestion

This section discusses the role of the vagus nerve in innervating parts of the gastrointestinal tract (GIT), promoting secretion, and increasing motility.

Vagus Nerve Innervation

• The vagus nerve innervates parts of the GIT, particularly the stomach and duodenum.

• It promotes secretion by stimulating hydrochloric acid production by the stomach and other molecules within the intestines.

Increased Motility

• The vagus nerve causes increased motility of the GIT, leading to peristalsis.

• It also works to increase motility and defecation in lower parts of the abdomen and pelvis.

Cholinergic Pathways in Sympathetic Nervous System

This section discusses cholinergic pathways that act within sympathetic nervous system, particularly on skin and sweat glands.

Sympathetic Fibers

• Sympathetic fibers from T1 to L2 supply acetylcholine to preganglionic fibers.

• Postganglionic fibers release acetylcholine on skin, inducing sweating.

Effects on Body Functions

• Cholinergic pathway can cause pupillary constriction, lacrimation, salivation, lower heart rate or bradycardia.

• It can induce bronchoconstriction, increase GI secretions and motility, induce defecation, increase bladder motility or contraction causing urination and sweating.

Cholinergic Pathways in Cerebrum

This section discusses cholinergic pathways that play a role in cognitive function within the cerebrum.

Cognitive Function

• Cholinergic pathways within the cerebrum play a role in cognitive function.

• As patients age or suffer from specific diseases, they may experience a decrease in acetylcholine pathways within their cerebrum.

Working at Target Sites

The speaker discusses working at target sites.

Acetylcholine Production

• Acetyl CoA is combined with choline using choline transferase to produce acetylcholine.

• Acetylcholine is stored in vesicles and released via exocytosis when a neuron becomes activated.

• Calcium rushes into the synaptic neuron, stimulating the fusion of vesicles containing acetylcholine with the membrane of the synaptic terminal.

• Acetylcholine binds onto nicotinic receptors, which are ligand-gated ion channels that open up to allow sodium ions to rush into muscle cells, depolarizing them and inducing muscle contraction.

Relaxation

• Acetylcholinesterase breaks down acetylcholine into its constituents, rendering it ineffective and causing acetylcholine levels within the synapse to drop.

• Drugs can be used to potentially work at nicotinic receptors or inhibit acetylcholinesterase to indirectly increase acetylcholine levels.

Introduction to Muscarinic Receptors

In this section, the speaker introduces the concept of muscarinic receptors and explains how they work.

Muscarinic Receptors

• Acetylcholinesterase inhibitors cause an increase in acetylcholine which stimulates an increase in the pathway causing inhibition of that cell.

• Stimulatory receptors are usually coupled to Gq proteins. The primary stimulatory receptor is M3.

• Acetylcholine binds to M3 receptor and activates a G protein which activates phospholipase C.

• Phospholipase C breaks down parts of the cell membrane into DAG and IP3, increasing calcium outflow from sarcoplasmic reticulum or endoplasmic reticulum.

• Increase in protein kinase and calcium causes phosphorylation of particular types of proteins, increasing their activity.

• Activation of M3 receptor increases activity of phospholipase C, DAG, IP3, protein kinase C, and calcium levels. This leads to depolarization and contraction.

Direct Agonists and Acetylcholinesterases Inhibitors

• Direct agonists work either directly at muscarinic or nicotinic receptors. Examples include bethanechol, methacholine, pilocarpine, and carvacrol.

• Methanocal, methacholine, and pilocarpine work on muscarinic receptors only. The type of muscarinic receptor they work on depends on the target organ or indication.

• Acetylcholinesterases inhibitors increase acetylcholine indirectly and produce the same type of effect.

Mechanism of Action and Indications for Cholinergic Drugs

In this section, the speaker discusses the mechanism of action of cholinergic drugs and their indications.

Mechanism of Action

• Cholinesterase inhibitors put an alkyl group on the acetylcholinesterase enzyme, inhibiting it from performing its function.

• Removing a piece of the alkyl group is irreversible and leads to aging. Giving antidote pralidoxime at this stage will not work.

• Antidote can only reverse toxicity if given before phosphorylation occurs.

Indications

• Cholinergic drugs are used to increase motility in postoperative ileus, postpartum urinary retention, and gastroparesis caused by diabetes.

• Bethanechol, neostigmine, and pyridostigmine are potential agents for increasing GI motility.

Conclusion

The speaker concludes the video by summarizing the key points discussed in previous sections.

• No other significant indications for cholinergic drugs were discussed.

• Neostigmine is preferred over physostigmine due to lower CNS toxicity.

• Pralidoxime cannot reverse aging caused by removal of a piece of the alkyl group.

Pilocarpine and Carbocarpisostigmine

In this section, the speaker discusses the use of pilocarpine and carbocarpisostigmine in medical treatment.

Use of Pilocarpine and Carbocarpisostigmine

• Pilocarpine is a drug used to treat various conditions such as shogren syndrome, an autoimmune disease that destroys salivary glands and lacrimal glands. It can also be used to improve salivation and lacrimation in patients who have undergone radiation therapy.

• Carbocal is another drug that can be used for similar purposes but has more side effects than pilocarpine.

• Both drugs cause contraction of the ciliaris, which opens up the angle allowing for better venous drainage into the canal slim or dilating the pupil narrowing out their base last compression of the canal slim. They also act on muscarinic type 3 receptors to increase lacrimation and salivation.

• The two drugs that are primarily used for improving lacrimation and salivation are pilocarpine and carbicol.

Myasthenia Gravis

In this section, the speaker discusses myasthenia gravis, a disease in which autoantibodies attack nicotinic receptors causing muscle weakness.

Treatment for Myasthenia Gravis

• Acetylcholinesterase inhibitors such as pyridostigmine are commonly used to treat myasthenia gravis by inhibiting acetylcholinesterase from breaking down acetylcholine. This increases acetylcholine levels in synapses, which can compete with the autoantibodies and knock them out of the receptor sites.

• By increasing acetylcholine levels in synapses, acetylcholinesterase inhibitors can improve muscle contraction and reduce weakness in patients with myasthenia gravis.

Contraction that Decreases Weakness

This section discusses the use of physostigmine to treat anticholinergic overdoses and neostigmine to reverse the effect of neuromuscular blocking agents.

Physostigmine for Anticholinergic Overdoses

• Anticholinergics like tricyclic antidepressants and atropine can cause toxicity by decreasing acetylcholine levels.

• Physostigmine is a drug that can displace anticholinergics from their receptor sites, reversing their toxic effects.

Neostigmine for Neuromuscular Blockade Reversal

• Neuromuscular blocking agents are used during surgical procedures to inhibit muscle contraction.

• Neostigmine can competitively knock neuromuscular blocking agents out of receptor sites, allowing for muscle contraction and reversal of paralysis.

Alzheimer's Disease and Acetylcholine

This section discusses how a reduction in acetylcholine levels in the brain can lead to cognitive decline in patients with Alzheimer's disease, and how drugs like donepezil and rivastigmine can increase acetylcholine levels to improve cognitive function.

• The nucleus basalis of Meynert releases cholinergic fibers that stimulate the cortex, which is important for cognitive function.

• In patients with Alzheimer's disease, there is a reduction in acetylcholine levels due to degeneration of these cholinergic pathways.

• Drugs like donepezil and rivastigmine can increase acetylcholine levels in the synapses, improving cognitive function.

Alzheimer's Disease and Cholinergic Crisis

In this section, the speaker discusses the use of drugs to increase acetylcholine levels in Alzheimer's patients. They also explain the concept of cholinergic crisis and its symptoms.

Drugs for Alzheimer's Disease

• Acetylcholine levels can be increased with drugs to improve cognitive function and memory.

• These drugs do not stop or cure Alzheimer's disease but only slow down its progression.

• Adverse effects of these drugs include a cholinergic crisis.

Cholinergic Crisis

• Symptoms of a cholinergic crisis include pinpoint pupils, excessive lacrimation, salivation, hypotension, bronchospasm, diarrhea, increased urination, weakness, restlessness, agitation and convulsions.

• A mnemonic to remember these symptoms is DUMBELS (diarrhea, urination, miosis/pinpoint pupils, bradycardia/bronchospasm/bronchorrhea/breathing difficulties/bladder emptying/bowel movements/emesis/lacrimation/salivation/sweating).

• Anticholinergic agents can be used to reverse the effects of a cholinergic crisis.

Note that timestamps are provided for each bullet point where applicable.

Don't Forget This

The speaker reminds the audience not to forget something important.

Key Points:

• The speaker emphasizes that the audience should not forget something, but it is unclear what that thing is.

Bronchoconstriction and Muscarinic Receptors

The speaker discusses how muscarinic receptors cause bronchoconstriction and how atropine can oppose this effect.

Key Points:

• Three drugs bind to muscarinic receptors and cause bronchoconstriction.

• Atropine is an anticholinergic drug that opposes the normal function of muscarinic receptors, inhibiting them and preventing bronchoconstriction.

• If an ophthalmologist wants to dilate a patient's pupils for an eye exam, they would need to use an antagonist drug that blocks the muscarinic 3 receptors in order to prevent constriction and allow dilation.

Treating Alzheimer's Disease

The speaker discusses strategies for treating Alzheimer's disease by increasing acetylcholine levels in the brain.

Key Points:

• In Alzheimer's disease, there is a deficiency of cholinergic neuronal function in the brain.

• Inhibiting the cholinergic receptors or release of acetylcholine would make symptoms worse.

• Inhibiting acetylcholinesterase enzyme in the brain would be beneficial because it prevents breakdown of acetylcholine and maintains its levels in synapses, stimulating neurons and improving cognitive function and memory.

• Activating acetylcholine esterase enzyme would be detrimental because it breaks down acetylcholine, decreasing its levels in synapses.

Cholinergic Crisis

The speaker describes the symptoms of cholinergic crisis and how they can be identified.

Key Points:

• A patient who ingests a liquid from an unlabeled bottle found near their bed may experience diarrhea, urination, convulsions, breathing difficulties, constricted pupils, excessive salivation, lacrimation, and sweating.

• These symptoms can be remembered using the mnemonic "dumbbells".

• Excessive salivation and lacrimation are common symptoms of cholinergic crisis.

Irreversible

In this section, the speaker mentions "irreversible" without providing any further context.

Neuromuscular Blockers and Cholinergic Agonists

• The speaker explains that neuromuscular blockers will be pushed out by neostigmine.

• Neostigmine also pushes out tricyclic antidepressants, atropine, antipsychotics, and physostigmine.

Cholinergic Agonist

In this section, the speaker discusses cholinergic agonists.

Pushing Out Drugs with Cholinergic Agonists

• The speaker explains that physostigmine pushes out drugs such as tricyclic antidepressants, atropine, and antipsychotics.

• The speaker hopes that the information provided about cholinergic agonists makes sense to the audience.

• The video concludes with a message of appreciation for the viewers.