Parasympathetic Mechanism And Drugs Affecting Cardiovascular system

Question 1

How does the PNS operate and what are it’s effects?

Answer 1

The parasympathetic nervous system operates primarily through acetylcholine-mediated signaling to promote relaxation and restoration of the body’s resources.

Its effects are generally antagonistic to those of the sympathetic nervous system, working to maintain homeostasis and support bodily functions during restful periods.

Question 2

The parasympathetic nervous system originates from what cranial nerves and what part of the sacral spinal cord?

Answer 2

The parasympathetic nervous system originates from the brainstem (specifically from cranial nerves III, VII, IX, and X) and the sacral spinal cord (S2-S4).

Question 3

What is the most significant CN and why?

Answer 3

The vagus nerve (cranial nerve X) is the most significant component, providing parasympathetic innervation to the heart, lungs, and most of the digestive tract.

Question 4

Where does the sacral portion of the PNS innervate?

Answer 4

The sacral portion of the PNS innervates the lower part of the digestive tract and pelvic organs.

Question 5

What is Acetylcholine?

Answer 5

Acetylcholine (ACh): The primary neurotransmitter used by the parasympathetic nervous system is acetylcholine. It acts at both the preganglionic and postganglionic synapses (where pre- and post-ganglionic neurons communicate) and at the target organs.

Question 6

ACh is released from parasympathetic nerve endings and binds to what two types of receptors?

Answer 6

Muscarinic receptors (M1-M5): Found in effector organs like the heart, blood vessels, gastrointestinal tract, and exocrine glands. Activation leads to typical parasympathetic effects.

Nicotinic receptors: Found at the neuromuscular junction and in autonomic ganglia. Activation leads to skeletal muscle contraction or transmission of signals in the ganglia.

Question 7

What occurs at the Pre-Ganglionic Neurons?

Answer 7

Pre-Ganglionic Neurons: ACh is released from the pre-ganglionic neurons (which originate in the brainstem or sacral spinal cord) into the ganglia (nerve cell clusters).

This neurotransmitter activates nicotinic acetylcholine receptors on the post-ganglionic neurons in these ganglia.

Question 8

What occurs at the Post-Ganglionic Neurons?

Answer 8

Post-Ganglionic Neurons: The post-ganglionic neurons then release ACh at the target organ, where it binds to muscarinic acetylcholine receptors on the target cells to elicit varieties of physiological responses

Question 9

What are M1 receptors?

Answer 9

M1 Receptors: Found mainly in the central nervous system and in some exocrine glands. They are involved in cognitive functions and glandular secretion.

The M1 is primarily a neuronal receptor located
on ganglion cells and central neurones, especially in cortex, hippocampus and corpus striatum. It plays a major role in mediating gastric secretion, relaxation of lower esophageal sphincter (LES) caused by vagal stimulation, and in learning, memory, motor functions, etc

Question 10

What are M3 receptors?

Answer 10

M3 Receptors: Located in various smooth muscles and glands. They are involved in smooth muscle contraction and glandular secretion, such as in the respiratory and digestive systems.
Visceral smooth muscle contraction and glandular secretions are elicited through M3 receptors, which also mediate vasodilatation through EDRF release. Together the M2 and M3 receptors mediate most of the well-recognized muscarinic actions including contraction of LES

Question 11

What are M2 receptors?

Answer 11

M2 Receptors: Predominantly located in the heart. They work to decrease heart rate by reducing the firing rate of the sinoatrial (SA) node.

Cardiac muscarinic receptors are predominantly M2 and mediate vagal bradycardia.
Autoreceptors on cholinergic nerve endings are also of M2 subtype. Smooth muscles express some M2 receptors as well which, like M3, mediate
contraction.

Question 12

What are M4 & M5 receptors?

Answer 12

The M4 and M5
receptors are present mainly on nerve endings in
certain areas of the brain and regulate the release
of other neurotransmitters.

Question 13

What classes do M1-M5 fall into?

Answer 13

Functionally, M1, M3
and M5 fall in one class while M2 and M4 fall in
another class.

Question 14

How is Ach used for parasympathetic effects on the CVS (the heart)?

Answer 14

Cardiovascular System (Heart): ACh binds to M2 muscarinic receptors on the cardiac cells, particularly in the sinoatrial (SA) node.

This leads to a decrease in heart rate (negative chronotropic effect) and a reduction in the force of heart contractions (negative inotropic effect). The overall effect is a slowing down of the heart rate and a decrease in cardiac output.

Question 15

How is Ach used for parasympathetic effects on the Respiratory System (Lungs)?

Answer 15

Respiratory System (Lungs): ACh binds to M3 muscarinic receptors on the smooth muscle cells of the bronchi. This causes bronchoconstriction, which is the narrowing of the airways.

Additionally, it increases mucus secretion from mucus glands in the respiratory tract, which helps trap and expel particles and pathogens

Question 16

How is Ach used for parasympathetic effects on the Digestive System (Gastrointestinal Tract)?

Answer 16

Digestive System (Gastrointestinal Tract): ACh acts on M3 muscarinic receptors in the smooth muscles and glands of the digestive system.

This action stimulates smooth muscle contraction (increased peristalsis) to facilitate the movement of food through the gastrointestinal tract.

Enhances the secretion of digestive enzymes and juices to aid in digestion.

Relaxes the sphincters, allowing for the passage of food and waste products.

Question 17

How is Ach used for parasympathetic effects on the Urinary System (Bladder)?

Answer 17

Urinary System (Bladder): ACh binds to M3 muscarinic receptors in the bladder’s detrusor muscle. This causes the muscle to contract, facilitating urine expulsion and aiding in urination.

Question 18

How is Ach used for parasympathetic effects on the eye?

Answer 18

ACh acting on M3 receptors in the eye’s circular muscles (sphincter pupillae) causes constriction of the pupil (miosis).

It also promotes accommodation (focusing on near objects) by contracting the ciliary muscle.

Question 19

How is Ach used for parasympathetic effects on the Salivary Glands?

Answer 19

Salivary Glands: ACh stimulates M3 receptors on salivary glands, leading to increased saliva production.

In summary, acetylcholine’s effects on the parasympathetic nervous system are primarily mediated through muscarinic receptors on target organs, leading to a range of actions that support the body’s restorative processes and maintain homeostasis.

Question 20

What are Cholinergic agonists and examples?

Answer 20

These drugs mimic the action of acetylcholine and can be further divided into direct-acting agonist and indirect acting agonist

Direct-Acting Agonists: These drugs directly bind to and activate acetylcholine receptors. They can be further classified based on their receptor specificity into Muscarinic agonist and Nicotinic Agonists

Muscarinic Agonists: These drugs primarily activate muscarinic receptors. Examples include Bethanechol, Pilocarpine

Nicotinic Agonists: These drugs primarily activate nicotinic receptors. Examples include: Nicotine

Question 21

What are Cholinergic drugs and their classification?

Answer 21

Cholinergic drugs are drugs that influence the cholinergic system, which uses acetylcholine (ACh) as its primary neurotransmitter.

They can be classified into agonists, which activate acetylcholine receptors, and antagonists, which blocks acetylcholine receptors.

Question 22

Briefly discuss BETHANECOL under the following headings:
I) MOA
II) Pharmacological actions (ADME),
III) Therapeutic effect
IV) Side/adverse effects

Answer 22

Muscarinic Agonist

Bethanechol is a medication used primarily to treat conditions involving decreased muscle tone in the bladder and gastrointestinal tract.

Receptor Activation: They activates muscarinic receptors (M3 receptors) on smooth muscles of the bladder and gastrointestinal tract.

Effects: This stimulation leads to increased bladder contraction and improved gastrointestinal motility.

Absorption: Bethanechol is generally administered orally and is absorbed from the gastrointestinal tract.

Distribution: It has a moderate distribution throughout the body but is predominantly effective where muscarinic receptors are present, such as in the bladder and gastrointestinal tract.

Metabolism: Unlike acetylcholine, bethanechol is resistant to hydrolysis by acetylcholinesterase, which prolongs its action. However, it is still metabolized to some extent in the body.

Excretion: The drug is excreted mainly through the kidneys.

Adverse Effects: Increased salivation, sweating, and gastric acid secretion.Nausea, vomiting, and diarrhea.

Question 23

What are Indirect-Acting Agonists (Cholinesterase Inhibitors)?

Answer 23

These drugs increase the availability of acetylcholine by inhibiting the enzyme acetylcholinesterase, which breaks down ACh. They can be reversible or irreversible.

Reversible Inhibitors: Act by binding temporarily to acetylcholinesterase. Examples include Physostigmine, Neostigmine, Donepezil, Rivastigmine, Galantamine

Irreversible Inhibitors: These drugs form a permanent bond with acetylcholinesterase, leading to long-term effects and requiring new enzyme synthesis for recovery.

Examples include Organophosphates (e.g., Sarin, Malathion): Found in some insecticides and nerve agents. They can cause severe poisoning and are generally not used therapeutically. They bind permanently to acetylcholinesterase, leading to prolonged effects.

Question 24

Briefly discuss PILOCARPINE under the following headings:
I) MOA
II) Pharmacological actions (ADME),
III) Therapeutic effect
IV) Side/adverse effects

Answer 24

Muscarinic Agonist

Pilocarpine is a potent, naturally occurring muscarinic agonist with a range of therapeutic uses, particularly in ophthalmology and in treating dry mouth.

Effects: due to stimulation of M3 receptors, which are found in various tissues including smooth muscles and exocrine glands.

Absorption: Ophthalmic Administration; Pilocarpine is typically administered as eye drops, where it acts locally in the eye with minimal systemic absorption.

Oral Administration: Pilocarpine is also available in oral forms for systemic effects, such as in the treatment of dry mouth.

Distribution: When used topically in the eye, it exerts its effects locally with minimal systemic distribution.
When taken orally, pilocarpine is absorbed into the bloodstream and distributed throughout the body, but its primary effects are on glandular secretions and smooth muscles.

Metabolism: Metabolized in the liver and other tissues.

Excretion: Excreted primarily through the kidneys.

Question 25

Briefly discuss NICOTINE under the following headings:
I) MOA
II) Pharmacological actions (ADME),
III) Therapeutic effect
IV) Side/adverse effects

Answer 25

Nicotinic Agonist

Nicotine: Primarily used in smoking cessation programs. It stimulates nicotinic receptors in the central nervous system and peripheral nervous system.

MOA: Binds to and activates nicotinic receptors, leading to the opening of ion channels and the influx of cations (mainly sodium and calcium). This results in depolarization of the neuron and subsequent neurotransmitter release.

Absorption: Rapidly absorbed through mucous membranes. It can also be inhaled, where it is quickly absorbed into the bloodstream through the lungs.

Distribution: Nicotine is widely distributed throughout the body, including the brain, where it crosses the blood-brain barrier easily due to its lipophilic nature.

Metabolism: It is metabolized primarily in the liver by cytochrome P450 enzymes, particularly CYP2A6, to form cotinine and other metabolites.

Excretion: The metabolites are excreted mainly in the urine. Nicotine and its metabolites can be detected in various bodily fluids.

Question 26

Briefly discuss PHYSOSTIGMINE under the following headings:
I) MOA
II) Pharmacological actions (ADME),
III) Therapeutic effect
IV) Side/adverse effects

Answer 26

Reversible Cholinesterase Inhibitor

MOA: Physostigmine, also known as eserine, is a reversible inhibitor of acetylcholinesterase (AChE). The increase in ACh affects both muscarinic and nicotinic receptors.

Absorption: Oral Administration: Physostigmine is not well absorbed from the gastrointestinal tract, so it is typically not given orally.
Parenteral Administration: It is more commonly administered via intravenous (IV) or subcutaneous routes.

Distribution: Physostigmine crosses the blood-brain barrier (BBB) because it is a tertiary amine, which allows it to have central nervous system (CNS) effects.

Metabolism: The drug is metabolized in the liver and other tissues.

Excretion: Excretion occurs through the kidneys, with some of the drug and its metabolites being eliminated in the urine.

Clinical Uses: Glaucoma, Myasthenia Gravis (Historical Use)
Adverse Effects: Nausea, vomiting, diarrhea, and abdominal cramps, Muscle Twitches, Fatigue and Muscle Weakness

Question 27

Briefly discuss MALATHION under the following headings:
I) MOA
II) Pharmacological actions (ADME),
III) Therapeutic effect
IV) Side/adverse effects

Answer 27

Irreversible Cholinesterase Inhibitor

Malathion is used primarily as an insecticide. Its pharmacological properties are similar to those of other organophosphates.

MOA: It irreversibly inhibits AChE, an enzyme responsible for breaking down acetylcholine (ACh) in the synaptic cleft.

Absorption:
Dermal: Absorbed through the skin, especially when used in its commercial formulations.
Inhalation: Vapors can be inhaled, leading to respiratory exposure.

Distribution: Once absorbed, malathion is distributed throughout the body, including the central nervous system (CNS), although its lipophilic nature means it can accumulate in fatty tissues.

Metabolism: Malathion is metabolized primarily in the liver. It is broken down into inactive metabolites by enzymes such as carboxylesterase.

Unlike other organophosphates, malathion is more rapidly metabolized into less toxic compounds, which contributes to its lower toxicity compared to some other organophosphates.

Receptor Activation: Muscarinic Receptors: Overstimulation leads to symptoms such as increased secretions (salivation, lacrimation, urination, defecation), miosis (pupil constriction), and gastrointestinal distress (nausea, vomiting, diarrhea).

Nicotinic Receptors: Results in muscle twitching, tremors, weakness, and, in severe cases, paralysis.
Excretion: Metabolites and unchanged malathion are excreted in the urine and feces.

Question 28

What are Cholinergic Antagonists?

Answer 28

Cholinergic antagonists, also known as anticholinergics, are class of drugs that block the action of acetylcholine at muscarinic receptors. By inhibiting acetylcholine’s action, these drugs can produce a range of effects throughout the body

Cholinergic antagonists primarily block muscarinic receptors (M1-5). These receptors are G-protein-coupled receptors involved in various physiological processes.

Although many anticholinergics are non-selective and affect all types of muscarinic receptors, some drugs may have preferential binding to specific receptor subtypes, leading to targeted therapeutic effects.

By preventing acetylcholine from binding to these receptors, these drugs inhibit the parasympathetic nervous system’s activity.

Examples of CA include Atropine, Scopolamine, Ipratropium, Benztropine, Oxybutynin

Question 29

Briefly discuss ATROPINE under the following headings:
I) MOA
II) Pharmacological actions (ADME),
III) Therapeutic effect
IV) Side/adverse effects

Answer 29

Muscarinic antagonist

Atropine is a tropane alkaloid derived from the Atropa belladonna plant and other Solanaceae family members. It has a range of effects and uses in medicine due to its anticholinergic properties.

MOA: Atropine primarily works as a competitive (non-selective) antagonist at muscarinic acetylcholine receptors (M receptors) in the parasympathetic nervous system.

Absorption: Atropine can be administered orally, intravenously, intramuscularly, or topically. It is well-absorbed from the gastrointestinal tract when taken orally.

Distribution: After administration, atropine is widely distributed throughout the body, including the central nervous system (CNS). It crosses the blood-brain barrier and can affect CNS functions.

Metabolism: Atropine is metabolized in the liver and to a lesser extent in the blood. Its metabolism involves hydrolysis and conjugation.

Excretion: The drug and its metabolites are primarily excreted in the urine.

Therapeutic Uses: To reduce salivation and secretions during surgery, Treatment of Bradycardia
Antidote for Cholinergic Poisoning in cases of organophosphate poisoning or other cholinesterase inhibitor exposures.

Adverse effects:
Dry mouth, constipation, urine retention, tachycardia

Question 30

Briefly discuss SCOPALAMINE under the following headings:
I) MOA
II) Pharmacological actions (ADME),
III) Therapeutic effect
IV) Side/adverse effects

Answer 30

Muscarinic antagonist

Scopolamine, like atropine, is a tropane alkaloid with a range of clinical applications due to its anticholinergic properties. It is derived from plants in the Solanaceae family, such as Hyoscyamus niger and Scopolia carniolica.

MOA: Scopolamine acts primarily as a competitive (non-selective) antagonist at muscarinic acetylcholine receptors, particularly M1 and M3 subtypes. By blocking these receptors, scopolamine inhibits the effects of acetylcholine in the parasympathetic nervous system.

Absorption: Scopolamine can be administered via several routes, including transdermal (as a patch), oral, intramuscular, and intravenous. The transdermal route is particularly useful for providing sustained release and minimizing side effects.

Distribution: Scopolamine is distributed throughout the body, including the central nervous system (CNS). It crosses the blood-brain barrier effectively, which is significant for its CNS effects.

Metabolism: Scopolamine is metabolized in the liver, primarily through hydrolysis and conjugation processes.

Excretion: The drug and its metabolites are excreted mainly in the urine.

Therapeutic Uses: Motion Sickness, Postoperative Nausea and Vomiting, reduce salivation and secretions before surgery.
Historically, scopolamine has been used to manage symptoms of Parkinson’s disease, though it is less common now due to the availability of more effective treatments.

Question 31

What are Nicotinic antagonists?

Answer 31

Nicotinic antagonists also known as neuromuscular blockers or muscle relaxants, are agents that block nicotinic acetylcholine receptors. These receptors are found at the neuromuscular junction (NMJ) in skeletal muscles and in the autonomic ganglia.

NA are primarily used in anesthesia to induce muscle relaxation during surgery or mechanical ventilation.

They can be categorized into two main classes: non-depolarizing and depolarizing neuromuscular blockers.

Non-Depolarizing Neuromuscular Blockers: These drugs act as competitive antagonists at nicotinic acetylcholine receptors at the neuromuscular junction, preventing acetylcholine from binding and thus inhibiting muscle contraction.

Examples include Curare (d-Tubocurarine), Rocuronium, Vecuronium.

Depolarizing Neuromuscular Blockers: These drugs work by mimicking acetylcholine and binding to nicotinic receptors, causing an initial muscle contraction (fasciculation) followed by paralysis.
Unlike non-depolarizing agents, they cause continuous depolarization and prevent repolarization of the muscle membrane, example include Succinylcholine

Question 32

What is Oxybutynin?

Answer 32

Muscarinic anatagonist

Oxybutynin is a medication primarily used to treat overactive bladder (OAB) and other conditions involving increased urinary urgency and frequency. It is an anticholinergic agent that works by targeting the muscarinic acetylcholine receptors in the bladder.

MOA: Oxybutynin works as a competitive antagonist at muscarinic acetylcholine receptors, particularly the M3 subtype, which are found in the detrusor muscle of the bladder.

Absorption: Oxybutynin is absorbed well from the gastrointestinal tract when taken orally. The immediate-release formulation has a peak plasma concentration usually reached within 1 to 2 hours after administration, whereas extended-release formulations provide more prolonged absorption.

Distribution: Oxybutynin is widely distributed throughout the body, including the central nervous system (CNS), though its CNS effects are less pronounced compared to some other anticholinergic drugs.

Metabolism: Oxybutynin undergoes extensive first-pass metabolism in the liver to produce several metabolites, including the active metabolite, desethyloxybutynin.

Excretion: The drug and its metabolites are primarily excreted in the urine.

Therapeutic Uses: Overactive Bladder (OAB), Neurogenic Bladder

Question 33

What is Rocuronium?

Answer 33

Nicotinic antagonist
Rocuronium is a widely used neuromuscular blocker in anesthesia, known for its rapid onset and intermediate duration of action. It is a non-depolarizing neuromuscular blocker, which means it works by competitively antagonizing nicotinic acetylcholine receptors at the neuromuscular junction.

MOA: They competes with acetylcholine for binding at the nicotinic acetylcholine receptors located at the neuromuscular junction. By blocking these receptors, rocuroium prevents acetylcholine from binding and inducing muscle contraction, leading to muscle paralysis.

Absorption: administered intravenously (IV), which ensures immediate and complete absorption into the bloodstream.

Distribution: Rocuronium distributes well into the extracellular space but does not significantly cross the blood-brain barrier.

Onset of Action: Rocuronium has a rapid onset of action, typically within 1 to 2 minutes, making it suitable for rapid sequence induction.

Duration of action: 25-40minutes

Metabolism: Rocuronium is metabolized in the liver, primarily through the process of hepatic biotransformation.

Excretion: The majority of rocuronium is excreted unchanged in the urine. A smaller portion is excreted in bile.

Question 34

What is Succinylcholine?

Answer 34

Nicotinic antagonists
Succinylcholine is a depolarizing neuromuscular blocker used primarily in anesthesia to induce muscle relaxation and facilitate endotracheal intubation. It is unique among neuromuscular blockers due to its mechanism of action and pharmacological properties.

MOA: Succinylcholine acts as a depolarizing neuromuscular blocker by mimicking acetylcholine (ACh) and binding to nicotinic acetylcholine receptors at the neuromuscular junction.

Unlike non-depolarizing blockers, succinylcholine initially causes an activation of the receptor, resulting in a transient muscle contraction or fasciculation. Following this, it causes sustained depolarization of the muscle membrane, preventing further muscle contraction.

Absorption: Succinylcholine is administered intravenously (IV) due to its poor oral absorption and rapid action requirements.

Distribution: Succinylcholine is distributed rapidly to the bloodstream and peripheral tissues. It has a high affinity for skeletal muscle but does not significantly cross the blood-brain barrier.

Onset of Action: The onset of action is very rapid, typically within 30 to 60 seconds, making it useful for rapid sequence intubation.

Metabolism: Succinylcholine is metabolized by plasma cholinesterase (also known as pseudocholinesterase), which is present in the blood. This enzyme hydrolyzes succinylcholine into inactive metabolites.

Duration of Action: The duration of neuromuscular blockade is short (5 to 10 minutes) due to the rapid metabolism by plasma cholinesterase.

Excretion: The metabolites of succinylcholine are excreted through the urine.