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Nervous Systems

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Nervous Systems
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The Central and Peripheral Nervous Systems

Major control systems:

- Nervous system

- Endocrine system

Nervous system includes:

a) Central Nervous System (CNS)

b) Peripheral Nervous System (PNS)

The Nervous System in details

Central Nervous System (CNS)

- Brain

- Spinal cord

Peripheral Nervous System (PNS)

- Arc reflex

- Autonomic Nervous System (ANS)

a) Parasympathetic branch (PNS)

b) Sympathetic branch (SNS)

The drugs action and the physiological action of the system

If a drug produces the same action, it is said that the drug mimics the action of the system.

If a drug produces the opposite action, it is said that the drug blocks or inhibits the action of the system.

Ex. SNS action over the bronchial smooth muscle (dilation) = Albuterol bronchodilating action

Peripheral Nervous System

Arc reflex, also named sensory-somatic:

- Sensory or afferent neuron, which carries information from peripheral receptors to the spinal cord.

- Spinal cord "relay center"

- Somatic or efferent neuron, which carries commands from the spinal cord to peripheral effectors as responses to stimuli received by the receptor, ex. pain, heat, pressure and light.

:- Autonomic Nervous System

- Components are the parasympathetic (PNS) and the sympathetic branches (SNS).

- Features:

It is not under voluntary control.

It controls body functions, ex. heart rate, pupils, glandular secretions, smooth muscle tone in blood vessels and bronchi.

Parasympathetic branch

It arises from the cranial and sacral portions of the spinal cord.

It is made up by one presynaptic (preganglionic) neuron, a ganglionic synapse, one postsynaptic (postganglionic) neuron and a neuroeffector site.

Specificity is high, ex. eye and heart.

Sympathetic branch

It arises from the thoracic and lumbar portions of the spinal cord.

It is made up by a presynaptic (preganglionic) neuron, a ganglionic synapse, more than one postsynaptic (postganglionic) neurons and multiple neuroeffector sites.

Some presynaptic neurons reach directly the adrenal medulla.

Action is widespread, with multiple-organ involvement.

Parasympathetic vs. Sympathetic

Neurotransmitters

Nerve impulse propagation is a rather complex phenomenon:

- Along uninterrupted nerve fibers, nerve impulses are transmitted by means of electrical potentials (depolarization-repolarization cycle).

- At the synaptic and neuroeffector sites, where the continuity of the nerve fiber is interrupted, substances named neurotransmitters work as "chemical bridges".

Therefore, nerve impulse transmission is described as an electrochemical process.

Types of neurotransmitters and action sites

Arc reflex:

- Neuroeffector sites: Acetylcholine (ACH).

Parasympathetic branch:

- Ganglionic synapses: ACH

- Neuroeffector sites: ACH

Sympathetic branch:

- Ganglionic synapses: ACH

- Neuroeffector sites: Norepinephrine (NE)

- Sweat glands: ACH

- Adrenal medulla: ACH

Terminology used for drugs related to the Autonomic Nervous System

1- Based on anatomic characteristics:

Parasympathetic branch

- Parasympathomimetics: P-stimulators,

they resemble the action of the system.

- Parasympatholytics: P-inhibitors, they block or

inhibit the action of the system (opposite action)

Sympathetic branch:

- Sympathomimetics: S-stimulators, they resemble the action of the system.

- Sympatholytics: S-inhibitors, they block or inhibit the action of the system (opposite action).

Terminology used for drugs related to the Autonomic Nervous System

2- Based on the type of neurotransmitter involved:

ACH

- Cholinergic: Stimulates an ACH receptor.

- Anticholinergic: Blocks or inhibits an ACH receptor.

NE

- Adrenergic: Stimulates a NE receptor.

- Antiadrenergic: Blocks or inhibits a NE receptor.

Both different naming systems dont mean exactly the same!

ACHs origin and action mechanism

Remember: ACH is the universal neurotransmitter at the P-branch.

Origin: ACH results from a chemical reaction, as follows:

Acetyl-CoA + Choline = Acetylcholine

(enzyme involved is named Choline-acetyl transferase)

Storage: ACH is stored in vesicles at the end of the presynaptic fibers (synapses) and the postsynaptic fibers (in neuroeffector sites where ACH is the neurotransmitter involved).

Steps of the ACH-linked transmission process

1- When the nerve impulse reaches the vesicles, ACH is released to the synaptic cleft.

2- ACH exerts its effect by stimulating receptors located proximally on the postsynaptic neuron.

3- Immediately after, ACH is inactivated by the action of Cholinesterase.

4- Simultaneously, auto-receptors located in the presynaptic neuron are activated and prevent further ACH release (negative feedback).

5- Once the nerve impulse reaches the postsynaptic neuron, nerve transmission continues as a depolarization-repolarization cycle.

Parasympathetic effects

Most important effects related to the cardio-respiratory system are:

- Constriction (narrowing) of the bronchial smooth muscle, with subsequent reduced airflow.

- Slow heart rate.

- Increased secretion at the respiratory gland level.

Parasympathomimetic drugs may be used in Respiratory Therapy, ex. Metacholine used for the bronchial challenge test, but their use is very limited, due to their bronchoconstricting action.

Parasympatholytics are widely used due to their bronchodilating effects, ex. Ipratroprium bromide (Atrovent)

ACH receptor subtypes

Muscarinic (chemically related to the fungus Amanita Muscaria)

Nicotinic (chemically related to the alkaloid Nicotine, contained in tobacco leaves)

Muscarinic receptors are found at the parasympathetic neuroeffector sites, such as airway smooth muscle, cardiac muscle, gastrointestinal tract and exocrine glands.

Nicotinic receptors make up the rest of the ACH receptors.

Muscarinic receptors

Five different groups of muscarinic receptors have been identified:

- M1

- M2

- M3

- M4

- M5

Among them, only M3, M4 and M5 have been found in human lungs.

M3 receptors are the most important ones, because they are grounds for the action of the parasympatholytic bronchodilators, also named M3 antagonists.

Parasympathetic branch ACH receptors-Summary

Ganglionic synapses: ACH-nicotinic

Neuroeffector sites: ACH-muscarinic

In some textbooks, the terms muscarinic and antimuscarinic are used to describe medications which stimulate or inhibit muscarinic receptors, respectively.

Ex. Parasympathomimetic = Muscarinic

Parasympatholytic = Antimuscarinic

Sympathetic branch and arc reflex ACH and NE receptors summary

Sympathetic branch

Ganglionic synapses: ACH-nicotinic

Most neuroeffector sites: NE

Sweat glands and adrenal medulla: ACH-nicotinic

Arc reflex: ACH-nicotinic (at the neuroeffector sites)

Parasympathomimetic agents

They mimic the action the system normally causes, that is, they resemble the ACH action at the parasympathetic sites. They are also referred to as "muscarinic drugs".

Direct action

They are structurally similar to ACH. Ex Metacholine, used for test purposes.

Indirect action

They are Cholinesterase inhibitors and do not act over receptors.

Some of them are reversible, with effects limited to a number of hours, others are irreversible and potentially lethal.

Parasympatholytic agents

Classes:

- Belladona alkaloids, ex Atropine

Synthetic compounds

Semisynthetic compounds

Atropine is a competitive antagonist to ACH at the neuroeffector site level.

Uses in Respiratory Therapy:

It decreases secretions and relaxes the bronchial smooth muscle (bronchodilation).

Atropine is in use for no longer due to its side effects, but newer aerosolized analogues are now in clinical use, ex. Atrovent.

They block ACH receptors at parasympathetic neuroeffector sites, but do not have any effect at the arc reflex neuroeffector sites.

Parasympatholytics:
Common clinical uses

Bronchodilators

Preoperative drying of secretions

Antidiarrheics

Prevention of bed wetting in children

Treatment for peptic ulcers

Treatment for organophosphate poisoning

Treatment for mushroom poisoning

Treatment for bradychardia

Sympathetic effects

Sympathetic effects are produced in three different ways:

When NE receptors are stimulated at most sympathetic neuroeffector sites.

When ACH receptors are stimulated at sweat glands and adrenal medulla sites.

By means of catecholamines (epinephrine and norepinephrine) released under sympathetic stimulation of the adrenal medulla.

Most important sympathetic effects related to the cardio-respiratory system are:

Relaxation of the bronchial smooth muscle with bronchodilation and improved airflow.

Increased heart rate and cardiac output.

Increased blood pressure.

Increased metabolic activity.

Improved brain activity.

Steps of the NE-linked transmission process

NE is stored in vesicles located by the end of the postsynaptic neuron.

When the nerve impulse reaches the vesicles, NE is released to the synaptic cleft.

NE exerts its "bridge" action, by stimulating receptors located proximally on the effector organ.

Immediately after, NE is removed from the synaptic cleft, in three different ways:

- Uptake 1: NE is returned to the postsynaptic neuron.

- Uptake 2: NE flows into tissues located nearby the postsynaptic neuron.

- Diffusion away from the receptor site and further metabolism in the plasma and liver. Enzymes involved are named COMT and MAO.

Auto-receptor activation prevents further NE release.

COMT plays a critical role in the metabolism of some sympathomimetic bronchodilators and will be studied in greater detail in that chapter.

NE receptor subtypes

Alpha (α)

Most of them excite, with the exception of those located in the intestine and the CNS, where inhibition occurs.

Beta (β)

Most of them inhibit or relax, with the exception of those located in the heart, where stimulation occurs.

Beta receptors:

Beta 1: Located in the heart. Its stimulation increases rate and contractile force.

Beta 2: Located in the bronchi. Its stimulation relaxes the bronchial smooth muscle.

Beta 3: Located in fat cells. Its stimulation results in lipolysis.

Alpha receptors:

Alpha 1: Located in the blood vessels. Its stimulation constricts blood vessel walls.

Alpha 2: Auto-receptor. Its stimulation inhibits further ACH and NE release.

Examples of drugs related to the sympathetic branch

Sympathomimetics:

Beta 2 agonists, with bronchodilating effect.

Beta 1 agonists (heart muscle stimulators).

Alpha 1 agonists with topical vasoconstricting action, widely used in common cold remedies.

Sympatholytics:

- Alpha 1 antagonists used to reduce and control high blood pressure.

Neural control of the lung function

Both branches exert control of the lungs and the respiratory tract.

Parasympathetic activity is direct: ACH-muscarinic receptors are stimulated at the bronchial smooth muscle level. Greater density of P-fibers is found in the hilar region.

Sympathetic activity is indirect, since there is little or no sympathetic innervation of airway smooth muscle in human lungs. Circulating epinephrine and norepinephrine stimulate alpha and beta receptors. Beta 2 receptors density is higher in peripheral areas.

Classes of respiratory care drugs which modify airway smooth muscle tone

1- Adrenergic bronchodilator group (beta 2 agonists, sympathomimetics)

Ex. Albuterol, Salmeterol, Isoproterenol, Terbutaline, etc.

2- Anticholinergic bronchodilator group (M3 antagonists, parasympatholytics)

Ex. Ipratropium bromide, Tiotropium bromide.