Autonomic Nervous System

• Module 02 introduces the nervous system, its organization, and its two autonomic nervous system divisions: parasympathetic and sympathetic

Integrity Reminder

• It is a direct violation of the Academic Integrity Policy to distribute this Module Companion Guide to students not enrolled in PHAR 370
• Sanctions may be imposed if students are found in violation

Course Structure

• Section 01: Introduction to Autonomic Pharmacology
• Section 02: Parasympathetic Nervous System
• Section 03: Sympathetic Nervous System
• Section 04: Neuromuscular Blocking Drugs and Anesthetics
• Section 05: Substance Use Disorders

Introduction to the Nervous System

• Module 02 introduces the nervous system and its organization
• It explores the parasympathetic and sympathetic nervous systems (divisions of the autonomic nervous system)
• Receptors that target these systems are also discussed
• You will learn about factors influencing substance use disorders
• The foundational knowledge will help with Module 03, which covers drugs that excite/depress the nervous system and treat neurodegenerative diseases

Learning Outcomes

• Describe the sympathetic and parasympathetic nervous systems
• Explain how drugs are used to target these nervous systems
• Describe the use of drugs to produce muscle paralysis and anesthesia
• Discuss the factors that influence substance use disorders.

Autonomic Pharmacology

• Pharmacology that is related to involuntary bodily functions

The Nervous System

• The nervous system is the body's control and communication network
• It is made up of the brain, spinal cord, sensory organs, and all the nerves within the body
• The nervous system controls both voluntary and involuntary bodily activities
• Many medicines have been created to target the nervous system

Review of Three Basic Functions of Nervous System

• Recognize: The nervous system detects internal or external environment changes (e.g., a temperature increase)
• Process and Integrate: The nervous system analyzes environmental changes (e.g., feeling hot)
• React: The nervous system responds to environmental changes by producing an action or response to counteract the change (e.g., sweating)

Neurotransmission Process

• Neurons, the functional units of the brain, are nerve cells that generate/transmit electrical signals
• Neurons in the nervous system communicate through synaptic transmission (neurotransmission)
• Synaptic transmission generally relies on chemicals; the release of a substance is needed to activate the other neuron or pass on the message

Mechanisms for Removing Neurotransmitters from the Synaptic Cleft

• Neurotransmitters can be taken back up into the presynaptic neuron through transporters, neurotransmitters can change conformation,
• Neurotransmitters break down by enzymes, neurotransmitters can be taken up by adjacent glial cells

Division of the Nervous System

• It is divided into the central nervous system (CNS) and peripheral nervous system (PNS)
• CNS: the brain and spinal cord
• PNS: all nerve fibres outside the CNS

Peripheral Nervous System

• The PNS has sensory and motor divisions, motor division includes the somatic and autonomic nervous systems (ANS)
• The parasympathetic and sympathetic nervous systems - make up the ANS
• It's important to review the function of each PNS subdivision
• The main focus of this section is on the function/organization of the autonomic nervous system

PNS Subdivisions

• Sensory (afferent): Sends sensory data from the periphery to the CNS
• Motor (efferent): Sends motor directives from the CNS to the periphery
• Autonomic nervous system: Involuntary motor control of smooth and cardiac muscle
• Somatic nervous system: Voluntary motor control of skeletal muscle
• Parasympathetic nervous system: Rest and digest response
• Sympathetic nervous system: Fight or flight response

Autonomic Nervous System (ANS)

• The ANS is a PNS division that regulates involuntary responses
• It affects organs, glands, and smooth muscle, and helps sustain a stable internal environment
• ANS governs crucial bodily functions normally performed without conscious effort, such as sweating, bowel motions, blood pressure, and heart rate
• The autonomic nervous system is often known as the involuntary nervous system because these processes are performed without conscious effort

Autonomic Nervous System: A Two-Neuron System

• Two neurons are needed in the ANS to reach the target organ.
• The first neuron's cell body is located in the CNS, while the second neuron's cell body is located in the ganglion. The preganglionic nerve is the neuron that comes before the ganglia, and the postganglionic nerve is the neuron that comes after the ganglia

Divisions of the Autonomic Nervous System

• The ANS has two distinct divisions: the parasympathetic and the sympathetic nervous systems

Two Divisions of the ANS

• Parasympathetic Nervous System: Responsible for "Rest and Digest", activated during non-stressful times

• The effects of the parasympathetic nervous system include pupil constriction, decreased heart rate, and increased digestive intestinal activity.

• Sympathetic Nervous System: Responsible for "Fight or Flight", activated under stressful times

• Pupil dilation, increased heart rate, sweating, and blood pressure are all effects of the sympathetic nervous system

Balance within the Systems

• Both parasympathetic and sympathetic nervous systems have higher centres in the brain, that monitor and control them
• These systems usually operate in an opposed, balanced way
• An organ's activity at any moment results from the two systems' opposing influences
• Most organs have dual innervation from both systems but not all

Abnormalities & Paravertebral Ganglia

• Abnormal autonomic nervous system function is associated with many medical conditions, such as hypertension, congestive heart failure, and atrial fibrillation
• Overview of the organization, neurotransmitters, and receptors involved with the sympathetic and parasympathetic nervous systems
• The sympathetic trunk, or sympathetic chain, is sometimes referred to as the paravertebral ganglia

Parasympathetic Nervous System

• Stimulation of the parasympathetic nervous system raises or promotes vegetative functions like digestion

Neurons of the Parasympathetic Nervous System Arise in Two Spinal Cord Locations:

• Sacral (bottom) region
• Cervical (top) region

Organization of the PNS

• The parasympathetic nervous system features long preganglionic fibres that release acetylcholine, which then binds to receptors in the ganglia
• The activation of N№ receptors on postsynaptic membrane leads to propagation and depolarization of the impulse along postganglionic fibre
• Postganglionic fibres are short and release acetylcholine, which binds to the muscarinic receptors on the target organ

Parasympathetic Neurotransmitters and Receptors

• Acetylcholine is the neurotransmitter released by all parasympathetic nerves i.e cholinergic
• Acetylcholine binds to nicotinic (N) and muscarinic (M) receptors of the parasympathetic system
  • Nicotinic receptors: ligand-gated channels.
  • Muscarinic receptors: G-protein coupled receptors

Parasympathetic Receptors, Primary Locations, and Response

• Nicotinic (Nn) receptors are at the ganglia, generate impulse to postganglionic neuron;
• Muscarinic (M) receptors
  • are at the heart, and decrease heart rate/force of contraction
  • Smooth muscle, and produce smooth muscle contraction
  • the glands and result in gland secretion

Termination of PNS Response

• Acetylcholinesterase (AchE) breaks down acetylcholine in the synaptic cleft into acetate and choline to end the acetylcholine-mediated response in the parasympathetic nervous system

Activation of the Parasympathetic Nervous System

• Drugs can stimulate or activate the parasympathetic nervous system (PSNS) through 3 routes:
  • Drugs can bind to and activate nicotinic receptors.
  • Drugs can bind to and activate muscarinic receptors.
  • Drugs can block acetylcholine, increasing its concentration in the synaptic cleft

Activation of the Parasympathetic Nervous System Actions

• Indirect-acting drugs block the metabolism of acetylcholine by inhibiting AchE
• Direct-acting drugs bind to receptors
• Both of these drug types (cholinomimetic or parasympathomimetic) can lead to parasympathetic activation

Activation and Specificity of Target Receptors

• Drugs that activate the parasympathetic nervous system show rest/relaxation effects
• Direct and indirect acting agents mimic acetylcholine at NN or M receptors i.e are cholinomimetics
• NN receptor activation activates postganglionic neurons of both sympathetic and parasympathetic systems
  • Drugs must bind to/activate just M receptors to specifically activate parasympathetic system

Clinical Uses of Activators

• Cholinergic drugs are not widely used due to side effects: constricted respiratory passages or slowing heart rate
• Clinical use of cholinergic activators: glaucoma, asthma, and poor muscle tone in the bladder

Glaucoma

• Glaucoma is when high intraocular eye pressure, due to poor fluid drainage, damages the optic nerve and impairs vision
• Muscarinic receptor agonists like pilocarpine treat glaucoma - These agonists rise parasympathetic nervous system activation, causing ciliary body contraction - Ciliary body contraction increases fluid drainage, reducing eye pressure - Beta antagonists are frequently used for glaucoma, but muscarinic agonists can also be utilized to treat it

Inhibitors

• Drugs that inhibit activity of parasympathetic nervous system - anticholinergic drugs which antagonize or block M or NN
• Effects of "fight or flight" are observed when effects on parasympathetic nervous system are inhibited
• Clinical use limited due to tachycardia
• Ganglion-blocking drugs (antagonize / inhibit NN receptors) use important physiological & pharmacological research as they block all autonomic outflow
• Adverse effects associated with ganglion-blocking drugs has limited use
• Muscarinic receptor blockers are more common

Atropine

• The prototypical muscarinic receptor antagonist
• Dilates the pupils for a week or more

Clinical Use of Inhibitors for Respiratory, Urinary, and GI Disorders

• Those with asthma or chronic obstructive pulmonary disease are sometimes prescribed muscarinic antagonists which allows good profile and better bronchodilation when inhaled
• Patients with urination urgency from minor bladder inflammation/incontinence benefit from muscarinic antagonists that will inhibit bladder contraction
• Muscarinic antagonists can treat GI cramps, hypermotility, and diarrhea by decreasing intestinal motility.

Review of Acetylcholine

• Poisoning can occur due to a toxic nerve gas
• Sarin, a potent acetylcholinesterase inhibitor, was released in Syria in August 2013
  • Sarin is colourless and odourless
  • Blocks acetylcholinesterase breaking down acetylcholine in synaptic cleft into acetate and choline

Indirect Activators

• An indirect activator of the parasympathetic nervous system starts a response by directly binding to acetylcholinesterase

Therapeutic Uses

• Dilating pupils is an appropriate therapeutic use of a parasympathetic nervous system antagonist

Introduction to the Sympathetic Nervous System

• Along with the parasympathetic nervous system, a second component of the autonomic nervous system
• The sympathetic nervous system activates when an individual perceives a threat; prepares its "fight or flight" response

Fight-or-Flight Response

• General stimulation of the sympathetic nervous system mobilizes resources for emergencies
• Mass sympathetic discharge increases body functions

Activation of the Sympathetic Nervous System Results in Increased

• Heart rate
• Blood pressure
• Blood supplied tissues
• Rate of cell metabolism
• Blood glucose

Sympathetic Neurons

• Neurons of the sympathetic system start in spinal cord's thoracic region at the lumbar region

Organization of the SN System

1. Sympathetic system has short preganglionic neurons release acetylcholine at the ganglia
2. Acetylcholine activates NN receptors at sympathetic ganglia and signal long postganglionic neurons
3. The postganglionic neurons mainly release norepinephrine which targets alpha (α) or beta (β) receptors

• Some exceptions to this rule are sympathetic postganglionic neurons innervating sweat glands and the renal vascular smooth muscle: releasing dopamine/acetylcholine that binds to D/M receptors

Adrenal Medulla

• Functions are a sympathetic autonomic ganglion.
• Receives innervation by short sympathetic preganglionic fibers that release NN
  • Activates NN: leads to mainly epinephrine release and norepinephrine release from the medulla

Epinephrine + Norepinephrine

• Released chemicals travel in blood and interact with a and b receptors
• Since adrenal medulla works in the circulation, it is acting as the hormones.
• Stress can also activate leading release leading to prolonged sympathetic effect.

Sympathetic Neurotransmitters and Receptors

• Acetylcholine, at the NN receptors on the ganglia, is the neurotransmitter, from preganglionic sympathetic neurons.
• Whereas, the neurotransmitter at postganglionic nerve ending ( sympathetic), is norepinephrine: which binds either α/β receptors.

Adrenergic Receptors

• These receptors (adrenergic), are typical g protein coupled receptors

Alpha Receptors

• Alpha (α) receptors can be subdivided into two main types: a1 and a2.
• Alpha 1 Receptors: Located post synaptic on: smooth muscle (blood vessels/ gastrointestinal muscel and uteus)
  • Activation of alpha 1: Contraction of muscles.

The Different Subtypes of Alpha 1 Receptors

• Are organ selective and drugs can be designed to target them.
• Alpha 2 Receptor: Located postsynaptically on Smooth muscle membrane and pre synaptically on the neuroal membrance
• The presynaptic located receptors are autoreaceptors
• The effects of the stimulation of ALpha1 is same in Alpha2

Beta

• Two main types: Beta 1 and Beta 2
  • Beta 1: the heart/ gastrointestinal mucle- increase force and rate of contraction of of heart
  • Beta2- found in: the lungs, blood vessels, gastrointestinal muslce and uterues
• Activation of the these receptors leads to muscle relaxation

Sympathetic Receptors

2. located: at the Presynaptic neuronal membrane, B1 )Location: Heart and gastro intestinal muscle, Beta2) location Lungs, blood vessels,gastro intestinal muscle, and uterus

Receptor for Sympathetic

• Alpha 1 receptor: Contracts smooth muscle in vasculature/uterus or decreases motility/tone in g tract

Release of Norepinephrine

• Sympathetic postganglionic neurons almost always release norepinephrine at the targeted organ
• Norepinephrine then binds to alpha and beta, to exert action
• Terminate N by reuptake back, this is followed by the enzyme degradation within the neuron

Activation

• Mimics actions of norephinephine increase. drugs is done through three methods. Review three mechanisms by which sympathetic system will get impacted

Direct

• A simple direct is a drug bing the receptor and produces an effect Example is: eneprine which binds beta and alpha receptors.

Indirect

• Inderect: drug will increase release of Ner from the pre synapic neuron amphetamine acts in this

combination:

• Binds at receptor and increases norephrine example ephedrine used as de constip

Activation of the Sympathetic System

• Direct stimulation: drug binds receptor and makes an effect
  • Example: epinephrine targets alpha and beta receptors
• Indirect stimulation: drug rises norepinephrine from the presynaptic neuron -Example: amphetamines
• Combo of the two: increases relase of norepinephrine drugs stimulate one or both recceptors
  • exampmle ephedrine which is a decongestant

Adrenergic

• Drugs: that activate process by the symptatic n system primarily used for their effects are the nasal passagae,bronchila tree

  -Drugs producess similar effects and beta) the actions of the drugs are: Specfic actions and are more predicrable to the the receptor sub type activated

• Anaphlaxis: severe reaction- hypersensiivty to the food or other subs- epirelnephrine relives symptom causing brocnhdialstion constriction in the muscle the blood vessels are constricted relieving the symptoms

Activation of Beta 1 Receptors

• Some symptoms: cardiac contraction to complete heart block as well. as cardiac arrest.

Alpha 1 Agents

• constriction - are useful for nasal congestion- can used to exam retina- they produce brocnodialtion- effectivly treat someone from asthma. Long short acting and beta agonists are avlaible- treats obstructive pupmanry
• Cqn and COPD- constricict and beta

Question,Adrenergic Adrenergic drugs:

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Adrenergic side effects

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Andriadgonic

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Explore the autonomic nervous system, its parasympathetic division, and neurotransmitters. Understand the origins of parasympathetic neurons and the effects of parasympathetic activity. Test your knowledge with related questions.