Autonomic Nervous System

Autonomic Nervous System

• component of the peripheral nervous system

• It regulates involuntary physiologic processes: HR, BP, pupil diameter, Respiration, Digestion and Excretion, Glandular activity, Renal function, Conversion glycogen to glucose

• Some features include: High-level integration in the brain, the ability to influence processes in distant regions of the body, Extensive use of negative feedback

• Controls Sympathetic Nervous System and Parasympathetic Nervous System

Preganglionic Fibers

• The ANS consists of neurons that give rise to prepanglionic fibers and other neurons that give rise to postganglionic fibers

• Originate from cells located in the brainstem or spinal cord and project to a ganglion

• All preganglionic fibers use acetylcholine (ACh) as their neurotansmitter

• Preganglionic gibers of the sympathetic NS exit the CNS from thoracic, lumbar, and sacral regions of the spinal cord

• Preganglionic fibers of the parasympathetic NS exit the CNS via the cranial nerves, particularly nIII, nVII, nIX, and nX

Ganglion

collection of nerve cell bodies

Postganglionic Fibers

• Postganglionic fibers of the sympathetic NS originate from ‘ganglia’ located either in a ‘chain’ next to the spinal cord (paravertebral) or located along the midline in front of the heart and spinal column (prevertebral)

• These fibers project to the end organs

• Postganglionic fibers of the parasympathetic NS originate from cells located near the end organ

Anatomic and Neurotransmitter Features of Autonomic and Somatic Motor Nerves

• The adrenal medulla, a modified sympathetic ganglion, receives sympathetic preganglionic fibers and releases epinerphrin and norepinephrine into the blood which goes the the tissue and muscles

• Cholinergic nerves are shown in blue

• Noradrenergic are shown in red

Parasympathetic: Cardiac and smooth muscle, gland cells, nerve terminals

acetylcholine goes to the nicotinic receptors which sends acetylcholine to the muscarinic receptors of the cardiac and smooth muscle, gland cells, nerve terminals

Sympathetic: Sweat glands

Spinal cords sends acetylcholine to the nicotinic receptors which sends acetylcholine to the muscarinic receptors of the sweat glands

Sympathetic: Cardiac and smooth muscle, gland cells, nerve terminals

Spinal cord sends acetylcholine to nicotinic receptors which send norepinephrine to adrenergic receptors on cardiac and smooth muscle, gland cells, nerve terminals

Sympathetic: Renal vascular smooth muscle

Spinal cord sends acetylcholine to nicotinic receptors which send norepinephrine and dopamine to adrenergic receptors on renal vascular smooth muscle

Neurotransmitters

• Preganglionic fibers of both the SNS and PNS use acetylcholine as their neurotransmitter. The ACh acts on nicotinic receptors located on the ganglion cells

• Most postganglionic fibers of the SNS use norepinephrine (NE) as their neurotransmitter. NE acts on adrenergic receptors located in the end organs. One exception is SNS innervation of sweat glands which uses ACh

• Postganlionic fibers of the PNS use ACh as their neurotransmitter. The ACh acts on muscarinic receptors located in the end organs

Neurotransmitter Receptors

• Each neurotransmitter can bind to multiple receptor subtypes

• Subtypes are organized into families and are classified as ‘type’ according to pharmacological effects and mechanism of action

Ionotropic Receptors

Form ion channel, activation alters membrane conductance, will cause ion channel to open changing membrane potential

Metabotropic Receptors

Act through G-proteins, Can activate or inhibit second messenger systems, also can be associated with an ion channel

Adrenergic Receptors

• All are metabotropic receptors, act through G-protein

• Have multiple receptor subtypes

Subtypes of Adrenergic Receptors

• The natural ligand for adrenergic receptors is norepinephrine

• The 2 main groups of adrenergic receptors, alpha and beta and at least 9 subtypes in total

• All are metabotropic

• Alpha receptors are divided into alpha₁ (G_q-coupled) and alpha₂ (G_i-coupled)

• Alpha₁ has 3 subtypes- a_1A, a_1B, and _1D

• Alpha₂ has 3 subtypes- a_2A, a_2B, a_2C

• Beta receptors are divided into b₁, b₂, and b₃

  • All couple with G_s, but b₂ and b₃ also can couple with G_i

Mechanism of Action of Adrenergic Receptors

• Epinephrine or norepinephrine are receptor ligands to either a₁, a₂, or b adrenergic receptors

• a₁- Smooth muscle contraction, increases BP

• a₂- Inhabitation of NE, release/sympathetic tone

• b- Heart muscle contraction, smooth muscle relaxation, glycogenolysis

• b₁- Increase cardiac output, BP

• b₂- Smooth muscle relaxation

Alpha-1 receptor

• Vasoconstriction

• Increase peripheral resistance (blood flow)

• Increase BP

• Mydriasis

• Increase Closure of bladder sphincters

• Norepinephrine is more potent than epinephrine

Alpha-2 receptors

• Inhibits Norepinephrine release

• Inhibits acetylcholine release

• Inhibits insulin release

• Inhibits neurotransmitters

• Decreases sympathetic, put brain sleep

• Epinephrine is more potent than Norepinephrine

Beta-1 receptors

• Increase HR

• Increase lipolysis

• Increase myocardial contractility

• Increase Renin

• Located mainly in the heart

• Activation of SNS

• Increase BP

• Increase vasoconstriction

• Epinephrine is equal to norepinephrine in potency

Beta-2 Receptor

• Vasodilation

• Decrease Peripheral resistance, blood flow

• Increase Glycogenolysis, muscle and liver

• Bronchodilation- smooth muscle relaxes

• Increase Glucagon release

• Relaxes uterine smooth muscle

• Epinephrine is more potent than Norepinephrine

Sympathomimetic Agents

• mimic activation of the SNS by increasing adrenergic receptor activity, cause release of NE

• Direct agonists- directly interact and activate adrenoceptors (NE, Epi, isoproterenol (b), albuterol (b₂)

• Direct a₂ antagonist- Yohimbine, helps to put the brain to sleep

• Indirect Agonists- dependent on ability to enhance the actions of endogenous catecholamines, don’t directly with the receptors

  • By enhancing release from nerve terminals (reserpine, amphetamines, tyramine)

  • By blocking re-uptake/removal of the transmitter (cocaine, methylphenidate)

  • By preventing enzymatic degradation of the neurotransmitter (MAOIs, COMT inhibitors)

Sympatholytic Agents

• reduce activation of the SNS by reducing adrenergic receptor activity, by blocking the actions of NE and Epi on adrenergic receptors

• Beta blockers (propranolol, metoprolol, atenolol) Lower BP

• a₁ antagonists (prazosin), a₂ agonists (clonidine)

Effects of SNS Activation

• Increase HR, arterial BP, and cardiac output

• Increased blood flow to brain, heart, and skeletal muscles

• Increased blood glucose

• Pupil dilation

• Increased rate of cellular metabolism

• Increased rate and depth of respiration

• Reduced saliva production

• Reduced gut motility and urine flow

Sympathomimetic and Sympatholytic drugs are very important because they are used in so many conditions

• Cardiogenic shock

• Anaphylactic shock

• Hypotension

• Congestive heart failure

• Bronchial asthma

• Nasal decongestion

• Narcolepsy

• ADHD

Hypertension

• Diuretics

• Beta-blockers (atenolol, metoprolol, propanolol) to reduce strength of contractions

• ACE inhibitors

• Angiotensin II receptor blockers

• Calcium channel blockers

• Alpha blockers (praxosin- a₁ blocker) relaxes smooth muscles of blood vessels

• Alpha-2 receptor Agonists (clonidine) relaxes smooth muscles of blood vessels

• Combined alpha and beta-blockers (carvediolol, labetalol, dilevalol)

Inadequate Heart Function

• Hypotension

  • NE, phenylephrine- causes vasoconstriction which increases BP

• Cardiogenic shock or acute heart failure

  • Dopamine, dobutamine- for inotropic effect (increase force and speed od cardiac output)

• Cardiac arrest

  • Isoproterenol, epinephrine- increases strength of contractions and causes vasoconstriction

Asthma

• Direct b₂ agonists- to relax smooth muscles in airways, bronchodilation

  • Albuterol

    • b₂ agonist

    • Levalbuterol

    • Metaproterenol

    • Terbutaline

  • Inhaled corticosteroids

Anaphylaxis

• Epinephrine

  • b₁- increase cardiac output

  • b₂- relaxes constricted bronchioles

  • a₁- constricts capillaries and increases BP

Glaucoma

• Beta blockers- betaxolol- lowers pressure by reducing aqueous humor production

• Now mostly replaced by prostaglandins

Nasal Congestion

• Oxymetazoline- a₁ and a₂ agonist in arterioles of nasal mucosa- vasoconstriction

• Phenylephrine- a₁ agonist in arterioles of nasal mucosa- vasoconstriction

• Pseudophedrine- acts on both a and b receptors to cause vasoconstriction

Cholinergic Receptors

• Receptors are classified as nicotinic or muscarinic, based on whether they have high affinity for nicotine or muscarine

• Nicotinic receptors are ionotropic- ion channel

• Muscarinic receptors are metabotropic

• There are multiple subtypes of each subclass of receptor

Nicotinic Receptors

• They are ionotropic and form a sodium channel

• Nicotinic receptors are ionotropic and pentomeric (made up of 5 subunits), consisting of alpha, beta, gamma, delta, epsilon subunits

• There are multiple isoforms of alpha and beta subunits

• There are 4 transmembrane domains

• Primarily act as sodium channels, Can also increase permeability to Ca

Muscarinic Receptors

• Metabotropic

• 2 subtypes

  • M1 (includes M1, M3, and M5 receptors) proteins that have been identified and cloned

  • M2 (includes M2 and M4 receptors)- proteins

Location and Function of M1 receptors

• GI tract

  • glands- secretion

Location and Function of M2 receptors

• Heart

  • SA node- decrease HR- negative chronotrophy

  • AV node- decreased conduction velocity- negative dromotropy

  • No effects on ventricles, purkinje system

Location and Function of M3 receptors

• Eye

  • Sphincter- Contraction- miosis

  • Ciliary muscle- Contraction- accommodation for near vision

• Lungs

  • Bronchioles- Contraction- bronchospasm

  • Glands- secretion

• GI tract

  • Stomach- Increased motility- cramps

  • Intestine- Contraction- diarrhea, involuntary defecation

• Bladder

  • Contraction, relaxation, voiding, urinary incontinence

• Sphincters

  • Relaxation, except lower esophageal which contracts

• Glands

  • Secretion- sweat, salivation, and lacrimation

• Blood vessels

  • Dilation (via NO/endothelium- derived relaxing factor)- no innervation, no effects of indirect agonists

Parasympathomimetic agents

• mimic activation of the PNS by increasing muscarinic cholinergic receptor activity

• Direct agonists- directly interact with and actiavte muscarinic cholinergic receptors (ACh, methacholine, bethanechol, muscarine, pilocarpine

• Indirect agonists- Enhance ACh effects by inhibiting cholinesterase thereby blocking degradation (neostigmine, physostigmine, donepezil, galantamine, rivastigmine)

Parasympatholytic Agents

• reduce activation of the PNS by

  • Blocking the actions of ACh on muscarinic receptors (atropine, scopolamine, and other muscarinic receptor antagonists)

Effects of PNS Activation

• Decreased HR, arterial BP, and cardiac output

• Decreased blood glucose

• Pupil constriction

• Increased sweating and tearing

• Increased saliva production

• Increased gut motility and urine flow

• Decreased rate of cellular metabolism

• Bronchoconstriction

Cholinergic mimetic drugs are very important because they are used to treat so many conditions

• GI and Urinary tract (urinary retention, atony or paralysis of the stomach or bowels after surgery) Treated with bethanechol or neostigmine

• Dry mouth (to stimulate salivary secretions) Treated with pilocarpine or cevimeline

• Dysfunction at the neuromuscular junction (Myasthenia gravis which is associated with reduced nAChR function) Treated with cholinesterase inhibitors like pyridostigmine

• As antidote to overdose of tricyclic antidepressants

• Memory disorders associated with AD, and PD (cholinesterase inhibitors like donepezil, galantamine, rivastigmine)

Parasympatholytic (anti-muscarinic) drugs treat a variety of disorders

• Atropine

  • Prototypical non-selective antimuscarinic agent

  • Used to treat bradycardia, to reduce salivation and bronchial secretions before surgery, and as antidote for overdose of cholinergic drugs

• Methantheline

  • Dries salivary secretions

• Propantheline

  • Reduces GI motility

• Diphenhydramine

  • In addition to blocking muscarinic cholinergic receptors, also blocks H1 histamine receptors

  • Dries nasal secretions

  • Antiemetic effects

  • Sedation

Atropine Poisoning

• Atropine is a relatively safe drug in adults; however poisoning can occur with extreme doses

• Symptoms include:

  • Dry mouth

  • Mydriasis

  • Tachycardia

  • Hot and flushed skin

  • Elevated body temperature

  • Agitation

  • Delirium for as log as 1 week

• Think: Dry as a bone, blind as a bat, red as a beet, mad as a hatter