ANS

Nervous system:

• branched out to two types of nervous system

  • peripheral nervous system (PNS)

    • Afferent (sensory)

    • Efferent (motor)

      • somatic nervous system (SNS): this is under conscious control

      • autonomic nervous system (ANS): this is under autonomous control

        • governs functions that are not under conscious control, such as heart rate, respiration, and digestion

        • ANS is also sub-divided into sympathetic and parasympathetic nervous system

          • sympathetic nervous system: activates the fight-or-flight response during stressful situations, increasing heart rate and energy mobilization

            
            

          • parasympathetic nervous system: promotes the rest-and-digest response, helping to conserve energy and maintain homeostasis.

        • most organs are under sympathetic and parasympathetic nervous system

          • sympathetic and parasympathetic have opposing effects:

            • during sympathetic, heart rate goes up meaning in parasympathetic heart rate will go down.

            • same effect for bronchial. in sympathetic, broncho-dilation happens and in parasympathetic, broncho-constriction happens

  • central nervous system (CNS)

    • brain

    • spinal cord

Dominant Tone

• although many organs are under influence of both SNS (sympathetic) and PSNS (parasympathetic), often one dominates over the other

Nomenclature

• PSNS:

  • cholinergic (acetylcholine)

  • muscarinic (muscarinic receptors)

• SNS

  • Adrenergic (adrenaline)

Anatomy

• PSNS nerves: cranioscaral

  • originate from the top (Cranio) and bottom (Sacral) regions of the spinal cord

• SNS nerves: Thoracolumbar

  • moddle (thoracic and lumbar) regions of the spinal cord

ANS Anatomy

• both SNS and PSNS have ganglia, a relay station

• the NT released onto receptors at the ganglia is acetylcholine

• the receptors at the ganglia are nicotinic receptors

• most drugs work at postganglionic receptors on target organs

• adrenal medulla is an important source of NT, it releases: 80% epinephrine and 20% norepinephrine

Neurotransmitters (NT)

• acetylcholine is synthesized from Acetyl CoA and choline

• the Ach is then stored in synaptic vesicles and released.

• Key NT like dopamine, NE, and Epi are all aynthesized from tyrosine, as a group these are called catecholamines:

  • Tyrosine —> DOPA —> DOPAMINE —> Norepinephrine —> epinephrine

receptor distribution: cholinergic

• there are two types of cholinergic receptor:

  • nicotinic and muscarinic

  • five sub-divisions of muscarinic receptors

  • two nicotinic found in muscle and ganglia adrenal CNS immune

receptor distribution: adrenergic

• adrenergic receptors are divided into alpha and beta

PSNS-receptors

• receptors in the PSNS are referred to as Muscarinic (M)

• several sub-types have been identified (M1-M5)

• there are fewer drugs that target muscarinic receptors than adrenergic receptors

• M1,M3,M5 receptors are G-protein coupled (Gq). associated with smooth muscle contraction

• M2,M4 receptors are G-protein coupled (Gi) associated with heart rate

• This means that while adrenergic agonists typically increase heart rate and promote smooth muscle relaxation, muscarinic agonists will decrease heart rate and induce smooth muscle contraction.

• the effects of a muscarinic agonist oppose those of an adrenergic agonist

  • heart (M2): decreased rate, contraction

  • lungs: bronchoconstriction

  • sphincters (Gi and bladder): relaxation

  • walls (bladder, GI tract): contraction

• ligands for muscarinic receptors

  • there are different ways to stimulate M receptors

  • direct:

    • using an agonist

  • indirect:

    • acetylcholinesterase inhibitors increase the concentration of acetylcholine

      • reversible

      • irreversible

• direct acting cholinergic drugs

  • there are three types of chemical reaction that can occur when cholinesterase is bound

    • acetylation

      • rapid recovery

      • physiological

    • carbamylation

      • slower recovery

      • reversible drugs (neostigmine)

    • phosphorylation

      • no recovery

      • irreversible drugs (‘nerve gases’)

• indirect-acting cholinergic drugs

  • irreversilble cholinesterase inhibitors have been used as poisonous gases in warfare

  • what would excessive cholinergic response look like?

    • secretion: increased (drooling, tearing, clogged airways)

    • lungs: bronchoconstriction (breath difficulty)

    • Heart: reduced heart rate

    • GI motility: increased (nausea, vomitting, diarrhea)

    • Urinary tract: contraction of bladder, relaxation of sphincters (urination)

• parasympatholytics

  • block PSNS responses

  • more commonly referred to as anticholingergics or anti-muscarinics

  • accomplished by antagonism of M receptors Eg. Atropine

    • atropine is the prototypical anticholinergic

      • used for:

        • intubation: clear airways by drying up secretions

        • ophthalmology: dilate pupils to facilitate eye exam

        • asthma: dilate bronchioles

        • antidote: counteract poisoning by cholinesterase inhibitor

      • side effects:

        • dry mouth

        • tachycardia

        • constipation

        • urination problem

Receptor distribution: adrenergic

• sub-group:

  • alpha

  • beta

• SNS:

  • alpha-1

  • function: constriction of smooth muscle

  • location:

    • sphincters: bladder, GI tract

    • blood vessels: vasoconstriction

  • Receptor types:

    • G-protein coupled

    • alpha-1 adrenergic receptors

  • Alpha-2

    • inhibition of presynaptic norepinephrine release

    • Alpha-2 agonists

      • binding of agonist to presynaptic a2 receptors inhibits release of NE

  • Beta-1

    • stimulate heart

    • located in heart

    • G-protein coupled

    • the liver, kidney, uterus are only innervated by SNS::

    • kideny: beta-1 receptors stimulate renin release

    • renin cause increase in blood pressure

  • beta-2

    • relaxation of smooth muscles

    • located in lung: bronchodilation

    • mostly associated with relaxation

    • G-protein coupled

    • similar to Beta-1, but they mediate glucose release by:

      • gluconeogenesis

      • glycogenolysis

• ligands for adrenergic receptors

  • sympathomimetics are drugs that mimic stimulation of SNS:

    • by directly activating adrenergic receptors

      • Eg. NORE or adrenaline

    • by increasing amount of sympathetic neurotransmitter in the synapse

      • how NT is increased?

        • increase NT release or inhibit re-uptake of NT

        • inhibiting will increase NT in synapse

        • it also inhibits metabolism of NT

          • Monoamine oxidase (MAO) is an enzyme that breaks down catecholamines like

            • NORE, Serotonin, dopamin

            • MAO inhibitors will thus inhibit breakdown of these NT

  • sympatholytics

    • drugs that block or reduce sympathetic activity:

      • by directly blocking adrenergic receptors (E.g propranolol)

      • by decreasing the amount of sympathetic NT released into the synapse (E.g clonidine)

ANS pharmacology and the eye

• Eye: two sets of muscles

  • iris muscle:

    • two iris muscles control the size of the pupil:

      • circular (sphincter) :

        • M3, M2 receptors

        • contraction constricts pupil

      • redial (longitudinal):

        • alpha-1 receptor

        • contraction dilates pupil

  • ciliary muscle

• Glaucoma

  • caused by increase in intraocular pressure (IOP)

  • due to buildup of aqueous humor (AH) due to:

    • decreased drainage

    • increased production

  • how to treat?

    • increase drainage of AH

    • decrease production of AH

  • Glaucoma and PSNS:

    • M2,M3 receptor stimulation:

    • contracts ciliary muscle, opens trabecular meshwork and canal of schlemm

  • Glaucoma and SNS:

    • beta-2 receptors

      • mediate vasodilation, which increases blood flow and AH secretion:

        • thus beta-2 antagnoists used in reducing AH secretion and treating glaucoma

    • Alpha-2 receptors

      • reduce NE release

        • facilitates drainage and reduce AH

        • thus alpha-2 agonists are used

• other ANS effects on EYE

  • PSNS:

    • stimulation of M receptors causes contraction of ciliary muscle

      • causes the lens of the eye to bulge, improving near vision and blurring far vision

Nueromuscular blockers

• NMB act at neuromuscular junction (NMJ) in the Peripheral nervous system

• NMJ is the connection between the neuron and muscle tissue

• acetylcholine (ACh) binds to nicotinic ACh receptors (Nm) on the motor end plate

• when enough Nm receptors are bound = contraction

• Receptor types:

  • ion channel: Nm receptor is associated with Na channels. agonist binding results in opening of the channel

  • Na entry leads to depolarization

  • resulting in Ca release, and muscle contraction

• there are tow types of NMB:

  • non-depolar, reversible

  • depolar, irreversible

  • main use:

    • surgery: skeletal muscle relaxants

    • skeletal muscles are paralyzed but smooth and cardiac are not.

• Example of NMB:

  • NON-depolar NMB:

  • rocuronium (ROC)

    • antagonists at NAchR, blocking action of Ach

  • initially induce muscle weakness then flaccid paralysis

  • small, rapidly moving muscles are paralyzed first:

    • eyes, jaw, larnyx

  • then:

    • limbs, trunk

    • intercostal

    • diaphragm

      • once this is paralyzed, respiration stops

    • recovery in reverse order

    • so it is important not to overdose it since it can stop respiration

    • how to reverse effects?

      • acetylcholinesterase inhibitor

  • Depolar NMB:

    • in ion channel, depolarization increase clacium, causing muscle contraction,

    • example of this: succinylbholine (SUX)

    • broken down by butyrylcholinesterase in blood

      • rapid breakdown, therefore injectionwill only last up to 5 minutes

      • preferable for short procedure such as intubation

      • this can be extended with infusion

    • some patients ave dificient in butyrylcholinesterase

      • which may result in prolonged activity of SUX

    • SUX have no reversal agent so it can

    • cause: hyperkalemia, due to release of K

    • phabdomyolysis

    • cardiac arrest

Other drugs

botulinum toxin or Botox

• inhibits release of Ach from presynaptic nerve terminals

  • prevents fusion of synaptic vesicle with membrane