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ANS:

CNS - Brain/Spinal Cord

Peripheral NS – Somatic NS & ANS

ANS - Parasympathetic and sympathetic

Preganglionic neuron – cell body in CNS, axon extends out of CNS

Postganglionic neuron – innervate an effector outside the CNS

Ganglion – Small mass of nerve tissue containing the cell bodies of neurons

Synapse – space b/w pre & post neurons or space b/w post neuron & effector where Neurotransmitter (NT) is released

Somatic NS:

-activates skeletal muscle contraction

-consists of sensory/motor neurons

-afferent (sensory) = AWAY from skeletal muscle to the CNS

-efferent (motor) = CNS to skeletal muscle

-VOLUNTARY

Autonomic NS:

-regulates activity of smooth musc, exocrine glands, cardiac tissue, certain metabolic activities

-Sensory neurons go from smooth muscle & cardiac muscle to CNS

-Motor neurons go from smooth muscle & cardiac muscle (and glands) from the CNS

-INVOLUNTARY

-Adjusts to internal env

-Neurotransmitters: ACH, NE, NA, Epinephrine, Dopamine

Enteric NS:

-Deals with network of autonomic nerves in GUT wall

-Receives innervation from SNS/PNS and regulates GI motility/secretion

-Responds to NEUROTRANSMITTERS (peptides/NO)


Sympathetic NS:

-Neurotransmitter: NOREPINPEHRINE/NORADRENALINE

Parasynpathetic NS:

-Neurotransmitter: ACETYLCHOLINE
General Effects of PNS/SNS:

PNS: Responses are specific, rest & digest, miosis (constrict pupil), inc gi motility and salivation, inc urination and defecation,
dec heart rate, bronchoconstriction, erection

SNS: responses diffuse, fight/flight, mydriasis (dilation of pupil), dec GI motility/salivation, bronchodilate, ejaculation, opposite
of PNS

Effected Organ Adrenergic (SNS) SNS effect Cholinergic (PNS) PNS effect
receptor receptor
NT: NT:

-epinephrine -acetylcholine
(adrenaline)
-nicotine
-norepinephrine
(noradrenaline)

Pupil 1 Mydriasis (dilation to Muscarinic Miosis (constriction)


see more)

Heart Rate 1 Increase Muscarinic Decrease

Arteries/Veins 1 Constriction Muscarinic Dilation

2 dilation

Smooth Muscle 2  motility Muscarinic  motility


Gastric Secretion  Inhibit Muscarinic Stimulate

Pancreas Secretion  Inhibit Muscarinic Stimulate

Salivary Secretion 1,  Inhibit Muscarinic Stimulate

Liver 1, 2 Glycogenolysis Muscarinic Glycogenesis

Gluconeogenesis

Cholinergic Receptors are Acetylcholine Receptors (ACH):

(A) There are muscarinic acetylcholine receptors which are located at the PNS nej, some SNS nej (sweat glands), CNS, and
autonomic ganglia.

-Activated by ACH and MUSCARINE

-Found in body in greater #s than nicotinic receptors

-EFFECTS MUSCARINIC RECEPTORS: SLUDGE – SALIVATION, LACRIMATION, URINATION, DEFECATION, GI MOTILITY, ERECTION

 Mediate smooth muscle contraction (except sphincter contraction)

 Stimulates gland secretion

 Decrease heart rate and conduction

 Bronchoconstriction

 Peripheral vasodilation

 Miosis

(B) There are also nicotinic acetylcholine receptors which is activated by ACH and NICOTINE

-Located on autonomic ganglia (excites neurotransmission) and somatic neuromuscular junctions (activates muscule
contraction)

-Nicotinic receptors have OPPOSING effects of MUSCARINIC (tachycardia, HTN)


Adrenergic Receptors (NE/Epi)

1 adrenergic receptors

• constricts vascular smooth muscle

• constricts blood vessels

• Increase basal metabolic rate

• Located at SNS nej effector (primarily smooth muscle)

2 adrenergic receptors [NEGATIVE FEEDBACK!!!!!!!!!!]

• It’s goal is inhibition of NE release from nerve endings at pre synaptic post ganglionic neuron (negative
feedback)

• Also located on some postsynaptic tissue & blood platelets

• Alpha2 activated by NE but also stops the release of NE

1 receptor

• Mediates cardiac stimulation ( HR & contractility)

• Located on SNS effector (cardiac muscle, vascular smooth muscle, renal cells -  renin release, inc BP)

• Increased lipolysis

2 receptor

• Mediates smooth muscle relaxation

• Located on SNS effector (dilates bronchioles in lung, uterine smooth muscle and vascular smooth muscle)

• In liver and muscle – mediate glycogenolysis

Mechanisms of Autonomic Drugs

Direct agonists: Activate postsynaptic receptors

Indirect agonists: stimulate release of NT, inhibit reuptake of NT, inhibit metabolism of NT

Direct antagonists: Block postsynaptic receptors

Indirect antagonists: Inhibit synthesis of NT, prevent vesicular storage of NT, inhibit release of NT
Cholinergic Agonists

Direct: bind and activate cholinergic receptors (activates PNS) [Choline esters, plant alkaloids]

CHOLINE ESTERS:

 ACH and Carbachol – activate both nicotinic and muscarinic. ACH has limited clinical indications

• Lack of specificity for muscarinic subtypes, therefore have a wide range of effects on many organ systems

 Bethanechol and methacholine– activates only muscarinic. Methacholine not commercially available

 Bethanechol (Urecholine)

• acts at muscarinic only*

• Stimulates bladder w/o significant effects on HR or BP

• TX of urinary retention post-op & post partum

 Carbachol (Isoptocarbachol, Miostat) [eyedrops]

• For chronic open-angle glaucoma

• Produce miosis during ophthalmic surgery

PLANT ALKALOIDS:

 muscarine – no current medical use

 nicotine – smoking cessation

 Pilocarpine (Isoptocarpine, Ocusert, Salagen)

• Higher affinity for muscarinic receptor

• Treats glaucoma: stimulate contraction of ciliary muscle fibers   aqueous humor outflow   Intraocular
pressure

 Cevimeline (Exovac)

• To treat dry mouth associated with Sjogren’s syndrome

Indirect: increase synaptic conc of ACH [cholinesterase inhibitors]

CHOLINESTERASE INHIBITORS:

An acetylcholinesterase inhibitor (often abbreviated AChEI) or anti-cholinesterase is a chemical or a drug that inhibits the
acetylcholinesterase enzyme from breaking down acetylcholine, thereby increasing both the level and duration of action of the
neurotransmitter acetylcholine.

 MOA: Inhibit breakdown of ACH at all cholinergic synapses  increase ACH concentration

 Reversible vs Irreversible

 Reversible agents

• Donepezil (Aricept)– Tx of Alzheimer's Disease

• Edrophonium (Enlon) - very short DOA. Used in Dx of Myasthenia gravis  muscle weakness disease

• Neostigmine (Prostigmin) - Tx of Myasthenia gravis, antidote for skeletal muscle relaxants (reverse anesthesia)

• Physostigmine (Eserine) - Tx Overdoses of drugs with anticholinergic effects (i.e. atropine, TCAs)
• Pyridostigmine (Mestinon) – Tx of Myasthenia gravis

 Irreversible (organophosphates)

• Bind covalently to acetyl cholinesterase resulting in a long lasting increase of acetylcholine

• Ecothiophate (Phospholine) – Tx of chronic refractory glaucoma. DOA of up to one week

• Pesticides (palathion and malathion)

• Soman (chemical warfare agent)

CHOLINERGIC ANTAGONISTS

 Muscarinic receptor antagonists

• Plant (belladonna) alkaloids - Atropine, Scopalamine, hyoscyamine

• Semi synthetic/synthetic – ipratropium, tolterodine, oxybutynin, propantheline, dicyclomine, benztropine

• Both types inhibit effects of PNS stimulation  SM relaxes, inc HR/CO, inhibit exocrine gland secretion

Cardiac Effects   HR & AV conduction  tx of sinus bradycardia

 ATROPINE

Ocular Effects  Mydriasis & inhibit lacrimal gland for dry eyes [therapeutic effect to facilitate eye exam]

 ATROPINE, TROPICAMIDE, SCOPOLAMINE

Respiratory Effects  Inc bronchodilation [COPD, emphysema, bronchitis]

 Ipratropium or tiotropium

GI/Urinary Effects  Relax GI muscle, reduce intestinal motility, inhibit gastric acid secretion, inc urinary retention

 Hysosamine, donnatal, dicyclomine, oxybutynin, tolterodine, darifenacin, solifenacin

CNS Effects  Tx motion sickness by blocking cholinergic transmission, tx of parkinson’s to reduce tremor

 scopolamine patch, benztropine, trihexyphenidyl

 Nicotinic receptor antagonists

• Ganglionic blockers – ex. Trimethaphan for rare HTN emergencies

• Neuromuscular blockers – “curium”

• Depolarizing neuromuscular blocker – succinylcholine

persistent depolarization used in surgery for paralysis/relax muscles

NOT REVERSED BY CHOLINESTERASE INHIBITORS NO ANTIDOTE IF OVERDOSE

• Nondepolarizing neuromuscular blocker – Curariforms, competitive antagonist of ACH @ nico receptors

Atracurium, pancuronium, vecuronium

Causes muscle relaxation and paralysis, reversed by cholinesterase inhibitors, used for surgery
Remember, physiological responses can be organized according to receptor type:

• Alpha 1: vasoconstriction and increased blood pressure and total peripheral resistance

• Beta 1: cardiac stimulation

• Beta 2: vasodilation (skeletal muscle) and bronchiolar relaxation

Adrenergic Agonists

 Direct Acting Agonists

Catecholamines

 Must be given parenterally (IV, IM, etc. doesn’t include GI tract due to rapid metabolization)

• Epinephrine – used in anaphylactic shock and cardiac arrest

binds to all adrenergic receptors, vasoconstriction and inc BP (a1)

cardiac stimulation (b1)

bronchodilation and skeletal muscle vasodilation (b2)

• Norepinephrine [doesn’t act on b2, acts on hypotension and shock]

vasoconstriction and inc BP (a1)

cardiac stimulation (b2)

• Isoproternol [treats asthma, AV block, and bradycardia]

cardiac stimulation (B1) & bronchodilation (B2)

• Dopamine - precursor to epi, NE [cardiogenic shock, septic shock, HF, hypovolemic shock]

 Renal vasodilation (D1)

Cardiac stimulation (B1)

Inc BP (a1)

• Dobutamine (cardiogenic shock, cardiac arrest, HF)

 Highest affinity for 1 receptor

 Less activity at 1 receptor

Non-catecholamines (albuterol, clonidine, phenylephrine) [selective to a specific receptor]

• Phenylephrine

 Vasoconstriction,  BP and mydriasis (1)

 Used as nasal decongestant, ocular decongestant and maintenance of BP during surgery

• Albuterol [asthma]
 Bronchodilation (2)

• Clonidine [chronic HTN and effects on CNS sedation]

 Inhibits NE release from nerve terminal of postganglionic neuron (feedback inhibition a2) and lows
BP

• Terbutaline [tx asthma and premature labor tocolytic]

 bronchodilation and uterine relaxation

 Indirect Agonists – enhance effects of NE/Epi by inhibition of re-uptake/degredation

• Amphetamine [inc mood/alertness dec appetite]

 inc release of NE/DA from SNS neurons

vasoconstriction, cardiac stimulation, inc BP

• Cocaine [anesthetic]

stimulates SNS by blocking reuptake of NE/DA in PNS/SNS

• Tyramine [causes release of stored catecholamines, found in foods]

 Mixed direct/indirect agonists

• Pseudoephedrine [nasal decongestant, binds a1 vasoconstrict, release NE from SNS]

ADRENERGIC ANTAGONISTS:

Nonselective alpha-blockers [blocks a1/a2]

Phenoxybenzamine

noncompetitive, irreversible

tx HTN episodes w/ pheochromocytoma (tumor w/in adrenal glands which secrete epi/NE)

Phentolamine

competitive, reversible

tx HTN episodes w/ pheochromocytoma + necrosis/ischemia from extravasations of epinephrine

Youtube Note: because they block a2, that means NE production is inc  stimulates beta 1 receptors on the heart  can lead
to tachycardia and cardiac arrhythmias

Selective Alpha1 Blockers

-vasodilator and smooth muscle in bladder/prostate

-dec BP

-treats HTN/urinary retention due to BPH/enlarged prostate

-medicines end with -azosin  -doxazosin, prazosin, terazosin, tamsulosin, alfuzosin [only for BPH because inc sensitivity for
for a1 receptors in prostate]
B1 block = dec bp, dec CO, dec renin, dec aqueous humor secretion

B2 block = bronchoconstriction, dec glycogenolysis, mask signs of hypoglycema

Nonselective beta-blockers [blocks b1/b2]

-Treats HTN, angina, arrhythmias, MI, migraine, glaucoma

-Propanolol, nadolol, timolol

Selective Beta1 Blockers

-primarily in cardiac tissue, tx HTN, angina, MI

-Atenolol, Metoprolol

Mixed A and B receptor Antagonists

-carvedilol, labetalol [HTN for both, CHF for former] {blocks beta and alpha 1}

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