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Autonomic Nervous System

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Autonomic Nervous System

• Ganglia close to theinnervated organs

• Myelinated axons

• Ganglia close to thespinal column

• Preganglionic axonsare myelinated;postganglionic axonsare unmyelinated

• Note:Somatic nervoussystem has noganglia!

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Autonomic Nervous System

Transmitters:

• Acetylcholine:– ALL preganglionic neurons– ALL parasympathetic postganglionic neurons

• Norepinephrine (= Noradrenalin):– MOST sympathetic postganglionic neurons– Exceptions: Sweat glands (Acetylcholine);

Renal arteries (Dopamine)

• Epinephrine (= Adrenalin):– Adrenal medulla upon sympathetic impulses

(no ganglion!)

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Adrenergic System

Termination of (nor)epinephrine action:• Reuptake into presynaptic nerve ending

– Predominant mechanism– active transport; inhibited by Cocaine

• Catechol-O-methyltransferase (COMT)– In the cytoplasm of post-junctional cells

• Monoamino-oxidase (MAO)– In mitochondria of nerve and post-junctional cells

• Presynaptic α2-receptors– Negative feedback that inhibits norepinephrine

release

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Adrenergic System

Adrenergic receptors:• alpha 1

– most vascular smooth muscles– Activate PLCβ => Ca++ => Contraction

• alpha 2– mostly presynaptic– Inhibit adenylate cyclase (Gαi)

• beta 1– mostly heart– Activate adenylate cyclase

• beta 2– respiratory and uterine smooth muscle– Activate adenylate cyclase

• beta 3– mostly adipocytes– Activate adenylate cyclase => lipolysis

• (Dopamine)

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Adrenergic System - Agonists

Sympathomimetics

Indirect Sympathicomimetics:

MAO - Inhibitors:– Inhibition of MAO causes increase in free Norepinephrine– In the CNS, MAO also metabolizes dopamine and serotonin => MAO inhibitors trigger

increase in these “happy hormones” => uses as antidepressants– Irreversible inhibition of MAO => long-lasting effect (weeks!)

• Tranylcypromine• Moclobemide

Possibility of severe adverse interactions of MAO inhibitors with numerous other drugs=> fatal hypertension

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Adrenergic System - AgonistsSympathomimetics

Indirect Sympathicomimetics :• Ephedrine

– Chief alkaloid in Ephedra, no clinical use– Displace norepinephrine in storage vesicle => forced norepinephrine release– Found in many dietary supplements: “Energy-Boosters”, Diet pills (Metabolife®) etc.– Ingredient in many herbal preperations: Ephedra, Ma Huang

The FDA has received more than 800 reports of adverse effects associated with use of productscontaining ephedrine alkaloid since 1994. These serious adverse effects, include hypertension (elevatedblood pressure), palpitations (rapid heart rate), neurophathy (nerve damage), myopathy (muscle injury),psychosis, stroke, memory loss, heart rate irregularities, insomnia, nervousness, tremors, seizures, heartattacks, and death.In Feb ‘04, the agency has banned the marketing of dietary supplements containingephedrine alkaloids (ban challenged by court order in April ‘05).

Epinephrine Ephedrine

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Adrenergic System - AgonistsSympathomimetics

Indirect Sympathicomimetics :Amphetamines

– Displace norepinephrine in storage vesicle => forced epinephrine release– Also inhibit norepinephrine re-uptake and degradation by MAO (“triple action”)

• Methylphenidate (Ritalin®)– Treatment of ADD

• Fenfluramine– Appetite suppressant (now banned in US)

(combined with Phentermine = “FenPhen”)• Metamphetamine/MDMA

– Effectiveness disappears due to catecholamine depletionof vesicles => post-use depression=> urge for re-administration!

Ephedrine

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Adrenergic System - Agonists

Sympathomimetics

Non-selective agonists:• Epinephrine (Adrenaline)

– Activates both α and β receptors;– Blood pressure increase, but effect on systolic pressure dominant– Dilates bronchii– Potent vasopressor => Clinical uses limited– Used for:

symptomatic treatment of anaphylactic shock (Epi-Pen®)adjuvant in local anesthetics (increases duration, reduces bleeding)

• Norepinephrine (Noradrenaline)– Activates mostly α receptors => systolic and diastolic blood pressure increase– Very potent vasopressor => Clinical uses limited to severe shock treatment

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Adrenergic System - AgonistsSympathomimetics

α1 - selective agonistsClinical applications:• Methoxamine

– Treatment of hypotensive state

• Phenylephrine– (Local) vasoconstrictor

nasal decongestant

Epinephrine Phenylephrine

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Adrenergic System - Agonists

Sympathomimetics

α1 - selective agonists (cont’d)

Clinical applications:

Nasal decongestants (mostly OTC):• Naphazoline (Privine®, Rhinon®)• Oxymetazoline (Afrin®, etc.)• Xylometazoline (Privin®)

Should be used less than 10 days, otherwise reactive hyperemia (“rhinitis medicamentosa”) develops!Continued used can result in local hypoxia => atrophic damage of the nasal mucosa

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Adrenergic System - Agonists

Sympathomimetics

α2 - selective agonistsPhenotypically produce sympatholytic effects!Activate presynaptic α2 receptors in the cardiovascular control center in the CNS

=> reduced sympathetic nervous system activity => blood pressure decrease

Clinical applications:Hypertension

• Clonidine

• Guanfacine

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Adrenergic System - Agonistsβ1 - receptors• Mostly in heart• Increase contractility = “positive inotrope”• Increase heart rate = “positive chronotrope”β2 - receptors• Respiratory system – located in bronchial smooth muscle• Produce bronchial dilation

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Adrenergic System - Agonists

Sympathomimetics

β1 - selective agonistsClinical applications:• Dobutamine

– Strong inotropic effect with little chronotropic effect =>increase in cardiac output without significant increase in heart rate

– Short-term treatment of impaired cardiac function after cardiac surgery, MI etc.– Also used in “Dobutamine Stress Test” = Heart sonogram: Dobutamine mimics exercise

Epinephrine Dobutamine

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Adrenergic System - Agonists

Sympathomimetics

β2 - selective agonistsClinical applications:Asthma:• Non-selective sympathomimetics => strong cardiac side effects• β2 - selective agonists target predominantly the respiratory system• Drugs differ in speed of onset and in duration of action => acute vs. long-term treatment• Additionally, preferential activation of pulmonary receptors due to application as aerosols

• Metaproterenol (Alupent®)• Albuterol = Salbutamol (Ventolin®)• Formoterol (Foradil®)• Etc…

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Adrenergic System - Antagonists

Sympatholytics

α - selective antagonistsPromote vasodilation => decreased peripheral resistance => blood pressure

(Side effects: reflex tachycardia and postural hypotension)Relaxation of the smooth muscles in the bladder neck

Clinical applications:Hypertension; Urinary retention

Non-selective α-antagonist:• Phentolamine (for pheochromocytoma)• Ergot alkaloids see 5HT receptor

α1 -selective antagonists:• Prazosin (Minipress®)

first α1 - selective antagonist• Terazosin longer half-life• Doxazosin longer half-life

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Adrenergic System - Antagonists

Sympatholytics

α2 - selective antagonists• Yohimbine

– Chief active compound in Pausinystalia yohimbine (bark)– Effects opposite of Clonidine– Enters CNS => increased sympathetic output => increased heart rate, blood

pressure, can cause severe tremors– Ingredient in many weight loss products– Extensive (past) use in treatment of male sexual dysfunction

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Adrenergic System - Antagonists

Sympatholytics

β - selective antagonists (”β - blockers”)β2 - selective antagonists would trigger bronchial constriction => no clinical useβ2 - antagonism is mostly an “undesired side effect” of β-selective antagonists

(goal is to antagonize β1 - receptors)Non-cardiac effects: CNS - anxiolytic; skeletal muscle - reduction of tremor

Clinical applications:• Angina pectoris• Hypertension• Cardiac dysrhythmias• MI• Heart failure• Familial tremor• “Stage fright”

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Adrenergic System - Antagonists

Sympatholytics

β - selective antagonists• First-generation β-receptor antagonists blocked β1 and β2-receptors =

noncardioselective (β-receptors in the heart are β1 - receptors).• Many β-receptor antagonists posses intrinsic agonist activity• Basic conserved structure: Norepinephrine side chain linked to aromatic structure by

a methylene-oxygen bridge.

Prototype:• Propranolol

Epinephrine

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Adrenergic System - Antagonists

Sympatholytics

β - selective, noncardioselective antagonists (cont’d):• Nadolol• Pindolol• Timolol• Labetalol - also antagonistic on α1 - receptors => potent antihypertonic drug

β1 - specific “cardioselective” antagonists:• Metoprolol• Atenolol• Esmolol - quick onset / short duration => used in urgent settings

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Adrenergic System - Antagonists

β-Sympatholytics

Epinephrine