Adrenergic Nervous System Lec 1-3 By Nohad AlOmari Atrushi

SYMPATHOMIMETIC Sympathomimetic drugs mimic the effects of sympathetic nerve stimulation Also adrenergic agonists Adrenergic receptors

Striated muscle Effector organs Summary of the neurotransmitters released and the types of receptors found within the autonomic and somatic nervous system. (according to Lippincott´s Pharmacology, 2006) AUTONOMIC SOMATIC Sympathetic innervation of adrenal medulla Parasympathetic Sympathetic Preganglionic neuron Ganglionic transmitter Acetylcholine Acetylcholine Acetylcholine No ganglia Nicotinic receptor Nicotinic receptor Nicotinic receptor Postganglionic neurons Adrenal medulla Neuroeffector transmitter Epinephrine release into the blood Acetylcholine Acetylcholine Norepinephrine Adrenergic receptor Adrenergic receptor Muscarinic receptor Nicotinic receptor Striated muscle Effector organs

Adrenergic Agonists Chemical classification Catecholamines Non-catecholamines

Adrenergic Agonists Differences Catecholamine Noncatecholamines Cannot use orally Cannot cross BBB Short-half live Examples: Norepinephrine Epinephrine Isoproteronol Dopamine Dobutamine Can use orally Can cross BBB Longer half life Examples: Ephedrine Phenylephrine Terbutaline

ENDOGENOUS CATECHOLAMINES Naturally occurring in body: Norepinephrine -Sites: postganglionic sympathetic sites (except sweat glands , erector pillorie, hair follicles, ) Epinephrine- Secreted by adrenal medulla Dopamine- Major transmitter in basal ganglia, CTZ, limbic system, anterior pitutory.

BIOSYNTHESIS

Catecholamine s Tyrosine ↓ Dopa Dopamine Norepinephrine Epinephrine In dopaminergic neurons, synthesis stops here In noradrenergic neurons, synthesis stops here Final step only in adrenal medulla and CNS neurons

STORAGE, RELEASE, UPTAKE L-Phenylalanine Hepatic hydroxylase

Adrenergic Receptors These are mainly 2 types (α) Alfa (β) Beta These are again subdivided into various types

ADRENERGIC RECEPTORS

ADRENERGIC DRUGS Symphathomimetics DIRECT SYMPHATHOMIMETICS Adrenaline Noradrenaline Isoprenaline Phenylephrine Methoxamine Salbutamol Xylometazoline INDIRECT SYMPHATHOMIMETICS Tyramine Amphetamine MIXED SYMPHATHOMIMETICS Ephedrine Dopamine Mephenteramine

THERAPEUTIC CLASSIFICATION OF ADRENERGIC DRUGS Pressor agents Noradrenaline Phenylephrine Ephedrine Methoxamine Dopamine Mephentermine Cardiac stimulants Adrenaline Dobutamine Isoprenaline Bronchodilators Adrenaline Terbutaline Isoprenaline Salmeterol Salbutamol Formoterol (Albuterol) Bambuterol THERAPEUTIC CLASSIFICATION OF ADRENERGIC DRUGS

Uterine relaxant and vasodilators Ritodrine Salbutamol Nasal decongestants Phenylephrine Naphazoline Xylometazoline Pseudoephedrine Oxymetazoline Phenyl propanolamine CNS stimulants Amphetamine Dexamphetamine Methamphetamine Anorectics Fenfluramine Dexfenfluramine Sibutramine Uterine relaxant and vasodilators Ritodrine Salbutamol Isoxsuprine Terbutaline

PHARMACOLOGICAL ACTIONS Cardiac effects Positive chronotropic effect An action that increases heart rate Positive dromotropic effect An action that speeds conduction of electrical impulses (↑ conduction velocity through AV node) Positive inotropic effect An action that increases the force of contraction of cardiac muscle

Cardiac effects of epinephrine Cardiac output is determined by heart rate and stroke volume Epi→ β1receptors at SA node→↑HR Epi→ β1receptors on ventricular myocytes→ ↑ force of contraction CO = HR x SV

vascular smooth muscle α1 In blood vessels supplying skin, mucous membranes, viscera and kidneys, vascular smooth muscle has almost exclusively alpha1-adrenergic receptors Also biphasic response

vascular smooth muscle In blood vessels supplying skeletal muscle, vascular smooth muscle has both alpha1 and beta2 adrenergic receptors α1 α1 stimulation β2 stimulation β2

Effects of epinephrine on blood vessel caliber Blood vessels to skin, mucous membranes, viscera and kidneys Stimulation of α1-adrenergic receptors causes constriction of vascular smooth muscle α1

Effects of epinephrine on blood vessel caliber: skeletal muscle At low plasma concentrations of Epi, β2 effect predominates→ vasodilation At high plasma concentrations of Epi, α1 effect predominates→ vasoconstriction α1 β2

Effects of Epi on arterial blood pressure Arterial BP = CO x PVR Epinephrine: ↑ CO Low doses ↓ PVR (arteriolar dilation in skeletal muscle) High doses ↑PVR

Effects of epinephrine on airways Epi→β2-adrenergic receptors on airway smooth muscle→ rapid, powerful relaxation→ bronchodilation

Effects of epinephrine in the eye Epi at α1-adrenergic receptors on radial smooth muscle → contraction→ mydriasis Epi at B2-adrenergic receptors→ relaxation of ciliary muscle α1 β2

Mnemonic for therapeutic uses of adrenaline ABCDEG A- Anaphylactic shock B- Bronchial asthma C- Cardiac arrest D- Delay absorption of local anesthetics E- Epistaxis, Elevate BP G- Glaucoma Others : Reduce nasal congestion, Induces mydriasis

Therapeutic uses Shock (moderate doses) ↑ blood flow to kidney and mesentery ↑ cardiac output Refractory congestive heart failure Moderate doses ↑ cardiac output without ↑PVR

Structures of Norepinephrine and Epinephrine Epinephrine (Adrenaline) Norepinephrine •Belong to chemical class of substances known as the Catecholamines. •Polar compounds, containing both basic and acidic functional groups. •Chiral compounds. Natural enantiomer has R-configuration. •Undergoes oxidation in prolonged exposure to air. •Limited therapeutic use.

Chemical Property of Catecholamines

Structures of several important adrenergic agonists Structures of several important adrenergic agonists. Drugs containing the catechol ring are shown in pink. (according to Lippincott´s Pharmacology, 2006)

Structure-activity relationships among catecholamines and related compounds Selective b-agonists Selective a-agonists Selective b-antagonists Non-selective agonist Indirectly acting sympathomimetic amines HO N Tyramine Dopamine OH Ephedrine Noradrenaline Amphetamine Adrenaline Metaraminol a-Me-noradrenaline Isoprenaline Salbutamol O Propranolol

Norepinephrine Potent stimulant of both α and β adrenoceptors Limited therapeutic value Used to maintain blood pressure in acute hypotensive states Substrate for MAO and COMT, not effective orally Chiral compounds. Natural enantiomer has R-configuration. Racemization occurs in heat or acid condition. Undergoes oxidation in prolonged exposure to air. Sodium bisulfite used as antioxidant in NE preparations 4-((R)- 1-hydroxy-2-amino- ethyl)- 1,2-benzenediol

Epinephrine Potent stimulant of both α and β adrenoceptors; Drug of choice for reversal of acute hypersensitivity reactions (anaphylaxis, Enhances the action of local anesthetics (restricts local blood flow); Poor oral absorption. Rapidly metabolized by MAO and COMT; Degrades on exposure to air and light; Serious side effects include cerebral hemorrhage and cardiac arrhythmias .

ALPHA1 AGONISTS Direct Acting Agents These are agents which directly active the alpha1 -adrenergic receptor. They are less potent than the endogenous agonists epinephrine or norepinephrine. However, because of structural modifications they are orally active and have longer plasma half-lives. There are 2 structural classes of alpha1 agonists the phenylethylamines which are close structural analogs of epinephrine and norepinephrine and the structurally unrelated imidazolines. The major action of these agents is to produce alpha1-receptor mediated vasoconstriction.

SAR of Direct. general, a primary or secondary aliphatic amine separated by 2 carbons from a substituted benzene ring is minimally required for high agonist activity

-OH Substituent: 1. By default must be present at β position to primary amine (i.e. spaced 2 carbons away). 2. being a chiral center the 1 position must be in R configuration for maximum activity (but many drugs sold as racemic i.e. R/S mixture)- exception dobutamine.

Amine moiety as the size increases – selectivity for β receptor increases over α receptors. 2. α and β activity is maximum when R1= methyl (e.g. epinephrine). 3. R1= isopropyl (e.g. isoproterenol) – α activity is negligible and only β activity present.

Benzene substituted 3′,4′- dihydroxy substitued benzene ring provides excellent receptor activity for both α and β sites. 2. However, there is poor oral bioavailablity due to COMT

INDIRECT-ACTING MIXED-ACTING DIRECT-ACTING Drug enhances release of norepinephrine from vesicles. Sites of action of direct-, indirect-, and mixed-acting adrenergic agonists. Neuron MIXED-ACTING Drug acts both directly and indirectly. Synapse DIRECT-ACTING Drug directly activates receptor. Postsynaptic target cell membrane (according to Lippincott´s Pharmacology, 2006)

Phenylethylamines Phenylephrine Pseudoephedrine  Methoxamine, Imidazolines Oxymetazoline Naphazoline Metaraminol Tetrahydrozoline

α-Adrenergic Receptor Agonists α1−Selective Adrenergic Agonists: • Stimulation of vascular smooth muscle. • Maintenance of blood pressure in hypotension or shock Phenylephrine Methoxamine Metaraminol

-Adrenergic Receptor Agonists Most of the -selective adrenergic agonists are used primarily as bronchodilators in asthma and other constrictive pulmonary conditions. Isoprenaline •Highly potent bronchodilator •Non-selective (β1 and β2) and leads to cardiac stimulation caused by its β1-activity. •Metabolized primarily by COMT (Poor substrate for MAO)

2-Agonists (Phenylethanolamines) •Primarily used as bronchodilators in the treatment of asthma •Selectivity (β1 vs. β2) is poor at high doses •Administration by inhalation (aerosol， enhances β2-selectivity (pulmonary) Specific agents: Salbutamol, Salmeterol

Salbutamol (Albuterol) 2-[(1,1-Dimethylethyl)amino]-1-[4-hydroxy-3- (hydroxymethyl)phenyl]ethanol Selective β2 agonist Orally active drugs, also available for inhalation therapy; Not metabolized by MAO or COMT; Bronchodilator used for the treatment of asthma, chronic bronchitis, and other breathing disorders

The Synthesis of Salbutamol

Metabolism of Salbutamol 从胃肠吸收, 在肠壁和肝代谢, 4-O-glucuronide mostly metabolised in dog, rabbit and rat While for human, 4-O-sulfate

Salmeterol •Long lipophilic substituent •Prolonged duration of action (~ 12 hrs) •Slow onset (not suitable alone for prompt relief of bronchospasm，

1-Adrenergic Agonists Dopamine Dobutamine

Dopamine Not strictly an adrenergic drug, acts on dopamine receptors. Stimulates cardiac 1-AR through both direct and indirect mechanisms. Used to correct hemodynamic imbalances induced by shock, trauma, or congestive heart failure. Rapidly metabolized by MAO and COMT. Not effective orally.

Indirect Acting Agents These agents require the presence of endogenous monoamine neurotransmitters (norepinephrine, epinephrine, dopamine, serotonin) to produce their effects. Indirect acting agonists work at the nerve terminal to promote the release and/or block the reuptake of endogenous neurotransmitters. These agents have little activity if these neurotransmitters are depleted. Cocaine and amphetamine interact with cell surface monoamine transporters for dopamine (DAT), serotonin (SERT) and norepipephrine (NET). These transporters are expressed peripherally and in specific brain loci and are the site of action of psychostimulants and antidepressant drugs.

Amphetamine: Promotes the release of monoamines from nerve endings from the terminal cytoplasm. There is only a limited amount of neurotransmitter in this pool. Amphetamine also blocks the reuptake of monoamines. Several structural analogs of amphetamine and "amphetamine like" agents are available for clinical use. These include: Dexamphetamine (the resolved and more potent d-isomer of amphetamine) Hydroxyamphetamine Methamphetamine Methylphenidate

Sympathomimetics with Mixed Mechanism of Action Ephedrine Hydrochloride (1R,2S)-2-methylamino-1-phenylpropan-1-ol hydrochloride

Actions and Uses ① not be affected by COMT, prolonged duration Decreased molecular polarity, easily enter CNS, cause stimulation. ② ：-methyl group, not be easily affected by MAO. prolonged duration, decreased molecular polarity, increased CNS toxicity.

Ephedrine Hydrochloride •Natural product, isolated from various species of Ephedra. •Long history of use in traditional Chinese medicine (Ma Huang) Four isomers of Ephedrine (-)-Ephedrine (+)-Ephedrine (+)-Pseudoephedrine (-)-Pseudoephedrine

(+)-Pseudoephedrine • An alkaloid. A diastereoisomer of ephedrine, • Used as a nasal decongestant (many OTC preparations available) • To be used with caution in hypertensive individuals Enantiomer：

Synthetic Catecholamines: Isoproterenol Very powerfully stimulates β1- and β2-adrenergic receptors No significant effect at α1-adrenergic receptors SA nodal cells→↑HR β1 AV nodal cells→↑ conduction velocity β1 β1 Ventricular muscle cells→ ↑ force of contraction

Synthetic Catecholamines: Isoproterenol Very powerful β-adrenergic receptor agonist; no effect at α-adrenergic receptors α1 α1 stimulation β2 stimulation β2

↓arterial BP = ↑CO x ↓↓PVR Isoproterenol ↓arterial BP = ↑CO x ↓↓PVR Decreased arterial blood pressure triggers autonomic reflex arc

Effects of isoproterenol on airways Powerfully stimulates β2-adrenergic receptors on airway smooth muscle→ rapid, powerful relaxation→ bronchodilation

Synthetic Catecholamines: Dobutamine It’s a derivative of DA but not a D1 or D2 receptor agonist Stimulates β1- and β2-adrenergic receptors, but at therapeutic doses, β1-effects predominate Increases force of contraction more than increases heart rate ↑CO = ↑HR x ↑ ↑ SV

Dobutamine: Therapeutic uses Shock MI Cardiac surgery Refractory congestive heart failure

Major toxic effects of catecholamines All are potentially arrhythmogenic Epi and isoproterenol more arrhythmogenic than dopamine and dobutamine Some can cause hypertension Epinephrine, in particular, can cause CNS effects – fear, anxiety, restlessness Dobutamine can cause vomiting and seizures in cats – must be used at very low doses

Adverse effects CNS: CVS: Restlessness Palpitation Anxiety, tremors Increase BP….cerebral haemmorrhage Ventricular tachycardia, fibrillation May precipitate angina or AMI

Non-catecholamine direct-acting adrenergic agonists Ephedrine Stimulates α1-, β1 and β2-adrenergic receptors and ↑ NE release from noradrenergic fibers Repeated injections produce tachyphylaxis It is resistant MAO, orally Longer acting (4-6), cross BBB

Marketed as dietary supplement promoted to aid weight loss, ↑ sports performance and ↑ energy. Ingredient in OTC nasal decongestants and bronchodilators Uses : Mild chronic Bronchial asthma, hypotension during spinal anaesthesia ,occasionally for postural hypotension Sale prohibited by FDA in 2004 due to risks of life-threatening cardiac arrhythmias, stroke and death

Non-catecholamine direct-acting adrenergic agonists: Phenylpropanolamine (PPA) Actions much like ephedrine in the PNS In veterinary medicine, used to treat urinary incontinence in dogs Available in OTC products for treatment of nasal decongestion and as appetite suppressant FDA has requested all companies discontinue marketing products containing PPA due to risk of hemorrhagic stroke

β2-selective adrenergic agonists Due to selectivity for β2 receptors at recommended doses, little-to-no direct stimulation of β1 receptors in heart Inhalant administration maximizes local effect and minimizes systemic effects

Mephenteramine Uses: It is mixed sympathomimetic COP, BP, heart rate are increased Active orally with longer DOA (2-6 hrs),can crosses BBB Uses: To treat hypotension due to spinal anesthesia and surgical procedures Shock in MI and other hypotensive states

Adrenergic Agonists Indirect: Amphetamine Cause NE release only Example: Amphetamine CNS stimulant Increases BP by alpha effect on vasculature, beta effect on heart

Drug affecting neurotransmitter Summary of blocking agents and drugs affecting neurotransmitter uptake or release Adrenergic blockers a - blockers Doxazosin Phenoxybenzamine Phentolamine Prazosin Tamsulosin Terazosin b - blockers Acebutolol Atenol Carvediol Esmolol Labetalol Metoprolol Nadolol Pindolol Propranolol Timolol Drug affecting neurotransmitter uptake or release Cocaine Guanethidine Reserpine (according to Lippincott´s Pharmacology, 2006)