Sympathomimetics (Adrenergic Drugs)

By

Dr. N. C. Baruah

Sympathetic Nervous System

• The sympathetic nervous system controls the Functions of – cardiovascular system,

– respiratory system,

– metabolism of carbohydrate (glycogenolysis) and

– Metabolism of fat (lipolysis),

– Modulate the secretion of insulin,

– Enhance wakefulness (CNS)

– Regulate secretion of sympathetic amines.

Sympathomimetics

• The drugs that mimic the actions of sympathetic nervous system are known as Sympathomimetics or adrenergic drugs or adrenergic agonists.

• Or

• The drugs that mimics the actions sympathetic neurotransmitter, the Noradrenaline and the adrenal hormone Adrenaline.

Sympathomimetics

• The neurotransmitter Noradrenaline (Norepinephrine; NE) is synthesized in the nerve cell or the neuron.

• The adrenaline (Epinephrine; EPI) is synthesized in the adrenal medulla.

Biosynthesis of Adrenaline & Noradrenaline

• L-Tyrosine Tyrosine hydroxylase L-DOPA

• L-DOPA L-AA Decarboxylase Dopamine

• Dopamine is transported to storage vesicles

• Dopamine β-Hydroxylase Noradrenaline

• In the adrenal medulla,

• Noradrenaline N-Methylation Adrenaline

• Tyrosine DOPA

• Dopamine Noradrenaline

• Adrenaline

Metabolism of Noradrenaline and adrenaline

• NE is synthesized and stored in the storage vesicles until depolarization of the neuron.

• Upon release it binds with the adrenergic receptors to produce its action.

• Immediately the excess of NE is taken up by the neuron for recycling (Uptake 1).

• The remaining NE is metabolized at the effectors site by the enzyme mono amine oxidase (MAO) to an aldehyde.

• MAO also metabolize drug molecule having amine groups.

• NE is metabolized by catechol-o-methyl transferase (COMT) in the meta-hydroxyl group.

Adrenergic drugs

• The exogenous agents mimicking the actions of NE & EPI are adrenergic drugs.

• The NE and EPI produce their actions by binding through the adrenergic receptors.

• Alpha-1 receptors, found in the fine peripheral capillaries

• Alpaha-2 receptors are found pre-synaptic in the nerve terminals, (Regulatory receptors).

• Beta-1 receptors are found the Heart muscles. • Beta-2 receptors are found in the bronchial muscles,

muscles of the blood vessels supplying through skeletal muscles, All tissues for glycogen, lipid metabolism.

Adrenergic drugs

• The adrenergic drug can be divided into three classes,

• Direct acting

• Mixed acting and

• Indirect acting

Direct acting drugs

• The direct acting drugs bind in the receptors and produce action.

• Binding can be

– Selective

– Non-selective

Selective adrenergic drugs

• Alpha-1 receptor selective drugs:

• (the Phenylethanolamines derivatives):

– Phenylephrine,

– Metaraminol and

– Methoxamine

• (2-Arylimidazoline derivatives):

– Xylometazoline,

– Oxymetazoline,

– Tetrahydrozoline and

– Naphazoline

Selective adrenergic drugs

• Alpha-2 receptor binding drugs:

• (2-Aminoimidazolines derivatives ): – Clonidine,

– Apraclonidine,

– Tizanidine

– Brimonidine

• (Guanidine derivatives): – Guanabenz and

– Guanfacine

• Others: – Methyldopa

Selective Alpha-1 agonists

• Phenylephrine

• Metaraminol

• Methoxamine

Selective Alpha-1 agonists

• Xylometazoline

• Oxymetazoline

• Tetrahydrozoline • Naphazoline

Selective Alpha-2 agonist, 2-Aminoimidazolines

• Clonidine

• Apraclonidine

• Tizanidine

Selective Alpha-2 agonist , Guanidine derivatives

• Guanabenz

• Guanfacine

• Methyldopa

Selective beta-1 agonists

• Beta-1 receptor selective drugs:

– Dopamine,

– (-) Dobutamine

Selective beta-2 agonists

• Beta-2 receptor selective drugs are used as short acting bronchodilator drugs : – Orciprenaline, – Terbutaline, – Salbutamol (Albuterol), – Isoetharine and – Pirbuterol The Terbutaline, Salbutamol and Pirbuterol are selective

β2-directing and resistant to MAO because the have bulky t-butyl group. They are resistant to COMT because none of them are catechol. But Orciprenaline and Isoetharine both have less β2-directing isopropyl group; Isoetharine has β2-directing α-ethyl group moiety but metabolized by COMT whereas Orciprenaline is not metabolized by COMT.

• Orciprenaline Terbutaline

• Albuterol (Salbutamol) Isoetharine

• Pirbuterol

Short acting Beta-2 agonists, DOA:3-6 hr

Long acting Beta 2 agonists, DOA: 12-24 hrs

• The long acting selective β2 agonists the

– Salmeterol,

– Formoterol,

– Indicaterol

– Have higher lipophilicity and high β2 receptor selectivity.

– Their DOA is more than 12 hours.

Long acting Beta 2 agonists, DOA: 12-24 hrs

• Salmeterol

– DOA 12 hr

• Formoterol

– DOA 12 hr

• Indicaterol

– DOA 24 hr

Non-selective adrenergic drugs • Beta-1 & beta-2 receptor binding drugs:

Isoprenaline.

• Alpha-1, 2 & Beta-1, 2 receptor binding drugs: Adrenaline (EPI).

• Alpha-1, 2 & Beta-1 receptor binding drugs: Noradrenaline (NE).

Mixed acting Drugs

• Act by binding the receptors as well as by increasing the release of neurotransmitter.

• Mixed acting drugs : L(+)-Ephedrine (primarily mixed), Metaraminol, Amphetamine, Hydroxyamphetamine,

p-Tyramine. D(-)Ephedrine (primarily direct) acts on both α and β

receptor directly. It lacks phenolic hydroxyl group and hence is less polar. It crosses BBB and exhibit CNS stimulant action. It is not metabolized by MAO and COMT and active in oral route and has long duration of action(DOA).

• D(-)Ephedrine L(+)Ephedrine

• Amphetamine

• Hydroxyamphetamine

• p-Tyramine

Indirect acting drugs

• Three types of indirect acting drugs:

–Neurotransmitter Releasing agents:

–Neurotransmitter reuptake inhibitors:

–Neurotransmitter metabolizing enzyme inhibitors (MAO inhibitors & COMT inhibitors)

Indirect acting drugs

• Neurotransmitter Releasing agents:

Pseudoephedrine. (Amphetamine, p-Tyramine and Methamphetamine has mixed mechanism of action)

• Neurotransmitter reuptake inhibitors: Cocaine and TCA like Imipramine, Desipramine & Nortriptylline.

• Neurotransmitter metabolizing enzyme inhibitors: MAO inhibitors: Pargyline, Phenelgine, Moclobemide.

• COMT inhibitors: Tolcapone and Entacapone

Uses of adrenergic agonists

• Adrenergic: • Alpha-1 agonists are used for raising Blood pressure

in shock, used as nasal decongestants and as vasoconstrictor in combination with local anesthetics to prolong the action. Adrenaline is commonly used with local anesthesia.

• Alpha-2 agonists are used for treatment of hypertension.

• Beta-1 agonists are hypertensive, generally are not used. In contrast Beta-1 antagonists are used as antihypertensive.

• Beta-2 agonists are used as bronchodilators in the treatment of asthma and also used to inhibit uterine contractions.

References • Textbook of Medical Physiology , 11th edition,

Guyton and Hall,748-760.

• Wilson & Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry, 12th edition, 519-557.

• Burger’s Medicinal Chemistry & Drug Discovery, sixth edition, 1-38.

• Foye’s Principles of Medicinal Chemistry, 7th edition,340-364.