Andrenergic Agonists

Overview

• Adrenergic drugs stimulate the same receptors as norepinephrine and epinephrine. Drugs that stimulated the adrenergic receptors are also called sympathomimetics. Drugs that block the adrenergic system are called sympathoplegics.

• Drugs that directly stimulate the receptor are called direct acting agonist and drugs that block the reuptake or enhance the release of catecholamines are called indirect acting agonists.

Synthesis of Epinephrine

• The synthesis of norepinephrine begins with the transport of tyrosine into the adrenergic neuron.

• Tyrosine is then hydroxylated to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase. This is the rate limiting step.

• DOPA is then decarboxylated by the aromatic I-amino acid decarboxylase to form dopamine in the presynaptic neuron.

• Dopamine is then transported to the synaptic vesicles where dopamine beta-hydroxylase hydrolates dopamine to norepineprhrine.

• Norepinephrine is acted on by phenyethanolamine N – Methyl Transferase to form Epinephrine.

Removal of Catecholamines

• Catecholamines have a half-life of a few minutes when circulating in the blood. They are degraded either by methylation by catechol-O-methyltransferases (COMT) or by deamination by monoamine oxidases (MAO).

• Norepinephrine may 1. Diffuse out of the presynaptic cleft, 2) Be metabolized by COMT in the synaptic cleft, 3) re-uptaked by the presynaptic neuron.

• Once in the presynaptic neuron it may be degraded in the mitochondria by MAO

Adrenergic Receptors

• Alpha 1: Vasoconstriction, increased peripheral resistance, increased blood pressure, mydriasis, increased closure of bladder sphincter

• Alpha 2: Inhibition of norepinephrine release, inhibition of acetylcholine release, inhibition of insulin release

• Beta 1: Tachycardia, increased myocardial contractility, increased release of renin

• Beta 2: Vasodilation, decreased peripheral resistance, bronchodilation, increased release of glucagon, relaxed uterine smooth muscle.

• Beta 3: Enhancement of lipolysis in adipose tissue and thermogenesis in skeletal muscle.

a1 a2 b1 b2 b3

↑cAMP ↑cAMP ↑cAMP↑IP3 /DAG ↓ cAMP

↑ I K+

↓ I Ca2+ ↑ PKA ↑ PKA ↑Ca2+

↑ PKC ↑ PKA

Adrenergic Receptors

ISO>A>NA NA>AResponsiveness-NA>A>ISO

* ISO - isoproterenol

MAO A & MAO B

• MAO A : Monoamine oxidase A is an isoform of monoamine oxidase. It deaminates norepinephrine (noradrenaline), epinephrine, serotonin, and dopamine (which is equally deaminated by MAO-A and MAO-B). High-activity variants of the MAOA gene is associated with major depressive disorder

• MAO B: This protein preferentially degrades benzylamine and phenylethylamine. Like MAOA, it also degrades dopamine. Alzheimer's disease and Parkinson's disease are both associated with elevated levels of MAO-B in the brain. The normal activity of MAO-B creates reactive oxygen species, which directly damage cells.

Monoamine Oxidase Inhibitor (MA0I)

• Monoamine oxidase inhibitors (MAOIs) inhibit the monoamine oxidase enzyme. These drugs are effective in treating atypical depression. They can also be used to treat Parkinson’s disease.

• These drugs can have potentially lethal dietary and drug interactions, and often are used as drugs of last resort for depression.

• MAOIs can also treat panic disorder, agoraphobia, social phobia, atypical depression, anxiety, depression, bulimia, and post-traumatic stress disorder, and with limited efficacy borderline personality disorder

Characteristics of Adrenergic Agonists

• When we look at the agonists epinephrine, norepinephrine and isoproterenol we have to take a look at their comparative potency at receptors.

• At the α receptor the relative potency is:• Epinephrine > Norepinephrine >> Isoproterenol.

• At the β receptor the relative potency is :• Isoproterenol > Epinephrine > Norepinephrine

Non-Specific Direct Acting Adrenergic Agonists

• Epinephrine: is both a neurotransmitter and hormone. Pharmacological doses of epinephrine stimulate α1, α2, β1, β2, and β3 receptors of the sympathetic nervous system. It is used to treat cardiac arrest, anaphylaxis, superficial bleeding and croup. It is also a backup for β2 agonist failure in asthma.

• LOW DOSE-Vasodilatation,high dose- Vasoconstriction.

• Adverse affects: palpitations, tachycardia, arrhythmia, anxiety, panic attack, headache, tremor, hypertension, and acute pulmonary edema.

• Half-Life 2 minutes

Non-Specific Direct Acting Adrenergic Agonists

• Epinephrine in croup it works by stimulation of the α-adrenergic receptors in the airway, with resultant mucosal vasoconstriction and decreased subglottic edema, and by stimulation of the β-adrenergic receptors in the bronchial smooth muscles with resultant relaxation of the bronchial smooth muscle.

• In cardiac arrest epinephrine actions are to increase peripheral resistance via α1receptor-dependent vasoconstriction and to increase cardiac output by binding to β1 receptors. The goal of reducing peripheral circulation is to increase coronary and cerebral perfusion pressures.

Non-Specific Direct Acting Adrenergic Agonists

• Norepinephrine is a hormone and neurotransmitter. Pharmacological doses of norepinephrine stimulate α1, α2, β1, β2, and β3 receptors.

• Norepinephrine is primarily used to treat severe hypotension. Its effects are often limited to the increasing of blood pressure through agonist activity on α1 and α2 receptors, and causing a resultant increase in peripheral vascular resistance. At high doses it can lead to limb ischemia and sloughing off of skin.

Non-Specific Direct Acting Agonists

• Isoproterenol is a β1- and β2-adrenoreceptor agonist which was commonly used to treat asthma before the more widespread use of albuterol, which has more selective effects on the airways. Its route of administration is either intravenous, oral, intranasal, subcutaneous, or intramuscular, depending on use medication used for the treatment of bradycardia, A.V. heart block, Torsades de pointes.

• α-receptors are not that sensitive to isopreterenol.

• This medication not be administered to patients with myocardial ischemia.

• Half – Life 2 minutes

Dopamine Type Direct Acting Adrenergic Agonists

• Dopamine: can activate both α and β receptors. At higher levels it stimulates α1 receptors at lower levels it stimulates β1 receptors. Dopamine also stimulates the D1 and D2 receptors where they produce vasodilation. D1 and D2 receptors are found in the mesentery and renal areas.

• Dopamine is the drug of choice for cardiogenic and septic shock. It is given continuously by IV. Not only does it stimulate the heart and raise blood pressure it enhances perfusion to the kidney and splanchnic areas. The break down product of dopamine is homovanillic acid.

• Side effects for: headache, flushing, nausea, hypotension, reflex tachycardia, and increased intraocular pressure

• Fenoldopam: acts as a partial agonist on the D1 receptor causing vasodilation and can be used to treat hypertensive crisis.

Beta -1 Direct Acting Adrenergic Agonists

• Dobutamine is predominantly a β1-adrenergic agonist, with weak β2 activity, and α1 selective activity.

• Dobutamine is used to treat acute but potentially reversible heart failure, which can occur during cardiac surgery or in cases of septic or cardiogenic shock, increasing ionotropic action

• Dobutamine can also be used in cases of congestive heart failure to increase cardiac output. It is indicated when parenteral therapy is necessary for inotropic support in the short-term treatment of patients with cardiac decompensation due to depressed contractility. Does not significant increase the energy needs of the heart.

• Side effects are hypertension, angina, arrhythmia, and tachycardia.

• Half Life 2 minutes

Alpha 1 & Alpha 2 Direct Acting Adrenergic Agonists

• Oxymetazoline: is a selective - α1 agonist and partial -α2 agonist. It is used as a decongestant and to treat nosebleeds.

• Rebound congestion known as rhinitis medicamentosa can occur.

• Half-Life is 5-6 hours.

Alpha-1 Direct Acting Adrenergic Agonists

• Phenylephrine is a selective α1-adrenergic receptor agonist used primarily as a decongestant, and also to dilate the pupils, and to increase blood pressure. Phenylephrine is marketed as an alternative for the decongestant pseudoephedrine, though clinical studies suggest that phenylephrine is less effective than pseudoephedrine .

• Phenylephrine is used to abort priapism. It is diluted with normal saline and injected directly into the corpora cavernosa’; causing constriction of the blood vessels.

• Side effects: Hypertension, rebound bradycardia, rebound congestion.

• Half Life 2.1 – 3.4 hours.

Alpha-2 Direct Acting Adrenergic Agonists

• Clonidine: Clonidine is a sympatholytic medication that is an agonist at the α - 2 receptor. It is used to treat high blood pressure, attention deficit hyperactivity disorder, anxiety disorders, withdrawal (from either alcohol, opioids, or smoking), migraine, menopausal flushing, and diarrhea.

• Methyldopa: is an α -2 -adrenergic agonist pro-drug used as a sympathoplegic medication. It is converted to α-methylnorepinephrine by dopamine beta-hydroxylase (DBH). This binds to the α -2 receptor. This medication is used in gestational hypertension. Rebound hypertension, depression, sexual dysfunction, memory impairment and tolerance may be significant.

Beta-2 specific Direct Acting Adrenergic Agonists

• Albuterol: (salbutamol) is a short acting β-2 Agonist used to treat asthma and chronic obstructive pulmonary disease. The most common side effects are a fine tremor, anxiety, headaches, muscle cramps, dry mouth, and palpitations.

• Terbutaline: is used as a fast-acting bronchodilator and as a tocolytic to delay premature labor. The inhaled form of terbutaline starts working within 15 minutes and can last up to 6 hours. Side effects are tachycardia, anxiety, nervousness, tremors, headache, hyperglycemia, hypokalemia, hypertension and, rarely, pulmonary edema.

• Albuterol is a little faster acting but shorter acting.

Beta-2 specific Direct Acting Adrenergic Agonists

• Salmeterol: is a long-acting β2 -adrenergic receptor agonist drug used in the maintenance and prevention of asthma symptoms and maintenance of chronic obstructive pulmonary disease (COPD) symptoms. It is also used to prevent exercise induce asthma.

• Side effects: The common side effects of salmeterol are dizziness, sinus infection, and migraine headaches. Half-Life 5 Hours

• Formoterol: This medication is similar to salmeterol and has a half-life of 10 hours. Though it has a longer half-life than salmeterol it has a shorter onset of action due to a much lower volume of distribution.

Indirect – Acting Adrenergic Agonists

• Cocaine acts as a serotonin–norepinephrine–dopamine reuptake inhibitor, also known as a triple reuptake inhibitor (TRI). At higher levels it can also block the sodium channel causing sudden death. Topical cocaine can be used as a local numbing agent to help with procedures in the mouth or nose. It is appetite inhibitor also. Cocaine can also be used as part of cauterize to stop bleeding of the nose.

• Side effects drug can cause itching, fast heart rate, hallucinations, and paranoid delusions. Overdoses can cause hyperthermia, a marked elevation of blood pressure, and cardiac arrhythmias

Indirect – Acting Adrenergic Agonists

• Amphetamine: This drug stimulates the release of catecholamines and is a weak inhibitor of MAO. It is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy.

• Half-Life 11 hours

• Tyramine: is a naturally occurring compound. stimulates the release of catecholamines. It is unable to cross the blood-brain barrier, resulting in only nonpsychoactive peripheral sympathomimetic effects. A hypertensive crisis can result from ingestion of tyramine-rich foods in conjunction with monoamine oxidase inhibitors (MAOIs).

Mixed Action Adrenergic Agonists.

• Ephedrine: The mechanism of action relies on its indirect stimulation of the adrenergic receptor system by increasing the activity of norepinephrine at the postsynaptic α- and β-receptors. It is a natural medicine used to treat asthma and in combination with caffeine is used by professional body builders to cut fat. Side effects acne, tachycardia, insomnia, restlessness

• • Pseudoephedrine: Pseudoephedrine acts on α and β2 adrenergic

receptors, to cause vasoconstriction and relaxation of smooth muscle in the bronchi. It is used as a decongestant and does not cause rebound congestion. Side effects: hypertension, sweating, insomnia, and anxiety.