Adrenergic Drugs and Catecholamines

• Adrenergic drugs affect receptors stimulated by norepinephrine or epinephrine, known as adrenergic receptors or adrenoceptors.
• Sympathomimetics activate adrenergic receptors.
• Sympatholytics block the activation of adrenergic receptors.
• Direct-acting agonists directly activate adrenergic receptors.
• Indirect-acting agonists enhance norepinephrine release or block its reuptake.

Catecholamines

• Catecholamines contain a catechol moiety (benzene ring with two adjacent hydroxyl groups) and an amine side chain.
• The most important catecholamines are norepinephrine, epinephrine, dopamine, and isoprenaline.
• Norepinephrine is a neurotransmitter released by sympathetic nerve terminals.
• Epinephrine is a hormone secreted by the adrenal medulla.
• Dopamine is the metabolic precursor of norepinephrine and epinephrine, and also a neurotransmitter/neuromodulator in the central nervous system.
• Isoprenaline is a synthetic derivative of noradrenaline, not present in the body.

Adrenergic Neurons

• Adrenergic neurons release norepinephrine as the primary neurotransmitter.
• These neurons are found in the central nervous system (CNS) and the sympathetic nervous system, linking ganglia and effector organs.
• Adrenergic drugs act on adrenergic receptors located presynaptically on the neuron or postsynaptically on the effector organ.

Neurotransmission at Adrenergic Neurons

• Neurotransmission closely resembles that of cholinergic neurons, with norepinephrine as the neurotransmitter.
• The steps are synthesis, storage, release, receptor binding, and removal of norepinephrine from the synaptic gap.

Synthesis of Norepinephrine

• Tyrosine is transported into the adrenergic neuron and hydroxylated to DOPA by tyrosine hydroxylase.
• This hydroxylation is the rate-limiting step.
• DOPA is decarboxylated by aromatic I-amino acid decarboxylase to form dopamine.

Storage of Norepinephrine in Vesicles

• Dopamine is transported into synaptic vesicles by an amine transporter system, which is blocked by reserpine.
• Dopamine is hydroxylated to form norepinephrine by dopamine β-hydroxylase.

Release of Norepinephrine

• An action potential triggers calcium influx, causing synaptic vesicles to fuse with the cell membrane and release their contents into the synapse.
• Guanethidine blocks this release.

Binding to Receptors

• Norepinephrine diffuses into the synaptic space and binds to postsynaptic receptors on the effector organ or presynaptic receptors on the nerve ending.
• Binding triggers intracellular events, forming second messengers like cAMP and IP3/DAG.
• Norepinephrine also binds to presynaptic α2 receptors, modulating neurotransmitter release.

Removal of Norepinephrine

• Norepinephrine can diffuse out of the synaptic space, be metabolized by COMT, or undergo reuptake back into the neuron.
• Reuptake is mediated by a Na+/Cl--dependent norepinephrine transporter (NET), which is inhibited by TCAs, SNRIs, or cocaine.
• Reuptake is the primary mechanism for terminating norepinephrine's effects.

Fates of Recaptured Norepinephrine

• Norepinephrine can be taken up into synaptic vesicles for future release or persist in a protected pool in the cytoplasm.
• Alternatively, norepinephrine can be oxidized by MAO in neuronal mitochondria.

Adrenergic Receptors (Adrenoceptors)

• Two main families of receptors, α and β, are classified based on their responses to epinephrine, norepinephrine, and isoproterenol.
• Each receptor type has specific subtypes.

α-Adrenoceptors

• α-Adrenoceptors show a weak response to isoproterenol but are responsive to epinephrine and norepinephrine.
• The rank order of potency is epinephrine ≥ norepinephrine >> isoproterenol.
• α-Adrenoceptors are subdivided into α1 and α2 based on their affinities for agonists and blocking drugs.
• α1 receptors have a higher affinity for phenylephrine than α2 receptors, while clonidine selectively binds to α2 receptors.

α1 Receptors

• α1 receptors are present on the postsynaptic membrane of effector organs.
• They mediate constriction of smooth muscle.
• Activation initiates a series of reactions through G protein activation of phospholipase C, resulting in the generation of IP3 and DAG.
• IP3 initiates Ca2+ release, and DAG turns on other proteins within the cell.

α2 Receptors

• α2 receptors are located primarily on sympathetic presynaptic nerve endings.
• They control the release of norepinephrine.
• Stimulation causes feedback inhibition and inhibits further norepinephrine release.
• They act as inhibitory autoreceptors.
• α2 receptors are also found on presynaptic parasympathetic neurons, where they inhibit acetylcholine release.
• Effects are mediated by inhibition of adenylyl cyclase and a fall in cAMP levels.

Further Subdivisions of α-Adrenoceptors

• The α1 and α2 receptors are further divided into α1A, α1B, α1C, α1D, and α2A, α2B, α2C.
• Tamsulosin is a selective α1A antagonist used to treat benign prostatic hyperplasia with fewer cardiovascular side effects.

β-Adrenoceptors

• β receptors show a strong response to isoproterenol, with less sensitivity to epinephrine and norepinephrine.
• The rank order of potency is isoproterenol > epinephrine > norepinephrine.
• The β-adrenoceptors are subdivided into β1, β2, and β3.
• β1 receptors have approximately equal affinities for epinephrine and norepinephrine.
• β2 receptors have a higher affinity for epinephrine than for norepinephrine.
• β3 receptors are involved in lipolysis and have effects on the detrusor muscle of the bladder.
• Binding of a neurotransmitter at any of the three types of β receptors results in activation of adenylyl cyclase and increased concentrations of cAMP within the cell.

Distribution of Receptors

• Adrenergically innervated organs and tissues usually have a predominant type of receptor.
• The vasculature of skeletal muscle has both α1 and β2 receptors, but the β2 receptors predominate.
• The heart contains predominantly β1 receptors.

Characteristic Responses Mediated by Adrenoceptors

• Stimulation of α1 receptors typically produces vasoconstriction and increases total peripheral resistance and blood pressure.
• Stimulation of β1 receptors causes cardiac stimulation (increase in heart rate and contractility).
• Stimulation of β2 receptors produces vasodilation and smooth muscle relaxation.
• β3 receptors are involved in lipolysis and also have effects on the detrusor muscle of the bladder.

Desensitization of Receptors

• Prolonged exposure to catecholamines reduces receptor responsiveness, known as desensitization.
• Mechanisms include sequestration of the receptors, down-regulation (disappearance of receptors), and an inability to couple to G protein (due to phosphorylation).

Characteristics of Adrenergic Agonists

• Most adrenergic drugs are derivatives of β-phenylethylamine.
• Substitutions on the benzene ring or ethylamine side chains produce compounds with varying abilities to differentiate between α and β receptors and to penetrate the CNS.
• Two important structural features are the number and location of OH substitutions on the benzene ring and the nature of the substituent on the amino nitrogen.

Catecholamines (as Adrenergic Agonists)

• Sympathomimetic amines containing the 3,4-dihydroxybenzene group (e.g., epinephrine, norepinephrine, isoproterenol, and dopamine) are called catecholamines.
• They share high potency, rapid inactivation, and poor penetration into the CNS.
• Catecholamines show the highest potency in directly activating α or β receptors.
• They are metabolized by COMT and MAO, resulting in a brief period of action when given parenterally, and are ineffective when administered orally.
• Catecholamines are polar and do not readily penetrate into the CNS.

Non-catecholamines

• Compounds lacking the catechol hydroxyl groups have longer half-lives because they are not inactivated by COMT.
• These compounds include phenylephrine, ephedrine, and amphetamine.
• Non-catecholamines are poor substrates for MAO, resulting in a prolonged duration of action.
• Increased lipid solubility permits greater access to the CNS.

Mechanism of Action of Adrenergic Agonists

• Direct-acting agonists act directly on α or β receptors, producing effects similar to those following sympathetic nerve stimulation or epinephrine release.
• Examples include epinephrine, norepinephrine, isoproterenol, and phenylephrine.
• Indirect-acting agonists block the reuptake of norepinephrine or cause the release of norepinephrine from the cytoplasmic pools or vesicles of the adrenergic neuron.
• Examples of reuptake inhibitors and agents that cause norepinephrine release include cocaine and amphetamines, respectively.
• Mixed-action agonists stimulate adrenoceptors directly and release norepinephrine from the adrenergic neuron.
• Ephedrine and pseudoephedrine are examples.

Direct-Acting Agonists

• Direct-acting agonists bind to adrenergic receptors on effector organs without interacting with the presynaptic neuron.
• They are widely used clinically.

Epinephrine

• One of the four catecholamines (epinephrine, norepinephrine, dopamine, and dobutamine) commonly used in therapy.
• In the adrenal medulla, norepinephrine is methylated to yield epinephrine, which is stored in chromaffin cells.
• The adrenal medulla releases about 80% epinephrine and 20% norepinephrine directly into the circulation on stimulation.
• Epinephrine interacts with both α and β receptors.
• At low doses, β effects (vasodilation) predominate, whereas at high doses, α effects (vasoconstriction) are the strongest.

Epinephrine Actions

• Cardiovascular: Strengthens myocardial contractility (positive inotrope: β1 action) and increases heart rate (positive chronotrope: β1 action).
• Increases cardiac output and oxygen demands on the myocardium.
• Activates β1 receptors on the kidney to cause renin release (a potent vasoconstrictor).
• Constricts arterioles in the skin, mucous membranes, and viscera (α effects), and it dilates vessels going to the liver and skeletal muscle (β2 effects).
  • Decreases renal blood flow
  • Increases systolic blood pressure, coupled with a slight decrease in diastolic pressure due to β2 receptor–mediated vasodilation.
• Respiratory: Causes powerful bronchodilation by acting directly on bronchial smooth muscle (β2 action).
• Inhibits the release of allergy mediators such as histamines from mast cells.
• Hyperglycemia: Increases glycogenolysis in the liver (β2 effect), increases release of glucagon (β2 effect), and decreases release of insulin (α2 effect).
• Lipolysis: Initiates lipolysis through agonist activity on the β receptors of adipose tissue.
• Increased levels of cAMP stimulate a hormone-sensitive lipase, which hydrolyzes triglycerides to free fatty acids and glycerol.

Epinephrine Therapeutic Uses

• Bronchospasm: Primary drug used in the emergency treatment of respiratory conditions when bronchoconstriction has resulted in diminished respiratory function.
• Anaphylactic shock: Drug of choice for the treatment of type I hypersensitivity reactions (including anaphylaxis) in response to allergens.
• Cardiac arrest: May be used to restore cardiac rhythm in patients with cardiac arrest.
• Anesthetics: Increases the duration of local anesthesia by producing vasoconstriction at the site of injection.
• Intraocular surgery: Used in the induction and maintenance of mydriasis.

Epinephrine Pharmacokinetics

• Rapid onset but a brief duration of action (due to rapid degradation).
• Preferred route for anaphylaxis in the outpatient setting is intramuscular (anterior thigh) due to rapid absorption.
• In emergencies, epinephrine is given intravenously (IV) for the most rapid onset of action.
• Can also be given subcutaneously, by endotracheal tube, or by inhalation.
• Rapidly metabolized by MAO and COMT, and the metabolites metanephrine and vanillylmandelic acid are excreted in urine.

Epinephrine Adverse Effects

• CNS effects include anxiety, fear, tension, headache, and tremor.
• Can trigger cardiac arrhythmias, particularly if the patient is receiving digoxin.
• Can also induce pulmonary edema.
• May have enhanced cardiovascular actions in patients with hyperthyroidism, and the dose must be reduced in these individuals.
• Increases the release of endogenous stores of glucose.
• Nonselective β-blockers prevent vasodilatory effects of epinephrine on β2 receptors, leading to increased peripheral resistance and increased blood pressure.

Norepinephrine

• Norepinephrine is the neurotransmitter of adrenergic nerves.
• In therapeutic doses, the α-adrenergic receptor is most affected.

Norepinephrine Cardiovascular Actions

• Vasoconstriction: Causes a rise in peripheral resistance due to intense vasoconstriction which increases both systolic and diastolic blood pressures.
• Baroreceptor reflex: Increases blood pressure, stimulating the baroreceptors to induce a rise in vagal activity, producing a reflex bradycardia.

Norepinephrine Therapeutic Uses

• Used to treat shock because it increases vascular resistance and, therefore, increases blood pressure.

Norepinephrine Pharmacokinetics

• Given IV for rapid onset of action.
• Duration of action is 1 to 2 minutes following the end of the infusion.
• Rapidly metabolized by MAO and COMT, and inactive metabolites are excreted in the urine.

Norepinephrine Adverse Effects

• Similar to epinephrine.
• Potent vasoconstrictor that may cause blanching and sloughing of skin along an injected vein.
• Extravasation can cause tissue necrosis.

Isoproterenol

• Direct-acting synthetic catecholamine that stimulates both β1- and β2-adrenergic receptors.
• Produces intense stimulation of the heart, increasing heart rate, contractility, and cardiac output.
• Dilates the arterioles of skeletal muscle (β2 effect), resulting in decreased peripheral resistance.
• Potent bronchodilator (β2 effect).
• May be useful in atrioventricular (AV) block.

Dopamine

• Immediate metabolic precursor of norepinephrine.
• Occurs naturally in the CNS in the basal ganglia and in the adrenal medulla.
• Can activate α- and β-adrenergic receptors.
• Activates α1 receptors at higher doses, causing vasoconstriction, and stimulates β1 cardiac receptors at lower doses.
• D1 and D2 dopaminergic receptors occur in the peripheral mesenteric and renal vascular beds, producing vasodilation.
• D2 receptors are also found on presynaptic adrenergic neurons, interfering with norepinephrine release.

Dopamine Actions

• Cardiovascular: Exerts a stimulatory effect on the β1 receptors of the heart, having both positive inotropic and chronotropic effects.
• Renal and visceral: Dilates renal and splanchnic arterioles by activating dopaminergic receptors, increasing blood flow to the kidneys and other viscera.

Dopamine Therapeutic Uses

• Drug of choice for cardiogenic and septic shock and is given by continuous infusion.
• Raises blood pressure.
• Enhances perfusion to the kidney and splanchnic areas.
• Also used to treat hypotension, severe heart failure, and bradycardia unresponsive to other treatments.

Fenoldopam

• Agonist of peripheral dopamine D1 receptors.
• Used as rapid-acting vasodilators to treat severe hypertension in hospitalized patients.
• Acts on coronary arteries, kidney arterioles, and mesenteric arteries.
• Has a 10-minute elimination half-life after IV infusion.
• Side effects include headache, flushing, dizziness, nausea, vomiting, and tachycardia.

Dobutamine

• Synthetic, direct-acting catecholamine that is a β1 receptor agonist.
• Increases cardiac rate and output with few vascular effects.
• Used to increase cardiac output in acute heart failure, as well as for inotropic support after cardiac surgery.

Oxymetazoline

• Direct-acting synthetic adrenergic agonist that stimulates both α1- and α2-adrenergic receptors.
• Found in many over-the-counter short-term nasal spray decongestants and ophthalmic drops.
• Stimulates α receptors on blood vessels, producing vasoconstriction and decreasing congestion.
• Use for greater than 3 days is not recommended, as rebound congestion and dependence may occur.

Phenylephrine

• Direct-acting, synthetic adrenergic drug that binds primarily to α1 receptors.
• Vasoconstrictor that raises both systolic and diastolic blood pressures.
• Induces reflex bradycardia when given parenterally.
• Used to treat hypotension and acts as a nasal decongestant.

Midodrine

• Prodrug that is metabolized to the pharmacologically active desglymidodrine.
• Selective α1 agonist that increases arterial and venous tone.
• Indicated for the treatment of orthostatic hypotension.

Clonidine

• α2 agonist that is used for the treatment of hypertension and to minimize the symptoms that accompany withdrawal from opiates, tobacco smoking, and benzodiazepines.
• Acts centrally on presynaptic α2 receptors to produce inhibition of sympathetic vasomotor centers.
• Abrupt discontinuance must be avoided to prevent rebound hypertension.

Albuterol, Metaproterenol, and Terbutaline

• Short-acting β2 agonists (SABAs) used primarily as bronchodilators.
• Albuterol is the SABA of choice for the management of acute asthma symptoms.
• One of the most common side effects of these agents is tremor.

Salmeterol, Formoterol, and Indacaterol

• Long-acting β2 selective agonists (LABAs) used for the management of respiratory disorders such as asthma and chronic obstructive pulmonary disease.
• Not recommended as monotherapy for the treatment of asthma.

Mirabegron

• β3 agonist that relaxes the detrusor smooth muscle and increases bladder capacity.
• Used for patients with overactive bladder.

Indirect-Acting Adrenergic Agonists

• Cause the release, inhibit the reuptake, or inhibit the degradation of epinephrine or norepinephrine.
• They potentiate the effects of epinephrine or norepinephrine produced endogenously, but do not directly affect postsynaptic receptors.

Amphetamine

• Increases blood pressure significantly.
• Mediated primarily through an increase in nonvesicular release of catecholamines such as dopamine and norepinephrine from nerve terminals.

Tyramine

• Found in fermented foods.
• Can precipitate serious vasopressor episodes if the patient is taking MAOIs.

Cocaine

• Blocks the sodium-chloride (Na+/Cl-)-dependent norepinephrine transporter.
• Results in enhanced sympathetic activity and potentiation of the actions of epinephrine and norepinephrine.

Mixed-Action Adrenergic Agonists

• Ephedrine and pseudoephedrine release stored norepinephrine from nerve endings and also directly stimulate both α and β receptors.
• Have a long duration of action.
• Ephedrine raises systolic and diastolic blood pressures by vasoconstriction and cardiac stimulation and can be used to treat hypotension.
• Pseudoephedrine is primarily used orally to treat nasal and sinus congestion.