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Adrenergic Agonists OVERVIEW • The adrenergic drugs affect receptors that are stimulated by norepinephrine or epinephrine. • Drugs affecting adrenergic system: 1. Sympathomimetics: act directly on the adrenergic receptor (adrenoceptor) by activating it. 2. Sympatholytics: block the action of the neurotransmitters at the receptors THE ADRENERGIC NEURON • Primary neurotransmitter: norepinephrine • These neurons are found in: – CNS – sympathetic nervous system. • The adrenergic neurons and receptors, located either: – presynaptically on the neuron or – postsynaptically on the effector organ A. Neurotransmission at adrenergic neurons • Neurotransmission takes place at numerous beadlike enlargements called varicosities. • The process involves five steps: 1. 2. 3. 4. 5. Synthesis Storage Release receptor binding of norepinephrine removal of the neurotransmitter 1. Synthesis of norepinephrine: 1. Tyrosine is transported by a Na+-linked carrier into the axoplasm of the adrenergic neuron 2. Tyrosine is hydroxylated to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase. 3. DOPA is then decarboxylated by the enzyme dopa decarboxylase (aromatic l-amino acid decarboxylase) to form dopamine in the cytoplasm of the presynaptic neuron. 4. Dopamine is hydroxylated by dopamine b-hydroxylase to NE rate-limiting step 2. Storage of norepinephrine in vesicles: 1. Dopamine transport into the vesicles by: – an amine transporter system • same transporter is involved in the reuptake of preformed norepinephrine. 2. Dopamine is hydroxylated to form norepinephrine by the enzyme, dopamine β-hydroxylase. • Synaptic vesicles contain: DA or NE plus ATP, β-hydroxylase and other cotransmitters. In the adrenal medulla: • Norepinephrine is methylated to yield epinephrine, which is stored in chromafin cells along with norepinephrine. • On stimulation, the adrenal medulla releases contents directly into circulation: – about 80 percent epinephrine – 20 percent norepinephrine 3. Release of norepinephrine: • An action potential arriving at the nerve junction triggers an influx of calcium ions from the extracellular fluid into the cytoplasm of the neuron. • The increase in calcium causes vesicles inside the neuron to fuse with the cell membrane and expel (exocytose) their contents into the synapse. 4. Binding to receptors: • NE binds to either: – post-synaptic receptors or – Pre-synaptic receptors. 1. Post-synaptically, the recognition of NE by receptors triggers a cascade of events within the cell resulting in the formation of intracellular second messengers that act as links (transducers) in the communication between the neurotransmitter and the action generated within the effector cell. 2. Binding of NE to presynaptic receptors will modulate the release of the neurotransmitter. 5. Removal of norepinephrine: • Fate of synaptic norepinephrine, it may: 1. diffuse out of the synaptic space and enter the general circulation 2. be metabolized by catechol O-methyltransferase (COMT) in the synaptic space 3. be reuptaken back into the presynaptic neuron. • Primary mechanism for termination of norepinephrine’s effects. 6. Potential fates of recaptured norepinephrine: • Once norepinephrine reenters the cytoplasm of the adrenergic neuron: 1. it may be taken up into adrenergic vesicles 2. it may persist in a protected pool in the cytoplasm. 3. It can be oxidized by monoamine oxidase (MAO) present in neuronal mitochondria. • The inactive products of are excreted in urine as vanillylmandelic acid, metanephrine, and normetanephrine. B. Adrenergic receptors (adrenoceptors) 1. α1 and α2 Receptors: • The α-adrenoceptors – show weak response to the synthetic agonist isoproterenol – they are responsive to the naturally occurring catecholamines epinephrine and norepinephrine. – For α receptors, the rank order of potency is epinephrine ≥ norepinephrine >> isoproterenol • The α-adrenoceptors : α1 and α2 • based on their affinities for α agonists and blocking drugs. • For example – Affinity for phenylephrine: α1 > α2 – Affinity for clonidine: α2 >>> α1 A. α1 Receptors: Located post synaptically NH 3 Phospho lipase C Second messengers: IP3 DAG (+) Gq PIP 2 COOH IP 3 Diacylglycerol Increase Ca 2+ Activate Protein Kinase C Response B. α2 Receptors: • Located: primarily on: – presynaptic nerve endings – other cells, such as the β cell of the pancreas – certain vascular smooth muscle cells • Second messenger: a fall in the levels of intracellular cAMP. α2 Receptors NH3 (-) Adenylate Cyclase GI K+ X (+) ATP cAMP COOH Reduce cAMP-Dependent Protein Kinase Activity Response Activation of presynaptic α2 receptor on adrenergic neurons inhibition of the release of norepinephrine Modulation of sympatrhitic neurotransmission Activation of presynaptic α2 receptor on cholinergic neurons inhibition of the release of ACh Modulation of parasympatrhitic neurotransmission c. Further subdivisions: • α1 : α1A, α1B, α1C, and α1D • a2: α2A, α2B, and α2C. Tamsulosin – is a selective α1A antagonist – used to treat benign prostate hyperplasia. – The drug is clinically useful because it targets α1A receptors found primarily in the urinary tract and prostate gland. 2. β Receptors: • The rank order of potency is isoproterenol > epinephrine > norepinephrine • The β-adrenoceptors: β1, β2, and β3 b receptors NH3 (+) Adenylate Cyclase GS ATP cAMP COOH Increase cAMP-Dependent Protein Kinase Activity Response Affinity of binding: • β1 receptors: epinephrine = norepinephrine • β2 receptors: epinephrine > norepinephrine. Binding of a neurotransmitter at any of the three β receptors activation of adenylyl cyclase increased cAMP Drugs affecting alpha receptors 4. Characteristic responses mediated by adrenoceptors: As a generalization 1. Stimulation of α1 receptors: – – produces vasoconstriction (particularly in skin and abdominal viscera) increase in total peripheral resistance and blood pressure. 2. Stimulation of β1 receptors: causes cardiac stimulation 3. Stimulation of β2 receptors produces: • vasodilation (in skeletal vascular beds) • smooth muscle relaxation. 5. Desensitization of receptors: • Prolonged exposure to catecholamines reduces responsiveness of receptors. • Suggested mechanisms: 1. Sequestration of the receptors 2. down-regulation: – a disappearance of the receptors either by: • • destruction or decreased synthesis 3. inability to couple to G protein, because the receptor has been phosphorylated on the cytoplasmic side. III. CHARACTERISTICS OF ADRENERGIC AGONISTS • Most drugs are derivatives of β-phenylethylamine. • Two important structural features of these drugs are 1) the number and location of OH substitutions on the benzene ring 2) the nature of the substituent on the amino nitrogen. Mixed action A. Catecholamines • Catecholamines are sympathomimetic amines that contain the 3,4-dihydroxybenzene group such as: 1. 2. 3. 4. Epinephrine Norepinephrine Isoproterenol Dopamine 5 4 3 6 2 1 Catecholamines share the following properties: 1. High potency: a or b 3. Poor penetration into CNS: 2. Rapid inactivation: • are polar • Most of these drugs have some clinical effects (anxiety, tremor, and headaches) that are attributable to action on the CNS. • Catecholamines metabolized by: – COMT postsynaptically – MAO intraneuronally • Peripherally: – COMT in the gut wall – MAO is in the liver and gut wall. B. Noncatecholamines: lack catechol hydroxyl groups • These include: • Phenylephrine • Ephedrine • Amphetamine • Longer half-lives: – they are not inactivated by COMT. – These are poor substrates for MAO • Increased lipid solubility better access to the CNS D. Mechanism of action of the adrenergic agonists 1. Direct-acting agonists: • They act directly on α or β receptors • Examples of direct-acting agonists: • Epinephrine • Norepinephrine • Isoproterenol • phenylephrine. 2. Indirect-acting agonists: • They may – block the uptake of norepinephrine (uptake blockers) e.g. cocaine – – Cause the release of norepinephrine e.g. amphetamines. Enzyme inhibitors 3. Mixed-action agonists: – Ephedrine – Pseudo ephedrine • Agonists that have the capacity to: 1. Direct actions on receptors 2. Indirect: release norepinephrine IV. DIRECT-ACTING ADRENERGIC AGONISTS • They bind to adrenergic receptors without interacting with the presynaptic neuron. • The activated receptor initiates synthesis of second messengers and subsequent intracellular signals. • As a group, these agents are widely used clinically. A. Epinephrine • Epinephrine is synthesized in the adrenal medulla and released into the bloodstream. • Epinephrine interacts with both α and β receptors: • Effect on blood vessels is dose dependent: – At low doses causes vasodilation: β effects – At high doses causes vasoconstriction: α effects 1. Actions of epinephrine: a. Cardiovascular: 1. Positive inotropic: β1 action 2. Positive chronotropic: β1 action 3. Activates β1 receptors on the kidney to cause renin release. • Renin results in production of angiotensin II, a potent vasoconstrictor • Effect of epinephrine on vessels: 1. constricts arterioles in the skin, mucous membranes, and viscera (α effects) 2. it dilates vessels going to the liver and skeletal muscle (β2 effects). 3. Renal blood flow is decreased. • The cumulative effect: • increase in systolic blood pressure • slight decrease in diastolic pressure. b. Respiratory: 1. bronchodilation by acting directly on bronchial smooth muscle (β2 action). 2. Inhibits the release of allergy mediators such as histamines from mast cells. c. Hyperglycemia: • Epinephrine has a significant hyperglycemic effect because of: 1. increased glycogenolysis in the liver (β2 effect) 2. increased release of glucagon (β2 effect) 3. a decreased release of insulin (α2 effect). d. Lipolysis: Stimulation of β receptors • Epinephrine initiates lipolysis through its agonist activity on the β receptors of adipose tissue activate adenylyl cyclase increase cAMP levels. Stimulates lipase hydrolyzes triacylglycerols to free fatty acids and glycerol. 2. Biotransformations of Epi: • Epinephrine is metabolized by two enzymatic pathways: MAO and COMT, which has S-adenosylmethionine as a cofactor. • The final metabolites found in the urine are: 1. Metanephrine 2. Vanillylmandelic acid 3. Therapeutic uses a. Bronchospasm: • Used in the emergency treatment of bronchoconstriction – Treatment of acute asthma – Treatment of anaphylactic shock • Chronic treatment of asthma: – selective β2 agonists, such as albuterol, are presently favored because • a longer duration of action • minimal cardiac stimulatory effect. b. Anaphylactic shock: • Epinephrine is the drug of choice for the treatment of Type I hypersensitivity reactions in response to allergens. c. Cardiac arrest: • Epinephrine may be used to restore cardiac rhythm in patients with cardiac arrest regardless of the cause. d. Local anesthetics: • Provides vasoconstriction: 1. increases the duration of the local anesthesia. 2. Minimizes systemic effects 4. Pharmacokinetics: 5. Adverse effects of epinephrine: a. CNS disturbances: anxiety, fear, tension, headache, and tremor. b. Hemorrhage: The drug may induce cerebral hemorrhage as a result of a marked elevation of blood pressure. c. Cardiac arrhythmias: Epinephrine can trigger cardiac arrhythmias, particularly if the patient is receiving digoxin. d. Pulmonary edema: Epinephrine can induce pulmonary edema. 6. Interactions: a. Hyperthyroidism: • In hyperthyroidism: – increased production of adrenergic receptors on the vasculature – leading to a hypersensitive response. • Epinephrine enhances cardiovascular actions in these patients. • The dose of epinephrine must be reduced. b. Cocaine: • reuptake inhibitor of catecholamines c. Diabetes: • Epinephrine increases the release of endogenous stores of glucose. • In the diabetic, dosages of insulin may have to be increased. d. β-Blockers: • These prevent epinephrine’s effects on β receptors, leaving α receptor stimulation unopposed. • This may lead to an increase in peripheral resistance and an increase in blood pressure. e. Inhalation anesthetics: • These agents sensitize the heart to the effects of epinephrine, which may lead to tachycardia. B. Norepinephrine • In therapeutic doses, the α- receptor is most affected. 1. Cardiovascular actions: A. Vasoconstriction: • Increases TPR: due to intense vasoconstriction of most vascular beds, including the kidney (α1 effect). • Both systolic and diastolic blood pressures increase. B. Baroreceptor reflex: • Negligible cardiac stimulation. Increased BP Induces a reflex rise in vagal activity by stimulating the baroreceptors Reflex bradycardia C. Effect of atropine pretreatment: When atropine is given before norepinephrine it blocks the vagal effects tachycardia. 2. Therapeutic uses • Treatment of shock: increases TPR and BP • Norepinephrine causes extravasation (discharge of blood from vessel into tissues) along the injection site. • Impaired circulation from norepinephrine may be treated with the α -receptor antagonist phentolamine. 3. Pharmacokinetics of NE: • Given IV for rapid onset of action. • Duration of action is 1 to 2 minutes following the end of the infusion period. • Poorly absorbed after subcutaneous injection • It is destroyed in the gut if administered orally. • Metabolism is similar to that of epinephrine. 4. Adverse effects of NE • Similar to those of epinephrine. – CNS disturbances – Cerebral hemorrhage – Cardiac arrhythmias – Pulmonary edema • May cause blanching and sloughing of skin along an injected vein (due to extreme vasoconstriction). C. Isoproterenol • Direct-acting synthetic catecholamine • Predominantly stimulates both β1- and β2adrenergic receptors. • Insignificant action on α receptors. 1. Actions of isoproterenol: a. Cardiovascular: • Increases HR and force of contraction increased CO • Decreases peripheral resistance because it dilates the arterioles of skeletal muscle (β2 effect). • May slightly increase systolic blood pressure • It greatly reduces mean arterial and diastolic blood pressure. b. Pulmonary: Inhalation products of isoproterenol are no longer available in the United States. c. Other effects: not clinically significant • On β receptors, such as: – increased blood sugar – increased lipolysis 2. Therapeutic uses: • Isoproterenol can be used to stimulate the heart in emergency situations. 3. Pharmacokinetics: • Isoproterenol is a marginal substrate for COMT and is stable to MAO action. 4. Adverse effects: • Similar to those of epinephrine. D. Dopamine • Occurs naturally in – CNS in the basal ganglia – Adrenal medulla. • Dopamine can activate αand β-adrenergic receptors. • For example 1. 2. at lower doses, it stimulates β1 cardiac receptors. at higher doses, it can cause vasoconstriction by activating α1 receptors • Dopamine activates D1 and D2 receptors in the mesenteric and renal vascular beds: produces vasodilation. • Dopamine activates presynapptic D2 receptors o adrenergic neurons: inhibits NE release. 1. Actions of Dopamine : a. Cardiovascular: – Inotropic and chronotropic effects: B1 – At very high doses, dopamine activates α1 receptors on the vasculature, resulting in vasoconstriction. b. Renal and visceral: – Vasodilation of the renal and splanchnic arterioles: • Dopamine receptors • Therefore, dopamine is clinically useful in the treatment of shock, in which significant increases in sympathetic activity might compromise renal function. 2. Therapeutic uses of dopamine: A. Dopamine is the drug of choice for cardiogenic and septic shock – Dopamine is given by continuous infusion. – It raises the blood pressure by stimulating: • β1 receptors on the heart to increase cardiac output • α1 receptors on blood vessels to increase total peripheral resistance. • Dopamine enhances perfusion to the kidney and splanchnic areas enhances GFR and causes sodium diuresis. • It is also used to treat: B. hypotension C. severe congestive heart failure 3. Adverse effects: • Dopamine is rapidly metabolized to homovanillic acid by MAO or COMT • Adverse effects are short-lived: • Nausea • Hypertension • Arrhythmias Fenoldopam • Fenoldopam is an agonist of: – Peirpheral D1receptors – Moderate α2 receptors. • It is used as a rapid-acting vasodilator to treat severe hypertension in hospitalized patients, acting on coronary arteries, kidney arterioles, and mesenteric arteries. • Fenoldopam undergoes extensive first-pass metabolism • has a 10-minute elimination half-life after IV infusion. Adverse effects: • Headache, flushing, dizziness, nausea, vomiting, and tachycardia. Dobutamine 1. Actions: – Direct-acting β1 receptor agonist. – It increases HR and CO. 2. Therapeutic uses: – Treatment of acute congestive heart failure – for inotropic support after cardiac surgery. 3. Adverse effects: • Dobutamine should be used with caution in atrial fibrillation, because the drug increases AV conduction. • Other adverse effects are the same as those for epinephrine. • Tolerance may develop on prolonged use. Oxymetazoline • Agonist at α1- and α2- receptors. Adverse effects: 1. • Used locally in the eye or the nose as a vasoconstrictor. – short-term nasal spray decongestant – ophthalmic drops for the relief of redness of the eyes associated with swimming, colds, and contact lenses. Oxymetazoline when absorbed in the systemic circulation may produce nervousness, headaches, and trouble sleeping. 2. When administered in the nose, burning of the nasal mucosa and sneezing may occur. 3. Rebound congestion and dependence are observed with long-term use. Phenylephrine • Selective α1 agonist. • Phenylephrine is a vasoconstrictor that raises both systolic and diastolic blood pressures. • It has no effect on the heart itself but, rather, induces reflex bradycardia when given parenterally. • It is often used topically on the: – nasal mucous membranes – in ophthalmic solutions for mydriasis. • Phenylephrine acts as a nasal decongestant (applied every 4 hours) and produces vasoconstriction. • The drug is used to: – raise blood pressure – terminate episodes of supraventricular tachycardia. • Large doses can cause hypertensive headache and cardiac irregularities. a 2 receptor agonists • • • • Clonidine (Catapres) Methyldopa (Aldomet) Guanabenz (Wytensin) Guanfacine (Intuniv, Tenex) Clonidine • α2 agonist: acts centrally to produce inhibition of sympathetic vasomotor centers, decreasing sympathetic outflow to the periphery. • used in: – essential hypertension – to minimize the symptoms of withdrawal from opiates, tobacco smoking, and benzodiazepines. • Side effects: – lethargy, sedation, constipation, and xerostomia. • Abrupt discontinuance must be avoided to prevent rebound hypertension. a2-Adrenergic Agonists Brain Brain Stem (Cardiovascular Control Center) a Receptors Sympathetic ganglion 2 Decreased sympathetic tone • Decr. HR • Decr. Contractility • Decr. Renin release • Decr. Vasoconstriction b1 Receptors Heart b1 Receptors Kidney a1 Receptors Albuterol and Terbutaline • Short-acting β2 agonists • Used primarily as bronchodilators. • Duration: less than 3 hours • Terbutaline is used oflabel as a uterine relaxant to suppress premature labor. • Side effects of β2 agonists – CNS effects: • tremor, restlessness, apprehension, and anxiety. – Cardiovascular effects: • With concomitant use of monoamine oxidase inhibitors (MAOIs) • It is recommended that there be about a 2-week gap between the use of a MAOI and a β2-receptor agonist. Salmeterol and formoterol • Are long-acting β2-agonists that are bronchodilators. • Duration: 12 hours • Salmeterol has a delayed onset of action. • Used to treat nocturnal asthma in symptomatic patients taking other asthma medications • Inhaled β2-receptor agonists should not be used in excess. INDIRECT-ACTING ADRENERGIC AGONISTS • They may either: 1. Increase release norepinephrine from pre-synaptic terminals or 2. inhibit the uptake of norepinephrine. • They potentiate the effects of norepinephrine produced endogenously • They do not directly affect postsynaptic receptors. A. Amphetamine • MOA: increases release of norepinephrine. • Effect: A. Increases blood pressure significantly by: 1. 2. α1-agonist action on the vasculature β-stimulatory effects on the heart. B. The CNS stimulation • Therapeutic use: – Treatment of ADHA in children – Narcolepsy – Appetite control • • • • Dextroamphetamine Methamphetamine Methylphenidate Dexmethylphenidate • Closely related in structure or have similar to amphetamine. • Used for similar indications as amphetamine. B. Tyramine • Found in fermented foods, such as aged cheese and Chianti wine. • MOA of Tyramine: increase release stored norepinephrine. • The released catecholamine then acts on adrenoceptors. • Normally, it is oxidized by MAO in the gastrointestinal tract • if the patient is taking MAOIs, it can precipitate serious vasopressor episodes. VI. MIXED-ACTION ADRENERGIC AGONISTS • Mixed-action drugs induce: 1. release of norepinephrine from presynaptic terminals 2. activate adrenergic receptors on the postsynaptic membrane. A. Ephedrine and pseudoephedrine • Plant alkaloids purified from Ephedra sinica. Now it is synthetic • These drugs are mixed-action adrenergic agents. • They release stored norepinephrine from nerve endings • They directly stimulate both α and β receptors. • They have a long duration of action: – They are poor substrates for COMT and MAO • They have excellent absorption orally • They penetrate into the CNS • Ephedrine is eliminated largely unchanged in urine • Pseudoephedrine undergoes incomplete hepatic metabolism before elimination in urine. • Effects of ephedrine: 1. raises blood pressures 2. produces slow and less potent bronchodilation 3. produces mild CNS stimulation . • • This increases alertness, decreases fatigue, and prevents sleep Suppresses appetite 4. It improves athletic performance. • Pseudoephedrine is primarily used orally to treat: – Nasal and sinus congestion – Congestion of the eustachian tubes. • Ephedrine-containing herbal supplements (mainly ephedracontaining products) were banned by the U.S. Food and Drug Administration in April 2004 because of life-threatening cardiovascular reactions. • Pseudoephedrine has been illegally converted to methamphetamine. Some side effects of adrenergic agonists