Adrenergic agonists. Chapter 6 pages from (77-82) Done by : & سالي ابورمان. Mohammad Jomaa & Zaid Abadi

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1 Adrenergic agonists Done by : & سالي ابورمان Mohammad Jomaa & Zaid Abadi Chapter 6 pages from (77-82)

2 activate adrenergic receptors block the activation of adrenergic receptors

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10 It does not matter how slowly you go as long as you do not stop.

11 Direct-acting adrenergic agonists Direct-acting adrenergic agonists do t i d to presy apti neuron A. B. C. D. E. F. G. H. I. J. K. L. Epinephrin Norepinephrine Isoproterenol Dopamine Fenoldopam Dobutamine Oxymetazoline Phenylephrine Clonidine Albuterol and terbutaline Salmeterol and formoterol Mirabegron A. Epinephrine * is one of the four catecholamines (epinephrine, norepinephrine, dopamine, and dobutamine) commonly used in therapy * On stimulation, the adrenal medulla releases about 80% epinephrine and 20% norepinephrine directly into the circulation * Epi ephri e i tera ts ith oth α a d β re eptors At low doses, β effects (vasodilation) on the vascular system predominate, whereas at high doses, α effects (vasoconstriction) are the strongest 1. Actions: a. Cardiovascular : The major actions ** Epi ephri e stre gthe s the o tra tility of the yo ardiu positi e i otrope: β a tio a d i reases its rate of o tra tio positi e hro otrope: β a tio.so that increase heart rate and oxygen demand حاجة ااكسجين

12 *Epi ephri e a ti ates β re eptors ause re i release which cause finally to vasoconstriction *vascular contraction by epinephrine is mediated by α effe ts) *vascular dilations by epinephrine is mediated by β2 effects) * the cumulative effect is an increase in systolic blood pressure, coupled with a slight decrease in diastolic pressure b. Respiratory has two functions 1) bronchodilation 2) inhibits the release of allergy mediators c. Hyperglycemia epinephrine has signficaent effect in Hyperglycemia because of 1) i reased gly oge olysis i the li er β effe t, 2) increased release of glucagon β effe t, 3) a d a de reased release of i suli α effe t. d. Lipolysis : Epinephrine initiates lipolysis 2. Therapeutic uses: a. Bronchospasm: * Epinephrine is the primary drug used in the emergency treatment of respiratory conditions when bronchoconstriction *treatment of asthma and anaphylactic shock * sele ti e β ago ists, su h as al uterol favored in the chronic treatment b. Anaphylactic shock * Epinephrine is the drug of choice for the treatment of hypersensitivity reactions c. Cardiac arrest: *used to restore cardiac rhythm

13 d. Anesthetics *Local anesthetic solutions, greatly increases the duration of local anesthesia 3. Pharmacokinetics * has a rapid onset but a brief duration of action * The preferred route is intramuscular,may be given subcutaneously and by inhalation * In emergency is given intravenously (IV) * It is rapidly metabolized by MAO and COMT 4. Adverse effects * can produce adverse CNS effects that include (anxiety, fear, tension, headache, and tremor) * trigger cardiac arrhythmias, 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 which is harm to diabetic patients prevention by increased insulin dosage * No sele ti e β- lo kers pre e t asodilatory effe ts of epi ephri e o β re eptors, lea i g α re eptor stimulation (contraction) unopposed. B. Norepinephrine * Administered norepinephrine therapeuti doses, the α-adrenergic receptor are most affected. 1. Cardiovascular actions a. Vasoconstriction * cause vasoconstriction of most vascular beds, including the kid ey α effe t. * Both systolic and diastolic blood pressures increase * Norepinephrine causes greater vasoconstriction than epinephrine

14 b. Baroreceptor reflex * Norepinephrine increases blood pressure, and this stimulates the baroreceptors which finally produces a reflex bradycardia, which is sufficient to counteract the actions of norepinephrine on the heart. 2. Therapeutic uses Norepinephrine is used to treat shock, because it increases blood pressure. 3. Pharmacokinetics * is given IV, The duration of action is 1 to 2 minutes, It is rapidly metabolized by MAO and COMT, excreted in the urine. 4. Adverse effects *These are similar to epinephrine * may cause blanching and sloughing of skin along an injected vein * If extravasation (leakage of drug from the vessel into tissues surrounding the injection site) occurs, it can cause tissue necrosis *I paired ir ulatio fro orepi ephri e ay e treated ith the α receptor antagonist phentolamine (to block the action of norepinephrine) C. Isoproterenol * direct-a ti g sy theti ate hola i e that sti ulates oth β - a d β -adrenergic receptors, Its a tio o α re eptors is i sig ifi a t * Its nonselectivity so it is rarely used therapeutically * produces intense stimulation of the heart, dilates the arterioles of skeletal us le β effe t,it may increase systolic blood pressure slightly, but it greatly reduces mean arterial and diastolic blood pressures,is a pote t ro hodilator β effe t) * The adverse effects of isoproterenol are similar to those of epinephrine D. Dopamine * metabolic precursor of norepinephrine * Dopa i e a a ti ate α- a d β-adrenergic receptors

15 * at higher doses, it auses aso o stri tio it sti ulates β ardia re eptors y a ti ati g α re eptors, whereas at lower doses, * D a d D dopa i ergi re eptors, disti t fro the α- a d β-adrenergic receptors, occur in the peripheral mesenteric and renal vascular beds, where binding of dopamine produces vasodilation * D2 receptors are also found on presynaptic adrenergic neurons, where their activation interferes with norepinephrine release. 1. Actions a. Cardiovascular *stimulate effe t o the β re eptors of the heart * At ery high doses, dopa i e a ti ates α re eptors resulti g i aso o stri tio b. Renal and visceral * Dopamine dilates renal and splanchnic arterioles by D receptor * Not affe ted y α- or β-blocking drugs 2. Therapeutic uses * The drug of choice for cardiogenic and septic shock and is given by continuous infusion * It raises lood pressure y sti ulati g the β re eptors o the heart to i rease ardia output a d α re eptors o lood essels to i rease total peripheral resista e * It enhances perfusion to the kidney and splanchnic areas * It is also used to treat hypotension and severe heart failure. 3. Adverse effects * Overdose of dopamine produces the same effects as sympathetic stimulation * Rapidly metabolized by MAO or COMT ** Its adverse effects (nausea, hypertension, and arrhythmias) E. Fenoldopam * an agonist of peripheral dopamine D1 receptors

16 * It is used as a rapid-acting vasodilator to treat severe hypertension * has a 10-minute elimination half-life after IV infusion * Headache, flushing, dizziness, nausea, vomiting, and tachycardia (due to vasodilation) may be observed with this agent. as adverse effect F. Dobutamine * direct-a ti g ate hola i e that is a β re eptor ago ist * It increases cardiac rate and output with few vascular effects * is used to increase cardiac output in acute heart failure therapeutic use * does not significantly elevate oxygen demands of the myocardium, * should be used with caution in atrial fibrillation(abnormal heart failure), because it increases AV conduction. Other adverse effects are similar to epinephrine adverse effects G. Oxymetazoline * is a direct-acting that sti ulates oth α - a d α -adrenergic receptors * is found short-term nasal spray decongestants, as well as in ophthalmic drops for the relief of redness of the eyes associated with swimming, colds, and contact lenses therapeutic uses * dire tly sti ulates α re eptors so that producing vasoconstriction and decreasing congestion * It is absorbed in the systemic circulation regardless of the route of administration * may produce nervousness, headaches, and trouble sleeping, Local irritation and sneezing may occur adverse effect

17 Phenylephrine Phenylephrine is a direct-acting, synthetic adrenergic drug that binds primarily to Ș1 receptors. 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.the drug is used to treat hypotension Large doses can cause hypertensive headache and cardiac irregularities. Phenylephrine is also used in ophthalmic solutions for mydriasis. Clonidine Clonidine is an Ș2 agonist that is used for the treatment of hypertension. Clonidine acts centrally on presynaptic Ș2 receptors to produce inhibition of sympathetic vasomotor centers, decreasing sympathetic outflow to the periphery. The most common side effects of clonidine are lethargy, sedation, constipation, and xerostomia. Clonidine and another Ș2 agonist methyldopa Albuterol and terbutaline Albuterol and terbutaline are short-acting ș2 agonists used primarily as bronchodilators and administered by a metered-dose inhaler. Albuterol is the short-acting ș2 agonist of choice for the management of acute asthma symptoms. One of the most common side effects of these agents is tremor. When these drugs are administered orally, they may cause tachycardia or arrhythmia (due to ș1 receptor activation), especially in patients with underlying cardiac disease. Salmeterol and formoterol Salmeterol and formoterol are longacting ș agonists (LABAs) that are ș2 selective. Unlike formoterol, however, salmeterol has a somewhat delayed onset of action. These agents are not recommended as monotherapy. Salmeterol and formoterol are the agents of choice for treating nocturnal asthma in symptomatic patients taking other asthma medications. Mirabegron Mirabegron is a ș3 agonist that relaxes the detrusor smooth muscle and increases bladder capacity. It is used for patients with overactive bladder. Mirabegron may increase blood pressure and should not be used in patients with uncontrolled hypertension. INDIRECT ACTING ADRENERGIC AGONISTS Indirect-acting adrenergic agonists cause the release, inhibit the reuptake,

18 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 Its actions are mediated primarily through an increase in nonvesicular release of catecholamines such as dopamine and norepinephrine from nerve terminalsthus, amphetamine is an indirect-acting adrenergic drug. Tyramine It is a normal by-product of tyrosine metabolism. Normally, it is oxidized by MAO in the gastrointestinal tract, but, if the patient is taking MAOIs, it can precipitate serious vasopressor episodes. amphetamines, tyramine can enter the nerve terminal and displace stored norepinephrine. The released catecholamine then acts on adrenoceptors. Cocaine Cocaine is unique among local anesthetics in having the ability to block the sodium-chloride (Na+/Cl-)-dependent norepinephrine transporter required for cellular uptake of norepinephrine into the adrenergic neuron. Consequently, norepinephrine accumulates in the synaptic space, resulting in enhanced sympathetic activity and potentiation of the actions of epinephrine and norepinephrine MIXED ACTION ADRENERGIC AGONISTS Ephedrine and pseudoephedrine are mixed-action adrenergic agents. They not only release stored norepinephrine from nerve ending but also directly stimulate both Ș and ș receptors. Ephedrine and pseudoephedrine are not catechols and are poor substrates for COMT and MAO. Therefore, these drugs 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. Ephedrine produces bronchodilation, but it is less potent and slower acting than epinephrine or isoproterenol. Ephedrine produces a mild stimulation of the CNS. This increases alertness, decreases fatigue, and prevents sleep. It also improves athletic performance. Pseudoephedrine is primarily used orally to treat nasal and sinus congestion. Pseudoephedrine has been illegally used to produce methamphetamine.