Adrenergic Agonists I PDF

Adrenergic Agonists I Dr. Sura Al Zoubi Faculty of Medicine 1  DIRECT-ACTING ADRENERGIC AGONISTS Direct-acting agonists bind to adrenergic receptors on effector organs without interacting with the presynaptic neuron. As a group, these agents ar...

Adrenergic Agonists I Dr. Sura Al Zoubi Faculty of Medicine 1  DIRECT-ACTING ADRENERGIC AGONISTS Direct-acting agonists bind to adrenergic receptors on effector organs without interacting with the presynaptic neuron. As a group, these agents are widely used clinically. 2  A. Epinephrine > - 11 -34) 220 CNS S : % Epinephrine is one of the four catecholamines (epinephrine, norepinephrine, dopamine, and dobutamine) commonly used in therapy. The first three are naturally occurring neurotransmitters, and the latter is a synthetic compound. ↳ adrenergic 81.& adrenal gland In j99 neuron %. S Norepinephrine I i sis & In the adrenal medulla, norepinephrine is methylated to yield epinephrine, which is stored in chromaffin cells along with norepinephrine. 4 M adrenergic neuron % On stimulation, the adrenal medulla releases about 80% epinephrine and 20% norepinephrine directly into the circulation. *& i Affinity His 4 Epinephrine interacts with both α and β receptors. At low doses, β effects (vasodilation) on the vascular system predominate, whereas at high doses, α effects (vasoconstriction) are the strongest. 3  1. Actions: a. Cardiovascular: The major actions of epinephrine are on the cardiovascular system. positive inotrope ‫ منحكي عنه‬contractiliy ‫زياده ال‬ Epinephrine strengthens the contractility of the myocardium (positive inotrope: β1 action) and increases its rate of contraction (positive chronotrope: β1 action). positive chronotrope ‫ منحكي عنه‬heart rate ‫زياده ال‬ Therefore, cardiac output increases. These effects increase oxygen demands on the myocardium. 4  Epinephrine activates β1 receptors on the kidney to cause renin release. Renin is an enzyme involved in the production of angiotensin II, a potent vasoconstrictor. 7 wa bes - & ‫وعيه الدموية الي حوال; الكلى فهو بقلل كميه الدم الي بتوصل الكلى‬0‫نه بضيق ا‬0‫و‬ Epinephrine constricts arterioles in the skin, mucous membranes, and viscera (α effects), and it dilates vessels going to the liver and skeletal muscle (β2 effects). Renal blood flow is decreased. >: o - - Therefore, the cumulative effect is (‫ضغط الدم عند انقباض القلب)فضغط الدم بكون عالي‬ - 1. increase in systolic blood pressure, ↳ - systolic pressure ‫ للقلب بزيد ال‬contractility ‫ل ما زاد ال‬ (‫نه قوه النبضه بتزيد فبزيد ضغط الدم الي بطلع من القلب‬0).... oris epin S's.. 2. a slight decrease in diastolic pressure > - (‫وعيه‬0‫نبساط)بكون الدم با‬0‫ا القلب يكون في حالة ا‬N ‫ضغط الدم‬ - due to β2 receptor–mediated vasodilation in the ‫)كل ما‬peripheral resistance ‫بعتمد على ال‬ ( ‫ بكون ضغط الدم فيهم اقل‬dilated ‫وعيه‬0‫كانت ا‬ I skeletal muscle vascular bed. is epin -si. B21 M ja dilation I two fraction of diastol)‫ )متوسط ضغط الدم(وهو عبارة عن ال‬mean arterials pressure ‫اما ال‬ # ‫(…بكون مرتفع بشكل عام‬+1fraction of systol 5  Blood pressure b - 0 - B cystolic & diastolic 11 & 6  X i.. o =3 -2-19 i Lis heart rate s insid % sis Cystolic I E. - mining heart rate sic 81 sig Is heart I pulse dis - · rate rate B1 so epiness - & diastolic I vasodilation st - 11 - - = vasodilation 7 b. Respiratory: Epinephrine causes powerful bronchodilation Anaphylactic shock by acting directly on bronchial smooth muscle (β2 action). It also inhibits the release of allergy mediators such as histamines from mast cells. 8 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), and a 3. decreased release of insulin (α2 effect). 9 d. Lipolysis: Epinephrine 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. 10 2. Therapeutic uses: a. Bronchospasm: Epinephrine is the primary drug used in the emergency treatment of respiratory conditions when bronchoconstriction has resulted in diminished respiratory function. (wiggins wi-n Thus, in treatment of anaphylactic shock, epinephrine is the drug of choice and can be life saving in this setting. I -i - - - elega si -14 9m -.. -3 14 - - Within a few minutes after subcutaneous administration, respiratory function greatly improves. 11 b. Anaphylactic shock: Epinephrine is the drug of choice for the treatment of type I hypersensitivity reactions (including anaphylaxis) in response to allergens. angioedema 12  ‫‪Types of shock‬‬ ‫)‪ Cardiogenic shock (due to heart problems‬‬ ‫اخطر اشي بصير هو‬ ‫انخفاض الضغط الحاد‬ ‫بالذات عند ا‪N‬رضى الي بعانوا من فشل القلب‪،،،‬حيث هاد النوع من ال‪ shock‬حتقل كمية الدم‬ ‫‪0‬نه معناه وصول الدم‬ ‫الي بتطلع من القلب فالحل نعطي دواء يزيد ال‪heart rate and contractility‬‬ ‫لبعض ‪ vital organ‬رح‬ ‫)‪ Hypovolemic shock (caused by too little blood volume‬‬ ‫يقل واهمها ال‪brain‬‬ ‫مث‪ n‬عند التعرض لنزيف او اسهال او استفراغ لفترة طويله فحيقل كتير حجم السوائل بجسمهم فالحل‬ ‫منعطي سوائل للمريض او نعطيه دم بحاله النزيف يعني هون منفكر بالتعويض فما منحتاج ادويه‬ ‫)‪ Anaphylactic shock (caused by allergic reaction‬‬ ‫)‪ Septic shock (due to infections‬‬ ‫ببلش بالتهاب بالدم بعدين بصير ‪ multiple organ failure‬اهمها انه القلبب‬ ‫ببطل يضخ دم كافي فممكن نعطي كع‪n‬ج ‪dopamine or norepinephrine‬‬ ‫)‪ Neurogenic shock (caused by damage to the nervous system‬‬ ‫‪13‬‬  ‫&‬ ‫تجمع سؤال بال‪mucus‬‬ ‫‪ membrane‬حوال; الع;‬ ‫الحلق واللسان بتضخموا وحتى الشفايف فبختنق ا‪N‬ريض‬ ‫‪E‬‬ ‫‪jji‬‬ ‫‪I‬‬ ‫وطبعا من ا‪0‬عراض ا‪0‬خرى ا‪0‬خطر انه بتتضيق‬ ‫‪:‬‬ ‫القصبات وبصير في هبوط حاد بالضغط‬ ‫وغالبا ا‪0‬شخاص بكونوا عارف; سبب تحسسهم بعد ا‪N‬رة ا‪0‬ولى لذلك غالبا بضل معهم قلم بشبه‬ ‫قلم ا‪0‬نسول; لكن فيه ‪ epinephrine‬بحيث لو اتعرضوا للصدمه التحسسيه عطول ياخدوا الجرعه‬ ‫خ‪n‬ل اقل من دقيقه بتحسن التنفس عندهم لكن ا‪0‬نتفاخ بطول شوي‬ ‫‪14‬‬‫ف‬ c. Cardiac arrest: Epinephrine may be used to restore cardiac rhythm in patients with cardiac arrest. ‫ثن; مع بعض‬0‫ او منعطيهم ا‬Atropine ‫ او‬epinephrine ‫ممكن نعطي بهذه الحالة‬ 15 d. Local anesthesia: lidocaine Local anesthetic solutions may contain low concentrations (for example, 1:100,000 parts) of epinephrine. Epinephrine greatly increases the duration of local anesthesia by producing vasoconstriction at the site of injection. Epinephrine also reduces systemic absorption of the local anesthetic and promotes local hemostasis 16 e. Intraocular surgery pupil of eye 145. I Epinephrine is used in the induction and maintenance of mydriasis during intraocular surgery. 17  3. Pharmacokinetics: Epinephrine has a rapid onset but a brief duration of action (due to rapid degradation). The preferred route for anaphylaxis in the outpatient setting is intramuscular (anterior thigh) due to rapid absorption. In emergency situations, epinephrine is given intravenously (IV) for the most rapid onset of action. It may also be given subcutaneously, by endotracheal tube, and by inhalation. It is rapidly metabolized by MAO and COMT, and the metabolites metanephrine and vanillylmandelic acid are excreted in urine. 18 19  4. Adverse effects: Epinephrine can produce adverse CNS effects that include anxiety, fear, tension, headache, and tremor. It can trigger cardiac arrhythmias, particularly if the patient is receiving digoxin. ‫ لكن في قاعده انه اي‬arrhythmia ‫ج ال‬,‫(يعطى لع‬anti arrhythmia) ‫هو دواء‬ arrhythmia ‫ ممكن يسبب‬arrhythmia ‫ج ال‬,‫دواء يعطى لع‬ Epinephrine can also induce pulmonary edema. 20  Epinephrine may have enhanced cardiovascular actions in patients with hyperthyroidism, and the dose must be reduced in these individuals. ‫شخاص‬N‫ اكثر من عددهم عند ا‬adrenergic receptors ‫ا@رضى الي بعانوا من فرط نشاط في الغده الدرقيه بكون عدد ال‬ ‫زم انقلل الجرعه‬N ‫ اعلى من ا@فروض فاحنا‬effect ‫شخاص رح يادي ل‬N‫فلما نعطي الجرعه الطبيعيه لهدول ا‬،، ‫صحاء‬N‫ا‬ Patients with hyperthyroidism may have an increased production of adrenergic receptors in the vasculature, leading to a hypersensitive response. Inhalation anesthetics also sensitize the heart to the effects of epinephrine, which may lead to tachycardia. ‫ستنشاق يؤدي إلى تحسس القلب‬N‫كما أن التخدير عن طريق ا‬ ‫بينفرين مما قد يؤدي إلى عدم انتظام دقات القلب‬m‫لتأثيرات ا‬. Epinephrine increases the release of endogenous stores of glucose. In diabetic patients, dosages of insulin may have to be increased. Nonselective β-blockers prevent vasodilatory effects of epinephrine on β2 receptors, leaving α receptor stimulation unopposed. This may lead to increased peripheral resistance and increased blood pressure. 21  ‫عند اعطاء ‪:Nonselective β-blockers‬‬ ‫يتم تثبيط مستقب‪,‬ت ال ‪ B2 receptors‬وعليه لن يستطيع ال‪، epinephrine‬عمل‪ vasodilation‬ل‪,‬وعيه‬ ‫الدمويه التي تمد ال‪skeletal muscle‬‬ ‫يستمر نشاط ال‪ a1 receptors‬عن طريق ارتباط ال‪، epinephrine‬ورح يتم تضيق ا‪N‬وعيه الدمويه ‪،‬وبالتالي‬ ‫زياده ال‪ peripheral resistance‬دون معارضه‬ ‫بسبب زياده ال‪ peripheral resistance‬رح يتم زياده ال‪diastolic pressure‬‬ ‫ورح يتم زياده ال‪ systolic pressure‬بسبب زياده ال‪ heart rate‬وال‪contractility‬‬ ‫وزياده ال‪prephral resistance‬‬ ‫اًذا رح يتم ارتفاع ضغط الدم بشكل كبير‬  B. Norepinephrine Because norepinephrine is the neurotransmitter of adrenergic nerves, it should, theoretically, stimulate all types of adrenergic receptors. However, when administered in therapeutic doses, the α-adrenergic receptor is most affected. 22  1. Cardiovascular actions: a. Vasoconstriction: Norepinephrine causes a rise in peripheral resistance due to intense vasoconstriction of most vascular beds, including the kidney (α1 effect). Both systolic and diastolic blood pressures increase Norepinephrine causes greater vasoconstriction than epinephrine, because it does not induce compensatory vasodilation via β2 receptors on blood vessels supplying skeletal muscles. The weak β2 activity of norepinephrine also explains why it is not useful in the treatment of bronchospasm or anaphylaxis. 23 b. Baroreceptor reflex: Norepinephrine increases blood pressure, and this stimulates the baroreceptors, inducing a rise in vagal activity. The increased vagal activity produces a reflex bradycardia, which is sufficient to counteract the local actions of norepinephrine on the heart, although the reflex compensation does not affect the positive inotropic effects of the drug When atropine, which blocks the transmission of vagal effects, is given before norepinephrine, stimulation of the heart by norepinephrine is evident as tachycardia. 24  ‫ا@فروض انه هو بادي لزياده ال ‪heart rate and‬‬ ‫‪ contractility‬وعليه رح يزيد ال ‪systolic pressure‬‬ ‫برضه ال ‪ peripheral resistance‬رح تزيد بسبب زياده‬ ‫التضيق وعليه ‪ diastolic pressure‬رح يزيد‬ ‫لكن الجسم @ا يشوف انه كل هاد زاد رح يصير في ‪ activation of para receptors‬الي‬ ‫موجودين عند القلب وال ‪ aortic arch‬وهدول رح يطلعوا اشارات للدماغ والدماغ رح يعالج هاي‬ ‫ا‪N‬شارات ورح يرسل اوامر لتقليل ال ‪ heart rate‬دون التاثير بال ‪contractility‬‬ ‫فالتاثير كمحصله ‪:‬ال ‪ heart rate‬قل بسبب ال ‪negative feedback‬‬ ‫ال ‪ systolic pressure‬زاد ‪N‬نه ال‪ contractility‬ما تاثرت ضلت زايده وال‬ ‫‪ peripheral resistance‬زاد وعليه برضه ال ‪ diastolic pressure‬زاد‬ ‫طيب بالنسبه لل ‪ peripheral resistance‬هو صح باثر على ال ‪diastolic‬‬ ‫‪ pressure‬لكن برضه اله تاثير على ال ‪ systolic pressure‬ليش؟‬ ‫)الدم يا بكون موجود بالقلب يا با‪N‬وعيه(‬ ‫فلما يكون ال ‪ peripheral resistance‬عالي رح تكون ا‪N‬وعيه متضيقه فسعتها‬ ‫للدم بتكون قليله فرح يرجع الدم للقلب بكميه كبيرة فيعني القلب صار فيه دم كتير‬ ‫فلما ينقبض حيطلع دم كتير فبزيد ال ‪systolic blood pressure‬‬ ‫‪25‬‬  2. Therapeutic uses: Norepinephrine is used to treat shock (septic shock), because it increases vascular resistance and, therefore, increases blood pressure. It has no other clinically significant uses. 26  3. Pharmacokinetics: Norepinephrine is given IV for rapid onset of action. ‫وردة لصغيرة رح‬N‫ فلو اعطيناه با‬very potent vasoconstricted ‫نه يعتبر‬N،، N ‫وردة الكبيره اما الصغيره‬N‫عطاء بكون با‬N‫وا‬ ‫ حيتجمع فيه الدم ويصير غرغرينا‬،،‫ فالعضو الي الوريد الصغير هاد برجع الدم منه للقلب‬collapse ‫يصرله‬ The duration of action is 1 to 2 minutes, following the end of the infusion. It is rapidly metabolized by MAO and COMT, and inactive metabolites are excreted in the urine. 27  4. Adverse effects: These are similar to epinephrine. In addition, norepinephrine is a potent vasoconstrictor and 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. It should not be administered in peripheral veins, if possible. Impaired circulation from norepinephrine may be treated with the α receptor antagonist phentolamine. Alternatives to phentolamine include intradermal terbutaline and topical nitroglycerin -g ‫وعيه الدموية‬N‫قه بهاد ا@ستقبل لكن بسبب توسع با‬,‫او ممكن نعطي دواء ما اله ع‬ 28  blanching & Edem 29  C. Isoproterenol Isoproterenol is a direct-acting synthetic catecholamine that stimulates both β1- and β2-adrenergic receptors. Its nonselectivity is one of its drawbacks and the reason why it is rarely used therapeutically. Its action on α receptors is insignificant. Isoproterenol produces intense stimulation of the heart, increasing heart rate, contractility, and cardiac output. It is as active as epinephrine in this action. 30  Isoproterenol also dilates the arterioles of skeletal muscle (β2 effect), resulting in decreased peripheral resistance. Because of its cardiac stimulatory action, it may increase systolic blood pressure slightly, but it greatly reduces mean arterial and diastolic blood pressures. Isoproterenol is a potent bronchodilator (β2 effect). The adverse effects of isoproterenol are similar to those of epinephrine. 31  ‫هسا بسبب نشاط الدواء على ال ‪ B2‬ادى الى زياده بال‬ ‫‪vasodilation‬‬ ‫و‪N‬نه ما في نشاط لل ‪ a1‬ما في انقباض ليعادل هاد ال‬ ‫‪vasodilation‬‬ ‫وعليه ال ‪ peripheral resistance‬رح تكون قليله ‪،،‬اقل حتى‬ ‫من تاثير ال ‪epinephrine‬‬ ‫وعليه برضه ال ‪ diastolic pressure‬رح يقل‬ ‫وحكينا هاد الدواء يادي الى زياده ال ‪heart rate and‬‬ ‫‪ contractility‬بسبب نشاط ال ‪.. B1‬فيعني في زياده‬ ‫على ال ‪systolic pressure‬‬ ‫وبرضه ال ‪ pulse pressure‬حتزيد‬ ‫‪32‬‬  D. Dopamine Dopamine, the immediate metabolic precursor of norepinephrine, occurs naturally in the CNS in the basal ganglia, where it functions as a neurotransmitter, as well as in the adrenal medulla. Dopamine can activate α- and β-adrenergic receptors. For example, at higher doses, it causes vasoconstriction by activating α1 receptors, whereas at lower doses, it stimulates β1 cardiac receptors. In addition, D1 and D2 dopaminergic receptors, distinct from the α- and β- adrenergic receptors, occur in the peripheral mesenteric and renal vascular beds, where binding of dopamine produces vasodilation. epinephrine ‫فكمية الدم الي بتوصل الكلى بتكون منيحة فبهاي النقطه هو احسن من ال‬ ‫ يستخدم لهذا الغرض‬N ‫ لكن حاليا‬renal protective effect ‫فكانوا زمان يعتبروا انه اله‬ D2 receptors are also found on presynaptic adrenergic neurons, where their activation interferes with norepinephrine release. ‫فارتباط‬،،،، ‫ لهدف التثبيط‬pre‫ الي بكون على ال‬a2 and muscarnic receptors ‫مثل ال‬ presynaptic of dopaminergic neuron ‫ الي على ال‬D2 receptors ‫ بال‬dopamine‫ال‬ 33 norepinephrine‫ بقلل تحرير ال‬adrenergic receptors ‫ وبال‬dopamine‫بقلل تحرير ال‬ 1. Actions: a. Cardiovascular: Dopamine exerts a stimulatory effect on the β1 receptors of the heart, having both positive inotropic and chronotropic effects. At very high doses, dopamine activates α1 receptors on the vasculature, resulting in vasoconstriction. 34 b. Renal and visceral: Dopamine dilates renal and splanchnic arterioles by activating dopaminergic receptors, thereby increasing blood flow to the kidneys and other viscera. These receptors are not affected by α- or β- blocking drugs. In the past, low-dose (“renal-dose”) dopamine was often used in the prevention or treatment of acute renal failure. However, more recent data suggest there is limited clinical utility in the renal protective effects of dopamine. 35  2. Therapeutic uses: Dopamine can be used for cardiogenic and septic shock and is given by continuous infusion. It raises blood pressure by stimulating the β1 receptors on the heart to increase cardiac output and α1 receptors on blood vessels to increase total peripheral resistance. It enhances perfusion to the kidney and splanchnic areas. 36  Increased blood flow to the kidney enhances the glomerular filtration rate and causes diuresis. ‫ بزيد‬diuresis ‫ اكتر وعليه ال‬filtration ‫كل ما كان كميه الدم الي بتوصل للكلى اكتر معناها ال‬ ،،،، ‫ فيزيد وصول الدم للكلى‬vasodilation ‫ بعمل‬dopamine ‫وبما انه ال‬ By contrast, norepinephrine can diminish blood supply to the kidney and may reduce renal function. Dopamine is also used to treat hypotension, severe heart failure, and bradycardia unresponsive to other treatments. 37  3. Adverse effects: An overdose of dopamine produces the same effects as sympathetic stimulation. Dopamine is rapidly metabolized by MAO or COMT, and its adverse effects (nausea, hypertension, and arrhythmias) are, therefore, short-lived. ‫عراض‬N‫ السريع برضه ا‬degradation ‫دام بتوقف مفعوله بسرعه بسبب ال‬ ‫الجانبيه رح تنتهي بسرعه‬ 38 Thank you 39