Adrenergic receptors lec 9, part 2. 16/10/2014 Dr. Laila M. Matalqah Rama Kamal Ali Treany

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1 Adrenergic receptors lec 9, part 2 16/10/2014 Dr. Laila M. Matalqah Rama Kamal Ali Treany

2 Pharmacology of ANS Adrenergic Agonists Adrenergic receptors:- - It is a receptor which is located in the peripheral nervous system specifically in sympathetic, between the post ganglionic and the effector organ. - The main neurotransmitters are epinephrine and norepinephrine. Mechanism of Neurotransmission Like acetylcholine, norepinephrine is synthesized and released into the synaptic space. 1) Synthesis of norepinephrine:- Norepinephrine is synthesized from Tyrosine as a precursor. The tyrosine is converted to DOPA and then to Dopamine. Tyrosine DOPA Dopamine. 2) Uptake of Dopamine into storage vesicles. Dopamine is then transported into synaptic vesicles, Inside the vesicles Dopamine will be changed into norepinephrine. Dopamine Norepinephrine. (Completes the synthesis) 3) Release of neurotransmitter: Influx of Ca +2 causes fusion of the vesicle with the cell membrane in a process known as exocytosis, releasing the neurotransmitter into the synaptic cleft.

3 4) Binding to receptor: Postsynaptic receptor (adrenergic receptor) is activated by the binding of the neurotransmitter (norepinephrine). 5) Going back to the presynaptic receptors: Norepinephrine also goes back to the presynaptic receptors causing feedback inhibition of the release, so there is less action. 6) Metabolism: Norepinephrine is metabolized and inactivated by two enzymes (COMT and MAO) which are inhibitors to the action. Then the produced inactive substance will be removed by urine. Norepinephrine in the synaptic space Bind to the Postsynaptic receptor and make the action. Go back to Presynaptic receptors and inhibit the action. Metabolized by COMT and MAO and inhibit the action.

4 Drugs effecting the Synthesis and Release: Reserpine Step 2 Transport of Dopamine into vesicles is inhibited by Reserpine. Reserpine Causes Norepinephrine (That s why we use Reserpine for Hypertension) Guanethidine Step 3 Release of norepinephrine from vesicle to postsynaptic space is inhibited by Guanethidine. - Inhibition of COMT and MAO by some drugs causes more action of norepinephrine. COMT Catechol-O-Methyltransferase MAO Monoamine Oxidase Isoproterenol We have a neurotransmitter called isoproterenol. It makes the same action like epinephrine and norepinephrine but it is not so common. That's why the doctor didn t focus on it.

5 Adrenergic receptors (adrenoceptors) - Two types of receptors can be distinguished pharmacologically α and β. α Adrenoceptors: They have high affinity for epinephrine and low affinity for norepinephrine. Epinephrine Norepinephrine» Isoproterenol. The α adrenoceptors are subdivided into two subgroups α 1 and α 2.

6 ص α 1 - They are found in the postsynaptic membrane of the effector organs (make more action), That s why It s considered the main (more important) receptor. -They make vasoconstriction. - Smooth muscles have just sympathetic innervations (no parasympathetic). So, α 1 makes vasoconstriction, increases peripheral resistance, and increases blood pressure. - when I want to decrease blood pressure (as in hypertension case) I use α 1 blockers. - α 1 blocker prazosin. It treats high blood pressure by stopping vasoconstriction and making vasodilation (α1 antagonist). - mydriasis (a dilation of the pupil): Atropine can do mydriasis So, the adrenergic can do mydriasis. (The same as anticholinergic). - increased closure of internal sphincter of the bladder. This - means less urination (as anticholinergic).

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8 α 2 - α 2 receptors are located on presynaptic nerve endings, and have an inhibitory effect (stops action). - A portion of the released norepinephrine circles back" and reacts with α 2 receptors of the presynaptic membrane, stimulation of α 2 does feedback inhibition and stops the release of The norepinephrine and stopping the action caused by α 1 stimulation. (Homeostatic Job) α 1 is the main one and does the action. α 2 Its job is to inhibit regulate α 1 action. Nonselective and selective drugs - some blockers can affect α1 and α2 receptors (they are called nonselective drugs). - the most useful drugs are those which affect only one type of receptors (selective drugs). They have less side effects. example: an agonist drug blocks α1 and α2 receptors, so, it inhibits the - release of insulin and leads to hyperglycemia, so, the doctor should be careful when he gives such drugs to diabetes patient. β adrenoceptors: These receptors are characterized by strong affinity to - isoproterenol. Isoproterenol epinephrine norepinephrine.

9 The β adrenoceptors can be subdivided into three major subgroups,β1,β2,β3. β 1 and β 2 - β 1 and β 2 are found everywhere in the organs but there are more β 1 receptors in cardiac muscles and more β 2 receptors in smooth muscles which are near the blood vessels. Bronchodilation Bronchioles are air passageways (tubes) that have smooth muscles, when these smooth muscles relax this tube become bigger (dilates) Bronchodilation- and more air can become in, Giving you more Air and oxygen for every single breath you take. -When these smooth muscles contract The tube becomes smaller (constricts) and less air can come in -Bronchoconstriction- as in asthmatic patients.

10 β 1 - it is stimulated during fight and flight (in stress) more sympathetic. leading to more contractility of the heart, more heart rate, and more blood pressure. - Positive inotropic effect (more muscle contraction) and positive chronotropic effect (increase heart rate). - It increases Renin, an enzyme which is found in the kidney, it converts the angiotensin I to angiotensin II (a vasoconstrictor), so the renal blood flow decreases and there is less urine output, the kidney will be damaged (this process is bad for the kidney). also, this increases the total peripheral resistance and blood pressure Stimulation of the Renin enzyme is an indirect mechanism to do vasoconstriction. β 2 stimulation of β 2 receptors produces vasodilation and reduces the blood pressure. Also, it can cause bronchodilation. what does β2 agonist do?- 1- Makes bronchodilation during asthma. 2- Makes vasodilation during hypertension. 3- Glycogenolysis (breakdown of glycogen to glucose) + increases glucagon release More blood glucose (might cause hyperglycemia). 4- Relaxation of uterine smooth muscles (enhance urine delivery) β 3 - This receptor acts in metabolism of the lipids. so, it is involved in lipolysis. -β3 is not so important in therapeutic and we will not focus on it. Lipolysis:- the lipids (triglyceride) is converted to fatty acids and glycerol.

11 Summery of receptors:-

12 Adrenergic Agonists We classify adrenergic agonists depending on their chemical structure into: 1) Catecholamines:- Such as epinephrine, norepinephrine, isoproterenol, dopamine. - These drugs share the same chemical structures and Characteristics which are: - High potency to α and β receptors. (High potency means that you can give a small dose and have high action) - Rapid inactivation: metabolized by COMT and MAO. (Short duration of action) - Poor penetration into the CNS (BBB) Because of their polarity. So they can't act on the brain. *Epinephrine, norepinephrine are Neurotransmitters, they can also be made outside the body and given as drugs.

13 2) Noncatecholamines: - They include phenylephrine, ephedrine, and amphetamine. - Less potency to α and β receptors. - They are not inactivated by COMT and MAO.(have longer half life) - Greater Penetration to the CNS (BBB) Because they re more lipophilic. Amphetamine Can penetrate into the CNS by the BBB, it s used to treat Attention Deficit Hyperactivity disorder (ADHD) in children. It leads to addiction because it is CNS stimulus. #ممنوعات: دوا بفیدك بالامتحان وبساعد على زیادة التركیز ولازم تاخد 8mg منو بس مشكلتو بعمل ادمان وعشان تشتریھ من الصیدلیھ لازم یوصفلك الطبیب صعوبة تعلم ونقص تركیز. بس اصرفو اذنك شاطر :p ھ ملوا النیردات -_- There are three Courses of action For Adrenergic Agonists: Direct binds to the postsynaptic receptors. (Acts like a Neurotransmitter) Indirect enhances the release Of Norepinephrine from vesicles. (Strengthens the Neurotransmitter) Mixed Can both enhance releasing of Norepinephrine and bind to the receptors.

14 Direct-Acting adrenergic agonists: Epinephrine: The dose is 1:100,000 so one unit of epinephrine will be diluted in one hundred thousand units because epinephrine is very small molecules. But ephedrine, phenylephrine, and amphetamine should be taken by microgram and milligram. Epinephrine action : Epinephrine is not a selective drug (acts on all receptors).

15 In medicine we have 4 therapeutic uses for epinephrine:- 1- For cardiac arrest in emergency, a dose of epinephrine should be taken to stimulate cardiac muscles and increase heart rate. 2- Anaphylactic shock.(allergic Shock) Because Allergic shock causes Bronchoconstriction And a drop in Blood pressure. Epinephrine is given to do Bronchodilation and Raise Blood pressure back to normal. 3- Treatment of acute asthma: Because Epinephrine is a bronchodilator. 4-Anesthetics: Allergy = release of Histamine For local anesthetic solutions (in certain sites of the body) usually contain 1:100,000 parts epinephrine which helps in vasoconstriction to greatly increase the duration of local anesthesia. (The epinephrine holds the anesthetic solution in its location to make more action).

16 Norepinephrine - Norepinephrine is more selective to α 1 receptor. So, it can cause more vasoconstriction than epinephrine. Norepinephrine α1. Epinephrine β1, β2, α1, α2. it increases Systolic and Diastolic pressure. Norepinephrine can't be used for hypertension Or asthma because of the weak activity on β2 receptors. (It Does vasoconstriction only and increases Blood pressure) It is used for Cardiac shock. Shock decrease in blood pressure. It has 3 types: cardiogenic shock, septic shock, and hypovolemic shock. Dopamine Cardiogenic shock Means the heart can't contract, with less ejection of blood by the heart, the blood pressure decreases to treat cardiogenic chock there are many choices such as epinephrine and dopamine. The doctor prefers to use dopamine, why? Because there is a side effect of epinephrine which is the action of renin on the kidney (decreases blood flow to the kidney -vasoconstriction- and decreases the urine output, damaging the kidney). But dopamine Stimulates β1 receptors of the heart, (having both inotropic and chronotropic effects) and it doesn't have β1 activation of Renin, instead Dopamine activates dopaminergic receptors, which increase blood flow to the kidney and protect it. Notes:- Patients with cardiac problems often have kidney problems.

17 Albuterol, terbutaline, salmeterol, formoterol - β2 agonists used primarily as bronchodilators and administered by inhaler for treatment of asthma. Indirect- Acting adrenergic agonists: They cause more release of epinephrine from synaptic vesicles, Or inhibit It s uptake by presynaptic Neuron (inhibit the inhibition). Amphetamine - can cross the BBB (It s a stimulant of the CNS) - Increases blood pressure significantly by α 1 activation. - β-stimulatory effects on the heart. - Used for treating hyperactivity in children. الي قبل شوي حكینا عنو اصرفو اذا بتقدر! Mixed Action adrenergic agonists: Ephedrine and pseudoephedrine - Release stored norepinephrine from nerve endings. - Directly stimulate both α and β receptors. They are used as Nasal decongestants. α1 agonists that constricts the nasal mucosa (Nasal airway becomes wider). Actifed better than alerfin for blood flow because Actifed has pseudoephedrine. Pharmacology Of ANS part 2 Slides 1 to 24 التفریغ یحتوي على كل شرح الدكتورة مع السلایدات

18 اللي بلاقي غلط تراني أفق ع وجھھ ಠ_ಠ

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