Adrenergic & Antiadrenergic Drugs By Prof. Alhaider

Adrenergics & Antiadrenergics  Anatomy of the sympathetic nervous system  Neurotransmission at adrenergic neurons  Adrenoceptors  Adrenergic Drugs  Centrally-acting sympatholytic drugs

Anatomy of the sympathetic nervous system  The origin is from thoracolumbar segments “ all thoracic + lumbers L1, L2, L3 and L4 ”  They have short preganglionic fibers, and it relays in sympathetic chain ganglia & release Ach in these ganglia  They have long postganglionic fibers that innervate their body organs & release Norepinephrine as a neurotransmitter there

Neurotransmission at adrenergic neurons Synthesis of NE Storage of DA and NE in vesicles Release of NE Metabolism (COMT 20% + MAO 80%) Binding to receptors Uptake mechanism

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Adrenoceptors  The adrenergic receptors are classified into α1 α2 β1 β2 β3  There are some subtypes

α 1 – Adrenoceptors  Mechanism of action  Site of α 1 – adrenoreceptor & the effects of their stimulation  Drugs effects at these receptors

Molecular Mechanism of Action of Sympathomimetics

α 1 – adrenoceptors (continue) Site of α 1 – adrenoceptors & the effects of their stimulation  In vascular smooth muscle. α 1 stimulation cause VC :  Vasoconstriction in the skin & viscera cause increase TVR causing increase BP α1 – adrenoreceptorare the most determine of arteriolar tone. When their stimulated no others receptors have an affects on BP. So, hypertension may be treated by blocking α1  Vasoconstriction in the nasal blood vessels cause relief congestion  In the radial muscle of iris. α1 stimulation causes contraction of the radial muscle causing mydriasis (dilation of the pupil)

Cont ….  In the smooth muscle of the sphincters of GIT. α1 stimulation cause contraction of all sphincters. opposite to ACH In the smooth muscle of internal sphincter of urinary bladder (Very important). α 1a subtypes stimulation cause contraction and closure of the sphincters (ppt urinary retention) opposite to ACH  In the seminal vesicles. (with α 2 ) α stimulation cause ejaculation. Thus, all α blockers inhibit ejaculation  In the liver. α1 stimulation causes increase glycogenolysis & gluconeogenesis  In the fat cells. α1 stimulation causes increased lipolysis

Adrenoceptors α 1 – adrenoceptors Drugs effects :  α 1 selective agonist E.g.  Phenyl ephrine  α1 selective antagonists E.g.  Prazosin  Terazosin  Doxazosin  Tamsolusin ( α 1a ) (has a different clinical use)

α 2 – adrenoceptors  Mechanism of action  Site of α 2 – adrenoreceptors & the effects of their stimulation  Drugs effects at these receptors

Molecular Mechanism of Action of Sympathomimetics

α 2 – adrenoceptors Mechanism of action  α 2 stimulation leads to either Decreased adenylyl cyclase activity.  Lead to decrease cAMP causing decrease NE release causing relaxation of smooth muscle & decreased glandular secretion Increase K+ - channel activity.  This is mediated by the inhibitory regulatory Gi protein What is the main difference between α1 and α2 adrenoceptors?

α 2 – adrenoceptors Site of α 2 – adrenoceptors & the effects of their stimulation  In adrenergic nerve terminals (presynaptic). α 2 stimulation cause decreased Norepinephrine release (autoregulatory mechanism). Very important effect Why?  In pancreas. causes decreased insulin release  In platelets. Increase platelets aggregation via c-AMP  In liver (same as α 1 – adrenoceptors)  Fat cells (same as α 1 – adrenoceptors).

Cont …  In ciliary epithelium. Increase the out flow of aqueous humor. Is it good for glaucoma or not?. In the smooth muscle of GIT wall. (with β 2 ) α 2 stimulation cause relaxation of the wall causing decreased peristalsis (This is attributed to decrease in ACH release)

α 2 – adrenoceptors (Continue) Drugs effects :  α 2 selective agonists E.g.  Clonidine; Methyldopa (Antihypertensive)  α 2 selective antagonists E.g.  Yohimbine; Mertazapine (Antidepressant)  Apraclonidine (Topical for Eye)

β 1 – adrenoceptors  Mechanism of action  Site of β 1 – adrenoreceptors & the effects of their stimulation  Drugs effects at these receptors

Molecular Mechanism of Action of Sympathomimetics

Adrenoceptors β 1 – adrenoceptors Site of β 1 – adrenoceptors & the effects of their stimulation  In the heart. β 1 stimulation causes  In S.A node : increase HR (+ve chronotropic)  In Myocardium tissue : increase contractility (+ve inotropic)  In Conducting system : increase conduction velocity (+ve dromotropic)  Increase ectopic beats  In the Juxtaglomerular Apparatus of the kidney. β 1 stimulation cause increased renin release. Then causes increase in BP  In fat cells (with α1, α2 & β 3) β 1 stimulation causes increased Lipolysis  In fat cells (with α1, α2 & β 3)

Adrenoceptors β 1 – adrenoceptor Drugs affecting them  β 1 selective agonists E.g.  Dobutamine  β 1 selective antagonists E.g.  Atenolol  Esmolol  Metoprolol

β 2 – adrenoceptors  Mechanism of action  Site of β 2 – adrenoreceptors & the effects of their stimulation  Drugs affecting these receptors

Molecular Mechanism of Action of Sympathomimetics

β 2 – adrenoceptor Site of β 2 – adrenoceptor & the effects of their stimulation  In the bronchial smooth muscle (very important clinically). β 2 stimulation causes relaxation of smooth muscle (bronchodilatation)  In the smooth muscle of blood vessels supplying the skeletal muscle. β 2 stimulation causes relaxation of smooth muscle (Vasodilatation)  This VD effects is usually masked by the potent VC effect of α1 – receptors

Cont ….  In the smooth muscle of GIT wall. β 2 stimulation cause relaxation of the wall leading to decreased peristalsis  In the smooth muscle of the wall of urinary bladder. β 2 stimulation causes relaxation of the wall (opposite to ACH) Note: Adrenergic stimulation is opposite to the cholinergic in the wall and sphincters in GIT and GUS.

Cont ….  In the smooth muscle of the uterus β 2 stimulation causes relaxation of the uterus So, β 2 agonists  In the liver. β 2 stimulation causes increased Glycogenolysis & Gluconeogenesis  In the pancreas. β 2 stimulation causes slight increase in insulin secretion Then, what is the effect of β 2 stimulation on blood sugar?  Effect on potassium. β 2 stimulation increase potassium influx. Useful Clinically

Cont ….  In ciliary muscle. β 2 stimulation causes relaxation of the ciliary muscle leading to  Accommodation for far vision  Decrease outflow of aqueous humor via the canal of Schlemm  In the ciliary epithelium β 2 stimulation causes increased production of aqueous humor Can we use b-adrenergic agonists for glaucoma?

Adrenoceptors β 2 – adrenoceptors Drugs affecting them  β 2 selective agonists E.g.  Salbutamol  Salmetrol  Terbutaline  Ritodrine  Formetrol  β 2 selective antagonists E.g.  ICI (still under investigation)

1 and 2 – adrenoceptor agonists Mechanism of action  β stimulation causes increase adneylyl cyclase activity leading to increase cAMP leading to cellular effect. E.g. β 1 in the heart cause increase c-AMP leading to increased intracellular Ca ++ release leading to increased contractility β 2 in smooth muscle cause increase cAMP leading to inhibition of myosin kinase enzyme causing relaxation β 2 in the liver cause increase in cAMP leading to increased Glycogen phosphorylase enzyme activity causing increased glycogenolysis

β 3 – adrenoceptors  Site of β 3 – adrenoceptors & the effects of their stimulation  Drugs affecting them  Mechanism of action

Adrenoceptors β 3 – adrenoceptors Site of β 3 – adrenoceptors & the effects of their stimulation  In brown adipose tissue β 3 stimulation causes increased Lipolysis

Adrenoceptors β 3 – adrenoceptors Drugs affecting them  β 3 selective agonist E.g.  BRL  β 3 selective antagonist E.g.  CGP 20712A

Adrenergic Drugs  Adrenoreceptor Agonists Non selective Selective  Adrenoreceptor Antagonists α – blockers β – blockers

Adrenoceptor Agonists I. Non selective drugs  These drugs include  1) Catecholamine Drugs A. endogenous:  Norepinephrine  Epinephrine  Dopamine b) Synthetic (exogenous)  Isoprenaline 2) Non-catecholamine Drugs Amphetamine Ephedrine Pseudo ephedrine Phenylpropranolamine What are the differences between catechoamines and non-catecholamines?

Norepinephrine (Noradrenaline)  Introduction  Synthesis  Metabolism of NE  Pharmacokinetics

Norepinephrine Introduction  NE is a neurotransmitter released from the postganglionic sympathetic fiber in most organs  It also released from the adrenal medulla (20% of medulla secretion)  It is a direct non – selective adrenergic agonist which acts on all adrenoceptors, Except β2

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Cont ….  Sites of metabolism In adrenergic nerves  80% by MAO in presynaptic nerve terminals after reuptake (This is very important clinically) If MAO is inhibited, NE will be reuptake but not metabolized, leads to release of NE again  15% by COMT in postsynaptic membrane (This is not important clinically)  5% reach the blood and metabolized In the Liver

Norepinephrine Pharmacokinetics  T 1/2 of NE = 2 – 3 min Very short because it has rapid metabolism  NE causes increased SBP & DBP So, in shock, it will increase BP  Why NE cannot be given orally?

 Clinical Uses:  Note: NE is not commonly used in clinical practice like Epinephrine, However it can be used in: Cardiac Arrest Shock

Epinephrine (Adrenaline)  Introduction  Synthesis (Methylated form of NE)  Therapeutic uses

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Epinephrine Introduction  EP is released from adrenal medulla 80% and in certain areas of the brain  EP is a direct acting non-selective adrenergic agonist in all receptors including β 2 receptor.  T 1/2 = 2 – 5 min  Like NE, It is given parenterally (SC, I.V and I.M) not orally  Does PK of Epinephrine different from NE?

Epinephrine Therapeutic use  Epinephrine is commonly used in practice as compared to NE.  In bronchial asthma It is given SC to act on β2 receptors to cause bronchodilation Now it is not commonly used because of its side effects (tachycardia and arrhythmia)  In cardiogenic shock It is given I.V to increase SBP, BP, HR and CO  In anaphylactic shock It is given SC to act on  α1 cause VC, lead to increase BP & relief of congestion  β 1 cause increase HR leading to increase CO, so, increase BP  β 2 cause bronchodilation so, relieve bronchospasm What are the main differences between Epinephrine and NE? b

Cont …  In cardiac arrest (for Bradycardia) It is given I.V. if there is no response, EP given directly into the lung, and if there is no response, it given intracardially, and if there is no response, direct current is applied for 3 times at most  During surgery EP is added to the local anesthetic to cause VC in the surgery area in order to  Decrease bleeding  Decrease the amount of local anesthetic which will reach the systemic circulation. Therefore, it will decrease the cardiodepressant effect of the local anesthetic

Iso pre naline  Introduction  Actions  Therapeutic uses

Iso pre naline Introduction  It is directly acting synthetic adrenoreceptor agonist acting only on β – receptors, with no effects on  adrenoceptos.  T 1/2 = 5 – 7 min  Like all catecholamines, It is given parenterally (not orally) The I.V must be given carefully because the overdoses cause cardiac arrest

Iso pre naline Action  Isoprenaline will stimulate β 1 in the heart to cause  Increased HR & cause arrhythmia & may lead to cardiac arrest β 2 in the blood vessels to cause  VD leads to decreased BP (mainly DBP) It has no effects on α receptors

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Isoprenaline Therapeutic uses:  It is no longer used to treat the bronchial asthma because of it ’ s side effects on the heart  It ’ s only used now to reverse the heart block which is produced by overdoses of β – blockers N.B. cardiac arrest means : complete cessation of heart ’ s activity. While heart block means : partial or complete inhibition of the spread of conduction of the electrical impulse from the atria to the ventricles

Effects of I.V. infusion of Epinephrine, Norepinephrine & Isoprenaline in Humans

Dopamine  DA is a non – selective adrenergic agonist, which acts either directly on DA – receptors in addition to  1 - adrenergic receptors or indirectly by releasing NE  Like all catecholamines, It is given parenterally only (not orally)  It doesn ’ t cause tolerance  T 1/2 = 3 – 5 min  Metabolized by either Converted to NE in adrenergic neurons or By MAO in the Liver

Dopamine (Cont … )  Clinical Uses : In small dose of DA (=< 5ug / Kg / min by I.V infusion) Renal dose:  It will stimulate DA – receptors only It will cause vasodilatation (VD) in:  Renal vascular bed  Cerebral vascular bed  Coronary vascular bed  Mesenteric vascular bed Therefore, it is useful in treatment of shock to save these vital organs from hypoxia (also see Dobutamine) N.B : At higher doses, VD effect of DA – receptors is masked by the VC effect of α1 – receptors

Cont …. In medium dose : (5-15ug/Kg/min by I.V infusion) Cardiac dose  It will stimulate β1 – receptors to cause increase HR, CO and BP In high dose of DA (> 15ug / Kg / min by I.V infusion)  It will stimulate α1 receptors (direct + Via release of NE) to cause VC leading to increase BP and decrease organ perfusion So, the high dose of DA is not recommended in shock.

 What is the effect of Dopamine on Bronchioles?

Centrally Acting Sympathomimetic Agents: e.g: 1. Amphetamine  Introduction  Clinical uses  Side – effects

Amphetamine Introduction  It is non-selective adrenergic agonist, non- catecholamine Acts mainly, indirectly via enhancing NE release and DA. Since it is non-catecholamine, it can be given orally It is lipid – soluble enough to be absorbed from intestines and goes to all parts including CNS (This leads to CNS stimulation like Restlessness and Insomnia). t 1/2 = 45 – 60 min (long duration of action) It is metabolized in the Liver

Clinical use of Amphetamine-like drugs  To suppress appetite In very obese persons Amphetamine can act centrally on the hunger center in the hypothalamus to suppress appetite  In narcolepsy Narcolepsy is irresistible attacks of sleep during the day in spite of enough sleep at night Amphetamine stimulates the CNS & make the patient awake  In ADHD “ Attention Deficit Hyperactivity Disease ”

Clinical use of Amphetamine-like drugs (controlled Drugs)  Note: Amphetamine is a drug of abuse, that should not be prescribed. However, amphetamine-like drugs can be prescribed for the following conditions:  In ADHD “ Attention Deficit Hyperactivity Disease: (Methylphenidate, Dexamfetamine)  In narcolepsy Narcolepsy is irresistible attacks of sleep during the day in spite of enough sleep at night Amphetamine-like drugs stimulats the CNS & make the patient awake (Dexamfetamine and Modafinil)  To suppress appetite In very obese persons Amphetamine can act centrally on the hunger center in the hypothalamus to suppress appetite (Considers as obsolete use)

Amphetamines Side effects  The side effects are due to chronic use  These include : Tolerance Dependence Addiction Paranoia جنون العظمة Psychosis انفصام الشخصية Hypertension

2. Ephedrine  It is non selective adrenergic agonist  It Directly acts on the receptors (and 2) Indirectly by releasing NE PK almost similar to amphetamine It causes tolerance but no addiction Like amphetamine, it is CNS and respiratory stimulants. It does not suppress the appetite Why?

Ephedrine Clinical uses:  Pressor agent  Decongestant  It is no longer used to treated bronchial asthma. Why?

3. Pseudoephedrine:  Has similar pharmacological activities to ephedrine  It is not controlled : OTC (over the counter) يباع بدون وصفة طبية

4. Phenylpropranolamine:  Again it is similar to pseudoephedrine, and was used as decongestant, but it was stopped because it may cause cerebral hemorrhage

Side – effects of centrally acting sympathomimetics:  Sympathomimetic means : These drugs can produce sympathatic actions similar to EP and Nor EP  They include: Amphetamine Ephedrine Pseudo ephedrine Phenyl Pro Pranolamine  They are lipid – soluble and can pass BBB to cause Insomnia Restlessness Confusion Irritability Anxiety Loss of appetite Hypertension  Amphetamine has additional side effect see slide 57see slide 57

Adrenoreceptor Agonist Selective drugs  These drugs include : Phenyl Ephrine relatively α1 – agonist Clonidine α2 – agonist Dobutamine β 1 – agonist Salbutamol β 2 – agonist Ritodrine β 2 – agonist

Adrenoreceptor Agonists 1. Phenyl Ephrine (others: methoxamine, metaraminol, mephentermine  Introduction  Metabolism  Clinical uses

Adrenoreceptor Agonists 1. Phenyl Ephrine  It is relatively selective α 1 – agonist  It is directly acting  PK: not-catecholamine and thus not metabolized by COMT  It has longer duration of action than other catecholamines  Uses: see next 

Phenylephrine Clinical uses:  As a mydriatic agent to examine the fundus of the eye It acts on α1 – receptors in the radial dilator pupillary muscle  As a decongestant Used as nasal drops to cause VC in the nasal blood vessels & relief congestion  As a vasopressor agent in case of hypotension α1 stimulation causes VC leading to increase BP  In case of paroxysmal tachycardia It cause VC & elevate BP. This stimulate the baroreceptors resulting in increased reflex vagal discharge which brings the heart into the normal sinus rhythm (not used any more)

Adrenoreceptor Agonists (Cont … ) 2. Clonidine:  It is α 2 – selective agonist  However, this is sympatholytic agent, used in treatment of hypertension It acts centrally at presynaptic α 2- adrenoceptor. This leads to decrease in NE release and to decrease in TVR. Note: Although it is adrenergic agonist, clonidine acts as a central sympatholytic drug.

 3. Apraclonidine (Like clonidine it is selective alpha 2 adrenoceptor agonist, however, main uses as adjuvant therapy for glaucoma via decrease of aqueous humor formatiom What is methyldopa and does it differ from clonidine?

Adrenoreceptor Agonists (Cont..) 4. Dobutamine:  It is direct acting β 1 – selective agonist (only)  T1/2 = 10 – 15 min  It is metabolized in the liver by oxidative deamination  There is tolerance to its action  Given only parenterally (not orally)  It causes increases in CO with minimal effect on HR. Why?  It has less arrhythmogenic effects than dopamine  Uses: Inotropic agent for Heart Failure; in septic and cardiogenic shock. Can you make comparison between Dopamine and Dobutamine?

Adrenoreceptor Agonists 5. Salbutamol:  It is β 2 – selective agonist  Can be used orally, IV and by inhalation  Clinical Uses  Formulations: (Tablets; Syrup; Injection; solution and Inhalation) bronchial asthma by β 2 stimulation, which leads to relaxation of bronchial smooth muscle and bronchodilation. Treatment of refractory hyperkalemia (I.V)

6 Salmetrol and Formoterol: These selective beta agonists, have longer duration of action as compared to Salbutamole. Uses: As inhalors for B. Asthma

Adrenoreceptor Agonist 7. Ritodrine:  It is another β2 – selective agonist but  It is used to delay premature labour β 2 stimulation leads to relaxation of uterine smooth muscle leading to delay of labour  This is done to ensure adequate maturation of foetus

Adrenoreceptor Agonists Side – effects of sympathomimetic drugs:  On the CVS Hypertension Cardiac arrhythmia Myocardial infarction Increased severity of angina pectoris and of myocardial infarction  On the eye Increased I.O.P leading to Glaucoma  On the CNS See slide 64

Glaucoma  a disease of the eye characterized by increased intraocular pressure and excavation and atrophy of the optic nerve; produces defects in the visual field and may result in blindness.

Clinical applications of Sympathomimetic drugs  In hypotensionhypotension we use Phenyl Ephrine  In shock Type of shock include  Hypovolamic shock  Septic shock  Anaphylactic shock Symptoms include  Congestion in the Lung, Heart & Kidney due to VD & V.Per  Bronchoconstriction  Hypotension We use EP with steroid and antihistamine to cause  Bronchodilation  Increase BP  Decongestant  Neurogenic shock  Cardiogenic shock We use DA & Dobutamine together All type lead to increases in BP

Cont ….  To reduce BF in certain organs We use Adrenaline with local anesthetic for minor surgery in order to  Decrease bleeding  Prevent spread of local anesthetic into systemic circulation  In paroxysmal tachycardiaparoxysmal tachycardia  In bronchial asthmabronchial asthma  In cardiac arrestcardiac arrest  For mydriasismydriasis  For delaying of labordelaying of labor  For hyper kinetic children syndromehyper kinetic children syndrome  For narcolepsynarcolepsy

Adrenoreceptor Antagonists  α – blockers Non selective Relatively selective Selective  β – blockers Non selective Relatively selective Selective