Adrenergic Receptors and DrugsBy: Naghman Zuberi Adrenergic receptor The adrenergic receptors (or adrenoceptors) are a class of G protein-coupled receptors that are targets of the catecholamines, especially norepinephrine (noradrenaline) and epinephrine (adrenaline). Many cells possess these receptors, and the binding of a catecholamine to the receptor will generally stimulate the sympathetic nervous system. The sympathetic nervous system is responsible for the fight-or-flight response, which includes widening the pupils of the eye, mobilizing energy, and diverting blood flow from nonessential organs to skeletal muscle. Naghman Zuberi 2 Categories There are two main groups of adrenergic receptors, α and β, with several subtypes. α receptors have the subtypes α1 (a Gq coupled receptor) and α2 (a Gi coupled receptor). Phenylephrine is a selective agonist of the α receptor. β receptors have the subtypes β1, β2 and β3. All three are linked to Gs proteins (although β2 also couples to Gi),which in turn are linked to adenylate cyclase. Agonist binding thus causes a rise in the intracellular concentration of the second messenger cAMP. Downstream effectors of cAMP include cAMP-dependent protein kinase (PKA), which mediates some of the intracellular events following hormone binding. Isoprenaline is a non-selective agonist. Naghman Zuberi 3 Molecular Basis of Adrenergic Receptors Also glycogenolysis in liver Inhibition of Insulin release and Platelet aggregation Gluconeogene sis Naghman Zuberi 4 . Adrenergic receptors .alpha Type α1 Acts by phospholipase C activation. which forms IP3 and DAG In blood vessels these cause vasoconstriction Blood vessels with alpha-1 receptors are present in the skin and the genitourinary system. and during the fight-or-flight response there is decreased blood flow to these organs Acts by inactivation of adenylate cyclase. cyclic AMP levels within the cell decrease These are found on pre-synaptic nerve terminals Type α2 Naghman Zuberi 5 . Differences between α1 and α2 Alpha-1 Alpha-2 Location Function Post junctional Stimulatory – GU. Vasoconstriction. gland secretion. Methoxamine Prejunctional Inhibition of transmitter release. decreased central symp. Outflow. Glycogenolysis Phenylephrine. Gut relaxation. platelet aggregation Clonidine Agonist Antagonist Prazosin Yohimbine Naghman Zuberi 6 . vasoconstriction. Eye -- Mydriasis Arterioles – Constriction Uterus -- Contraction Skin -- Sweat Platelet - Aggregation Male ejaculation Hyperkalaemia Bladder Sphincter Contraction α2 adrenoceptors on nerve endings mediate negative feedback which inhibits noradrenaline release 7 α1 adenoceptor Clinical effects Naghman Zuberi Beta receptors All β receptors activate adenylate cyclase, raising the intracellular cAMP concentration Type β1: Type β2: These are present in heart tissue, and cause an increased heart rate by acting on the cardiac pacemaker cells Type β3: These are in the vessels of skeletal muscle, and cause vasodilatation, which allows more blood to flow to the muscles, and reduce total peripheral resistance Stimulated by adrenaline, but not noradrenaline Beta-2 receptors are also present in bronchial smooth muscle, and cause bronchodilatation when activated Bronchodilator salbutamol work by binding to and stimulating the β2 receptors Beta-3 receptors are present in adipose tissue and are thought to have a role in the regulation of lipid metabolism Naghman Zuberi 8 Differences between β1, β2 and β3 Beta-1 Location Heart and JG cells Beta-2 Bronchi, uterus, Blood vessels, urinary tract, eye Salbutamol Alpha-methyl propranolol Weak Beta-3 Adipose tissue Agonist Dobutamine - Antagonist Metoprolol, Atenolol Action on NA Naghman Zuberi Moderate Strong 9 Tremor Hypokalaemia Hepatic Glycogenolysis Naghman Zuberi 10 .Dilatation Uterus – Relaxation Skeletal Muscle .Relaxation Arterioles -.β2 Adrenoceptor – Clinical Effects Bronchi -. Dopamine receptors D1-receptors are post synaptic receptors located in blood vessels and CNS D2-receptors are presynaptic present in CNS. renal cortex Naghman Zuberi 11 . ganglia. Noradrenergic transmission Nor-adrenaline is the major neurotransmitter of the Sympathetic system Noradrenergic neurons are postganglionic sympathetic neurons with cell bodies in the sympathetic ganglia They have long axons which end in varicosities where NA is synthesized and stored 12 Naghman Zuberi . Adrenergic transmission Catecholamines: Natural: Adrenaline. Dopamine Synthetic: Isoprenaline. Noradrenaline. Methoxamine. Mephentermine Also called sympathomimetic amines as most of them contain an intact or partially substituted amino (NH2) group 13 Naghman Zuberi . Amphetamines. Dobutamine Non-Catecholamines: Ephedrine. Phenylepherine. Biosynthesis of Catecholamines Phenylalanine PH Alpha-methyl-ptyrosine Rate limiting Enzyme 5-HT. alpha Methyldopa Naghman Zuberi 14 . Storage of Noradrenaline Naghman Zuberi 15 . Release of NA – Feedback Control Naghman Zuberi 16 . Regulators of NA release Naghman Zuberi 17 . Uptake of Catecholamines Naghman Zuberi 18 . Reuptake Sympathetic nerves take up amines and release them as neurotransmitters Uptake I is a high efficiency system more specific for NA Uptake 2 is less specific for NA Located in neuronal membrane Inhibited by Cocaine. TCAD. Amphetamines Located in smooth muscle/ cardiac muscle Inhibited by steroids/ phenoxybenzamine No Physiological or Pharmacological importance Naghman Zuberi 19 . Metabolism of CAs Mono Amine Oxidase (MAO) Intracellular bound to mitochondrial membrane Present in NA terminals and liver/ intestine MAO inhibitors are used as antidepressants Catechol-o-methyl-transferase (COMT) Neuronal and non-neuronal tissue Acts on catecholamines and byproducts VMA Naghman Zuberi levels are diagnostic for tumours 20 . Metabolism of CAs (Homovanillic acid) (Vanillylmandelic acid) Naghman Zuberi 21 . ganglia.Dopamine receptors D1-receptors are post synaptic receptors located in blood vessels and CNS D2-receptors are presynaptic present in CNS. renal cortex Naghman Zuberi 22 . Adrenaline as prototype Potent stimulant of alpha and beta receptors Complex actions on target organs Naghman Zuberi 23 . Blood Pressure Most potent vasopressor known – Both systolic and Diastolic BP rise Has a characteristic effect on BP Rapid rise to a peak: +ve ionotropic Direct myocardial stimulation Increased heart rate +ve chronotropic Vasoconstriction which leads to increased peripheral resistance Reflex Bradycardia Naghman Zuberi 24 . Blood Vessels Seen mainly in the smaller vessels .(Beta2 effect) counterbalanced by a vasoconstrictor effect of alpha receptors If alpha receptors are blocked there is no opposing effect and this leads to fall of BP 25 Naghman Zuberi .arterioles Decreased blood flow to skin and mucus membranes – alpha effect Increased blood flow to skeletal muscles. Heart Powerful Cardiac stimulant Acts on beta-1 receptors in myocardium. pacemaker cells and conducting tissue Heart rate increases Rhythm is altered Cardiac systole is shorter and more powerful Cardiac output is enhanced Oxygen consumption is increased Cardiac efficiency is markedly decreased 26 Naghman Zuberi . Histamine Smooth Muscles: Effects on vascular smooth muscle are important GIT and Urinary tract smooth muscle are relaxed but are clinically unimportant In the pregnant uterus there is inhibition of tone and contractions Naghman Zuberi 27 .g.Actions of Adrenaline Respiratory: Powerful bronchodilator Relaxes bronchial smooth muscle Beta-2 mediated effect Physiological antagonist to mediators of bronchoconstriction e. Metabolic effects Increases concentration of glucose and lactic acid Calorigenesis (β-2 and β-3) Inhibits insulin secretion (α-2) Decreases uptake of glucose by peripheral tissue Simulates glycogenolysis .Beta effect Increases free fatty acid concentration in blood Naghman Zuberi 28 . ADME Ineffective orally Absorbed slowly from subcutaneous tissue Faster from IM site Inhalation is locally effective Not usually given IV Rapidly inactivated in Liver by MAO and COMT 29 Naghman Zuberi . 5 mg sc of 1: 10000 solution Used in: Anaphylactic shock Prolong action of local anaesthetics Cardiac arrest Topically.Adrenaline – Clinical uses Injectable preparations are available in dilutions 1:1000. 1:10000 and 1:100000 Usual dose is 0. to stop bleeding Naghman Zuberi 30 .3-0. Throbbing headache. cardiac arrhythmias Naghman Zuberi 31 .Adverse Drug Reactions Restlessness. Tremor. Palpitations Cerebral hemorrhage. COMT Short duration of action 32 Naghman Zuberi .Noradrenaline Neurotransmitter released from postganglionic adrenergic nerve endings (80%) Orally ineffective and poor SC absorption IV administered Metabolized by MAO. mean pressure.P. pulse pressure and stroke volume Total peripheral resistance (TPR) increases due to vasoconstriction Decreases blood flow to kidney. but No effect on β2 Increases systolic.Actions and uses Agonist at α1. α2 and β1 Adrenergic receptors Equipotent on β1. liver and skeletal muscles Increases coronary blood flow Uses: Injection Noradrenal bitartrate slow IV infusion at the rate of 2-4mg/ minute used as a vasopressor agent in treatment of hypovolemic shock and other hypotensive states in order to raise B. diastolic B.P Naghman Zuberi 33 . respiratory difficulty Rise of B. photophobia.Noradrenaline – Adverse Drug Reactions Anxiety. anginal pain. gangrene Contracts gravid uterus Severe hypertension. palpitation. headache Extravasations causes necrosis. pallor and sweating in hyperthyroid and hypertensive patients 34 Naghman Zuberi . violent headache.P. Short T 1/2 (3-5minutes) 35 Naghman Zuberi .Dopamine Immediate metabolic precursor of Noradrenalin High concentration in basal ganglia. IV use only. regulates body movements ineffective orally. limbic system and hypothalamus Central neurotransmitter. Dopamine Agonists at dopaminergic D1. D2 receptors Agonist at adrenergic α1 and β1 Naghman Zuberi 36 . GFR an causes natriuresis 37 Naghman Zuberi .Dopamine In small doses 2-5μg/kg/minute. it stimulates D1-receptors in renal. mesenteric and coronary vessels leading to vasodilatation Renal vsoconstriction occurs in CVS shock due to sympathetic overctivity Increases renal blood flow. stimulates β1-receptors in heart producing positive inotropic and chronotropic actions actions Releases Noradrenaline from nerves by β1stimulation Does not change TPR and HR Great Clinical benefit in CVS shock and CCF High dose (10-30 μg/kg/minute). stimulates vascular adrenergic α1-receptors – vasoconstriction and decreased renal blood flow 38 Naghman Zuberi .Dopamine Moderate dose (5-10 μg/kg/minute). Oxymetazoline. Phenylepherine. Naphazoline an d Tetrahydrazoline Naghman Zuberi 39 . Xylometazoline. Guanabenz Ephederine.Alpha adrenergic agonists Selective Alpha-1 Agonists: Selective Alpha-2 Agonists: Phenylepherine Methoxamine Metaraminol Mephentermine Nasal Decongestants: Clonidine α-methyldopa Guanfacine. Β-2 Adrenergic agonists Salbutamol Terbutaline Salmeterol Reproterol Oxiprenaline Fenoterol Isoxsuprine Rimiterol Ritodrine Bitolterol Isoetharine 40 Naghman Zuberi . nose) Long duration of action Resistant to MAO and COMT Peripheral vasoconstriction leads to rise in BP Reflex bradycardia Produces mydriasis and nasal decongestion Used in hypovolaemic shock as pressor agent Sinusitis & Rhinitis as nasal decongestant Mydriatic in the form of eye drops and lowers intraocular pressure Does not cross BBB. so no CNS effects Actions qualitatively similar to noradrenaline ADRs: Photosensitivity. synthetic and direct α1 –agonist Administered parenteraly & topically (eye. conjunctival hyperemia and hypersensitivity 41 Naghman Zuberi .Phenylepherine Selective. indirect sympathomimetic actions resembling adrenaline peripherally Centrally – Increased alertness. tremor and nausea in adults. anxiety. mydriatic.Ephedrine Plant alkaloid. mucosal vasoconstriction & in myasthenia gravis. Sleepiness in children Effects appear slowly but lasts longer (t1/2-4h) achyphylaxis on repeated dosing Used as bronchodilator. in heart block. Pseudoephedrine is similar Phenylpropanolamine(PPA) on prolonged administration to woman as anorectic causes pulmonary valve abnormality 42 Naghman Zuberi . insomnia. coughs and sinusitis as nasal drops Sympathomimetic vasoconstrictors with α.What are Mucosal Decongestants? Nasal and bronchial decongestants are used in allergic rhinitis. xylometazoline for only a few days since longer application reduces ciliary action Do not use Naphazoline and Adrenaline Do not use mixtures of vasoconstrictor. colds. antihistaminic. adrenal steroid & antibiotic Oily drops & sprays may cause lipoid pneumonia They lead to failure of antihypertensive therapy Fatal hypertensive crisis in patients on MAOIs 43 Naghman Zuberi .effects are used Mucosal ischaemic damage occurs if used excessively (more often than 3hrly) or for prolonged periods (>3weeks) Rebound congestion leads to overuse Use ephedrine. phenylepherine. Clonidine Naghman Zuberi Agonist to postsynaptic α2A adrenoceptors in brain. stimulation suppresses sympathetic outflow and reduces blood pressure High dose activates peripheral presynaptic autoreceptors on adrenergic nerve ending mediating negative feedback suppression of noradrenaline release Overdose stimulates peripheral postsynaptic α1 adrenoceptors & cause hypertension by vasoconstriction Clonidine reduces blood pressure 44 . Abrupt or gradual withdrawal causes rebound hypertension Onset may be rapid (a few hours) or delayed for as long as 2 days and subsides over 2-3 days Never use Clonidine with β-adrenoceptor blockers Naghman Zuberi 45 .Clonidine – contd. dry mouth TCAs antagonize antihypertensive action & increase rebound hypertension of abrupt withdrawal Low dose Clonidine (50-100μg/dl) is used in migraine prophylaxis. Rilmenidine – Newer Imidazolines 46 Naghman Zuberi .ADRs Sedation. menopausal flushing and chorea Moxonidine.Clonidine . Terbutaline. pirbuterol Selective for β2 receptor subtype Used for acute inhalational treatment of bronchospasm.β2 Adrenergic Agonists Short acting : Salbutamol. colterol Naghman Zuberi 47 . Onset of action within 1 to 5 minutes Bronchodilatation lasts for 2 to 6 hours Duration of action longer on oral administration Directly relax airway smooth muscle Relieve dyspnoea of asthmatic bronchoconstriction Long acting: Salmeterol. Bitolterol. Metaproterenol. infusion to inhibit premature labour Isoxsuprine. Ritodrine.v. increase by 50 μg/min every 10 minutes until contractions stop or maternal heart rate is 140 beats/minute. Salbutamol Tachycardia & hypotension occur Use minimum fluid volume using 5% dextrose as diluents Ritodrine 50 μg/min. Continue for 12-48 hours after contractions stop Naghman Zuberi 48 .Uterine Relaxants Antioxytocics or tocolytic agents β2 agonists relax uterus Used by i. Terbutaline. What to Remember ? Biosynthesis of Catecholamine Distribution of adrenergic receptors Functions of Adrenergic receptors Pharmacological actions of adrenaline Dopamine/Dobutamine actions Nasal decongestants Tocolytic drugs (Uterine Relaxants) 49 Naghman Zuberi . Alfa-adrenoblockers Naghman Zuberi 50 . acute cardiac insufficiency complex therapy of hypovolemic and cardiogenic shock Naghman Zuberi 51 . decubitus complex treatment of hypertensive crises. Reino’s disease. 2-аdrenoblockers administration diagnostics and symptomatic treatment of feochromocytoma disturbances of peripheral blood circulation in case of endarteriitis.Phentolamine. trophic ulcers. tropaphen are synthetic 1. adrenoblocker Administration treatment of arterial hypertension Side effects “phenomenon of first dose”: sudden decreasing of blood pressure and even development of orthostatic collapse after first administrations of the drug Prophylaxis: administration of half-dose before sleep Naghman Zuberi 52 .Prasosin Selective 1. Beta-adrenoblockers Naghman Zuberi 53 . ･ This class of drugs may decrease the sympathetic outflow from the central nervous system and/or suppress the release of reninﾑa substance that is elevated in some patients with high blood pressure and is involved in a cascade of events leading to constriction of blood vessels. Beta-blockers also block the impulses that can cause an arrhythmia (abnormal heart beat). which means that they block beta 1 receptors more than they block beta 2 receptors. Beta 1 receptors are responsible for heart rate and the strength of your heartbeat. and lessens the need for nitrates. Naghman Zuberi 54 . This slows the nerve impulses that travel through the heart. Some beta-blockers are selective. Beta 2 receptors are responsible for the function of your smooth muscles (muscles that control body functions but that you do not have control over).･ Beta-blockers generally work by affecting the response to some nerve impulses. As a result. Your body has 2 main beta-receptors: beta 1 and beta 2. This decreases heart rate. Nonselective beta-blockers block both beta 1 and beta 2 receptors.How do -blockers work? Mechanism for How It Works･Beta-blockers "block" the effects of adrenaline on your body's beta-receptors. your heart does not have to work as hard because it needs less blood and oxygen. blood pressure. In addition. some speculate that beta-blockers may have possible antioxidant and cholesterol lowering effects. Adrenergic Blockers (antagonists/sympatholytics) Block alpha & beta receptor sites (nonselective) direct or indirect acting on the release of norepinephrine and epinephrine Uses . bronchospasm. HTN ( cardiac output). angina ( O2 demand) Side Effects .CHF. wheezing 55 Naghman Zuberi .Cardiac arrthymias ( HR). bradycardia. use with caution on clients with cardiac failure or asthma Selective B1 helpful in asthma clients Naghman Zuberi 56 .Nonselective vs Selective Beta blockers Nonselective have an equal inhibitory effect on B1 & B2 receptors .Drugs have lots of interactions due to lots of alpha/beta receptor sites throughout body . Anaprilin Is a β1.β2-adrenoblocker Administration ischemic heart disease arterial hypertension cardiac tachyarrhythmias acute myocardium infarction Naghman Zuberi 57 . paroxysmal tachycardia. Naghman Zuberi . fibrillation and scintillation of atria) disorders of cardiac rhythm ischemic heart disease arterial hypertension 58 .Talinolol or cordanum is a cardioselective β-adrenoblocker Administration (extrasystolies. Atenolol (tenormin) Indications for administration cardioselelctive -adrenoblocker with long duration of action ischemic heart disease arterial hypertension cardiac arrhythmias acute myocardium infarction Naghman Zuberi 59 . Acebutolol (sectral) 1-adrenoblocker with inner sympathomimetic activity Indications disorders of cardiac rhythm (tachyarrhythmias) hypertension ischemic heart disease Naghman Zuberi 60 . Labetolol -. 2. 1 and 2-adrenoreceptors Administration treatment of patients with arterial hypertension hypertensive crisis Contraindications Atrio-ventricular blockade. cardiac insufficiency Naghman Zuberi 61 . The drug blocks 1. -adrenoblocker. NEBIVOLOL increase the production of Nitric Oxide in blood vessels.CARVEDILOL. They are used now for chronic cardiac insufficiency (congestive heart failure) Naghman Zuberi 62 . Nebivolol – Nebilet Stimulates Nitric OXide synthesis in endothelium Naghman Zuberi 63 . Sympatholytics Naghman Zuberi 64 . hydrochlorothiazide) Naghman Zuberi 65 .Еsidrex Rauwolfia Serpentina (Reserpine.Reserpine Adelfan . dihydralazine. Maximal hypotensive action develops after 5-7 days of regular administration of the drug. brinerdin) Administration Side effects manifestations of parkinsonism fatigue. depression. adelfan. acute attacks of ulcer disease. Reserpin treatment of different forms of essential hypertension (drugs of a second row.is a sum of Rauvolfia (plant) alkaloids. bradycardia increasing of motor and secretory activity of gastrointestinal tract. After the treatment coarsed effect can still stay for two weeks. diarrhea swelling of nose mucous membrane with complication of nose breathing Naghman Zuberi 66 . second line) (combined drugs trirezid. cristepin. somnolence. nausea. During administration of the drug decreasing of blood pressure develops gradually. vomiting.Octadin Is a sympatholytic with strong hypotensive effect. After abolition of drug administration the effect still stays for 2 weeks. liquid retention in the organism. diarrhea. orthostatic collapse Naghman Zuberi 67 . Administration heavy forms of arterial hypertension Side effects general weakness. swelling of nose mucous membrane. after 2-3 days.