Adrenergic Drugs - drdhriti

Adrenergic System: 

Adrenergic System Department of Pharmacology NEIGRIHMS, Shillong

Neurotransmission in ANS: 

Neurotransmission in ANS

Noradrenergic transmission: 

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

Adrenergic transmission: 

Adrenergic transmission Catecholamines: Natural: Adrenaline, Noradrenaline, Dopamine Synthetic : Isoprenaline, Dobutamine Non-Catecholamines: Ephedrine, Amphetamines, Phenylepherine, Methoxamine, Mephentermine Also called sympathomimetic amines as most of them contain an intact or partially substituted amino (NH2) group

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Catecholamines: Compounds containing a catechol nucleus (Benzene ring with 2 adjacent OH groups) and an amine containing side chain Non-catecholamines lack hydroxyl (OH) group

Biosynthesis of Catecholamines: 

Biosynthesis of Catecholamines Phenylalanine PH Rate limiting Enzyme 5-HT, alpha Methyldopa Alpha-methyl-p-tyrosine

Storage of Noradrenaline: 

Storage of Noradrenaline

Release of NA – Feedback Control : 

Release of NA – Feedback Control

Regulators of NA release: 

Regulators of NA release

Uptake of Catecholamines: 

Uptake of Catecholamines

Reuptake: 

Reuptake Sympathetic nerves take up amines and release them as neurotransmitters Uptake I is a high efficiency system more specific for NA Located in neuronal membrane Inhibited by Cocaine, TCAD, Amphetamines Uptake 2 is less specific for NA Located in smooth muscle/ cardiac muscle Inhibited by steroids/ phenoxybenzamine No Physiological or Pharmacological importance

Metabolism of CAs: 

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 levels are diagnostic for tumours

Metabolism of CAs: 

Metabolism of CAs ( Homovanillic acid ) ( Vanillylmandelic acid )

Adrenergic Receptors: 

Adrenergic Receptors Adrenergic receptors (or adrenoceptors ) are a class of G-protein coupled receptors that are the target of catecholamines Adrenergic receptors specifically bind their endogenous ligands – catecholamines (adrenaline and noradrenline) Increase or decrease of 2 nd messengers cAMP or IP3/DAG Many cells possess these receptors, and the binding of an agonist will generally cause the cell to respond in a flight-fight manner. For instance, the heart will start beating quicker and the pupils will dilate

Types of Adrenergic Receptors: 

Types of Adrenergic Receptors Alpha ( α ) and Beta ( β ) Agonist affinity of alpha ( α ) : adrenaline > noradrenaline > isoprenaline Phenoxybenzamine IP3/DAG, cAMP and K+ channel opening A and gonist affinity of alpha ( β ) : isoprenaline > adrenaline > noradrenaline Propranolol cAMP and Ca+ channel opening

DRC of catecholamines on Adrenergic Receptors: 

DRC of catecholamines on Adrenergic Receptors Adr NA Iso Iso Adr NA Log Concentration Aortic strip contraction Bronchial relaxation

Adrenergic receptors - alpha: 

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 Type α2 Acts by inactivation of adenylate cyclase, cyclic AMP levels within the cell decrease These are found on pre-synaptic nerve terminals

Differences between α1 and α2: 

Differences between α 1 and α 2 Alpha-1 Alpha-2 Location Post junctional Prejunctional Function Stimulatory – GU, Vasoconstriction, gland secretion, Gut relaxation, Glycogenolysis Inhibition of transmitter release, vasoconstriction, decreased central symp. Outflow, platelet aggregation Agonist Phenylephrine, Methoxamine Clonidine Antagonist Prazosin Yohimbine

α1 adenoceptor Clinical effects: 

α1 adenoceptor Clinical effects 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

Beta receptors: 

Beta receptors All β receptors activate adenylate cyclase, raising the intracellular cAMP concentration Type β1: These are present in heart tissue, and cause an increased heart rate by acting on the cardiac pacemaker cells Type β2: 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 Type β3: Beta-3 receptors are present in adipose tissue and are thought to have a role in the regulation of lipid metabolism

Differences between β1, β2 and β3: 

Differences between β 1 , β 2 and β 3 Beta-1 Beta-2 Beta-3 Location Heart and JG cells Bronchi, uterus, Blood vessels, urinary tract, eye Adipose tissue Agonist Dobutamine Salbutamol - Antagonist Metoprolol, Atenolol Alpha-methyl propranolol - Action on NA Moderate Weak Strong

β2 Adrenoceptor – Clinical Effects: 

β2 Adrenoceptor – Clinical Effects Bronchi -- Relaxation Arterioles -- Dilatation Uterus – Relaxation Skeletal Muscle - Tremor Hypokalaemia Hepatic Glycogenolysis

Molecular Basis of Adrenergic Receptors: 

Molecular Basis of Adrenergic Receptors Also glycogenolysis in liver Inhibition of Insulin release and Platelet aggregation Gluconeogenesis

Dopamine receptors: 

Dopamine receptors D1-receptors are post synaptic receptors located in blood vessels and CNS D2-receptors are presynaptic present in CNS, ganglia, renal cortex

Adrenaline as prototype: 

Adrenaline as prototype Potent stimulant of alpha and beta receptors Complex actions on target organs

Blood Pressure: 

Blood Pressure Most potent vasopressor known – Both systolic and Diastolic BP rise Has a characteristic effect on BP Rapid rise to a peak: Direct myocardial stimulation +ve inotropic Increased heart rate +ve chronotropic Vasoconstriction which leads to increased peripheral resistance Reflex Bradycardia

Blood Vessels: 

Blood Vessels Seen mainly in the smaller vessels - arterioles Decreased blood flow to skin and mucus membranes – alpha effect Increased blood flow to skeletal muscles- (Beta-2 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

Dale`s Vasomotor Reversal Phenomenon: 

Dale`s Vasomotor Reversal Phenomenon

Heart: 

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

Actions of Adrenaline: 

Actions of Adrenaline Respiratory: Powerful bronchodilator Relaxes bronchial smooth muscle Beta-2 mediated effect Physiological antagonist to mediators of bronchoconstriction e.g. 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

Metabolic effects: 

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

ADME: 

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

Adrenaline – Clinical uses: 

Adrenaline – Clinical uses Injectable preparations are available in dilutions 1:1000, 1:10000 and 1:100000 Usual dose is 0.3-0.5 mg sc of 1: 10000 solution Used in: Anaphylactic shock Prolong action of local anaesthetics Cardiac arrest Topically, to stop bleeding Hyperkinetic children – ADHD, minimal brain dysfunction Anorectic

ADRs: 

ADRs Restlessness, Throbbing headache, Tremor, Palpitations Cerebral hemorrhage, cardiac arrhythmias

Clinical: 

Clinical Question: A Nurse was injecting a dose of penicillin to a patient in Medicine ward without prior skin test and patient suddenly developed immediate hypersensitivity reactions. What would you do? Answer: As the patient has developed Anaphylactic reaction, the only way to resuscitate the patient is injection of Adrenaline 0.5 mg (0.5 ml of 1:1000) IM and repeat after 5-10 minutes Antihistaminics: Chlorpheniramine 10 – 20 mg IM or IV Hydrocortisone 100 – 200 mg

Noradrenaline: 

Noradrenaline Neurotransmitter released from postganglionic adrenergic nerve endings (80%) Orally ineffective and poor SC absorption IV administered Metabolized by MAO, COMT Short duration of action

Actions and uses: 

Actions and uses Agonist at α1, α2 and β1 Adrenergic receptors Equipotent on β1, but No effect on β2 Increases systolic, diastolic B.P, mean pressure, pulse pressure and stroke volume Total peripheral resistance (TPR) increases due to vasoconstriction Decreases blood flow to kidney, 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.P

Noradrenaline - ADRs: 

Noradrenaline - ADRs Anxiety, palpitation, respiratory difficulty Rise of B.P, headache Extravasations causes necrosis, gangrene Contracts gravid uterus Severe hypertension, violent headache, photophobia, anginal pain, pallor and sweating in hyperthyroid and hypertensive patients

Dopamine: 

Dopamine Immediate metabolic precursor of Noradrenalin High concentration in basal ganglia, limbic system and hypothalamus Central neurotransmitter, regulates body movements ineffective orally, IV use only, Short T 1/2 (3-5minutes)

Dopamine: 

Dopamine Agonists at dopaminergic D1, D2 receptors Agonist at adrenergic α1 and β1

Dopamine: 

Dopamine In small doses 2-5 μg/kg/minute, it stimulates D1-receptors in renal, mesenteric and coronary vessels leading to vasodilatation Renal vasoconstriction occurs in CVS shock due to sympathetic over activity Increases renal blood flow, GFR an causes natriuresis

Dopamine: 

Dopamine Moderate dose (5-10 μg/kg/minute), stimulates β1-receptors in heart producing positive inotropic and chronotropic actions actions Releases Noradrenaline from nerves by β1-stimulation 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

Dobutamine: 

Dobutamine Derivative of Dopamine MOA: Acts on both alpha and beta receptors but more prominently in beta-1 receptor Does not act on D1 or D2 receptors Increase in force of contraction and cardiac output but no change in heart rate Uses: Clinically give in dose of 2-8 mcg/kg/min IV infusion Heart failure in cardiac surgery Septic and cardiogenic shock Congestive Heart failure

Alpha adrenergic agonists: 

Alpha adrenergic agonists Selective Alpha-1 Agonists: Phenylepherine Methoxamine Metaraminol Mephentermine Selective Alpha-2 Agonists: Clonidine α-methyldopa Guanfacine, Guanabenz Nasal Decongestants: Ephederine, Phenylepherine, Xylometazoline, Oxymetazoline, Naphazoline an d Tetrahydrazoline

Β-2 Adrenergic agonists: 

Β-2 Adrenergic agonists Salbutamol Terbutaline Salmeterol Reproterol Oxiprenaline Fenoterol Isoxsuprine Rimiterol Ritodrine Bitolterol Isoetharine

Phenylepherine: 

Phenylepherine Selective, synthetic and direct α1 –agonist Administered parenteraly & topically (eye, 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, conjunctival hyperemia and hypersensitivity

Ephedrine: 

Ephedrine Plant alkaloid, indirect sympathomimetic actions resembling adrenaline peripherally Centrally – Increased alertness, anxiety, insomnia, tremor and nausea in adults. Sleepiness in children Effects appear slowly but lasts longer (t1/2-4h) Tachyphylaxis on repeated dosing Used as bronchodilator, mydriatic, in heart block, mucosal vasoconstriction & in myasthenia gravis. Pseudoephedrine is similar but less CNS and Cardiac effects Given in combination with antihistaminics, antitussives and NSAIDs in common cold and, allergic rhinitis, blocked Eustachian tube etc. Phenylpropanolamine (PPA) is similar to ephedrine and used as decongestants in many cold and cough preparations Also as weight loosing agent

What are Mucosal Decongestants?: 

What are Mucosal Decongestants? Nasal and bronchial decongestants are the drugs used in allergic rhinitis, colds, coughs and sinusitis as nasal drops Sympathomimetic vasoconstrictors with α- effects are used However, mucosal ischaemic damage occurs if used excessively (more often than 3 hrly) or for prolonged periods (>3weeks) Rebound congestion leads to overuse Use ephedrine, phenylepherine, xylometazoline for only a few days since longer application reduces ciliary action They lead to failure of antihypertensive therapy Fatal hypertensive crisis in patients on MAOIs

Amphetamine: 

Amphetamine Similar to Ephedrine: Known because of its CNS stimulant action – psychoactive drug and also performance enhancing drug Banned drug and included in the list of drugs of “Dope Test” Increased alertness, euphoria, talkativeness – thrill or kick Increased physical performance without fatigue – short lasting However, anxiety, restlessness, tremor and dysphoria occurs Anorectic – appetite suppression Repeated use – Behavioral abnormalities Anorectic agents: Noradrenergic agents – appetite centre, but serotonergic agents – satiety centre Fenfluramine, dexfenfluramine and sibutramine – Discussed elsewhere

Clonidine: 

Clonidine 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

Clonidine – contd.: 

Clonidine – contd. 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

Clonidine - ADRs: 

Clonidine - ADRs Sedation, dry mouth TCAs antagonize antihypertensive action & increase rebound hypertension of abrupt withdrawal Low dose Clonidine (50-100μg/dl) is used in migraine prophylaxis, menopausal flushing and chorea Moxonidine, Rilmenidine – Newer Imidazolines

β2 Adrenergic Agonists: 

β2 Adrenergic Agonists Short acting : Salbutamol, Metaproterenol, Terbutaline, pirbuterol Selective for β2 receptor subtype Used for acute inhalational treatment of bronchospasm. 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, colterol

Uterine Relaxants: 

Uterine Relaxants Antioxytocics or tocolytic agents β2 agonists relax uterus Used by i.v. infusion to inhibit premature labour Isoxsuprine, Terbutaline, Ritodrine, Salbutamol Tachycardia & hypotension occur Use minimum fluid volume using 5% dextrose as diluents Ritodrine: 50 μg/min, increase by 50 μg/min every 10 minutes until contractions stop or maternal heart rate is 140 beats/minute. Continue for 12-48 hours after contractions stop

What to Remember ?: 

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)

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