ADRENERGIC SYSTEM AND DRUGS/ SYMPATHOMIMETIC AGENTS MS.NAGESWARARAO DEPT OF MEDICAL PHARMACOLOGY ADRENERGIC TRANSMISSION Adrenergic transmission is restricted to the sympathetic division of the ANS There are three closely related endogenous catecholamines (CAs) Noradrenaline (NA) : It acts as transmitter at postganglionic sympathetic sites (except sweat glands, hair follicles and some vasodilator fibres) and in certain areas of brain Adrenaline (Adr) : It is secreted by adrenal medulla and may have a transmitter role in the brain Dopamine (DA) : It is a major transmitter in basal ganglia, limbic system, CTZ, anterior pituitary, etc. and a limited manner in the periphery 1. SYNTHESIS OF CAs: Catecholamines are synthesized from the amino acid phenylalanine Tyrosine hydroxylase is the rate limiting enzyme and its inhibition by - methyl-p-tyrosine results in depletion of Catecholamines. This can be used in pheochromocytoma before surgery and in inoperable cases Synthesis of NA occurs in all adrenergic neurons, while that of Adr occurs only in the adrenal medullary cells 2. STORAGE OF CAs: NA is stored in synaptic vesicles or granules within the adrenergic nerve terminal The vesicular membrane actively takes up DA from the cytoplasm and the final step of synthesis of NA takes place inside the vesicle which contains dopamine -hydroxylase NA is then stored as a complex with ATP (in a ratio of 4:1) which is adsorbed on a protein chromogranin In the adrenal medulla the NA thus formed within the chromaffin granules diffuses out into the cytoplasm, is methylated and Adr so formed is again taken up by a separate set of granules The cytoplasmic pool of CAs is kept low by the enzyme monoamine oxidase (MAO) present on the outer surface of mitochondria 3. RELEASE OF CAs: The nerve impulse coupled release of CA takes place by exocytosis and all the vesicular contents (NA or Adr, ATP, dopamine hydroxylase, chromagranin) are poured out In case of vesicles which in addition contain peptides like enkephalin or neuropeptide y (NPY), these cotransmitters are simultaneouly released The release is modulated by presynaptic receptors, of which 2 inhibitory control is dominant UPTAKE OF CAs: There is a very efficient mechanism by which NA released from the nerve terminal is recaptured. This occurs in 2 steps Axonal uptake: An active amine pump (NET) is present at the neuronal membrane which transports NA by a Na + coupled mechanism It takes up NA at a higher rate than Adr and has been labelled uptake-1 This uptake is the most important mechanism for terminating the postjunctional action of NA. This pump is inhibited by cocaine, desipramine and few other drugs Vesicular uptake: The membrane of intracellular vesicles has another amine pump the vesicular monoamine transporter (VMAT-2) which transports CA from the cytoplasm to within the storage vesicle The VMAT-2 transports monoamines by exchanging with H + ions The vesicular NA is constantly leaking out into the axoplasm and is recaptured by this mechanism This carrier also takes up DA formed in the axoplasm for further synthesis to NA Thus, it is very important in maintaining the NA content of the neurone This uptake is inhibited by reserpine resulting in depletion of CAs Extra neuronal uptake of CAs (uptake-2) is carried out by extra neuronal amine transporter (ENT or OCT3) and other organic cation transporters OCT1 and OCT2 into cells of other tissues Fate of released NA in the synaptic cleft ( summery ) Neuronal uptake which is either stored in the vesicles or inactivated by mitochondrial monoamine oxidase(MAO) in the cytosol Small amount of NA from the synaptic cleft diffuses into the circulation and gets inactivated in the liver by COMT and MAO Small quantity of NA interacts with and -receptors on the effector cells and gets inactivated by COMT. In both cases, the alternative enzyme can subsequently act to produce vanillylmandelic acid (VMA) The major metabolites excreted in urine are VMA and 3-methoxy-4-hydroxy phenylethylene glycol (a reduced product) along with some metanephrine, normetanephrine and 3,4 dihydroxy mandelic acid These metabolites are conjugated with glucuronic acid or sulfate before excretion in urine Only ug of NA and 2-5 ug of Adr are excreted in the free form in 24 hours However, metabolism does not play an important role in terminating the action of neuronally released CAs Vanillylmandelic acid (VMA) is the main metabolite of catecholamines excreted in urine Normal value of VMA is 4-8 mg per 24 hours urine. Its levels are raised in pheochromocytoma, a tumour of adrenal medulla and sympathetic ganglia. Estimation of the levels lf catecholamines and their metabolites in the blood and urine is great value in the diagnosis of Pheochromocytoma Adrenaline Noradrenaline COMT MAO Vanilylmandelic acid Metanephrine Normetanephrine ADRENERGIC RECEPTORS: Adrenergic receptors are membrane bound G-protein coupled receptors which function primarily by increasing or decreasing the intracellular production of second messengers cAMP or IP 3 / DAG In some cases the activated G-protein itself operates K + or Ca 2+ channels, or increase prostaglandin production Ahlquist (1948), on the basis of two distinct rank order of potencies of adrenergic agonists, classified adrenergic receptors into two types and This classification was confirmed later by the discovery of selective and adrenergic antagonists On the basis of relative organ specificity of selective agonists and antagonists the receptors were further subdivided into 1 2 3 subtypes receptors subdivided into 1 and 2 receptors ADRENERGIC RECEPTORS: receptors: 1 receptors: Presynaptic ( - ) 2 postsynaptic ( + ) Presynaptic 2 : Receptor mediate the negative feedback control on NA secretion(i.e stimulation of these receptors decreases the release of NA from the sympathetic nerve ending. Postsynaptic 2 : It mediate the stimulatory effect- vasoconstriction and venoconstriction. 2 receptor mediated inhibitory effects on various secretions: 1) Beta cells of islets of Langerhans in pancreas-decreases insulin secretion 2) Ciliary epithelium decreases aqueous secretion by ciliary body 1 receptor mediated stimulatory effects: Blood vessels : constriction GI spincter(anal) : increase in tone Urinary spincter : increase in tone Radial muscle of iris : contraction (mydriasis) 1- mediates the stimulatory effects on heart and kidney(renin secretion) 2- receptors are stimulatory at some sites and inhibitory at certain sites : 2- receptors mediates the inhibitory effects on Bronchi uterus (pregnant) vascular urinary bladder etcRELAXATION 2- receptors mediates the stimulatory effects on Glycogenolysis in the liver up take of K+ into the cells contraction of the skeletal muscle Enhancement of the secretions of the ciliary epithelium In GIT smooth muscles, both 2 and 2- receptors mediate the inhibitory effects relaxation In adipose tissue, 3 receptors mediate lipolysis ADRENERGIC DRUGS (SYMPATHOMIMETICS) These are drugs with actions similar to that of adrenaline or of sympathetic stimulation Direct sympathomimetics: They act directly as agonists on and / or adrenoceptors Adrenaline (Adr), Noradrenaline (NA), Isoprenaline (Iso), phenylephrine, methoxamine, xylometazoline, salbutamol and many others Indirect sympathomimetics: They act on adrenergic neurone to release NA, which then acts on the adrenoceptors tyramine, amphetamine Mixed action sympathomimetics: They act directly as well as indirectly ephedrine, dopamine, mephentermine ACTIONS The peripheral actions of Adr in most tissues have been clearly differentiated into those mediated by or receptors depending on the predominant receptor type present in a given tissue The actions of a particular sympathomimetic amine depend on its relative activity at different types of adrenergic receptors Adrenaline: 1 + 2+ 1 + 2 and weak 3 action Noradrenaline: 1 + 2 + 1 + 3 but poor 2 action Isoprenaline: 1 + 2 + 3 but no action Dobutamine : mainly 1 action The overall actions are 1. HEART: Adrenaline increases heart rate by increasing the slope of slow diastolic depolarization of cells in the SA node It also activates latent pacemakers in A-V node and Purkinje fibres; arrhythmias can occur with high doses that raise BP markedly Force of cardiac contraction is increased. And automaticity increases Cardiac output and oxygen consumption of the heart are markedly enhanced Conduction velocity through A-V node, bundle of His, atrial and ventricular fibres is increased; partial A-V block may be overcome Refractory period (RP) of all types of cardiac cells is reduced. All cardiac actions are predominantly 1 receptor mediated 2. BLOOD VESSELS: Both vaso constriction () and vasodilatation ( 2 ) can occur depending on the drug, its dose and vascular bed Constriction predominates in cutaneous, mucous membrane (1). Adrenaline also constricts renal, mesenteric, pulmonary and splanchnic vessels. (1) But dilates the blood vessels of skeletal muscle (2 )and coronary vessels (2,2 ). i.v dose of Adrenaline in moderate doses produces a typical biphasic effect- vasomotor reversal. 3. BP: The effect depends on the amine, its dose and rate of administration 4. RESPIRATION: Adrenaline and isoprenaline, but not noradrenaline are potent bronchodilators ( 2 ) This action is more marked when the bronchi are constricted It also inhibits the release of inflammatory mediators from the mast cells (2). It reduces secretions and relieves mucosal congestion by vasoconstrictor effect (1) 5. EYE: Mydriasis occurs due to contraction of radial muscles of iris ( 1 ), but this is minimal after topical application, because adrenaline penetrates cornea poorly 6. GIT: In isolated preparations of gut, relaxation occurs through activation of both 2 and 2 receptors peristalsis is reduced and sphincters are constricted (1) 7. BLADDER: Detrusor is relaxed (2) and trigone is constricted (1): both actions can cause difficulty in micturition. 8. UTERUS: Non pregnant-Contraction[1 > 2] Pregnant-Relaxation[2] 9.SKELETAL MUSCLE: Neuromuscular transmission is facilitated In contrast to action on autonomic nerve endings, receptor activation on motor nerve endings augments acetylcholne release, probably because it is of the 1 subtype The direct effect on muscle fibres is exerted through 2 receptors. 10. CNS: Adrenaline, in clinically used doses, does not produce any marked CNS effects because of poor penetration in brain, but restlessness, apprehension and tremor may occur Activation of 2 receptors in the brainstem results in decreased sympathetic outflow fall in BP and bradycardia 12. METABOLIC: Adrenaline increases blood glucose level by : stimulate hepatic glycogenolysis (2),which is predominant effect. reduction of insulin (2 ) and augmentation of glucagon (2) secretion Decreasing the uptake of glucose by peripheral tissues. ADMINISTRATION AND PREPARATIONS Catecholamines (CAs) are absorbed from the intestine but are rapidly degraded by MAO and COMT present in the intestinal wall and liver. They are thus orally inactive 1. Adrenaline (Epinephrine): For systemic action, mg s.c., i.m., action lasts to 2 hours PREP: 1 mg / ml inj 2. Noradrenaline (Norepinephrine,) 2-4 ug / min i.v. infusion PREP: 2 mg / 2 ml inj 3. Isoprenaline (Isoproterenol) 20 mg sublingual, 1-2 mg i.m., 5-10 ug / min i.v. infusion PREP: 20 mg sublingual tabs, 4 mg / 2 ml inj ADVERSE EFFECTS AND CONTRAINDICATIONS Transient restlessness, palpitation, anxiety, tremor, pallor may occur after s.c. / i.m. injection of adrenaline Marked rise in BP leading to cerebral haemorrhage, ventricular tachycardia / fibrillation, angina, myocardial infarction are the hazards of large doses or inadvertent i.v. injection of adrenaline Adrenaline is contraindicated in hypertensive, hyperthyroid and angina patients Adrenaline should not be given during anaesthesia with halothane (risk of arrhythmias) and to patients receiving blockers (marked rise in BP can occur due to unopposed action) Pharmacokinetics : Adrenaline is given I.M and S.C routes. In anaphylactic shock adrenaline is given by I.M route only. Because S.C absorption is very poor. Nor adrenaline is not suitable for I.M, or S.C routes because of necrosis and sloughing of the tissues at the site of injection. It is administered by I.V infusion. Isoprenaline is not effective orally because of high 1 st pass metabolism. It is given by parenterally. THERAPEUTIC CLASSIFICATION OF ADRENERGIC DRUGS 1. Pressor agents: Noradrenaline, Ephedrine, Dopamine, Phenylephrine, Methoxamine, Mephentermine II. Cardiac stimulants: Adrenaline, Isoprenaline, Dobutamine III. Bronchodilators: Isoprenaline, Salbutamol (Albuterol), Terbutaline, Salmeterol, Formeterol, Bambuterol IV. Nasal decongestants: Phenylephrine, Xylometazoline, Oxymetazoline, Naphazoline, Pseudoephidrine, Phenylpropanolamine V. CNS stimulants: Amphetamine, Dexamphetamine, Methamphetamine VI. Anorectics: Fenfluramine, Dexfenfluramine, Sibutramine VII. Uterine relaxant and vasodilators: Ritodrine, Isoxsuprine, Salbutamol, Terbutaline For allergic reactions (shock ) Adrenaline For local vasoconstrictor : Adrenaline. DOPAMINE (DA) : It is a dopamine (D1 and D2) as well as adrenergic 1, 2 and 1 (but not 2 ) agonist At low concentrations (10 mcg/kg/minute), it stimulates vascular 1 receptors and causes vasoconstriction. This reduces blood flow to renal, mesenterec and other vital organs. So beneficial effect seen with only low to moderate dose of DA is lost at higher concentrations. It is administered by i.v. infusion (0.2-1 mg/min) which is regulated by monitoring BP and rate of urine formation Uses: cardiogenic and septic shock : increases BP and blood flow to the vital organs Severe heart failure with renal impairment : DA improves both cardiac and renal functions. PREP: 200 mg in 5 ml amp DOBUTAMINE : (relatively selective 1 ) : A derivative of dopamine, but not a D1 or D2 receptor agonist. Though it acts on both 1, 1 and 2 adrenergic receptors, the only prominent action of clinically employed doses (2-8 ug/kg/min i.v.) is increased force of cardiac contraction and output, without significant change in peripheral resistance and BP. As such, it has been considered to be a relatively selective 1 agonist It is used as an inotropic agent in pump failure accompanying myocardial infarction, cardiac surgery, and for short term management of severe congestive heart failure PREP: 50 mg / 4 ml, 250 mg / 20 ml amp EPHEDRINE: (1 + 2 + 1 + 2+ release of NA)It is an alkaloid obtained from Ephedra vulgaris Mainly acts indirectly but has some direct action on and receptors also It is resistant to MAO, therefore, effective orally Ephedrine crosses to brain and causes stimulation. Ephedrine can be used for a variety of purposes, but it lack of selectivity, and efficacy is low Use is now restricted to that in mild chronic bronchial asthma and for hypotension during spinal anaesthesia A/E: Hypertension, tachycardia, palpitation, difficulty in urination and tachyphylaxis on repeated administration. DOSE: mg TDS PREP: 15, 30 mg tabs, 50 mg/ml inj, 0.75% nasal drops AMPHETAMINES: (indirectly acting sympathomimetic ) These are synthetic compounds having a pharmacological profile similar to ephedrine; orally active with long duration (4-6 hours) The CNS actions are more prominent; maximal selectivity is exhibited by dextroamphetamine (CNS stimulant) and methamphetamine, which in the usual doses produce few peripheral effects (CVS) The central effects include alertness, increased concentration and euphoria, talkativeness, increased work capacity,tremors and insomnia. Fatigue is allayed. Athletic performance is improved temporarily. On chronic use it causes depression. The reticular activating system is stimulated resulting in wakefulness and postponement of sleep deprivation induced physical disability High doses produce euphoria, marked excitement which may progress to mental confusion, delirium, hallucinations and acute psychotic state The L-isomer causes cardiac stimulant action. tachycardia, palpitation, increases BP and cardiac arrhythmias It suppress appetite (Anorexia ) Amphetamines are drugs of abuse and are capable of producing marked psychological but little or no physical dependence Uses: narcolepsy (uncontrollable desire for sleep) Anorexiant(reduce body weight by suppressing hypothalamic feeding Centre ) PREP: 5 mg tabs DOSE: 5-15 mg oral (children mg) PHENYLEPHRINE: It is a selective 1 agonist, has negligible action. It raises BP by causing vasoconstriction Topically it is used as a nasal decongestant and for producing mydriasis when cycloplegia is not required Phenylephrine tends to reduce intraocular tension by constricting ciliary body blood vessels It is also a frequent constituent of orally administered nasal decongestant preparations DOSE: 2-5 mg i.m., mg slow i.v. inj, ug/min i.v. infusion, 5-10 mg oral, % nasal instillation,, 5-10% topically in eye PREP: 10 mg/ ml inj, 0.25% nasal drops, 10% eye drops, METHOXAMINE: Another selective 1 agonist. Resembles phenylephrine very closely Occasionally used as a pressor agent DOSE: mg i.m.; 3-5 mg slow i.v. inj PREP: 20 mg/ml inj Phynylephrine directly acting 1 agonists Methoxamine Metaraminol directly acting 1 agonists + release NA(indirect action) Mephentermine Mephentermine also has cardiac stimulant effect. It is used to prevent and treat hypotension due to spinal anaesthesia and surgical procedures, shock in myocardial infarction and other hypotensive states DOSE: mg oral/i.m., also by slow i.v. infusion PREP: 10 mg tab, 15 mg/ml amp, 3 mg/ml in 10 ml vial SELECTIVE 2 STIMULANTS These include, salbutamol, terbutaline, salmeterol, formeterol and ritodrine They cause bronchodilatation, vasodilatation and uterine relaxation, without producing significant cardiac stimulation They are primarily used in bronchial asthma Ritodrine is a selective 2 agonist with selective action on uterus. It is used as an uterine relaxant to suppress premature labour. NASAL DECONGESTANTS These are agonists which on topical application as dilute solution ( %) produce local vasoconstriction The imidazole compounds naphazoline, xylometazoline and oxymetazoline are 1 + 2 agonists. Nasal decongestants action is mainly due to 1 action in the mucous membrane in the nose. They have a longer duration of action (12 hours) than ephedrine They may cause initial stinging sensation (specially naphazoline) Regular use of these agents for long periods should be avoided because mucosal ciliary function is impaired: atrophic rhinitis and anosmia can occur due to persistent vasoconstriction They can be absorbed from the nose and produce systemic effects CNS depression and rise in BP These drugs should be used cautiously in hypertensives and in those receiving MAO inhibitors PREP & DOSE: Xylometazoline: % topical in nose; 0.05% (paediatric), 0.1% nasal drops Oxymetazoline: % topical in nose; 0.025% (paediatric), 0.05% nasal drops Naphazoline: 0.1% topical in nose: 0.1% nasal drops PSEUDOPHEDRINE: A stereoisomer of ephedrine; causes vasoconstriction, especially in mucosae and skin, but has fewer CNS and cardiac effect and is a poor bronchodilator It has been used orally as a decongestant of upper respiratory tract, nose and eustachian tubes Combined with antihistaminics, mucolytics, antitussuves and analgesics, it is believed to afford symptomatic relief in common cold, allergic rhinitis, blocked eustachean tubes and upper respiratory tract infections. DOSE: mg TDS PREP: 60 mg tab, 30 mg / ml syrup PHENYLPROPANOLAMINE (PPA): Chemically and pharmacologically similar to ephedrine; causes vasoconstriction and has some amphetamine like CNS effects It is included in a large number of oral cold / decongestant combination remedies Increased risk of haemorrhagic stroke is seen in elderly hypertensives hence it is not recommended for these patients. PREP: 25 mg + chlorpheniramine 2 mg + paracetamol 500 mg tab ANORECTIC AGENTS Because of adverse central effects, the use of amphetamines to suppress appetite cannot be justified A number of related drugs have been developed which inhibit feeding centre (like amphetamine) but have little/no CNS stimulant action or abuse liability SIBUTRAMINE: It can cause loss of 3-9 kg weight, but many subjects regain the same when therapy is discontinued Side effects include dry mouth, constipation, anxiety, insomnia, chest pain and a mild increase in BP and HR A number of serious adverse reaction reports including cardiovascular events and deaths have been reported DOSE: Start with 10 mg OD, increase to 15 mg OD if tolerated PREP: 5 mg, 10 mg caps THERAPEUTIC USES 1. VASCULAR USES: (i) Hypotensive states (shock, spinal anaesthesia, hypotensive drugs) One of the pressor agents can be used for neurogenic and haemorrhagic shock. Adrenaline 0.5 mg injected promptly i.m. is the drug of choice in anaphylactic shock It not only raises BP, but counteracts bronchospasm / laryngeal edema that may accompany Because of the rapidity and profile of action adrenaline is the only life saving measure (ii) Along with local anaesthetics: Adrenaline 1 in 200,000 to 1 in 100,000 for infiltration, nerve block and spinal anaesthesia Duration of anaesthesia is prolonged and systemic toxicity of local anaesthetic is reduced. Local bleeding is minimized (iii) Control of local bleeding: From skin and mucous membranes, e.g. epistaxis : compresses of adrenaline 1 in 10,000, phenylephrine / ephedrine 1% soaked in cotton can control arteriolar and capillary bleeding (iv) Nasal decongestant: In colds, rhinitis, sinusitis, blocked nose or eustachian tube one of the -agonists is used as nasal drops Shrinkage of mucosa provides relief. The imidazoles should be used in lower concentrations in infants and young children, because they are more sensitive to central effects of these drugs Nasal decongestants should be used very cautiously in hypertensive patients and in elderly males Pseudoephedrine, phynylpropronalamine PPA, and phenylephrine have been used orally as decongestants, but effective doses will constrict the blood vessels as well and cause rise in BP 2. CARDIAC USES (i) Cardiac arrest Adrenaline may be used to stimulate the heart; i.v. administration is justified in this setting with external cardiac massage (ii) Partial or complete A-V block: Isoprenaline may be used as temporary measure to maintain sufficient ventricular rate 3. BRONCHIAL ASTHMA: Adrenergic drugs, especially 2 stimulants are the primary drugs for relief of reversible airway obstruction 4. ALLERGIC DISORDERS: Adrenaline is a physiological antagonist of histamine which is an important mediator of many acute hypersensitivity reactions It affords quick relief in urticaria, angioedema; is life saving in laryngeal edema and anaphylaxis It is ineffective in delayed, retarded and other types of allergies, because histamine is not involved 5. MYDRIATIC: Phenylephrine is used to facilitate fundus examination; cycloplegia is not required It tends to reduce intraocular tension in wide angle glaucoma 6. CENTRAL USES (i) Hyperkinetic children (minimal brain dysfunction, attention deficit hyperkinetic disorder) Amphetamines have an apparently paradoxical effect to calm down hyperkinetic children This disorder is recognized as the mildest grade of mental retardation or a reduction in the ability to concentrate. (ii) Obesity: The anorectic drugs can help the obese to tolerate a reducing diet for short periods, but do not improve the long term outlook Their use (for 2-3 months) may be considered in severe obesity Currently sibutramine is being used, though its long term safety is not established 7. NOCTURNAL ENURESIS IN CHILDREN AND URINARY INCONTINENCE: Amphetamine affords benefit both by its central action as well as by increasing tone of vesicular sphincter 8. UTERINE RELAXANT: Isoxsuprine has been used in threatened abortion and dysmenorrhea, but efficacy is doubtful Selective 2 stimulants, specially ritodrine, infused i.v. have been successfully used to postpone labour 9. INSULIN HYPOGLYCAEMIA: Adrenaline may be used as an expedient measure, but glucose should be given as soon as possible 10. Hyperkalemia : 2 agonists are useful in this situation. It increases the uptake of K+ in to the cells, especially into skeletal muscles. THANK YOU