Adrenergic Transmission (Sympathomimetics) α and β PDF

ADRENEGIC TRANSIMISSION (SYMPATHOMIMETICS) α AND β AGONIST. INTRODUCTION The sympathomimetics mimic the effects of adrenergic sympathetic nerve stimulation on sympathetic effectors. The adrenergic transmitter norepinephrine and the adrenal medullary hormone epinephrine also are included under th...

ADRENEGIC TRANSIMISSION (SYMPATHOMIMETICS) α AND β AGONIST. INTRODUCTION The sympathomimetics mimic the effects of adrenergic sympathetic nerve stimulation on sympathetic effectors. The adrenergic transmitter norepinephrine and the adrenal medullary hormone epinephrine also are included under this broad heading. The sympathomimetics are an important group of therapeutic agents that can be used to maintain blood pressure or to relieve a life-threatening attack of acute bronchial asthma. They are also present in many over the-counter cold preparations because they constrict mucosal blood vessels and thus relieve nasal congestion. NERVOUS SYSTEM The nervous system is divided into Central nervous system 9CNS) and the peripheral nervous system (PNS). The PNS is further subdivided into the autonomic nervous system (ANS) and somatic nervous system (SNS). In the ANS, activities here are not under conscious control and are concerned with visceral functions such as cardiac output, blood flow, and digestion. The SNS is concerned with actions under conscious control such as movement, posture, respiration. The ANS is highly integrated in the brain and controls processes in distant regions of the body and uses negative feedback mechanisms. The ANS also uses chemicals termed transmitters for transmission of information. This transmission occurs between nerve cells and between nerve cells and effector cells. Transmission occurs via the release of small amount of transmitter substances called catecholamines for the adrenergic transmission from the nerve terminal to the synaptic cleft. These catecholamines crosses the cleft by diffusion and interacts with specialized receptors to either activate or inhibit post synaptic cell. Drugs can be used to mimic or block the actions of these transmitters (catecholamines). The ANS is further sub divided into the sympaththetic (thoracolumbar) and the 1 parasympathetic nervous system (cranioscarial). The adrenergic transmission falls majorly under the sympaththetic nervous system, and drugs that mimic the transmitters (catecholamines) that activates the sympathetic system are termed sympathomimetics. The sympathetic preganglionic fibers leave the CNS via the thoracic and lumbar spinal nerves. A 3rd division of the ANS is the enteric nervous system (ENS) located within the walls of the GIT. CHEMISTRY The sympathomimetics can be divided into two major groups on the basis of their chemical structure: the catecholamines and the non-catecholamines. The catecholamines include norepinephrine, epinephrine, and dopamine, all of which are naturally occurring, and several synthetic substances, the most important of which is isoproterenol (isopropyl norepinephrine). The L-isomers are the naturally occurring forms of epinephrine and norepinephrine and possess considerably greater pharmacological effects than the D-isomers. Throughout most of the world, epinephrine and norepinephrine are known as adrenaline and noradrenaline, respectively. Non- catecholamines differ from the basic catecholamine structure primarily by having substitutions on their benzene ring. An important classification of the autonomic nerves is based on the primary transmitter molecule. For the sympathetic, the primary transmitter substance secreted on activation is norepinerphrine; NE (noradrenalin) / Epinerphrine; EPI (adrenalin). For most post ganglionic sympathetic fibers, they release NE/EPI and are termed adrenergic fibers that means they act by releasing NE/EPI. A few sympathetic fibers release acetylcholine, dopamine another catecholamine. NE. EPI, Dopamine are termed catecholamines. 2 Most autonomic nerves release other transmitter substances in addition to their primary transmitter, these are termed co-transmitter. Examples of these co-transmitter for adrenergic transmission is dopamine. These catecholamines, chemical transmitter exert their effect by interacting with specialized receptors termed adrenergic receptors (adrenoceptors). These adrenoceptors are further subdivided based on agonist and antagonist selectivity into alpha (α) and beta (β) receptors. These 2 principal receptors (α and β) were rationalized by Raymond Ahlquist in 1948. The α receptors are subdivided into α1 and α2, there exist 3 subtypes of the α1 receptors based on the affinity of drugs and compounds, they are α1A, α1B, α1D. Subtypes of α2 receptors also exist, they are: α2A, α2B. α2C. While the β receptors are subdivided into β1, β2 and β3. Activation of the α receptors generally results in decreased intracellular calcium level with an increase in 2 second messengers, inositol 1,4,5 triphosphate and diacyl glycerol and inhibition of adenylyl cyclase with a corresponding decrease in cyclic AMP (CAMP). β receptors activation on the other hand activates adenylyl cyclase and increases CAMP. LOCATION OF RECEPTORS α1: Smooth muscles α2: presynaptic nerve terminals, platelets, lipocytes, smooth muscles β1: heart, lipocytes brain, presynaptic adrenergic and cholinergic nerve terminals β2: smooth muscles and cardiac muscles β3: lipocytes. Drugs that mimic the actions of NE/EPI are termed sympathomimetics, e.g isoprenaline. Αlpha receptors exhibit potency for these catechoalmines in this order: EPI > NE >>Isoprenaline (isoproterenol), while for β receptors the potency is in this order: isoprenaline > EPI > NE. 3 Sympathomimetics are grouped by their mechanism of action and spectrum of receptors they affect. Some act directly on the adrenergic receptors like NE, EPI while some are indirect based on the release of the endogenous catecholamines either by: Displacing stored catecholamines from adrenergic nerve endings e,g amphetamine and tyramine Or by inhibiting the reuptake of catecholamines release e.g Tricyclic anti- depressant and Cocaine. EXAMPLES α1 agonists: Drugs that mimic the endogenous catecholamines are termed agonist and for α1, they act via activation of α1 receptors, they include EPI, NE which are both non- selective for all adrenergic receptors, Phenylephrine, methoxamimine, ozymetazoline, metaraminol. α2 agonist: Clonidine, oxymetazoline, guanfacine, guanabenz, dexmedetomide, medetomide, (EPI, NE which are non-selective) β1 agonist: EPI, NE have equal affinity for this receptor, isoproterenol (isoprenaline), dobutamine, denopamine. Xamoterol (partial). Note that isoprenaline is a non-selective β agonist. Hence it will activate all β receptor subtype. β2 agonist: procaterol, terbutaline, salbutamol, albuterol. EPI has a higher affinity for β 2 receptor than NE. The β2 agonist are divided into short acting and long acting. Examples of the short acting include salbutamol, terbualine that have an onset of 15 mins and duration of 4 hours. The long acting include salmeterol and formoterol. These beta 2 agonist are prominent bronchodilators and have Broncho protective effects. They have strong action on bronchial and vascular β receptors than cardiac. β3 agonist: Mirabegron used for bladder over activity caused by urinary urgency and incontinence. They ease the urinary urge and increase bladder capacity by relaxing the detrusor muscle of the bladder. Some of these adrenergic agonists show selectivity for particular receptor subtypes. Phenylephrine and methoxamine show selectivity in this order: α1 > α2 > β. 4 Clonidine, methynorepinerphrine in this order: α2 > α1 >>> β Non selective agonist (mixed α and β agonist): NE: α1=α2, β1 >> β2. EPI: α1=α2, β1=β2 Dobutamine: β1 > β2 >>> α Isoprenaline: β1=β2 >>>> α Terbutaline, metaproterenol, albuterol, ritodrine: β2 >>β1 >>>> α Epinerphrine (adrenaline) is a potent vasoconstrictor/cardiac stimulant. Norepinerphrine (noradrenaline) has similar effects. Isoproterenol (isoprenaline) is a non-selective beta agonist, Dobutamine is a beta agonist. Methoxamine acts like phenylephrine an alpha agonist, midodrine a prodrug is an alpha 1 agonist. Indirect sympathomimetics Ephedrine is found in plants and acts via the release of stored catecholamines, it has a long duration of action and used as a nasal decongestant and a pressor agent, Pseudoephedrine is a common component of many nasal decongestant. Xylometazoline and oxymetazoline are direct alpha agonist topical decongestant. Amphetamine is similar to ephedrine i.e acts via release of stored catecholamines but crosses the BBB more readily hence it has marked CNS stimulant effect on mood and alertness. Tyramine is an indirect sympathomimetics that acts by causing the release of stored catecholamines, it is found in high concentration in fermented food like chesse. Cocaine is a sympathomimetic that inhibits the reuptake of catecholamines especially dopamine at noradrenergic synapse. It functions as a local anaesthetic. It crosses the BBB and has an amphetamine like effect more intense but short duration of action. Exogenous Sympathomimetics effects cannot be inactivated by COMT (catechol-o- methyl transferase) responsible for terminating the effects of adrenergic neurotransmitters, i.e endogenous catecholamines. Their effects can also be terminated 5 via reuptake mechanism. Hence these Sympathomimetics have longer duration of action that the endogenous catecholamines. Dopamine is one of the co-transmitters of adrenergic stimulation, its effects is mediated via dopamine receptors termed D1-D5. These receptors are found in the brain and are important for understanding the efficacy and adverse effects of most antipsychotics. Dopamine is a precursor of NE D1 agonist: Dopamine, fenolodapam D2: Bromocriptine D3: Quinpirol The effect of a given sympathominetic on a particular type of effector cell depends on the receptor selectivity of the drug, the response characteristics of the effector cells, and the predominant type of adrenergic receptor found on the cells. For example, the smooth muscle cells of many blood vessels have only or predominantly alpha receptors. The interaction of compounds with these receptors initiates a chain of events in the vascular smooth muscle cells that leads to activation of the contractile process. Thus, norepinephrine and epinephrine, which have high affinities for alpha receptors, cause the vascular muscle to contract and the blood vessels to constrict. Since bronchial smooth muscle contains beta 2 receptors, the response in this tissue elicited by the action of beta-adrenoceptor agonists is relaxation of smooth muscle cells. Epinephrine and isoproterenol, which have high affinities for beta 2-adrenoceptors, cause relaxation of bronchial smooth muscle. Sympathomimetics can be divided into two major groups on the basis of their mechanism of action. Norepinephrine, epinephrine, and some closely related sympathomimetics produce responses in effector cells by directly stimulating adrenergic receptor and are referred to as directly acting. Many other such 6 as amphetamine, do not themselves interact with the receptors, yet they produce sympathetic effects by releasing norepinephrine from neuronal storage sites (vesicles). The norepinephrine that is released by these compounds interacts with the receptors on the effector cells. These sympathomimetics are called indirectly acting. The effects elicited by indirectly acting drugs resemble those produced by norepinephrine. An important characteristic of indirectly acting sympathomimetics is that repeated injections or prolonged infusion can lead to tachyphylaxis (gradually diminished responses to repeated administration).This is a result of a gradually diminishing availability of releasable norepinephrine stores on repeated drug administration. The time frame of the tachyphylaxis will vary with individual agents. The actions of many indirectly acting sympathomimetics are reduced or abolished by the prior administration of either cocaine or tricyclic antidepressant drugs (e.g., imipramine). These compounds can block the adrenergic neuronal transport system and thereby prevent the indirectly acting drug from being taken up into the nerve and reaching the norepinephrine storage vesicles. Lipophilic drugs (e.g.,amphetamine),however, can enter nerves by diffusion and do not need membrane transport systems. Destruction or surgical interruption of the adrenergic nerves leading to an effector tissue renders indirectly acting agents ineffective because neuronal norepinephrine is no longer available for release since the nerves have degenerated. Also, patients being treated for hypertension with reserpine or guanethidine, which deplete the norepinephrine stores in adrenergic neurons, respond poorly to administration of indirectly acting sympathomimetics. Some act both directly and indirectly; that is, they release some norepinephrine from storage sites and also directly activate tissue receptors. Such drugs are called mixed-action 7 sympathomimetics. However, most therapeutically important sympathomimetic drugs in humans act either directly or indirectly. MECHANISM OF ACTION Many sympathimimetics produce responses by interacting with the adrenergic receptors on sympathetic effector cells. They vary in their affinities for each subgroup of receptors. Some, like epinephrine, have a high affinity for all of the adrenergic receptors. Others are relatively selective. When alpha receptors are activated, polyphosphoinositide hydrolysis is stimulated leading to the formation of inositol 1,4,5 triphosphate (IP3) and diacylglycerol (DAG) and this facilitates the influx of calcium, increases cytoplasmic concentration of free calcium, DAG activates protein kinase C, alpha receptors activation also inhibit adenylyl cyclase activity and cause CAMP levels to decrease. For beta receptors activation, it leads to activation of adenylyl cyclase and increase conversion of ATP to CAMP which is the major second messenger of beta receptor activation. This leads to activation of glycogen phosphorylase. In the heart, beta activation increases calcium influx while on smooth muscles, it promotes relaxation this may involve phosphorylation of myosin light chain kinase to an inactive form. For dopamine receptors stimulation leads to activation of adenylyl cyclase leading to increase CAMP levels. 8 STRUCTURES. The parent compound from which sympathomimetics are derived is phenlyethylamine. Modification of which gives rise to drugs with affinity for α and β receptors. Phenylethlamine has a catechol group common to all catechoalmines. HO HO CATECHOL GROUP, COMMON TO ALL CATECHOLAMINES CH2 CH2 NH2 PHENYLETHYLAMINE, THE PARENT COMPOUND FROM WHICH ALPHA AND BETA AGONISTS ARE DERIVED VIA MODIFICATION HO OH HO CH CH2 NH CH3 EPINERPHRINE HO OH 9 HO CH CH2 NH2 NOREPINERPHRINE PHARMACOLOGICAL EFFECTS Blood vessels: Alpha receptor agonist increases arterial resistance while beta 2 promotes smooth muscle relaxation. The skin vessels are constricted by alpha receptor activation especially by EPI and NE. The skeletal muscle may constrict or dilate depending on either alpha or beta activation. Heart: Βeta1 agonist have a direct effect on the heart mainly, although β2 and α receptors are also involved. Βeta activation increases calcium influx resulting in positive chronotropic effect, increased force of contraction and rate of contraction with an increase in heart rate and contractility. On the blood pressure, α activation increases blood pressure from an increase in peripheral arterial resistance. Βeta activation increases cardiac output, decreases peripheral resistance by dilating the vascular beds with a net effect of a slight increase in systolic blood pressure and a decrease in diastolic blood pressure. Eye: α1 agonist produces contraction of the pupillary dilatator muscle thus dilating the pupils resulting in mydriasis. Αlpha agonist also increases outflow of aqueous humor thus decreasing intraocular pressure important in the treatment of glaucoma. β agonists relaxes the ciliary muscle causing a decrease in accommodation. Respiratory tract: β2 activation relaxes the bronchial smooth muscle leading to bronchodialatation important in the treatment of asthmas. α1 receptors are also present in the upper respiratory tract mucosa and exert decongestant effect here. 10 GIT: Both α1 and β1 agonist relaxes the GIT smooth muscles, α2 agonist decreases muscle activity here indirectly by decreasing the release of ACH and other stimulants within the enteric nervous system. Genitourinary tract: The uterus contains both alpha and beta receptors. Βeta agonist mediates relaxation of the uterus and this is useful in pregnancy, to prevent threatened abortion or premature labour. The bladder and prostrate contains α receptors which mediate contraction and this promotes urinary continence. α1A specifically plays a major role here. β2 activation will mediate relaxation of the bladder. Ejaculation is mediated by alpha receptor activation either by NE or EPI or other agonist. Exocrine gland: The salivary glands have both receptors that mediate the release of amylase and water. Although there are exceptions like clonidine that causes dry mouth, mechanism behind this is not clear. On the skin, sweat production is enhanced by activation of both receptors. Metabolic effects: Lipolysis increases via beta activation specifically β3 which could have use in metabolic disorders α2 receptor activation inhibits lipolysis via decrease in CAMP. Thus they enhance glycogenolysis in the liver facilitating glucose release into the blood stream. This effect is mainly via beta receptor activation. Endocrine function: Catecholamines regulate hormone secretion from a number of glands. Insulin secretion for example from the pancreas is stimulated by beta receptors and inhibited by α 2. Renin 11 is secreted from the kidney and stimulated by β1 and inhibited by α2. Beta antagonist may thus lower plasma renin. Parathyroid hormone, calcitone, thyroxine and gastrin secretion from the gland is also modulated by both receptors. EPI via both receptors can cause leukocytosis (high WBC) via promotion of demargination of WBC (Movement of WBC). α2 agonist enhances platelet aggregation. CNS: The effect of adrenergic agonist here varies depending on their ability to cross the Blood brain barrier (BBB) hence effect seen is at high concentration. Nervousness, anxiety, feeling of impending disaster, undesirable sensations are some of the effects. Beta activation causes tachycardia with tremors. PHARMACOLOGICAL ACTIONS OF DOPAMINE Dopamine is a naturally occurring catecholamine; it is the immediate biochemical precursor of the norepinephrine found in adrenergic neurons and the adrenal medulla. It is also a neurotransmitter in the CNS, where it is released from dopaminergic neurons to act on specific dopamine receptors. Dopamine is a unique sympathomimetic drug in that it exerts its cardiovascular actions by releasing norepinephrine from adrenergic neurons, interacting with alpha 1- receptors, and interacting with specific dopamine receptors. The cardiovascular response to dopamine in humans depends on the concentration infused. Low rates of dopamine infusion can produce vasodilation in the renal, mesenteric, coronary, and intercerebral vascular beds with little effect on other blood vessels or on the heart. The vasodilation produced by dopamine is not antagonized by beta blockers but is antagonized by haloperidol and other dopamine receptor–blocking agents. Dopamine can exert pronounced cardiovascular and renal effects through the activation of both D1- and D2-receptor subtypes. Stimulation of the D1-receptor, which 12 is present on blood vessels and certain other peripheral sites, will result in vasodilation, natriuresis, and diuresis. D2-receptors are found on ganglia, on sympathetic nerve terminals, on the adrenal cortex, and within the cardiovascular centers of the CNS; their activation produces hypotension, bradycardia, and regional vasodilation (e.g.,renal vasodilation).The kidney appears to be a particularly rich source for endogenous dopamine in the periphery. The infusion of moderately higher concentrations of dopamine increases the rate and contractile force of the heart and augments the cardiac output. This action is mediated by alpha 1 receptors and norepinephrine release and is antagonized by propranolol. In contrast to isoproterenol, which has a marked effect on both the rate and the contractile force of the heart, dopamine has a greater effect on the force than on cardiac rate. The advantage of this greater inotropic than chronotropic effect of dopamine is that it produces a smaller increase in oxygen demand by the heart than does isoproterenol. Systolic blood pressure is increased by dopamine, whereas diastolic pressure is usually not changed significantly. Total peripheral resistance is decreased because of the vasodilator effect of dopamine. CLINICAL BENEFITS /USES Hypertension: α2 agonist e.g clonidine is useful in the treatment of hypertension. Also it can be used in diarrhea in diabetics with autonomic neuropathy. Clonidine is also useful in combating various drug dependence. α2 agonist decrease blood pressure via the CNS although local application can cause vasoconstriction. Other examples include methyldopa, guanfacine, guanabenze all useful in treating hypertension. Uterine relaxant and Overactive bladder: In the genitourinary system, β 2 agonist relaxes the uterus examples terbutaline, ritodrine, salbutamol, which all suppresses premature labour/threatened abortion thus delaying labour to give enough time for the maturation of the fetus. Also beta agonist find use in overactive bladder, β3 agonist mirabegron relaxes 13 the detrusor muscle of the bladder thus increasing the bladder capacity and combats overactive bladder. α2 agonist can also be used in overactive bladder. Asthma: Beta agonist specifically β2 agonist are very useful in the treatment of asthma. Non selective agonist like EPI and beta selective agonist like isoprenaline are also useful. All Beta 2 agonist like salbutamol, terbutaline, albuterol are more effective and less toxic than the non-selective agonist. They have a strong action on bronchial and vascular beta receptors. Isoprenaline a non-selective beta agonist is useful in the treatment of bradycardia, heart block and rarely used in asthma because isoprenaline increases cardiac output, has a positive inotropic and chronotropic effect with increase in heart rate and cardiac contractility. Hence it finds more use in heart block or cardiac arrest with bradycardia. Beta 2 agonist activation may increase cardiac output though with less reflex tachycardia as seen with the non-selective beta agonist like isoprenaline. Alpha agonist are also useful as nasal decongestants. They are good mucous membrane decongestants that decrease the volume of nasal mucosa especially via α1 receptor. However rebound hyperemia may occur following its use. Short acting alpha agonist like phenylephrine is preferred in nasal sprays and ophthalmic drops. Safer longer acting decongestants include xylometazoline and oxymetazolin topically both applied. Opthalmic use: Sympathomimetics have mydriatic effect on the eyes specifically phenylephrine which is used to induce mydriasis to facilitate examination of the retina. They are also useful as a decongestant for allergic hyperemia of the conjuctival membranes. Sympahthomimetics are also useful in the treatment of glaucoma, EPI topically applied lowers intraocular pressure by increasing aqueous outflow. However because of the adverse effect of EPI there are safer drugs now used for glaucoma. Dipivefrin is a prodrug rapidly converted to EPI within the anterior chamber of the eye via hydrolysis and is readily used. α2 selective agonist also lowers intraocular pressure and are preferred to EPI. E.g Apraclonidine, brimonedine. Epinephrine also has been used to lower intraocular pressure in open-angle glaucoma. Its use promotes an increase in the outflow of aqueous humor. Because epinephrine administration will decrease the filtration angle formed by the cornea and the iris, its use is contraindicated in angle-closure 14 glaucoma; under these conditions the outflow of aqueous humor via the filtration angle and into the venous system is hindered, and intraocular pressure may rise abruptly. Anaphylaxis: Anaphylactic shock with symptoms like bronchospam, mucous membrane congestion, CVS collapse induced by drugs or allergens can be reversed with the sub cutaneous administration of EPI that stimulates all 3 receptors (α, β1, β2). EPI is the initial treatment although glucocorticoids and antihistamines are also useful. Epinephrine is also useful for the treatment of allergic reactions that are due to liberation of histamine in the body, because it produces certain physiological effects opposite to those produced by histamine. It is the primary treatment for anaphylactic shock and is useful in the therapy of urticaria, angioneurotic edema, and serum sickness. Hypotension: where there is need to enhance the blood pressure such as in cases of decrease blood volume, cardiac arrhythmias, neurologic disease or adverse effects to drugs such as anti-hypertensives and infections. Sympathomimetics are the last resort in elevation of Blood pressure as it may increase patient’s morbidity. The underline problem should be addressed. So Sympathomimetics are used in emergency situations e.g severe hemorrhage, spinal cord injury or overdose of anti-hypertensive. Oral ephedrine is the first drug of choice, midodrine may also be used. Norepinephrine is infused intravenously to combat systemic hypotension during spinal anesthesia or other hypotensive conditions in which peripheral resistance is low, but it is not used to combat the hypotension due to most types of shock. In shock, marked sympathetic activity is already present, and perfusion of organs, such as the kidneys, may be jeopardized by norepinephrine administration. Shock: Shock is usually associated with hypovolemia and cardiac insufficiency, a complex CVS syndrome that decrease perfusion of vital organs/tissues. There is altered mental state, metabolic acidosis and it can lead to death if untreated. Although treating the underlying cause and volume replacement are the main focus, sympathomimetics have use in all forms of shock. However in cardiogenic shock due to intense myocardiac infarction, its use has poor prognosis. Rather emergency cardiac surgery and mechanically assisted perfusion is preferred. 15 Dopamine is also used in the treatment of shock owing to inadequate cardiac output (cardiogenic shock), which may be due to myocardial infarction or congestive heart failure. It is also used in the treatment of septic shock, since renal circulation is frequently compromised in this condition. An advantage of using dopamine in the treatment of shock is that its inotropic action increases cardiac output while dilating renal blood vessels and thereby increasing renal blood flow. CNS: Sympathomimetics that finds use in the CNS is amphetamine that has a mood elevating effect (euphoria). The drug also has an alerting sleep deferring effect hence used in the treatment of narcolepsy. Amphetamine in conjunction with other drugs may be used in weight control. They are also useful in attention deficit hyperkinetic syndrome in children. CVS: Paroxysmal atrial tachycardia (PAT) is effectively treated with α agonist like phenylephrine. However marked vasoconstriction with a rise in blood pressure makes its use difficult, it has to be monitored when used for PAT and should be given via slow IV infusion. Caution must be exercised to prevent a rise in systolic blood pressure. Safer alternatives are available such as verapamil. Isoprenaline and EPI are also used as emergency measures in complete heart block or cardiac arrest via redistribution of blood flow during cardiopulmonary resuscitation to coronaries and the brain. Congestive heart failure: CHF may also be treated with dobutamine from its positive inotropic effect, although development of tolerance is a major setback to the use of catecholamines in CHF. In summary the clinical uses of catecholamines are based on their actions on bronchial smooth muscle, blood vessels, and the heart. The vasoconstrictor actions of epinephrine and norepinephrine have been used to prolong the action of local anesthetics by reducing local blood flow in the region of the injection. Epinephrine has been used as a topical hemostatic agent for the control of local hemorrhage. 16 ADVERSE EFFECTS Their adverse effects are an extension of their pharmacological effects in the CVS and the CNS. They include marked increase in the blood pressure leading to cerebral hemorrhage, pulmonary edema, sever angina and myocardial infarction from increase cardiac work. Because they increase the force of the heartbeat, all three catecholamines may produce an excessively rapid heart rate. Palpitations produced by epinephrine and isoproterenol are accompanied by tachycardia, whereas those produced by norepinephrine usually are accompanied by bradycardia owing to reflex slowing of the heart. Headache and tremor are also common. Beta agonist will cause sinus tachycardia which may provoke ventricular arrhythmias. CNS adverse effects though rare however there could be restlessness, tremor, insomnia, anxiety and at high dose there could be a paranoid state from amphetamine. Cocaine may cause convulsion, cerebral hemorrhage, arrhythmia and myocardial infarction. Epinephrine is especially likely to produce anxiety, fear, and nervousness. The greatest hazards of accidental over-dosage with epinephrine and norepinephrine are cardiac arrhythmias, excessive hypertension, and acute pulmonary edema. Large doses of isoproterenol can produce such excessive cardiac stimulation, combined with a decrease in diastolic blood pressure, that coronary insufficiency may result.It also may cause arrhythmias and ventricular fibrillation. Tissue sloughing and necrosis due to severe local ischemia may follow extravasation of norepinephrine at its injection site. CONTRA-INDICATIONS FOR SYMPATHOMIMETICS Special caution in the elderly and hypertensive patients or those patients with coronary artery disease. Tachycardia, heart block, ventricular arrthymia, angina pectoris DRUG/DRUG INTERACTION Amiodarone, anti-pshychotics ANTIDOTE TO OVERDOSE 17 Any of the adrenergic antagonist should be used, e.g EPI OR NE administration can be reversed by alpha adrenergic blockers. Owolabi OJ 18