1. Introduction Most of the actions ofcatecholamines and sympathomimetic agents can be classified into seven broad types1.A peripheral excitatory action on certain types of smoothmuscle, such as those in blood vessels supplying skin,kidney, and mucous membranes, and on gland cells.2.A peripheral inhibitory action on certain other types ofsmooth muscle, such as those in the wall of the gut, inthe bronchial tree, and in blood vessels supplyingskeletal muscle

2. 3. A cardiac excitatory action that increases heart rate and force of contraction.4. Metabolic actions, such as an increase in the rate of glycogenolysis in liver and muscle and liberation of free fatty acids from adipose tissue.5. Endocrine actions, such as modulation (increasing or decreasing) of the secretion of insulin, renin, and pituitary hormones. 3. 6. Actions in the central nervous system (CNS), such as respiratory stimulation, an increase in wakefulness and psychomotor activity, and a reduction in appetite.7. Prejunctional actions that either inhibit or facilitate the release of neurotransmitters, the inhibitory action being physiologically more important. 4. CATECHOLAMINES Catecholamines are compounds containing a catechol moiety (abenzene ring with two adjacent hydroxyl groups) and an amineside-chain. Pharmacologically, the most important ones are: Noradrenaline (norepinephrine), a transmitter released bysympathetic nerve terminals Adrenaline (epinephrine), a hormone secreted by the adrenalmedulla 5. Dopamine, the metabolic precursor of noradrenaline and adrenaline, also a transmitter/neuromodulator in the central nervous system Isoproterenol (previously isoprenaline), a synthetic derivative of noradrenaline, not present in the body. 6. Noradrenergic Neuron Noradrenergicneuronsin the periphery are postganglionicsympathetic neurons whose cell bodies lie in sympathetic ganglia. These varicosities contain numerous synaptic vesicles, which are thesites of synthesis and release of noradrenaline and of coreleasedmediators such as ATP and neuropeptide Y. Fluorescence histochemistry shows that noradrenaline is present athigh concentration in these varicosities, where it is stored in largedense-core vesicles, and released by exocytosis. 7. With the exception ofthe adrenal medulla, sympathetic nerve terminals account for all the noradrenaline content of peripheral tissues. Organs such as the heart, spleen, vas deferens and someblood vessels areparticularly rich in noradrenaline (5-50 nmol/g of tissue) and have been widely used for studies of noradrenergic transmission. 8. The metabolic precursor for noradrenaline is L-tyrosine, anaromatic amino acid that is present in the body fluids, and istaken up by adrenergic neurons. Tyrosine hydroxylase, a cytosolic enzyme that catalyses theconversion of tyrosine to dihydroxyphenylalanine (dopa) isfound only in catecholamine-containing cells. This first hydroxylation step is the main control point fornoradrenaline synthesis. 9. Tyrosine hydroxylase is inhibited by the end-product of the biosynthetic pathway, noradrenaline. This provides the mechanism for the moment-to- moment regulation of the rate of synthesis; much slower regulation, taking hours or days, occurs by changes in the rate of production of the enzyme. 10. The tyrosine analogue -methyltyrosine strongly inhibits tyrosine hydroxylase and may be used experimentally to block noradrenaline synthesis. 11. Dopa to Dopamine The next step, conversion of dopa to dopamine, is catalysedby dopa decarboxylase, a cytosolic enzyme that is by nomeans confined to catecholamine-synthesising cells. It is a relatively non-specific enzyme, and catalyses thedecarboxylation of various other L-aromatic amino acids,such as L-histidine and L-tryptophan, which are precursorsin the synthesis of histamine and 5-HT, respectively. 12. Dopa decarboxylase activity is not rate-limiting for noradrenaline synthesis. Althoughvariousfactors,includingcertain drugs, affect the enzyme, it is not an effective means of regulating noradrenaline synthesis. 13. Dopamine--hydroxylase (DBH) is also a relativelynon-specific enzyme,but is restricted tocatecholamine-synthesising cells. It is located in synaptic vesicles, mainly in membrane-bound form. A small amount of the enzyme is released fromadrenergic nerve terminals in company withnoradrenaline, representing the small proportion in asoluble form within the vesicle. 14. Unlike noradrenaline, the released DBH is not subject torapid degradation or uptake, so its concentration in plasmaand body fluids can be used as an index of overallsympathetic nerve activity. Many drugs inhibit DBH, including copper-chelatingagents and disulfiram. Such drugs can cause a partial depletion of noradrenalinestores and interference with sympathetic transmission. 15. Noradrenaline to Adrenaline Phenylethanolamine N-methyltransferase (PNMT)catalyses the N-methylation ofnoradrenaline toadrenaline. The main location of this enzyme is in the adrenal medulla,which contains a population of adrenaline-releasing (A)cells separatefrom thesmaller proportionofnoradrenaline-releasing (N) cells. 16. The A cells lie adjacent to the adrenal cortex, and the production of PNMT is induced by an action of the steroid hormones secreted by the adrenal cortex. PNMT is also found in certain parts of the brain, where adrenaline may function as a transmitter, but little is known about its role. 17. Noradrenaline storage Most of the noradrenaline in nerve terminals or chromaffin cellsis contained in vesicles; only a little is free in the cytoplasmunder normal circumstances. The concentration in the vesicles is very high (0.3-1.0 mol/l) andis maintained by the vesicular monoamine transporter. Certain drugs, such as reserpine block this transport and causenerve terminals to become depleted of their noradrenalinestores. 18. The vesicles contain two major constituents besides noradrenaline, namely ATP (about four molecules per molecule of noradrenaline) anda protein called chromogranin A. These substances are released along with noradrenaline, and it is generally assumed that a reversible complex, depending partly on the opposite charges on the molecules of noradrenaline and ATP, is formed within the vesicle. 19. Noradrenaline release The processes linking the arrival of a nerve impulse at anoradrenergic nerve terminal to the release ofnoradrenaline are basically the same as those at otherchemically transmitting synapses. Depolarisation of the nerve terminal membrane openscalcium channels in the nerve terminal membrane, and theresulting entry of Ca2+ promotes the fusion and dischargeof synaptic vesicles. 20. A single neuron possesses many thousand varicosities, so one impulse leads to the discharge of a few hundred vesicles, scattered over a wide area. 21. Classification of adrenoceptors Adrenoceptor subtypes: two main -receptor subtypes, 1 and 2, each divided into three further subtypes three -adrenoceptor subtypes (1, 2, 3) all belong to the superfamily of G-protein-coupled receptors. 22. Second messengers: 1-receptors activate phospholipase C, producing inositol trisphosphate and diacylglycerol as second messengers 2-receptors inhibit adenylate cyclase, decreasing cAMP formation all types of -receptor stimulate adenylyl cyclase. 23. The main effects of receptor activation are as follows. 1-receptors: vasoconstriction, relaxation ofgastrointestinal smooth muscle, salivary secretion andhepatic glycogenolysis 2-receptors: inhibition of transmitter release (includingnoradrenaline and acetylcholine release from autonomicnerves), platelet aggregation, contraction of vascularsmooth muscle, inhibition of insulin release 24. 1-receptors: increased cardiac rate and force 2-receptors: bronchodilatation, vasodilatation,relaxation of visceral smooth muscle, hepaticglycogenolysis and muscle tremor 3-receptors: lipolysis. : noradrenaline > adrenaline > isoproterenol : isoproterenol > adrenaline > noradrenaline. 25. 1-receptors are found mainly in the heart, where theyare responsible for the positive inotropic andchronotropic effects of catecholamines. 2-receptors are responsible for causing smoothmuscle relaxation in many organs. The latter is often a useful therapeutic effect, while theformer is more often harmful; consequently,considerable efforts have been made to find selective2 agonists, which would relax smooth muscle withoutaffecting the heart. 26. And selective 1 antagonists, which would exert auseful blocking effect on the heart without at the sametime blocking 2-receptors in bronchial smoothmuscle. It is important to realise that the selectivity of thesedrugs is relative rather than absolute. Thuscompounds used as selective 1-antagonists invariablyhave some action on 2-receptors as well, which cancause unwanted effects such as bronchoconstriction. 27. UPTAKE AND DEGRADATIONOFCATECHOLAMINES The action of released noradrenaline is terminatedmainly by reuptake of the transmitter intonoradrenergic nerve terminals. Circulating adrenaline and noradrenaline aredegraded enzymically, but much more slowly thanacetylcholine. The two main catecholamine-metabolising enzymesare located intracellularly, so uptake into cellsnecessarily precedes metabolic degradation. 28. Uptake mechanisms Uptake 1: is also known as neuronal uptake Uptake 2: is also known as extraneuronal uptake 29. Uptake 1 About75% of the noradrenaline released bysympathetic neurons is recycled via uptake1. Thus uptake 1 serves to cut short the action of thetransmitter, and to recycle it. Uptake 1 is a high-affinity system, relatively selectivefor noradrenaline, with a low maximum rate ofuptake, and it is important in maintaining releasablestores of noradrenaline. 30. Uptake 2 The remainder being captured by other cells in thevicinity via uptake 2. Uptake 2 serves mainly to limit its spread. Uptakes 1 and 2 are associated with distincttransporter molecules, the noradrenaline transporter(generally known as NET, the norepinephrinetransporter) and the vesicular monoamine transporter(VMAT), respectively. They have different kinetic properties as well asdifferent substrate and inhibitor specificity, 31. Uptake 2 has low affinity, and transports adrenaline and isoproterenol as well as noradrenaline, at a much higher maximum rate than uptake 1. 32. Metabolic degradation ofcatecholamines Endogenousand exogenous catecholamines aremetabolised mainly by two enzymes: monoamineoxidase (MAO) and catechol-O-methyl transferase(COMT). MAO occurs within cells, bound to the surfacemembrane of mitochondria. It is abundant innoradrenergic nerve terminals but is also present inmany other places, such as liver and intestinalepithelium. 33. MAO converts catecholamines to their corresponding aldehydes, which, in the periphery, are rapidly metabolised by aldehyde dehydrogenase to the corresponding carboxylic acid (3,4- dihydroxyphenylglycolbeingformedfrom noradrenaline. 34. The second major pathway for catecholamine metabolisminvolves methylation of one of the catechol hydroxylgroups to give a methoxy derivative. COMT is absent from noradrenergic neurons but presentin the adrenal medulla and many other cells and tissues.The final product formed by the sequential action of MAOand COMT is 3-hydroxy-4-methoxyphenylglycol (MHPG). This is partly conjugated to sulfate or glucuronidederivatives, which are excreted in the urine, but most of itis converted to vanillylmandelic acid (VMA) and excreted inthe urine in this form.3 35. In patients with tumours of chromaffin tissue that secretethese amines (a rare cause of high blood pressure), theurinary excretion of VMA is markedly increased, this beingused as a diagnostic test for this condition. In the periphery, neither MAO nor COMT is primarilyresponsible for the termination of transmitter action, mostof the released noradrenaline being quickly recaptured byuptake 1. Circulating catecholamines are usually inactivated by acombination of uptake 1, uptake 2 and COMT, the relativeimportance of these processes varying according to theagent concerned. 36. Thus circulating noradrenaline is removed mainly by uptake 1, whereas adrenaline is more dependent on uptake 2. Isoproterenol, on the other hand, is not a substrate for uptake1, and is removed by a combination of uptake2 and COMT. 37. DRUGS ACTING ON NORADRENERGICTRANSMISSION Adrenoceptors Monoamine transporters Catecholamine-metabolising enzymes 38. DRUGS ACTING ON ADRENOCEPTORS Clinical uses 39. Noradrenaline and adrenaline show relatively littlereceptor selectivity. Selective 1 agonists include phenylephrine andoxymetazoline. Selective 2 agonists include clonidine and -methylnoradrenaline. They cause a fall in bloodpressure, partly by inhibition of noradrenaline releaseand partly by a central action. Methylnoradrenaline isformed as a false transmitter from methyldopa,developed as a hypotensive drug (now largelyobsolete). 40. Selective 1 agonists include dobutamine. Increasedcardiac contractility may be useful clinically, but all 1agonists can cause cardiac dysrhythmias. Selective 2 agonists include salbutamol, terbutalineand salmeterol, used mainly for their bronchodilatoraction in asthma. Selective 3 agonists may be developed for the controlof obesity. 41. Smooth muscle Alltypes of smooth muscle, except that of thegastrointestinal tract, contract in response to stimulationof 1-adrenoceptors, through activation of the signaltransduction mechanism. agonists : vascular smooth muscle, particularly in the skin and splanchnic vascular beds, which are strongly constricted. Large arteries and veins, as well as arterioles, are also constricted, resulting in decreased vascular compliance, increased central venous pressure and increased peripheral resistance, all of which contribute to an increase in systolic and diastolic arterial pressure and increased cardiac work. 42. Baroreceptor reflexes are activated by the rise in arterialpressure produced by agonists, causing reflexbradycardia and inhibition of respiration. The -receptors involved in smooth muscle contractionare mainly 1 in type, although vascular smooth musclepossesses both 1 and 2-receptors. It appears that 1-receptors lie close to the sites of release(and are mainly responsible for neurally mediatedvasoconstriction), while 2-receptors lie elsewhere onthe muscle fibre surface and are activated by circulatingcatecholamines. 43. The sphincters of the gastrointestinal tract arecontracted by -receptor activation. In gastrointestinal smooth muscle -receptors causerelaxation in most regions. Part of the effect is due to stimulation of presynaptic 2-receptors, which inhibit the release of excitatorytransmitters (e.g. acetylcholine) from intramural nerves. The sphincters of the gastrointestinal tract arecontracted by -receptor activation. 44. -Adrenoceptors also mediate a long-lasting trophicresponse, stimulating smooth muscle proliferation invarious tissues, for example in blood vessels and in theprostate gland, which is of pathological importance. Benign prostatic hyperplasia is commonly treated with-adrenoceptor antagonists 45. -receptors Causes relaxation of most kinds of smooth muscle byincreasing cAMP formation. Additionally, -receptoractivation enhances Ca2+ extrusion and intracellularCa2+ binding, both effects acting to reduce intracellularCa2+ concentration. Bronchial smooth muscle is strongly dilated byactivation of 2-adrenoceptors, and selective 2agonists are important in the treatment of asthma. Uterine smooth muscle responds similarly, and thesedrugs are also used to delay premature labour 46. Heart 1-receptors, exert a powerful stimulant effect on theheart (see Ch. 18). Both the heart rate (chronotropiceffect) and the force of contraction (inotropic effect)are increased, resulting in a markedly increasedcardiac output and cardiac oxygen consumption. The cardiac efficiency (see Ch. 18) is reduced. Disturbance of the cardiac rhythm 47. Cardiac hypertrophy occurs in response to activation of 1-receptors, probably by a mechanism similar to the hypertrophy of vascular and prostatic smooth muscle. 48. Metabolism encourage the conversion of energy stores (glycogenand fat) to freely available fuels carbohydrate metabolism of liver and muscle aremediated through 1-receptors stimulation of lipolysis is produced by 3-receptors 49. Other effects The twitch tension of fast-contracting fibres (whitemuscle) is increased by adrenaline, particularly if themuscle is fatigued, whereas the twitch of slow (red) muscleis reduced. These effects depend on an action on the contractileproteins, rather than on the membrane, and themechanism is poorly understood. In humans, adrenaline and other 2 agonists cause amarked tremor, the shakiness that accompaniesfear, excitement or the excessive use of 2 agonists (e.g.salbutamol) in the treatment of asthma being examples ofthis. 50. It probably results from an increase in muscle spindledischarge, coupled with an effect on the contractionkinetics of the fibres, these effects combining to producean instability in the reflex control of muscle length. -Receptor antagonists are sometimes used to controlpathological tremor. The 2 agonists also cause long-term changes in theexpression of sarcoplasmic reticulum proteins that controlcontraction kinetics, and thereby increase the rate andforce of contraction of skeletal muscle. Clenbuterol, ananabolic drug used illicitly by athletes to improveperformance, is a 2 agonist that acts in this way. 51. Histamine release by human and guinea pig lung tissue in response to anaphylactic challenge is inhibited by catecholamines, acting apparently on 2- receptors. 52. -Adrenoceptor antagonists Non-selective-receptorantagonists (e.g.phenoxybenzamine, phentolamine) 1-selectiveantagonists(e.g.prazosin, doxazosin, terazosin) 2-selective antagonists (e.g. yohimbine, idazoxan) ergotderivatives (e.g.ergotamine, dihydroergotamine). This group ofcompounds has many actions in addition to -receptorblock, and is discussed in. Their action on -adrenoceptors is of pharmacological interest but notused therapeutically. 53. Non-selective -adrenoceptorantagonists Phenoxybenzamine is not specific for -receptors, andalso antagonises the actions of acetylcholine, histamineand 5-HT. It is long-lasting because it binds covalently tothe receptor. Phentolamine is more selective, but it binds reversiblyand its action is short-lasting. In humans, these drugscause a fall in arterial pressure (because of block of -receptor-mediatedvasoconstriction)andposturalhypotension. The cardiac output and heart rate are increased. This is areflex response to the fall in arterial pressure, mediatedthrough -receptors. 54. The concomitant block of 2-receptors tends to increase noradrenaline release, which has the effect of enhancing the reflex tachycardia that occurs with any blood pressure-lowering agent. 55. Labetalol and carvedilol are mixed and -receptor-blocking drugs, although clinically they actpredominantly on -receptors. Much has been madeof the fact that they combine both activities in onemolecule. To a pharmacologist, accustomed to putting specificityof action high on the list of pharmacological saintlyvirtues, this may seem like a step backwards ratherthan forwards. 56. Carvedilol is used mainly to treat hypertension and heart failure; labetalol is used to treat hypertension in pregnancy. 57. Selective 1 antagonists Prazosin was the first 1-selective antagonist. Similardrugs with longerhalf-lives(e.g.doxazosin, terazosin), which have the advantage ofallowing once-daily dosing, are now available. They are highly selective for 1-adrenoceptors andcause vasodilatation and fall in arterial pressure, butless tachycardia than occurs with non-selective -receptor antagonists, presumably because they do notincrease noradrenaline release from sympathetic nerveterminals. Some postural hypotension may occur. 58. The 1-receptor antagonists cause relaxation of thesmooth muscle of the bladder neck and prostatecapsule, and inhibit hypertrophy of these tissues, andare therefore useful in treating urinary retentionassociated with benign prostatic hypertrophy. Tamsulosin, an 1A-receptor antagonist, shows someselectivity for the bladder, and causes less hypotensionthan drugs such as prazosin, which act on 1B-receptorsto control vascular tone. 59. It is believed that 1A-receptors play a part in the pathological hypertrophy not only of prostatic and vascular smooth muscle, but also in the cardiac hypertrophy that occurs in hypertension, and the use of selective 1A-receptor antagonists to treat these chronic conditions is under investigation. 60. Selective 2 antagonists Yohimbine is a naturally occurring alkaloid; varioussynthetic analogues have been made, such asidazoxan. These drugs are used experimentally to analyse -receptor subtypes, and yohimbine, probably by virtueof its vasodilator effect, historically enjoyed notorietyas an aphrodisiac, but they are not usedtherapeutically. 61. Clinical uses Severe hypertension : 1-selective antagonists (e.g.doxazosin) in combination with other drugs. Benign prostatic hypertrophy (e.g. tamsulosin, aselective 1A-receptor antagonist). Phaeochromocytoma:phenoxybenzamine(irreversible antagonist) in preparation for surgery 62. -Adrenoceptor antagonists Non-selective between 1 and 2 adrenoceptors:propranolol, alprenolol, oxprenolol. 1-selective: atenolol, nebivolol. Alprenolol and oxprenolol have partial agonistactivity. 63. Clinical uses of -adrenoceptorantagonists Cardiovascular: angina pectoris myocardial infarction dysrhythmias heart failure hypertension Other uses: glaucoma (e.g. timolol eye drops) Thyrotoxicosi,as adjunct to definitive treatment (e.g. preoperatively) anxiety, to control somatic symptoms (e.g. palpitations, tremor) migraine prophylaxis benign essential tremor (a familial disorder). 64. Unwanted effects Bronchoconstriction. This is of little importance in theabsence of airways disease, but in asthmatic patients theeffect can be dramatic and life-threatening. It is also ofclinical importance in patients with other forms ofobstructive lung disease(e.g. chronicbronchitis, emphysema). Cardiacdepression.Cardiac depressioncanoccur, leading to signs of heart failure, particularly inelderly people. Patients suffering from heart failure who aretreated with -receptor antagonists (see above) oftendeteriorate in the first few weeks before the beneficialeffect develops. 65. Bradycardia. This side effect can lead to life-threateningheart block and can occur in patients with coronarydisease, particularly if they are being treated withantiarrhythmic drugs that impair cardiac conduction Hypoglycaemia. Glucose release in response to adrenalineis a safety device that may be important to diabetic patientsand to other individuals prone to hypoglycaemic attacks. The sympathetic response to hypoglycaemia producessymptoms (especially tachycardia) that warn patients ofthe urgent need for carbohydrate (usually in the form of asugary drink). -Receptor antagonists reduce thesesymptoms, so incipient hypoglycaemia is more likely to gounnoticed by the patient. 66. The use of -receptor antagonists is generally to beavoided in patients with poorly controlled diabetes.There is a theoretical advantage in using 1-selectiveagents, because glucose release from the liver iscontrolled by 2-receptors. Fatigue. This is probably due to reduced cardiacoutput and reduced muscle perfusion in exercise. It isa frequent complaint of patients taking receptor-blocking drugs. 67. Cold extremities. These are presumably due to a lossof -receptor-mediated vasodilatation in cutaneousvessels, and are a common side effect. Theoretically, 1-selective drugs are less likely to produce this effect, butit is not clear that this is so in practice. Occurrence of bad dreams, which occur mainly withhighly lipid-soluble drugs such as propranolol, whichenter the brain easily. 68. DRUGS THAT AFFECT NORADRENALINESYNTHESIS -methyltyrosine, which inhibits tyrosine hydroxylase(used rarely to treat phaeochromacytoma), andcarbidopa, a hydrazine derivative of dopa, which inhibitsdopa decarboxylase and is used in the treatment ofparkinsonism. Methyldopa, a drug still used in the treatment ofhypertension during pregnancy is taken up bynoradrenergic neurons, where it is converted to the falsetransmitter -methylnoradrenaline. This substance is not deaminated within the neuron byMAO, so it accumulates and displaces noradrenaline fromthe synaptic vesicles. 69. -Methylnoradrenaline is released in the same way asnoradrenaline, but is less active than noradrenaline on1-receptors and thus is less effective in causingvasoconstriction. On the other hand, it is more active on presynaptic(2) receptors, so the autoinhibitory feedbackmechanism operates more strongly than normal, thusreducing transmitter release below the normal levels. Both of these effects (as well as a central effect,probably caused by the same cellular mechanism)contribute to the hypotensive action. 70. It produces side effects typical of centrally acting antiadrenergic drugs (e.g. sedation), as well as carrying a risk of immune haemolytic reactions and liver toxicity, so it is now little used, except for hypertension in late pregnancy. 71. 6-Hydroxydopamine is a neurotoxin of the Trojan horsekind. It is taken up selectively by noradrenergic nerveterminals, where it is converted to a reactivequinone, which destroys the nerve terminal, producing achemical sympathectomy. The cell bodies survive, andeventually the sympathetic innervation recovers. The drug is useful for experimental purposes but has noclinical uses. If injected directly into the brain, it selectivelydestroys those nerve terminals that take it up, but it doesnot reach the brain if given systemically. MPTP (1-methyl-4-phenyl-1,2,3,5-tetrahydropyridine) is arather similar selective neurotoxin. 72. DRUGS THAT AFFECTNORADRENALINE STORAGE Reserpine is an alkaloid from the shrub Rauwolfia,which has been used in India for centuries for thetreatment of mental disorders. Reserpine, at very low concentration, blocks thetransport of noradrenaline and other amines intosynaptic vesicles, by blocking the vesicularmonoamine transporter. Noradrenaline accumulates instead in the cytoplasm,where it is degraded by MAO. The noradrenalinecontent of tissues drops to a low level, and sympathetictransmission is blocked. 73. Reserpine also causes depletion of 5-HT and dopaminefrom neurons in the brain, in which these amines aretransmitters. Reserpine is now used onlyexperimentally, but was at one time used as anantihypertensive drug. Its central effects, especially depression, whichprobably result from impairment of noradrenergic and5-HT-mediated transmission in the brain are a seriousdisadvantage. 74. DRUGS THAT AFFECTNORADRENALINE RELEASE Drugs can affect noradrenaline release in four main ways: by directly blocking release (noradrenergic neuron-blocking drugs) by evoking noradrenaline release in the absence of nerveterminaldepolarisation(indirectly actingsympathomimetic drugs) by interacting with presynaptic receptors that indirectlyinhibit or enhance depolarisation-evoked release (e.g. 2agonists, angiotensin II, dopamine, and prostaglandins). by increasing or decreasing available stores ofnoradrenaline 75. NORADRENERGIC NEURON-BLOCKING DRUGS Guanethidine The main effect of guanethidine is to inhibit therelease of noradrenaline from sympathetic nerveterminals. It has little effect on the adrenal medulla, and none onnerve terminals that release transmitters other thannoradrenaline. Drugs verysimilar to it includebretylium, bethanidine, and debrisoquin. 76. Actions Drugs of this class reduce or abolish the response oftissues to sympathetic nerve stimulation, but do notaffect (or may potentiate) the effects of circulatingnoradrenaline. It is selectively accumulated by noradrenergic nerveterminals, being a substrate for uptake 1. Its initial blocking activity is due to block of impulseconduction in the nerve terminals that selectivelyaccumulate the drug. Its action is prevented by drugs,such as tricyclic antidepressants, which block uptake 1. 77. Guanethidine is also concentrated in synaptic vesicles bymeans of the vesicular transporter, possibly interferingwith their ability to undergo exocytosis, and also displacingnoradrenaline. In this way, it causes a gradual and long-lasting depletion of noradrenaline in sympathetic nerveendings, similar to the effect of reserpine. Extremely effective in lowering blood pressure, theyproduce severe side effects associated with the loss ofsympathetic reflexes. The most troublesome are posturalhypotension, diarrhoea, nasal congestion and failure ofejaculation. 78. INDIRECTLY ACTINGSYMPATHOMIMETIC AMINES Tyramine, amphetamine and ephedrine, which arestructurally related to noradrenaline. Drugs that actsimilarly and are used for their central effects includemethylphenidate and atomoxetine. These drugs have only weak actions on adrenoceptors, butsufficiently resemble noradrenaline to be transported intonerve terminals by uptake 1. Once inside the nerve terminals, they are taken up into thevesicles by the vesicular monoamine transporter, inexchange for noradrenaline, which escapes into the cytosol. Some of the cytosolic noradrenaline is degraded byMAO, while the rest escapes via uptake 1, in exchange forthe foreign monoamine, to act on postsynaptic receptors 79. Exocytosis is not involved in the release process, so their actionsdo not require the presence of Ca2+. They are not completely specific in their actions, and act partlyby a direct effect on adrenoceptors, partly by inhibiting uptake 1(thereby enhancing the effect of the released noradrenaline),and partly by inhibiting MAO. MAO inhibitors, on the other hand, strongly potentiate theireffects by preventing inactivation, within the terminals, of thetransmitter displaced from the vesicles. MAO inhibition particularly enhances the action of tyramine,because this substance is itself a substrate for MAO. Normally,dietary tyramine is destroyed by MAO in the gut wall and liverbefore reaching the systemic circulation. 80. When MAO is inhibited this is prevented, and ingestion of tyramine-rich foods such as fermented cheese (e.g. ripe Brie) can then provoke a sudden and dangerous rise in blood pressure. Inhibitors of uptake 1, such as imipramine (see below), interfere with the effects of indirectly acting sympathomimetic amines by preventing their uptake into the nerve terminals. 81. Actions The peripheralactions of the indirectly actingsympathomimetic amines include bronchodilatation,raised arterial pressure, peripheral vasoconstriction,increased heart rate and force of myocardial contraction,and inhibition of gut motility. They have important central actions, which account fortheir significant abuse potential and for their limitedtherapeutic applications. Apart from ephedrine, which is still sometimes used as anasal decongestant because it has much less central action,these drugs are no longer used for their peripheralsympathomimetic effects. 82. INHIBITORS OF NORADRENALINEUPTAKE The main class of drugs whose primary action isinhibition of uptake 1 are the tricyclicantidepressants, for example desipramine. These drugs have their major effect on the centralnervous system but also cause tachycardia and cardiacdysrhythmias, reflecting their peripheral effect onsympathetic transmission. Cocaine, known mainly for its abuse liability and localanaestheticactivity, enhances sympathetictransmission, causing tachycardia and increasedarterial pressure. 83. Its central effects of euphoria and excitement are probably a manifestation of the same mechanism acting in the brain. It strongly potentiates the actions of noradrenaline in experimental animals or in isolated tissues provided the sympathetic nerve terminals are intact.