SYMPATHOMIMETICS

PROF. DR.SHAH MURADHOD, Pharmacology, LM&DC,Lahore

shahhmurad65@gmail.comCELL: +923142243415

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FATE OF ADR/NADR• Adrenergic neurons store their

transmitter substance in membrane bound vesicles.In adrenal medulla & certain areas of brain,NADR is further converted to adrenaline.In noradr neurons,portion of NADR isn’t stored in vesicles but exists in protected form in neuronal cytoplasm,which isn’t released by AP,but may b expelled by sympathomimetic drugs(tyramine)

• Many important mechanisms in nor-adr nerve terminal r potential sites of drug action,wh r inhibited by cocaine and TCAs

• Second high-affinity carrier for catecholamines is located in wall of storage vesicles and can b inhibited by RESERPINE.Release of vesicular content from nor-adr n/endings is calcium dependent. ATP,dopamine-ß-hydroxylase,and certain polypeptides r also released into synaptic cleft.ADR/NADR can b metabolized by MAO/COMT.Because of high affinity of MAO in mitochondria of nerve terminal,there is significant turnover of NADR,which can be estimated by 24 h urine sample.

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DIRECTLY ACTING ADRGIC AGONISTS:ADR,NADR,Isoprenaline,Dopamine,Dobutamine,Phenylephrine,Methoxamine,Clonidine,Metaproterenol,Albuterol,Terbutaline,Form

oterol,Salmeterol

• Adrenoceptor agonists or sympathomimetic r drugs which cause activation of Alfa and/or ß adrenoceptors either by a direct action on the receptors or indirectly by release of catecholamines and produce effects similar to those produced by stimulation of sympathetic nervous system.

• The natural transmitters of adrenergic system,NADR,ADR,and dopamine are catecholamines.The synthetic adrenoceptor agonists except isoprenaline are all non-catecholamines.

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CLASSIFICATION OF NONCATECHOLAMINE ADRGIC AGONISTS

• alfa-1 agonists:vasopressive agents(mephentermine,methoxamine,phenylephrine)Nasal decongestants(pseudoephedrine,phenylpropanolamine,naphazoline,xylometazoline,oxymetazoline)Mydriatric(phenylephrine)

• alfa-2 agonists:clonidine,alpha-methyldopa• Beta-1 agonists:prenalterol• Beta-2

agonists:Bronchodilators(metaproterenol,salbutamol,terbutaline)Vasodilator(isoxsuprine,nylidrine)Uterine relaxants(terbutaline,ritodrine)

• Miscellaneous(central stimulants,appetite suppressant)Amphetamine,methylamphetamine,methylphenedate,ephedrine,ethylnoradrenaline,tyramine.

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INDIRECTLY ACTING ADRGIC AGONISTScause NADR release from presynaptic terminals and potentiate the effects of NADR produced endogenously,but no effect on postsyneptic receptors.eg:Amphetamine,Tyramine…..Ephedrine is mixed action adrgic agonist and induce the release of NADR from presynaptic terminals,and activate adrgic receptors on postsyneptic membrane

• Noncatecholamines:Although the catecholamines have very powerful adrgic activity,they have certain disadvantages(1)inactive orally(2)cause necrosis of surrounding tissue when given s/c or I/m.(3)rapidly metabolized by MAO & COMT(short DOA).(4)are non selective.(5)don’t cross BBB.

• To overcome these difficulties the basic structure of catecholamine(phenylethylamine)was modified in various ways which gave rise to no of compounds which enhanced oral bioavailability,lowered the rate of metabolism by MAO and COMT and acquired selective actions on alfa and beta receptors.

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Epinephrine

• It is secreted by adrenal medulla & is also present in chromaffin cells and nervous tissue.Naturally occurring ADR is optically active and I-form,which is used clinically is much more potent than d-form.it is easily oxidizable and if kept exposed to air and light is converted into a coloured inactive and toxic compound,adrenochrome.so it must b kept in amber colour bottles with reducing agent like Na metabisulphite or ascorbic acid

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Pharmacological actions• Act on both alpha and ß receptors and action depends on type of adrenoceptors

present and their relative activities on different organs.• CVS…..ON HEART(ß-1mainly,although ß-2 and alpha-1 r also present)

+chronotropic, inotropic,dromotropic and lusitropic action.increase in c/output,Oxygen consumption,excitability and incidence of cardiac arrhythmias.ON BLOOD VESSELS(mainly alfa-1,also beta-2 in sk/blood vessels)Const of arteries supplying skin,mucous membrane & Splanchnic vessels(visceral,pulmonary,renal).Dilates coronary arteries and those supplying sk/muscles.contracts veins.ON B.P:raise systolic BP,due to inc c/output but fall in diastolic BP,due to dilat of sk/muscle blood vessels.raise mean BP

• RT:B/vessels of muc/membrane of URT r const and hence decongested by adr.It is potent B/Dilator causing relaxation of br/muscle(ß-2 effect)

ß

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Metabolic/other effects• Mainly ß effect.There is activation of membrane bound adenyl cyclase with

inc in prod of cAMP from ATP,which activates inactive phosphorylase to active phosphorylase-a,which catalyses conversion of glycogen in liver to glucose and cause hyperglycemia.Activates lipase which breaks down fat to FFA and glycerol.Increases Oxygen-consumption 20-30%.BMR & body temp is inc:….ADR,by alfa-2 adrgic stimulation suppresses insulin secretion which results in dec: glucose utilization by the tissues.

• ENDOCRINE actions:It modulates insulin and renin (alfa-2 is inhibitary and beta-2 is stimulatory) and also the secretion of parathormone,calcitonin,thyroxine and gastrin.

• It doesn’t cross BBB,so no effect in CNS, in therap doses but in high doses it causes excitement,restlessness,and tremors

• Inceases sweating of palms of hand and piloerection(alfa-1 effect)• Relax ur bladder.ut muscle in non-pregnant uterus is contracted and in preg

ut,relaxed.causes ejaculations in males

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Actions on Eye,GIT,and Sk/Muscles

• By contrc: of radial muscles,causes dilat of pupil and inc: outflow of A/H(alfa effect)

• Relaxes gut through stim: of beta-2 rec: on muscles and presynaptic receptor on cholinergic fibers reducing release of Ach.Peristalsis is inhibited and sphincters r closed.

• ADR acts indirectly on sk/muscles.By acting through presynaptic receptor it facilitates NM transmission and by acting through beta receptor improves blood supply to the sk/muscles.Thus it produces antifatigue effect in stress.

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Therapeutic uses of ADR

• Bronchospasm• Anaphylactic shock• Glaucoma• In anesthetics• It has been used in insulin hypoglycemia as an

emergency measure to mobilize liver glycogen.it will not b effective if the glycogen stores r already depleted as in starvation

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Pharmacokinetics/SE of ADR• ADR has rapid onset but brief DOA.In emergency conditions it is

given I/V for the most rapid onset of action.it may also b given s/c,by endotracheal tube,by inhalation or topically to the eye.Oral adm: is ineffective b/c it is destroyed by GIT enzymes.Only metabolites r exc in urine.

• SE…ON CNS: anxiety,fear,tension,headache,tremors.• ON CVS:cardiac arrhythmias,specially when pt is already on digitalis

therapy• PULMONARY EDEMA• Hemorrhage• Inc production of adrgic receptors on vasculature of hyperthyroid

individuals leading to hypersensitivity response

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Noradrenaline

• It differs from adrenaline only by lacking methyl substitution into the amine group:the prefix ‘nor’ is derived from the word ‘Nitrogen Ohni Radikal’which means nitrogen without methyl group of adrenaline.It is liberated from postganglionic sympathetic n/endings,adrenal medulla and constitutes 97% of the secretions of the tumor pheochromocytoma.Naturally occurring nor adrenaline is I-isomer which is much more potent than d-isomer.Physical properties r similar to adrenaline

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Pharmacological actions• Nor-adrenaline acts on alpha-receptors(less potent than

adrenaline),beta-1 receptor(equipotent to adrenaline) and has no effect on beta-2 receptor.Main actions r on CVS and other effects r minimal.

• It causes const: of arterioles in the skin,mucous membrane and the Splanchnic vessels.Blood flow is reduced through the viscera,liver,kidney,pulmonary vessels and sk/muscle.Veins r also constricted.coronary flow is increased due to coronary dilatation and rise in BP

• Total peripheral resistance is increased,so systolic,diastolic BP is increased and pulse pressure is reduced

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Actions on Heart• In the isolated heart it produces tachycardia due to beta-1

stm:but in intact heart there is bradycardia,since the rise in total peripheral resistance stm: aortic and carotid baroreceptors leading to a compensatory Vagal reflex activity.Cardiac output is unchanged or decreased.There is increased oxygen-consumption of heart.

• In large doses it may produce hyperglycemia,sweating and uterine contraction which r not seen in therapeutic doses.It is inactive orally,poorly absorbed when given s/c and may cause necrosis.it is given by slow I/v infusion,as the action is short-lasting

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Uses of NADR(levarterenol)

• Used as vasopressive agent in hypotension• Used in anaphylactic shock where there is pooling

of blood in the peripheral blood vessels.• It may also b used to counteract postural

hypotension after spinal anesthesia and ganglion blocker agents.

• It is also given after surgical removal of pheochromocytoma to maintain the vascular tone and then slowly tapered off.

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Dopamine • Immediate metabolic precursor of norepinephrine,occurs

naturally in the CNS in the basal ganglia,where it acts as NT,as well as in the adrenal medulla.

• Can activate alfa and beta adrenergic receptors.At high doses it can cause vasoconstriction by activating alfa receptors,whereas at lower doses it stimulates beta-1 cardiac receptors.

• D-1 and D-2 dopaminergic receptors r present in peripheral mesenteric and renal vascular beds,where binding of dopamine produces vasodilatation.D-2 receptors r also found on presynaptic adrenergic neurons,where their activation interferes with NADR release.

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Pharmacological actions• CVS:exerts a stimulatory effect on the beta-1 receptors of

the heart,having both inotropic and chronotropic effects.at very high doses it activates alfa receptors on the vasculature,resulting in vasoconstriction.

• Renal and visceral effects:it dilates renal and Splanchnic arterioles by activating dopaminergic receptors,thus increasing blood flow to the kidneys and other viscera.these receptors r not affected by alfa or beta blocking drugs,so dopamine is clinically useful in the treatment of shock,in which significant increase in sympathetic activity might compromise renal function.

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Therapeutic uses/SEs• Used in conditions of low cardiac output with

compromised renal function,such as cardiogenic and hypovolumic shock.Steps for immediate correction of hypovolumia,if present,should b taken.

• Used in CCF,refractory to other drugs.Dopamine has advantage over NADR that there is increased cardiac output with renal vasodilatation.

• It is given in pheochromocytoma after surgical removal of the tumour

• SE:in very high doses excessive sympathetic stimulation will result in vasocons,c/arrhythmias,angina pectoris,N/V

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Dobutamine• Drugs with beta adrenergic and dopaminergic agonistic

actions have positive inotropic and vasodilator properties which may b used to combat emergency pump failure.Dobutamine(beta-1agonist)having prominent inotropic action has been infused for acute heart failure accompanying MI,cardiac surgery.

• It is used to increase cardiac output in CCF• It doesn’t significantly elevate oxygen demands of the

myocardium---a major advantage over other sympathomimetic drugs.

• SE:it increases atrioventricular conduction which may lead to atrial fibrillation.other s/e are same as those for adrenaline