sympathomimetics shah

8/2/2019 Sympathomimetics Shah

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SYMPATHOMIMETICS

DR.SHAH MURAD


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FATE OF ADR/NADR

Adrenergic neurons store theirtransmitter substance inmembrane bound vesicles.Inadrenal medulla & certain areas

of brain,NADR is furtherconverted to adrenaline.Innoradr neurons,portion of NADRisnt stored in vesicles but existsin protected form in neuronalcytoplasm,which isnt released byAP,but may b expelled by

sympathomimeticdrugs(tyramine)

Many important mechanisms innor-adr nerve terminal rpotential sites of drug action,wh rinhibited by cocaine and TCAs

Second high-affinity carrier forcatecholamines is located in wallof storage vesicles and can binhibited by RESERPINE.Releaseof vesicular content from nor-adr

n/endings is calcium dependent.ATP,dopamine--hydroxylase,andcertain polypeptides r alsoreleased into synapticcleft.ADR/NADR can bmetabolized byMAO/COMT.Because of high

affinity of MAO in mitochondria ofnerve terminal,there is significantturnover of NADR,which can be

estimated by 24 h urine sample.


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DIRECTLY ACTING ADRGIC

AGONISTS:ADR,NADR,Isoprenaline,Dopamine,Dobutamine,Phenyleph

rine,Methoxamine,Clonidine,Metaproterenol,Albuterol,Terbutaline,Form

oterol,Salmeterol

Adrenoceptor agonists or sympathomimetic r drugs which

cause activation of Alfa and/or 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 allnon-catecholamines.


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CLASSIFICATION OF NONCATECHOLAMINE

ADRGIC AGONISTS alfa-1 agonists:vasopressive

agents(mephentermine,methoxamine,phenylephrine)Nasaldecongestants(pseudoephedrine,phenylpropanolamine,naphazoline,xylometazoline,oxymetazoline)Mydriatric(phenylephrine)

alfa-2 agonists:clonidine,alpha-methyldopa

Beta-1 agonists:prenalterol

Beta-2agonists:Bronchodilators(metaproterenol,salbutamol,terbutaline)Vasodilator(isoxsuprine,nylidrine)Uterine relaxants(terbutaline,ritodrine)

Miscellaneous(central stimulants,appetitesuppressant)Amphetamine,methylamphetamine,methylphenedate,ephedrine,ethylnoradrenaline,tyramine.


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INDIRECTLY ACTING ADRGIC AGONISTS

cause 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 postsynepticmembrane

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 nonselective.(5)dont 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 presentin chromaffin cells and nervous tissue.Naturallyoccurring ADR is optically active and I-form,whichis used clinically is much more potent than d-form.it is easily oxidizable and if kept exposed toair and light is converted into a coloured inactiveand toxic compound,adrenochrome.so it must b

kept in amber colour bottles with reducing agentlike Na metabisulphite or ascorbic acid


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Pharmacological actions

Act on both alpha and receptors and action depends on type of adrenoceptors

present and their relative activities on different organs.

CVS..ON HEART(-1mainly,although -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(-2 effect)


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Metabolic/other effects

Mainly effect.There is activation of membrane bound adenyl cyclase with incin prod of cAMP from ATP,which activates inactive phosphorylase to activephosphorylase-a,which catalyses conversion of glycogen in liver to glucose andcause 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 resultsin dec: glucose utilization by the tissues.

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

It doesnt cross BBB,so no effect in CNS, in therap doses but in high doses itcauses 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 pregut,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.itwill 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 excin urine.

SEON 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 methylsubstitution into the amine group:the prefix nor isderived from the word Nitrogen OhniRadikalwhich means nitrogen without methylgroup of adrenaline.It is liberated from

postganglionic sympathetic n/endings,adrenalmedulla and constitutes 97% of the secretions of

the tumor pheochromocytoma.Naturally occurringnor adrenaline is I-isomer which is much more

potent than d-isomer.Physical properties r similar toadrenaline


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Nor-adrenaline acts on alpha-receptors(less potent thanadrenaline),beta-1 receptor(equipotent to adrenaline) andhas 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 throughthe viscera,liver,kidney,pulmonary vessels andsk/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-1stm:but in intact heart there is bradycardia,since the rise intotal peripheral resistance stm: aortic and carotid

baroreceptors leading to a compensatory Vagal reflexactivity.Cardiac output is unchanged or decreased.There isincreased oxygen-consumption of heart.

In large doses it may produce hyperglycemia,sweating anduterine contraction which r not seen in therapeutic doses.It

is inactive orally,poorly absorbed when given s/c and maycause necrosis.it is given by slow I/v infusion,as the actionis 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 ganglionblocker agents.

It is also given after surgical removal ofpheochromocytoma to maintain the vascular toneand 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 asNT,as well as in the adrenal medulla.

Can activate alfa and beta adrenergic receptors.At high

doses it can cause vasoconstriction by activating alfareceptors,whereas at lower doses it stimulates beta-1 cardiacreceptors.

D-1 and D-2 dopaminergic receptors r present in peripheralmesenteric and renal vascular beds,where binding of

dopamine produces vasodilatation.D-2 receptors r alsofound on presynaptic adrenergic neurons,where theiractivation interferes with NADR release.


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CVS:exerts a stimulatory effect on the beta-1 receptors ofthe heart,having both inotropic and chronotropic effects.atvery 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,thusincreasing blood flow to the kidneys and other viscera.thesereceptors r not affected by alfa or beta blocking drugs,so

dopamine is clinically useful in the treatment of shock,inwhich significant increase in sympathetic activity mightcompromise renal function.


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Therapeutic uses/SEs

Used in conditions of low cardiac output with compromisedrenal function,such as cardiogenic and hypovolumicshock.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 outputwith renal vasodilatation.

It is given in pheochromocytoma after surgical removal ofthe tumour

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


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Dobutamine

Drugs with beta adrenergic and dopaminergic agonisticactions have positive inotropic and vasodilatorproperties which may b used to combat emergencypump failure.Dobutamine(beta-1agonist)having

prominent inotropic action has been infused for acuteheart failure accompanying MI,cardiac surgery.

It is used to increase cardiac output in CCF

It doesnt significantly elevate oxygen demands of themyocardium---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 foradrenaline

sympathomimetics shah

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