Sympathomimetics Shah
-
Upload
drshah-murad -
Category
Documents
-
view
219 -
download
0
Transcript of Sympathomimetics Shah
-
8/2/2019 Sympathomimetics Shah
1/19
SYMPATHOMIMETICS
DR.SHAH MURAD
-
8/2/2019 Sympathomimetics Shah
2/19
04/30/12 2
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.
-
8/2/2019 Sympathomimetics Shah
3/19
04/30/12 3
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.
-
8/2/2019 Sympathomimetics Shah
4/19
04/30/12 4
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.
-
8/2/2019 Sympathomimetics Shah
5/19
04/30/12 5
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.
-
8/2/2019 Sympathomimetics Shah
6/19
04/30/12 6
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
-
8/2/2019 Sympathomimetics Shah
7/19
04/30/12 7
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)
-
8/2/2019 Sympathomimetics Shah
8/19
04/30/12 8
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
-
8/2/2019 Sympathomimetics Shah
9/19
04/30/12 9
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.
-
8/2/2019 Sympathomimetics Shah
10/19
04/30/12 10
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
-
8/2/2019 Sympathomimetics Shah
11/19
04/30/12 11
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
-
8/2/2019 Sympathomimetics Shah
12/19
04/30/12 12
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
-
8/2/2019 Sympathomimetics Shah
13/19
04/30/12 13
Pharmacological actions
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
-
8/2/2019 Sympathomimetics Shah
14/19
04/30/12 14
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
-
8/2/2019 Sympathomimetics Shah
15/19
04/30/12 15
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.
-
8/2/2019 Sympathomimetics Shah
16/19
04/30/12 16
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.
-
8/2/2019 Sympathomimetics Shah
17/19
04/30/12 17
Pharmacological actions
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.
-
8/2/2019 Sympathomimetics Shah
18/19
04/30/12 18
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
-
8/2/2019 Sympathomimetics Shah
19/19
04/30/12 19
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