adr pharmacology

7/28/2019 ADR Pharmacology

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Sumanth Dept of Pharmacology

Pharmacology of Adrenergic & Antiadrenergic Drugs

Introduction

Adrenergic pharmacology involves the study of agents that act on pathways mediated by

the endogenous catecholamines norepinephrine, epinephrine, and dopamine.The sympathetic nervous system is the major source of endogenous catecholamine

production and release.

Signaling through catecholamine receptors mediates diverse physiologic effects, including:

increasing the rate and force of cardiac contraction, modifying the peripheral resistance of

the arterial system, inhibiting the release of insulin, stimulating hepatic release of glucose,

and increasing adipocyte release of free fatty acids.

Drugs that target the synthesis, storage, release, and reuptake of norepinephrine and

epinephrine or that directly target the postsynaptic receptors for these transmitters are

frequent therapies for many major diseases, including hypertension, shock, asthma, and

angina.

Adrenergic Transmission

Synthesis of Catecholamines Storage of Catecholamines Release of Catecholamines Uptake of Catecholamines

Axonal Uptake Vesicular Uptake Extraneuronal Uptake

Metabolism of Catecholamines(MAO & COMT)


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Adrenoreceptors

Adrenergic receptors (adrenoceptors) are selective for norepinephrine and epinephrine.

Supraphysiologic concentrations of dopamine can also activate some adrenoreceptors.

Adrenergic receptors are membrane bound G-Protein coupled receptors which function

primarily by increasing or decreasing the intracellular production of secondary messengerscAMP or IP3/DAG.

In some cases the activated G-Protein itself operates K+ or Ca2+ channels.

Adrenoceptors have been divided into three main classes 1, 2& .

Each of these major classes has three subtypes

1 1A, 1B and 1D

2 2A, 2B and 2C

1, 2and 3

Location of Receptors

Type Tissue Actions

1 Vascular smooth muscle contractionGenitourinary smooth muscle contraction

Pupillary dilator muscle Contraction (dilates pupil)

Pilomotor smooth muscle Erects hair

Prostate contraction

Heart inotropy and excitability

Liver Glycogenolysis & gluconeogenesis

2 Nerve terminals Inhibits transmitter release

Pancreatic -cells insulin secretionPlatelets Aggregation

Vascular smooth muscle Contraction

1 Heart Chronotropy and inotropy

Heart AV node conduction velocity

Renal juxtaglomerular cells Renin secretion

2 Smooth muscle(uterine, respiratory, vascular)

Relaxation

Liver Glycogenolysis & gluconeogenesis

Skeletal muscle Glycogenolysis and K+ uptake3 Adipose tissue Lipolysis


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Signaling Pathways

1-Receptors

The prototypical signaling mechanism of 1-receptors involves Gq-mediated pathways that

activate Phospholipase C.

Phospholipase C cleaves phosphatidylinositol-4,5-bisphosphate, generating inositol

trisphosphate (IP3; which mobilizes intracellular Ca2+ stores) and diacylglycerol (DAG;

which activates protein kinase C).

These receptors may also signal via other proximal pathways.

Downstream signaling pathways activated by these receptors can be exceedingly complex

in some cells. Downstream targets include

L-type Ca2+ channels, K+ channels, several members of the mitogen-activated protein (MAP) kinase pathways & a variety of other kinases including phosphatidylinositol 3-kinase.

Receptor Type SignalingPathway

Mechanism

1 Gq Activation of Phospholipase C

2 Gi Inhibition of Adenylyl cyclase (1, 2& 3) Gs Activation of Adenylyl cyclase


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1-receptors are expressed in vascular smooth muscle, genitourinary tract smooth muscle,

intestinal smooth muscle, prostate, heart, liver and other cell types.

In vascular smooth muscle cells, stimulation of 1-receptors increases intracellular [Ca2+]-

via both release of endogenous Ca2+ stores and influx of Ca2+ from extracellular fluid

leading to activation of calmodulin, Phosphorylation of myosin light chain, increased actin-

myosin interaction, and muscle contraction.Therefore, 1-receptors are important in mediating increases in peripheral vascular

resistance, which can increase blood pressure and redistribute blood flow.

While 1-receptor antagonists would seem to be attractive in the therapy of Hypertension .

1-receptor activation causes contraction of genitourinary smooth muscle; 1-receptor

antagonists have been found to be clinically efficacious in the symptomatic treatment of

benign prostatic hyperplasia(BPH)

2-Receptors

2-Receptors activate Gi, an inhibitory G protein.

Gi has multiple signaling actions, including inhibition of adenylyl cyclase (thus decreasing

cAMP levels), activation of G protein-coupled inward rectifier K+ channels (causing

membrane hyperpolarization), and inhibition of neuronal Ca2+ channels.

Each of these effects tends to decrease neurotransmitter release from the target neuron.

2-Receptors are found on both presynaptic neurons and postsynaptic cells.

Presynaptic 2-Receptors function as autoreceptors to mediate feedback inhibition of

sympathetic transmission.

2-Receptors are also expressed on platelets and pancreatic -cells, where they mediate

platelet aggregation and inhibit insulin release, respectively.

2-Receptor agonists act at CNS sites to decrease sympathetic outflow to the periphery,

resulting in decreased norepinephrine release at sympathetic nerve terminals and,

therefore, decreased vascular smooth muscle contraction.

-Receptors

-Adrenoreceptors are divided into three subclasses, termed 1, 2& 3.

All three subclasses activate stimulatory G protein, Gs.

Gs activates adenylyl cyclase leading to an increase in the level of intracellular cAMP.

Increased cAMP activates protein kinases (especially protein kinase A), which

phosphorylate cellular proteins, including ion channels.


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1-adrenoceptors are localized primarily in the Heart and Kidney.

In kidney, they are present mainly on renal juxtaglomerular cells, where receptor activation

causes renin release.

Stimulation of cardiac 1-adrenoceptors causes an increase in both inotropy(force of

contraction) and Chronotropy(heart rate).

The inotropic effect is mediated by increased phosphorylation of Ca2+channels, including

calcium channels in the sarcolemma and phospholamban in the sarcoplasmic reticulum.

The increased Chronotropy results from a 1-mediated increase in the rate of phase 4

depolarisation of Sinoatrial node pacemaker cells.

Both effects contribute to increased cardiac output.

(Cardiac output =Heart rate X Stroke volume)

Activation of 1-receptors also increases conduction velocity in the atrioventricular (AV)

node because the 1-stimulated increase in Ca2+entry increases the rate of depolarisation of

AV node cells.

2-adrenoceptors are expressed in smooth muscle, liver, and skeletal muscle.

In smooth muscle, receptor activation stimulates Gs, adenylyl cyclase, cAMP, and protein

kinase A.

Protein kinase A phosphorylates several contractile proteins, especially myosin light chain

kinase(MLCK). Phosphorylation of MLCK reduces its affinity for calcium calmodulin,

leading to relaxation of the contractile apparatus (sm.muscle).

Evidence also suggests that 2-adrenoceptoractivation may relax bronchial smooth muscle

by Gs-independent activation of K+ channels.


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Increased K+ efflux leads to bronchial smooth muscle cell hyperpolarisation & therefore,

opposes the depolarisation necessary to elicit contraction.

In hepatocytes, activation of the Gs signaling cascade initiates a series of intracellular

phosphorylation events that result in glycogen phosphorylase activation and glycogen

catabolism.

The outcome of 2-adrenoceptor stimulation of hepatocytes is an increase in plasma

glucose.

In skeletal muscle, activation of these receptors stimulates Glycogenolysis and promotes K+

uptake.

3-adrenoceptors are expressed specifically in adipose tissue.

Stimulation of 3-adrenoceptors leads to an increase in lipolysis.

This physiologic action has led to speculation that 3-agonists may be useful in the

treatment of obesity, NIDDM and other potential indication.


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Adrenergic Drugs (Sympathomimetics)

These are the drugs with actions similar to that of Adrenaline or of sympathetic stimulation.

Direct Acting Sympathomimetics (directly act as agonists on and/or adrenoceptors)

Non-selective: Adrenaline, Noradrenaline, isoproterenol Selective:

1-agonists: Phenylephrine, Methoxamine, Mephentermine,Metaraminol, Midodrine

2-agonists: Clonidine, Apraclonidine, Brimonidine, Dexmedetomidine,Guanfacine, Guanabenz, methyldopa

1-agonists: Dobutamine 2-agonists: Metaproterenol, Terbutaline, , Salmeterol,

Albuterol(Salbutamol), Levalbuterol, Pirbuterol,

Bitolterol, Carmoterol, Indacaterol, Ritodrine, Isoxsuprine

Indirect Acting Sympathomimetics(act on adrenergic neuron to releaseNoradrenaline, which then acts on the adrenoceptors)

Releasing Agents: Tyramine, Amphetamine, Methamphetamine,Methylphenidate

Uptake Inhibitors: Cocaine, TCAsInhibitors of Catecholamine Metabolism:

MAO Inhibitors- Nonselective Agent: Phenelzine, Iproniazid, Tranylcypromine- Selective MAO-A: Clorgyline, Moclobemide, Brofaromine,

Befloxatone

- Selective MAO-B: Selegiline COMT Inhibitors: Tolcapone, Entacapone

Mixed acting Sympathomimetics: Ephedrine, Dopamine

Pharmacological Actions

On CVS:

Sympathomimetics have prominent cardiovascular effects because of widespread

distribution of and adrenoceptors in the heart, blood vessels, and neural and hormonal

systems involved in blood pressure regulation.


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The net effect of a given sympathomimetic in the intact organism depends not only on its

relative selectivity for or adrenoceptors and its pharmacologic action at those receptors;

any effect these agents have on blood pressure is counteracted by compensatory baroreflex

mechanisms aimed at restoring homeostasis.

The effects of sympathomimetic drugs on blood pressure can be explained on the basis of

their effects on heart rate, myocardial function, peripheral vascular resistance, and venous

return.

The endogenous catecholamines, norepinephrine and epinephrine, have complex

cardiovascular effects because they activate both and -receptors.

Effects of Alpha1-Receptor Activation:

Alpha1-receptors are widely expressed in vascular beds, and their activation leads toarterial and venous vasoconstriction.

Their direct effect on cardiac function is of relatively less importance.

A relatively pure agonist such as Phenylephrine increases peripheral arterial resistanceand decreases venous capacitance.

The enhanced arterial resistance usually leads to a dose-dependent rise in blood pressure. In the presence of normal cardio-vascular reflexes, the rise in blood pressure elicits a

baroreceptor-mediated increase in vagal tone with slowing of the heart rate.

Effects of Alpha2-Receptor Activation:

Alpha2-adrenoceptors are present in the vasculature, and their activation leads tovasoconstriction.

This effect, however, is observed only when 2-agonists are given locally, by rapidintravenous injection or in very high oral doses.

When given systemically, these vascular effects are obscured by the central effects of 2receptors, which lead to inhibition of sympathetic tone and blood pressure. Hence, 2

agonists are used as sympatholytics in the treatment of hypertension.

Effects of Beta-Receptor Activation:

Catecholamines, acting on 1-receptors, exert a powerful stimulant effect on the heart. Both the heart rate (chronotropic effect) and the force of contraction (inotropic effect) are

increased, resulting in a markedly increased cardiac output and cardiac oxygen

consumption.

The cardiac efficiency is reduced. Catecholamines can also cause disturbance of the cardiac rhythm, culminating in

ventricular fibrillation. (Paradoxically, but importantly, adrenaline is also used to treat

ventricular fibrillation arrest as well as other forms of cardiac arrest)


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On Respiration:

Activation of 2-receptors in bronchial smooth muscle leads to bronchodilation, this actionis more marked when the bronchi are constricted.

2-agonists are important in the treatment of asthma.

Decongestion of bronchial mucosa is by action. Rapid i.v. injection of adrenaline causes transient apnoea due to reflex inhibition of RC.

On Eye:

In the eye, the radial pupillary dilator muscle of the iris contains -receptors; activation (1-receptor) causes Mydriasis (contraction of radial muscles).

Alpha stimulants also have important effects on Intraocular Pressure. Alpha agonistsincrease the outflow of aqueous humor from the eye and can be used clinically to reduce

intraocular pressure.

In contrast, agonists have little effect, but -antagonists decrease the production of

aqueous humor. These effects are important in the treatment of glaucoma a leading cause of

blindness.

On Gut:

2-receptor activation hyperpolarises the cholinergic neuronsdecrease Achreleasereduced tone.

1-receptors located directly on smooth muscleincreases K+ effluxhyperpolarisationrelaxation.

On Genitourinary organs:

In genitourinary organs, the bladder base, urethral sphincter, and prostate contain -receptors that mediate contraction and therefore promote urinary continence.

The specific subtype of 1 receptor involved in mediating constriction of the bladder baseand prostate is uncertain, but 1A receptors probably play an important role.

Relaxation of the detrusor muscle of the bladder as a result of activation of -receptors andcontracts the trigone and sphincter muscles owing to its -agonist activity. This can result in

hesitancy in Urination.

On Uterus:

Both contraction and relaxation of uterine smooth muscle occur respectively through and receptors. The overall effect varies with hormonal and gestational status.

On Metabolism:

Catecholamines encourage the conversion of energy stores (glycogen and fat) to freelyavailable fuels (Glucose and free fatty acids), and cause an increase in the plasmaconcentration of the latter substances.


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Carbohydrate metabolism of liver and muscle are mediated through 1-receptors and thestimulation of lipolysis is produced by 3-receptors.

Decreased Insulin secretion is through 2-receptors, an effect that further contributes to thehyperglycaemia. Additionally, the production of leptin by adipose tissue is inhibited.

Selective 3-receptor agonists (e.g. BRL37344) have been developed as possible treatments

for obesity, but their action is too transient for them to be clinically useful. Activation of 2-receptors on -cells increases glucagon secretion.

On Skeletal muscle:

Althoughepinephrine does not directly excite skeletal muscle, it facilitates neuromusculartransmission, particularly that following prolonged rapid stimulation of motor nerves.

Epinephrine also acts directly on white, fast-twitch muscle fibres to prolong the active state,thereby increasing peak tension.

Of greater physiological and clinical importance is the capacity of epinephrine and selective2 agonists to increase physiological tremor, atleast in part due to -receptor mediated

enhancement of discharge of muscle spindles.


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On presynaptic Nerve terminals:

Presynaptic adrenoreceptors are of 2-type inhibit neuronal Ca2+ channels andintracellular availability of Ca2+ by increasing cAMP transmitter release is diminished.

On CNS:

Epinephrine in clinically used doses, doesnot produce any marked CNS effects because ofpoor penetration in brain.

Activation of 2-receptors in the brain stem results in decreased sympathetic outflow fallin Blood pressure and Bradycardia.

Miscellaneous:

The effects of epinephrine on secretory glands are not marked; in most glands secretionusually is inhibited, partly owing to the reduced blood flow caused by vasoconstriction.

Epinephrine stimulates lacrimation and a scanty mucous secretion from salivary glands. The apocrine sweat glands, located on the palms of the hands and a few other areas,

respond to adrenoceptor stimulants with increased sweat production.

These are the apocrine non- thermoregulatory glands usually associated with psychological

stress

Absorption, Fate and Excretion:

Epinephrine is not effective after oral administration because it is rapidly conjugated and

oxidized in the GI mucosa and liver.


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Absorption from subcutaneous tissues occurs relatively slowly because of local

vasoconstriction and the rate may be further decreased by systemic hypotension, for

example in a patient with shock.

Absorption is more rapid after intramuscular injection.

In emergencies, it may be necessary to administer epinephrine intravenously.

When relatively concentrated solutions (1%) are nebulized and inhaled, the actions of thedrug largely are restricted to the respiratory tract; however, systemic reactions such as

arrhythmias may occur, particularly if larger amounts are used.

Epinephrine is rapidly inactivated by MAO and COMT in the body.

Toxicity, Adverse Effects, and Contraindications

Epinephrine may cause disturbing reactions, such as restlessness, throbbing headache,

tremor, and palpitations.

The effects rapidly subside with rest, quiet, recumbency, and reassurance.More serious reactions include cerebral hemorrhage and cardiac arrhythmias.

The use of large doses or the accidental, rapid intravenous injection of epinephrine may

result in cerebral hemorrhage from the sharp rise in blood pressure.

Ventricular arrhythmias may follow the administration of epinephrine.

Angina may be induced by epinephrine in patients with coronary artery disease.

The use of epinephrine generally is contraindicated in patients who are receiving nonselective

- receptor blocking drugs, since its unopposed actions on vascular 1 receptors may lead to

severe hypertension and cerebral hemorrhage.

Therapeutic Uses:

The most common use of epinephrine was to relieve respiratory distress due to

bronchospasm; however, 2-selective agonists now are preferred.

A major use is to provide rapid relief of hypersensitivity reactions, including anaphylaxis,

to drugs and other allergens.

Epinephrine also is used to prolong the action of local anesthetics, presumably bydecreasing local blood flow.

Its cardiac effects may be of use in restoring cardiac rhythm in patients with cardiac arrest

due to various causes.

It also is used as a topical hemostatic agent on bleeding surfaces such as in the mouth or in

bleeding peptic ulcers during endoscopy of the stomach and duodenum.

In addition, inhalation of epinephrine may be useful in the treatment of post-intubation and

infectious croup.


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Therapeutic Classification of Adrenergic Drugs

Pressor Agents: Noradrenaline, Ephedrine, Dopamine, Phenylephrine, Mephenteramine Cardiac Stimulants: Adrenaline, Dobutamine, Isoprenaline Bronchodilators: Isoprenaline, Salbutamol, Salmeterol, Formoterol, Terbutaline,

Bambuterol

Nasal Decongestants: Phenylephrine, Xylometazoline, Oxymetazoline, Naphazoline,Pseudoephedrine, Phenyl propanolamine

CNS Stimulants: Amphetamine, Methamphetamine, Dexamphetamine Anorectics: Fenfluramine, Sibutramine, Dexfenfluramine Uterine relaxants and Vasodilators: Ritodrine, Isoxsuprine, Salbutamol, Terbutaline.

Specific DrugsDopamine

It is a dopamine (D1 and D2) as well as adrenergic and 1 (but not 2) agonist. The D1 receptors in renal and mesenteric blood vessels are the most sensitive: i.v.

infusion of low dose of DA dilates these vessels(by raising intracellular cAMP). This

increase g.f.r. and Na+excretion.

Moderately high doses produce a positive inotropic (direct 1 and D1 action + that dueto NA release), but little chronotropic effect on heart.

Vasoconstriction (1 action) occurs only when large doses are infused. At doses normally employed, it raises cardiac output and systolic BP with little effect

on diastolic BP. It has practically no effect on nonvascular and receptors; does not

penetrate blood-brain barrier no CNS effects.

Dopamine is used in patients of cardiogenic or septic shock and severe CHF wherein itincreases BP and urine outflow.

Dopamine may acutely improve cardiac and renal function in severely ill patients withchronic heart disease or renal failure.

Dobutamine

A derivative of Dopamine, but not a D1 or D2 receptor agonist. Though it acts on both and adrenergic receptors, the only prominent action of

clinically employed doses (2-8g/kg/min i.v. infusion) is increased force of cardiac

contraction and output, without significant change in heart rate, peripheral resistance

and BP.

As such, it has been considered to be a relatively selective 1 agonist. It is used as an inotropic agent in pump failure accompanying myocardial infarction,

cardiac surgery, and for short term management of severe congestive heart failure.

It is less arrhythmogenic than Adr.


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It is also used as a diagnostic agent, in conjunction with imaging of the heart, in theinvestigation of ischemic heart disease.

Phenylephrine

It is a selective 1 agonist, has negligible action. It raises BP by causing vasoconstriction. Because it has little cardiac action, reflex bradycardia is prominent. Topically it is used as a nasal decongestant and for producing mydriasis when cycloplegia

is not required.

Phenylephrine tends to reduce intraocular tension by constricting Ciliary body bloodvessels.

It is also a frequent constituent of orally administered nasal decongestant preparations. Central effects are not seen with usual clinical doses.

Methoxamine

Methoxamine acts pharmacologically like phenylephrine, since it is predominantly a direct-acting 1-receptor agonist.

It may cause a prolonged increase in blood pressure due to vasoconstriction; it also causes avagally mediated bradycardia.

Methoxamine is available for parenteral use, but clinical applications are rare and limitedto hypotensive states.

Mephentermine

Mephentermine is a sympathomimetic drug that acts both directly and indirectly; it hasmany similarities to ephedrine.

It produces both cardiac stimulation and vasoconstriction by directly activating and adrenergic receptors as well as by releasing NA. Cardiac outputs, systolic and diastolic BP

are increased.

The direct positive chronotropic effect on heart is generally counter balanced by vagalstimulation due to rise in mean BP.

Mephentermine is not a substrate for either MAO or COMT: active orally with longerduration of action (2-6 hr).

It crosses blood-brain barrier to some extent may produce excitatory effects at higher doses.It is used to prevent and treat hypotension due to spinal anaesthesia and surgical

procedures/shock in myocardial infarction and other hypotensive states.

Adverse effects are related to CNS stimulation, excessive rises in blood pressure, andarrhythmias.


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Metaraminol

Metaraminol is a sympathomimetic drug with prominent direct effects on vascular adrenergic receptors.

Metaraminol also is an indirectly acting agent that stimulates the release of norepinephrine. The drug has been used in the treatment of hypotensive states or off-label to relieve attacks

of paroxysmal atrial tachycardia; particularly those associated with hypotension.

Midodrine

Midodrine is a prodrug that is enzymatically hydrolysed to desglymidodrine, a selective1-receptor agonist.

The peak concentration of desglymidodrine is achieved about 1 hour after Midodrine isadministered.

The primary indication for Midodrine is the treatment of orthostatic hypotension, typicallydue to impaired autonomic nervous system function.

Although the drug has efficacy in diminishing the fall of blood pressure when the patient isstanding, it may cause hypertension when the subject is supine.

The Food and Drug Administration considered withdrawing approval of this drug in 2010because required post approval studies that verify the clinical benefit of the drug had not

been done. Action was suspended in response to prescriber and patient requests.

2-Stimulants

Metaproterenol, Terbutaline, Salmeterol,Albuterol (Salbutamol), Levalbuterol, Pirbuterol,Bitolterol, Carmoterol, Indacaterol, Ritodrine, Isoxsuprine

They cause bronchodilatation, vasodilatation and uterine relaxation, without producingsignificant cardiac stimulation.

2-selective agonists are valuable in the treatment of asthma. These drugs represent pharmacologic improvements over epinephrine (an agonist at all

adrenergic receptors) and isoproterenol (an agonist at 1- as well as 2- receptors) in that

their effects are more limited at non target tissues.

It is particularly important that these selective drugs have limited capacity to stimulate 1-adrenoceptors in the heart and, therefore, limited capacity to produce adverse cardiac

effects.

Specificity for the lung rather than the heart or other peripheral tissues has been furtherenhanced by generally delivering these drugs via aerosols inhaled into the lungs.

Administration of these drugs directly into the lungs lowers the amount of drug thatreaches the systemic circulation, again limiting the activation of cardiac 1-receptors and

skeletal muscle 2receptors.

The most important effects of these agents are relaxation of bronchial smooth muscle anddecrease in airway resistance.


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2-selective agonists are not completely specific for airway 2-receptors, however, andadverse effects can include skeletal muscle tremor (through 2 stimulation) and tachycardia

(through 1-stimulation).

Adverse effects of 2-stimulants:

Arrhythmias Tremors Tachycardia Insomnia

Isoxsuprine

It is an orally effective long-acting selective -receptor stimulant which has direct smoothmuscle relaxant property as well.

It has been used as uterine relaxant for threatened abortion and dysmenorrhoea, butefficacy is poor.

Nasal Decongestants

These are -agonists which on topical application as dilute solution (0.05-0.1%) producelocal vasoconstriction.

The imidazoline compounds-Naphazoline, Xylometazoline and Oxymetazoline arerelatively selective 2-agonist (like clonidine).

They have a longer duration of action (12 hours) than ephedrine.

They may cause initial stinging sensation (especially Naphazoline). Regular use of theseagents for long periods should be avoided because mucosal ciliary function is impaired:

atrophic rhinitis and anosmia can occur due to Persistent vasoconstriction.

They can be absorbed from the nose and produce systemic effects-CNS depression andrise in BP.

These drugs should be used cautiously in hypertensives and in those receiving MAOinhibitors.

Ephedrine

It is an alkaloid. Mainly acts indirectly but has some direct action on and receptors also. Repeated injections produce tachyphylaxis, primarily because the neuronal pool of NA

available for displacement is small.

It is resistant to MAO, therefore, effective orally. It is about 100times less potent than Adr, but longer acting (4-6 hours). Ephedrine crosses to brain and causes stimulation, but central: peripheral activity ratio is

lower than that of amphetamine.

Ephedrine can be used for a variety of purposes, but it lacks selectivity, and efficacy is low.


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Use is now restricted to that in mild chronic bronchial asthma and for hypotensionduring spinal anaesthesia; occasionally for postural hypotension; 75-60 mg TDS.

Pseudophedrine

A stereoisomer of ephedrine; causes vasoconstriction, especially in mucosae and skin, buthas fewer CNS and cardiac effect and is a poor bronchodilator (little

2

agonistic activity). It has been used orally as a decongestant of upper respiratory tract, nose and Eustachian

tubes.

Combined with antihistaminics, mucolytics, antitussives and analgesics, it is believed toafford symptomatic relief in common cold, allergic rhinitis, blocked Eustachian tubes upper

respiratory tract infections.

Phenylpropanolamine

Chemically and pharmacologically similar to ephedrine; causes vasoconstriction and hassome amphetamine like CNS effects.

It is included in a large number of oral cold/decongestant combination remedies. It is used as an appetite suppressant.

Alpha2-selective agonists

Clonidine

It is an imidazoline derivative having complex actions. Clonidine is a partial agonist with high affinity and high intrinsic activity at 2-receptors,

especially 2A subtype in brainstem.

The major haemodynamic effects result from stimulation of 2Areceptors present mainlypostjunctionally in medulla(vasomotor centre)decrease sympathetic out flowfall in

Bp and bradycardia. Plasma NA declines.

Though clonidine is capable of reducing NA release from peripheral adrenergic nerveendings (release inhibitory prejunctional 2 action), this is not manifest at clinically used

doses.

Clonidine is a moderately potent antihypertensive.

The major adverse effects of clonidine are dry mouth and sedation.Alpha2-selective agonists have an important ability to decrease blood pressure through actions in

the central nervous system even though direct application to a blood vessel may cause

vasoconstriction. Such drugs (eg: clonidine, methyldopa, Guanfacine, Guanabenz) are useful in the

treatment of hypertension. Sedation is a recognized side effect of these drugs, and newer 2-

agonists (with activity also at imidazoline receptors) with fewer central nervous system side

effects are available outside the USA for the treatment of hypertension (Moxonidine, Rilmenidine).

On the other hand, the primary indication of Dexmedetomidine is for sedation of initiallyintubated and mechanically ventilated patients during treatment in an intensive care setting. It


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also reduces the requirements for opioids in pain control. Finally, Tizanidine is used as a Central

muscle relaxant.

Apraclonidine

Apraclonidine is a relatively selective a2 receptor agonist that is used topically to reduceintraocular pressure(by 25%).

It can reduce elevated as well as normal intraocular pressure whether accompanied byglaucoma or not.

The reduction in intraocular pressure occurs with minimal or no effects on systemiccardiovascular parameters; thus, Apraclonidine is more useful than clonidine for

ophthalmic therapy. Apparently Apraclonidine does not cross the blood-brain barrier.

The mechanism of action of Apraclonidine is related to 2 receptor-mediated reduction inthe formation of Aqueous humor.

Brimonidine

Brimonidine, is another clonidine derivative that is administered ocularly to lowerintraocular pressure in patients with ocular hypertension or open-angle glaucoma.

Brimonidine is a 2-selective agonist that reduces intraocular pressure both by decreasingaqueous humor production and by increasing uveoscleral flow.

Guanfacine

Guanfacine is an 2 receptor agonist that is more selective for 2 receptors than is clonidine. Like clonidine, Guanfacine lowers blood pressure by activation of brainstem receptors with

resultant suppression of sympathetic activity.

Guanfacine and clonidine appear to have similar efficacy for the treatment of hypertension.Guanabenz

Guanabenz is a centrally acting 2 agonist that decreases blood pressure by a mechanismsimilar to those of clonidine and Guanfacine.

The adverse effects caused by Guanabenz (e.g., dry mouth and sedation) are similar to thoseseen with clonidine.

Dosage adjustment may be necessary in patients with hepatic cirrhosis.

Indirect Acting Sympathomimetics

Releasing Agents: Tyramine, Amphetamine, Methamphetamine,Methylphenidate


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Tyramine

Tyramine is a normal by product of tyrosine metabolism in the body and can be producedin high concentrations in protein-rich foods by decarboxylation of tyrosine during

fermentation.

It is readily metabolized by MAO in the liver and is normally inactive when taken orallybecause of a very high first-pass effect, ie, low bioavailability.

If administered parenterally, it has an indirect sympathomimetic action caused by therelease of stored catecholamines.

Consequently, tyramines spectrum of action is similar to that of norepinephrine.

In patients treated with MAO inhibitorsparticularly inhibitors of the MAO-A isoformthis effect of tyramine may be greatly intensified, leading to marked increases in blood

pressure.

This occurs because of increased bioavailability of tyramine and increased neuronal storesof catecholamines.

Patients taking MAO inhibitors must be very careful to avoid tyramine-containing foods.

Amphetamines (Amphetamine, Methamphetamine, Methylphenidate)

Amphetamine is a racemic mixture of phenylisopropylamine. Amphetamines resemble Noradrenaline. So, transported into Nerve terminals by

Uptake1and taken up into vesicles by VMAT in exchange for NA.

NA escapes into cytosol and some of cytosolic NA is degraded by MAO while remainingescapes via Uptake1 (Non-exocytotic release of NA)


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Cardiovascular Responses: Amphetamine given orally raises both systolic and diastolic blood

pressure. Heart rate often is reflexly slowed; with large doses, cardiac arrhythmias may occur.

Other Smooth Muscles. In general, smooth muscles respond to amphetamine as they do to other

sympathomimetic amines. The contractile effect on the sphincter of the urinary bladder is

particularly marked, and for this reason amphetamine has been used in treating enuresis and

incontinence.

Central Nervous System:

Amphetamine is one of the most potent sympathomimetic amines in stimulating the CNS. It stimulates the medullary respiratory center, lessens the degree of central depression

caused by various drugs, and produces other signs of CNS stimulation.

The psychic effects depend on the dose and the mental state and personality of theindividual.

The main results of an oral dose of 10 to 30 mg include wakefulness, alertness, and adecreased sense of fatigue; elevation of mood, with increased initiative, self-confidence, and

ability to concentrate; often, elation and euphoria; and increase in motor and speech

activities.

Performance of simple mental tasks is improved, but, although more work may beaccomplished, the number of errors may increase.

Physical performancein athletes, for exampleis improved, and the drug often is abusedfor this purpose.

These effects are not invariable and may be reversed by over dosage or repeated usage.Prolonged use or large doses are nearly always followed by depression and fatigue.

Many individuals given amphetamine experience headache, palpitation, dizziness,vasomotor disturbances, agitation, confusion, dysphoria, apprehension, delirium, or fatigue

Fatigue and Sleep: Amphetamine Prevent and reverse fatigue. Amphetamine reduces the

frequency of attention lapses that impair performance after prolonged sleep deprivation and thus

improves execution of tasks requiring sustained attention.

Analgesia: Amphetamine and some other sympathomimetic amines have a small analgesic effect,

but it is not sufficiently pronounced to be therapeutically useful.

Respiration: Amphetamine stimulates the respiratory center, increasing the rate and depth of

respiration.

Depression of Appetite:

Amphetamine and similar drugs have been used for the treatment of obesity, although thewisdom of this use is at best questionable.

Weight loss in obese humans treated with amphetamine is almost entirely due to reducedfood intake and only in small measure to increased metabolism.


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The site of action probably is in the lateral hypothalamic feeding center; injection ofamphetamine into this area, but not into the ventromedial region, suppresses food intake.

Neurochemical mechanisms of action are unclear.They also have weak anticonvulsant, analgesic and antiemetic actions: potentiate antiepileptic,

analgesics and antimotion-sickness drugs.

Amphetamines are drugs of abuse and are capable of producing marked psychological but little or

no physical dependence.

FDA approved for the treatment of narcolepsy and attention-deficit/hyperactivity disorder.

Treatment of amphetamine toxicity includes administration of Chlorpromazine which controls

both central as well as peripheral -adrenergic effects.

Sibutramine

This recently introduced anti-obesity drug inhibits the reuptake of both NA as well as 5-HT,but does not have clinically useful antidepressant property.

It suppresses appetite in a manner similar to fenfluramine and appears to stimulatethermogenesis by indirectly activating 3 system in adipose tissue.

It can cause loss of 3-9 kg weight, but many subjects regain the same when therapy isdiscontinued.

Side effects include dry mouth, constipation, anxiety, insomnia, mood swings, chest painand a mild increase in BP and HR.

A number of serious adverse reaction reports including cardiovascular events and deathshave been received by the US-FDA.

Anorectic Agents

Because of adverse central effects, the use amphetamines to suppress appetite cannot be justified.

A number of related drugs have been developed which inhibit feeding centre (like amphetamine)

but have little/no CNS stimulant or abuse liability. All of them act by inhibiting the reuptake of

NA/DA or 5-HT, enhancing monoaminergic transmission in the brain.

Nonadrenergic agents: Phentermine, Phenylpropanolamine(PPA),Diethylpropion, Mazindol

Serotonergic agents: Fenfluramine, DexfenfluramineNoradrenergic/serotonergic agent: Sibutramine


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Therapeutic Uses of Sympathomimetics Cardiac Arrest (adrenaline) Cardiogenic Shock (Dobutamine) Anaphylaxis(Adrenaline)

Bronchial Asthma (2-stimulants) Nasal Decongestion (Xylometazoline, Ephedrine) Premature Labour (Salbutamol, Ritodrine) 2-agonist (Clonidine)

lower BP, IOP As an adjunct during withdrawal in addicts. To reduce Menopausal flushing. To reduce frequency of Migraine attacks.

Vascular Uses Hypotensive States (Shock, Spinal anaesthesia) Along with Local anaesthetics. Control of Local Bleeding (Epistaxis) Nasal Decongestant.

Cardiac Uses Cardiac arrest (adrenaline) Partial or complete AV block (Isoprenaline) CHF (Dopamine/Dobutamine)

Allergic disorders (urticaria, angioedema, Laryngeal oedema, Anaphylaxis)-Adrenaline (Physiological antagonist of Histamine)

Mydriatic (without Cycloplegia)-Phenylephrine Central Uses

Hyperkinetic children (minimal brain dysfunction, attention deficithyperkinetic disorder)-amphetamines

Narcolepsy (amphetamines) Epilepsy (as adjunct) Parkinsonism (Amphetamines, improve mood & reduce rigidity) Obesity

Nocturnal enuresis in children and Urinary incontinence Uterine Relaxant (Ritodrine, Terbutaline, salbutamol) Glaucoma (Apraclonidine and Brimonidine) Dexmedetomidine is a 2 agonist used for sedation under intensive care

circumstances and during anesthesia.

Tizanidine is a 2 agonist that is used as a muscle relaxant.


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Antiadrenergic drugs (Sympatholytics)

These are drugs which antagonise the receptor action of adrenaline and related drugs. They are

competitive antagonists at or or & adrenergic receptors.

-Adrenoceptor Antagonists

These drugs inhibit adrenergic responses mediated through the -adrenoreceptors without

affecting those mediated through -receptors.

Non-selective -receptor Antagonists-Haloalkylamine: PhenoxybenzamineImidazolines: Tolazoline, PhentolamineErgot alkaloids: Ergotamine, ErgotoxineHydrogenated Ergot alkaloids: Dihydroergotoxine, Dihydroergotamine

1-Selective: Prazocin, Terazocin, Doxazocin, Tamsulosin 2-Selective: Yohimbine, Idazoxan

Pharmacological Effects

Blockade of vasoconstrictor 1(also 2) receptors reduces peripheral resistance and causespooling of blood in capacitance vessels venous return and cardiac output are reduced

fall in BP.

Postural reflex is interfered with marked hypotension occurs on standing dizziness

and syncope. Hypovolemia accentuates the hypotension.

The -blockers abolish the pressor action of Adr, which then produces only fall in BP

due to 2 mediated vasodilatation Vasomotor reversal of Dale.

Reflex tachycardia occurs due to fall in mean arterial pressure and increase release of NAdue to blockade of presynaptic 2-receptors.

Nasal stuffiness and Miosis result from blockade of -receptors in nasal blood vessels andin radial muscles of iris respectively.

Hypotension produced by -blockers can reduce renal blood flow g.f.r. is reduced andmore complete reabsorption of Na+and water occurs in the tubules Na+ retention and

increase in blood volume.

This is accentuated by reflex increase in renin release mediated through 1-receptors.

Tone of smooth muscle in bladder trigone, sphincter and prostate is reduced by blockade of1-receptors (mostly 1A) urine flow in patients with Benign hypertrophy of prostate is

improved

Contractions of Vas deferens and related organs which result in ejaculation are coordinatedthrough -receptors -blockers can inhibit ejaculation; this manifest as impotence.


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Specific Drugs

Phenoxybenzamine

Phenoxybenzamine, an agent related to the nitrogen mustards, forms a reactiveethyleneimonium intermediate that covalently binds to receptors, resulting in irreversible

blockade(duration of action 1448 hours or longer). It is somewhat selective for 1-receptors. The drug also inhibits reuptake of released norepinephrine by presynaptic adrenergic nerve

terminals.

Phenoxybenzamine blocks histamine (H1), acetylcholine, and serotonin receptors as well as-receptors.

The pharmacologic actions of Phenoxybenzamine are primarily related to antagonism of

receptormediated events.

The most significant effect is attenuation of catecholamine-induced vasoconstriction. While Phenoxybenzamine causes relatively little fall in blood pressure in normal supine

individuals, it reduces blood pressure when sympathetic tone is high, eg, as a result of

upright posture or because of reduced blood volume.

Cardiac output may be increased because of reflex effects and because of some blockade ofpresynaptic 2-receptors in cardiac sympathetic nerves.

Phenoxybenzamine is in the treatment of Pheochromocytoma. Most adverse effects of phenoxybenzamine derive from its -receptorblocking action; the

most important are orthostatic hypotension and tachycardia. Nasal stuffiness and inhibition of ejaculation also occur.

Phentolamine

Phentolamine is a potent competitive antagonist at both 1 and 2receptors. Phentolamine reduces peripheral resistance through blockade of 1 receptors and possibly

2 receptors on vascular smooth muscle.

Its cardiac stimulation is due to antagonism of presynaptic 2receptors (leading toenhanced release of norepinephrine from sympathetic nerves) and sympathetic activationfrom baroreflex mechanisms.

Phentolamine also has minor inhibitory effects at serotonin receptors and agonist effects atmuscarinic and H1 and H2 histamine receptors.

Phentolamines principal adverse effects are related to cardiac stimulation, which maycause severe tachycardia, arrhythmias, and myocardial ischemia.

Phentolamine has been used in the diagnosis & treatment of Pheochromocytoma. In addition it is sometimes used to reverse local anesthesia in soft tissue sites; local

anesthetics are often given with vasoconstrictors that slow their removal.


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Local phentolamine permits reversal at the end of the procedure. Used in control ofHypertension due to clonidine withdrawal, cheese reaction etc.,

Prazosin

Prazosin is a piperazinyl quinazoline effective in the management of hypertension.

It is highly selective for 1-receptors and typically 1000-fold less potent at 2-receptors. Prazosin relaxes both arterial and venous vascular smooth muscle, as well as smooth

muscle in the prostate, due to blockade of 1receptors.

The half-life is normally about 3 hours.Terazosin

Terazosin is another reversible 1-selective antagonist that is effective in hypertension; it isalso approved for use in men with urinary symptoms due to benign prostatic hyperplasia

(BPH).

The half-life of terazosin is 912 hours.Doxazosin

Doxazosin is efficacious in the treatment of hypertension and BPH. It differs from prazosin and terazosin in having a longer half-life of about 22 hours.

Tamsulosin

This is 1A/1D blocker (uroselective). It has been found effective in improving BHPsymptoms.

1A subtype predominate in bladder base and prostate, while 1B receptors are dominant inblood vessels.

Tamsulosin does not cause significant changes in BP or HR at doses which relieve urinarysymptoms.

Sideeffects are dizziness and retrograde ejaculation.Others:

Alfuzosin is a 1-selective quinazoline derivative that is approved for use in BPH. Trimazosin is a less potent congener of Prazosin. Silodosin resembles Tamsulosin in blocking the 1A-receptor and is used in treatment of

BPH.

Urapidilis a 1 antagonist (its primary effect) that also has weak 2-agonist and 5-HT1A-agonist actions and weak antagonist action at 1-receptors.

Indoramin is another 1-selective antagonist that also has efficacy as an antihypertensive.


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Yohimbine

Yohimbine, an indole alkaloid, is an 2-selective antagonist. It is sometimes used in the treatment of orthostatic hypotension because it promotes

norepinephrine release through blockade of 2 receptors in both the central nervous system

and the periphery.

This increases central sympathetic activation and also promotes increased norepinephrinerelease in the periphery.

It was once widely used to treat male erectile dysfunction but has been superseded byphosphodiesterase-5 inhibitors like sildenafil.

Idazoxan synthetic Analogue of Yohimbine

Therapeutic Uses of -blockers Pheochromocytoma

Pheochromocytoma is a tumour of the adrenal medulla. The tumour secretes

catecholamines, especially norepinephrine and epinephrine Persistent Hypertension.

Diagnosis:

Pheochromocytoma is confirmed on the basis of elevated plasma or urinary levels ofcatecholamines, metanephrine, and normetanephrine.

Phentolamine Test Provocative Tests performed by injecting Histamine, Methacholine or Glucagon. Techniques to localize a pheochromocytoma include computed tomography and

magnetic resonance imaging scans and scanning with radio markers such as 131I-

meta-iodobenzylguanidine (MIBG), a norepinephrine transporter substrate that is

taken up by tumour cells.

Treatment:

Surgical removal of tumour. Phenoxybenzamine, Phentolamine, Atenolol

Hypertension(1-antagonists) Benign Prostatic Hypertrophy (Urinary Obstruction) Peripheral Vascular Diseases

Raynauds Disease Buergers Disease

Erectile Dysfunction : Papaverine/Phentolamine Induced Penile Erection therapy forImpotence.


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-adrenoreceptor AntagonistsThese drugs inhibit adrenergic responses mediated through the -receptors.

Nonselective (1 & 2) blockers: Propranolol, Sotalol, Timolol, pindolol Selective 1 (cardioselective) blockers: Metoprolol, Atenolol, Acebutolol, Bisoprolol,

Esmolol, Betaxolol, Celiprolol, Nebivolol. With additional Blocking Property: Labetolol, Carvedilol

-blocker Distinctive Features

Sotalol Have K+ channel Blocking PropertiesClass III antiarrhythmic property

Timolol

-blockers used for the topical application to eye

Betaxolol

LevobunololCarteolol

Pindolol -blocker with prominent intrinsic sympathomimetic activity

Atenolol Longer duration of action

Acebutolol Has significant partial agonistic and membrane stabilizing Properties

Esmolol Ultra short acting 1-blocker

Carvedilol Non-selective -blocker with additional 1-blocking activity

Nebivolol 1-blocker that also causes vasodilatation through Endotheliumdependent mechanism

Practolol Withdrawn from market because of its toxicity

Therapeutic Uses of-blockers

Hypertension Angina Pectoris Cardiac Arrhythmias Myocardial Infraction Congestive Heart Failure Pheochromocytoma Thyrotoxicosis: Propranolol rapidly controls sympathetic symptoms without

significantly affecting thyroid status

Prophylaxis of Migraine (Propranolol) Essential tremor Glaucoma


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Labetolol

It is the first adrenergic antagonist capable of blocking both & receptors. It is moderately potent hypotensive and is especially used in Pheochromocytoma and

clonidine withdrawal.

Used in treatment of hypertension in pregnancy.Carvedilol

It is a 1+2+1 adrenoreceptor blocker. Produces vasodilatation due to 1 blockade as well as calcium channel blockade, and has

antioxidant property.

It has been used in hypertension and is the -blocker especially employed ascardioprotective in CHF.

Used for prevention of Cardiac Hypertrophy.

Noradrenergic Neuron-Blocking Drugs Guanethidine Bretylium Bethanidine Debrisoquin

These drugs reduce or abolish the response of tissues to sympathetic nerve stimulation but, do not

affect the effects of circulating Noradrenaline.

Guanethidine

It is accumulated in noradrenergic nerve terminals by Uptake1 block impulseconduction.

It also concentrates in synaptic vesicles by means of the vesicular transporter interferewith exocytosis and displaces NA.

In large doses cause structural damage to the NA neurons. Extremely effective in lowering BP but no longer used clinically.


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Treatment for Glaucoma

A.Open angle (Wide angle) glaucoma-adrenergic blockers: Timolol, Betaxolol, Levobunolol, Carteolol -adrenergic agonists: Adrenaline, Dipivefrine, Apraclonidine, BrimonidineProstaglandin Analogs: Latanoprost, Bimatoprost, Travoprost, Unoprostone CA Inhibitors: Acetazolamide, Dorzolamide, Brinzolamide Cholinomimetics: Pilocarpine, Carbachol, Physostigmine

B. Angle closure (Narrow angle)glaucoma Hypertonic Mannitol Acetazolamide Cholinomimetics (Miotic) Topical -blocker Apraclonidine


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References

Laurence Brunton, Bruce Chabner, Bjorn Knollman, Goodman & Gilmans ThePharmacological Basis Of Therapeutics, 12th Edition, Mc Graw Hill Medical,2011, Pg No: 277-330

David E.Golan, Armen H.Tashjian, Ehrin J. Armstrong, April W. Armstrong,Principles of Pharmacology, The Pathophysiologic Basis Of Drug Therapy,3rd

Edition, Lippincott Williams & Wilkins, 2012, Pg No: 132-146

H.P.Rang, M.M. Dale, J.M. Ritter, R.J. Flower, Rang and Dales Pharmacology,6th Edition, Churchill Livingstone Elsevier, 2007 Pg No: 168-188

Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor, Basic & ClinicalPharmacology, 12th Edition, Tata McGraw Hill Education Private Limited,

New Delhi, 2012, Pg No: 129-167

KD Tripathi. Essentials of Medical Pharmacology, Sixth Edition, JaypeeBrothers Medical Publishers(p)Ltd, new Delhi,2009, Pg No: 116-148

adr pharmacology

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