6. Non catecholamines

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Non-Non-CatecholaminesCatecholamines

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Important General Important General Properties Properties

Non CatecholaminesNon Catecholamines Do not contain catechol Do not contain catechol

(Dihydroxybenzene)(Dihydroxybenzene) Effective orally.Effective orally. Given in large doses.Given in large doses. Long duration of action.Long duration of action.

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esistant to inactivating enzymes (COMT& esistant to inactivating enzymes (COMT& MAO) of liver and other tissues Substantial MAO) of liver and other tissues Substantial fraction is excreted unchanged.fraction is excreted unchanged.

Cross BBB & are powerful CNS stimulants.Cross BBB & are powerful CNS stimulants. Not all are directly acting ,some are indirectly Not all are directly acting ,some are indirectly

acting , some are mixed.acting , some are mixed.

Classification Based on Receptor Classification Based on Receptor SelectivelySelectively

A:A: Mainly Alpha (Mainly Alpha () Receptor Agonists:) Receptor Agonists:1.1. 1 1 Agonists:-Agonists:- Phenylephrine , MethoxaminePhenylephrine , MethoxamineXylometazoline , Modafinil , Midodrine (Pro-Xylometazoline , Modafinil , Midodrine (Pro-

drug)drug)2. 2. 22 Agonists:- Agonists:- Clonidine , Clonidine , -Methyldopa -Methyldopa Guanfacine, Guanabenz, Dexmedetomidine , Guanfacine, Guanabenz, Dexmedetomidine ,

Apraclonidine, BrimonidineApraclonidine, Brimonidine3. 3. 11, , 22 combined agonists:- combined agonists:- OxymetazolineOxymetazoline

B.B. Mainly Beta (Mainly Beta () Receptor Agonists) Receptor Agonists::1.1. 11 Selective Agonists: Selective Agonists: Dobutamine , Dobutamine , Prenalterol (partial agonist)Prenalterol (partial agonist)2.2. 22 Selective Agonists: Selective Agonists: Salbutamol (Albuterol) , Terbutaline , Salbutamol (Albuterol) , Terbutaline , Metaproterenol , Metaproterenol , Pirbuterol , Pirbuterol , Salmeterol , FormeoerolSalmeterol , Formeoerol RitodrineRitodrine3.3. 11 & & 22 Agonists: Agonists:Isoproterenol (Isoproterenol (Isoprenaline) , Isoprenaline) , OrciprenalineOrciprenaline

C.C. BothBoth & & Agonists Agonists Epinephrine , Nor epinephrine, Epinephrine , Nor epinephrine, EphedrineEphedrine

D.D. Adrenergic & Dopaminergic Adrenergic & Dopaminergic receptor receptor Agonist:Agonist:

DopamineDopamine

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Classification According to Mode Classification According to Mode of Actionof Action

1.1. Direct Acting SympathomimeticsDirect Acting SympathomimeticsAll agonists in receptor classification (Except All agonists in receptor classification (Except Ephedrine)Ephedrine)

2.2. Indirect ActingIndirect Acting SympathomimeticsSympathomimetics a: Releasers of a: Releasers of Nor epinephrine Nor epinephrine

Amphetamine , Methylamphetamine, Amphetamine , Methylamphetamine, TyramineTyramine

b: Inhibitors of Reuptake of released nor epinephrine .b: Inhibitors of Reuptake of released nor epinephrine . Cocaine , Tricyclic antidepressant Cocaine , Tricyclic antidepressant

3.3. Drugs with mixed action (direct , Indirect Drugs with mixed action (direct , Indirect acting)acting) Ephedrine , MetraminolEphedrine , Metraminol

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EphedrineEphedrine First orally active sympathomimetic drug.First orally active sympathomimetic drug.Source:Source: Alkaloid of Ephedra plant, synthetic. Alkaloid of Ephedra plant, synthetic. Also a component of Ma-huang --Chinese herbal Also a component of Ma-huang --Chinese herbal

medicine. medicine. Prepared synthetically to be used as a drugPrepared synthetically to be used as a drugChemistryChemistry: : Non-catechol phenylisopropylamineNon-catechol phenylisopropylamine

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PharmacokineticsPharmacokinetics

High oral bioavailability.High oral bioavailability. Crosses BBB.Crosses BBB. Long DOA---in hrsLong DOA---in hrs Significant excretion of unchanged drug in urine.Significant excretion of unchanged drug in urine. It is weak base so excretion can be enhanced by It is weak base so excretion can be enhanced by

acidification of urineacidification of urine

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PharmacodynamicsPharmacodynamicsM.O.A: Dual action: M.O.A: Dual action: Indirect :Indirect : Promotes release of stored Promotes release of stored Nor-epinephrineNor-epinephrine

This does not require action potential & This does not require action potential & exocytosis. exocytosis.

Released Nor-epinephrine enters the synaptic Released Nor-epinephrine enters the synaptic cleft via Reuptake - 1cleft via Reuptake - 1

Direct : Direct : Receptor agonist like EpinephriReceptor agonist like Epinephrinene

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Therapeutics Uses: Therapeutics Uses: Used previously.Used previously.1. In chronic orthostatic hypotension.2. In acute hypotensive states associated with spinal anesthesia 3. As bronchodilator in:

• Bronchial asthma • Obstructive pulmonary disease

4. Stress incontinence in women.5. Myasthenia gravis in conjunction with Anti-cholinesterases.

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PseudoephedrinePseudoephedrine One of the four enantiomers of One of the four enantiomers of

EphedrineEphedrine Used orally as Nasal , eustachian

tube & sinus decongestant in: Common cold Hay fever

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AmphetamineAmphetamine Non-catechol phenylisopropylamineNon-catechol phenylisopropylamine

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M.O.AM.O.A: : Indirect sympathomimetic Indirect sympathomimetic drug:drug: Promotes release of stored Nor- Promotes release of stored Nor-epinephrine.epinephrine.

This does not require action potential & This does not require action potential & exocytosis. exocytosis.

Released Nor-epinephrine enters the Released Nor-epinephrine enters the synaptic cleft via Reuptake – 1 by synaptic cleft via Reuptake – 1 by revere transport.revere transport.

Hence effects of endogenously Hence effects of endogenously released NEreleased NE

are potentiated.are potentiated.

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CNS effects.CNS effects. Marked stimulant effect on mood & alertness.Marked stimulant effect on mood & alertness. Depressant effect on appetite.Depressant effect on appetite. Peripheral actionsPeripheral actions through release of through release of

catecholamines.catecholamines. It is highly abused drug due to its euphoriant It is highly abused drug due to its euphoriant

effect.effect. Some amphetamine variants also have abuse Some amphetamine variants also have abuse

potential. potential.

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Therapeutic Uses of Amphetamine variants:Therapeutic Uses of Amphetamine variants: Methamphetamine:Methamphetamine: Narcolepsy (abused drug), Narcolepsy (abused drug), Phenmetrazine: Phenmetrazine: weight reductionweight reduction Methylphenidate & PemolineMethylphenidate & Pemoline: Attention deficit : Attention deficit

hyper activity disorder (ADHD) in children.hyper activity disorder (ADHD) in children.PemolinePemoline can produce hepatic failure. can produce hepatic failure.

Modafinil:Modafinil: Narcolepsy, ADHD, less abuse Narcolepsy, ADHD, less abuse potential. Also affects central potential. Also affects central αα1B1B receptors, receptors, GABAergic , Glutaminergic & Serotonergic GABAergic , Glutaminergic & Serotonergic synapses.synapses.

Phenylpropolamine:Phenylpropolamine: weight reduction. weight reduction. WithdrawnWithdrawn– due to risk of hemorrhagic stroke.– due to risk of hemorrhagic stroke.

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TYRAMINETYRAMINE• Non-catecholamineNon-catecholamine• Parenteral Indirect acting sympathomimeticParenteral Indirect acting sympathomimetic• It releases stored Catecholamines. So Actions are like It releases stored Catecholamines. So Actions are like

NE NE • Ineffective orally due to high First Pass Met by MAO-A Ineffective orally due to high First Pass Met by MAO-A

in liver.in liver.• Normal by-product of tyrosine metabolism in body.Normal by-product of tyrosine metabolism in body.• High concentration in fermented food i.e Cheese or High concentration in fermented food i.e Cheese or

yeast.yeast.• In Patients on MAO-A inhibitors, hypertensive crises In Patients on MAO-A inhibitors, hypertensive crises

can occur if foods rich in Tyramine are taken, due to can occur if foods rich in Tyramine are taken, due to increased bioavailability.increased bioavailability.

So such patients should avoid these foods.So such patients should avoid these foods.

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Effect Of Topical Application To EyeEffect Of Topical Application To Eye• Mydriasis Mydriasis • Light reflex remains present. Light reflex remains present. • Absent corneal reflex.Absent corneal reflex.• Pallor of scleral conjunctiva.Pallor of scleral conjunctiva.

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Non-catecholamine Non-catecholamine -selective -selective agonistsagonists

1.1. 1 1 selective Agonists:-selective Agonists:- Phenylephrine , Phenylephrine , Methoxamine, Xylometazoline , Midodrine Methoxamine, Xylometazoline , Midodrine (Pro-drug)(Pro-drug)

2. 2. 22 selective Agonists:- selective Agonists:-Clonidine , Clonidine , - -MethyldopaMethyldopa

Guanfacine, Guanabenz, Dexmedetomidine Guanfacine, Guanabenz, Dexmedetomidine , Apraclonidine, Brimonidine, Apraclonidine, Brimonidine

3. 3. 11, , 22 combined agonists:- combined agonists:- OxymetazolineOxymetazoline

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Major effects of Major effects of 11 Receptor stimulation Receptor stimulation

Vasoconstriction Vasoconstriction Increased peripheral resistance Increased peripheral resistance MydriasisMydriasis Increased closure of internal sphincter of Increased closure of internal sphincter of

the bladder.the bladder.

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Major effects of Major effects of 22 Receptor Receptor stimulationstimulation Inhibition of NE release .Inhibition of NE release . Inhibition of Ach release.Inhibition of Ach release. Inhibition of insulin release .Inhibition of insulin release . Inhibition of central sympathetic out flow Inhibition of central sympathetic out flow

from VMC to the periphery.from VMC to the periphery. ..

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Phenylephrine:Phenylephrine: A relatively pure A relatively pure αα agonist. agonist. Acts directly on the receptors.Acts directly on the receptors. It is not a catechol derivative. It is not inactivated by COMT & It is not a catechol derivative. It is not inactivated by COMT &

has a much longer DOA than the catecholamines. has a much longer DOA than the catecholamines. It is an effective mydriatic & decongestant & can be used to It is an effective mydriatic & decongestant & can be used to

raise the blood pressure. raise the blood pressure.

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Methoxamine:Methoxamine: Acts pharmacologically like phenylephrine.Acts pharmacologically like phenylephrine. It may cause a prolonged increase in blood pressure due to It may cause a prolonged increase in blood pressure due to

vasoconstriction.vasoconstriction. It also causes a vagally mediated bradycardia.It also causes a vagally mediated bradycardia. Parenterally used in hypotensive states. Parenterally used in hypotensive states.

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Midodrine:Midodrine: A prodrug that is enzymatically hydrolyzed to A prodrug that is enzymatically hydrolyzed to

desglymidodrine, an desglymidodrine, an αα11-receptor selective agonist.-receptor selective agonist. The peak conc. of desglymidodrine is achieved about 1 hour The peak conc. of desglymidodrine is achieved about 1 hour

after midodrine is administered. after midodrine is administered. The primary indication for midodrine is the treatment of The primary indication for midodrine is the treatment of

orthostatic / postural hypotensionorthostatic / postural hypotension

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Therapeutic UsesTherapeutic Uses Nasal decongestant. Topically as nasal drops.Nasal decongestant. Topically as nasal drops.

(Phenylephrine, Methoxamine ---- short acting)(Phenylephrine, Methoxamine ---- short acting)(xylometazoline & oxymetazoline ----long acting).(xylometazoline & oxymetazoline ----long acting).

Phenylephrine eye drops are used :Phenylephrine eye drops are used : As mydriatic ----- to facilitate examination of the As mydriatic ----- to facilitate examination of the

retina (no cycloplegia) .retina (no cycloplegia) . As decongestant for allergic hyperemia of As decongestant for allergic hyperemia of

conjunctiva.conjunctiva. Localization of lesion in Horner’s syndrome with Localization of lesion in Horner’s syndrome with

methylamphtamine methylamphtamine

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In hypotensive emergencies for short term ↑ In hypotensive emergencies for short term ↑ BP to preserve cerebral or coronary blood BP to preserve cerebral or coronary blood flow ,flow ,

by I/V infusion (Phenylephrine, Methoxamine).by I/V infusion (Phenylephrine, Methoxamine). Midodrine: Midodrine: Orthostatic /postural hypotension Orthostatic /postural hypotension

due to impaired autonomic nervous system.due to impaired autonomic nervous system. Hypotensive emergencies Hypotensive emergencies Severe hemorrhage , spinal cord injurySevere hemorrhage , spinal cord injury

Overdoses of antihypertensive & CNS Overdoses of antihypertensive & CNS depressant medications.depressant medications.

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Adverse effectsAdverse effects Rebound nasal decongestion after Rebound nasal decongestion after

the effect wears off.the effect wears off. Ischemia after repeated prolonged Ischemia after repeated prolonged

use.use. Many drug interactions specially Many drug interactions specially

withwith anti hypertensive drugs.anti hypertensive drugs.

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ToxicityToxicityA.A. Catecholamines:Catecholamines:

Little CNS toxicity when given Little CNS toxicity when given systemically (poor penetration).systemically (poor penetration).

In the periphery, A/E are extensions of In the periphery, A/E are extensions of their pharmacologic alpha or beta actions.their pharmacologic alpha or beta actions.

Excessive vasoconstriction, cardiac Excessive vasoconstriction, cardiac arrhythmias, myocardial infarctionarrhythmias, myocardial infarction

Pulmonary edema .Pulmonary edema . Hemorrhage.Hemorrhage.

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B.B. Other sympathomimetics:Other sympathomimetics:PhenylisoprophylaminesPhenylisoprophylamines : mild to severe CNS : mild to severe CNS

toxicity. toxicity. In small doses:In small doses: nervousness, anorexia, and nervousness, anorexia, and

isomnia;isomnia;In higher doses:In higher doses: anxiety, aggressiveness, or anxiety, aggressiveness, or

paranoid behavior. Convulsions may occur.paranoid behavior. Convulsions may occur. Peripheral Peripheral αα11 agonists agonists : Hypertension : Hypertension ββ11 agonists agonists : Sinus tachycardia and serious : Sinus tachycardia and serious

arrhythmias, skeletal muscle tremors. arrhythmias, skeletal muscle tremors. CocaineCocaine ---- cardiac arrhythmias, , infarction & ---- cardiac arrhythmias, , infarction &

convulsions.convulsions.

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Non-catecholamineNon-catecholamineMainly Mainly ββ22 Selective Agonists Selective Agonists

Albuterol (salbutamol)Albuterol (salbutamol) TerbutalineTerbutaline MetaproterenolMetaproterenol BiotolterolBiotolterol PirbuterolPirbuterol FenoterolFenoterol FormoterolFormoterol SalmeterolSalmeterol RitodrineRitodrine

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Distribution & effects of Distribution & effects of ββ22 ReceptorsReceptors

Bronchiolar Smooth Muscles-- bronchodilationBronchiolar Smooth Muscles-- bronchodilation Uterine smooth muscles--- RelaxationUterine smooth muscles--- Relaxation Vascular smooth muscles in B.V of skeletal Vascular smooth muscles in B.V of skeletal

muscles--- vasodilation– decreased PVRmuscles--- vasodilation– decreased PVR Smooth Muscles of Gut & urinary bladderSmooth Muscles of Gut & urinary bladder Liver--- Increased glycogenolysisLiver--- Increased glycogenolysis Skeletal Muscles Increased Skeletal Muscles Increased

glycogenolysis ,tremors in high doses.glycogenolysis ,tremors in high doses. Pnacrease– Increased release of glucagonPnacrease– Increased release of glucagon

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Albuterol /Salbutamol (Prototype Albuterol /Salbutamol (Prototype Drug) ,Terbutalin & Pirbuterol:Drug) ,Terbutalin & Pirbuterol:

Short actingShort acting DOA:up to 3 hrsDOA:up to 3 hrsFormoterol , Salmeterol:Formoterol , Salmeterol: long actinglong acting DOA: 12 hrsDOA: 12 hrs Useful for nocternal asthma.Useful for nocternal asthma.

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Therapeutic UsesTherapeutic Uses1. Bronchodilator in1. Bronchodilator in

Bronchial Asthma Bronchial Asthma Chronic obstructive air way Chronic obstructive air way

diseasedisease2. To prevent premature labor 2. To prevent premature labor

( Ritodrine)( Ritodrine)

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Catecholamine reuptake inhibitorsCatecholamine reuptake inhibitorsCOCAINECOCAINE

A local anesthetic.A local anesthetic. A natural alkaloidA natural alkaloid Indirect acting sympathomimetic drug.Indirect acting sympathomimetic drug. Inhibits active reuptake-1 of released Nor-epinephrine at Inhibits active reuptake-1 of released Nor-epinephrine at

peripheral Nor-adrenergic synapses through Nor peripheral Nor-adrenergic synapses through Nor epinephrine transporter (NET)epinephrine transporter (NET)

In the CNS it inhibits dopamine reuptake into neurons in the In the CNS it inhibits dopamine reuptake into neurons in the “pleasure centers” of the brain.“pleasure centers” of the brain.

It is heavily abused drug.It is heavily abused drug.

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Therapeutic uses Therapeutic uses Sympathomimetics are used in Treatment of:Sympathomimetics are used in Treatment of:Bronchial Asthma:Bronchial Asthma:

22 Selective Agonists: Selective Agonists: Salbutamol (Albuterol), Terbutaline Salbutamol (Albuterol), Terbutaline , Metaproterenol , Pirbuterol , Salmeterol , Formoterol., Metaproterenol , Pirbuterol , Salmeterol , Formoterol.11 & & 22 Agonists: Agonists: Isoprenaline, Orciprenaline– in acute Isoprenaline, Orciprenaline– in acute severe asthma / status asthamaticussevere asthma / status asthamaticusBoth Both & & Agonists: Agonists: Epinephrine used in acute severe Epinephrine used in acute severe asthma / status asthamaticus onlyasthma / status asthamaticus onlyNasal Congestion:Nasal Congestion: Naphazoline, Oxymetazoline Naphazoline, Oxymetazoline Xylometazoline, Pseudoephedrine.Xylometazoline, Pseudoephedrine.

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Shock:Shock: Complex acute CVS syndrome, due to Complex acute CVS syndrome, due to

hypovolumia, cardiac insufficiency & altered hypovolumia, cardiac insufficiency & altered vascular resistance. vascular resistance.

Critical reduction in perfusion of vital tissues Critical reduction in perfusion of vital tissues Hypotension, an altered mental state, oliguria & Hypotension, an altered mental state, oliguria &

metabolic acidosis. metabolic acidosis. It is an emergency if untreated may deteriorate It is an emergency if untreated may deteriorate

resulting in death.resulting in death.

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Management:Management: Volume replacement with monitoring of Volume replacement with monitoring of

pulmonary capillary wedge pressure.pulmonary capillary wedge pressure. The goal should be to optimize tissue perfusion, The goal should be to optimize tissue perfusion,

not blood pressure. not blood pressure. Efficacy of sympathomimetic drugs is Efficacy of sympathomimetic drugs is unclear. unclear. Due to Sympathetic NS stimulation, Due to Sympathetic NS stimulation,

vasoconstriction may be intense & vasoconstriction may be intense & use of use of vasoconstrictors may deteriorate cerebral, vasoconstrictors may deteriorate cerebral, coronary or renal perfusion.coronary or renal perfusion.

Treatment of underlying disease.Treatment of underlying disease.

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Cardiogenic / Hypovolumic sshock:Cardiogenic / Hypovolumic sshock: Dopamine, Dopamine, Dobutamine.Dobutamine.

Anaphylactic shock:Anaphylactic shock: Epinephrine (0.3-0.5 ml of Epinephrine (0.3-0.5 ml of 1:1000 solution I/M)1:1000 solution I/M)

Heart block & Cardiac arrest:Heart block & Cardiac arrest: Epinephrine ,Isoprenaline (Temporary Epinephrine ,Isoprenaline (Temporary management), electronic pace maker should be management), electronic pace maker should be inserted as soon as possible.inserted as soon as possible.

Acute Heart failure:Acute Heart failure: Dobutamine. Dobutamine.Hypotension:Hypotension: Norepinephrine , Phenylephrine, Norepinephrine , Phenylephrine,

MethoxamineMethoxamine

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Orthostatic hypotension:Orthostatic hypotension:, Midodrine. Ephedrine, Midodrine. EphedrineIt is typically due to impaired ANS function. Although the drug It is typically due to impaired ANS function. Although the drug

diminishes fall of blood pressure when the patient is standing, it diminishes fall of blood pressure when the patient is standing, it may cause hypertension when the subject is supine.may cause hypertension when the subject is supine.

Hypertension:Hypertension: Clonidine , Clonidine , -Methyldopa -Methyldopa Guanfacine, Guanabenz , Fenoldopam.Guanfacine, Guanabenz , Fenoldopam.Topical hemostatic:Topical hemostatic: Epinephrine & Epinephrine & 1 1 agonists , agonists ,

1:200,000. solution1:200,000. solutionTo prolong DOA of infiltration nerve block: To prolong DOA of infiltration nerve block:

Epinephrine & Epinephrine & 11 agonists, 1:200,000 combined agonists, 1:200,000 combined with local anesthetics.with local anesthetics.

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Used in eye:Used in eye:Mydriatics , Allergic conjunctivitis:Mydriatics , Allergic conjunctivitis: Phenylephrine , Xylometazoline, Phenylephrine , Xylometazoline,

Oxymetazoline.Oxymetazoline.Glaucoma:Glaucoma: Apraclonidine, Brimonidine , Apraclonidine, Brimonidine ,

Dipivefrin, Epinephrine.Dipivefrin, Epinephrine.Localization of lesion of Horner’s Localization of lesion of Horner’s

syndrome:syndrome:Hydroxyamphetamine & PhenylephrineHydroxyamphetamine & Phenylephrine

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GUTGUTPrevention of Premature labour:Prevention of Premature labour: Ritodrine (DOC), Terbutaline & other Ritodrine (DOC), Terbutaline & other ββ22 agonists. agonists.Urinary incontinenceUrinary incontinence: : Ephedrine , Ephedrine ,

PseudoephedrinePseudoephedrine..

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Use in CNS:Use in CNS: Attention deficit hyper activity Attention deficit hyper activity

disorder (disorder (ADHDADHD) in children.) in children. Clonidine Clonidine , Methylphenidate. , Methylphenidate.

Narcolepsy:Narcolepsy: Modafinil , Modafinil , Methamphetamine (abused drug).Methamphetamine (abused drug).

Weight reduction as Anorexic agents, Weight reduction as Anorexic agents, in obesity: in obesity: Phenmetrazine, Phenmetrazine, Amphetamine, MethylphenidateAmphetamine, Methylphenidate

Withdrawal symptoms of Withdrawal symptoms of alcohol, smoking & narcoticalcohol, smoking & narcotic analgesicsanalgesics:: Clonidine Clonidine

Muscle relaxantMuscle relaxant:: Tizanidine Tizanidine -- -- 2 2 agonistagonist

Analgesic /Blunting of Analgesic /Blunting of sympathetic response during GAsympathetic response during GA:: Dexmeditomidine --- Dexmeditomidine --- 2 2 agonistagonist

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