6. Non catecholamines

DRUGS

1. 1
Non-CatecholaminesNon-Catecholamines

2. 2
Important General Properties Important General Properties
Non CatecholaminesNon Catecholamines
Do not contain catechol (Dihydroxybenzene)Do not contain catechol (Dihydroxybenzene)
Effective orally.Effective orally.
Given in large doses.Given in large doses.
Long duration of action.Long duration of action.

3. 3
esistant to inactivating enzymes (COMT& MAO) of liver and esistant to inactivating enzymes (COMT& MAO) of liver and
other tissues Substantial fraction is excreted unchanged.other tissues Substantial fraction is excreted unchanged.
Cross BBB & are powerful CNS stimulants.Cross BBB & are powerful CNS stimulants.
Not all are directly acting ,some are indirectly acting , some are Not all are directly acting ,some are indirectly acting , some are
mixed.mixed.

4. Classification Based on Receptor SelectivelyClassification Based on Receptor Selectively
A:A: Mainly Alpha (Mainly Alpha (aa) Receptor Agonists:) Receptor Agonists:
1.1. aa
1 1 Agonists:-Agonists:- Phenylephrine , MethoxaminePhenylephrine , Methoxamine
Xylometazoline , Modafinil , Midodrine (Pro-drug)Xylometazoline , Modafinil , Midodrine (Pro-drug)
2. 2. aa
22 Agonists:- Agonists:-Clonidine , Clonidine , aa -Methyldopa -Methyldopa
Guanfacine, Guanabenz, Dexmedetomidine , Guanfacine, Guanabenz, Dexmedetomidine ,
Apraclonidine, BrimonidineApraclonidine, Brimonidine
3. 3. aa
11, , aa
22 combined agonists:- combined agonists:- OxymetazolineOxymetazoline

5. B.B. Mainly Beta (Mainly Beta (bb) Receptor Agonists) Receptor Agonists::
1.1. bb
11 Selective Agonists: Selective Agonists: Dobutamine , Dobutamine ,
Prenalterol (partial agonist)Prenalterol (partial agonist)
2.2. bb
22 Selective Agonists: Selective Agonists:
Salbutamol (Albuterol) , Terbutaline , Salbutamol (Albuterol) , Terbutaline ,
Metaproterenol , Metaproterenol , Pirbuterol , Salmeterol , Pirbuterol , Salmeterol ,
FormeoerolFormeoerol
RitodrineRitodrine
3.3. bb
11 & & bb
22 Agonists: Agonists:
Isoproterenol (Isoproterenol (Isoprenaline) , OrciprenalineIsoprenaline) , Orciprenaline

6. C.C.BothBoth aa & & bb Agonists Agonists
Epinephrine , Nor epinephrine, EphedrineEpinephrine , Nor epinephrine, Ephedrine
D.D.Adrenergic & Dopaminergic receptor Adrenergic & Dopaminergic receptor Agonist:Agonist:
DopamineDopamine

7. 7
Classification According to Mode of ActionClassification According to Mode of Action
1.1.Direct Acting SympathomimeticsDirect Acting Sympathomimetics
All agonists in receptor classification (Except Ephedrine)All agonists in receptor classification (Except Ephedrine)
2.2.Indirect ActingIndirect Acting SympathomimeticsSympathomimetics
a: Releasers of a: Releasers of Nor epinephrine Nor epinephrine
Amphetamine , Methylamphetamine, TyramineAmphetamine , Methylamphetamine, Tyramine
b: Inhibitors of Reuptake of released nor epinephrine .b: Inhibitors of Reuptake of released nor epinephrine .
Cocaine , Tricyclic antidepressantCocaine , Tricyclic antidepressant
3.3.Drugs with mixed action (direct , Indirect acting)Drugs with mixed action (direct , Indirect acting)
Ephedrine , MetraminolEphedrine , Metraminol

8. 8

9. 9
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 medicine. Also a component of Ma-huang --Chinese herbal medicine.
Prepared synthetically to be used as a drugPrepared synthetically to be used as a drug
ChemistryChemistry: : Non-catechol phenylisopropylamineNon-catechol phenylisopropylamine

10. 10
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 acidification of It is weak base so excretion can be enhanced by acidification of
urineurine

11. 11
PharmacodynamicsPharmacodynamics
M.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 & exocytosis. This does not require action potential & exocytosis.
Released Nor-epinephrine enters the synaptic cleft via Reuptake - 1Released Nor-epinephrine enters the synaptic cleft via Reuptake - 1

Direct : Direct : Receptor agonist like EpinephriReceptor agonist like Epinephrinene

12. 12

13. 13
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.

14. 14
PseudoephedrinePseudoephedrine
One of the four enantiomers of EphedrineOne of the four enantiomers of Ephedrine
Used orally as Nasal , eustachian tube &
sinus decongestant in:
Common cold
Hay fever

15. 15
AmphetamineAmphetamine
Non-catechol phenylisopropylamineNon-catechol phenylisopropylamine

16. 16
M.O.AM.O.A: : Indirect sympathomimetic drug:Indirect sympathomimetic drug:
Promotes release of stored Nor-epinephrine.Promotes release of stored Nor-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 – 1 by revere transport.cleft via Reuptake – 1 by revere transport.
Hence effects of endogenously released NEHence effects of endogenously released NE
are potentiated.are potentiated.

17. 17
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 catecholamines. through release of catecholamines.
It is highly abused drug due to its euphoriant effect.It is highly abused drug due to its euphoriant effect.
Some amphetamine variants also have abuse potential. Some amphetamine variants also have abuse potential.

18. 18
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 hyper : Attention deficit hyper
activity disorder (ADHD) in children.activity disorder (ADHD) in children.
PemolinePemoline can produce hepatic failure. can produce hepatic failure.
Modafinil:Modafinil: Narcolepsy, ADHD, less abuse potential. Narcolepsy, ADHD, less abuse potential.
Also affects central Also affects central αα
1B1B receptors, GABAergic , receptors, GABAergic ,
Glutaminergic & Serotonergic synapses.Glutaminergic & Serotonergic synapses.
Phenylpropolamine:Phenylpropolamine: weight reduction. weight reduction. WithdrawnWithdrawn– –
due to risk of hemorrhagic stroke.due to risk of hemorrhagic stroke.

19. 19
TYRAMINETYRAMINE
•Non-catecholamineNon-catecholamine
•Parenteral Indirect acting sympathomimeticParenteral Indirect acting sympathomimetic
•It releases stored Catecholamines. So Actions are like NE It releases stored Catecholamines. So Actions are like NE
•Ineffective orally due to high First Pass Met by MAO-A in liver.Ineffective orally due to high First Pass Met by MAO-A 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 yeast.High concentration in fermented food i.e Cheese or yeast.
•In Patients on MAO-A inhibitors, hypertensive crises can occur if foods In Patients on MAO-A inhibitors, hypertensive crises can occur if foods
rich in Tyramine are taken, due to increased bioavailability.rich in Tyramine are taken, due to increased bioavailability.
So such patients should avoid these foods.So such patients should avoid these foods.

21. 21

22. 22
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.

23. 23
Non-catecholamine Non-catecholamine aa-selective agonists-selective agonists
1.1. aa
1 1 selective Agonists:-selective Agonists:- Phenylephrine , Phenylephrine ,
Methoxamine, Xylometazoline , Midodrine (Pro-drug)Methoxamine, Xylometazoline , Midodrine (Pro-drug)
2. 2. aa
22 selective Agonists:- selective Agonists:-Clonidine , Clonidine , aa -Methyldopa -Methyldopa
Guanfacine, Guanabenz, Dexmedetomidine , Guanfacine, Guanabenz, Dexmedetomidine ,
Apraclonidine, BrimonidineApraclonidine, Brimonidine
3. 3. aa
11, , aa
22 combined agonists:- combined agonists:- OxymetazolineOxymetazoline

24. 24
Major effects of Major effects of aa
11 Receptor stimulation Receptor stimulation

Vasoconstriction Vasoconstriction
Increased peripheral resistance Increased peripheral resistance
MydriasisMydriasis
Increased closure of internal sphincter of the bladder.Increased closure of internal sphincter of the bladder.

25. 25
Major effects of Major effects of aa
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 from VMC Inhibition of central sympathetic out flow from VMC
to the periphery.to the periphery.
..

26. 26

27. 27
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.

28. 28
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.

29. 29
Midodrine:Midodrine:
A prodrug that is enzymatically hydrolyzed to A prodrug that is enzymatically hydrolyzed to
desglymidodrine, an desglymidodrine, an αα
11-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

30. 30
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 retina (no As mydriatic ----- to facilitate examination of the retina (no
cycloplegia) .cycloplegia) .
As decongestant for allergic hyperemia of conjunctiva.As decongestant for allergic hyperemia of conjunctiva.
Localization of lesion in Horner’s syndrome with Localization of lesion in Horner’s syndrome with
methylamphtamine methylamphtamine

31. 31
In hypotensive emergencies for short term ↑ BP to In hypotensive emergencies for short term ↑ BP to
preserve cerebral or coronary blood flow ,preserve cerebral or coronary blood flow ,
by I/V infusion (Phenylephrine, Methoxamine).by I/V infusion (Phenylephrine, Methoxamine).
Midodrine: Midodrine: Orthostatic /postural hypotension due to Orthostatic /postural hypotension due to
impaired autonomic nervous system.impaired autonomic nervous system.
Hypotensive emergencies Hypotensive emergencies
Severe hemorrhage , spinal cord injurySevere hemorrhage , spinal cord injury
Overdoses of antihypertensive & CNS depressant Overdoses of antihypertensive & CNS depressant
medications.medications.

32. 32
Adverse effectsAdverse effects
Rebound nasal decongestion after the effect Rebound nasal decongestion after the effect
wears off.wears off.
Ischemia after repeated prolonged use.Ischemia after repeated prolonged use.
 Many drug interactions specially withMany drug interactions specially with
anti hypertensive drugs.anti hypertensive drugs.

33. 33
ToxicityToxicity
A.A.Catecholamines:Catecholamines:
Little CNS toxicity when given systemically (poor Little CNS toxicity when given systemically (poor
penetration).penetration).
In the periphery, A/E are extensions of their In the periphery, A/E are extensions of their
pharmacologic alpha or beta actions.pharmacologic alpha or beta actions.
Excessive vasoconstriction, cardiac arrhythmias, Excessive vasoconstriction, cardiac arrhythmias,
myocardial infarction myocardial infarction
Pulmonary edema .Pulmonary edema .
Hemorrhage.Hemorrhage.

34. 34
B.B.Other sympathomimetics:Other sympathomimetics:
PhenylisoprophylaminesPhenylisoprophylamines : mild to severe CNS toxicity. : mild to severe CNS toxicity.
In small doses:In small doses: nervousness, anorexia, and isomnia; nervousness, anorexia, and isomnia;
In higher doses:In higher doses: anxiety, aggressiveness, or paranoid anxiety, aggressiveness, or paranoid
behavior. Convulsions may occur.behavior. Convulsions may occur.
Peripheral Peripheral αα
11 agonists agonists : Hypertension : Hypertension
ββ
11 agonists agonists : Sinus tachycardia and serious arrhythmias, : Sinus tachycardia and serious arrhythmias,
skeletal muscle tremors. skeletal muscle tremors.
CocaineCocaine ---- cardiac arrhythmias, , infarction & ---- cardiac arrhythmias, , infarction &
convulsions.convulsions.

35. 35
Non-catecholamineNon-catecholamine
Mainly Mainly ββ
22 Selective Agonists Selective Agonists
Albuterol (salbutamol)Albuterol (salbutamol)
TerbutalineTerbutaline
MetaproterenolMetaproterenol
BiotolterolBiotolterol
PirbuterolPirbuterol
FenoterolFenoterol
FormoterolFormoterol
SalmeterolSalmeterol
RitodrineRitodrine

36. 36
Distribution & effects of Distribution & effects of ββ
22 Receptors Receptors
Bronchiolar Smooth Muscles-- bronchodilationBronchiolar Smooth Muscles-- bronchodilation
Uterine smooth muscles--- RelaxationUterine smooth muscles--- Relaxation
Vascular smooth muscles in B.V of skeletal muscles--- Vascular smooth muscles in B.V of skeletal muscles---
vasodilation– decreased PVRvasodilation– decreased PVR
 Smooth Muscles of Gut & urinary bladderSmooth Muscles of Gut & urinary bladder
Liver--- Increased glycogenolysisLiver--- Increased glycogenolysis
Skeletal Muscles Increased glycogenolysis ,tremors in high doses.Skeletal Muscles Increased glycogenolysis ,tremors in high doses.
Pnacrease– Increased release of glucagonPnacrease– Increased release of glucagon

37. 37

38. 38
Albuterol /Salbutamol (Prototype Drug) ,Terbutalin Albuterol /Salbutamol (Prototype Drug) ,Terbutalin
& Pirbuterol:& Pirbuterol:
 Short actingShort acting
DOA:up to 3 hrsDOA:up to 3 hrs
Formoterol , Salmeterol:Formoterol , Salmeterol:
long actinglong acting
DOA: 12 hrsDOA: 12 hrs
Useful for nocternal asthma.Useful for nocternal asthma.

39. 39
Therapeutic UsesTherapeutic Uses
1. Bronchodilator in1. Bronchodilator in
Bronchial Asthma Bronchial Asthma
Chronic obstructive air way diseaseChronic obstructive air way disease
2. To prevent premature labor ( Ritodrine)2. To prevent premature labor ( Ritodrine)

40. 40
Catecholamine reuptake inhibitorsCatecholamine reuptake inhibitors
COCAINECOCAINE
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 peripheral Nor-Inhibits active reuptake-1 of released Nor-epinephrine at peripheral Nor-
adrenergic synapses through Nor epinephrine transporter (NET)adrenergic synapses through Nor epinephrine transporter (NET)
In the CNS it inhibits dopamine reuptake into neurons in the “pleasure centers” of the In the CNS it inhibits dopamine reuptake into neurons in the “pleasure centers” of the
brain.brain.
It is heavily abused drug.It is heavily abused drug.

41. 41
Therapeutic uses Therapeutic uses
Sympathomimetics are used in Treatment of:Sympathomimetics are used in Treatment of:
Bronchial Asthma:Bronchial Asthma:
bb
22 Selective Agonists: Selective Agonists: Salbutamol (Albuterol), Terbutaline , Salbutamol (Albuterol), Terbutaline ,
Metaproterenol , Pirbuterol , Salmeterol , Formoterol.Metaproterenol , Pirbuterol , Salmeterol , Formoterol.
bb
11 & & bb
22 Agonists: Agonists: Isoprenaline, Orciprenaline– in acute severe Isoprenaline, Orciprenaline– in acute severe
asthma / status asthamaticusasthma / status asthamaticus
Both Both aa & & bb Agonists: Agonists: Epinephrine used in acute severe asthma / Epinephrine used in acute severe asthma /
status asthamaticus onlystatus asthamaticus only
Nasal Congestion:Nasal Congestion: Naphazoline, Oxymetazoline Xylometazoline, Naphazoline, Oxymetazoline Xylometazoline,
Pseudoephedrine.Pseudoephedrine.

42. 42
Shock:Shock:
Complex acute CVS syndrome, due to hypovolumia, cardiac Complex acute CVS syndrome, due to hypovolumia, cardiac
insufficiency & altered vascular resistance. insufficiency & altered vascular resistance.
Critical reduction in perfusion of vital tissues Critical reduction in perfusion of vital tissues
Hypotension, an altered mental state, oliguria & metabolic Hypotension, an altered mental state, oliguria & metabolic
acidosis. acidosis.
It is an emergency if untreated may deteriorate resulting in It is an emergency if untreated may deteriorate resulting in
death.death.

43. 43
Management:Management:
Volume replacement with monitoring of pulmonary capillary Volume replacement with monitoring of pulmonary capillary
wedge pressure.wedge pressure.
The goal should be to optimize tissue perfusion, not blood The goal should be to optimize tissue perfusion, not blood
pressure. pressure.
Efficacy of sympathomimetic drugs is Efficacy of sympathomimetic drugs is unclear. unclear.
Due to Sympathetic NS stimulation, vasoconstriction may be Due to Sympathetic NS stimulation, vasoconstriction may be
intense & intense & use of vasoconstrictors may deteriorate cerebral, use of vasoconstrictors may deteriorate cerebral,
coronary or renal perfusion.coronary or renal perfusion.
Treatment of underlying disease.Treatment of underlying disease.

44. 44
Cardiogenic / Hypovolumic sshock:Cardiogenic / Hypovolumic sshock: Dopamine, Dobutamine. Dopamine, Dobutamine.
Anaphylactic shock:Anaphylactic shock: Epinephrine (0.3-0.5 ml of 1:1000 solution I/M) Epinephrine (0.3-0.5 ml of 1:1000 solution I/M)
Heart block & Cardiac arrest:Heart block & Cardiac arrest:
Epinephrine ,Isoprenaline (Temporary management), electronic pace Epinephrine ,Isoprenaline (Temporary management), electronic pace
maker should be inserted as soon as possible.maker should be inserted as soon as possible.
Acute Heart failure:Acute Heart failure: Dobutamine. Dobutamine.
Hypotension:Hypotension: Norepinephrine , Phenylephrine, MethoxamineNorepinephrine , Phenylephrine, Methoxamine

45. 45
Orthostatic hypotension:Orthostatic hypotension:, Midodrine. Ephedrine, Midodrine. Ephedrine
It 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, diminishes fall of blood pressure when the patient is standing,
it may cause hypertension when the subject is supine.it may cause hypertension when the subject is supine.
Hypertension:Hypertension: Clonidine , Clonidine , aa -Methyldopa -Methyldopa
Guanfacine, Guanabenz , Fenoldopam.Guanfacine, Guanabenz , Fenoldopam.
Topical hemostatic:Topical hemostatic: Epinephrine & Epinephrine & aa
1 1 agonists , 1:200,000. agonists , 1:200,000.
solutionsolution
To prolong DOA of infiltration nerve block: To prolong DOA of infiltration nerve block: Epinephrine & Epinephrine & aa
11
agonists, 1:200,000 combined with local anesthetics.agonists, 1:200,000 combined with local anesthetics.

46. 46
Used in eye:Used in eye:
Mydriatics , Allergic conjunctivitis:Mydriatics , Allergic conjunctivitis:
Phenylephrine , Xylometazoline, Oxymetazoline.Phenylephrine , Xylometazoline, Oxymetazoline.
Glaucoma:Glaucoma: Apraclonidine, Brimonidine , Dipivefrin, Apraclonidine, Brimonidine , Dipivefrin,
Epinephrine.Epinephrine.
Localization of lesion of Horner’s syndrome:Localization of lesion of Horner’s syndrome:
Hydroxyamphetamine & PhenylephrineHydroxyamphetamine & Phenylephrine

47. 47
GUTGUT
Prevention of Premature labour:Prevention of Premature labour:
Ritodrine (DOC), Terbutaline & other Ritodrine (DOC), Terbutaline & other ββ
22 agonists. agonists.
Urinary incontinenceUrinary incontinence: : Ephedrine , PseudoephedrineEphedrine , Pseudoephedrine..

48. 48
Use in CNS:Use in CNS:
Attention deficit hyper activity disorder (Attention deficit hyper activity disorder (ADHDADHD) in ) in
children.children. Clonidine , Methylphenidate. Clonidine , Methylphenidate.
Narcolepsy:Narcolepsy: Modafinil , Methamphetamine (abused Modafinil , Methamphetamine (abused
drug).drug).
Weight reduction as Anorexic agents, Weight reduction as Anorexic agents, in obesity: in obesity:
Phenmetrazine, Amphetamine, MethylphenidatePhenmetrazine, Amphetamine, Methylphenidate

49.  Withdrawal symptoms of alcohol, smoking Withdrawal symptoms of alcohol, smoking
& narcotic& narcotic analgesics analgesics:: Clonidine Clonidine
Muscle relaxantMuscle relaxant:: Tizanidine Tizanidine -- -- aa
2 2 agonistagonist
Analgesic /Blunting of sympathetic Analgesic /Blunting of sympathetic
response during GAresponse during GA:: Dexmeditomidine --- Dexmeditomidine --- aa
2 2
agonistagonist
49