Adrenergic Drugs - Non selective; Selective.

adrenergic drugs ,, ppt

1. Anatomy of Sympathetic
(thoracolumber) Nervous System
Nervesarisefromspinalcord
Pre-ganglionicnervefibersarisefromthoraco-
lumberregionofsp.cord(T
1-L
2;containingcell
bodies)terminateinsym.ganglianear
spinalcolumn(eithersides)
Post-ganglionicfibersariseformganglia&
reachtoorgans

2. Chemical Mediators (neurotransmitters)
Preganglionic sympathetic nerve fibers secrete
Acetylcholine
Postganglionic sympathetic nerve fibers (except
sweat glands) secrete Noradrenaline

3. AUTONOMIC & SOMATIC MOTOR
NERVES

4. Classification of Adrenoceptors
ADRENOCEPTORS
-adrenoceptors -adrenoceptors
1 2 1 2 3
1A 2A
1B 2B
1D 2C
1L
Cont.

5. Allsubtypesof&belongtoG-protein
coupledreceptorfamily
1-receptoractivatePLC--IP3&DAGas2
nd
messenger
2-receptorsinhibitadenylatecyclase
CAMPformation
Alltypesof-receptorsstimulateadenylate
cyclase

6. Effects of Adrenoceptors
a)1-receptoractivation
Vasoconstriction,relaxationofGIsmooth
muscle,salivarysecretionstimulation&
hepaticglycogenolysis
b)2-receptorsactivation
Inhibitionoftransmitterrelease(includingNA&ACh
releaseforautonomic nerves),platelet
aggregation,contractionofvascularsmooth
muscle,inhibitionofinsulinrelease

7. c) 1-receptors
Increasedcardiacrate&force
d)2-receptors
Bronchodilation,vasodilation,relaxationof
visceralsmoothmuscle,hepaticglycogenolysis
&muscletremors
e)3receptors
lipolysis

8. Major effects mediated by & 
adrenoceptors

9. Neurotransmission at adrenergic
neurons
Six stages
Synthesis
Storage
Release
Bindingtoreceptors
Terminationofactionofnorepinephrine
Recyclingofprecursor

10. 1. Synthesis of Norepinephrine
Tyrosine(precursor)
Transported(Na-linkedcarrier)into
axoplasmofadrenergicneuron
hydroxylationtoDOPA
dopamine

11. 2) Storage of norepinephrine in
vesicles
Dopamine transported&storedinvesicles
tosynapticvesicleNE
Admedulla=NE(methylatedtoepinephrine)
storedinchromaffincells
Admedulla=releaseNE(20%)+EP(80%)

12. 3) Release of Noradrnaline
Arrivalofactionpotentialatnervejunction
triggersopeningofCa
2+
channels
passageofCa
2+
fromextracellular
fluidtocytoplasmofneurons
fusionofvesicleswithcellmemb.
ruptureofvesicles
releaseofNE

13. 4) Binding to receptors
NEreleasefromsynapticvesicles
Diffuseacrosssynapticspace
Bindstoeitherpostsynapticreceptorson
effectororganortopresynapticreceptors
onnerveending

14. 5) Removal of norepinephrine
NE
1)diffuseoutofsynapticspace&enter
generalcirculation---OR
2)metabolizedbyCOMTtoO-methylated
derivativesinsynapticspace------OR
3)recapturedbyuptakesystemthatpumps
backNEintoneurons

15. 6) Potential fate of recaptured
norepinephrine
OnceNEreenterscytoplasmofneurons
Maytakenupintovesicles&besequesteredfor
releasebyanotheractionpotential
Itmaypersistinapool
ItmaybeoxidizedbyMAOenzyme
InactiveNEmetabolites=excretedinurineas
vanillylmandelicacid,metanephrine&
normetanephrine

16. Synthesis & release of norepinephrine
from adrenergic neuron

17. Classification of Adrenoceptor
agonists
1)Accordingtotheirchemicalstructure
2)Bytypesofadrenoceptorstimulation
3)Bydirectorindirectaction

18. 1.Based on chemical structure
Twogroups
Catecholamines
Noncatecholamines

19. A-Catecholamines
Drugscontaincatecholnucleusintheir
chemicalstructure
Catecholnucleus=OHgroupatposition3&4
onbenzenering
e.g.,adrenaline(Ad),noradrenaline(NE),
isoprenaline(ISOP),dopamine(DA),
dobutamine(Dob)

20. Properties of Catecholamines
1. High potency
Highest potency in activating αor βreceptors
2. Rapid inactivation
Thesecatecholaminesmetabolizedby
COMT(postsynaptically)+MAO(intraneuronally)
Alsometabolizedinliver,gutwallby
MAO+COMT
Givenparenterally;ineffectivewhengiven
orally
Cont.

21. 3. Poor penetration into CNS
Catecholaminesarepolar=notreadily
penetrateintoCNS
MosthaveclinicaleffectsattributabletoCNS
effects=anxiety,tremor&headache

22. B) Noncatecholamines
Sympathomimetics do not contain catechol
nucleus in their chemical structure
e.g., amphetamine, ephedrine,
phenylepohrine (Phe),methoxamine,
salbutamol (Salb),terbutaline, fenoterol
Poor substrates for MAO
Prolonged duration of action
Lipid solubility permits greater access to
CNS

23. 2) Based on effects of drugs on
receptor types
A. Both alpha & beta agonists
e.g., Ad, NE, ephedrrine, amphetamine
B. Mainly alpha agonists
i) Mainly α
1agonists
e.g., Phe, methoxamine
ii) Mainly α
2agonists
e.g., clonidine, methyldopa, guanabenz,
guanfacine
Cont.

24. c) Mainly Beta agonists
i) Mainly β1 & β2 agonists
e.g., ISOP
ii) Mainly β1 agonists
e.g., Dob, prenalterol
iii) Mainly β2 agonists
e.g., Salb, terbutaline, ritoderine, fenoterol
iv) Dopamine agonists
e.g., DA, bromocriptine, fenoldopam, ibopamine

25. 3. Based on mechanism of
action of adrenergic agonists
A.Directactingagonists
Actdirectlyonαorβreceptorsproducingeffects
similartothosethatoccurfollowing
stimulationofsympatheticnerves
e.g.,Ad,NE,ISOP,Phe,Salb

26. B. Indirect acting agonists
Agentsactindirectly
Theiractionsdependentonreleaseof
endogenouscatecholamine
Theyhaveeitheroftwod/fmechanisms:
a)displacementofstoredcatecholaminesfrom
adrenergicnerveending
e.g.amphetamine&tyramine
Cont.

27. b)Inhibitionofreuptakeofcatecholamines
alreadyreleased
e.g.,cocaine,&tricyclicantidepressants

28. C. Mixed action agonists
Theyhavecapacitytostimulateadrenoceptors
directly+releaseNEfromadrenergicneurons
e.g.,Ephedrine&pseudoephedrine

29. Site of action of direct, indirect & mixed-
acting adrenergic agonists

30. Organ system effects of Sympathomimetic
drugs
Cardiovascular system
A. Blood vessels
Peripheral vascular resistance & venous
capacitance is controlled by catecholamines
Alpha receptors arterial resistance
β2 receptors promote sm muscle relaxation
Skin + splanchnic vessels= predominantly α
receptors & constrict by Ad & NE
Cont.

31. Blood vessels of skeletal muscle may constrict
or dilate depend on whether αor βreceptors
are activated
Overall effects of sympathomimetics on blood
vessels depends on activities of that drug at α
or βreceptors
D1 receptors promote vasodilation of renal,
splanchnic, coronary, cerebral & other
resistance vessels

32. B. Heart
Direct effect on heart determined by β1
a) Positive chronotropic effect
Beta receptor activation = Ca flux in cardiac
cells
pace maker activity both normal (SA node )
& abnormal (purkinje fibers) conduction velocity
in AV node + refractory period
b) Positive inotropic effect
in intrinsic contractility
c) Coronary blood flow 

33. C. Blood Pressure
Sympathomimetics= heart + PVR + venous
return
Phe (αagonist)= peripheral arterial
resistance + venous capacitance rise in
BP baroreceptor vagal tone slow HR
β-adrenoceptor agonist = stimulation of β-
receptors in heart CO
Cont.

34. ISOP
Peripheral resistance by 2 vasodilation=
maintain or slightly systolic pressure +fall in
diastolic pressure

35. Eye
Alphastimulants
i)Mydriasis
Phe=activationofradialpupillarydilatormuscle
oneye
ii)Outflowofaqueoushumor
Intraocularpressure---helpfulinglaucoma
Betaagonist=littleeffectoneye
Cont.

36. Betaantgonists
Productionofaqueoushumor
Adrenergic drugs directly protect neuronal
cells in the retina

37. Respiratory tract
Activation of β2 receptors of bronchial sm
muscles= bronchodilation
Blood vessels of upper respiratory tract
mucosa contain αreceptors= decongestant
action of adrenergic stimulant–clinically
useful

38. Gastrointestinal tract
β-receptors
Relaxation(viahyperpolarization)&d/cspike
activityinsmmuscles
α-selective agonists
D/cmuscleactivityindirectlybypresynaptically
reducingthereleaseofAch&possiblyother
stimulantswithinENS
α2 receptors
D/c salt & water flux into lumen of intestine

39. Genitourinary tract
Humanuterus=&2receptors
Bladderbase,urethralsphincter&
prostatecontainα-receptors----Mediate
contraction----promoteurinarycontinence
Bladderwallhasβ2---mediaterelaxation
Ejaculationdependsonnormalα-
receptorsactivationinductusdeferens,
seminalvesicles&prostate

40. Exocrine glands
Adrenoceptors present on salivary glands
regulate secretion of amylase & water
Clonidine =dry mouth symptom
Adrenergic stimulants---sweat
production (apocrine sweat glands on
palms of hands) during stress

41. Metabolic Effects
Activation of β3 of fat cells==lipolysis
with enhanced release of free FA &
glycerol
α2 receptors of lipocytes–inhibit lipolysis
by intracellular cAMP
Sympathomimetic glycogenolysis in liver
(by βreceptors)---glucose release into
circulation
Cont.

42. of catecholamine = metabolic acidosis
β-receptor insulin release
α2 insulin release

43. Effects on Endocrine functions
& Leukocytosis
Insulinstimulatedbyβ-receptors&inhibitedby
α2receptors
Reninstimulatedbyβ1&inhibitedbyα2
receptors(β-receptorantagonistplasma
renin&BPinHTNbythismechanism)
Adrenoceptorsalsomodulatesecretionof
PTH,calcitonin,thyroxin&gastrin
Athighconc.Adcauseleukocytosis

44. Effect on CNS
ActionofsympathomimeticsonCNSvary
dramaticallydependingonabilitytocrossBBB
Catecholamines---CNSeffectsathighdoses
(nervousness,tachycardia,tremor)
Noncatecholamineswithindirectactions
(amphetamine)mildalertingwithimproved
attentiontoboringtasks,elevationofmood,
insomnia,euphoria,anorexia,fullyblown
psychoticbehavior

45. Specific sympathomimetic drugs
Catecholamaines
1) Epinephrine (adrenaline)
Powerful vasoconstrictor & cardiac stimulant
It has +ve inotropic & chronotropic actions on
heart
Vasoconstriction due to effect on αreceptors
Also activates β2 receptors in some vessels
(sk muscle) –dilation---total Peripheral
resistance= BP---increased blood flow in
sk muscle during exercise

46. 2) Norepinephrine
(noradrenaline)
NE & Ad have similar effects on 1 receptors
in heart & similar potency at receptors
NE have little effect on 2 receptors --
peripheral resistance-+ sys & diastolic BP

47. Isoproterenol
Verypotent-receptoragonist
Littleeffectonreceptors
+vechronotropic&inotropicactions(b/cof-
receptoractivation)
ISOPispotentvasodilator
MarkedinCOassociatedwithfallindiastolic
&MAP&lesserd/corslightinsystolic
pressure

48. Dopamine
Activates D1 receptors = vasodilation (several
vascular beds including renal)
Activation of presynaptic D2
receptors=suppress NE release
Dopamine= activates β1 receptors on heart
Low dose of DA peripheral resistance
High doses DA activates vascular αreceptors
= vasoconstriction (including renal)

49. Dopamine agonists
Dopamine agonists with central actions
important for treatment of Parkinson’s disease
& prolactinemia
Dobutamine
Relatively β1 selective synthetic
catecholamine

50. Fenoldopam
D1 receptor agonist
Selectively leads to peripheral vasodilation in
some vascular beds
Intravenous treatment of severe hypertension

51. Other Sympathomimetics
Phenylephrine
Pure α-agonist
Acts directly on receptors
It is not catechol derivative so not inactivated
by COMT
Much longer duration of action than
catecholamine
Effective mydriatic & decongestant
Used to raise BP

52. Methoxamine
Acts pharmacologically like Phe, acting
directly on α1 receptors
Cause prolonged in BP due to
vasoconstriction
Vagaly mediated bradycardia

53. Midodrine
Prodrug,enzymaticallyhydrolyzedto
desglymidodrine(α1receptorselective
agonist)
Used fortreatmentofpostural
hypotension,typicallyduetoimpaired
ANSfunction

54. Ephedrine
Non catechol phenylisopropylamines
Occurs in various plants
High bioavailbility
Long duration of action (hours)
Its excretion can be accelerated by
acidification
Mild stimulant, gain access to CNS
Pseudoephdrine---component of many
decongestant mixture

55. Xylometazoline &
oxymetazoline
Direct acting αagonist
Used as topical decongestant (promote
constriction of nasal mucosa)
Cause hypotension at high doses b/c of
central clonidine like effects
Oxymetazoline has significant affinity for
α-2Areceptors

56. Amphetamine
Phenylisopropylamine
Important b/c of its use & misuse as a CNS
stimulant
Readily enter into CNS
Marked stimulant effect on mood & alertness
Depressant effect on appetite
Peripheral actins mediated through release of
catecholamines

57. Methamphetamine (N-
methylamphetamine)
Very similar to amphetamine
Phenmtrazine
Variant of phenylisopropylamine with
ampetamine like effects
Promoted as an anorexiant
Popular drug of abuse

58. Receptor-selective
Sympathomimetic Drugs
Alpha2-selective agonists
D/c BP through action in CNS
Direct application to blood vessels cause
vasoconstriction
e.g., clonidine, methyldopa, guanfacine,
guanabenz
All are useful for treatment of HTN