A. Adrenergic neurotransmitters and their biosynthesis and metabolism, adrenergic receptors their distribution and actions mediated by them B. Sympathomimetics 1. Direct acting: SAR, Endogenous catecholamines, a) Alpha adrenergic agonists: Phenylephrines, Methoxamine, Naphazoline, Xylometazolines, Oxymetazoline, Clonidines, Guanabenz, Methyldopa b) Dual agonist/antagonist: Dobutamine c) Beta adrenergic agonists: Isoproterenols, Metaproterenol, Terbutalins, Albuterol, Salbuterol, Bitolterol, Ritodrine 2. Indirect acting: Hydroxyamphetamine, Propylhexedrine 3. Mixed acting: Ephedrine, Metaraminol C. Adrenolytics: 1. Alpha blockers: a) Non selective: Tolazoline b) Irreversible blockers: Phenoxybenzamines c) Alpha1 blockers: Prazosins, Doxazosin, Tamsulosin d) Alpha2 blockers: Yohimbine, Coryanthine 2. Beta blockers: SAR a) Non selective blockers: Propranolols, Nadolol, Pindolol, Timolol, Sotalol b) Beta1 blockers: Acebutolol, Atenelol, Esmolol, Metaprolols c) Betablockers with alpha1 antagonistic activity: Labetalol, Carvedilol

1. AAdrenergics
An adrenergic drug is related to a chemical
compounds that especially exert its physiological
action by stimulation of peripheral sites of
sympathetic nerves system
An adrenergic nerve fibre is a neuron for which
the neurotransmitter is
either adrenaline (epinephrine), noradrenaline or
dopamine.

3. • Increased rate and force of heart contractions
• Rise in blood pressure
• Shift of blood flow to skeletal muscles
• Dilation of bronchioles and pupils
• • Increase in blood glucose levels
(gluconeogenesis)

4. 1. Nerve Transmission1. Nerve Transmission
Peripheral nervous systemPeripheral nervous system
CNS
(Somatic)
CNS
(Autonomic)
Sympathetic
Parasympathetic
NA
Ach
(N)
Synapse
Ach (N)
Ach
(N)
Ach
(N)
Ach
(M)
Adrenal
medulla
Adrenaline
Skeletal
muscle
Synapse
AUTONOMIC
Smooth muscle
Cardiac muscle

5. Biosynthesis

6. Biosynthesis
• Catecholamines( Dopamine, ephinephrine, Nor ephinephrine) are
synthesized from amino acid phenyl alanine obtained from diet is converted
into tyrosine by enzyme tyrosine hydroxylase. This reaction takes place in
the cytosol of adrenergic nerve cells.
• Conversion of L-tyrosine to L- dopa is carried out with the help of enzyme
tyrosine hydroxylase/ tyrosine oxidase,this step is considered as a rate
limiting step( feed back mechanism) since activity of this enzyme depend
on the amount of stored adrenaline.
• Conversion of L-dopa to L- dopamine is carried out by the enzyme aromatic
L- amino acid decarboxylase.
• Dopamine is converted into nor adrenaline by the enzyme dopamine
hydroxylase , Whenever there is an action potential calcium ion enter into
the cell and releases norephinephrine into the synapti cleft, where it
interact with adreno receptor and bring about the action.
•

7. • Nor ephinehrine is converted into ephinehrine by the enzyme
phenyl ethanolamine N-methyl transferase, where methy
group is added this step require methyl donor S- adenosyl
methionine,this reaction takes place in the cytoplasm.
Whenever there is a depolarisation of the membrane, calcium
ion enter into the cell cause exocytosis of the adrenaline into
the synapti cleft where it interact with adrenergic receptor to
bring about the action.

8. Metabolism/Catabolism/Degradation
• Catecholamines are stored in a synaptic vessicles and released
into synaptic cleft.
• Ephinephrine and nor ephinephrine are metabolised by two
main enzymes that is mono amino oxidase(MAO) and
catechol ortho methyl transferase(COMT),these enzymes are
widely present in a system especially in liver and kidney
• MAO present on the outer membrane of mitochondria and
COMT present in a cytoplasm.
• First step involves oxidative deamination by MAO followed by
reduction to form 3,4- dihydroxy phenyl ethylene glycol,
which then catalysed by COMT to form 3-methoxy-4-hydroxy
phenyl ethylene glycol

9. • After methylation it is followed by oxidation by alcohol dehydrogenase
and aldehyde dehydrogenase to form 3-methoxy-4-hydroxy mandelic acid.
 Catecholamine undergoes oxidative deamination at neuronal and
extraneuronal sites such as liver then undergoes oxidation with aldehyde
dehydrogenase to form 3,4- hydroxy mandelic acid which then undergoes
methylation to form 3-methoxy-4-hydroxy mandelic acid catalysed by
COMT.
In next metabolic pathway first step involves methylation of C-3
hydroxyl group to form nor metanephrine which then undergoes oxidative
deamination followed by reduction with aldehyde reductase to form 3-
methoxy-4-hydroxy phenyl ethylene gylcol, which then undergoes oxidation
with alcohol and aldehyde dehydrogenase to form 3-methoxy-4-hydroxy
mandelic acid
Nor metanephrine also converted into 3-methoxy-4-hydroxy mandelic acid
by alcohol and aldehyde dehydrogenase.

10. Metabolism

11. • Epinephrine
• Norepinephrine
• The adrenergic receptors or adrenoceptors are a class of G protein-
coupled receptors that are targets of
many catecholamines like norepinephrine(noradrenaline)
and epinephrine (adrenaline) produced by the body, but also many
medications like beta blockers, β2 agonists and α2 agonists, which are used
to treat high blood pressure and asthma for example.
• Many cells have these receptors, and the binding of a catecholamine to
the receptor will generally stimulate the sympathetic nervous
system (SNS). SNS is responsible for the fight-or-flight response, which is
triggered for example by exercise or fear causing situations. This
response dilates pupils, increases heart rate, mobilizes energy, and diverts
blood flow from non-essential organs to skeletal muscle. These effects
together tend to increase physical performance momentarily.

15. Structural Activity Relationship(SAR)
Catecholamines
Non catecholamines

16. • Adrenaline or noradrenaline are receptor
ligands to either α1, α2 or β-
adrenoreceptors. α1 couples to Gq, which results
in increased intracellular Ca2+ and
subsequent smooth muscle contraction. α2, on
the other hand, couples to Gi, which causes a
decrease in neurotransmitter release, as well as a
decrease of cAMPactivity resulting in smooth
muscle contraction. β receptors couple to Gs, and
increases intracellular cAMP activity, resulting in
e.g. heart musclecontraction, smooth muscle
relaxation and glycogenolysis.

17. Adrenaline Nor adrenaline

18. 1)Sympathomimetic action is shown by both
catecholamines and non catecholamines
a)Catecholamines posses dihydroxy benzene
nucleus and non catecholamines have phenyl
ethylamine ring
• Example for catecholamines-Ephinephrine and
nor ephinephrine
• Example for non catecholamines-Ephidrine

19. b)For maximum activity aromatic ring should be
separated from amino group by two carbon chain.
Increasing or decreasing this chain brings about
loss of activity,
substitution on amino group increase β-receptor
activity, primary or secondary amino groups have
more potent direct acting agonist activity than
tertiary or quaternary amines

20. Substitution on N atom with tertiary butyl
group increases β2 receptor agonist activity
Cloterol

21. C)For maximum α, β agonist activity the hydroxyl
group must be present on third and fourth position
of aromatic ring and also hydroxyl group must be
present in β-cabon atom
 Presence of hydroxyl group on the β-carbon
atom make the compound to have chairal center,
which in turn increase the sterioselectivity of the
compound there by making the compound better
to improve activity

22. Loss of hydroxyl group in the β-carbon atom
results in loss of direct sympathomimetic
activity becomes indirectly acting
sympathomimetics

23.  Removal of hydroxyl group at C-4 results in a
compound having α1 agonist activity.
Ex: Phenyl ephrine

24. d) Substitution on N atom with tertiary butyl
group increases β2 receptor agonist activity
Cloterol

25. e) Replacement of catechol nucleus with resorcinol
nucleus results in compound having selective β2
receptor activity
Terbutaline

26. 2) Addition of catecholamines and non
catecholamines with other group of compounds
are found to have α- receptor agonist activity

29. Classifications
1)Direct acting:
• Endogenous catecholamines: Adrenaline,
noradrenalin
• Alpha adrenergic agonists: Phenylephrine,
Methoxamine, Naphazoline,Xylometazoline,
Oxymetazoline, Clonidine, Guanabenz,
Methyldopa
• Dual agonist/antagonist: Dobutamine
• Beta adrenergic agonists: Isoproterenol,
Metaproterenol, Terbutalin,Albuterol, Salbuterol,
Bitolterol, Ritodrine

30. 2.Indirect acting: Hydroxyamphetamine,
Propylhexedrine
3. Mixed acting: Ephedrine, Metaraminol

31. Endogenous catecholamines are synthesized in
neurons and in the chromaffin cells of the adrenal
medulla, and stored in intracellular vesicles.
Epinephrine

32. • Potent stimulant of both α and β adrenoceptors;
• Drug of choice for reversal of acute
hypersensitivity reactions
• Enhances the action of local anesthetics
• Poor oral absorption. Rapidly metabolized by
MAO and COMT;
• Degrades on exposure to air and light;
• Serious side effects include cerebral
hemorrhage and cardiac arrhythmias.

33. Norepinephrine

34. • Potent stimulant of both α and β adrenoceptors
• Limited therapeutic value
• Used to maintain blood pressure in acute
hypotensive states
• Substrate for MAO and COMT, not effective
orally
• Undergoes oxidation in prolonged exposure to
air. Sodium bisulfite used as antioxidant in NE
preparations

35. Dopamine

36. • Not strictly an adrenergic drug, acts on
dopamine receptors.
• Stimulates cardiac 1-AR through both direct
and indirect mechanisms.
• Used to correct hemodynamic, or congestive
heart failure
• Rapidly metabolized by MAO and COMT. Not
effective orally.

37. Phenyl ephrine
It is a potent vasoconstrictor which is active orally
and its duration of action is twice than that of
ephinephrine
It is non toxic mainly used as nasal decongestion
and also dilation of pupil in glaucoma.

38. Methoxamine
Used during surgery to maintain
adequate blood pressure

41. • All are α1 agonist
• Used for their vasoconstrictor effect as nasal
decongestant and ophthalmic decongestant

42. Clonidine
 It has selective α2 adrenergic agonist activity
 Used in the treatment of hypertension

44. Guanabenz
 It has selective α2 adrenergic agonist activity
 Used as antihypertensive drug

45. Methyl dopa
 It has selective α2 adrenergic agonist activity
 Used as antihypertensive drug

46. Dobutamine
• It has dual action, it can act as both agonist at
one receptor and antagonist in another
receptor
• It exist in enantiomeric form and both the
enantiomers are potent
• The dextro form is form potent β1 agonist and
laevo form is more potent α1 agonist
• Used as cardiac stimulant after surgery or in
CHF

48. Isoproterenol
• It act on both β1 and β2 receptors
• It bring about the increasing in cardiac output
by stimulating β1 receptor and bronchodilator
effect by stimulating β2 receptors

49. Metaproterenol
It has β2 receptor activity
It works by relaxing smooth muscles in the airway to
improve breathing, hence it is used to treat
conditions such as asthma, bronchitis

50. Terbutaline
• It has selective β- receptor agonist property
• It has lower affinity to β2 receptor compare to
isoproterenol but it has longer duration of
action and it is orally effective

53.  Albuterol is a selective beta2-adrenergic
receptor agonist that relaxes muscles in the
airways and increases air flow to the lungs.
Albuterol inhalation is used to treat or
prevent bronchospasm in people with
reversible obstructive airway disease.

54. salmeterol
• Asthama
• Chronic obstructive pulmonary disease. ...
• Bronchitis. ...

55. • is a short-acting β2 adrenergic receptor
agonist used for the relief of bronchospasm in
conditions such as asthma and COPD
Bitolterol

56. • Ritodrine is a short-acting β2 adrenoreceptor
agonist — a class of medication used for
smooth muscle relaxation (Asthma)
Ritodrine

57. Indirectly acting
Hydroxyamphhetamine
 Hydroxyamphetamine is an indirect acting
sympathomimetic agent which causes the release of
norepinephrine from adrenergic nerve.
 It works by relaxing the muscles of the eye to cause
the pupil to dilate or widen (mydriasis).

58. Propylhexedrine
 Propylhexedrine binds to and activates alpha-
adrenergic receptors in the mucosa of the
respiratory .This results in vasoconstriction and
reduces swelling and inflammation of the
mucous membrane lining, therefore relieving
nasal and sinus congestion.

59. Mixed acting
Ephedrine is used for temporary relief of
shortness of breath, chest tightness, and
wheezing due to bronchial asthma.

60. Metaraminol
It is an adrenergic agonist that acts predominantly
at alpha-1 adrenergic receptors and also stimulates
the release of norepinephrine.
It has been used primarily as a vasoconstrictor in
the treatment of hypotension.

61. ADRENERGIC
BLOCKERS/ADRENOLYTICS/ADRENERGIC
ANTAGONIST
Are drugs that selectively inhibit certain response
of sympathetic stimulation or block the effect
produced by sympathomimetic agents

62. CLASSIFICATION
1. Alpha blockers:
• Non selective: Tolazoline
• Irreversible blockers: Phenoxybenzamine
• Alpha1 blockers: Prazosin Doxazosin, Tamsulosin
• Alpha2 blockers: Yohimbine, Coryanthine
2.Beta blockers
• Non selective blockers: Propranolol, Nadolol, Pindolol,
Timolol, Sotalol
• Beta1 blockers: Acebutolol, Atenelol, Esmolol,
Metaprolol
• Betablockers with alpha1 antagonistic activity:
Labetalol, Carvedilol

64. • Hypertension (PRAZOSIN)
• Congestive Heart Failure
TERAZOSIN
• Benign prostatic hyperplasia It relieves the
symptoms of BPH by relaxing the muscles of the
bladder and prostate.
• It also is used alone or in combination with other
medications to treat high blood pressure. It
lowers blood pressure by relaxing the blood
vessels so that blood can flow more easily
through the body.

65. Doxazosin is an antihypertensive medicine which
is used to treat high blood pressure and relieve
symptoms of Benign Prostatic Hypertrophy
(prostate enlargement).
This medicine should be used with caution since
it may cause a temporary loss of consciousness
due to the sudden decrease in blood pressure (.
This medicine is not recommended for use in
children.

68. PHENOXYBENZAMINE
• It is used to treat
adrenal pheochromocytoma

69. TAMSULOSIN
 Tamsulosin is used to improve urination in men with benign
prostatic hyperplasia (enlarged prostate).
 Tamsulosin is not approved for use in women or children.

70. TOLAZOLINE
Tolazoline is a non-selective competitive α-adrenergic receptor
antagonist.
It is a vasodilator that is used to treat spasms of peripheral
blood vessels as in acrocyanosis( condition marked by bluish or
purple colouring of the hands and feet, caused by slow
circulation).

71. Yohimbine is an indole
alkaloid derived from the
bark of the Central
African yohimbe tree
(Pausinystalia yohimbe)
that is a apha adrenergic
blocking agent widely
used as therapy for
erectile dysfunction
YOHIMBIN

72. 1)For the function of a β-blocker it's essential
for the compound to contain an aromatic
ring and a β-ethanolamine.
The aromatic ring can either be
benzoheterocyclic (such as indole)
or heterocyclic (such as thiadiazole) or fused
benzene ring :
SAR OF BETA BLOCKERS

73. • The X part of the side chain can either be
directly linked to the aromatic ring or linked
through a —OCH2— group
• When X is —CH2CH2—, —CH=CH—, —SCH2—
or —NCH2—, there is little or no activity
• The R1 group can only be a secondary
substitution or tertiary chain

74. 2)Aromatic substitution is: ortho > meta > para..
para-substituents usually decrease activity but
ortho-groups retain some activity.
• Poly substitution on carbon 2 and 6 makes the
compound inactive but when the substitution
is on carbon 3 and 5 there's some activity.
Pronethalol

75. 3)The major inovation in the drug development
of beta blocker was introduced when it was
discovered that intoduction of oxymethylene
bridge could be inserted into the
arylethanolamine structure of pronethalol to
produce propranolol.
PRONETHALOL
PROPANOLOL

76. • Propranolol is an aryloxypropanolamine,
which are more potent β-blockers than
arylethanolamines which was a first clinically
successful beta blocker . Today, most of the β-
blockers used clinically are
aryloxypropanolamines.

77. • The length of the side chain is increased when
an oxymethylene bridge is introduced.
• Substitution of ethereal carbon atom with S,
NCH3 retains the activity
• The most effective amines are isopropyl and
tertiary butyl amines.

78. Propanolol
 It act on both β1,β2 receptor.
 Propranolol is used to treat tremors, angina (chest
pain), hypertension (high blood pressure
 It is also used to treat or prevent heart attack, and to
reduce the severity and frequency of migraine headaches.

80. PINDALOL
• Pindolol belongs to the class of medications called beta-
1blockers. It is used to treat high blood pressure and
to prevent angina (chest pain).
• For treatment of high blood pressure, pindolol may be used
alone or in combination with other medications that reduce
high blood pressure, particularly thiazide diuretics

82. SOTALOL
Sotalol is used in people with ventricular
tachycardia or ventricular fibrillation.

83. ACETBUTANOL
• Acebutolol is used to treat high blood pressure.
Acebutolol also is used to treat an irregular
heartbeat.. It works by relaxing blood vessels and
slowing heart rate to improve blood flow and
decrease blood pressure.

84. ATENELOL
 This medication is also used to treat chest
pain (angina) and to improve survival after
a heart attack.

85. ESMOLOL
 Esmolol decreases the force and rate of heart contractions by
blocking beta-adrenergic receptors of the sympathetic nervous
system, which are found in the heart and other organs of the body.
Esmolol prevents the action of two naturally occurring
substances: epinephrine and norepinephrine.[3]

86. METAPROLOL
• Metoprolol is used with or without other
medications to treat high blood
pressure (hypertension). Lowering high blood
pressure helps prevent strokes, heart attacks, and
kidney problems. This medication is also used to
treat chest pain(angina) and to improve survival
after a heart attack.

88. • The principal physiologic action of these drugs
is to competitively block adrenergic
stimulation of β-receptors within the
myocardium (β1-receptors) and within
bronchial and vascular smooth muscle (β2-
receptors), and α1-receptors within vascular
smooth muscle. This causes a decrease in
systemic arterial blood pressure and systemic
vascular resistance because of its combined α-
and β-adrenergic blocking activity.

89. • Labetalol is an antihypertensive medication which
is used to lower the blood pressure and also used
in the treatment of heart failure. This medicine is
not recommended for children and in patients
with diabetes and lung disease.
• Carvedilol is used to treat congestive heart
failure (CHF). It is often taken with a diuretic and
an angiotensin converting enzyme (ACE) inhibitor.