The content deals with the sympathomimetic and sympatholytic drugs according to Pharmacy Council of India syllabus

1. The Race Horse and the Cow
Sympathetic Nervous System

2. SYMPATHETIC RESPONSES

3. Neurotransmitter i s
norepinephrine
“fight or flight”
= exercise, excitement,
emergency, and
embarrassment

4. Fight o r f l i g h t adaptive e f f e c t s include:
• increased cardiac a c t i v i t y, increased blood
pressure,
• c o n s t r i c t i o n o f blood vessels i n sk in
• d i l a t i o n o f p u p i l
• i n h i b i t i o n o f g u t and u r in a r y bladder
contractions
• increase i n blood glucose and f ree f a t t y acid
levels
• d i l a t i o n o f bronc hial smooth muscle
• secretion o f viscous saliva
• sweating
• l i v e r produces glucose t o provide energy f o r
muscle contraction.

5. SYMPATHOMIMETICS

6. SYMPATHOMIMETICS
• These are the drugs which have actions
similar to that of noradrenaline
(norepinephrine).
• They are also called as sympathetic
agonists or adrenergic agonists.
Adrenaline / Epinephrine Noradrenaline / Norepinephrine
•

7. BIOSYNTHESIS OF CATECHOLAMINES

9. Catabolism of Catecholamines
COMT: Catechol-O-methyl transferase;
MAO: Monoamino oxidase
Catabolism of Dopamine

10. Catabolism of Norepinephrine

11. Catabolism of Epinephrine

12. CLASSIFICATION OF SYMPATHOMIMETICS
1. Direct Acting: Interacts directly with the adrenergic receptors and show agonistic
action.
Examples: Norepinephrine, Epinephrine, Phenylephrine, Dopamine,
Methyldopa, Clonidine, Dobutamine, Isoproterenol,
Terbutaline, Salbutamol*, Bitolterol, Naphazoline,
Oxymetazoline and Xylometazoline.
2. Indirect acting: Will not interact with the receptors but will enhance the release of
norepinehrine from the vesicle.
Examples: Hydroxyamphetamine, Pseudoephedrine, Propylhexedrine.
3. Agents with mixed mechanism: Possess the actions of both directly and indirectly
acting agents.
Examples: Ephedrine, Metaraminol.

14. ADRENERGIC RECEPTORS

17. INDIRECTLY ACTING SYMPATHOMIMETICS
• Their actions are dependent on the release of
endogenous catecholamines. These indirect agents
mayhave either of two different mechanisms:
(1) displacement of stored catecholamines from the
adrenergic nerve ending (eg,amphetamine and
tyramine) or
(2) inhibition of reuptake of
catecholamines already released (eg, cocaine and
tricyclic antidepressants)

18. DIRECTLY & INDIRECTLY ACTING
(MIXED ACTION)
Drugs include Ephedrine & Pseudoephedrine

19. SAR
• Phenylethylamine may be considered the parent
compound from which sympathomimetic drugs are
derived
• This compound consists of a benzene ring with an
ethylamine side chain
CH2 CH2 NH2
ß
o
m
p
m
o

20. • Substitutions may be made
(1) on the terminal amino group,
(2) on the benzene ring, and
(3) on the alpha or beta carbons.
Substitution by –OH groups at the 3 and 4
positions yields sympathomimetic drugs
collectively known as catecholamines.

21. Theeffects of modificationof phenylethylamine are to
change the affinity of the drugs for alpha and beta
receptors as well as to influence the intrinsic ability to
activate the receptors.
In addition,chemical structure determines the
pharmacokinetic properties of these molecules.
Sympathomimetic drugs may activate both alpha and
beta receptors; however, the relative alpha -receptor
versus beta-receptor activity spans the range from
almost pure alpha activity (methoxamine) to almost
beta pure activity (isoproterenol)

23. Substitution on the Amino Group
• Increasing the size of alkyl substituents on the amino
group tends to increase beta -receptor activity.
• For example, methyl substitution on norepinephrine,
yielding epinephrine, enhances activity at
beta2receptors. Beta activity is further enhanced with
isopropyl substitution at the amino nitrogen
(isoproterenol).
• Beta2-selective agonists generally require a large
amino substituent group.
• The larger the substituent on the amino group, the
lower the activity at alpha receptors; eg,
isoproterenol is very weak at alpha receptors.

24. Substitution on the Benzene Ring
1) 3′,4′- dihydroxy substitued benzene ring provides
excellent receptor activity for both α and β sites.
2) However, there is poor oral bioavailablity due to
COMT.
3) 3′,5′-dihydroxy compounds are not good substrates
for COMT. Also 3′,5′-dihydroxy compounds are
more selective for β2- receptors.
4) Albuterol (Salbutamol) has 3′-hydroxymethyl (i.e.
3-CH2OH) and 4′-OH = β2 selective.

25. 5) At l e a s t one group must be capable o f
for ming hydrogen bonds. And i f o n l y one
group present i t should be a t 4 ′ -
p o s i t i o n ( t h e n β a c t i v i t y i s retained)
e.g. Ritodrine – h a s o n l y o n e 4′-OH, y e t i t
h a s g ood β - a c t i v i t y. Also since
Ritodrine has a large N - s u b s t i t u e n t = β2
s e l e c t i v i t y i s h i g h e r, t h e r e f o r e u s e d i n
premature l a b or t o r e l a x the uter us.

26. If o n l y a 3′-OH l o w e r e d α a c t i v i t y b u t
e l i m i n a t e s β a c t i v i t y.
T h e r e f o r e s e l e c t i v e α - a g o n i s t s can be
made e.g. phenylephrine and metaraminol.
PHENYLEPHERINE METARAMINOL

27. • α-receptors accept a wide range of tolerance for agonist
activity e.g. 2′,5′-dimethoxy substitution of methoxamine
which is an α-receptor agonist but also a β-blocker at
METHOXAMINE
higher concentrations.
Phenylephrine, metaraminol and
methoxamine are all agents
which cause Vasoconstriction

28. Cpds without any substitutions at 3rd & 4th are both
direct Acting & indirect acting.
absence of ring –OH groups on benzene ring tends
to increase the distribution of the molecule to the
central nervous system.
For example,
Ephedrine and amphetamine are orally active, have a
prolonged duration of action, and produce central
nervous system(CNS STIMULATION) effects not
typically observed with the catecholamines.

29. Amphetamine Ephedr in e

30. SUBSTITUTION ON ALPHA CARBON ATOM
Substituti o n s a t the alpha carbon block oxidation by
monoamine oxidase (MAO) and prolong the action o f such
drugs, p a r t i c u l a r l y the noncatecholamines.
Ephedrine and amphetamine are examples o f - s u b s t i t u t e d
compounds .
A l p h a - m e t hy l compounds are also called
phenylisopropylamines.
In ad d i t i o n t o t h e i r resistance t o oxidat i o n by MAO, some
phenylisopropylamines have an enhanced a b i l i t y t o displace
catecholamines f r o m storage sites i n noradrenergic nerves.
Therefore, a p o r t i o n o f t h e i r a c t i v i t y i s dependent upon t he
presence o f nor mal norepinephrine st ores i n the body; they
are i n d i r e c t l y acting sympathomimetics.

31. SUBSTITUTION ON BETA CARBON ATOM
Direct-acting agonists typically have a hydroxyl
group. In addition to activating adrenoceptors, this
hydroxyl group may be important for storage of
sympathomimetic amines in neural vesicles.
OH Substituent: By default must be present at
β position to primary amine (i.e. spaced 2
carbons away).
2. being a chiral center the 1 position must be in R
configuration for maximum activity (but many
drugs sold as racemic i.e. R/S mixture)- exception
dobutamine. R(-) / D(-) configuration o f NE
more a c t i v e

32. PHARMACOLOGICAL ACTIONS

34. SALBUTAMOL
methyl 5-(2-bromoacetyl)-2-hydroxybenzoate
benzyl tert-butylamine
Amino ketone
SALBUTAMOL
Amino alcohol
It is a selective beta-2 receptor agonist used in the treatment ofBronchial
asthma
Reduction

35. Use: Pressor agent
Nonadrenaline/Norepinephrine Adrenaline/Epinephrine
Use: Pressor agent, Cardiac
a r r e s t Anaphylac tic shock
Dopamine
It is used as a temporary agent for
treating hypotension and circulatory
shock caused by myocardial stroke,
trauma, kidney rejection, and
endogenous septicemia.
Alpha-MethylDopa
Use: Antihypertensive agent

36. ISOPRENALINE/ISOPROTERENOL
Use: Cardiogenic shock
DOBUTAMINE
Use: Congestive h e a r t
f a i l u r e I n o t r o p i c e f f e c t
( s e l e c t iv e b e t a - 1 agonist)
TERBUTALINE
Use: β2 adrenergic receptor agonist used for
the relief of bronchospasm in conditions
such as asthma and COPD.
( s e l e c ti ve b e t a - 2
agonist )
Use: β2 adrenergic receptor agonist used for
the relief of bronchospasm in conditions such
as asthma and COPD.
BITOLTEROL-Prodrug of
Colterol

37. IMIDAZOLINE TOPICAL NASAL DECONGESTANTS
 Imidazoline topical nasal decongestants are direct acting sympathomimetic
drugs, which acts on alpha-adrenergic receptors in the arterioles of the nasal
mucosa. This activates the adrenal system to yield systemic vasoconstriction. In
producing vasoconstriction, the result is a decrease in blood flow in the nasal
passages and consequently decreased nasal congestion.
 The vasoconstriction means that there is less pressure in the capillaries and
less water can filter out, thus less discharge is made.

38. HYDROXYAMPHETAMINE
Use: Hydroxyamphetamine is an intended
mainly as local eye drops for diagnostic
purposes. It cause dilation of the eye pupil
before diagnostic test. The main use of
Hydroxyamphetamine as eye drops is the
diagnosis of Horner's syndrome which is
characterized by nerve lesions.
INDIRECT ACTING SYMPATHOMIMETICS
PROPYLHEXEDRINE
Use: Like Phenylephrine and
imidazoline sympathomimetics it is also
used as NASAL DECONGESTANT
CLONIDINE-AN IMIDAZOLINE ANTIHYPERTENSIVE AGENT
Th e a nt ih yp er te ns i v e e f f e c t o f c l o n id i n e i s due
t o agonism on t h e I 1 - r e c e p t o r (IMIDAZOLINE
RECEPTOR), which mediates t h e s y m p a t h o -
i n h i b i t o r y a c ti o n s o f c lo nid ine t o l o we r blood
pressure.

39. AGENTS WITH MIXED MECHANISM
EPHEDRINE
Use: It is mainly used for bronchial asthma, allergic illnesses, as
an antiedemic for mucous membranes in rhinitis, and also as a
drug to increase blood pressure during surgical interventions.
It is used locally in ophthalmology as a vasoconstricting agent
for dilating pupils.
METARAMINOL
Use: It is used in hypotensive shock for the purpose of
elevating blood pressure, which can result from spinal
anesthesia, surgical complications, and head trauma.

40. SYMPATHOLYTICS

41. Classification
1. Alpha adrenergic blockers:
Tolazoline*, Phentolamine, Phenoxybenzamine,
Prazosin, Dihydroergotamine, Methysergide.
2. Beta adrenergic blockers:
Propranolol*, Metipranolol, Atenolol, Betaxolol,
Bisoprolol, Esmolol, Metoprolol, Labetolol, Carvedilol.
Adrenergic antagonists/Sympatholytics:
These are the drugs which antagonize the actions of catecholamines
at adrenergic receptors.

42. -adrenergic receptor antagonists
O
Ar
NH R
OH
Ar = aromatic ring structure
R = bulky alkyl group (isopropyl or tert-butyl)
Note: non-carbon atom
in s i d e chain

43. SAR of -adrenergic receptor antagonists

44. Stereochemistry of beta adrenergic antagonists

45. TOLAZOLINE
I t i s a Nonselective, re v e r s i b l e c o mp e t i t i v e adrenoblockers
It has been used to treat Raynaud syndrome and other conditions involving
peripheral vasospasm. Tolazoline is available in an injectable form and is
indicated for use in persistent pulmonary hypertension of the newborn when
supportive measures are not successful.

46. PROPRANOLOL

47. ALPHA BLOCKERS- Tolazoline*, Phentolamine,
Phenoxybenzamine, Prazosin, Dihydroergotamine, Methysergide.
PHENTOLAMINE PHENOXYBENZAMINE-Irreversible alpha blocker
Use: 1) Phentolamine is used to
prevent or control hypertensive
episodes that occur in patients
with pheochromocytoma.
2) It also has been used in
combination with papaverine to
treat impotence.
It is a irreversible alpha-blockers, because beta-
haloalkylamines in the molecules alkylate alpha-
receptors.
Use: Oral phenoxybenzamine is used for the
preoperative management of patients with
pheochromocytoma and in the chronic management of
patients whose tumors are not amenable to surgery.

48. PRAZOSIN- Selective α1-blocker
Use: Antihypertensive. It is also used to
treat Benign Prostate Hyperplasia (BPH)
due to its ability to inhibit α1A receptors
in the prostate glands
DIHYDROERGOTAMINE- ANTIMIGRAINE AGENT
Use: It is an 5-HT1D receptor agonist. Agonism at this
receptor leads to vasoconstriction in the cerebral blood
vessels leading to the decrease in the symptoms of
MIGRAINE HEADACHE.
It also interacts with serotonin, adrenergic and dopamine
receptors
Quinazoline
Ring
Piperazine ring
Furan Ring

49. METHYSERGIDE- ANTIMIGRAINE AGENT
Use: Methysergide is a congener of lysergic acid diethylamide and is used
prophylactically in migraine and other vascular headaches

50. BETA BLOCKERS- Propranolol*, Metipranolol,
Atenolol, Betazolol, Bisoprolol, Esmolol, Metoprolol, Labetolol,
Carvedilol
GENERAL USES: Used as Antihypertensive, Antiarrhythmic, Antianginal and antiglaucoma
agents
METIPRANOLOL
Uses: A beta-adrenergic antagonist
effective for both beta-1 and beta-2
receptors. It is used as an
antiarrhythmic, antihypertensive,
and antiglaucoma agent.
ATENOLOL-Acetamido
group
Uses: Selective beta-1 agonist used
as antihypertensive agent.

51. BISOPROLOL
Use: Bisoprolol is a cardioselective β1-adrenergic blocking
agent used for secondary prevention of myocardial
infarction (MI), heart failure, angina pectoris and mild to
moderate hypertension.
ESMOLOL
Esmolol is a cardio selective beta1 receptor blocker with rapid onset, a
very short duration of action used to treat ventricular tachycardia

52. METOPROLOL
Metoprolol is a cardioselective β1-adrenergic blocking agent used for acute myocardial
infarction (MI), heart failure, angina pectoris and mild to moderate hypertension. It may also
be used for supraventricular and tachyarrhythmias and prophylaxis for migraine headaches.
BETAXOLOL
Betaxolol is a selective beta₁ receptor blocker used in
the treatment of hypertension and glaucoma.

53. β-BLOCKERS WITH α1-ANTAGONIST ACTIVITY
LABETALOL- Salcylamide arylethanolamine derivative
Use: Labetalol is a clinically useful as antihypertensive agent.
* *

54. CARVEDILOL-Carbazole aryloxypropanolamine
derivative
CARBAZOLE RING
Uses: It is used in treating hypertension and congestive heart failure.
This drug is also unique in that it possesses antioxidant
activity and an antiproliferative effect on vascular smooth
muscle cells. It thus has a neuroprotective effect and the ability
to provide major cardiovascular organ protection

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