3/13/2021

 Epinephrine (also known as adrenaline) is a hormone and a

neurotransmitter
 Epinephrine and norepinephrine are two separate but related hormones
secreted by the medulla of the adrenal glands.
 They are also produced at the ends of sympathetic nerve fibres, where
they serve as chemical mediators for conveying the nerve impulses to
effector organs.
 Epinephrine remains a useful medicine for several emergency
indications.
 The word adrenaline is used in common parlance to denote increased
activation of the sympathetic system associated with the energy and
excitement of the fight-or-flight response.

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 The influence of adrenaline is mainly limited to

a metabolic effect and bronchodilation effect on organs
devoid of direct sympathetic innervation.

 In chemical terms, epinephrine is one of a group

of monoamines called the catecholamines. It is produced in
some neurons of the central nervous system, and in
the chromaffin cells of the adrenal medulla from the amino
acids phenylalanine and tyrosine

Biosynthesis
Storage
Release
Mechanism of action
Adrenergic receptors: alpha and beta

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Increased epinephrine
secretion is observed in

Benign
Phaeochro- myocardial essential
Hypoglycaemia
mocytoma infarction familial
tremor(BFT)

Low, or absent,
concentrations of
epinephrine can be seen in

autonomic Failure of the

neuropathy or adrenal cortex,
following as with Addisons
adrenalectomy. disease

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 As a hormone and neurotransmitter, epinephrine acts on nearly

all body tissues.

 Its actions vary by tissue type and tissue expression

of adrenergic receptors.

 For example, high levels of epinephrine causes

1) smooth muscle relaxation in the airways

2) but causes contraction of the smooth muscle that

lines most arterioles.

 Epinephrine acts by binding to a variety of adrenergic

receptors. Epinephrine is a nonselective agonist of all
adrenergic receptors, including the major
subtypes α1, α2, β1, β2, and β3.

 Epinephrine's binding to these receptors triggers a

number of metabolic changes:
Binding to α-adrenergic receptors
1) inhibits insulin secretion by the pancreas
2) Stimulates glycogenolysis in the liver and muscle
3) and stimulates glycolysis in muscle.

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β-Adrenergic receptor binding

1) triggers glucagon secretion in the pancreas

2) increased adrenocorticotropic hormone (ACTH)

secretion by the pituitary gland and

3) increased lipolysis by adipose tissue

Together, these effects lead to

increased blood glucose and fatty acids,
providing substrates for energy
production within cells throughout the
body

Organ Effects

Heart Increases heart rate

Lungs Increases respiratory rate

Systemic Vasoconstriction and vasodilation

Liver Stimulates glycogenolysis

Systemic Triggers lipolysis

Systemic Muscle contraction

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 Adrenaline is synthesized in the medulla of the adrenal gland in

an enzymatic pathway that converts the amino acid tyrosine into
a series of intermediates and, ultimately, adrenaline.

 Tyrosine is first oxidized to L-DOPA, which is subsequently

decarboxylated to give dopamine.

 Oxidation of Dopamine gives norepinephrine.

 Methylation of the primary amine of noradrenaline. This reaction

is catalyzed by the enzyme phenylethanolamine N-

methyltransferase (PNMT)

which utilizes S-adenosylmethionine (SAMe) as the methyl donor.

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 fh

 biosynthesis of norepinephrine takes place within adrenergic

neurons near the terminus of the axon and junction with the
effector cell.
 the biosynthetic pathway begins with the active transport of the
amino acid L-tyrocine into the adrenergic neuron cell
 in the first step within the cytoplasm, the enzyme tyrocine
hydroxylase (tyrocine-3-monooxygenase) oxidizes the 3'
position of tyrocine to form the catechol amino acid L-dopa.this
is the rate limiting step in norepinephrine biosynthesis, and the
activity of tyrocine hydroxylase is carefully controlled.
 the enzyme is under feedback inhibition control by product
catecholamines and is controlled through a complex pattern of
phosphorylation/dephosphorilation, in which phosphorylation by
protein kinases activates the enzyme and dephosphorylation by
phosphatases decreases activity.

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Drug Adrenergic
receptor
 Each adrenoreceptor is coupled through a G protein to an
effector mechanism. Effector mechanisms are proteins that
are able to translate the conformational change caused by
activation of the receptor into a biochemical event within the
cell.
 All the β-adrenoreceptors are coupled via specific G proteins
(GS) to the activation of adenylyl cyclase. thus, when the
receptor is stimulated by an agonist, adenynyl cyclase is
activated to catalyse the formation of cyclic AMP (cAMP)
from ATP.

 Called a second messenger for the β-adrenoreceptors, cAMP

is known to function as a second messenger for a number of
other receptor types. cAMP is considered to be a messenger,
because it can diffuse through the cell for at least short
distance to modulate biochemical events remote from the
synaptic cleft.
 Modulation of biochemical events by cAMP is rapidly
deactivated by hydrolysis of thr phosphodiester bond by the
enzyme phosphodiesterase.
 The α2 - receptor may use more than one effector system
depending on the location of the receptor. To date however,
the best understood effector system of the α2 - receptor
appears to be similar to that of the β-receptors, except that
linkage via a G protein (Gi) leads to inhibition of adenynyl
cyclase instead of activation.

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SYLLABUS

Adrenergic Drugs
Alpha adrenergic agonists:
phenylephrine*, naphazoline, xylometazoline, oxymetazoline,
methyldopa, clonidine, guanabenz, guanafacine
Beta agonists :
Isoproterenol, colterol, metaproterenol, terbutaline*, albuterol,
isoxsuprine, ritodrine
Alpha antagonist :
tolazoline, phentolamine, phenoxybenzamine, prazosin,
doxazosin
Beta Antagonists :
pronethalol, propranolol*, sotalol, timolol, atenolol,
metoprolol, esmolol, acebutolol, carvedilol, labetalol* (last two
for self study, including synthesis of labetalol)
Other adrenergic agents (Self study-2 hrs) : pseudoephedrine,
ephedrine, guanethidine, propylhexedrine, reserpine

Selective α-Adrenergic
Agonist

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 3-[(1R)-1-hydroxy-2-(methylamino)ethyl]phenol

 It is a selective α1-agonist, with minimal cardiac stimulant

activity

 It is not a substrate for COMT. Therefore the duration of

action is significantly longer than that of norepinephrine.

 Their α1-agonist activity makes them stong vasoconstrictor,

however its primary systemic use is limited to treating
hypotension during surgery or severe hypotension
accompaniying shock.

 It also has widespread use as a non-prescription nasal

decongestantc in both oral and topical preparations.

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 Its oral bioavailability is less than 10% because of its

hydrophilic properties and intestinal 3’-o-glucuronidation/
sulfation

 Phenylepinephrine preparations applied directly to the eye

constrict the dilated blood vessels of bloodshot, in higher

concentration, are used to dilate the pupil during eye surgery.

2-Arylalkylimidazolines: Alpha 1
agonist

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 The imidazoline derivatives also are selective α1-agonist

and therefore are called Vasocontrictor/vasopressors

 They all contain a one carbon bridge between C2 of the

imidazoline ring and a phenyl substituent. Therefore the
general skeleton of a phenyl ethylamine is contains within
the structures.

 Bulky Lipophilic substitution on the phenyl ring

ortho to the phenyl ring at the meta or Para positions
provide selectivity for the α1-receptors.

Xylometazoline

Oxymetazoline

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 Modification of the imidazoline ring generaly results in

compounds with significantly reduced agonist activity.
However there are open ring imidazolines that are highly
active.

 The nature of aromatic ring and how it is substituted is quite

flexible. Hoever, agonist activity is enhanced when the
aromatic ring is substituted with halogen substituent like
chlorine or small alkyl groups like methyl group,
particularly when they are placed in the two ortho positions

 Imidazolines interact with α-receptors differently from the

way the β-phenylethylamines do, particularly with regard to
the aromatic moiety.

 They have limited access to the CNS, because they

essentially exist in an ionized form at physiological pH
caused by the very basic nature of the imidazoline ring.

1) Naphazoline

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 2-Arylalkylimidazoline α1-agonist:

1) Xylometazoline

2) Oxymetazoline

3) Naphazoline

 2-[(4-tert-butyl-2,6-dimethylphenyl)methyl]-
4,5-dihydro-1H-imidazole

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 6-tert-butyl-3-(4,5-dihydro-1H-imidazol-2-
ylmethyl)-2,4-dimethylphenol

 2-(naphthalen-1-ylmethyl)-4,5-dihydro-1H-
imidazole

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 Xylometazoline and oxymetazoline are used for their

vasocontrictive effects as nasal and ophthalmic
decongestants.

 Systemically, they are potent vasoconstrictors.

 When taken in large doses, oxymetazoline may cause

hypotention, presumbly because of a central clonidine-like
effect.

 Oxymetazoline also has significant affinity for α2A receptors.

Aminoimidazolines: Alpha 2
selective

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Clonidine

 Clonidine differs from 2-arylimadazoline α1-agonist mainly

by the presence of o-Chlorine groups and a NH bridge.
 The o-Chlorine group affords better activity than o-methyl
groups at α2 sites.
 Clonidine contains NH bridge instead of CH2 bridge in 2-
arylimidazolines.
 The uncharged form of clonidine exist as a pair of tautomers.
 Clonidine is an example of a ‘phenylimino’ imidazoline
derivative that possess central α2-selectivity.
 The α1:α2 ration is 300:1
 Clonidine can exhibit vasoconstrictive activity as a result of
stimulation of peripheral α-receptors(causing hypertension).

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 However this hypertensive effect, if it occurs, is

followed by a much longer lasting hypotensive effect
as a result of the ability of clonidine to enter into CNS
and stimulate α2 –receptor located in regions of the brain
such as the nucleus tractus solitarius.

 Stimulation of these α2-receptors bring about a decrease in

sympathetic outflow from the CNS, which in turn leads to
decrease in peripheral vascular resistance and blood pressure.

 Bradicardia is also produced by clonidine as a result of a

centrally induced facilitation of the vagus nerve and
stimulation of cardiac prejunctional α2-receptors.

These pharmacological actions have made clonidine quite

useful in the treatment of hypertension.

 The ability of clonidine and its analogs to exert an

antihypertensive effect depends on the ability of these
compounds not only to interact with the α2-receptor in the
brain but also to gain entry into the CNS.

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 In the case of clonidine, the basicity of the guanidine group

(pKa=13.6) is decreased to pKa=8 (for clonidine) because of
the inductive and resonance effects of the dichlorophenyl
ring.

 At physiologic pH, clonidine will exist to a significant extent

in the nonionised form required for passage into CNS.

It has an oral bioavailability of more than 90%.

 Although various halogen and alkyl substitutions can be

placed at the two ortho positions of the
(phenylamino)imidazoline nucleus without affecting the affinity
of the derivative for α2-receptors, methyl analogs are much
more readily metabolized to the corresponding acids
(inactive) and thus have short Duration of action.

 Halogen substutuents such as chlorine seem to provide the

optimal characteristics in this regard.

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 N-(2,6-dichlorophenyl)-4,5-dihydro-1H-
imidazol-2-amine;hydrochloride

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 2-[(E)-(2,6-dichlorophenyl)methylideneamino]guanidine

 N-(diaminomethylidene)-2-(2,6-dichlorophenyl)acetamide

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 (2S)-2-amino-3-(3,4-dihydroxyphenyl)-2-
methylpropanoic acid

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1) Size:-
 increase in the size from hydrogen to methyl to
isopropyl: activity at α –receptor decreases and activity at β-
receptor increases
 R1: Methyl :- agonist activity at α and β receptors is
maximum (Epinephrine)
 R1:- larger than methyl: α agonist activity is
dramatically decreased
R1:- Isopropyl: negligible α agonist activity, leaving
only β activity. (Isoproterenol:-more
than epi and norepi)
Presumbly, the β-receptor has a large lipiphilic binding
pocket adjusant to the amine binding aspartic acid residue

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 R1: larger than t-butyl to aryl-α-methylalkyl group,

affinity for α1 receptor, but not intrinsic activity,
returns
Large lipophilic groups can afford compounds with α1blocking
activity . Example: Labetolol: mixed α/β- antagonist

2) The N-substituent: can provide selectivity for diiferent

β receptors: with t-butyl grp: selective for β2 receptor
Example: colterol: selective for β2 receptor
When considering use as a bronchodilator a non-
selective β-agonist, such as isoproterenol has
undesirable cardiac stimulatory activity which is
greatly diminished in a selective β2 agonist.

An aryl alkyl group with alkyl chain ranging from 2-11

carbon/oxygen atoms can provide β selectivity with increased
lipophilicity and cell penetration for longer duration of
action.

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4-[1-hydroxy-2-(propan-2-ylamino)ethyl]benzene-1,2-diol

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 Non-selective β-agonist.
 Short duration of action (1-3 hours). Because it is metabolised
by sulfate and glucorunide conjugation of phenolic –OH Group
and o-methylation by COMT.
 Does not undergo oxidative deamination by MAO.
 It is sensitive to light and air because it contains catechol ring.
 No α-activity, because it contains N-isopropyl group.
 Isoproterenol increases cardiac output by stimulation of cardiac
β1 –receptors and bronchodilation through stimulation of β2 -
receptor in the respiratory tract.
 Cardiac stimulation is an occasionally dangerous adverse
effect—this effect of ISO on heart is sometimes used in the
treatment of heart block.
 ISO lack oral activity. It is available for use by inhalation and
injection.

https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?
cid=4086&t=l

 5-[1-hydroxy-2-(propan-2-ylamino)ethyl]benzene-
1,3-diol

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 4-[2-(tert-butylamino)-1-hydroxyethyl]benzene-
1,2-diol

[4-[2-(tert-butylamino)-1-hydroxyethyl]-2-(4-
methylbenzoyl)oxyphenyl] 4-methylbenzoate

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 Bitolterol is a prodrug of colterol.

 It has a rapid onset of action (2–5 minutes) and
may last up to 6–8 hours.
 The drug, alone or in co-administration with
theophylline, doesn't show cardiotoxic effect

-It contains resorcinol ring

-it is a N-tert-butyl analog
of metaproterenol

5-[2-(tert-butylamino)-1-hydroxyethyl]benzene-1,3-diol

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 Terbutaline is an N-tert-butyl analog of Metaproterenol.

 Terbutaline relaxes the bronchial musculature in patients

with asthama but cause less direct cardiac stimulation than
do the non-selective β-agonist.

 Terbutaline is effective orally with duration of action as

compared to ISO. because they are resistant to metabolism
by COMT or MAO.

 Their metabolism involves glucorunide conjugation .

 Cardiac stimulation is observed in high doses.

3-hydroxymethyl
group: gives selectivity
towards β2 agonist.

(S)-Albuterol
enhances bronchial
muscle contraction

For brochodilation
pure (R)-Albuterol must
be used

 4-[2-(tert-butylamino)-1-hydroxyethyl]-2-
(hydroxymethyl)phenol

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 It’s a β2 -selective agonist because of the replacement of m-

hydroxy group with hydroxymethyl group.

 Not metabolised by COMT or MAO. Instead they are

metabolised by conjugation and sulfation.

 Orally active and exhibit longer duration of action (3-6

hours) than ISO.

 (S)-Albuterol enhances bronchial muscle contraction and this

undesirable effect can be avoided by using more pure (R)-
Albuterol.

N-phenylbutoxyhexyl
substituent in combination
with salicyl phenyl ring for
optimal direct β2 receptor
selectivity and potency

Very long acting (12 hours)

Not metabolized by MAO
or COMT

Presence of highly
lipophilic phenylalkyl
substituent

(RS)-2-(hydroxymethyl)-4-{1-hydroxy-2-[6-(4-phenylbutoxy)
hexylamino]ethyl}phenol

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 Salmeterol has an N-phenylbutoxyhexyl substituent in

combination with salicyl phenyl ring for optimal direct β2
receptor selectivity and potency.

 It has potency similar to ISO.

 This drug associates with the β2 receptors slowly resulting in

slow onset of action and dissociates from the receptors at an
even slower rate.

 Not metabolised by COMT or MAO. Instead they are

metabolised by conjugation and sulfation. It is thus very long
acting (12 hours), because of the presence of highly lipophilic
phenylalkyl substituent.

Uterine
Relaxant

 4-[2-[[(1R,2S)-1-hydroxy-1-(4-hydroxyphenyl)propan-
2-yl]amino]ethyl]phenol

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 it is a selective β2 -agonist.

 Used as uterine relaxant.

 Its uterine inhibitory effects are more sustained than its effects
on the cardiovascular system, which are minimal compared
with those caused by nonselective β-agonists.

 The cardiovascular effect usually associated with its

administration are mild tachycardia and slight diastolic
pressure decrease.

 It is administered initially by intravenous infusion to stop

premature lobour and subsequently it may be given orally.

Causes direct
relaxation of uterine
and vascular smooth
muscle via β2 receptors

 4-[1-hydroxy-2-(1-phenoxypropan-2-
ylamino)propyl]phenol

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α-Adrenergic
Antagonist

Nonselective α- Selective α1-

antagonist antagonist
1) Phenoxybenzamine 1)Prazocin
2) Tolazoline 2) Doxazocin
3) Phentolamine

A β-haloalkylamine

 N-benzyl-N-(2-chloroethyl)-1-phenoxypropan-
2-amine

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 Other biomolecules besides the target α-receptor also are

alkylated

 Because of its receptor non-selectivity and toxicity, the use of

phenoxybenzamine is largely limited to alleviating the
sympathetic effects of pheochromocytoma (it produces
hypertension and generalized sympathetic stimulation).

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Antihypertensive

 2-benzyl-4,5-dihydro-1H-imidazole

 3-[N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-4-
methylanilino]phenol

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 Tolazoline and Phentolamine stimulate

gastrointestinal smooth muscle and stimulate
gastric secretion trough release of Histamine
because of these side-effects, the clinical
applications of Tolazoline and phentolamine is
limited to treating the symptoms of
Pheochromocytoma

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Antihypertensive
Half-life: 2-3 hrs
Duration of action: 2-3 hrs
Bioavailability: 45-65%

 [4-(4-amino-6,7-dimethoxyquinazolin-2-
yl)piperazin-1-yl]-(furan-2-yl)methanone

Antihypertensive
Half-life: 22 hrs
Duration of action : 18-
36 hrs
Alleviate the symptoms
of benign prostatic
hyperplasia(BPH)

 [4-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-
1-yl]-(2,3-dihydro-1,4-benzodioxin-3-
yl)methanone;methanesulfonic acid

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Beta-Antagonist

Development of
β-blockers

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 3/13/2021

1] Non-selective β-blocker: 1) Propranolol 5) Pronethalol

(First generation) 2) Timolol
3) Sotalol
4) Pindolol
2] β1-selective blockers: 1) Atenolol
(Second generation) 2) Acebutolol
3) Metoprolol
4) Esmolol
3] β-blockers with α1 –Antagonist activity: 1) Labetolol
(Third generation) 2) Carvidilol

 Refer class notes: very important

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 3/13/2021

 When an oxymethylene ‘OCH2’ is inserted into the

arylethanolamine structure of Pronethalol afforded
Propranolol, first clinically successful β-blocker
 The side-chain has been moved from C2 of Naphthyl
group to the C1 position.
 Aryloxypropranolamines are more potent β-
blockers than the corresponding
arylethanolamines.

A β-Blocker with
toxicity

1-naphthalen-2-yl-2-(propan-2-ylamino)ethanol

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 1-naphthalen-1-yloxy-3-(propan-2-
ylamino)propan-2-ol

The ways that beta-blockers combat hypertension

are still not poorly understood.
Possible mechanisms are:
 Lowered cardiac output;

 Inhibition of renin release

 A centrally-mediated lowering in sympathetic

nervous system activity!

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Active
metabolite

 Propranolol is the prototypical and non-selective β-

blocker and does not block α-receptor.
 Propranolol is the competitative blocker whose receptor
blocking action can be reversed with sufficient
concentration of β-agonist.
 Use: Propranolol is approved for use in the treatment of
hypertension, cardiac arrhythmias, angina pectoris,
postmyocardial infarction, hypertrophic
cardiomyopathy, pheochromocytoma, migrane
prophylaxis and essential tremor.

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 Propranolol because of its high lipophilicity and

thus its ability to penetrate the CNS, has found use
in treating anxiety and is under investigation for
treating Schizophrenia, Alcohol withdrawal
syndrome, and aggressive behavior.
 Propranolol has prominent effect on cardiovascular
system by blocking the β-receptors of the heart,
propranolol slows the heart, reduces the force
of contraction, and reduces cardiac output.
 The reflex sympathetic activity and blockade of
vascular β2 receptors by administration of
propranolol may result in increased peripheral
resistance.

 The antihypertensive action, at least in part, may be

attributed to its ability to reduce cardiac output, as
well as to its suppression of renin release from the
kidney.
 It is contraindicated in the presence of conditions
such as asthama and Bronchitis.
 Propranolol has membrane stabilizing activity,
which is also reffered to as a local anesthetic effect.
The concentration required to produce this effect far
exceed those obtained with normal therapeutic doses
of propranolol.
 Propranolol is well absorbed after oral administration,
but it undergoes first pass metabolism before it

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 3/13/2021

 Reaches the systemic circulation. In addition, the

active enantiomer is cleared more slowly than the
inactive enantiomer.
 The half life of propranolol after a single oral dose
is 3-4 hours, which increases to 4-6 hours after long
term therapy.
 Propranolol is the most lipophilic amongst all β-
blockers and thus it enters the CNS.
 Side-effects: CNS side effects such as dizziness,
confusion, or depression.

Not given in the

syllabus

 1-(propan-2-ylamino)-3-(2-prop-2-
enylphenoxy)propan-2-ol

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 (2S)-1-(tert-butylamino)-3-[(4-morpholin-4-yl-
1,2,5-thiadiazol-3-yl)oxy]propan-2-ol

 It is used to treat open angle glaucoma with no

effect on pupil size and accomodation by
reducing the production of aqueous humor.
 Although used topically it can undergo
systemic absorbtion to produce side-effects as
bradycardia and Bronchosplasm
 Its Half-life value is same as that of
propranolol. (3-4 hours)
 Timolol undergoes first pass metabolism but
not to the extent propranolol undergoes.

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Sotalol is a drug used

in individuals with
rhythm disturbances of
the heart (cardiac
arrhythmias).

N-[4-[1-hydroxy-2-(propan-2-
ylamino)ethyl]phenyl]methanesulfonamide

Pindolol is a
nonselective beta
blocker with partial beta-
adrenergic receptor agonist
activity and also
possesses intrinsic
sympathomimetic activity.

1-(1H-indol-4-yloxy)-3-(propan-2-ylamino)propan-2-
ol

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 Also referred to as intrinsic sympathomimetic

effect, this term is used particularly with beta
blockers that can show both agonism and
antagonism at a given beta receptor, depending on
the concentration of the agent (beta blocker) and the
concentration of the antagonized agent (usually an
endogenous compound, such as norepinephrine).

 β1-blockers are drugs that have a greater affinity for the

β1-receptors of the heart than for β2-receptors in other
tissues.
 Therapeutic advantages of β1-blockers:
 The first advantage of using selective β1-blockers
should be lack of a blocking effect on the β2-receptors in
the Bronchi.
 second advantage should be the absence of blockade of
the vascular β2-receptors, which mediate vasodilation.
This would be expected to reduce or eliminate the
increase in peripheral resistance that sometimes occurs
after the administration of non-selective β1-blockers.

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 2-[4-[2-hydroxy-3-(propan-2-
ylamino)propoxy]phenyl]acetamide

 It is indicated for the treatment of hypertension,

angina pectoris and therapy following miocardial
infarction.
 Atenolol has low-lipid solubility and does not
readily cross BBB.
 Absorbed incompletely from the GI- tract, and oral
bioavailability is approximately 50%.
 Little of the absorbed portion of the dose is
metabolized and most of it is excreted unchanged in
the urine.

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 N-[3-acetyl-4-[2-hydroxy-3-(propan-2-
ylamino)propoxy]phenyl]butanamide;hydrochloride

 It is used in the treatment of Hypertension.

 Acebutolol is one of the very few β-blockers
whose metabolite plays significant role in its
pharmacological actions.
 This drug is absorbed well from the GI-tract, but it
undergoes extensive first pass metabolism to
diacetolol by hydrolytic conversion of the amide
group to amine, followed by acetylation of the
amine. diacetolol is also a selectiveβ1 –blocker with
partial agonistic activity.
 It has little membrane stabilizing activity.
 It has a longer half life (8-12 hours)
 than the parent drug and is excreted in the kidney

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 1-[4-(2-methoxyethyl)phenoxy]-3-(propan-2-
ylamino)propan-2-ol

 Metaprolol is approved for use in treating angina

pectoris and in therapy following myocardial
infarction.
 The Half-life values of Metaprolol is comparable to
that with Propranolol.
 Metaprolol has low bioavailability because of
significant first pass metabolism.

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 methyl 3-[4-[2-hydroxy-3-(propan-2-
ylamino)propoxy]phenyl]propanoate

 Esmolol has very short duration of action as a

result of rapid hydrolysis of its ester
functionality by esterases present in the
erythrocytes. The resulting carboxylic acid is
extremely weak β-blocker.
 It is administered by continuous intravenous fusion
for control of ventricular rate in patients with atrial
flutter, attrial fibrilation or sinus tachycardia.
 Its rapid onset and short DOA render it useful
during surgery, after an operation or during
emergencies for short term control of heart rate.

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1
1’

 2-hydroxy-5-[1-hydroxy-2-(4-phenylbutan-2-
ylamino)ethyl]benzamide

 Labetalol is a Phenylethanolamine derivative

 It is a representative of a class of drugs that act as
competative blockers at α1 -, β1 -, and β2 - receptors.
 It is a more potent β-blocker than α-blocker.
 Because it has two asymmetric carbon atoms (1 and
1ꞌ ), it exist as a mixture of four isomers.
 It is used as a mixture of four isomers in treating
Hypertension. The different isomer possess different
α- and β-blocking activity.

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 The β-blocking activity resides solely in the (1R, 1ꞌ

R) isomer, whereas the α1 –blocking activity is seen
in the (1S, 1ꞌR ) and (1S, 1ꞌS) isomers, with the (1S,
1ꞌR) isomer possessing the greater therapeutic
activity
 Labetalol is the clinically useful antihypertensive
agent
 The rational for its use in th emanagement of
hypertension is that its α-receptor –blocking effects
produce vasodilation and its β-receptor-blocking
effects prevent the reflex tachycardia usually
associated with vasodilation .
 Labetalol is very well absorbed, but it undergoes
first pass metabolism.

 (I) Drugs affecting Catecholamine Storage and Release:

1) Reserpine 2) Guanethidine

 (II) Direct Acting Sympathomimetics:

Drugs acting on alpha and beta Receptors

 (III) Indirect Acting Sympathomimetics:

1) Amphetamine 2) Propylhexedrine 3) L(+)-Pseudoephedrine

 (IV) Sympathomimetics with a mixed mechanism of action:

1) D-(-)-Ephedrine

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methyl (1R,15S,17R,18R,19S,20S)-6,18-dimethoxy-17-(3,4,5-
trimethoxybenzoyl)oxy-1,3,11,12,14,15,16,17,18,19,20,21-
dodecahydroyohimban-19-carboxylate

 A Prototypical and Historically important drug

 It is an Indole Alkaloid obtained from the roots of Rauwolfia
serpentina found in India.
 Reserpine is susceptible to decomposition by light and Oxidation.
Reserpine is extensively metabolized through hydrolysis of the
Ester function at position 18 and yields methyl reserpate and
3,4,5-trimethoxybenzoic acid.

Methyl Reserpate 3,4,5-Trimethoxybenzoicacid

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 MOA: It not only depletes the vesicle storage of NE in

sympathetic neurons in PNS, neurons of the CNS, and E
in the adrenal medulla, but also depletes the storage of
serotonine and Dopamine (DA) in their respective
neurons in the Brain.

 Reserpine binds extremely tightly with and blocks

VMAT (Vesicular monoamine transportor) that
transports NE and other biogenic amines from the
cytoplasm into the storage vesicles.

 Thus in sympathetic neurons, NE which normally is

transported into the storage vesicles, is instead
metabolized by mitochondrial MAO in the cytoplasm.

 In addition there is gradual loss of vesicle stored NE as

it is used up by release resulting from sympathetic
nerve activity so that the storage vesicles eventually
become dysfunctional.

 The end result is depletion of NE in the sympathetic

neuron. Analogous effects are seen in the adrenal
medulla with E and with 5-HT in serotonergic neurons.

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 When reserpine is given orally, its maximum effect

(sustained effect ) is seen upto several weeks after the
last dose is given. This is because the tight binding of
reserpine to storage vesicles continues for a
prolonged time, and recovery of sympathetic function
requires synthesis of new vesicles over a period days to
weeks after discontinuation of drug.

 Adverse effects: Sedation and inability to concentrate

or perform complex tasks. (because it readily enters
CNS). More serious is the Psycotic depression.

 2-[2-(azocan-1-yl)ethyl]guanidine

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 Guanethidine is seldom used orally active

Antihypertensive.
 It enters adrenergic neuron by way of the uptake-1
process and accumulate within the neuronal storage
vesicles. There it binds to the storage vesicles and
stabilize the neuronal storage vesical membranes.
Making them less responsive to nerve impulses.
 The ability of the vesicles to fuse with the neuronal
membrane is also diminished, resulting in inhibition of
ne release into the synaptic cleft in response to a
neuronal impulse and generalized decrease in
sympathetic tone.
 long term administration of some of these agents also
can produce a depletion of NE stores in sympathetic
neurons.

 Guanethidine, a neuronal blocking drug possess a

guanidino group. (pka > 12) than ordinary amino
group means that at physiologic pH , they are
essentially completely protonated. Thus these agents
do not penetrate CNS. As a result this drug has none of
the central effects seen with many other
antihypertensive agents.
 It is absorbed incompletely after oral administration
(3-50%).
 It has a half-life of 12 hours.
 Both agents are partially metabolized (≈50%) by the
liver, and is used to treat moderate to severe
hypertension, either alone or in combination with other
antihypertensive drugs.

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 Indirect acting sympathomimetics act by releasing

endogenous NE.
 They also enter the nerve ending by way of the active-
uptake process and displace NE from its storage
granules.
SAR
 As with the direct acting agents, the presence of the
catechol OH groups enhances the potency of indirect
acting phenylethylamines. However, the indirect acting
drugs that are used therapeutically are not catechol
derivatives and, in most cases, do not even contain an
OH group.

 In contrast with the direct acting agents, the presence of

a β-hydroxyl group decreases, and an α-methyl group
increases, the effectiveness of indirect acting agents.

 The presence of nitrogen substituents decreases indirect

activity, with substituents larger than methyl groups
rendering the copmpound virtually inactive.

 Phenylethylamines that contain a tertiary amino group

are also ineffective as NE-releasing agents.

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 1-phenylpropan-2-amine

 Amphetamine dose-dependently increases the level

of synaptic norepinephrine, the direct precursor
of epinephrine.
 Amphetamine induces:
1) TAAR1(trace amine-associated receptor)-
mediated efflux and
2) non-competitive reuptake inhibition at
phosphorylated NET(Nor-epinephrine transporter),
3) competitive NET reuptake inhibition, and
4)norepinephrine release from VMAT2(vesicular
monoamine transporter 2).

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 Amphetamine is a potent central nervous

system (CNS) stimulant of the phenethylamine
class that is used in the treatment of attention deficit
hyperactivity disorder (ADHD) and narcolepsy
(chronic neurological disorder caused
by autoimmune destruction of hypocretin-
producing neurons)
 Amphetamine properly refers to a specific chemical,
the racemic free base, which is equal parts of the
two enantiomers, levoamphetamine and
dextroamphetamine, in their pure amine forms.
 Therapeutic Applications: to treat nasal
congestion, depression, and obesity.
Amphetamine is also used as
a performance and cognitive enhancer

 At therapeutic doses, this causes emotional and

cognitive effects such as euphoria (a feeling of
well-being) , improved cognitive control.

 It induces physical effects such as decreased

reaction time, fatigue resistance, and increased
muscle strength.

 Much larger doses of amphetamine are likely to

impair cognitive function and induce rapid
muscle breakdown.

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 Substance dependence (addiction) is a serious

risk of amphetamine abuse.

 Very high doses can result in psychosis

 1-cyclohexyl-N-methylpropan-2-amine

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 It is the analogue of Amphetamine in which the

aromatic ring has been replaced with cyclohexane ring.

 This drug produces vasoconstriction and decongestant

effect on the nasal membranes, but it has only about
half the pressor effect of Amphetamine and produces
fewer effects on the CNS.

 Its major use is for local vasoconstrictive effect on nasal

mucosa in the symptomatic relief of nasal congestion
caused by common cold, allergic rhinitis, or sinusitis.

Threo isomer
(1S, 2S)
Diastereomer

L-(+)-isomer

 (1S,2S)-2-(methylamino)-1-phenylpropan-1-ol

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 It is a naturally occurring alkaloid from the Ephedra

species
 It is the (S,S) Diastereoisomer of Ephedrine
 Ephedrine has a mixed mechanism of action, whereas
pseudoephedrine acts mostly by indirect mechanism and
has virtually no direct activity. The structural basis for this
difference in mechanism is the stereochemistry of the
carbon atom possessing the β-OH group.
 In pseudoephedrine this carbon possesses the (S)
configuration, the wrong stereochemistry at this center for
a direct acting effect at adrenoreceptors.
 L-(+)-Pseudoephedrine crosses BBB but lacks direct
activity and affords fewer CNS effects than does
ephedrine.

 Use: it is used in many OTC nasal decongestant

and cold medications.

 It should be used with caution in hypertensive

patients, and it should not be used in combination
with MAO inhibitors.

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Those Phenylethylamines
considered to have a mixed
mechanism of action usually
have no hydroxyls on the
aromatic ring but do have a β-
hydroxyl group

Erythro isomer
(1R, 2S)
DIASTERIOMER

D(-) isomer

D(-) isomer

 (1R,2S)-2-(methylamino)-1-phenylpropan-1-ol

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 The pharmacological activity of (1R, 2S)-(D)-(-)-

ephedrine resembles that of E.

 It is the classic example of a sympathomimetic with

mixed mechanism of action. The drug acts on both α
and β-receptors. Its ability to activate β-receptors
probably accounted for its earlier use in asthma.

 Structural features: lacking hydrogen bonding

phenolic OH groups, ephedrine is less polar
and, thus, crosses the BBB far better than do
other CAs. Therefore, ephedrine has been used
as a CNS stimulant and exhibits side-effects
related to its action in the brain

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 M etabolism: the drug is not metabolized by either

MAO or COMT and therefore has more oral activity
and longer DOA than E.
 Like many other phenylisopropylamines, a significant
fraction of the drug is excreted unchanged in the urine
although it can be p-hydroxylated and N-methylated by
cytochrome P450 mixed-function oxidases. Because it
is a week base, its excretion can be accelerated by
acidification of the urine.
 Ephedrine has two asymmetric carbon atoms; thereby
creating four optically active isomers. The erythro
isomer is called Ephedrine, and the threo racemate is
known as Pseudoephedrine.

 Natural ephedrine is the D(-) isomer, and it is the most

active of the four isomers as a pressor amine. This is
largely because of the fact that this isomer has the
correct (1R, 2S) configuration for optimal direct
activity at adrenergic receptors.
 Use: Ephedrine and its salts are used orally,
intravenously , intramuscularly, and topically for
various conditions, such as allergic disorders, colds,
hypotensive conditions and narcolepsy.
 It is used locally to constrict the nasal mucosa and cause
decongestion and to dilate the pupil or the bronchi.
 Systemically it is effective for asthma, hay fever and
urticaria.

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