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PRESENTATION ON
CATECHOL AMINES
&
TRICYCLIC AMINES
Catecholamines?
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(3,4-dihydroxylphenyl group and an amine group)
Catecholamines are hormones produced
by the adrenal glands, brain and nerve
tissues released into the blood during
emotional or physical stress, fright or
the ‘fight or flight’ response.
They are part
nervous system
of
the
sympathetic
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An amino group attached to an aromatic ring that contains
two Hydroxyl groups situated ortho to each other is catechol
amine
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Roles
Increase heart rate,
Catechol
 breathing rate,
 muscle strength,
 mental alertness and blood pressure,
 increasing the blood to major organs e.g. the
Kidneys, heart and brain.
History of Adrenergic drugs
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In 1896 Oliver and Schafer demonstrated that injection of
extracts of adrenal gland caused a rise in arterial pressure.
Simultaneous ,biogenic amine adrenaline was isolated
From the suprarenal gland as active principle by Dale(1899)
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Dale observed adrenaline caused two distinct kinds of effects
namely vasoconstriction in certain vascular beds and vasodilatation
In others.
Ahlquist 1948 has shown clearly that several subclasses of
adrenoceptor exist in body
Adrenaline(epinephrine) was only thought to be the neurotransmitter in the adrenergic
nervous system
1940, nor adrenaline (nor epinephrine, NE) was identified with true neurotransmitter at
Terminus of the sympathetic nervous system.
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Defining….!
These are the drugs which are chemical agents that exert their
principal pharmacological and therapeutic effects by either
enhancing or reducing the activity of the various components of
the sympathetic division of the ANS
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Drugs coming under Adrenergic and which are catechol
amines only, viz:
-Dopamine,
-Epinephrine (adrenalin) and
-Nor epinephrine
-Isoprenaline(Isoproterenol)
-Colterol
First 3 comes from Tryosine
Tyrosine is created from phenylalanine by hydroxylation
by the enzyme phenylalanine hydroxylase.
Tyrosine is also ingested directly from dietary protein. It
is then sent to catecholamine-secreting neurons.
Here, many kinds of reactions convert
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***Levodopa to dopamine, to nor epinephrine, and
eventually to epinephrine.
Important features of catecholamine are biosynthesis,
uptake and signaling
1. Biosynthesis
2. Release
3. Uptake
(transporter)
4. Receptormediated
signaling
5. Catabolism
Biosynthesis
s0
Both epinephrine and Nor epinephrine each possess a chiral carbon
2
atom thus, each can exist as an enationmeric pair of isomers the
enantiomer with the (R) configuration is biosynthesized by the body
and possess the biological activity.
Location
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1. Adrenergic and dopaminergic neurons in CNS (in sympathetic neurons
of ANS)
2. Adrenal medulla
Starting material
Amino acid L-Tyrosine (into axoplasm)
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*Acted on by Tyrosine hydroxylase (Tyrosine 3monooxygenase.
*Whichleads to the formation of L-dihydroxy
phenylalanine(L-dopa).
*Second enzymatic step in cateholamine
biosynthesis is the decarboxylation of L-dopa to give
dopamine. The enzyme that carries out this
transformation is L-aromatic amino acid
decarboxylase (dopa decarboxylase).
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*The dopamine formed in the cytoplasm of the
neuron is actively transported into storage vesicles,
where it is hydroxylated stereo specifically by the
cu2+ containing enzyme dopamine betamonooxygenase(dopamine beta-hydroxylase) to give
Nor Epinephrine
*later Nor epinephrine is converted to epinephrine,
which is catalyzed by PNMT(phenyl etanolamne NMethyltransferase). Which is stored in chromaffin
cells
1.Cofactor: Molecular oxygen &Tetrahydrobiopterin has been used by
Fe2+containing Tyrosine hydroxylase
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2.Cofactor: above enzyme that used pyridoxal phosphate as a cofactor
3. Cofactor: dopamine beta-hydroxylase requires molecular oxygen and
uses ascorbic acid as a cofactor
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Catecholamines packed into
the synaptic vesicles
VMAT2:
Non-selective
and has high
affinity to
reserpine
Reuptake Mechanism
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Viz:
1. uptake1
2. uptake2
NA released from the nerve terminal is recaptured
Uptake1
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Axonal uptake: An active amine pump is present at the neuronal
Membrane which transports NA at high rate.This uptake is the most
Important mechanism for terminating postjunctional action of NA
Inhibitors:
Cocaine, desipramine, guanethidine and H1 antihistamines
Granular uptake: cell body of neuron has granules has another
amine pump which transports CA from the cytoplasm to with in the
granules. This carrier also takes up DA formed in the axoplasm for
For further synthesis of Nor epinephrine .Thus it is very
Important in maintaining the NA content of the neuron.
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Inhibitor:Reserpine
Uptake2(Extra neuronal uptake)
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Occurs in other tissue cells, but this is not of physiological or
Pharmacological importance. It is not inhibited by the uptake 1
Inhibitors.
e.g present in a wide variety of cells, including glial, hepatic, and
myocardial cells.
Uptake of catecholamines: transporter
Metabolism
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Two principle enzymes involved in catecholamine metabolism
are
1.Monoamine oxidase(MAO)
2.Catechol-0-methyltransferase (COMT)
Source:*MAO is associated with outer membrane of Mitochondria
*COMT is found primarily in cytoplasm.
or
Both can be administered exogenously.
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MAO oxidatively deaminates a variety of compounds that contain
an amino group attached to a terminal carbon.
2 types of MAOs
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1. MAO-A shows substrate preference for NE and serotonin,
2. MAO-B shows substrate selectivity for β-phenyl ethylamine and
benzyl amine.
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COMT catalyzes the methylation of a variety of catechol
containing molecules.
Step1: NE is deaminated oxidatively by MAO to give 3,4dihyroxyphenylglycolaldehyde.
Step2: Reduced by aldehyde reductase to 3,4dihydroxyphenylethylene glycol.
Step3: This (glycol) is primarily metabolite that is released into
the circulation, where it undergoes methylation by the COMT
that it encounters in non-neuronal tissues.
Step4: The product of methylation, 3-methoxy-4hydroxyphenyl-ethylene glycol, is oxidized by alcohol
dehydrogenase and aldehyde dehydrogenease to give 3methoxy-4-hydroxymandelic acid( vanillylmandelic acid[VMA])
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NOTE1: In the oxidative deamination of NE and epinephrine at
extra-neuronal sites such as the liver, the aldehyde that is
formed is oxidized usually by aldehyde dehydrogenase to
give3,4-dihydroxymandelic acid.
NOTE2: Methylation by COMT occurs almost exclusively on the
meta hydroxyl group of the catechol, regardless of whether the
catechol is NE, epinephrine, or one of the metabolic products.
e.g. The action of COMT on NE and epinephrine give normetanephrine and metanephine, respectively.
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NOTE: A converging pattern of NE metabolism of NE and
epinephrine in which 3-methoxy-4-hydroxymandelic acid and 3methoxy-4-hydroxyphenylethylene glycol are common end
products thus occurs, regardless of whether the first metabolic
step is oxidation by MAO or methylation by COMT.
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Pharmacokinetics:
1.Under normal circumstances 3-methoxy-4-hydroxymandelic
acid is the principal urinary metabolite of NE
2.3-methoxy-4-hyroxyphenyethylene glycol are excreted along
with varying quantities of other metabolites, both in the free form
and as sulfate or glucoronide conjugates
3. Endogenous epinephrine is excreted primarily as metanephrine
and 3-methoxy-4hydroxymandelic acid.
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Metabolism of dopamine
Major acidic metabolites:
A. 3,4-dihydroxy
phenylacetic acid
(DOPAC)
B. Homovallic acid (HVA)
Catecholamine receptors
1.
Postsynaptic receptors locate on dendrites or cell
body, axons or nerve terminals
2.
Presynaptic autoreceptors locate on the same
neuron:
a. terminal auto receptor: control release
b. somatodendritic auto receptor: synthesis control
c. major autoreceptor type: 2-adrenergic receptor
in PNS/CNS; D2-dopamine receptor
d. exception: -adrenergic receptor facilitates NE
release
Autoreceptor: inhibit transmitter release
Feature of Dopamine receptors
1. Two subtypes of dopamine receptor: D-1 (short i3, long Cterminal) and D-2 like (long i3, short C-terminal) receptors
2. D2 receptors contain splicing isoform: D2L and D2S (87 bp)
3. D3 receptor has high affinity to atypical neuroleptics; D4
receptor bind tightly with clozapine
4. Chronic antagonist treatment up-regulate D2 receptors;
agonist treatment might down-regulate the D2 receptor
5. Pharmacological application: anti-Parkinson (D2 agonist),
anti-psychotic (D2 antagonist), addictive drugs (DA
transporter)
Features of Adrenergic receptors
1. Both NE and epinephrine bind to  and  receptors
2. 1 locates mainly in the heart and cortex; 2
predominate in the lung and cerebellum; 3 in the
adipose tissue (significance in obesity)
3. 1 is a post-synaptic receptor (three subtypes: 1A, 1B
and 1D); while 2 is both post- and pre-synaptic
receptor (three subtypes: 2A, 2B and 2C)
4. Representative ligands: propranolol ( antagonist),
yohimbine ( agonist)
GPCR-mediated signal and internalization
SAR
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The parent structure for many of the sympathomeminetic
drugs is Beta-phenylethylamine.
The manner in which beta-phenyl ethylamine is substituted
on the meta and para positions of aromatic ring and on the
amino, α and β positions of the aromatic ring .
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And on the amino, alpha and beta positions of the
ethylamine side chain influences not only the mechanism of
sympathomemimetic action but also the receptor selectivity
of the drug.
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For
alpha
the
direct-acting
sympathomimetic amines,
maximal activity is seen in
H2N
β-phenylethylamine
derivatives containing
hydroxyl groups in the beta
meta and para positions
phenylethylamine
of the aromatic ring
meta
para
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(a catechol) and a beta-hydroxyl group of the correct stereo
chemical configuration on the ethylamine portions of the
molecule.
Phenyl ethylamine is the basic structure for several Adrenergics
And modification of that is a result of catechol amines.
e.g. Amphetamine, Ephedrin, Noradrenaline, Adrenaline, Isoproterenol, Colterol
Albuterol, Ritodrine,Dipivefrin.HCL, Ritodrine.HCL, Aramine etc
Direct acting sympathomimetics that exhibit chirality by virtue
of the presence of a beta-hydroxyl group (phenylethanolamines)
invariably exhibit high stereo selectivity in producing their
agonistic effects; i.e one enantiomeric form has more affinity for
the receptor than the other form
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e.g Epinephrine , NE and related
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compounds, the more potent enantiomer has(R)
configuration.(100fold more potent)
Easson-Stedman hypothesis
Explanation of stereo selectivity of three important
pharmacophoric groups , i.e.;
1)Catechol group 2) Amino group 3) β-hydroxyl group
Explanation :
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More potent enantiomer is capable of assuming a conformation
that results in the arrangement in space of the catechol group,
the amino group, and the beta-hydroxyl group in a fashion
resembling that of (-)-(R)-NE.
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This explanation of stereo selectivity is based on the presumed
interaction of these three critical pharmacophoric groups with
three complementary binding areas on the receptor and is called
as Easson-stedman hypothesis
Presence of amino group in phenyl ethylamine is important
for direct agonist activity.
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The amino group should be separated from the aromatic
ring by two carbon atoms for optimal activity.
Both 10 and 20 amines are found among the potent directacting agonist, but 30 or quaternary amines tend to be poor
direct agonists.
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Bulk of nitrogen substituent increases, α-receptor agonist
activity decreases and β-receptor activity increases.
HO
H2N
OH
HO
NH
HO
H
N
OH
HO
OH
noradrenaline
OH
adrenaline
OH
isoproterenol
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alpha
meta
The nature of substituent can also affect
H2N
β1 and β2 receptor selectivity.
para
N-tert butyl group enhances β2
selectivity.
beta
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phenylethylamine
e.g N-tert-butylnorepinephrine(Colterol) is
9-10 times as potent an agonist at tracheal β2 receptors than at
cardiac β1 receptors.
Large substituents on the amino group also protect the amino
group from undergoing oxidative deamination by MAO.
Methyl or Ethyl substitution on the
α carbon of ethylamine side chain
reduces direct receptor agonist activity
at both α and β receptors.
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alpha
meta
H2N
para
How ever, α alkyl group
beta
increases the duration of action of the
phenylethylamine
phenyl ethylamine agonist by making
the compound resistant to metabolic deamination by MAO.
Receptor selectivity
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•α-methyl or ethyl substitution results in compounds with
selectivity toward the β2 receptor
•α-methyl substitution gives compounds with selectivity toward
the α 2 receptor.
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Another effect , introduction of chiral center, which has
pronounced effects on the sterochemical requirements for activity.
e.g. alpha-methylnorepinephrine, it
is the erythro(1R, 2s) isomer that possesses significant activity
at alpha receptors.
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α-methylnorepinephrine
Stability of catechol amines
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Solution of catecholamine drugs are often stabilized by
addition of an antioxidant(reducing agent) such as Ascorbic
acid or sodium bisulfate, why?
Catechol amines under go oxidation in the presence of
oxygen (air) or with other oxidizing agents to produce othroquinone-like compounds, which undergo further reactions to
give mixtures of colored products .
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ADVERSE REACTIONS
&
THERAPEUTIC USES OF CA
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Nor Epinephrine(Nor Adrenaline)
Cardiovascular
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•The drug can produce profound hypertension, local
vasoconstriction, and tissue hypoxia.
•NE-induced hypertension typically presents as headache,
photophobia, stabbing chest pain, pallor, intense sweating, and/or
vomiting.
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•Adequate intravascular volume replacement is strongly
recommended before, during, and upon withdrawal of therapy.
Inadequate intravascular volume before and during NE therapy
can result in decreased perfusion of vital organs, including the
heart, liver, and kidney. Inadequate intravascular volume upon NE
withdrawal can result in recurrent and profound hypotension.
Hypotension, tissue hypo perfusion, and tissue hypoxia can
produce ischemic injury and systemic lactic acidosis.
Nervous system
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Side effects include headache, anxiety, and photophobia.
Local
Phentolamine is an effective antidote to nor epinephrine
extravasation. To prevent sloughing and necrosis in areas in
which extravasation has taken place, it is recommended that the
area be infiltrated as soon as possible with 10 mL to 15 mL of
saline solution containing from 5 mg to 10 mg of phentolamine,
an adrenergic receptor antagonist
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Therapeutic effects
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Anti-Inflammatory agent role in Alzheimer’s Disease
The norepinephrine from locus ceruleus cells in addition
to its neurotransmitter role locally defuses from
"varicosities".
As such it provides an endogenous Anti-inflamamtory
agent in the microenvironment around the neurons, glial
cells, and blood vessels in the neocortex and
hippocampus Up to 70% of norepinephrine projecting
cells are lost in Alzheimer’s Disease.
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Epinephrine
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Serious Reactions
•pulmonary edema
•arrhythmias
•HTN
•angina
•cerebral hemorrhage (IV)
•tissue necrosis (SC, IM)
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Common Reactions
palpitations
tachycardia
nausea/vomiting
pallor
sweating
dizziness
weakness
tremor
headache
apprehension
nervousness
anxiety
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02
Therapeutic uses
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Cardiac arrest
Adrenaline is used as a drug to treat
cardiac
arrest
and
other
cardiac
dysrhythmias resulting in diminished or
absent cardiac output. Its actions are to
increase peripheral resistance via α₁
receptor-dependent vasoconstriction and to
increase cardiac output via its binding to β₁
receptors.
Shock and anaphylaxis
Allergy patients undergoing immunotherapy
may receive an adrenaline rinse before the
allergen extract is administered, thus
reducing the immune response to the
administered allergen
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Epinephrine ampule
1 mg (Suprarenin)
Because of various expression of α₁or β₂receptors, depending on
the patient, administration of adrenaline may raise or lower blood
pressure, depending whether or not the net increase or decrease
in peripheral resistance can balance the positive inotropic and
chronotropic effects of adrenaline on the heart, effects which
respectively increase the contractility and rate of the heart.
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Use in local anesthetics
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•Epinephrine is added to injectable forms of a number of local
anesthetics, such as bupivacaine and lidocaine, as a
vasoconstrictor to retard the absorption and therefore prolong the
action of the anesthetic agent.
•Some of the adverse effects of local anesthetic use, such as
tachycardia and tremor, may be caused by epinephrine
Treating Croup
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Racemic epinephrine has historically been used for the treatment
of croup.
Racemic epinephrine is a 1:1 mixture of the
(D) and (L) isomers of epinephrine. The L form is the active
component.
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Racemic epinephrine works by stimulation of the α-adrenergic
receptors in the airway with resultant mucosal vasoconstriction
and decreased subglottic edema and by stimulation of the βadrenergic receptors with resultant relaxation of the bronchial
smooth muscle
Dopamine
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Serious Reactions
•anaphylaxis
•asthma exacerbation
•extravasation necrosis
•Gangrene
Common Reactions
•hypotension
•tachycardia
•headache
•nausea
•vomiting
•conduction abnormalities
•necrosis at injection site
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Therapeutic Effects
Used in Parkison’s disease..
Cocaine and Heroin…areDopamine reuptake inhibitor
The combination of heroin and
cocaine is known by users as
a "speed-ball." This
combination of drugs is
extremely dangerous, and
users show very rapid
psychological and
physiological deterioration.
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Synthesis of Catechol amines
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Levodopa
Since dopamine does not cross the blood-brain barrier, it has no
therapeutic utility. How ever , its immediate metabolic precursor,
levodopa, is transported into the brain by the large, neutral amino
acid transporter and permeates into straital tissues where it is
decarboxylated to dopamine
02
OH
02
O
O
NBS
O
acetone
C(CH3)2
C(CH3)2
OH
BrH2C
O
4-methyl catechol
O
CH3-SO-CH2-S-CH3
NaH THF
O
C(CH3)2
O
H+
O
HCN
O
CH2
HOH2C
NC
C(CH3)2
C(CH3)2
NH3
O
H3C-OHS-CH2C
O
CH
H3CS
02
NH2
H+ 6N HCL
HO
Reduction
HO
NH2
Levodopa COOH
95% of levodopa is decarbocylated
Aromatic
to
L-amino acid decarboxylase
dopamine mediated byHOan enzyme that is
pyridoxin-dependant,
HO
MAO
Dopamine
Aldehyde dehydrogenase
NH2
COMT
HO
HO
NH2
HO
COOH
H3OC
3,4-Dihydroxyphenyl acetic acid
MAO
3-Methoxytyramine
COMT
HO
COOH
H3OC
3-Methoxy-4-hyroxy phenyl acetic acid(HVA)
Isoproterenol
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Isoprenaline(Isoproterenol)
HO
ClH2C-OC-O
O
-HCL
HO
Cl
HO
Fries rearrangement
Cl
chloroacetyl chloride
catechol
02
HO
HO
HO
Pd, H2
H
N
COCH2NHCH(CH3)2
OH
OH
OH
isoprenaline
H2N-CH(CH3)2
HO
COCH2Cl
Colterol
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Bitolteral mesylate(Tornalate)
HO
COCH3
HO
Br2
CH3COCl
HO
H2NC(CH3)3
HO
HO
COCH2NHC(CH3)3
HO
O
H3C
H3C
C
COCl
O
COCH2NHC(CH3)3
O
H3C
Pd-C, H2
C
O
Esterases
HO
O
H3C
Pd-C, H2
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CHCH2NHC(CH3)3
OH
HO
C
O
CHCH2NHC(CH3)3
Colterol
OH
O
H3C
C
O
Bitolterol
It is a prodrug of colterol a selective beta2 agonist. The ester provides increase lipid solubility
and proglonged duration of action.It is administered b inhalation for bronchial astham and the ester
groups are hydrolysed by esterases to active colterol
02
Epinephrine(Adrenaline)
Synthesis
02
VIP points
1.Amanditine .HCl is an Antiviral drug but It is a drug which
“Enhances the Dopamine level at Synapses .
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2.Levodopa when administred with carbidopa enchances the
activity by increasing the Plasma t/2 life of drug from 0.5-1hrs to
1-2 to 3hrs. And also increases the dopamine reaching brain.
02
02
Tricyclic amines
02
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Serval classes of drugs contains, tricylic amine structure
they may be notated as follows..
Classification
1. Anti Depressants.
2. Anti Histamines.
3. Anti Psychotics.
4. Miscellaneous drugs.
02
These are main classes of drugs which contain tricyclic
amine sturctures .
Tricylic compound of Antidepressants
02
First generation drugs
**Dibenazepines derivatives of Antidepressants
e.g. Imiprmaine, desipramine(pertfroane)
clomipramine(anafranil)
02
**Dibenzocycloheptanes derivatives of Antidepressants
e.g. Amitriptyline(Elavil),Nortriptyline(Aventyl)
**Diabenzodiazepine derivatives:
e.g. Dibenzepine, Noveril, doxepin HCl
Amitriptyline
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History
•Initially Amitriptyline is used in ankylosing spondylitis for pain
relief and in some European countries it is officially approved as
a preventive for patients with frequent/chronic migraines, usually
25 to 75 mg. It is also used as a preventive for patients with
recurring biliary dyskinesia (sphincter of Oddi dysfunction),
usually 10 mg daily.
•The most widely used TCA and
has at least equal efficacy against
depression as the newer class of
SSRIs
02
MOA
Amitriptyline additionally functions as a 5-HT2A, 5-HT2C,
5-HT6, 5-HT7, α1-adrenergic, H1, and mACh receptor
antagonist, and σ1 receptor agonist.
02
Recently, amitriptyline has been demonstrated to act
as an agonist of the TrkA and TrkB receptors.
02
It promotes the heterodimerization of these proteins in
the absence of NGF and has potent neurotrophic
activity both in-vivo and in-vitro in mouse models
Side effects
02
Common side effects of using amitriptyline are mostly due to its
anticholinergic activity.
weight gain, dry mouth, changes in appetite, drowsiness,
muscle stiffness, nausea, constipation, nervousness, dizziness,
blurred vision, urinary retention, insomnia and changes in
sexual function. Some rare side effects include tinnitus,
hypotension, mania, psychosis, sleep paralysis, hypnagogia,
hypnopompia, heart block, arrhythmias, lip and mouth ulcers,
extrapyramidal symptoms,, and hepatic toxicity
02
02
02
Imipramine
02
Sold as: Antideprin, Deprimin, Deprinol, Depsonil, Dynaprin,
Eupramin, Imipramil, Irmin, Janimine, Melipramin, Surplix, Tofranil
Imipramine is mainly used in the treatment of major depression
and enuresis.
02
It has also been evaluated for use in panic disorder
History
Imipramine was, in the late 1950s, the
first tricyclic antidepressant to be
developed (by Ciba-Geigy). It was first
tried against psychotic disorders, such
as
schizophrenia,
but
proved
insufficient.
As an antidepressant, it did well in most severe cases of
depression.
02
It is not surprising, therefore, that Imipramine is also known to
cause a high rate of manic and hypo manic reactions, especially
in patients with preexisting bipolar disorder.
02
Imipramine has additional indications for the treatment of panic
attacks, chronic pain, and Kleine-Levin syndrome.
In pediatric patients, it is relatively frequently used to treat pavor
nocturnus and nocturnal enuresis
MOA
02
The mechanisms of Imipramine's medicinal action include
Nor-epinephrine (NE) Reuptake inhibition (strong).
Serotonin (SE) Reuptake inhibition (moderate to strong).
Epinephrine Imipramine antagonizes adreno-receptors (II), thus
sometimes causing increased heart rate (contributed to by other
effects as well), orthostatic hypotension, and a general decrease in
the responsiveness of the central nervous system (hence, a
contribution to its potent anti-anxiety properties).
Dopamine Reuptake and release at D1 and D2 receptors,
Enhancement of brain dopamine activity has been implicated in
Imipramine's ability to stimulate motor activity
Histamine Imipramine is an antagonist at histamine H1 receptors.
This contributes to the acute sedative effect that it has in most
people. In turn, its anti-histaminergic and general calming effects
take place immediately, and, thus, Imiparmine is sometimes
prescribed as a sleep aid in low doses.
02
02
Acetylcholine (ACh) Imipramine is an anticholinergic. Thus, it is
prescribed with caution to the elderly and with extreme caution to
those with pyschosis, anticholinergics increases the potential of
Imipramine to cause hallucinations, confusion and delirium in this
population.
Imipramine is an antagonist at M2 muscarinic acetylcholine
receptors . The blockade of cholinergic (muscarine) receptors
is known to cause Euphoria. potentially contributing to the mood
lifting effects of Imipramine as well.
02
Antimuscarinic effect is also responsible for rapid heart rate
(tachycardia).
Imipramine has been shown to interact with opioid systems in the
central nervous system, possibly explaining some of its painrelieving properties.
Adverse reactions
02
•Allergy: isolated cases ofpneumonitis(fever, chills, cough, difficulty with
breathing, unusual weight loss, feeling sick, puffy, swollen face, tongue or body)
•Arrhythmias: irregular heart rhythms.
•Weight gain has been reported frequently
02
• Isolated cases of enlarged mammary glands,production or over-production
of breast milk, increased or decreased blood sugar levels Low levels of salt in
the blood have been reported, usually in elderly patients.
•Tremor has been reported frequently. Headache, confusion, orthostatic
hypotension (resulting in dizziness upon standing), numbness/tingling,
agitation, anxiety, restlessness, mood swings, exaggerated behavior, delusions
and hallucinations have been reported occasionally and are more common in
the elderly or in patients on high doses.
•Aggressiveness, weakness, lack of co-ordination, sudden muscle spasms,
difficulty speaking have been reported in isolated cases.
If the medicine is stopped too quickly, there is the possibility the
user may suffer from feeling or being sick, stomach pains,
diarrhea, headache, sleeplessness, nervousness, anxiety,
irritability and increased sweating.
02
02
Metabolism
02
02
Desipramine
It inhibits the reuptake of norepinephrine and to a lesser
extent serotonin. It is used to treat depression, but not
considered a first line treatment since the introduction of
SSRI antidepressants. Desipramine is an active
metabolite of imipramine
02
02
The mechanism of action seems to involve the
activation, through norepinephrine reuptake inhibition, of
descending pathways in the spinal cord that block pain
signals from ascending to the brain.
It may also be used to treat symptoms of cocaine
withdrawal.
Dangers
Along with amitriptyline and imipramine, desipramine is one of
the most toxic antidepressants still available on the market.
02
Cardiac arrhythmia
Antidepressant desipramine hydrochloride(Norpramin) , is
prescribed carefully in patients with family history of dysrhythmia
or sudden cardiac death.
02
Desipramine overdose is more likely to result in death than
overdose with other tricyclic antidepressants
The "warnings" and "overdosage" sections of the drug's labeling
are being changed to reflect these potential adverse events.
Genotoxicity
02
Desipramine is associated with an increased risk of Breast
cancer in women.
Metabolism
It undergoes metablic N-demethylation to form desipramine,
which appear to have a somewhat shorter onset of action than
imipramine and less sedating. The compound as a tendency
toward a high 5HT/NE uptake block ratio.
02
Doxepin (Adapine, Deptran, Sinquan
02
and Sinequan)
History
Doxepin was synthesized by Stach and
Spingler from the German drug
manufacturer C. F. Boehringer & Söhne
GmbH in Mannheim.
It was tested from 1963 to 1968 in
different German and Swiss psychiatric
institutions and was approved in
Germany and elsewhere thereafter. The
antidepressive effects were found to
be excellent. Strong anxiolytic and
sedative properties were also
demonstrated. Doxepin has been in
clinical use for several decades. The
drug plays an important role in many
indications today, not only in
psychiatry/neurology.
02
Mechanism of action:
02
•Doxepin inhibits the reuptake of serotonin and norepinephrine.
• Its actions of the reuptake of dopamine are negligible.
• Doxepin also has antagonistic effects at a variety of receptors:
Extremely strong: H1, H2
Strong: 5-HT2, α1-adrenergic, mACh
Moderate: 5-HT1
Weak: D2, α2-adrenergic
02
Like other tricyclic antidepressants, doxepin also blocks
sodium channels possibly accounting for its analgesic
action.
Additionally, doxepin exerts a strong local anaestic
action.
02
Side effects
CNS : fatigue, dizziness, drowsiness, lightheadedness, confusion,
nightmares, agitation, increased anxiety, insomnia, seizures
(infrequently), delirium, rarely induction of hypomania and
schizophrenia (stop medication immediately), extrapyramidal
side-effects (rarely), abuse in patients with polytoxikomania
(rarely), tinnitus
02
Anticholinergic : dry mouth, obstipation, even ileus (rarely),
difficulties in urinating, sweating, precepitation of glaucoma
Antiadrenergic : hypotension, postural collapse (if patient arises
too fast from lying/sitting position to standing), arrhythmias (sinustachycardia, bradycardia, av-blockade)
Allergic/toxic : skin rash, photosensitivity, liver damage of the
cholostatic type (rarely), hepatitis (extremely rare), leuko- or
thrombopenia (rarely), agranulocytosis (very rarely), hypoplastic
anemia (rarely)
02
Others : frequently increased appetite, weight gain, rarely
nausea, frequently impaired sexual function in men (impotence,
ejaculation-difficulties), rarely hypertension, rarely polyneuropathy,
in both sexes breast-enlargement and galactorrhea (rarely)
02
Anti depressants –S.A.R
Maximum potency of antidepressant dihydrobenzepine occures whenthe basic
nitrogen is separated from the tricyclic nucleus by a propylene bridge(3 carbon
distance is necessary) .
Side chain -CH2-CH2-CH2-NH2
Branching of propylene chain e.g. trimipramine has little effect on antidepressant
activity.
Activity is confined to methyl-subsituted or unsubstitued amines. Larger alky groups
abolish activity and introduce toxicity.
Side chain with quinuclidine, morpholine nuclei claimed to be potent.
•Secondary amines and tertiary amines are important in side because of their
inhibitory reuptake activity of Nor epinephrine and 5-HT respectively.
•Introduction of substituent at 3-position has little effect. 3-Cholroimipramine is
similar to imiprmaine.
•2,8 dimethyl or 3,7-dichloro are inactive.
•Ring nitrogen of desipramine can be replaced by carbon to give active compounds.
•Introduction of 10,11 –double bond into nortriptyline enhances antidepressant
activity.
•Nortriptyline and Protriptyline with exocyclic and indocyclic double bonds
respectively differs in their metabolism pattern. The later one is lesser metabolized.
•Several amitriptyline analogues with replacement of c11 with O, S, SO2 , NH, NCH3
are clinically effective antidepressants.
Other drugs which are Anti depressants
02
Trimipramine
Cianopramine
Butriptyline
Nortriptyline
Amineptine
02
Anti Histamines
02
Phenothiazine derivatives
e.g.



Promethazine(phenergan),
Trimeprazine(Temasril)
Alimemazine
02
Promethazine(phenergan)
02
Phenergan, Promethegan, Romergan, Fargan,
Farganesse, Prothiazine, Avomine, Atosil,
Receptozine, Lergigan)
Is a first-generation H1 receptor
antagonist.
It has a strong sedative effect and in
some countries is prescribed for insomnia
whenbenzodiazipines are contraindicated.
It is available OTC in the UK,Australia
Canada switzerland and many other
countries, but by prescription in the U.S
02
Mechanism of action
02
•Promethazine is a phenothiazine derivative that competitively
blocks histamine H1 receptors without blocking the secretion of
histamine.
•It also is a very weak dopamine antagonist.
02
•It has sedative, anti-motion-sickness, anti-emetic, and anticholinergic effects.
•Used medically as an antihistamine and antiemetic.
Side effects
02
•Confusion in the elderly drowsiness, dizziness, fatigue, more
rarely vertigo
•Dry mouth
•Respiratory depression in patients under age of 2 and in those
with severely compromised pulmonal function
•Constipation
02
•Chest Discomfort/Pressure. (typically in cases when patient is
already taking medication for high blood pressure)
•Euphoria (very rare, except with high IV doses and/or coadministration with opioids/CNS depressants).
•Paresthesia
•Short temper/Irritability
Synthesis
02
02
Other drugs which are Anti histamines
02
Alimemazine
clobenzepam
oxomemazine
tandamine
Isothipendyl
propiomazine
02
dacemazine
Antipsychotics
phenothiazine derivatives
e.g. Diethazine, chlorpromazine
02
Sulfur substituted
e.g. chlorprothixene
Benzoquinolines
e.g. Benzo quinamide
02
Chlorpromazine(CPZ)
02
Marketed in the United States as
Thorazine and elsewhere as Largactil) is
a typical antipsychotic.
First synthesized on December 11, 1950,
chlorpromazine was the first drug
developed with specific antipsychotic
action, and would serve as the prototype
for the phenothiazine class of drugs
Chlorpromazine works on a variety of
receptors in the CNS producing
anticholinergic,
antidopaminergic,
antihistaminic, and
weak antiadrenergic effects
02
History
02
In 1933, the French pharmaceutical company Laboratories
Rhône-Poulenc began to search for new anti-histamines.
The chemist Paul Charpentier produced a series of compounds
and selected the one with the least peripheral activity, known as
RP4560 or chlorpromazine, on 11 December 1950
02
The first published clinical trial was that of Jean Delay and Pierre
Deniker at the Hôpital Sainte-Anne in Paris in 1952, in which they
treated 38 psychotic patients with daily injections of
chlorpromazine without the use of other sedating agents.
The response was dramatic; treatment with chlorpromazine went
beyond simple sedation with patients showing improvements in
thinking and emotional behaviour.
Chlorpromazine, in widespread use for 50 years, remains a
"benchmark" drug in the treatment of schizophrenia, an effective
drug although not perfect
02
Uses
Chlorpromazine is classified as a low-potency typical
antipsychotic and in the past was used in the treatment of both
acute and chronic psychoses, including schizophrenia and the
manic phase of bipolar disorder as well as amphetamineinduced psychoses.
02
Chlorpromazine has also been used in porphyria and as part of
tetanus treatment. It still is recommended for short term
management of severe anxiety and aggressive episodes.
Resistant and severe hiccups, severe nausea/emesis and
preanesthetic conditioning are other uses.Symptoms of delirium
in medically hospitalized AIDS patients have been effectively
treated with low doses of chlorpromazine.
Adverse effects
02
•The main side effects of chlorpromazine are due to its
anticholinergic properties
•These include sedation, slurred speech, dry mouth, constipation,
urinary retention and possible lowering of seizure threshold
02
•lowers blood pressure with accompanying dizziness
•Three types of skin disorders are observed: hypersensitivity
reaction, contact dermatitis, and photosensitivity(abnormal
pigmentation of the skin) on exposure to sun.
•Have significant effects on gonadal hormones including
significantly lower levels of estradiol and progesterone in women
whereas men display significantly lower levels of testosterone
and DHEA
•Cardiac arrhythmia and apparent sudden death have been
associated with therapeutic doses of chlorpromazine, however they
are rare cases.
• Patients on chlorpromazine therapy exhibit abnormalities on the
electrocardiographic T and U waves. These major cardiac
arrhythmias that are lethal are a potential hazard even in patients
without heart disease who are receiving therapeutic doses of
antipsychotic drugs.
Metabolism
•The cytochrome P450 isoenzymes 1A2 and 2D6 are needed for
metabolism of chlorpromazine.
• CYP 2D6 is the main enzyme catalyzing 7-hydroxylation of
chlorpromazine, the reaction being partially catalyzed by CYP1A2.
02
02
•Chlorpromazine is typically degraded by the liver by the action of
cytochrome-P450 family enzymes, usually CYP2D6. Less than
1% of the unchanged drug is excreted via the kidneys in the urine.
In which 20-70% is excreted as conjugated or unconjugated
metabolites, whereas 5-6% is excreted in feces.
There are on the order of 10 or more major metabolites generated by the
hepatic pathway in appreciable concentrations. The three most common appear
in the following image.
02
•
•
•
N-demethylated species,
7-hydroxylated form, and finally
chlorophenothiazine, in which the entire R1 side chain is missing.
Mechanism of action
02
Chlorpromazine acts as an antagonist (blocking agent) on different
postsynaptic receptors:
Dopamine receptors (subtypes D1, D2, D3 and D4), which account for
its different antipsychotic properties on productive and unproductive
symptoms; in the mesolimbic dopamine system accounts for the
antipsychotic effect whereas the blockade in the nigrostriatal system
produces the extra pyramidal effects.
•serotonin receptors (5-HT1 and 5-HT2), with anxiolytic, and
antiaggressive properties as well as an attenuation of
extrapyramidal side effects, but also leading to weight gain, fall in
blood pressure, sedation and ejaculation difficulties),
02
•histamine receptors (H1 receptors, accounting for sedation,
antiemetic effect, vertigo, fall in blood pressure and weight gain),
02
•α1- and α2-adrenergic receptors (antisympathomimetic
properties, lowering of blood pressure, reflex tachycardia, vertigo,
sedation, hypersalivation and incontinence as well as sexual
dysfunction, but may also attenuate pseudoparkinsonism—
controversial).
•M1 and M2 muscarinic acetylcholine receptors (causing
anticholinergic symptoms such as dry mouth, blurred vision,
constipation, difficulty or inability to urinate, sinus tachycardia,
electrocardiographic changes and loss of memory, but the
anticholinergic action may attenuate extrapyramidal side effects).
02
Synthesis
02
Other drugs
02
Cis-Chlorprothixen
02
Fluotracen
clomipramine
ciclindole
Triflupromazine
zotepine
L-mepromazine
02
Miscellaneous drugs
02
Carbamazepine is a dibenzazepine
02
Carbamazepine (CBZ) is an anticonvulsant and mood
stabilizing drug used primarily in the treatment of
epilepsy and bipolar disorder, as well as trigeminal
neuralgia.
History
Carbamazepine was discovered by chemist Walter
Schindler at J.R. Geigy AG (now part of Novartis) in
Basel, Switzerland, in 1953.Schindler then synthesized
the drug in 1960, before its anti-epileptic properties
had been discovered.
Carbamazepine was first marketed as a drug to treat
trigeminal neuralgia (formerly known as tic douloureux)
in 1962. It has been used as an anticonvulsant in the
UK since 1965, and has been approved in the U.S.
since 1974.
Dr. Okuma, working independently, did the same thing
with success. As they were also epileptologists, they
had some familiarity with the anti-aggression effects of
this drug. Carbamazepine would be studied for bipolar
disorder throughout the 1970s.
02
Sold as: Tegretol, Biston, Calepsin, Carbatrol, Epitol, Equetro, Finlepsin, Sirtal,
02
Stazepine, Telesmin, Teril, Timonil, Trimonil, Epimaz, Carbama/Carbamaze (New
Zealand), Amizepin (Poland), Hermolepsin (Sweden), and Degranol (South Africa)
Metabolism
Carbamazepine exhibits autoinduction: it induces the expression
of the hepatic microsomal enzyme system CYP3A4, which
metabolizes carbamazepine itself.
02
After enough carbamazepine has been presented to the liver
tissue, the CYP3A4 activity increases, speeding up drug
clearance and shortening the half-life
Mechanism of action
02
The mechanism of action of carbamazepine and its derivatives
is relatively well understood. Voltage-gated sodium channels are
the molecular pores that allow brain cells (neurons) to generate
action potentials, the electrical events that allow neurons to
communicate over long distances. After the sodium channels
open to start the action potential, they inactivate, essentially
closing the channel.
02
•Carbamazepine stabilizes the inactivated state of sodium
channels, meaning that fewer of these channels are available to
subsequently open, making brain cells less excitable (less likely
to fire).
•Carbamazepine has also been shown to potentiate GABA
receptors made up of alpha1, beta2, gamma2 subunits.
Adverse effects
Common adverse effects include drowsiness, headaches and
migraines, motor coordination impairment and/or upset stomach.
Carbamazepine preparations typically greatly decrease a person's
alcohol tolerance.
Less common side effects include cardiac arrhythmias, blurry or
double vision and/or the temporary loss of blood cells or
platelets and in rare cases can cause aplastic anemia. With
normal use, small reductions in white cell count and serum
sodium are common, however, in rare cases, the loss of platelets
may become life-threatening
02
02
There are also reports of an auditory side effect for
carbamazepine use, whereby patients perceive sounds about a
semitone lower than previously
Carbamazepine may cause Syndrome of inappropriate antidiuretic
hormone (SIADH), since it both increases the release and
potentiates the action of ADH (vasopressin).
Synthesis
02
02
02
02
Thanks for your patience……….!