Download - adrenergic agents
Steps of Biosynthesis of
Catecholamine
Distribution of adrenergic
receptors
Individual Functions of
Adrenergic
Adrenergic Agonists and
their uses
Adrenergic drugs acts either by enhancing or reducing the
activity of the various components of the sympathetic
divisions of the ANS.
Sympathomimetic or adrenergic stimulants
Sympatholytics, antiadrenergic or adrenegic blocking
agents.
Catecholamines:
Natural: Adrenaline,
Noradrenaline, Dopamine
Synthetic: Isoprenaline,
Dobutamine
Non-Catecholamines:
Ephedrine, Amphetamines,
Phenylepherine,
Methoxamine,
Mephentermine
Also called sympathomimetic
amines as most of them
contain an intact or partially
substituted amino (NH2)
group
Nor-adrenaline is the major neurotransmitter of the Sympathetic system
Noradrenergic neurons are postganglionic sympathetic neurons with cell bodies in the sympathetic ganglia
They have long axons which end in varicosities where NA is synthesized and stored
L-dihydroxyPhenylalanine
PH
Rate limiting Enzyme
5-HT, alpha Methyldopa
Alpha-methyl-p-
tyrosine
Sympathetic nerves take up amines and release them as neurotransmitters
Uptake I is a high efficiency system more specific for NA Located in neuronal
membrane Inhibited by Cocaine, TCAD,
Amphetamines
Uptake 2 is less specific for NA Located in smooth muscle/
cardiac muscle Inhibited by steroids/
phenoxybenzamine No Physiological or
Pharmacological importance
Mono Amine Oxidase (MAO)
Intracellular bound to mitochondrial membrane
Present in NA terminals and liver/ intestine
MAO inhibitors are used as antidepressants
Catechol-o-methyl-transferase(COMT)
Neuronal and non-neuronal tissue
Acts on catecholamines and byproducts
VMA levels are diagnostic for tumours
(Homovanillic acid) (Vanillylmandelic acid)
In 1948, Ahlquist
proposed and
designated a- and b-
receptors based on their
apparent drug
sensitivity.
Alpha (α) Beta (β)
Adenoreceptors
α 1 β3β 2β1α 2
α 2B α 2Cα 2A
α 1A α 1B α 1D
Adrenergic receptors (or adrenoceptors) are a class of G-protein coupled receptors that are the target of catecholamines
Adrenergic receptors specifically bind their endogenous ligands –catecholamines (adrenaline and noradrenline)
Alpha (α) and Beta (β)
Agonist affinity of alpha (α):
adrenaline > noradrenaline > isoprenaline
Antagonist: Phenoxybenzamine
IP3/DAG, cAMP and K+ channel opening
Agonist affinity of beta (β):
isoprenaline > adrenaline > noradrenaline
Antagonist: Propranolol
cAMP and Ca+ channel opening
α Receptors:
IP3/DAG
cAMP
K+ channel opening
β Receptors:
cAMP
Ca+ channel opening
DRUGS AFFECTING CATECHOLAMINE BIOSYNTHESIS
Metyrosine (a-Methyl-L-tyrosine, Demser).
Much more effective competitive inhibitor of E and NE production
One example of of a CA-biosynthesis inhibitor in clinical use
Metyrosine, which is given orally in dosages ranging from 1 to 4 g/day, for the preoperative management of pheochromocytoma (chromaffin cell tumors that produce large amounts of NE and E).
DRUGS AFFECTING CATECHOLAMINE STORAGE AND
RELEASE
Reserpine (an NT Depleter).
a prototypical and historically important drug, an indole
alkaloid obtained from the root of Rauwolfia serpentina
found in India.
yields methyl reserpate and 3,4,5-trimethoxybenzoic
acid
When reserpine is given orally, its maximum effect is
seen after a couple of weeks.
Guanethidine (Ismelin) and Guanadrel (Hylorel)
seldom used orally active antihypertensives
they have the same mechanism of action on sympathetic
neurons, they differ in their pharmacokinetic efffects
guanethidine is absorbed incompletely after oral
administration (3%–50%),
guanadrel is well absorbed, with a bioavailability of 85%.
Guanethidine has a half-life of about 5 days,
whereas guanadrel has a half-life of 12 hours.
Agents that produce effects
resembling those produced by
stimulation of the sympathetic
nervous system.
They may be classified as;
Direct-acting agents
Indirect-acting agents
mixed mechanism of action
OPTICAL ISOMERISM
A critical factor in the interaction of
adrenergic agonists with their
receptors is stereoselectivity.
Substitution on either carbon-1 or
carbon-2 yields optical isomers.
(1R,2S) isomers seem correct
configuration for direct-acting
activity.
For CAs, the more potent
enantiomer has the (1R)
configuration.
This enantiomer is typically several
100-fold more potent than the
enantiomer with the (1S)
configuration
Separation of Aromatic Ring and Amino Group
the greatest adrenergic activity occurs when two
carbon atoms separate the aromatic ring from the
amino group
R1, Substitution on the Amino Nitrogen Determines
- or -Receptor Selectivity
R2, Substitution on the a-Carbon (Carbon-2).
Small alkyl substitution slows metabolism by MAO
Methyl or ethyl substitution on the a-carbon of the
ethylamine side chain reduces direct agonist activity at
both a- and b-receptors.
OH substitution on the -carbon (carbon-1)
generally decreases CNS activity largely because it lowers lipid solubility
ephedrine is less potent than methamphetamine as a central stimulant, but it is more powerful in dilating bronchioles and increasing blood pressure and heart rate.
OH group is important but not essential.
Substitution on the Aromatic Ring
because the resorcinol ring is not a substrate for COMT, B-
agonists that contain this ring structure tend to have better
absorption characteristics and a longer DOA than their catechol-
containing counterparts.
CAs without OH Groups.
Phenylethylamines that lack OH groups on the ring and
the B-OH group on the side chain act almost exclusively
by causing the release of NE from sympathetic nerve
terminals and thus results in a loss of direct
sympathomimetic activity.
substitution of OH groups on the phenylethylamine
structure makes the resultant compounds less lipophilic,
unsubstituted or alkylsubstituted compounds cross the
BBB more readily and have more central activity
CAs per oral have only a brief DOA and are almost
inactive,
In contrast, compounds without one or both phenolic OH
substituents are, however, not metabolized by COMT, and
they are orally active and have longer DOA.
Imidazolines and a-Adrenergic Agonists.
A second chemical class of a-agonists
give rise to a-agonists; vasoconstrictors.
most imidazolines have their heterocyclic imidazoline nucleus
linked to a substituted aromatic moiety via some type of bridging
unit
Dopamine.
(DA, 3,4-dihydroxyphenylethylamine)
differs from NE in lacking of 1-OH
group
DA is rapidly metabolized by COMT
and MAO
It is used intravenously in treatment of
shock
ENDOGENOUS CATECHOLAMINESDA, NE, and E
Norepinephrine (NE, Levophed)
differs from DA only by addition of
a 1-OH substituent (-OH-DA) and
from E only by lacking the N-
methyl group
It is used to counteract various
hypotensive crises
It has limited clinical application
ENDOGENOUS CATECHOLAMINES
Epinephrine (E, Adrenalin)
differs from NE only by the addition of
an N-methyl group.
It is used in aqueous solution for
inhalation as the free amine.
much more widely used clinically than
NE.
E is a potent stimulant of all a1-, a2-,
B1-, B2-, and B3- adrenoceptors
potent vasoconstrictor and cardiac
stimulant.
used to stimulate the heart in cardiac
arrest.
in the treatment of heart block,
circulatory collapse is limited
treat hypotensive crises and nasal
congestion, open-angle glaucoma,
dipivefrin
Dipivefrin (Propine, DipivalylEpinephrine)
Dipivefrin is a prodrug of E that is
formed by the esterification of the
catechol OH groups of E with
pivalic acid.
improved bioavailability.
increased lipophilicity Increase
DOA is also achieved because
the drug is resistant to the
metabolism by COMT.
less easily oxidized by air due to
the protection of the catechol OH
groups
it is converted to E by esterases
less irritating to the eye than E.
ENDOGENOUS CATECHOLAMINES
All selective 1-agonists have therapeutic activity as
vasoconstrictors. Structurally, they include;
(a) phenylethanolamines such as phenylephrine,
metaraminol, and methoxamine
(b) 2-arylimidazolines such as xylometazoline,
oxymetazoline, tetrahydrozoline, and naphazoline.
Phenylephrine
Neo-Synephrine, a prototypical selective
direct-acting 1-agonist) differs from E only in
lacking a p-OH group.
orally active, and its DOA is about twice that
of
similar to metaraminol and methoxamine for
hypotension
nonprescription nasal decongestant in both
oral and topical preparations
used to dilate the pupil in the eye and to
treat open-angle glaucoma
used in spinal anesthesia to prolong the
anesthesia and to prevent a drop in blood
pressure during the procedure
Methoxamine (Vasoxyl)
another a1-agonist and parenteral vasopressor
few cardiac stimulatory properties.
bioactivated by O-demethylation to an active m-phenolic
metabolite
used primarily during surgery to maintain adequate arterial blood
pressure
does not stimulate the CNS because it is not a substrate for
COMT, its DOA is significantly longer than NE.
Midodrine (ProAmatine)
orally active and represents
another example of a
dimethoxy-B-
phenylethylamine
it is used in the treatment of
symptomatic orthostatic
hypotension.
Naphazoline (Privine),
Tetrahydrozoline (Tyzine, Visine),
Xylometazoline (Otrivin), and
Oxymetazoline (Afrin)
These agents are used for their
vasoconstrictive effects as nasal and
ophthalmic decongestants.
They have limited access to the CNS
Xylometazoline and oxymetazoline
have been used as topical nasal
oxymetazoline may cause
hypotension Oxymetazoline also has
significant affinity for a2A-receptors.
Clonidine (Catapres)
differs from 2-arylimidazoline a1-
agonists mainly by the presence of o-
chlorine groups and a NH bridge
(aminoimidazolines)
Clonidine is an example of a
(phenylimino) imidazolidine derivative
as intravenous infusion, it can briefly
exhibit vasoconstrictive activity
Apraclonidine (Iopidine) and
Brimonidine (Alphagan)
Apraclonidine does not cross the BBB
brimonidine can cross the BBB and hence
can produce hypotension and sedation
Both apraclonidine and brimonidine are
selective 2-agonists with 1:2 ratios of 30:1
and 1,000:1, respectively.
Brimonidine is a firstline agent for treating
glaucoma
Apraclonidine is used specifically to
control elevations in intraocular pressure
that can occur during laser surgery on the
eye
Another example is tizanidine
(Zanaflex), which finds use in treating
spasticity associated with multiple
sclerosis or spinal cord injury.
Guanabenz (Wytensin) and Guanfacine (Tenex)
clonidine analogs
used as antihypertensive drugs.
the 2,6- dichlorophenyl moiety found in clonidine is connected to a
guanidino group by a two-atom bridge
The elimination half-life of clonidine ranges from 20 to 25 hours,
whereas that for guanfacine is about 17 hours. Guanabenz has the
shortest DOA of these three agents, with a half-life of about 6 hours.
Guanabenz has the shortest DOA of these three agents, with a
half-life of about 6 hours.
Clonidine and guanfacine are excreted unchanged in the urine to the
extent of 60% and 50%, respectively
Methyldopa (L-a-methyldopa, Aldomet)
differs structurally from L-DOPA only in the presence of a - methyl
group
decreases the concentration of DA, NE, E, and serotonin in the
CNS and periphery
Absorption can range from 8% to 62%
40% of that absorbed is converted to methyldopa-O-sulfate by the
intestinal mucosal cells
used only by oral administration because its zwitterionic character
limits its solubility
the ester hydrochloride salt of methyldopa, methyldopate (Aldomet
ester), was developed as a highly water-soluble derivative
It is converted to methyldopa in the body through the action of
esterases
Dobutamine (Dobutrex)
is a positive inotropic agent
administered intravenously for
congestive heart failure
possesses a bulky 1-(methyl)- 3-(4-
hydroxyphenyl)propyl group on the
amino group
contains a catechol group and is
orally inactive
given by intravenous infusion.
plasma half-life of about 2 minutes
metabolized by COMT and by
conjugation, although not by MAO.