adrenergic agents report

2.  Steps of Biosynthesis of
Catecholamine
 Distribution of adrenergic
receptors
 Individual Functions of Adrenergic
 Adrenergic Agonists and their uses

3.  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

4. 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

5. • Catecholamines:
Compounds containing
a catechol nucleus
(Benzene ring with 2
adjacent OH groups)
and an amine
containing side chain
• Non-catecholamines
lack hydroxyl (OH)
group

6. Phenylalanine
PH
Rate limiting Enzyme
5-HT, alpha Methyldopa
Alpha-methyl-p-
tyrosine

10. 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

11.  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

12. (Homovanillic acid) (Vanillylmandelic acid)

15.  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)
 Increase or decrease of 2nd
messengers cAMP or IP3/DAG
 Many cells possess these
receptors, and the binding of an
agonist will generally cause the
cell to respond in a flight-fight
manner.
 For instance, the heart will
start beating quicker and the
pupils will dilate

16. Alpha (α) Beta (β)
Adenoreceptors
α1
β3β2β1α2
α2B α2Cα2A
α1A α1B α1D

17.  In 1948, Ahlquist proposed and
designated a- and b- receptors
based on their apparent drug
sensitivity.

19.  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
 Propranolol
 cAMP and Ca+ channel opening

21.  α Receptors:
 IP3/DAG
 cAMP
 K+ channel opening
 β Receptors:
 cAMP
 Ca+ channel opening

22. DRUGS AFFECTING CATECHOLAMINE
BIOSYNTHESIS
Metyrosine (-Methyl-L-tyrosine, Demser).
 Much more effective competitive
inhibitor of E and NE production than
agents that inhibit any of the other
enzymes involved in CA biosynthesis.
 Metyrosine, which is given orally in
dosages ranging from 1 to 4 g/day, is
used principally for the preoperative
management of pheochromocytoma,
chromaffin cell tumors that produce
large amounts of NE and E.

23. DRUGS AFFECTING CATECHOLAMINE STORAGE AND RELEASE
Reserpine (an NT Depleter).
 a prototypical and historically important drug, is an indole alkaloid
obtained from the root of Rauwolfia serpentina found in India.
 extensively metabolized through hydrolysis of the ester function at
position 18 and yields methyl reserpate and 3,4,5-trimethoxybenzoic
acid
 When reserpine is given orally, its maximum effect is seen after a
couple of weeks.

24. Guanethidine (Ismelin) and Guanadrel (Hylorel)
 are seldom used orally active antihypertensives
 they have the same mechanism of action on sympathetic neurons, they
differ in their pharmacokinetic efffect
 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.
 Both agents are partially metabolized (50%) by the liver, and both are
used to treat moderate-to-severe hypertension, either alone or in
combination with another antihypertensive agent.

25.  Agents that produce effects resembling those
produced by stimulation of the sympathetic
nervous system.
 They may be classified as;
 Direct-acting agents elicit a sympathomimetic
response by interacting directly with
adrenergic receptors.
 Indirect-acting agents produce effects
primarily by causing the release of NE from
adrenergic nerve terminals; the NE that is
released by the indirect-acting agent activates
the receptors to produce the response.
 mixed mechanism of action interact directly
with adrenergic receptors and indirectly
cause the release of NE.

27. 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

28. 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

29. R2, Substitution on the -Carbon (Carbon-2).
 Methyl or ethyl substitution on the a-carbon of the ethylamine side
chain reduces direct agonist activity at both a- and b-receptors.
 a-Substitution also significantly affects receptor selectivity.
 a-methylnorepinephrine, it is the erythro (1R,2S) isomer that
possesses significant activity at a2-receptors.

30. 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.

31. 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.
 replacement of the catechol function of ISO with the resorcinol structure
gives a selective B2-agonist
 replacement of the meta-OH of the catechol structure with a hydroxymethyl
group gives agents
 Modification of the catechol ring can also bring about selectivity at a-
receptors as it appears that the catechol moiety is more important for a2-
activity than for a1-activity.

32. 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.

33. Imidazolines and a-Adrenergic Agonists.
 A second chemical class of a-agonists
 which give rise to a-agonists and are thus vasoconstrictors.
 most imidazolines have their heterocyclic imidazoline nucleus linked to a
substituted aromatic moiety via some type of bridging unit
 Because the SARs of the imidazolines are quite different from those of
the B-phenylethylamines, it has been postulated that the imidazolines
interact with B-receptors differently from the way the B-
phenylethylamines do, particularly with aromatic moiety

34. Dopamine.
(DA, 3,4-dihydroxyphenylethylamine)
 differs from NE in lacking of 1-OH groupDA is
rapidly metabolized by COMT and MAO
 It is used intravenously in treatment of shock
ENDOGENOUS CATECHOLAMINES
DA, NE, and E

35. 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

36. 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
 It is a very potent vasoconstrictor and
cardiac stimulant.
 E is used to stimulate the heart in cardiac
arrest.
 its use in the treatment of heart block or
circulatory collapse is limited
 E is used to treat hypotensive crises and
nasal congestion, open-angle glaucoma,
 dipivefrin
Dipivefrin (Propine, Dipivalyl
Epinephrine)
 Dipivefrin is a prodrug of E that is
formed by the esterification of the
catechol OH groups of E with pivalic
acid.
 improved bioavailability.
 The greatly increased lipophilicity
allows much greater penetrability
into the eye
 Increased 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

38. 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.

39. Phenylephrine
 (Neo-Synephrine, a prototypical selective direct-
acting 1-agonist) differs from E only in lacking a p-OH
group.
 It is orally active, and its DOA is about twice that of E
because it lacks the catechol moiety and thus is not
metabolized by COMT
 It is used similarly to metaraminol and methoxamine
for hypotension
 treatment of severe hypotension resulting from either
shock or drug administration.
 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

40. Methoxamine (Vasoxyl)
 is another a1-agonist and parenteral vasopressor
 have 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.

41. Midodrine (ProAmatine)
 orally active and represents
another example of a dimethoxy-B-
phenylethylamine
 it is used in the treatment of
symptomatic orthostatic
hypotension.

42. 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.

43. 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

44. 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.

45. 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

46. Methyldopa (L--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

48. 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.