leeds report

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

3.  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.

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.  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

7. L-dihydroxyPhenylalanine
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

12.  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

13. (Homovanillic acid) (Vanillylmandelic acid)

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

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

18.  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)

20.  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

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

23. 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).

24. 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.

25. 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.

26.  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

28. 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

29. 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

30. 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.

31. 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.

32. 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.

33. 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.

34. 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

35. 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 CATECHOLAMINES
DA, NE, and E

36. 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

37. 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, 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.
 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

39. 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.

40. 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

41. 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.

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

43. 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.

44. 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

45. 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.

46. 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

47. 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

49. 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.