leedsphcem adrenergic agents
TRANSCRIPT
Steps of Biosynthesis of Catecholamine
Distribution of adrenergic receptors
Individual Functions of Adrenergic
Adrenergic Agonists and their uses
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
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 partiallysubstituted amino (NH2) group
• 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
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
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
In 1948, Ahlquist proposed and designated a- and b- receptors based on their apparent drug sensitivity.
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
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.
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.
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.
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.
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 -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.
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.
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 hydroxymethylgroup 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.
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
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
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 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
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, DipivalylEpinephrine)
Dipivefrin is a prodrug of E that is formed by the esterification of the catechol OH groups of E with pivalicacid.
improved bioavailability.
The greatly increased lipophilicityallows 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
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.
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 methoxaminefor 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 anesthesiaand to prevent a drop in blood pressure during the procedure
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.
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 oxymetazolinehave 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 guanidinogroup 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--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.