adrenergic agents lady ann
TRANSCRIPT
Steps of Biosynthesis of Catecholamine
Distribution of adrenergic receptors
Individual Functions of Adrenergic
Adrenergic Agonists and their uses
Objectives:
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
Adrenergic Neurotransmitters
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
Noradrenergic transmission
Biosynthesis of Catecholamines
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 NALocated in neuronal membraneInhibited by Cocaine, TCAD, Amphetamines
Uptake 2 is less specific for NALocated in smooth muscle/ cardiac muscle
Inhibited by steroids/ phenoxybenzamine
No Physiological or Pharmacological importance
Reuptake
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
Metabolism of CAs
In 1948, Ahlquist proposed and designated a- and b- receptors based on their apparent drug sensitivity.
Adrenergic Receptors
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)
Adrenergic Receptors
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: PropranololcAMP and Ca+ channel opening
Differences Adrenergic
Receptors (α and β)
α Receptors: IP3/DAG cAMP K+ channel opening
β Receptors: cAMP a Ca+ channel opening
Molecular Effector
Differences - α Vs β
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).
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 antihypertensivesguanethidine 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 agentsmixed mechanism of action
SYMPATHOMIMETIC AGENTS
OPTICAL ISOMERISMA 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
STRUCTURE-ACTIVITY
RELATIONSHIPS
Separation of Aromatic Ring and Amino Group
the greatest adrenergic activity occurs when two carbon atoms separate the aromatic ring from the amino group
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-agonistsgive 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 CATECHOLAMINESThe three naturally occurring catecholamines DA, NE,
and E are used as therapeutic agents.
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, 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
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.
a-ADRENERGIC RECEPTOR AGONISTS
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
hypotensionnonprescription nasal decongestant in both
oral and topical preparationsused to dilate the pupil in the eye and to treat
open-angle glaucomaused in spinal anesthesia to prolong the
anesthesia and to prevent a drop in blood pressure during the procedure
PHENYLETHANOLAMINES
Methoxamine (Vasoxyl)another a1-agonist and parenteral vasopressorfew 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 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 CNSXylometazoline and oxymetazoline have been used as topical nasal
oxymetazoline may cause hypotension Oxymetazoline also has significant affinity for a2A-receptors.
2-ARYLIMIDAZOLINES
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
a-1 ADRENERGIC AGENTS
Apraclonidine (Iopidine) and Brimonidine (Alphagan)
Apraclonidine does not cross the BBB while brimonidine can cross the BBB and hence can produce hypotension and sedation
Both 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 analogsused 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
OPEN-RING IMIDAZOLINES
Methyldopa (L-a-methyldopa, Aldomet) differs structurally from L-DOPA only in the presence of a
- methyl groupdecreases 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 cellsused 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.
DUAL a- AND b-AGONISTS/ANTAGONISTS