ADRENERGIC AGENTS

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

Storage of Noradrenaline

Release of NA – Feedback Control

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

Uptake of Catecholamines

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

Metabolism of CAs

(Homovanillic acid) (Vanillylmandelic acid)

Adrenergic neurotransmission

Adrenergic R

eceptors

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

Adrenergic Receptors

How Many of them ????

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)

Adrenergic Receptors

Distribution and Effects of Adrenoceptors and Main Uses of the Adrenergic Drugs

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)

Subtypes of Adrenoceptors and Their Effector Sysytem

α Receptors: IP3/DAG cAMP K+ channel opening

β Receptors: cAMP a Ca+ channel opening

Molecular Effector

Differences - α Vs β

DRUGS AFFECTING ADRNERGICC

NEUROTRANSMISSION

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

DIRECT-ACTING SYMPATHOMIMETIC(STRUCTURE-ACTIVITY

RELATIONSHIP)

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

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-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