Leedsphcem ADRENERGIC AGENTS

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

Phenylalanine

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 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

(Homovanillic acid) (Vanillylmandelic acid)

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

Alpha (α) Beta (β)

Adenoreceptors

α 1 β3β 2β1α 2

α 2B α 2Cα 2A

α 1A α 1B α 1D

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

α Receptors:

IP3/DAG

cAMP

K+ channel opening

β Receptors:

cAMP

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.