Steps of Biosynthesis of

Catecholamine

Distribution of adrenergic

receptors

Individual Functions of

Adrenergic

Adrenergic Agonists and

their uses

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

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

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 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)

In 1948, Ahlquist

proposed and

designated a- and b-

receptors based on their

apparent drug

sensitivity.

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)

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

α Receptors:

IP3/DAG

cAMP

K+ channel opening

β Receptors:

cAMP

Ca+ channel opening

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).

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.

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.

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

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 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-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

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 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

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, DipivalylEpinephrine)

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.

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

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.

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 oxymetazoline

have 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

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

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

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.