ADRENERGIC AND ANTI-ADRENERGIC DRUGS

Manju Prathap

Chemical agents that exert their principal pharmacological & therapeutic effects by either enhancing or reducing the activity of various components of sympathetic division of ANS

DIVISIONS OF HUMAN NERVOUS SYSTEM

Human Nervous system

Central Nervous System Peripheral Nervous System Autonomic Nervous System

NERVOUS SYSTEM
Includes neurons and ganglia outside of the brain and spinal cord
Peripheral Nervous System

*Either fight and flight mode or rest and digest

*Autonomic Nervous System (involuntary)

Somatic Nervous System (voluntary)

With neurotransmitters norepinephrine and acetylcholine

Sympathetic Nervous System (adrenergic)

Parasympathetic Nervous System (cholinergic)

SYMPATHETIC NERVOUS SYSTEM

Fight or flight response results in: 1. Increased BP 2. Increased blood flow to brain, heart and skeletal muscles 3. Increased muscle glycogen for energy 4. Increased rate of coagulation 5. Pupil dilation

Neurotransmittors
OH HO NH2 HO OH NH CH3 HO Norepinephrine HO Epinephrine

OH HO + NH2R

HO Cationic

Chemistry of Adrenergic Neurotransmitters: NE and epinephrine contain catechol function (3,4-dihydroxyphenyl moiety) in their structure, and they belong to a class known as catecholamines. They contain both acidic (aromatic hydroxyls OHs) and basic (aliphatic amine) functional groups. At physiological pH (7.4), NE and epinephrine have been found to exist in more than 95% in the cationic form in which nitrogen is protonated. This largely accounts for the higher degree of water solubility of these chemicals.

Biosynthesis of catecholamines
Norepinephrine biosynthesis takes place by a three-step process: 1. Conversion of tyrosine to L-dihydroxyphenylalanine (LDOPA)

catalyzed by tyrosine hydroxylase. This step is the rate-limiting process in catecholamine biosynthesis. Tyrosine hydroxylase is inhibited by -methyltyrosine (metyrosine). 2. Decarboxylation of LDOPA to produce dopamine catalyzed by Laromatic amino acid decarboxylase (DOPA decarboxylase) and is inhibited by Methyldopa. 3. Stereospecific hydroxylation of dopamine to produce NE catalyzed by dopamine hydroxylase which is inhibited by disulfiram.

Metabolism of Catecholamines
Monoamine oxidase (MAO) and catechol Omethyltransferase (COMT). MAO metabolism of intraneuronal catecholamines- (oxidative deamination)

COMT - catecholamines that enter the circulation and the extraneuronal tissues

VMA

Norepinephrine to DOPGAL (3,4dihydroxyphenylglycolaldehyde) by MAO and to normetanephrine by catechol-O-methyltransferase. The aldehyde group of DOPGAL reduced to glycol by aldehyde reductase, yielding 3,4-dihydroxyphenylethylene glycol (DOPEG) Aldehyde dehydrogenase converts DOPGAL to 3,4-dihydroxy-mandelic acid (DOMA)

Final metabolite is VMA- vanilyl mandelic acid or 3Methoxy-4-hydroxymandelic acid

ADRENERGIC RECEPTORS

Postganglionic sympathetic neuron, synaptic cleft, and effector cell.

AlphaA1 (blood vessels, kidney, liver, pregnant

uterus, male sexual organs, intestinal smooth muscle. Causes vasoconstriction, decreased renin secretion , uterine contraction)

and A2 BetaB1, B2, B3

Receptor activation

1: Vasoconstriction so they B.P. (used in treatment of hypotension) relaxation of GIT smooth muscle, salivary secretion and hepatic glycogenolysis. 2: Transmitter release, including Ach, NE from the autonomic nerves, i.e., it reduces sympathetic responses (used in treatment of hypertension i.e. lowers B.P.). 1-: Cardiac rate and force (used in treatment of heart failure and shock) and relaxation of GIT smooth muscle. 2-: Bronchodilatation, vasodilatation and smooth muscle relaxation (used in treatment of asthma). Also uterine contraction (during premature labour), hepatic glycogenolysis and muscle tremors.

REVIEW OF FUNCTIONS OF SYMPATHETIC NERVOUS SYSTEM RECEPTORS

Alpha 1smooth muscle contraction Alpha 2-negative feedback causes less norepinephrine to be released so BP is reduced Beta 1increased heart rate Beta 2bronchodilation Beta 3actual site for lipolysis

Adrenergic Drugs

Drugs affecting adrenergic neurotransmission

Drugs

affecting catecholamine biosynthesis Drugs affecting catecholamine storage and release

Sympathomimetic drugs (agonists) Adrenergic antagonists

Adrenergic Agonists (Sympathomimetics)

According to the mechanism of action, sympathomimetic agents may be classified as producing their effects into: Direct-acting Agents that elicit their response by interacting directly with adrenergic receptors. Indirect-acting Agents which initiate the release of NE from storage granules in the sympathetic nerve terminals or through inhibition of nor adrenaline uptake at the neuronal membrane resulting in activation of the receptors. Mixed Function agonists that interact directly with adrenergic receptors and initiate the release of NE.

Chemical classification

Phenyl ethylamines and related compounds Adrenaline, Nor Adrenaline(NE), Dopamine, Phenyl ephrine, Methoxamine, Methyl dopa, Isoproterinol(Isoprenaline), Salbutamol, Terbutaline, Dobutamine, Amphetamine, Ephedrine, Pseudo Ephedrine, Ritodrine, Salmeterol Imidazoline derivatives Naphazoline, Tetrahydrazoline, Oxymetazoline, Xylometazoline, Clonidine.

SAR

Prototypical directacting sympathomimetics are NE, epinephrine and isoproterenol. Compounds are phenylethanolamine derivatives (phenethylamine) that contain the appropriate substituents.

meta NH2

para

 meta NH2

Catechol hydroxyl groups in the meta- and para-positions of the aromatic ring relative to the phenethylamine moiety. -Hydroxyl group on the ethylamine portion of the molecule is imp. Presence and position of Amino group is important, either primary or secondary, but the tertiary analogues are poor direct agonists. Two carbon atoms separating the amino group from the aromatic ring for providing optimal activity.
Proper stereochemistry of the -hydroxyl group enhances the activity of NE and other catecholamines since it is involved in the binding of the compound with the adrenoreceptor, e.g. (L) NE is more active than the other enantiomer (stereoselectivity).(R) isomer is 800 times more potent

para

A). Substitution in the Phenyl ring system The receptor selectivity of the drugs depends on the substituent at aromatic ring , ,,- Carbon and Amino group. The maximal sympathomimetic activity shown by substitution of hydroxyl group in M and P position of aromatic ring. Catechol moiety may be replaced by other substituted phenyl moieties to provide selectivity.

The dihydroxy substitution at 3,5 position (resorcinol),Eg-Metaproterinol) gives good oral activity and selectivity for b2-Adrenergic receptors, resist metabolism by COMT. :., sed bioavailability prolonged duration of action.
The substituent like3-hydroxy methyl (albuterol), 3- trifluoro methyl, 4 amino, 5 chloro (Mebuterol) have good oral activity and 2 selectivity. Removal of p-hydroxy grp from E gives phenylephrine, selective for 1. (catechol nucleus is imp for agonistic activity only at 2.

B). Substitutions at Nitrogen (Amino group) The presence of amino group is important for direct agonist activity. Primary and secondary amines are more potent direct acting agonist than tertiary amine. Size in alkyl group of nitrogen increases, a-recptor agonist activity decreses and beta-receptor agonist activity increases (Ex-Isoproterenol). N-substitution also provides selectivity for different b-receptor sub types. Large t-butyl group have selectivity to b2 receptor (E.g.Colterol). Ritordrine with large P-Hydroxy phenyl ethyl substitution is a selective b2 agonist . Nitrogen in the part of heterocyclic ring such as imidazoline possess anti hypertensive property e.g Clonidine.

C). Substitutions on Carbon in the side chain There are two carbon atoms and to nitrogen function. Substitution of ethyl side chain both in reduces direct agonistic activity except for single small alkyl groups such as methyl or ethyl present in the -carbon, which increases the duration of action. substitution at this position diminish the -activity for more than -activity.e.g Isoetharine
The presence of -alkyl group increases the duration of action by making the compound resistant to metabolic deamination by MAO. - carbon has should possess hydroxyl group in the (R) absolute configuration for maximal direct activity.

IMIDAZOLINES
H2C X---- R = bridging unit Aromatic moiety R X N HN CH2 imidazoline ring H3C OH oxymetazoline C(CH 3)3 Naphazoline H3C

H3C CH2 H3C C(CH 3)3 Xylometazoline

Cl NH Cl Clonidine

Heterocyclic imidazoline nucleus linked to a substituted aromatic moiety via a bridging unit. Optimum unit methylene, amino Activity enhanced with halogen or small alkyl substitution on aromatic ring

Endogeneous catecholamines Noradrenaline (Norepinephrine)

Chemistry:

l--[3,4-dihydroxyphenyl]--methyl-aminoethanol Chemical mediator liberated at mammalian post-ganglionic adrenergic nerve terminals. Available as acid tartarate salt. odorless, bitter taste, White crystalline powder soluble in water and slightly soluble in alcohol. Protected from air and light as it darkens on exposure to air and light. differs from adrenaline only by lacking the methyl substitution on the aminoethanol Only l-isomer is pharmacologically active. Use: To maintain B.P in acute hypotensive states

[R(-)-1-(3,4-dihydroxyphenyl)-2-(isopropylamino)ethanol]

Isoproterenol is a potent non-selective -adrenergic agonist with no effect on receptors (bulkiness of isopropylamino group). Use: Treatment of bronchial asthma, (relief of bronchospasms) Cardiac side effects limit the use. Advantageous when heart block is seen with asthma. Short duration of action, orally inactive

Synthesis of Isoproterenol

Terbutaline (bricanyl, Brithine)

N-tert-butyl-N-[2-(3,5-dihydroxyphenyl)-2-hydroxymethyl]amine

Non-catecholamine, resistant to COMT, MAO, 2 selectivity longer duration of action Metabolised by glucuronide conjugation Uses: It is given orally for treatment of asthma

SALBUTAMOL (ALBUTEROL)

The hydroxymethyl group has a blocking effect towards the action of COMT which leads to a longer duration of action. It is more selective 2-agonist. Uses: As a bronchodialator in asthma, other conditions associated with airway obstruction, bronchitis. In management of premature labour.

O H3CO HO
methyl salicylate

O O

O CH3 H3COOC Br 2 Br HO

+
Cl CH3 H3COOC
NHC(CH3 ) 3

AlCl 3
Friedal craft's Acylation

H3COOC

HO
Ketoester

Bromoketone

O HO

H3C C N

OH CH3 CH3 LiAlH 4 HO HOH 2C

CH 2Ph N C H3C CH3 CH3

ucleophilic substitution reaction

OH H2 /Pd
Hydrogenolysis

HO HO Salbutamol

NH C H3C

CH3 CH3

NAPHAZOLINE

CH2 N HN

2-(1-naphthylmethyl)-2-imidazoline
Naphazoline is direct acting sympathomimetic drug, which has only -agonistic activity. It is used topically as nasal decongestant.

Xylometazoline
CH3 H3C CH3

CH3

NH CH3 N

2-(4-tert-butyl)2, 6-dimethylbenzyl)-2imidazoline.

Uses. Xylometazoline is a sympathomimetic decongestant. It is a sympathomimetic with marked alpha-adrenergic action. It acts as a vasoconstrictor when applied topically to mucus membrane and thus reduces swelling and congestion.

Clonidine (Catapres, Captopress)

N-(2,6-dichlorophenyl)-4,5-dihydro1H-imidazol-2-amine

Selective 2 adrenergic receptor agonist, slight initial 1 Activity; 300:1 (Phenyl imino)imidazolidine derivative The initial dose of clonidine may produce a transient vasoconstriction causing transient B.P. but it is soon overcome by vasodilatation as clonidine penetrates the blood brain barrier (BBB) and interacts with 2-receptors of brain causing decrese in sym outflow, causing decrease in B.P. (antihypertensive or hypotensive).

2-(methylthio)-4,5dihydro-1H-imidazole

Imidazolidine-2thione

Clonidine

Use: Antihypertensive agent

Indirectly acting
Mode of Action:
Act by releasing endogeneous NE. Taken up by pre-synaptic neurons, where they cause the release of NE by displacing. SAR Catechol moiety ses activity but drugs used usually are not catechols. Hydroxyl grp may or maynot be present n methy grp ses and hydroxyl grp ses activity Nitrogen can be primary, secondary or part of heterocyclic ring system. Tertiary amino grp inactive.

Compounds are resistant to COMT and MAO enzymes due to lack of phenolic hydroxyl groups and presence of -methyl groups. pass more readily through blood brain barrier because of increased lipophilicity. Central sympathomimetic agents eg amphetamine.

Cyclopentamine (Clopane, Cyclonarol)

1-cyclopentyl-N-methyl-propan-2-amine

Cyclopentamine is an analogue of amphetaminearomatic ring replaced by cyclopentane. Produces vasoconstriction and nasal decongestant effects Reduced potency than amphetamine. Use: nasal decongestant Propylhexedrine - cyclohexyl group.

(a)

Cyclopentanone is condensed with cyanoacetic acid by Knovenagel reaction, followed by decarboxylation to get an unsaturated nitrile

(b)

The unsaturated nitrile is reduced to get 2-cyclopentylmethyl nitrile.

(c) 2-cyclopentyl methyl nitrile is allowed to react with methyl magnesium bromide to give a methyl ketone which on reductive amination with methylamine yields cyclopentamine

Pseudoephedrine

(S,S)-2-methylamino-1-phenylpropan-1-ol

Pseudoephedrine is the (S,S) diastereomer of ephedrine. Alkaloid from Ephedra species Ephedrine mixed mechanism Pseudoephedrine is a chiral molecule, meaning it occurs in both "left-handed" and "right-handed" configurations which

are not superimposable. Use; nasal decongestant, cold medications Other drugs: Amphetamine, hydroxyamphetamine, propyl hexedrine etc.

Sympathomimetics with mixed MOA

Chemistry: usually have no hydroxyl grp on aromatic ring but have a hydroxyl grp eg: epinephrine, phenylpropanolamine, metaraminol(has a hydroxy grp on aromatic ring)

EPHEDRINE

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