SYMPATHOMIMETIC AGENTS

SYMPATHOMIMETIC AGENTS

Sympathomimetic drugs are agents which stimulate the sympathetic or adrenergic nerve by mimic the action of Nor epinephrine or indirectly by stimulating the release of Nor epinephrine.

Adrenergic Receptors
Sympathomimetic or Adrenergic drugs exert their effects by direct action on adrenergic receptors. There are two types.
1. alpha-Adrenergic receptors 2. beta- Adrenergic receptors

1. alpha-Adrenergic receptors
alpha-Adrenergic receptor sites have three parts
i) Anionic site(Phosphate) which binds with +ve ammonium group.
ii) One hydrogen binding area
iii) One flat area for aromatic ring binding.
Nor epinephrine activates primarily alpha-Adrenergic receptors

alpha-Adrenergic receptors have two types
a) alpha-1-Adrenergic receptors- which are found in smooth muscles of iris, arteries, arterioles and veis. It exerts their effect on post synoptic nerves. a1-Adrenergic receptor activation increase the influx of extracellular Ca2+ at calcium channels.
b) alpha-2-Adrenergic receptors – which mediate the inhibition of adrenergic neuro transmitter release. It exerts their effect on pre synoptic nerves. Activation of a2-Adrenergic receptors leads to a reduction in the catalytic activity of adenylyl cyclase.

2. beta- Adrenergic receptors
beta- Adrenergic receptor sites have the following parts
i) Anionic site which binds with +ve ammonium group.
ii) One hydrogen binding area
iii) One flat area for aromatic ring binding.
Epinephrine activates primarily b- Adrenergic receptor. b- receptor activation relaxes bronchial smooth muscles which cause bronchi of the lungs to dilate and also increases the rate and force of heart contractions.
beta- Adrenergic receptors are three types. They are
a) beta-1-Adrenergic receptors- found in myocardium where their stimulation increases the rate and force of myocardial contractions. They are located mainly in the heart, where they mediate the +ve inotropic and chronotropic effects of the catecholamines. They exhibit the agonist potency in the order of Isopreterenol > Epinephrine = Nor Epinephrine.
b) beta-2-Adrenergic receptors- found in bronchial and vascular smooth muscles where their stimulation causes smooth muscle dilatation and relaxation. They exhibit the agonist potency in the order of Isopreterenol > Epinephrine > Nor Epinephrine.
c) beta-3-Adrenergic receptors- They are expressed on fat cells and their stimulation causes lipolysis. They are located on brown adipose tissue and is involved in the stimulation of lipolysis. They exhibit the agonist potency in the order of Isopreterenol = Nor Epinephrine > Epinephrine.

Classification of Adrenergic Drugs
1.Direct acting Adrenergic Agonists
They are bind and activate a1, a2, b1, b2 receptors
Examples – Nor Epinephrine (binds with a1, a2, b1, receptors), Epinephrine (binds with a1, a2, b1, b2, receptors), Dopamine (with a1, a2, b1, , receptors), Xylometazoline, Phenyl ephrine, Methoxamine, Isoprenaline, Salbutamol.
2. Indirect acting Adrenergic Agonists
They produce Nor Ephidrine (NE) like actions by stimulating NE release, preventing its reuptake and thus its inactivation.
Example – Tyramine
3.Dual acting Adrenergic Agonists
These agents act as direct and indirect adrenergic agonists. They binds to adrenergic receptors and stimulate NE release.
Example – Ephedrine, Amphetamine, Mephentermine.

Chemical classification
1.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
2. Imidazoline derivatives
Naphazoline, Tetrahydrazoline, Oxymetazoline, Xylometazoline, Clonidine.

1.Direct acting Adrenergic Agonists
A. Endogenous Catecholamines

B. alpha-Adrenergic receptor Agonist

Clonidine Imidazolines C. b-Adrenergic receptor Agonist

Bitolterol D. Both a and b-Adrenergic receptor Agonist

2. Indirect acting Adrenergic Agonists

3.Dual acting Adrenergic Agonists

Ephedrine
SAR for Adrenergic Agonists

General structure

SAR for sympathomimetic drugs are discussed in the following category.
A). Substitution in the Phenyl ring system

1. The receptor selectivity of the drugs depends on the substituent at aromatic ring , a,b- Carbon and Amino group.


2. The maximal sympathomimetic activity shown by substitution of hydroxyl group in M and P position of aromatic ring.


3. The amino group should be separated from the aromatic ring by two carbon atoms for optimal activity.


4. The naturally occurring Nor Adrenaline has 3’,4’-dihydroxy benzene ring active at both a and b-Adrenergic receptors.


5. The dihydroxy substitution at 3’,4’ position(Ex-Metaproterinol) gives good oral activity and selectivity for b2-Adrenergic receptors.


6. Ther substituents like3’-hydroxy methyl (albuterol), 3’- trifluoro methyl, 4’ amino, 5’ chloro (Mebuterol) have good oral activity.


7. One hydrogen bonding group is essential at the 4’ position for beta activity and 3’- OH substitution for Alpha activity.

B). Substitutions at Nitrogen (Amino group)

1. The presence of amino group is important for direct agonist activity.


2. Primary and secondary amines are more potent direct acting agonist than tertiary amine.


3. Size in alkyl group of nitrogen increases, a-recptor agonist activity decreses and beta-receptor agonist activity increases (Ex-Isoproterenol).


4. N-substitution also provides selectivity for different b-receptor sub types. Large t-butyl group have selectivity to b2 receptor (Ex-Colterol). Ritordrine with large P-Hydroxy phenyl ethyl substitution is a aelective b2 agonist .


5. Nitrogen in the part of heterocyclic ring such as imidazoline possess anti hypertensive property.

C). Substitutions on Carbon in the side chain

1. There are two carbon atoms a and b to nitrogen function. Small alkyl groups such as methyl or ethyl present in the a-carbon, an ethyl group at this position diminish the a-activity for more than b-activity.


2. The presence of a-alkyl group increases the duration of action by making the compound resistant to metabolic deamination by MAO.


3. Maximal direct activity in a-methyl nor adrenaline in the erythro enantiomers.
   b- carbon has hydroxyl group in the (R) absolute configuration for maximal direct activity.
   

Mechanism of Action

1.For Directly acting Sympathomimetics
They act through complexation with specific receptors. For the activation of b-receptor phenolic hydroxy group in meta position of aromatic group and an alcoholic hydroxyl group in b-position of side chain and an amine with bulky group.

2.For InDirectly acting Sympathomimetics
They act either by releasing catecholamines mainly norepinephrine from storage granules in the sympathetic nerve terminals or through inhibition of nor adrenaline uptake at the neuronal membrane.

3. Sympathomimetics of Mixed action
They act by both mechanisms described above.

DRUGS ACTING ON ANS

DRUGS ACTING ON ANS
The drugs acting on the autonomic nervous system is known as Autonomic drugs. They are mainly classified as
1. Adrnergic drugs 2. Cholinergic drugs

ADRENERGIC NEURO TRANSMITTERS
Adrenergic nerves release the neurotransmitters like Nor Epinephrine(Nor Adrenaline), Epinephrine(Adrenaline) and Dopamine.

Structure and Physico chemical Properties:

1.Nor Epinephrine(Nor Adrenaline)

It is a neurotransmitter of post ganglionic sympathetic neurons. As a result of sympathetic nerve stimulation, it is released from sympathetic nerve endings in to the synoptic cleft, where it interacts with specific pre synoptic and post synoptic Alpha and beta adrenergic receptors. It has chiral carbon and exist as enantiomeric pair of isomers.

2.Epinephrine(Adrenaline)

It is not released from nerve endings, but synthesized and stored in the adrenal medulla, from which it is released in to the circulation. Epinephrine is also biosynthesized in certain neurons of the CNS. It belongs to the chemical class of substances known as catecholamines. They are easily oxidized in the presence of air or other oxidizing agents. So they are stabilized by anti oxidants such as ascorbic acid or sodium bi sulphite. It has chiral carbon and exist as enantiomers. Catecholamines are polar substance that contain both acidic(Phenolic -OH) and basic(Aliphatic amine) has pKa values 8.7 and 9.9.

3.Dopamine

It is a neurotransmitter in the basal ganglia of CNS. Dopamine b- hydroxylase enzyme converts dopamine in to nor epinephrine. The enzyme is not presnt in dopaminergic neuron. Hence it remains in original form to carry out the function of neuro transmitter.

Bio synthesis of neuro transmitters

The biosynthesis of catecholamines, Dopamine, Nor epinephrine and Epinephrine involves a sequence of enzymatic reactions.
Catecholamine biosynthesis takesplace in adrenergic and dopaminergic neurons in CNS, in sympathetic neurons of the ANS and in the adrenal medulla.
The aminoacid L-Tyrosine serves as the precursor for the catecholamines. It is acted by tyrosine hydroxylase to form L-dihydroxy phenyl alanine(L-dopa). The second step is the decarboxylation of L-Dopa to dopamine by L-aromatic aminoacid decarboxylate. Then this dopamine is hydroxylated by b- Mono oxygenase in presence of Cu2+ to give Nor epinephrine.
The bio synthesis is represented as follows.

Metabolism
The actions of adrenaline and nor adrenaline are terminated by the following three process.
Reuptake in the nerve terminal
Dilution by diffusion from the junctional cleft and uptake at non neuronal sites.
Metabolic transformation.
Two enzymes namely mono amino oxidase (MAO) and Catechol-O-Methyl Transferase (COMT) are important for the biotransformation of catecholamines. These enzymes are distributed through out the body.