What are Adrenergic Drugs? | Animals | Pharmacology

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These are the drugs that mimic the actions of the sympathetic nervous system. Their effects are mediated by the adrenergic receptors on the effector cells, hence these are also called as adrenergic drugs.

Classification of Adrenergic Drugs:

(A) On the Basis of Mechanism of Action:

Direct acting drugs act directly on adrenergic receptors to elicit responses. Indi­rect acting drugs act by releasing norepinephrine from adrenergic nerve endings. Mixed acting drugs act by both direct and indirect mechanisms.

B. On the Basis of Chemical Structure:

Catecholamines are the drugs which have catechol nucleus in their structures.

Chemistry and Structure-Activity Relationship of Adrenergic Drugs:

The parent compound of the sympathomimetic amines is β phenyl-ethylamine where hydrogen molecules are attached with the amino, C_α and C_β molecules. Differ­ent adrenergic drugs are formed by the structural modifications of this parent com­pound. Modification takes place at amino, C_α, C_β, C₃ and C₄ atoms to produce newer drugs.

The structure activity relationship of adrenergic drugs is as follows:

1. Maximum sympathomimetic activity is achieved when two carbon atoms sepa­rate the aromatic ring from the amino group (e.g., all above mentioned drugs).

2. Increase in the bulkiness of substituents on the N- atom increases β-receptor activity (adrenaline, isoprenaline, salbutamol, terbutaline).

3. Less is the substitution on N-atom greater is the selectivity for a activity (epinephrine >>> isoproterenol) though N-methylation increases the potency (epinephrine, NE).

4. Addition of methyl group on α carbon atom increases β receptor selectivity and renders the compounds resistant to MAO (metaraminol)

5. Substitution of OH group on β carbon atom greatly enhances both the α & β-receptor activity (ephedrine > amphetamine); but decreases CNS actions due to lowering of lipid solubility (ephedrine < amphetamine).

6. Removal of β-OH group greatly reduces interaction with adrenoceptors (dopamine).

7. In general, the catechol nucleus (benzene ring with OH group at 3 & 4 posi­tions) is necessary for maximum α and β potencies (catecholamines).

8. Removal of one or both OH groups, without other aromatic substitution, reduces the overall α and β potency (ephedrine, amphetamine, tyramine) especially the β activity is greatly reduced (phenylephrine)

9. Substitution of the catechol -OH groups (albuterol) or their transfer to other ring positions (terbutaline, metaproterenol) renders compounds resistant to COMT, but retains their activity.

10. OH groups in the 3 and 5 positions of ring with large substitution on N-atom confers β₂ receptors selectivity (terbutaline, metaproterenol)

11. Lack of polar groups (e.g. OH) makes compounds more lipophilic which have more CNS activity but loss of direct sympathomimetic activity (amphetamine, ephedrine).

12. Substances having lack of OH groups on both the ring as well as the β-carbon atom act almost exclusively by releasing NE from adrenergic nerve endings (indirect acting sympathomimetics- amphetamine)

13. Increase in the length of alkyl side chain, isopropyl substitution on the N-atom, and modification of catechol-OH groups produces potent β antagonists (propranolol).

Action of Adrenergic Drugs:

Epinephrine:

Epinepherine (adrenaline) acts strongly on both α and β adrenoceptors. Its pharmacological effects depend on the concentration and the type and number of available receptors, Generally, it has more affinity for β receptors. So, at lower concentration, β effect predominates. But if the number of a receptors is more in an organ (e.g., blood vessels), higher concentration of epinephrine will produce α-mediated action.

(a) Action on Cardiovascular System:

1. On Blood Vessels:

Epinephrine mainly acts on small arterioles and precapillary sphinctors. It also exerts its action, to some extent, on veins and large arteries. It causes constriction of cutaneous, renal, pulmonary, arterial and venous, and other visceral blood vessels because of the presence of predominant α receptors.

Epinephrine dialates blood vessels of skeletal muscles (at low doses), coronary and liver and this is mediated by powerful β₂ receptors. At higher dose, it causes vasoconstriction in skeletal muscle. [Epi → β₂ rec. → ↑ Gs → ↑Ad. cycl. → cAMP → PKA ↑ → → dephosphorylation of MLC → relaxation of VSM].

2. On Heart:

The direct β₁ receptor mediated actions of epinephrine are positive chronotropic (↑ heart rate) and ionotropic (↑ force of contraction) effect on heart, increased cardiac output, myocadical contractility, coronary blood flow and so oxygen consumption by heart. The conduction velocity through A-V node, bundle of His, parkinje fibre, atrias and ventricular fibres is increased by epinephrine to cause the above responses.

[Epi → β₁ recep. ↑ → Gs ↑ → Ad. cycl. ↑ → cAMP ↑ → PKA ↑ → Ca²⁺-channels open → [Ca²⁺]_i ↑ → Ca²⁺-calmodulin complex → MLCK ↑ → Phosphorylation of MLC → Contraction of myocardial fibre.]

3. On Blood Pressure (B.P):

At lower concentration slow i.v infussion or S.C. injection of epinephrine causes fall in peripheral resistance because vascular β₂ receptors are more sensitive than α receptors.

Higher dose or rapid i.v. infusion produces marked increase in systolic as well as diastolic B.P. (as the number of a receptors are more than β₂ receptors in blood vessels), which is followed by a fall in the mean B.P. (because when the epinephrine concentration is reduced by degradation, rest of the amount remain attached on more sensitive β₂ receptors). This is called as biphasic response of epinephrine on blood pressure.

Dale’s Reversal Phenomenon or Epinephrine Reversal:

Scientist Dale first recorded that the contractile effect of epinephrine on blood vessel was reversed by the presence of an α receptor blocker, ergot. Epinephrine causes increase, which is followed by decrease, in B.P. The drug is having more affinity for β₂ receptors than α receptors.

The rise, in B.P. is mediated by α receptors as these are more in number than more powerful and sensitive β₂ receptors in blood vessels. Here though the β₂ receptors are also occupied by the drug, their effect is suppressed by the activation of large number of α receptors.

As the concentration of epinephrine is decreased by metabolism or elimination, it disso­ciates first from the less sensitive α receptors. So, at later stage, the number of activated β₂ receptors remains more than the activated a receptors which causes decrease in B.P.

The presence of α receptor blocker like phenoxybenzamine or ergotamine renders the blockade of α receptors on blood vessels and inhibits the rising phase of the epinephrine-induced B.P.

But the β₂ receptors-mediated action (fall in B.P.) predomi­nates even at higher concentration of the drug as their suppressors (α receptors) are blocked. As the effect of epinephrine is reversed by the presence of α blockers and this was first observed by Dale, the phenomenon is called as Dale’s reversal phenomenon.

(b) Effects on Smooth Muscle:

The GIT smooth muscle is relaxed by epinephrine. This effect is mediated by both α₁ and β₂ receptors on effector cells and α₂ receptors on the membrane of para sympathetic nerve endings. α₁ receptor activation causes increase in K⁺ efflux and thereby hyperpolarization of the muscle cell. Β₂ receptor activation increases cytosolic concentration of cAMP. cAMP stimulates protein kinase A which stimulates another enzyme.

After 2-3 such steps this leads to dephosporylation and inactivation of myosin light chain (MLC). Stimulation of presynaptic α₂ receptors renders inhibition of release of excitatory neurotransmitter Ach from intramural nerve. These three responses combindly cause relaxation of GIT smooth muscles.

Epinephrine usually increases sphincter contraction via α₁ receptors (by activation of phospholipase C)

Bronchial smooth muscle relaxes (β₂ receptors activation → cAMP ↑).

On the uterus, its action varies according to the species, stage of gestation and sexual cycle. In cat, epinephrine relaxes (via β₂ receptors) non-gravid uterus but con­tracts (via α₁ receptors) gravid uterus. In rabbits, both gravid and non-gravid uterus are contracted by epinephrine. In rats, both uterus are relaxed. The non-pregnant uterus of human is contracted and pregnant one is relaxed (at term) by the drug.

Epinephrine relaxes detrusor muscle (β₂ receptors) and contracts the trigone and sphinctor muscles (α receptors) of the bladder.

(c) Effect on Metabolism:

Epinephrine stimulates glycogenolysis (β₂ mediated) in liver and muscle, causes inhibition of insulin secretion (α mediated) and increases free fatty acids in blood (β₁ mediated → activation of triglyceride lipase → breakdown of triglycerides into free fatty acids and glycerol)

(d) Effect on Eye:

Mydriasis occurs due to contraction of radial muscles (α₁ receptors) of iris by epinephrine. The intraoccular pressure falls, specially in wide angle glaucoma, due to relaxation of ciliary muscle (β₂ receptors).

(e) Effect on Skeletal Muscle:

Epinephrine does not directly excite skeletal muscle but facilitates neuromuscular transmission through the activation of α and β₂ receptors of somatic Moto neurons releasing Ach rapidly. The twitch tension of white muscle (fast contracting fibres) is increased. Whereas that of red muscle (slow fibres) is reduced. Other β₂ agonists (e.g. salbutamol) may also act similarly.

(f) Effect on CNS:

Being polar compound, epinephrine cannot enter into the CNS, but restlessness, apprehension, headache and tremor may occur due to its secondary to some peripheral effects on CNS, skeletal muscles, and intermediary metabolism.

Pharmacokinetics:

Though epinephrine is absorbed from the GIT, but its bioavailability is poor because it is rapidly degraded in the intestinal wall and liver (by MAO and COMT). The absorption from i.m. inj. site is more rapid than s.c. inj. site, (due to local vasoconstriction).

Preparation:

Adrenaline inj (BAIF, 180pg/0.1 ml). Dogs-0.1 to 0.3 ml, i.v. inj.

Other Adrenergic Drugs:

Norepinephrine (Levarterenol):

It is pharmacologically equipotent to epinephrine in respect of its action on β₁ receptors, but very less potent on β₂ receptors. Norepinephrine is a potent agonist of α receptors. However, it is less potent than epinephrine on these (α) receptors.

Isoproterenol (Isoprenaline):

Like epinephrine and norepinephrine, isoproterenol is also ineffective orally. It acts most entirely on β receptors and have very little effect on α receptors. It increases the heart rate and force of contraction (β₁ mediated), reduces blood pressure (β₂ mediated), relaxes smooth muscle (β₂, mainly bronchial and GIT) and stimulates insulin secretion (β₂ mediated).

Clinical Uses of Adrenergic Drugs:

1. Cardiovascular System:

(a) Cardiac arrest → adrenaline

(b) Cardiogenic shock → dobutamine, dopamine.

(c) Heart block (A-V block) → isoproterenol

2. Anaphylactic reactions:

(a) Acute anaphylactic (or type I hypersensitivity) reaction → Adrenaline.

3. Miscellaneous uses:

(a) Used with local anaesthetic to prolong the action → adrenaline (vasoconstrictor agent)

(b) Bronchial asthma → epinephrine, isoproterenol, salbutamol

(c) As decongestant (allergic rhinitis) → epinephrine

(d) Ophthalmic use (to dilate pupil) → ephedrine, phenylephrine.