Sympathomimetic / Adrenergic Drugs

The sympathomimetic or adrenergic drugs are agent that mimics the responses obtained as a result of stimulation of the sympathetic or adrenergic nerves.

Therapeutic classification of adrenergic drugs used for raising adrenergic drugs:

  1. Adrenergic drugs used or raising blood pressure (Vasoconstrictive) – Noradrenaline, metarominal
  2. These used as central stimulants – Amphetamine.
  3. Those used for their inotropic action on the heart – Dopamine, dobutamine, isoprenaline and xamoterol
  4. Those used as smooth muscle relaxants – Adrenaline, isoprenaline and salbutamol.
  5. Those used in allergic reactions – Adrenaline, ephedrine.
  6. Those used for local vasoconstrictor effect – Adrenaline, naphazoline, phenylephrine.
  7. These used for suppressing the appetite – Fenfluramine, phentermine.

 

Adrenergic drugs are classified depending upon their site of action are as follows:

  • Drugs which directly act on adreno receptors:
    1. α – Receptor Agonist:
      1. α1-Receptor – Cirazoline, Methoxamine, Mepheteramine, Phenylephrine, Metaraminol.
      2. α2-Receptor – Clonidine, Apraclonidine, Methyldopa, Guanfacine.
      3. Both α1 and α2 Receptor – Noradrenaline.
    2. β  Receptors Agonist:
      1. β1-Receptor – Isoproterenol, Dobutamine
      2. β2-Receptor – Salbutamol, Terbutaline, Orciprenaline, Isoethharine.
      3. Both β1 & β2-Receptor – Isoprenaline.
    3. Both α and β receptor agonist – Adrenaline.
  • Drugs which indirectly acts on Adrenoceptors:
    1. Drugs which acts by releasing Noradrenaline from stores at nerve endings – Amphefamine, Ephedrine.
    2. Drugs which acts by preventing reuptake of Noradrenaline of nerve endings – Cocaine, Tricyclic antidepressants.
  • Enzyme Inhibitors:
    1. MAO (Monoamino oxidase) Inhibitor – Selegiline.
    2. COMT (Catechol methyl transferase) Inhibitors – Pyrogallol.

ADRENALINE

It is synthesized in adrenal medulla. It is the agonist of both α & β receptors.

Mechanism of action:

The catecholamine’s (Adrenaline, nor adrenaline, dopamine and isoprenaline) produce their action by direct combination with receptors located on the cell membrane. The cut come of this drug receptor combination is either an increase (excitation) or a decrease (inhibition) in the tissue activity. The alpha receptor stimulation is mainly responsible for the excitatory effects of the catecholamine’s and the beta receptor stimulation usually produces inhibitory effects. Adrenaline acts nonspecifically on both α and β receptors, isoprenaline acts on β-receptors, noradrenaline acts on α and β receptors.

The α-receptors are excitatory and β-receptors are inhibitory in character, there are certain exceptions to this rule. Thus β–receptors are mostly present in the heart. They are exciting in character, their stimulation increases the rate and force of contraction of the myocardium. But both α and β-receptors of the gastrointestinal tract are inhibitory in character, their stimulation proudeces a relaxation of smooth muscles.

There are Two Types of β-Receptors:

  1. β1 – Receptors – Responsible for myocardial stimulation and renin release.
  2. β2– Receptors – Responsible for bronchial muscle relaxation, skeletal muscle vasodilation and uterine relaxation.

α Adrenergic Receptors are of Two Types:

  1. α1-receptors (post synaptic)– Which are excitatory in nature increases the extracellular concentration of calcium.
  2. α2-receptors (presynaptic)– the effects of drugs acting on the presynaptic α2-receptors are inhibitory to the tissues. Thus, activation of α2-receptors in the adrenergic nerves inhibits noradrenaline release. Whereas excitation of the vascular α2-receptors causes release of endothelium derived relaxing factor (EDRF) which brings about vasodilation. But activation of venous α2receptors causes vasodilation.

Alpha adrenergic receptors are also present at the post junctional or nonjunctional sites in several tissues such as brain.

Pharmacological Actions:

Adrenaline acts as a non-selective α and β receptors agonist.

  • Cardiovascular System: Adrenaline increases heart rate by increasing the slop of sloe diastolic depolarization of cells in SA node. It also increases force of cardiac contraction and cardiac output. Adrenaline produces its effects on both α & β These drugs due to itsα effects constrict the blood vessels of the skin and mucous membranes. But dilates the blood vessels of skeletal muscle due to its effect on β-receptors. So, the administration of adrenaline initially there is an increase the BP due to α-receptor activating followed by decrease in BP due to β-receptor activating.

Ergot alkaloids are used which are α-receptor blocker, prior to administration of adrenaline in increase in BP is observed. But BP is decreased due to β-receptor activity of adrenaline. This is known as Dale`s vasomotor reversal.

  • Respiration: Adrenaline is a potent bronchodilator. This action is more marked when the bronchi is constricted. Adrenaline given by aerosol also decongests bronchial mucosa by α-action.
  • Eye: Mydriasis occurs due to contraction of radial muscles of iris (α1), but this is minimal after topical application because adrenaline penetrates cornea poorly.
  • Gastrointestinal Tract: Adrenaline relax the smooth muscles of the gut and reduces its motility and tone.
  • Bladder: Adrenaline relax detrusor (muscle that pushes down) due to β-receptor, both action tend to inhibit micturition.
  • Uterus: He human non pregnant uterus is stimulated to contract by adrenaline relaxes the human uterus.
  • Skin: Adrenaline increase sweating of palms (hand).
  • Skeletal Muscles: Adrenaline act indirectly on the skeletal muscle contractions by acting on both sides of the neuromuscular junction. The α-effect in themotor nerve endings increases the amount of Ach released. The β-action on the muscle fibres itself contribute to the improvements of muscle contraction and tremor. It improve blood supply to the skeletal muscle and produces anti fatigue effect in stress.
  • CNS: Adrenaline in clinically used doses, does not produce any marked CNs effects because of poor penetration in brain, but restlessness, apprehension (anxiety) and tremor (Involuntary movement and coarse voice) may occur. Injected in the brain it produces excitation followed by depression.
  • Metabolic: Adrenaline produces glycogenolysis, hyperglycemia, hyperlactacemia, lipolysis (rise in plasma free fatty acid) and hyperkalemia followed by hypokalemia by direct action on liver, muscle and adipose tissue cells. Adrenaline inhibits the release of insulin and stimulates the release of glucagon.
  • Anti-Allergic Action: Adrenaline inhibits the cellular anaphylactic mechanisms and thus tend to prevent the release of mediators of allergic bronchospasm like histamine.
  • Miscellaneous: Adrenaline produces a thick viscid secretion from salivary glands. It also produces leukocytosis and eosinopenia and accelerates blood coagulation.

Pharmacokinetics:

Adrenaline is not administered orally because of their rapid inactivation in the gut and liver. On inhalation of adrenaline aerosols, small quantities may be absorbed into the systemic circulation.

Adrenaline is metabolized by catechol ortho methyl transferase (OMT) and mono amino oxidase (MAO) enzyme to VMA (vanillylmandelic acid).

The normal 24 hours urinary excretion of VMA and free adrenaline is 4 – 8 g and 50 – 100 mg respectively. A significant increase in these values is considered diagnostic of pheochromocytoma (an adrenal medullary tumor).

Adverse Reactions:

Restlessness, palpitation, tremor, pallor, raise in blood pressure leading to cerebral hemorrhage, angina pain and headache.

Contra Indications:

Hypertension, hypersensitivity, hyper thyroidism, angina and arteriosclerosis.

Dose: 0.2 – 0.5 ml by S.C (Subcutaneous) or I.N.

Therapeutic Uses:

  1. Allergic Reaction: Adrenaline is the drug of choice in the treatment of anaphylactic shock.It is lifesaving in angioneurotic edema of the larynx.
  2. Bronchial Asthma: Adrenaline given subcutaneous or by inhalation, It is a potent drug in the treatment of an acute attack of bronchial asthma.
  3. Cardiac Resuscitation: Cardiac arrest is diagnosed if the central arterial pulse is absent in a patient who has suddenly collapse and has become unconscious
  4. Control of Hemorrhage: It is some time used topically for the controlling bleeding from arterioles and capillaries.
  5. Used with Local Anaesthetic: Adrenaline is used along with local anaesthetic due to its vasoconstrictor effect. It reduces systemic absorption of the local anaesthetic, thus prolonging its action and minimizing its systemic toxicity.
  6. Insulin Hypoglycemia: adrenaline may be used as an expedient measured, but glucose should be as soon as possible.
  7. Adrenaline Hydrochloride 0.5 – 2% can be used to reduce the production of aqueous humorand decrease the intra ocular tension in patients with glaucoma.

NORADRENALINE

This neurotransmitter is liberated by post ganglionic sympathetic nerve fibres and synthesized in the nerve endings. Adrenal medulla also synthesis small amount of noradrenaline.

Mechanism of Action:

Same as adrenaline. Noradrenaline also constrict the blood vessels of the skin and mucous membrane but do not dilates the vessels of the skeletal muscle like adrenaline. So, dale’s vasomotor reversal is absent in case of noradrenaline. Noradrenaline is metabolized by the enzyme COMT and MAO.

Uses:

Noradrenaline is used to increase B.P. As it constrict arterioles, so peripheral resistant is also increase. It is mainly used for elevating blood pressure in case of shock.

ISOPRENALINE

It is a synthetic compound having a selective β – receptor stimulant effect.

Mechanism of Action:

The drug is a most powerful β – receptor stimulant agent & effects both β12 receptor but it’s α – effect is negligible. It stimulates the myocardium, but produces peripheral vasodilatation. So it produces fall in blood pressure & tachycardia. It relaxes smooth muscles of bronchi & gastrointestinal tract.

Isoprenaline is not completely absorbed on oral administration. Absorption is better on I.M route or through inhalation. It is mostly administered as sublingual tablets.

Dose: 5 to 20 mg sublingually, Isoprenaline inhalation & injections are also available.

Adverse Effects:

Tachycardia, palpitation, tremor & angina pain.

Uses:

Isoprenaline is mainly used as a bronchodilator & as a cardiac stimulant in heart block.

SALBUTAMOL

These are specific β2 – receptor stimulant. So, their cardiac effect is less prominent.

Mechanism of Action:

These drugs produce a potent bronchodilator action without producing any significant cardio vascular effect it is resistance to the enzyme COMT and cannot be taken up by the neurons. Thus it has a longer duration of action; it is more effective in inhalation than by mouth.

Uses:

These drugs are mainly used in the treatment of asthma.

Dose: 2 – 4mg 4 times daily.

EPHEDRINE

It is an alkaloid obtained from the stem of the ephedra plant.

Mechanism of Action:

It stimulates CNS. It acts by release of noradrenaline & inhibiting MAO which destroy adrenaline & noradrenaline. It also increases the function of noradrenaline. Ephedrine produces mydriasis on local as well as systemic administration.

Adverse Effect:

Insomnia, nervousness, precordial pain, anxiety & increased mental activity.

Dose: 15 – 16 mg in divided dose (Orally).

Uses:

It is useful in bronchial asthma, myasthenia gravis, bronchial cough, nasal congestion & in sudden heart block. It is also used in nocturnal enuresis.

ISOXSUPRINE

(DUVADILAN)

This has a stimulant β – receptor & direct action.

Mechanism of Action:

It has a potent inhibitory effect on vascular & uterine smooth muscle, both in vivo & in vitro, & has been demonstrated to produce some increase in the blood flow of resting uterine muscle.

Adverse Effect:

Nausea, vomiting, palpitation, nervousness &trembling.

Uses:

It is used for the treatment of dysmenorrhoea, threatened abortion, premature labour & peripheral vascular diseases.

Dose: 10 – 30mg in divided dose
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