Catecholamines

3, 4, di-hydroxybenzene is called catechol and hence the drugs that have this structure are called catecholamines.

Epinephrine, norepinephrine and dopamine are known as endogenous catecholamines and Isoproterenol is a synthetic catecholamine.

Epinephrine (EPI), norepinephrine (NE) and isoproterenol exhibit varying agonistic actions on the adrenoceptors. The effect of alpha adrenergic action of catecholamines (contraction of smooth muscle) is in the order of- EPI ≥ NE >> ISO

and the beta adrenergic effect (relaxation of smooth muscle ) is in the order of- ISO > EPI

Effects of catecholamines

Synthesis of catecholamines

The precursor for catecholamine synthesis is tyrosine.

Conversion of phenylalanine to tyrosine takes place in the liver and conversion of tyrosine to DOPA and DOPA to dopamine takes place in the adrenergic neuronal cytoplasm.

Dopamine gets converted to norepinephrine in the granules and norepinephrine to epinephrine in the adrenal medulla.

Tyrosine hydroxylase is the rate limiting enzyme and its inhibition by alpha methyl-ρ-tyrosine results in depletion of catecholamines. All enzymes of catecholamine synthesis are rather non-specific and can act on closely related substrates. Tyrosine hydroxylase is activated by cAMP dependent protein kinases and inhibited by catecholamines.

Storage within the granular vesicles is accomplished by complexation of the catecholamines with adenosine triphosphate and a specific protein, chromogranin. This complexation makes the amines inactive until their release. The vesicles also contain ascorbic acid and dopamine beta hydroxylase. Catecholamines are taken up from the cytoplasm into the granules by an active transport system that is ATP and Mg⁺⁺ dependent. This intragranular pool of norepinephrine is believed to be the principal source of the neurotransmitter that is released upon nerve stimulation.

Release from the storage vesicles is calcium dependent exocytosis induced by depolarization of the nerve ending. Drugs can also induce release by destruction of storage vesicles or displacement of catecholamines from the storage vesicles.

Amines within, the cytoplasm may be taken up by the granules for storage or, they may be inactivated by a deaminating enzyme monoamine oxidase (MAO) that is located in the neuronal mitochondria. Intracytoplasmic dopamine may also be deaminated by MAO.

Norepinephrine that has been taken back into the nerve may be restored in granules or it may be deaminated by MAO. Reuptake is an active mechanism and requires energy. Norepinephrine termination of action by enzymatic conversion accounts for 20% of released norepinephrine. Initial inactivation involves two enzymes- Monoamine oxidase (MAO) and Catechol-O-methyl transferase (COMT).

Catecholamines in the blood are metabolized in the liver by COMT and MAO. Aldehyde reductase and aldehyde dehydrogenase further metabolize the aldehydes formed by the deamination by MAO. Aldehyde reductase catalyzes the formation of alcohol products and aldehyde dehydrogenase catalase the formation of acid products. Products of the above enzymatic reactions can sub-serve as substrates for others. The major final products are 3-methyl-4-hydroxymandelic acid (VMA) or 3-methoxy-4-hydroxy-phenylethyleneglycol (MOPEG).

Structure activity relationship

• Maximum sympathomimetic activity is noticed when two carbon atoms separate the aromatic ring from the amine group.
• Increased bulkiness of substitution on the N-atom increases the beta receptor activity.
• Lesser the substitution in the N-atom greater is the activity.
• Removal of one or both the OH^– groups reduces the β activity.
• Substitution of ring hydroxyl group reduces potency.
• Beta  carbon side chain substitution results in less active central actions.
• A carbon substitution gives a compound not susceptible to MAO.
• Alkyl substitution in amino group affects both alpha and beta agonist properties.

Pharmacological actions

1. Excitatory
   • Blood vessels – constriction (including veins, increased venous return to heart).
   • Iris – contraction of the radial muscle with mydriasis .
   • GI & Urinary – contraction of the sphincters.
   • Sweat glands – secretion in horse.
   • Salivary glands – viscous secretion .
   • Male genetalia – ejaculation .
2. Inhibitory
   • Bronchioles – dilatation.
   • Blood vessels – dilatation.
   • GI Tract – relaxation of smooth muscle .
   • Urinary bladder – relaxation of detrusor .
3. Cardio excitatory effects
   •  SA node – increased heart rate
   •  Atria & Ventricles – increased force of contraction, conduction velocity.
   • AV node & His Purkinje System – increased automaticity, conduction velocity.
4. Metabolic effects
   • Liver – glycogenolysis and gluconeogenesis, hyperglycemia.
   • Pancreas decrease (α) and increased (β) secretion.
   • Fat cells – lipolysis, increased plasma free fatty acids .
   • Skeletal – Muscle glycogenolysis, increased blood lactate .

Therapeutic uses

1. Acute anaphylactic reaction – to counter hypotension (α) and bronchospasm (β), epinephrine is the drug of choice.
2. Allergic disorders, asthma – Objective is to produce brnchodilatation via β₂ receptors.  Isoproterenol or epinephrine can be used by inhalation or by intramuscular or intravenous injection. They are short acting and also produce marked cardiac stimulation via the β1 receptors. Ephedrine can also be used. Though it is long acting, it produces marked CNS stimulation.
3. Cardiac arrest/heart block – intracardiac injections of epinephrine or isoproterenol followed by IV infusion or subcutaneous and intramuscular injections are useful.
4. In combination with local anaesthetics – to produce local vasoconstriction and retard the removal of the anaesthetic thereby, increasing the duration of anaesthetic action. Epinephrine is preferred for this use.
5. Control of bleeding – epinephrine when applied locally arrests bleeding from arterioles and capillaries.
6. Decongestion of mucous membrane – phenylephrine and pseudoephedrine are used in rhinitis, sinusitis and hay fever as decongestant.
7. Ophthalmology – ephedrine or phenylephrine can be used to examine the eye as they induce mydriasis without cyclopegia.
8. Shock – Use of α agonists to maintain blood pressure in shock may be harmful by reducing the perfusion to the kidney and brain, which are already affected. But dopamine is useful in the treatment of cardiogenic, traumatic and hypovolemic shock because it selectively dilates the kidney blood vessels, increasing glomerular filtration and increasing urine production. In addition dopamine increases blood supply to abdominal organs.
9. Hypertension – clonidine is effective in hypertension and its effect is primarily central. It may partially activate peripheral presynaptic α₂ receptors.
10. Uterine relaxants – isoxuprine can be used to produce uterine relaxation (tocolytic).