Adrenaline (Epinephrine)

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INTRODUCTION

Catecholamine contains a benzene ring with two H- atoms attached to it at position 3 and 4. The catecholamine target adrenergic receptors ( and receptors).(Sigola and Zinyama, 2000). The most vital endogenous catecholamine drugs are adrenaline and nor-adrenaline which stimulate and receptors causing vasoconstriction and vasodilation respectively (Chen-Izu et al., 2000). Adrenaline is preferred over noradrenaline as it stimulates both and receptors, while noradrenaline stimulates only receptors. It means by putting a methyl- group on N-atom affinity for receptors can be increased. This fact can be exploited for further improvement in this drug.

Figure 1. Structures of Adrenaline and Nor-adrenaline

1.1 HISTORY AND EFFECTS OF ADRENALINE

John Abel, an American biochemist devised the term epinephrine in 1897.(Bennett, 1999). Adrenaline (Epinephrine) is a sympathomimetic monoamine produced from amino acids (Garcia-Sainz, 1995). The Latin origins ad and renes mean on the kidney as this hormone is secreted from adrenal gland present on the kidneys. Adrenaline aids the body to deal with physical and emotional extremities and to either safeguard itself or to run from danger fight or flight.

1.2 BIOSYNTHESIS
Blood plasma contains approximately 50nM adrenaline. It is produced in medulla of adrenal glands by an enzymatic reaction starting from L-tyrosine. Hydroxylation of tyrosine forms Levodopa from which removal of a carboxylic group gives Dopamine. Dopamine in turn, forms nor-adrenaline, methylation of which produces the wonder drug adrenaline (Wurtman and Axelrod, 1965).

Figure 2. Biosynthesis of Epinephrine (Adrenaline)

1.3 METABOLISM
Two enzymes participate in the metabolism of adrenaline; MAO (monoamine oxidase) and COMT (catechol-O-methyl transferase). (De Schaepdryver and Kirshner, 1961)

Figure 3. Metabolism of Epinephrine (Adrenaline) by enzymes into various metabolites

1.4 PHARMACOLOGY
Adrenergic receptors ( and ) are responsible for the action of epinephrine in our body. 1 receptors present in the liver cells bind to epinephrine and initiates insulin phosphorylation which inhibits binding of insulin to its receptors. Along with this, -adrenergic receptors are also activated by epinephrine, which increases glycogenolysis (Kjaer et al., 2000).

1.5 PHARMACOLOGICAL ACTIONS

Table 1. Physiological responses of various organs to adrenaline. Sr.No ORGANS Effects (receptor involved) Ref.

1.

CVS In small dose In large dose Decrease in B.P () Increase in B.P () Glycogenolysis ()

(De Mattia et al., 2013)

2. LIVER

(Kjaer et al., 2000)

3. LUNGS

Bronchodilation ()

(Miraglia Del Giudice et al., 2012)

4. GIT

Sphincters constriction(1) Hyperglycemia. (1 and ) Pupil dilation (1)

(Krejci et al., 2006)

5. LIVER

(Jones et al., 1975)

6. EYE

(Jones et al., 1975)

ELECTROLYTES 7. Uptake of K+ ions by cell membranes () (DeFronzo et al., 1981)

1.6 THERAPEUTIC USES

1.6.1 ANAPHYLACTIC SHOCK A multi component, severe and life threatening allergic reaction, where heart stops bleeding is called anaphylaxis shock.(Kemp et al., 2008) It is caused when a person is exposed to some foreign agent, to which he is already allergic. A minute amount of this allergen can cause death in minutes if untreated. Epinephrine when administered directly into blood (0.3 to 0.5mg) can restore blood flow to vital organs.(Muraro et al., 2010). It constricts the blood vessels by activating 1 receptors, which increases the pressure flow of blood.(Roberts, 2011). At the same time it also activates - receptors of bronchioles, and dilates the passage and breathing becomes easy.(Frew, 2011a) Epi-pen is a registered brand, auto-injector used in anaphylactic shock.(Frew, 2011b) 1.6.2 CARDIAC ARREST According to American heart association, cardiac arrest causes sudden death by malfunctioning of hearts electrical system. Electric cardioversion is generally used when heart suddenly stops beating. (De Mattia et al., 2013),(Woodhouse et al., 1995). But if it is not available, adrenaline is given to the patient (0.5mg) via intracardiac injection. It increases cardiac output by stimulating and adrenoceptors (Raymondos et al., 2000), (Stiell et al., 1992). 1.6.3 HEMOSTASIS Adrenaline is a vasopressor or vasoconstrictor as it stimulates adrenoceptors. It is widely used to stop superficial bleeding during surgeries of face, nose, buccal cavity and eyes etc. For example Epifrin and Glaucon are used in treating eye diseases; glaucoma. But it cant be used in surgery of hands and toes because it can cause gangrene by stopping blood. Adrenaline is also used along with other anesthetics to stop local bleeding during surgeries.(Kalra et al., 2011) 1.6.4 ASTHMA An amount 300-500mg of adrenaline is given to the patients of asthma. It stimulates adrenoceptors and cause bronchodilation making breathing easier.(Rodrigo and Nannini, 2006). In practice it increases athletic abilities by opening lungs and improvising muscles functioning.(Lieberman et al., 2006).

1.7 CONTRAINDICATIONS
1.7.1 HYPERTHYROIDISM Adrenaline can cause hyperthyroidism which can initiate various cardiac diseases; cardiac arrhythmias. (McCance and Forfar, 1991),(Biondi, 2010) 1.7.2 ISCHEMIC HEART DISEASES If a patient is old or has a history of ischemic heart diseases, adrenaline is not given to him, because it can cause myocardial infarction.(McCance and Forfar, 1991) 1.7.3 HYPERTENSION It can cause severe anxiety, nausea and restlessness, difficulty in speaking, drowsiness and nervousness due to increase in blood pressure.(Sun et al., 2002)

1.8 IMPROVEMENTS
It is well known that adrenaline stimulates both and receptors because of the presence of methyl group on N-atom.(Sigola and Zinyama, 2000). It generated the idea that putting a longer alkyl chain may increase -selectivity. This paved the way to the discovery of a new drug Isoprenaline, which was used for 20 years as asthma treatment.(Calixto and Simas, 1984) Another improvement was made in the basic structure of adrenaline to make it more 2-selective in the lungs, which formed the basis of still widely used Salbutamol (Farid et al., 2013)and Salmeterol.

Figure 4. Structures of Isoprenaline and Salbutamol

1.10 AREAS FOR FURTHER IMPROVEMENT

1.10.1 A PROPOSAL

Figure 5. These amendments in the core structure may still enhance 1 receptors affinity to the drug and be helpful in further asthma treatment.

REFERENCES

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