Adrenaline

Adrenaline is a prototypical sympathomimetic drug (used as a template against which other drugs are compared); this is because it acts on both alpha and beta receptors. It produces its effects through the second messenger system.

On alpha 1 receptors, it acts through IP3 second messenger system by increasing Ca++ levels.

On alpha 2 receptors, it acts by decreasing the cAMP levels.

On beta 1, 2 and 3 receptors it acts by causing an increase in the cAMP levels.

Pharmacological Actions

CVS

Predominantly acts on:

Blood Pressure
Blood vessels
Heart
ECG

Blood Pressure:

Adrenaline acts on both alpha and beta receptors, thus the blood is redistributed.

Arterial Pressure = Cardiac Output x Total Peripheral Resistance

Cardiac Output = Heart rate x Stroke volume

Beta 1 receptors stimulate the heart and produce a positive ionotropic (increased force of contraction) and a positive chronotropic (increased heart rate) effect.

Vasodilatation occurs in the limbs while vasoconstriction occurs elsewhere, beta 1 receptors cause vasodilatation in the heart, alpha receptors are also stimulated, and thus an interplay between alpha and beta receptors occurs. At physiological concentrations, beta receptors are stimulated first. At higher concentrations alpha receptors are stimulated first. Thus the total peripheral resistance either remains the same, increases or decreases, depending on the type of receptors stimulated.

The action of drugs depends on:

Receptor type
Affinity of drugs for receptors
Intrinsic activity of drugs
Compensatory responses (e.g. reflex bradycardia)

Systolic blood pressure, under adrenaline influence, is increased. The diastolic pressure may not increase, decrease or increase very slightly. It mainly depends on the total peripheral resistance, in excessive vasodilatation it may even fall.

The net result is that the pulse pressure gets widened.

Blood Vessels:

Blood vessels are constricted or dilated.

The skin, mucous membrane, kidney and pulmonary blood vessels constrict under the influence of adrenaline.

The skeletal muscle blood vessels are dilated.

Coronary blood flow increases due to:

Intrinsic activity, by the release of adenosine, which causes vasodilatation.
Beta 2 receptors may also be present.

Cerebral blood flow depends mostly on systolic pressure, but is auto regulated. It generally increases.

Heart

Due to positive chronotropic and positive ionotropic effect, the work load on the heart increases, this increases the oxygen consumption. Apart from this the conduction velocity also increases (positive dromotropic effect). The effective refractory period decreases. The excitability of the heart increases (positive bathmotropic effect). In higher doses, arrhythmias may occur. Positive lusiotropic effect is also seen (increase in calcium uptake by cardiomyocytes leading to increased myocardial relaxation).

ECG:

Adrenaline may produce ST elevation or depression. It may also produce flattening or inversion of T wave especially in individuals prone to heart diseases (above 40 yrs etc.). Both these findings indicate ischemia.

The coronary blood flow increases but the oxygen consumption is much more. There is thus relative ischemia.

Epinephrine Reversal or Vasomotor Reversal Phenomenon of Dale*

It states that “If alpha 1 blockers are given before administering epinephrine, there will be no increase in total peripheral resistance due to lack of vasoconstriction and there will be a fall in blood pressure due to decreased TPR”.

Eye:

The pupils are dilated. In the iris two muscles are present, dilator papillae (alpha 1 receptors) and sphincter papillae (muscarinic) are present.

Adrenaline, by agonist action, produces mydriasis or dilatation of pupil.
Alpha 1 receptors also act on the blood vessels, thus the conjunctiva becomes pale due to vasoconstriction.
Reduction in intraocular pressure takes place.

Glaucoma is of two types; open angle and narrow angle (shallow anterior chamber of eye). Normal intraocular pressure is 17-18 mmHg due to the aqueous humor secreted from ciliary processes. These secretions enter the anterior compartment of eye and drain through the canal of Schlemm. Episcleral plexus of brain is drained in to the systemic circulation. This route accounts for 80-90% of drainage. Uveoscleral pathway is the one in which fluid passes through the intercellular spaces among ciliary muscle fibers to enter the choroidal space.

Normal intraocular pressure can only be maintained by balance between the production and drainage of the fluid; otherwise it may rise, leading to glaucoma. This may damage the optic nerve.

Adrenergic drugs and prodrugs like Dipevefrin were used in older days for open angle glaucoma. This drug acts by reducing the production and improving the drainage through the uveoscleral pathway. Vasoconstriction causes decreased production, while possible prostaglandins are released to improve the drainage.

GIT:

Adrenaline has a milder effect on GIT. This is the only place where both alpha and beta receptors produce the same effects. Smooth muscles relax resulting in decreased motility. Pyloric and ileocecal sphincters are constricted (alpha 1 effect).

Urinary Bladder

The detrusar muscles relax (beta effect). Trigone and sphincters are constricted. The smooth muscles of the prostate in male are constricted as well (alpha effect). There is, thus, hesitancy in voiding urine.

Uterus:

Acting on beta 2 receptors, adrenaline produces relaxation. In order to defer labour, beta 2 stimulants are used in the form of infusions for relaxation of uterine contractions. Beta 2 agonists are used; adrenaline has the same effects as well.

In premature labour, fetus is given corticosteroids; otherwise respiratory distress syndrome might develop.

Respiratory System:

In the older days adrenaline was used for status asthmaticus. It was injected subcutaneously in children suffering from bronchial asthma producing bronchodilatation. But adrenaline is non-selective in action. Albuterol and Salbutamol are used now. Vasoconstriction of respiratory mucosa and upper respiratory tract appears and has decongestion effect. Thus reducing respiratory tract secretions. This might be beneficial may be used in form of inhalation. Beta agonists are used now.

Central Nervous System

Adrenaline is a catecholamine and does not cross the blood brain barrier. At higher concentration person becomes apprehensive, restless and anxiety is visible as well as the feeling of doom. This is because of somatic manifestation of anxiety (as tachycardia, tremors occur because of adrenaline due to synchronous and enhanced firing and increased metabolism).

Anti allergic Effect

Adrenaline is the drug of choice in anaphylactic shock. Type 1 hypersensitivity occurs and histamine is released by mast cells. There are four types of histamines (H1,2,3,4), amongst which H1 and H2 are important. H1 is important because of respiratory tract effect of bronchoconstriction, laryngeal edema and generalized edema. By excessive dilatation by histamine, blood pressure decreases and may lead to shock. Effects of histamine are reversed by adrenaline injected subcutaneously, intramuscularly or intravenously in diluted form. It acts on both alpha 1(causing vasoconstriction and decreased plasma exudation) and alpha 2 receptors as well as beta 1 (increasing force of contraction of heart) and beta 2 (causing bronchodilatation) receptors. This is a good example of physiological antagonism. As a result total peripheral resistance is increased, resulting in increased blood pressure. Thus all effects of histamine are reversed.

In addition, adrenaline decreases the release of inflammatory mediators from mast cells. It is thus a wonderful anti allergic drug.

Metabolic Effects

Beta 3 receptors are present in the lipocytes and adipose tissue. Adrenaline acts to cause breakdown of triglycerides into free fatty acids and glycerol. Adrenaline stimulates the triglyceride lipase which causes this breakdown.
Increased glucose levels or hyperglycemia occurs due to :
1. Insulin secretion as a whole is decreased. In beta cells of pancreas beta receptors increase the secretion, while alpha 2 receptors cause a decrease. Alpha 2 effect predominates.
2. Decreased peripheral utilization
3. Increased glucagon secretion (beta effect)
4. Increased glycogenolysis (beta effect) in both liver and skeletal muscles.
5. Reduction in potassium levels in the blood, increasing reuptake by skeletal muscles. As more potassium is released, therefore, by virtue of adrenaline more is transported back. There is a narrow range within which the potassium levels are maintained (3.5-5.5 mEq).

Miscellaneous Effects:

Effects on blood leukocytosis (increased neutrophils). Adrenaline causes de-margination of the neutrophils in the vessels, thus their concentration in circulation is increased.
Increased coagubility because of increase in factor 5.
Sweat glands are of two types:
1. Thermoregulatory
2. Non-thermoregulatory

An increase in the secretion of non-thermoregulatory sweat glands takes place (mainly present in palms). These sweat glands are cholinergic.

Adrenaline is acted upon by:

COMT (liver and GIT)
MAO (adrenergic neurons, liver, CNS)

First one acts then the other. Vanillyl mandelic acid (VMA) is excreted. Its quantity is estimated over 24 hours when there is doubt of tumor secreting adrenaline (e.g. pheocytochroma).

Therapeutic Uses:

In adults concentration used is in ampoules. It is 1 in 1000. About 0.3-0.5ml are used in adults. In children, concentration is same (1 in 1000), while dosage is calculated according to body weight i.e. 0.1 ml/kg body weight. But not more than 0.5 ml.

Route:

Subcutaneous, intramuscular, intravenous (in diluted form slowly, otherwise rapid rise is heart rate and hypertension results).

1. Anaphylaxis

Already discussed

2. Prolongation of local anesthetic activity

a. Adrenaline produces vasoconstriction due to alpha 1 receptors, when combined with a local anesthetic, its effect is enhanced due to the fact that the drug stays in that particular area for a longer duration

b. Total dose of local anesthetic may be reduced as stays for a longer duration

c. Local anesthetic is generally used where surgical procedures are performed. If adrenaline is combined, vasoconstriction causes a reduction in bleeding.

One particular anesthetic is cocaine, which should not be combined with adrenaline. Reuptake of nor-epinephrine is blocked by cocaine and thus noradrenaline stays for a longer duration prolonging its effects.