Adrenergic receptors

S No	Receptor	Location	G - protein	Mechanism	Result
1	Alpha 1	Smooth muscle	Gs	Increased IP3/ Ca	Contraction
2	Alpha 2	GIT	Gi	Decreased c AMP	Relaxation
3	Beta 1	Heart	Gs	Increased  c AMP	Contraction
4	Beta 2	Bronchial smooth muscle, skeletal muscle &  uterine	Gs	Increased  c AMP	Relaxation

The action of a particular sympathomimetic amine depend on its relative activity at different types of adrenergic receptors

Adrenaline has Alpha ₁ + Alpha₂ +  Beta₁ + Beta ₂ +weak Beta ₃ action

Nor-adrenaline has Alpha ₁ + Alpha₂ +  Beta₁ +  Beta ₃ action but no Beta ₂ action

Isoprenaline has  Beta₁ + Beta ₂ +  Beta ₃ action  but no Alpha action

Alpha action

All types of smooth muscle, except that of the GIT , contract in response to stimulation of Alpha₁ adrenergic receptor through activation of the signals transduction mechanism

Alpha receptors are excitory in nature except in GIT

Alpha ₁

 The smooth muscle are contracted through the Alpha1 receptor +  NT  ----- activation of G- protein ----- stimulation of phospholipase ----  increase of             IP3 / DAG production  ---  mobilization of Ca from intercellular organelle --- activation of calmodulin dependent myosin light chain kinase --------  phosphorylation of myosin -----   contraction    

The Vasoconstrictor alpha₂ receptors probably enhance Ca influx  without utilizing IP₃     

_{Alpha 2}

 The smooth muscle are relaxed through the Alpha ₂ receptor  present in the GIT  +  NT  ----- activation of G- protein -----  inhibition of adenyl cyclase ----  decrease of c AMP  ---  decrease of Ca availability from intercellular organelle ---  inactivation of calmodulin dependent myosin light chain kinase  --------  de phosphorylation of myosin -----   relaxation   

_{In pancreatic Beta cells , stimulation of Alpha 2 receptors reduces the formation of c AMP decreased insulin release}

Beta action

Beta _I receptor

In heart ,  stimulation of G – protein --- stimulation of adenyl cyclase ----  increased levels of c AMP ---- increased Ca levels ------- proteins like troponin and phospholamban are phosphorylated ----------   contraction 

Beta ₂ receptor

 In smooth muscle ---  stimulation of G – protein --- stimulation of adenyl cyclase ----  increased levels of  c AMP  -- Relaxation

Pharmacological actions

 1. Heart

 Adrenaline acts on beta 1 receptors of the heart and produces an increase in

Rate of contraction

Force of contraction

Cardiac output oxygen consumption of  he heart are increased

It stimulates the conductive system from SA node 

2. Blood vessels

It effect the alpha₁ and alpha₂ and beta ₂ receptor 

The effect of adrenaline on both alpha₁ and alpha₂ produces the contraction  on the blood vessels of skin and mucous membrane  

But it dilates the blood vessels of the skeletal muscles  and liver due to the effect on the beta receptors

The action is most marked on arterioles , larger arteries and veins are affected at higher doses

The vasoconstriction and vasodilatation can occur depending on the drug , its dose and vascular bed

 3. Blood pressure

 On IV administration of adrenaline , it produces biphasic effect on blood pressure

There is an initial rise due to stimulation of alpha receptors due to vasoconstriction

( alpha receptor )

Later there is a fall in blood pressure due to an effect on beta  receptor sand produces vasodilatation

If adrenaline is injected after the administration of ergotoxine,  an receptor blocking agent , it produces only a fall in blood pressure

This phenomenon is called as Dales vasomotor reversal

Adrenaline rise in systolic pressure but fall in diastolic pressure

4. Respiration

Adrenaline causes powerful bronchodilation by acting directly on bronchial smooth muscle ( beat ₂ receptor)

This action relieves all known allergic or histamine- induced bronchoconstrictin

In the case of anaphylactic shock, this can be lifesaving

In individuals suffering from an acute asthmatic attack , adrenaline rapidly relieves the dyspnea ( labored breathing ) and increases the tidal volume ( volume of gases inspired and expired)

 5. GIT

Adrenaline produces the relaxation action on GIT,through the effect on alpha ₂ and beta ₂ receptors

Due to the relaxation , it produces the reduction of peristalsis and sphincters are constricted, but this effects are brief and of no clinical import

 6. Uterus

The response of uterus to the catecholamines varies according to species, the phase of cycle , presence or absence of gestation  , period of gestation and the dose administered

Contraction is exerted through alpha receptors while relaxation is mediated by beta receptors

Adrenaline contracts the  uterus of  the non- pregnant women

In last month of the pregnancy adrenaline inhibits uterine contraction and causes uterine relaxation

7. Bladder

 Detrusor is relaxed ( beta)  and trigone is constricted (alpha)

Both actions tend to hinder micturition

8. Eye

 Sympathetic stimulation results in mydriasis due to contraction of the radial muscle fibers of the iris  

Adrenaline on topical administration , does not readily penetrate the eyeball

Adrenaline penetrate cornea poorly

It produces moderate reduction in intraocular tension in the normal and the glaucomatous eye 

9. Metabolic effects

 Adrenalin produces glycogenolysis , hyperglycemia and lipolysis, rise in plasma free fatty acid hyperkalemia followed by hypokalemia &  reduction of insulin (alpha 2)

Hyperglycemia

Adrenaline has significant hyperglycemic effect because of increased glycogenolysis in the liver ( beta2 effect ) , increased release of glucagon ( beta 2 effect ) and decreased release of insulin (alpha 2 )

Lipolysis

Adrenaline initiates lipolysis through its agonist activity in the beta receptors of adipose tissue , which upon stimulation activate adenyl cyclase to increase cyclic AMP levels

Cyclic AMP stimulates a hormone – sensitive lipase , which hydrolyzes triglycerides to free fatty acids and glycerol

Serum potassium levels

Adrenaline promote cellular uptake of potassium  and produces hypokalemia  

_Insulin

Activation of alpha ₂ receptors by adrenaline leads to inhibition of insulin release

Beta 2 adrenergic receptor agonists and vagal nerve stimulate the  enhance of insulin release

10. CNS

The catecholamines  do not cross the BBB satisfactorily and their central actions are limited

Adrenaline may produce excitement, tremors,  vomiting and restlessness

Pharmacokinetics

Oral administration is ineffective, because adrenaline are inactivated by intestinal enzymes

It is given inv for the most rapid onset of action

It also given by inhalation or topically to the eye

The adrenaline is metabolized MAO and COMT

The metabolites are excreted through the urine

Dose

0.2   -  0.5 mg s.c , i.m ,  0.5% by aerosol, action lasts  1/2 to  2 hours

Adverse effects

CNS

Anxiety, fear, tension, headache  &  tremor

CVS  

Cardiac arrhythmias, particularly if the patient is receiving digitalis

Lungs

Pulmonary edema

Hemorrhage

It induce cerebral hemorrhage as a result of a marked elevation of blood pressure

Therapeutic uses

1. Bronchospasm

Adrenaline is primary drug used in the emergency treatment of any condition of the respiratory tract when bronchoconstriction has resulted in diminished respiratory  exchange

In the treatment of acute asthma and anaphylactic shock , adrenaline is drug of choice

2. Glaucoma

In ophthalmology, a 2% adrenaline solution may be used topically to reduce intraocular pressure  in glaucoma  

It reduces the production of aqueous humor by vasoconstriction of the ciliary body blood vessels

3. Anaphylactic shock

Adrenaline is the drug of choice for the treatment of hypersensitivity reactions in response to allergens

4. In anesthetics

Local anesthetic solutions usually contain 1: 100, 000 parts adrenaline

The effect of the drug is to greatly increase the duration of the local anesthesia

It does this by producing vasoconstriction at the site of injection, thereby allowing the local anesthetics to persist at the site before being absorbed into the circulation and metabolized