Increase heart rate. Noradrenaline



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Adrenergic System

Lecture (3)

Comparison of effect of Noradrenaline, adrenaline and Isoprenaline:

  1. Heart rate :

  • Adrenaline & Isoprenaline increase heart rate.

  • Noradrenaline decreases heart rate due to increased blood pressure that induces a reflex rise in vagal activity by stimulating the baroreceptors.

  • If atropine is given before Noradrenaline, or the vagas is cut ,or the patient is in shock then there will be tachycardia.

  • Note: the Baroreceptors reflex predominates over noradrenaline effects.



  1. Force of contraction: ( ↑ contractility → ↑ SV )

  • Noradrenaline, Adrenaline and Isoprenaline increase contractility and stroke volume.

  • The reflex compensation doesn't affect the positive entropic effect of Noradrenaline.



  1. Cardiac output :

  • Adrenaline and Isoprenaline increase cardiac output .

  • Noradrenaline has little or no effect on cardiac output (due to weak beta1 effect)



  1. Myocardial oxygen consumption :

  • Increase with all (least with Noradrenaline).



  1. Conductivity :

  • Increased by all and may cause arrhythmias.



  1. Blood vessels of skeletal muscles :

  • Noradrenaline causes constriction (i.e. increase total peripheral resistance TPR) through αlpha action .

  • Adrenaline & Isoprenaline dilate vessels going to the skeletal muscles & liver also . the effect, therefore, is a decreasing in total peripheral resistance more evident with Iso. (β₂ action).



  1. Skin blood vessels:

  • Noradrenaline & Adrenaline constrict skin and mucus membrane arterioles (αlpha action).

  • Isoprenaline has no effect because there are no beta receptors in the skin & mucus membrane .



  1. Renal blood vessels :

The same of the skin.

  1. Veins :

  • Adrenaline & Noradrenaline produce venoconstriction which leads to increased venous return .

  • Isoprenaline produces dilation of veins which leads to decreased venous return.

  • Veins contain α and β₂ receptors (alpha are more than beta).



  1. Blood pressure :

  • Noradrenaline increases systolic and diastolic blood pressure (alpha action).

  • Adrenaline increases systolic blood pressure (Beta1) with slight decrease in diastolic blood pressure (Beta2  vasodilation).

  • The mean blood pressure (MBP) = (diastolic + 1⁄3 pulse pressure) may be slightly increased because the increase in systolic pressure is much more than the decrease in diastolic pressure. So Adrenaline increases the mean blood pressure but the increase is less with Noradrenaline.

  • Isoprenaline may increase systolic pressure slightly but it greatly reduces the diastolic pressure & the mean arterial pressure.



  1. Capillaries:

  • Adrenaline reduces capillary permeability due to widening of the endothelial cells that decreases the pores.

  • Noradrenaline and Isoprenaline have no effect.

Note: endothelial cells are separated by pores everywhere inside human body except: BBB, placenta, eyes and prostate where they have junctions in between.

Note: Increased permeability is due to direct effect of adrenaline on the cell membrane "not" by Beta effect.

  1. Bronchiolar smooth muscle :

  • Adrenaline and Isoprenaline cause powerful bronchiodilation (β₂ effect).

  • Noradrenaline has no effect. (Because there are no αlpha receptors in the bronchiolar smooth muscles).



  1. Gastrointestinal Tract:

  • Noradrenaline (αlpha₂ action) , Adrenaline (alpha₂ and beta₂ action) and Isoprenaline (βeta₂ action) cause relaxation .

Important Note: it's the only site where alpha₂ and beta₂ act on the same direction.

  1. Pregnancy uterus :

  • Noradrenaline (alpha action ) causes contraction.

  • Adrenaline and Isoprenaline (beta₂ action) causes relaxation.



  1. Radial muscles of the iris :

  • Adrenaline (alpha₁ action) causes contraction of radial muscles (mydriasis).

  • Noradrenaline has little effect because it is not absorbed (causes severe vasoconstriction).

  • Isoprenaline has no effect.



  1. Blood glucose: (increased by all)

  • Adrenaline has significant hyperglycemic effect because it :

  • increases glycogenolysis in the liver (beta₂ effect) and

  • increases the release of glucagon (beta₂ effect) and

  • Decreases the insulin (alpha₂ effect on Beta cells of Pancreas).

  • Iso. cause increase in blood suger (β₂ effect).

  • Nor. may increase blood suger.



  1. Lipolysis:

  • Adrenaline initiates Lipolysis (through its agonist activity on BETA₃ receptors).

  • The increased Lipolysis induced by Isoprenaline is not clinically significant.

  • Lipolysis is least increased by Noradrenaline.



  1. Serum pottasium k:

  • Adrenaline & Isoprenaline lead to hypokalemia because the biochemical pump that shifts k into the cells is activated by beta₂ agonists.

  • However Noradreanline may cause hyperkalemia through alpha₁ effect.



  1. Release of mediators from mast cells :

  • The release is inhibited by Adrenaline & Isoprenaline (beta₂ effect)

  • Noradrenaline has no effect.



  1. Muscle tremor :

  • Adrenaline & Isoprenaline cause muscle tremor (beta₂ effect) while it less with Noradrenaline.

Note: Adrenaline constricts skin blood vessels and dilates skeletal muscle blood vessels.

Therapeutic uses of Noradrenaline:

  1. To treat shocks:

To treat Hypovolemic shock because it increases vascular resistance which leads to increased blood pressure , however dopamine is better because it doesn't decrease blood flow to the kidney as does Nor.

* nor is given by I.V. infusion 2- 4 mg⁄min .

  1. As a local vasoconstrictor:

Mixed with local anesthetic to prolong its action because it delays its absorption into the blood stream. However Adrenaline is preferred.

*Noradrenaline is not used as nasal decongestant because it is not absorbed (it causes severe vasoconstriction).

Therapeutic uses of Adrenaline:

  1. Anaphylactic shock :

(Type І) hypersensitivity reaction in response to allergens that cross-link IgE fixed to mast cells and basophiles leading to degeneration and release of histamine and other mediators.

  • Adrenaline is the drug of choice in anaphylactic attacks.

  • Adrenaline is given intramuscularly of intravenously .

  • It acts as physiological antagonist to histamine.

Drugs of Anaphylactic Shock: (Adrenaline, Corticosteroids and anti-histamines).

  1. Acute asthma :

  • In the presence of bronchoconstriction, the respiratory exchange is greatly improved within few minutes after subcutaneous administration of Adrenaline (beta₂ action).



  1. Glaucoma :

  • Adrenaline solution may be used topically to reduce intraocular pressure in open angle glaucoma.

  • It reduces the production of aqueous humor by vasoconstriction of the ciliary body blood vessels and by enhanced outflow of aqueous humor.

  • In closed angle glaucoma mydriasis (including Adrenaline)are contraindicated .



  1. with Local anesthetics :

  • Local anesthetic solution usually contains 1:100,000 adrenaline.

  • The effect is to greatly increase the duration of local anesthesia by producing vasoconstriction at the site of injection, thereby allowing local anesthetic to persist at the site before being absorbed into the circulation and metabolized.

  • In addition, Adrenaline controls bleeding during surgery. (Vasoconstriction as in dental extraction).



  1. Epsitaxis: very weak solution of Adrenaline can also be used topically to vasoconstrict mucus membranes to control oozing of capillary blood.



  1. Cardiac arrest: Adrenaline is given by intracardiac injection.

Therapeutic uses of Isoprenaline:

  1. Complete heart block : (Stokes –Adman attack)

Isoprenaline can be absorbed systemically when given orally or sublingually . It is less deactivated by COMT & MAO.

  1. Beta blockers poisoning : Isoprenaline is used as an antidote.

  2. Acute asthma: Isoprenaline is now rarely used as bronchodilator because it's not selective and has side effects.

Pharmacokinetics:

Catecholamines have a t½ of 2 minutes (very short) because they are rapidly metabolized by MAO & COMT; therefore, they are given in continuous I.V. infusion.

Common adverse effects of catecholamines :

  1. CNS disturbances: anxiety, insomnia, headache and tremor.

  2. Cardiovascular disturbances: palpitation, cardiac arrhythmias, pulmonary edema, hypertension & sometimes cerebral hemorrhage.

  • Isoprenaline causes hypotension , Noradrenaline may cause tissue necrosis.

Contra indication of Adrenaline and Isoprenaline:

  1. Angina pectoris (due to increased O2 consumption).

  2. Cardiac arrhythmias.

  3. Thyrotoxicosis.

  4. With halogenated general anesthetics because they sensitize the heart to catecholamine.

  5. Patients taking tricyclic antidepressant TCA.

Dopamine:

It's the immediate metabolic precursor of Noradrenaline occurs naturally in the CNS in the basal ganglia as well as adrenal medulla.

  • Dopamine activates D₁ receptors in peripheral mesenteric and renal vascular beds, which leads to Vasodilation.

  • The activation of Presynaptic D₂ receptors on adrenergic neurons , which suppresses Nor. release, contributes to these effect (renal Vasodilation) .

  • A continuous I.V. infusion of dopamine 2-5 mg⁄kg⁄min causes increased renal blood flow, by activation of dopaminergic receptors (mainly D₁).

  • As the dose raises 5-15 mg⁄kg⁄min, dopamine activates beta receptors in the heart with tachycardia and increased contractility and cardiac output. It causes slight reduction in total peripheral resistance.

  • Higher doses more than 15 mg ⁄kg⁄min can cause vasoconstriction and hypertension by activating alpha receptors.

Therapeutic uses of dopamine:

  1. Shocks : dopamine is the drug of choice for shock (hypovolemic) because:

-it raises blood pressure by stimulating the heart (beta₁ action).

-it enhances perfusion of the kidney and splanchnic areas, enhances GFR and causes Na diuresis.

2. Congestive heart failure.

Adverse effects :

  1. tachycardia

  2. Angina worsening

  3. arrhythmia

  4. Vomiting (because of the stimulation of chemoreceptors triggers on in the area of postrima and pituitary gland outside blood brain barrier )

  5. Tissue necrosis (subcutaneous leakage)

Dobutamine : (works on heart more than vessels).

  • It's a synthetic direct acting catecholamine, that is the beta₁ receptors agonist.

  • It's available as racemic mixture.

  • It stimulates the heart with few vascular effects (beta₁ action).

  • The drug increases cardiac output with little tachycardia (side effect) and doesn't significantly elevate O₂ consumption of myocardium (i.e.: it has greater intropic than chronotropic effect on the heart).

Therapeutic uses of Dobutamine :

  1. Congestive heart failure.

  2. Shock: in patient with ischemic heart diseases (cardiogenic shock) because it doesn't elevate O₂ consumption by the heart..

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