I
"Pharmacology
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.
2. 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.
3. Cardiac output :
 Adrenaline and Isoprenaline increase cardiac output .
 Noradrenaline has little or no effect on cardiac output (due to weak beta1
effect)
4. Myocardial oxygen consumption :
 Increase with all (least with Noradrenaline).
5. Conductivity :
 Increased by all and may cause arrhythmias.
6. 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).
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7. 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 .
8. Renal blood vessels :
The same of the skin.
9. 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).
10.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.
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11. 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.
12.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).
13.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.
14.Pregnancy uterus :
 Noradrenaline (alpha action ) causes contraction.
 Adrenaline and Isoprenaline (beta₂ action) causes relaxation.
15.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.
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16.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.
17.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.
18.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.
19.Release of mediators from mast cells :
 The release is inhibited by Adrenaline & Isoprenaline (beta₂ effect)
 Noradrenaline has no effect.
20.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.
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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 .
2- 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).
2) Acute asthma :
 In the presence of bronchoconstriction, the respiratory exchange is greatly
improved within few minutes after subcutaneous administration of
Adrenaline (beta₂ action).
3) Glaucoma :
 Adrenaline solution may be used topically to reduce intraocular pressure
in open angle glaucoma.
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 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 .
4) 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).
5) Epsitaxis: very weak solution of Adrenaline can also be used topically to
vasoconstrict mucus membranes to control oozing of capillary blood.
6) 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.
2. Beta blockers poisoning : Isoprenaline is used as an antidote.
3. Acute asthma: Isoprenaline is now rarely used as bronchodilator because it's
not selective and has side effects.
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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:
1234-
Angina pectoris (due to increased O2 consumption).
Cardiac arrhythmias.
Thyrotoxicosis.
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.
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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)
2)
3)
4)
tachycardia
Angina worsening
arrhythmia
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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