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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 lpha 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. ( action).
7. Skin blood vessels:
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Noradrenaline & Adrenaline constrict skin and mucus


membrane arterioles (lpha 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 and 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 + 13
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 ( effect).
Noradrenaline has no effect. (Because there are no
lpha receptors in the bronchiolar smooth muscles).
13.
Gastrointestinal Tract:
Noradrenaline (lpha action) , Adrenaline (alpha and
beta action) and Isoprenaline (eta action) cause
relaxation .
Important Note: it's the only site where alpha and beta act
on the same direction.
14.
Pregnancy uterus :
Noradrenaline (alpha action ) causes contraction.
Adrenaline and Isoprenaline (beta action) causes
relaxation.
15.
Radial muscles of the iris :
Adrenaline (alpha 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 (beta effect)
and
- increases the release of glucagon (beta effect) and
- Decreases the insulin (alpha effect on Beta cells of
Pancreas).
Iso. cause increase in blood suger ( effect).
Nor. may increase blood suger.
17.
Lipolysis:
Adrenaline initiates Lipolysis (through its agonist
activity on BETA 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 beta agonists.
However Noradreanline may cause hyperkalemia
through alpha effect.
19.
Release of mediators from mast cells :
The release is inhibited by Adrenaline & Isoprenaline
(beta effect)
Noradrenaline has no effect.
20.
Muscle tremor :
Adrenaline & Isoprenaline cause muscle tremor (beta
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 mgmin .
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 ) 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
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subcutaneous administration of Adrenaline (beta


action).

3) 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 .

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)

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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.

Pharmacokinetics:
Catecholamines have a t 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:
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It's the immediate metabolic precursor of Noradrenaline


occurs naturally in the CNS in the basal ganglia as well as
adrenal medulla.

Dopamine activates D receptors in peripheral


mesenteric and renal vascular beds, which leads to
Vasodilation.
The activation of Presynaptic D receptors on adrenergic
neurons , which suppresses Nor. release, contributes to
these effect (renal Vasodilation) .
A continuous I.V. infusion of dopamine 2-5 mgkgmin
causes increased renal blood flow, by activation of
dopaminergic receptors (mainly D).
As the dose raises 5-15 mgkgmin, 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 kgmin 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 (beta
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)
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Dobutamine : (works on heart more than vessels).


It's a synthetic direct acting catecholamine, that is
the beta receptors agonist.
It's available as racemic mixture.
It stimulates the heart with few vascular effects
(beta action).
The drug increases cardiac output with little
tachycardia (side effect) and doesn't significantly
elevate O 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 O
consumption by the heart..

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