Transcript Noradrenergic Transmission

Synthesis & Release of
Neurotransmitters
Sympathetic Nervous System
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Origin
Transmitters
Receptors
Sympathomimetic drugs
Sympathetic Antagonists
Noradrenergic Transmission
Classification of Adrenoceptors:
-adrenoceptors : Subtypes ( 1 & 2 )
α1 causes vasoconstriction , mydriasis
α2 inhibit insulin & renin release
-adrenoceptors :
Subtypes ( 1 , 2 & 3 )
β1 increases all cardiac properties ,renin &
insulin release & lipolysis
β2 vasodilation, relax all non vascular
smooth muscles, increase liver & muscle
glycogenolysis
β3inhibit production of leptin
Classification of Adrenoceptor Agonists
A: Catecholamines:
epinephrine, norepinephrine, isoproterenol
& dopamine.
b) inactivation by COMT MAO enzymes
inactivate within other tissues as
in liver & gut wall.
c) Short duration of action.
d) Poor penetration into the C.N.S.
Classification of Adrenoceptor Agonists
B: Non Catecholamines:
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Lacking hydroxyl group.
Long half-life.
Given orally.
. Phenylephrine, ephedrine, amphetamine.
Penetrate better to C.N.S.
Classification According to
Mechanism of Action
1- Direct-acting Agonists:
e.g.: Epinephrine, norepinephrine,
isoproterenol, phenylephrine.
2- Indirect-acting Agonists:
Taken up into the presynaptic neuron &
cause the release of norepinephrine
e.g. amphetamine
3- Mixed-acting Agonists:
E.g.: Ephedrine
Pharmacological Actions of
Sympathomimetic Drugs
1- CVS:
1 (Heart): Positive inotropic
&chronotropic &C.O.
Increase oxygen demands on the
myocardium.
2 :
Vasodilation of sketal muscles blood vessels.
α 1- V.C. of blood vessels in the skin & mucous
membranes leading to  in mean blood
pressure.
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2- Eye:
1 :  mydriasis.
In open-angle glucoma decrease production of
aqueous humor by vasoconstriction of the ciliary
body blood vessels.
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3- Respiratory Tract:
2 : potent bronchodilator
1: causes vasoconstriction of blood vessels of
the upper respiratory tract
mucosa  decongestion.
4- GIT:
Relaxation of GIT S.M through 2 & 2–
5- Exocrine Glands:
Regulate secretion of amylase & water
from salivary gland,  sweat production
6- Metabolic:
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1) β2 :
Hyperglycemia
 Release of glucagon
- Lipolysis
- 2) 2: Decrease insulin release
- 3) β3Inhibit the production of leptin by
adipose tissue
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7- Uterine Smooth Muscle:
β2: Delay premature labour through
relaxing uterine smooth muscles
8- Genitourinary system
α1 :stimulate smooth muscle
proliferation in various tissues. E.g.:
prostate.
β1: stimulate renin secretion
α2 : inhibit renin secretion
9- SK.M.:
β2
Improve rate & force of contraction
used by sport-men to improve
performance
10- C.N.S.:
Indirect catecholamines have a marked
stimulant effect .
Specific Sympathomimetic Drugs
Direct Acting:
1- Epinephrine: prototype
Stimulates both 1&2 & 1&2
receptors.
Pharmacokinetics
- Rapid onset. - Short duration of action.
- Given: I.V, S.C, endotracheal tube,
inhalation, topically on eye.
- Excreted in urine.
Clinical uses
1- Bronchospasm.
2- Anaphylactic shock.
3- Acute asthma (S.C. ).
4- Glaucoma.
2% Topically to reduce I.O.P. in open-angle
glaucoma.
5- Cardiac arrest.
6- In anaesthesia with local anaesthetic:
a) Increase the duration of L.A. ( by V.C. at
the site of injection ).
b) Decrease the dose of L.A.
c) Decrease the side effects of L.A.
d) Control blood oozing of capillary blood
( Local haemostatic effect by V.C. ).
Adverse Effects:
1- C.N.S.: Anxiety, fear, tension, headache,
tremor.
2- Hemorrhage: Cerebral hemorrhage as a
result of  B.P.
3- Cardiac arrhythmias.
4- Hyperglycemia
2- Norepinephrine:
- Acts on all types of adrenergic
receptors but mainly on α drenoceptors.
- Increase peripheral resistance & both
systolic & diastolic B.P.
- Reflex bradycardia .
Clinical Uses:
I.V.I to treat shock
3- Isoproterenol ( Isoprenaline):
Stimulates both 1 & 2.
1-Used in atrioventricular block or cardiac arrest.
2- Acute attack of asthma
Adverse Effects:
As epinephrine.
4- Dopamine:
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Activates α &β adrenoceptors.
D1 & D2 dopaminergic receptors
vasodilation
Theraplutic Uses:
1- Shock (I.V.I.) increase B.P & improves
blood flow to viscera.
2- Acute heart failure
Adverse Effects:
Hypertension, arrhythmias, angina.
5- Dobutamine:
Selective 1–receptor agonist .
Uses: Acute heart failure
Adverse Effects:
6- Phenylephrine:
- Acts primarily on  mainly 1 receptors.
- V.C.   both systolic & diastolic B.P.
- Reflex bradycardia .
Topically as nasal decongestant ( produce
prolonged vasoconstriction ).
Adverse Effects:
Hypertensive headache, cardiac irregularities.
7- Clonidine:
Is an 2 agonist, used in essential
hypertension to lower BP ( action on
CNS ). Used to minimize the symptoms of
withdrawal from opiates or
benzodiazepines .
8- Metaproterenol:
- Is not a catecholamines.
- Not metabolized by COMT.
- Given: orally or by inhalation.
- Acts on β1 &β2 mainly on 2–receptors.
- Used to treat asthma & bronchospasm.
9- Terbutaline:
- Short acting 2 agonist.
- By inhalation to treat acute asthma.
- Produces less cardiac stimulation.
Indirect-Acting Adrenergic Agonists
1- Amphetamine:
- Acts on  &  receptors.
- Marked central stimulatory action .
a) Attention-deficit hyperactivity disorder of children.
b) Narcolepsy(alerting effect &improved attention).
c) Appetite control (suppressing effect) as in obesity
d) Contraindicated in pregnancy
Adverse effects : C.N.S. , Addiction.
2- Methamphetamine:
Has a higher CNS effect used as
anorexigenic.
3- Tyramine:
Found in fermented food as cheese.
With MAOI  serious vasopressor
Effects causing increasing in B.P.
Mixed-Acting Adrenergic Agonists
1- Ephedrine: ( a plant alkaloid )
Indirect & direct acting on  &  receptors.
- Similar to epinephrine but less potent.
- Not a catecholamine drug.
- Long duration.
- C.N.S. stimulant better than epinephrine.
- Absorbed well orally.
- Used as prophylactic in chronic asthma.
- Enhances skeletal muscle contractility &
improves motor function in myasthenia
gravis.
- Mild stimulation to CNS  alertness, 
fatigue, insomnia.
- Improves athletic performance.
- Nasal decongestant.
-  BP.
Ephedrine (cont.)
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Is useful in the treatment of stress
incontinence.
Pseudoephedrine(stereoisomer of ephedrine)
used orally for the relief of nasal congestion.
Less potent than ephedrine in producing
tachycardia, hypertension, C.N.S. stimulation.
Used in the treatment of stress incontinence.
Classification of
-receptor Antagonists
* non-selective e.g. phenoxybenzamine &
phentolamine.
* 1-selective antagonists e.g. prazosin/
terazosin, doxazosin.
* 2-selective antagonists e.g. yohimbine,
idazoxan.
Non-Selective - Adrenoceptor
Antagonists
Phenoxybenzamine:
Blocks both 1 and 2 irreversibly .
Blocks the action of histamine ,Ach &
5HT.
Long-acting (24hrs).
Phentolamine:
Produces a competitive blocking of 1 &
2 receptors.-short acting (few hrs).
Both drugs cause:
1) Postural hypotension.
2) Reflex tachycardia.
- Increase in C.O. & H.R. ( reflex response
to the fall in B.P, mediated through adrenoceptors, also due to block 2 in
heart ).
N.B.: The block of 2–adrenoceptors
increase in noradrenaline release which
make the drug unsuccessful in
maintaining lowered blood pressure.
Therapeutic Uses:
1- Pheochromocytoma.
2- Raynaud,s disease.
Adverse Effects:
- Phenoxybenzamine causes postural
hypotension, nasal stuffiness, nausea,
vomiting, impotence, tachycardia.
- Phentolamine: As phenoxybenzamine
but more to induce cardiac arrhythmias
and anginal pain. Both are contraindicated in patients with decreased
coronary perfusion.
Selective 1- Antagonists
Prazosin (short half-life) ,doxazocin&
terazocin (long half life )allowing oncedaily dosing.
1–antagonists cause vasodilatation &
fall in arterial pressure,
but less tachycardia than with nonselective  blockers.
Selective 1- Antagonists
2- relaxation of the smooth muscles of
the bladder neck & prostate capsule,
which may be useful in patients with
urinary retention due to prostate
hypertrophy. E.g. tamsulosin
Selective 2- Antagonists
Yohimbine is a natural alkaloid. Idazoxan is a
synthetic drug.
Inhibit insulin secretion, used in the treatment of
diabetes .
in the treatment of peripheral vascular diseases.
Adverse Effects of 1 &α2 Blockers:
Dizziness, lack of energy, nasal
congestion, headache, drowsiness,
postural hypotension. Impotence or
sexual dysfunction .
- Adrenoceptors
Antagonists Drugs
Classification:
a) Non selective: e.g. propranolol,
carvedilol, labetalol, sotalol, timolol.
b) Selective(1): Atenolol, bisoprolol,
esmolol, metoprolol
Pharmacokinetis of –blockers:
a) Absorption:
Most of them are well absorbed
orally.
c) Distribution :
They are rapidly distributed,
propranolol cross readily BBB. Most
of them have half-life from 3-10hrs
except esmolol (10min.)
Most of them metabolized in liver &
excreted in urine.
Pharmacodynimcs of –Adrenoceptors
Antagonists :
* Blocking the β-receptors.
• Local anaesthetics
• Partial agonist action
Pharmacological Actions:
CVS: Negative inotropic & chronotropic effects.
•  BP .
* Respiratory tract: Blockade of 2 
bronchoconstriction.
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* Eye: Reduce intraocular pressure
(In open-angle glaucoma) due to 
aqueous humor production from the
ciliary epithelium e.g. timolol.
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Metabolic & endocrine effects:
- Inhibit lipolysis , glycogenolysis & decrease
glucagon secretion.
- Increased Na+ retention.
* Effects not related to beta blockade:
- Partial -agonist activity.
- Local anaesthetic action ( blockade on
sodium channels).
Clinical Uses of –receptor Blocking
Drugs:
1) Hypertension:
Labetalol a competitive , antagonsits
is effective in hypertension.
-blockers are less effective in blacks &
the elderly.
2) Ischemic heart disease:
- Reduce the frequency of anginal episodes.
- Improve exercise tolerance.
- Decrease cardiac work & oxygen
demand.
- Reduce heart rate.
3) Cardiac arrhythmias:
In supraventricular & ventricular
arrhythmias. Sotalol has potassium
channel blockade in addition to its –
blockade
4) Other cardiovascular disorders:
- Chronic heart failure with metoprolol,
& carvedilol ( myocardial remodeling
&  risk of sudden death).
5) Glaucoma:
 I.O.P.
Through  the production of aqueous
humor by the cliliary body, which is
activated by cAMP.
Timolol & related -antagonists are
suitable for local use in the eye because
they lack local anaesthetic properties.
Systemic timolol may be absorbed from
the eye to cause serious adverse effects
on the heart & airways.
Topical timolol may interact with orally
administered verapamil & increase the
risk of heart block.
6) Hyperthyroidism:
To diminish catecholamine action
which play an important part of the pathophysiology of the disease.
7) Neurologic disease:
- Chronic migraine :blockade of
catecholamine-induced vasodilation
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Adverse Effects & Toxicity of
- Adrenoceptors Antagonists
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Bronchoconstriction
-Arrhythmias
-Sexual impairment
-Hypoglycemia
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(Cardioselective β blockers are
preferred in insulin –dependent
asthmatics.).
Choice of –adrenoceptor antagonists:
1- Pindolol & acebutolol.
with partial agonist activity.
[ Intrinsic sympathominetic activity ISA ].
- They have the ability to stimulate
1 & 2 receptors.
- They are effective in hypertensive
patients with moderate bradycardia.
- Carbohydrate metabolism is less
affected , making them valuable in
treatment of diabetics.
2- Labetalol & carvedilol.
Antagonists of both  &  adrenoceptor
blockers.
Are reversible -blockers with concurrent
1-blockers that cause peripheral
vasodilatation  B.P effective for
treatment of hypertension in patients with
increased peripheral vascular resistance.
They do not alter serum lipid or blood
glucose levels.
Used in the treatment of heart failure
Labetalol may by used as an alternative
to hydralazine in the treatment of
pregnancy-induced hypertension.
Treatment of hypertensive emergencies as it is
rapidly lowering B.P.
Adverse Effect:
Orthostatic hypotension & dizziness are
associated with 1-blockade.
Nonselective β Antagonists
Timolol ,Propranolol, nadolol
Blocks both β1 & β2 receptors.
Timolol & Pindolol are more
potent than propranolol.
Nadolol has a very long duration
of action.
Selective β1 Antagonists
Acebutolol, Atenolol, Metoprolol,
Esmolol
They have little effect on
pulmonary function ,peripheral
resistance ,& carbohydrate
metabolism.
Esmolol has a very short duration
of action and given only I.V.
Therapeutic uses
They are useful in hypertensive
patients with impaired pulmonary
function.
Also, are effective in diabetic
hypertensive patients .
Drugs Affecting Neurotransmitter
Release or Uptake
1- Reserpine:
Depletion of norepinephrine levels in the
adrenergic neurons.
Hypertensive patients show a
gradual decline in B.P & H-R.
Reserpine has a slow onset & long
duration of action.
2- Guanethidine:
Blocks the release of stored
norepinephrine. This lead to gradual
Drop in B.P & H-R.
Used in the treatment of hypertension.
Guanethidine causes orthostatic
hypotension & male sexual dysfunction.
3- Cocaine:
Has a local anaesthetic action by
blocking sodium channels across the
cell membrane of the adrenergic
neuron.
Norepinephrine accumulates in the
synaptic space resulting in the
potentiation of the actions of
Sympathomimetics. Cocaine is a C.N.S
stimulant drug.