Noradrenergic transmission

S A Z A N J . A L I

M S . C S T U D E N T / M E D I C I N A L C H E M I S T R Y D E P A R T M E N T

NORADRENERGIC TRANSMISSION

NORADRENERGIC TRANSMISSION

-receptors

1 (causes

vasoconstriction,

mydriasis)

2 (inhibit insulin &renin release)

-receptors

1 (increases all cardiac properties ,renin & insulin release & lipolysis)

2 (vasodilation, relax all non vascular

smooth muscles, increase liver & muscle

glycogenolysis)

3 (inhibit production of leptin)Leptin is a protein produced and secreted by adipose tissue & has a role in regulation of eating

CLASSIFICATION OF ADRENOCEPTOR AGONISTS

.Epinephrine

.Norepinephrine

.Isoprotrenol

.Dopamine

catecholamines

.Phenylephrine

.Ephedrine

.Amphetamine

Non catecholamines

• inactivation by COMT, MAO enzymes inactivate within other tissues as in liver & gut wall.

• Short duration of action.

• Poor penetration into the C.N.S.

• Lacking hydroxyl group.

• Long half life.

• Given orally.

• Penetrate better to C.N.S.

CLASSIFICATION ACCORDING MECHANISM OF ACTION

1//Direct -acting agonists

Ex//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

Ex//Ephedrine

PHARMACOLOGICAL ACTION OF SYMPATHOMIMETIC DRUGS

CVS effect

1 in the heart: positive inotropic and chronotropic,increase cardiac out put and increase oxygen demands on myocardium.

2 in smooth muscle : dilate smooth muscle of blood vessels.

1 in the vascular smooth muscle : Vaso constriction of blood vessels in the skin & mucous membranes leading to in mean blood pressure

Effect on Eye1 : mydriasis.

In open-angle glaucoma decrease production of aqueous

humor by vasoconstriction of the ciliary body blood vessels.

Effects on respiratory tract

2 : potent bronchodilator

1: causes vasoconstriction of blood vessels of the upper respiratory tract

mucosa causes decongestion.

GIT :

Relaxation of GIT S.M through 2 & 2

PHARMACOLOGICAL ACTION CONT…

Metabolic effect

2:

• glycogenolysis (hyperglycemia).

• Lipolysis .

2:

• Decrease insulin release.

3 :

• Inhibit the production of leptin by adipose tissue

CONT….

Other effects

• 2 : Delay premature laboure through

relaxing uterine smooth muscles.

o α1 : stimulate smooth muscle proliferation in

various tissues. E.g.: prostate.

o 1 : stimulate renin secretion.

o α2 : inhibit renin secretion.

Clinical uses of adrenoceptore agonists

• Cardiovascular system :

-cardiac arrest: Adrenalin

-cardiogenic shock: Dobutamine (beta1-

agonist)

• Anaphylaxis : Adrenalin

• Respiratory system:

-asthma(selective 2 –receptor agonists)

salbutamol, terbutaline ,salmetrol, formoterol

- nasal decongestion: drops containing

xylometazolin ,ephedrin for short term use.

• Miscellaneous indication :

-adrenalin prolong the duration of local

anesthetics.

• Premature labour : salbutamol

- 2 agonists : (clonidine) to lower blood

pressure and to reduce frequency of migraine

attacks.

ALPHA-RECEPTOR ANTAGONISTS

• Phenoxybenzamin and phentolamine

Non selective

• Prazosin , terazosin , doxazosin

1 - selective antagonists:

•Yohimbine , idazoxan

2 –selective antagonists

-adrenoceptor antagonists

• phenoxybenzamine : Blocks both 1 and 2

irreversibly . Blocks the action of histamine ,Ach

& 5HT. Long-acting (24hrs).

• Pentolamine : 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 ).

• Prazosin (short half-life) ,doxazosin & terazosin

(long half life ) allowing once-daily dosing.

• 1–antagonists cause vasodilatation & fall in

arterial pressure, but less tachycardia than with

non-selective blockers.

• tamsulosin : is a selective 1A antagonist

,useful in patients with urinary retention due to

prostate hypertrophy.

• Yohimbin: selective 2 antagonist , its not used

clinically.

Phenoxybenzamine

used in case

pheochromocytoma

in preparation for

surgery.

BETA-ADRENOCEPTOR ANTAGONISTS

Non selective

•Propranolol , l, Labetalol ,Sotalol .

•Carvedilo)also act as alpha blocker)

Selective 1

•Atenolol , Bisoprolol ,Esmolol , Metoprolol

PHARMACOLOGICAL ACTION

• CVS :Negative inotropic and chronotropic effects.

Lowering blood pressure.

• Respiratory tract:bronchoconstriction

• Eye :Reduce intraocular pressure (In open-angle glaucoma) due to decresing aqueous humor production from the ciliary epithelium e.g. timolol.

• Metabolic and effects on endocrine secretion :

• Inhibit lipolysis , glycogenolysis & decrease glucagon secretion.

• Increased Na+ retention.

• Labetalol a competitive ,antagonsits is

effective in hypertension. -blockers are less

effective in blacks & the elderly.

• IHD

• Reduce the frequency of anginal episodes.

Improve exercise tolerance. Decrease

cardiac work & oxyge demand. Reduce

heart rate.

• In supraventricular & ventricular arrhythmias.

Sotalol has potassium channel blockade in

addition to its –blockade .

• Chronic heart failure with metoprolol, &

carvedilol ( myocardial remodeling & risk of

sudden death).

• Decrease intra ocular presure through

decreasing the production of aqueous

humor. Timolol & related -antagonists are

suitable for local use in the eye .

• Blockade of catecholamine-induced

vasodilation propranolol as a prophylactic

agent used for migraine.

• Hypertension

• Ischemic heart

disease

• Arrhythmia

• Glaucoma

• Hyperthyroidism

• Neurological

disease

C L I N I C A L U S E S

CHOICE OF -ADRENOCEPTORANTAGONISTS

• Pindolol & acebutolol (Intrinsic sympathominetic activity )

• They are effective in hypertensive patients with moderate

bradycardia.

• Carbohydrate metabolism is less affected , making them valuable in treatment of diabetics

• Labetalol & carvedilol (,-blocker)

• Are reversible -blockers with concurrent 1-blockers that

cause peripheral vasodilatation decrease B.P, effective for

treatment of hypertension in patients with increased

peripheral vascular resistance.

DRUGS AFFECTING NEUROTRANSMITTER

RELEASE/UPTAKE

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.

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.

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.