Synthesis & Release of Neurotransmitters

Sympathetic Nervous System 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:- 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.

α1-

- V.C. of blood vessels in the skin & mucous membranes leading to in mean blood pressure.

2- Eye: 1 : mydriasis.In open-angle glucoma decrease production of

aqueous humor by vasoconstriction of the ciliary body blood vessels.

.

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: - 1) β2 : - Hyperglycemia

Release of glucagon - Lipolysis

- 2) 2: Decrease insulin release

- 3) β3Inhibit the production of leptin by adipose tissue

7- Uterine Smooth Muscle:

β2: Delay premature labour through relaxing uterine smooth muscles

8- Genitourinary systemα1 :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:- 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 obesityd) 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.) 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 contra-indicated in patients with decreased coronary perfusion.

Selective 1- Antagonists

Prazosin (short half-life) ,doxazocin& terazocin (long half life )allowing once-

daily dosing.

1–antagonists cause vasodilatation & fall in arterial pressure,

but less tachycardia than with non-

selective 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.

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

• 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.

- Reduce the frequency of anginal episodes.

- Improve exercise tolerance.

- Decrease cardiac work & oxygen demand.

- Reduce heart rate.

2) Ischemic heart disease:

In supraventricular & ventricular

arrhythmias. Sotalol has potassium channel blockade in addition to its –blockade

3) Cardiac arrhythmias:

- Chronic heart failure with metoprolol, & carvedilol ( myocardial remodeling & risk of sudden death).

4) Other cardiovascular disorders:

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.

5) Glaucoma:

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.

To diminish catecholamine action

which play an important part of the patho-

physiology of the disease.

6) Hyperthyroidism:

- Chronic migraine :blockade of catecholamine-induced vasodilation

-

7) Neurologic disease:

Adverse Effects & Toxicity of

- Adrenoceptors Antagonists

- Bronchoconstriction- -Arrhythmias- -Sexual impairment- -Hypoglycemia

- (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, nadololBlocks 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.