Pharmacology of Autonomic System 2

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بسم الله نبدأ..

The Noradrenergic Junction

*Notes about picture :

-This picture like to Cholinergic Junction in Parasympathetic System

*Neurotransmitter is norepinephrine

*norepinephrine start from tyrosine

*Tyrosine is converted to dopa and then to dopamine which is then

transported into the vesicle by the vesicular monoamine transporter

(VMAT), which can be blocked by reserpine.

*Dopamine is converted to NE in the vesicle

1) tyrosine dopa (Who controls this transformation is tyrosine

hydroxylase)

2) dopa dopamine

3) dopamine norepinephrine ( بالحويصلة)

4) secrete norepinephrine (exocytosis)

5) action on receptors

6) go to circulation or go back to the cell by norepinephrine transporter

(NET)

*cocaine , tricyclic anti depressant (prevent back of norepinephrine to

the cell )

*reserpine (help to leave norepinephrine from vesicles)

*metyrosine compete with tyrosine hydroxylase to convert tyrosine to

dopa

*bretylium guanethedine prevent exocytosis of norepinephrine

*Tyrosine is transported into the noradrenergic ending or varicosity.

*Life Cycle of Noradrenaline -Physiologic release of transmitter occurs when an action potential opens voltage-sensitive calcium channels and increases intracellular calcium. Fusion of vesicles with the surface membrane results in expulsion of norepinephrine. -elease can be blocked by drugs. -Norepinephrine diffuses out of the cleft or is transported back into the cytoplasm of the terminal by the norepinephrine transporter (NET), which can be blocked by cocaine and tricyclic antidepressants, or into postjunctional or perijunctional cells. -Regulatory receptors are present on the presynaptic terminal.

*Sympathomimetic Drugs or adrenergic agonists:

-These are the drugs which are given to mimic the actions of the

sympathetic nervous system.

-They are given in high concentrations relative to the endogenously, and

locally released, released neurotransmitters after sympathetic nerve

endings.

-Normally : the body secreat acetulcholine in parasympathetic and

norepinephrine in sympathetic in amount and location that necessary to

stimulate receptors then stimulate the cell to performe tasks

-But when give a drug by GI the drug mixed with gastric content then go

to liver and circulation (the travel to the target organ is long )

*types :

1-Directly Acting : directly on the receptors

2-Indirectly Acting: enhance the release of norepinephrine

*indirect action of cholorengic differ than indirect in Noradrenergic

Organophosphate : action indirectly , inhibit breakdown of acetylcholine

But In the Noradrenergic act to enhance the release of norepinephrine

*type of receptors :

1- alpha

2- beta

*each subtype agonist and antagonist ,effect,relation with gene

,mode of action

Ex:alpha1B controlled by chromosome C8

.. غيركاتعب هالكم سنة عشان تقدر تنقذ

**Directly Acting Drugs:

-These work directly on the adrenergic receptors.

1-Norepinephrine or Noradrenaline

Is neurotransmitter synthesize in peripheral nerve ending

2-Epinephrine or Adrenaline

-Metabolite from norepinephrine

-Ex :adrenal gland secret epinephrine more than norepinephrine

(80%epinephrine ,20%norepinephrine )

-Adrenal gland is one of endocrine system but considered sympathetic

ganglia consist of preganglionic fiber but not post ganglionic fiber

-When stress come suddenly the sympathetic work but the adrenal

gland secreat high amount of epinephrine and norepinephrine

3-Isoprenaline

4-Dopamine

5-Salbutamole

**Indirectly Acting:

-These work to release NE.(norepinephrine , don’t work on receptors )

1-Cocaine.

2-Amphetamine

3-Ephedrine

..نبلش بالشرح عن كل نوع

**Directly Acting:

1)Norepinephrine or Noradrenalin:

-Natural product which is mainly α receptor agonist, so causes

vasoconstriction.

-Uses ( acetylcholine not used )

-Given only IV.

-Raises both systolic and diastolic pressure.

-Was widely used in shock but caused limb gangrene because sever

vasoconstriction, and so, was replaced by dopamine(dopamine is useful

than norepinephrine to treat shock )

2-Epinephrine or Adrenaline:

-Has mixed α and β agonistic activities.

-Given IM, SC, also intracardiac.

-Increases force and rate of contraction of the heart.

-Raises systolic blood pressure.

-Bronchodilator.

-Increases blood sugar.

-Used in anaphylactic shock because large amount

of histamine that lead to bronchoconstriction and

vasodilation, epinephrine action opposite to these

effect of histamine (physical antagonist)

- and as a last resort in cardiac arrest .

3-Isoprenaline:

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اروي الحياة سعادة وتفاؤلا ...

-Pure β1 and β2 agonist.

-Has little effects on BP

-Can cause cardiac arrhythmias.

-Was used in bronchial asthma, but cardio toxic because this another

drug is safer than Isoprenaline

4-Salbutamol:

-Selective β2 agonist. (if increase the dose ,selectivity decrease β2

receptors and work on β1 receptors)

-Powerful bronchodilator.

-Can inhibit uterine muscle.

-Given orally, IV, inhalation.

-Very useful to treat bronchial asthma , to delay labor

In high doses can cause tremor and tachycardia

5-Dopamine: -Has mixed α , β, and dopamine receptor (DA) agonistic activities.

ح اله علاقة بالفر ■ -DA receptors are present in the renal vessels and cause vasodilation. When stimulate dopamine receptors in the kidney cause vasodilation and increase activity of kidney -Vasoconstriction elsewhere. working in alpha receptors -Increases BP. -Stimulates the heart. -If give in high dose , work on beta receptors but when high more stimulate alpha receptors

Very useful in shock

-Dopamine:Widely used in cardiogenic shock.

-The first organ affect from cardiogenic shock is kidney

-If cardiac output reduce , the kidney suffers

Low doses: stimulates DA1 receptors leading to renal vasodilation

and improved renal function, so used to prevent renal failure.

Intermediate doses: works on β1 receptors leading to positive

inotropic actions.increase contractility and heart rate

High doses: stimulates α receptors leading to vasoconstriction and elevation of blood pressure.

Can cause arrhythmias and ischemic changes.

*Indirectly Acting:

1-Cocaine.:natural product

2-Amphetamine : similar to cocaine in function but not in structure

3-Ephedrine.

-These are lipophilic compounds, so can cross the BBB causing mainly CNS effects:

-Advantages :Euphoria, abolish fatigue, increase activity, and reduce appetite.

-Disadvantage :Carry the risk of dependence.

-Use limited to narcolepsy(irresistible attack of sleep ) and hyperactive children.( التعلم ,الحفظ قليل بالحقيقة هو خمول وكسل,لا يستطيع )

-Were used for appetite suppression.(not efficient because is toxic )

Bronchial Asthma

*Is a chronic relapsing disease characterized by wheezing due to

bronchospasm, infection, and excessive mucus production.

*Caused by antigen -antibody interaction which causes the release of

inflammatory mediators, mainly histamine.

*Precipitated by cold exposure, exercise, infection, stress, dust,

etc… شعر الحيوانات , الابخرة , صعود ناطحات السحاب , ادوية , دخان

*Treatment :

1-Bronchdilators. Ex:sympathomymatics

2-Corticosteroids.: to prevent allergy

3-Mast cell stabilizers.: prevent break down of mast cell(break down of

mast cell lead to release histamine )

4-Leukotriene Modifiers.: تعزز استجابة الجسم للعوامل الحساسية

5-Antimicrobials.: to treat infection

6-Hydration, expectorants and mucolytic drugs : تليين الافرازات لاخراجها

*drug enhance bronchoconstriction: acetylcholine , adenosine

*drug interrupt bronchoconstriction: muscarinic antagonists , theophylline

* theophylline inhibit AMP cyclic by inhibit PDE

1-Bronchdilators.

-Β2 agonists: e.g. Salbutamol, Terbutaline

-Methylxanthines; e.g. Aminophylline and

Theophylline.

2-Ipratropium Bromide

-Anticolengic drug

a-Β2 agonists: e.g. Salbutamol, Terbutaline

-Used just before, or during the attack, or regularly.

-Can be given by inhalation, IV, or orally.

-In high doses Can cause tremor and tachycardia

b-Methylxanthines; e.g. Aminophylline and Theophylline: موجودة بالقهوة

-Inhibit Phosphodiesterase enzyme which breaks down cAMP.

-Toxic: so blood levels should be monitored. Narrow therapeutic window

-Given slowly IV, or orally, and rectally.

-Can cause nausea, anxiety, tachycardia, arrhythmias, and convulsions.

-Interactions are very common.

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c-Ipratropium Bromide:

-Atropine-like drug which is given by inhalation.

-Localized action, no systemic side effects

Adrenergic blockers :

a) α-adrenergic blockers: 1)alpha 1 receptors : in vessels 2)alpha 2 receptors

-Block the sympathetic effects on α -adrenergic receptors.

-Used in hypertension and bladder neck obstruction (benign prostatic hypertrophy). a-Prazosin.: treat hypertension b-Terazosin. c-Doxazocin (Cardura) :widely use to treat prostatic problems

b) β-adrenergic blockers: 1)beta 1 receptors : in heart 2)beta 2 receptors : in bronculs

-Block the sympathetic effects on β -adrenergic receptors. If increase the dose , block the alpha receptors

-Differ in their Selectivity and Pharmacokinetics -Have wide applications in medicine. Because different selectivity ” a)Nonselective β-Blockers:

-Block both β1

and β2 receptors.

-Propranolol: prototype. IV , go to brain, اول دواء

-Nadolol

-Sotalol.

*block of beta 1 lead to bronchoconstriction

b)Selective β-Blockers:

-Block β1

more than β2 receptors.

*treat cardio vascular disease

1-Metoprolol

2-Atenolol

3-Bisoprolol

c)Combined α and β-Blockers:

-treat hypertension

1-Labetalol

2-Carvedilol

**β-adrenergic Blockers

*Actions:

1-Prevent the actions of the sympathetic system on beta receptors, i.e.

more active when the system is overactive(in adolescence )

-In adult : lead to heart failure

2-Reduce heart’s: rate, contractility, and excitability, and consequently

reduce cardiac output.

3-Reduce BP.

4-Bronchoconstriction.

5-Prevent glycogenolysis (the rise in blood sugar). Because breakdown

of glycogen

6-Mask the symptoms of hypoglycemia.in DM

CNS: sedation, dreams, hallucinations, depression

*Clinical Uses:

1-Ischemic heart disease.

2-Hypertension.

3-Cardiac arrhythmias.

4-Thyrotoxicosis.; increase synthesis of beta receptors

5-Essential tremor.

6-Migraine.

7-Anxiety: actually only block the sympathetic symptoms of anxiety. So

very effective in Stage-Fright. الخوف من الظهور امام الجمهور

*Adverse Effects:

1-Cardiac suppression( rate and contractility),

possibility of heart failure with high doses.

2-Bronchospasm or bronchial asthma.

3-CNS effects بسبب دخول بعضها للدماغ: fatigue, bad dreams, depression,

sexual impairment.

4-Cold extremities, due to unmasking of α receptors.

Mask the symptoms of hypoglycemia which might lead to more

hypoglycemia and coma

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