PHARMACOLOGY OF SYMPATHETIC NERVOUS SYSTEM

PHARMACOLOGY OF SYMPATHETIC NERVOUS

SYSTEM

Sympathomimetics

2

Catecholamines compounds with different pharmacodynamic effects, but have a

common structure group "catechol” (ortho-diphenols)

OH

CH NH

OH

HO CH 2 CH 3

ADRENALINA

HO

"catecol"

OH

OH

CH NH

OH

HO CH 2 2

NORADRENALINA

CH NH

OH

HO CH 2 22

DOPAMINA

3

4

5

Catecholamines Adrenaline (epinephrine)

is released from the adrenal medulla and other chromaffin tissues.

equally stimulates receptors 12 şi 123

Noradrenaline (norepinephrine) is released from postganglionic sympathetic fibers,

neurons of the CNS and adrenal medulla. stimulates receptors 12 and 12

Dopamine is released from peripheral autonomic endings and CNS

neurons stimulate receptors D1= D2 D3D4D5

In the body, the synthesis of catecholamines from tyrosine and phenylalanine starts and stops

depending on physiological needs at one of the three stages of training.

HO

NH2

CO2H

L-Tyrosine

Tyrosine

hydroxylase HO

NH2

CO2H

Levodopa

HO

HO

NH2

Dopamine

HODopa

Decarboxylase

Dopamine

-hydroxylase

HO

HO

NH2

OH

Norepinephrine(Noradrenaline)

HO

HO

NHMe

OH

Epinephrine(Adrenaline)

N-methyl transferase

(in Adrenal medulla)

Biosynthesis of adrenaline and noradrenaline

7

Adrenergics Receptors

8

Adrenergics Receptors

Catecholamine receptors are located on the surface of cell membranes and coupled to specific G protein (Gs and Gi).

Catecholamines exist in a polarized form, which allows the coupling of receptors and explains the very difficult crossing the blood-brain barrier.

9

SETTING adrenergic receptor presynaptic setting - 2, 1, D2

receptors 2 inhibits release of noradrenaline peripheral sympathetic activity is inhibited

receptors 1 stimulates the release of noradrenaline peripheral sympathetic activity is stimulated

receptors D2 inhibits release of noradrenaline postsynaptic setting

sequestration in the membrane receptor decreased receptor synthesis ("down

regulation") phosphorylation and thus inactivation of

receptor

10

NORADRENALINEPost receptor signal transmision

1.

EFFECTS OF CATECHOLAMINES NORADRENALINE (NA)

dominant action on the cardio-vascular ↑ adrenergic receptor affinity on α şi β1 + β3 (↓β2 )

ADRENALINE (A)

dominant action on smooth muscle and metabolism

adrenergic receptor affinity ↑ on α şi β1 + β2 (↓β3)

DOPAMINE dominant action on the cardio-vascular : inotrop+

and ↓TPR receptors types : DA1(excitators) and DA2 (inhibitors)

EFFECTS OF SYMPATHETIC STIMULATION

Pupillary diameter increased(mydriasis )

Heart rate increased (tachycardia orpositive chronotrop effect)

Myocardial contractility increased(positive inotrop effect )

Bronchial smooth muscle relaxation

Salivary secretion increased (increases viscosity of secretion)

Sweat secretion increased

Gastro-intestinal motility decreased

Gastro-intestinal secretion decreasedDefecation ?

Skeletal muscle tone no effect

Urination decreasedUrinary frequency decreasedBladder tone decreased

EFFECTS OF SYMPATHETIC STIMULATION

14

PHARMACODYNAMICS OF CATECHOLAMINESeye

2 – ciliary relaxation2 – mydriasis use of adrenaline in glaucoma (promote

drainage of aqueous humor) – eye drops

heart 1 – inotrop +1 – inotrop +, increases syno-atriale, A-V, Hiss

fasc, Purkinje fibr driving

15

PHARMACODYNAMICS OF CATECHOLAMINES vessels

ADRENALINE small and medium doses - vasodilation and decreased BP,

reflex tachycardia (vascular 2 receptors stimulation - the most sensitive)

high doses of adrenaline - vasoconstriction – increase systolic and diastolic BP, reflex bradycardia (1 a vascular

receptor stimulation)

NORADRENALINE At all doses - vasoconstriction - increases blood pressure,

increased peripheral vascular resistance, reflex bradycardia

16

PHARMACODYNAMICS OF CATECHOLAMINES vessels

DOPAMINE vasodilation in the territory of the kidneys, bowel,

decreased peripheral resistance strong positive inotropic effect, increasing cardiac

output remain unchanged BP and peripheral pulse

Dopamine is the only catecholamine that may be indicated in cardiogenic shock!!!

Adrenaline and noradrenaline are contraindicated in cardiogenic shock în şocul cardiogen because they produce vasoconstriction in the mesenteric and renal vessels, increasing organs ischemia

17

PHARMACODYNAMICS OF CATECHOLAMINES

coronaro-dilatation (1, 1, 2, D1, D2) vasoconstriction in visceral vessels except

for liver and lung vessels that causes vasodilation effect

Decrease capillary and post-capillary permeability (increased by pathological factors, type I allergy) - anaphylactic shock

Anaphylactic shock is the only form of shock is indicated A and NA!

18

PHARMACODYNAMICS OF CATECHOLAMINES Bronchial smooth muscle – bronhodilation (2) Gastro-intestinal smooth muscle - relaxation (2

and 2) Gastro-intestinal sphincters - contraction (1) inhibarea plexurilor mezenterice ()

Secretion is not influenced by SNV gastrointestinal sympathetic.

Genito-urinary smooth muscle Bladder smooth muscle - relaxetion (2), bladder sphincter - contraction (1) uterine muscles - relaxation during pregnancy (2) and

contraction in labor (1)

stimulation ejaculation (1)

19


Metabolic effects

Hyperglycemia (physiological doses) 2 stimulation– increase glycogenolysis and inhibit

glycogen synthesis 1, 2 stimulation– stimulates glyconeogenesis,

decreases the glucose prelevation from periphery 2 stimulation– inhibit insulin secretion by the

endocrine pancreas

Metabolic acidosis (supraphysiological doses) stimulation 2 – up-take of potassium into cells

causes the decrease in extracellular potassium (this is a protective effect during stress increases the serum potassium can be dangerous)

20

PHARMACODYNAMICS OF CATECHOLAMINESMetabolic effects

hyperlipidemia 1 and 3 stimulation ( 2 receptors inhibit

lipolysis)

renal release of renin 1 presynaptic activation - stimulates synthesys

(2 presynaptic stimulation - inhibition of renin release)

increase basal metabolism (20-30%) noradrenaline has a role in defending the body

against cold increase cardiac oxygen consumption

21


exocrine glands– inhibits salivary and pancreatic exocrine water secretion (2)

endocrine glands – increases synthesis of melatonin by pineal gland (1)

increases release of prostaglandins platelet agregation - (2 A)

22

FARMACOCINETICA CATECOLAMINELOR

rapidly inactivated in the digestive tract and liver (oral adm.)

form stable salts with acids - may be given by injection. Metabolism is made by specific enzymes

COMT (catechol ortho-methyltransferase) - liver and intestine

MAO (monoamine oxidase) - liver and kidneyexogenous catecholamines and that released from

adrenal medulla are inactivated first by COMT and then by MAO.

Catecolaminlele from nervous tissue are inactivated first by intraneuronaly MAO and than by extraneuronal COMT

Noradrenaline is re-up-taked in most of the nerve endings that released her.

Elimination of active metabolites of catecholamines are excreted in the urine

23

CLASIFICATION OF SYMPATHOMIMETICS

şi Sympathomimetics direct

AdrenalineNoradrenalineDopamineIbopamine

indirect (Noradrenaline release) and directEfedrine

24

CLASIFICATION OF SYMPATHOMIMETICS Sympathomimetics

systemic administrationEtilephrinePhenilephrineMetoxamineMidodrineMetaraminol -metil-Noradrenaline

local administration (topic)NaphazolineOximetazolineTetrizolineXylometazoline

25


Sympathomimetics non-selective 1 and 2

Sympathomimetics Isoprenaline (Isoproterenol) Orciprenaline Bufenine Bametan Etil-Noradrenaline

26

CLASIFICATION OF SYMPATHOMIMETICS 2 selective Sympathomimetics

Salbutamol Fenoterol Terbutaline Salbutamol Clenbuterol Pirbuterol Procaterol Bambuterol Isoxuprine Isoetarine

1 selective Sympathomimetics Dobutamine Prenalterol

27


Catecholamines releasers (other than ephedrine, phenylephrine, naphazoline)

Amfetamine Hidroxiamfetamine Fenmetrazine Pemolin Metilfenidat Fenilpropanolamine

special Sympathomimetics Cocaine Tyramine

28

THERAPEUTIC USE OF SYMPATHOMIMETICS

Adrenaline (1 = 2, 1 = 2 =3 agonist)

Clinical uses: diffuse bleeding from mucous membranes and

skin surface (1/50000-1/10000) is associated as a vasoconstrictor to local

anesthetic bronchial asthma with mucosa edema (0.3 -0.8 mg

sc) glaucoma (1-2% ophthalmic solution) intracardiac administration as an alternative

therapy in the cardiac arrest (the first alternative is isoproterenol)

Type I allergies (including anaphylactic shock)

29

THERAPEUTIC USE OF SYMPATHOMIMETICSAdrenaline (1 = 2, 1 = 2 =3 agonist)

Side effects: Pallor Anxiety Palpitations at higher doses arrhythmia, ventricular

fibrillation, hypertension, acute pulmonary edema

30

THERAPEUTIC USE OF SYMPATHOMIMETICS Adrenaline (1 = 2, 1 = 2 =3 agonist)

Contraindication: HTA angina pectoris Tachyarrhythmias not associated with local anesthetics in anesthesia

extremities (nose, ears, penis, fingers) - ischemic necrosis

preparations is not associated with calcium - contributes tachyarrhythmias

31

THERAPEUTIC USE OF SYMPATHOMIMETICSNoradrenaline (1 = 2, 1 2 agonist )

Clinical use:

diffuse bleeding from mucous membranes and skin surface (1/500.000 - 1/10.000)

is associated as a vasoconstrictor to local anesthetic

Side effects:

Pallor Anxiety Palpitations at higher doses arrhythmia, ventricular

fibrillation, hypertension, acute pulmonary edema

32

THERAPEUTIC USE OF SYMPATHOMIMETICSNoradrenaline (1 = 2, 1 2 agonist )

Contraindication: HTA angina pectoris Tachyarrhythmias not associated with local anesthetics in anesthesia

extremities (nose, ears, penis, fingers) - ischemic necrosis

preparations is not associated with calcium - contributes tachyarrhythmias

33


Dobutamine

Catecholamine is only indicated in cardiogenic shock.

Side effects: can give you chest pain,

nausea, vomiting

It is given intravenously slowly infusion under medical supervision

34

THERAPEUTIC USE OF SYMPATHOMIMETICSEphedrine (NA releaser, şi agonist)

is a natural alkaloid - structură non-catechol structure

Crosses the blood-brain barrier and cause the release of catecholamines in the CNS psyhoanaleptic inducing effects (cortical

awakening, increase the concentration of attention, memory, learning)

anorexines, so the effect of "amphetamine" (much lower than amphetamines).

35


Pharmacodynamic effects: systolic and diastolic blood pressure increases positive inotropic effect, increase SA and AV

drivind bronchodilation amphetamine-type effects at central decrease capillary permeability and increased

postcapillary pathological factorslocal vasoconstriction (antiedema effect)

36


Side effects: tachyarrhythmias, ventricular fibrillation excessive blood pressure increases Tachyphylaxis psychological dependence

Contraindication: high blood pressure arrhythmia endogenous psychoses angina pectoris

37


Clinical use: AV block astm bronşic cu edem al mucoasei (pentru iniţierea terapiei, bronchial asthma with mucosa edem (treatment

initiation and then continues with two selective 2 stimulators)

hTA (therapeutic alternative - increased BP for several hours

local solutions in rhinitis, allergic conjunctivitis (antiedema effect)

Etilefrina is indicated for the background treatment of hypotension. There are also forms of storage, slow release of active substance.

38

THERAPEUTIC USE OF SYMPATHOMIMETICSPhenilephrine - 12 agonist

non-catechol structure Cross blood-bain barrier Release noradrenaline from cell storage – can

cause tachyphylaxis Pharmacodynamic Effects

increases systolic and diastolic blood pressure produce mydriasis of short duration (few minutes) reduce mucosal edema by reflex compensatory, increase in blood pressure

occurs after a brief period of bradycardia (will be shown in PSVT)

39

THERAPEUTIC USE OF SYMPATHOMIMETICSFenilephrine - 12 agonist

Clinical use Damage to the sympathetic cervical syndrome

Claude Bernard HornerHTA

produce diagnostic mydriasis the solutions applied locally - antiedematos of

mucosal PSVT It is associated as a vasoconstrictor to local

anesthetic

40


Metoxamine not cross the blood-brain barrier, produces a long lasting increase in blood pressure

(limits its clinical utility) It is indicated as an alternative in the treatment of

hypertension. Midodrine

N-acetamide derivative of metoxamine It is indicated for the background treatment of

orthostatic hypertension It is administered orally..

Metaraminol Increase bloog preasure increase in venous tone pulmonary vessels produces vasoconstriction decreases renal blood flow and cerebral

41

THERAPEUTIC USE OF SYMPATHOMIMETICSNaphasoline (1 şi 2 agonist)

a small proportion is a deposits cell noradrenaline releaser - may produce tachyphylaxis

In chronic administration (nasal instillation) - can lead to atrophy of nasal mucosa - atrophic rhinitis

physiological barriers across immature children - carries significant systemic concentrations and stimulates CNS 2 presynaptic receptors resulting sympatholysis (TA and collapse)

In adult at high doses - significant systemic concentrations stimulates the vascular 1 receptors and excitoconductor tissue (hypertension, ventricular fibrillation)

42


Oxymetasoline atrophic rhinitis occurs less frequently.

Isoprenaline (Isoproterenol)- (non-selectiv 1 2 agonist) AV block Indicated cardiac arrest asthma (initiation, then continues with 2

stimulators)

Side effects: anginal pain nausea, vomiting Headache tachyarrhythmias, ventricular fibrillation

43


Bufenine and Bametane - relatively selective 2 vascular receptors indicated in the treatment of intermittent

claudication Raynaud's syndrome.

Dobutamine – increased pozitiv inotrop effect (and negligible influence heart rate and BP ) It is indicated in congestive heart failure Cardiogenic shock.

44


Prenalterol is 1 agonist.

Indicated in congestive heart failure

Salbutamol, Fenoterol, Terbutaline, Salmeterol indicated in asthma / inhalator / injectable, orally way.

Isoetarine, Isoxuprine (1 antagonists and inhibitors with direct action on uterine smooth muscle) Indicated in premature labor

45


Amphetamines rapidly crosses the blood-brain barrier to reach

CNS where release noradrenaline and dopamine from central warehouses

acts directly through stimulation of ascending activating reticulate fibers

inhibit MAO

46

THERAPEUTIC USE OF SYMPATHOMIMETICSPharmacodynamic effects

Central - psihoanaleptice effects, anorexines Peripheral - sympathomimetics type effects

Clinical uses: stimulation of psychomotor performance Narcolepsy hyperkinetic syndrome in children adjunct in Parkinson's disease adjuvant seizures "petit mal“ nocturnal enuresis

47


Contraindication: schizophrenia, bipolar psychosis mental instability SDR. Tourette Hypertension, tachyarrhythmias

Coronary sclerosis, cerebral Glaucoma

Side effects: headache chest pain nausea, vomiting, constipation Hypertension, tachyarrhythmias Outbreak of acute episodes of endogenous psychoses Amphetamines cause psychological dependence,

coherent thought disorder - "amphetamine psychosis"

48


Acute intoxication with amphetamine - at doses above 100 mg. DL is less than 1 g.

The patient presentes• Hypertension, palpitations, tachyarrhythmias - fibrillated

fibrillation or ventricular• pallor, anxiety

chills,• sweating,• paranoid psychosisThere is no antidote for acute poisoning with amphetamines.

Treatment benzodiazepines, barbiturates Haloperidol Chlorpromazine

Clonidine, methyldopa, 1 –blockers loop-diuretic furosemide iv urine acidification (ammonium chloride) to spur removal

49


COCAINE- natural alkaloid obtaned from din Eritroxilon coca leaves (Peru, Bolivia).

It uses non-medical purposes for euforizante effects.

It is a very fine powder, white. It is administered by smoking, snuff nasal

injection. The therapy is indicated only as a surface

anesthetic ENT oftalmolgie.

Mechanism of action - inhibits the uptake of noradrenaline in nerve endings, increases norepinephrine turnover

50


Effects Mydriasis Tachyarrhythmias high blood pressure Nasal septal perforation - the chronic

administration by nasal snuff Cocainomanul is on alert (mydriatic) quickly earning their "followers" and provides the

first dose entourage, with great pleasure, the following will be taken at doses voluntarily recruited.

After intravenous administration of cocaine creates a sense of physical and mental strength, even orgasm (cocaine is called "girl" or "boy ").As there is no antidote for cocaine intoxication

51


Tyramine - blocks reuptake of norepinephrine and causes the release of norepinephrine from storage.

It is a substance found in fermented foods: cheese, beer, wines.

Results from normal metabolism of tyrosine in the body .

Practical conclusion: fermented foods are not eated during treatment

with MAO inhibitors (antidepressants) These foods are contraindicated or are take them

with caution by people with hypertension.

52

Thank you!!

You are free!!

Documents

PHARMACOLOGY OF SYMPATHETIC NERVOUS SYSTEM