AUTONOMIC PHARMACOLOGY SYMPHATETIC NERVOUS SYSTEM Magdalena Šustková

AUTONOMIC PHARMACOLOGY

SYMPHATETIC NERVOUS SYSTEM

Magdalena Šustková

NERVOUS SYSTEMPERIPHERAL CENTRAL

AUTONOMIC NERVOUS SYSTEM SOMATIC NERVOUS SYSTEM

BRAINSPINAL CORD

Afferent part

Efferent part Senzoric part

(=effe-rent)

Moto-ric

part(=affe-rent)

Sympathetic

(adrenergic nervous system)

Parasympathetic

(cholinergic system)

ganglions periphery

Sympathetic and parasympathetic

Activation of sympathetic NS – phylogenetically old adaptive reaction

„fight-or-flight“

Sympathetic activation

State of maximal work capacity as reguired in „fight or flight“ situations

- activity of skeletal muscles and CNS - supply of oxygen and nutrients – increased blood flow - increased heart rate and contractility, peripheral (splanchnic blood vessels) vasoconstriction - enhanced bronchodilatation

- GIT – restrained and slowed – peristaltic dimishes, sphincteric tonus increases

- Etc.

parasympathetic nervous system sympathetic

Sympathetic stimulation• initiating mechanisms – stimulation of CNS

cortex and suprarenal medulla

• neurotransmitters – adrenaline (epinephrine),

noradrenaline (norepinephrine), dopamine

• target organs – skeletal muscles and CNS

• energy sources – aerobic glycolysis

• substrate transport – heart, vessels, lung and

airways

Catecholamines

Biosynthesis

Catecholamines

Degradation

Adrenergic synapse

Consequences of sympathetic stimulation

organ effect consequences

heart (β1)increased contractilityincreased heart rateincreased conduction velocity

increased heart output and blood circulation maintenance

vesselsperipheral vasoconstriction α1/skeletal vasodilatation β2 /

sufficient blood pressure maintenance

kidneysstimulation of reninsecretion

homeostasis and sufficient blood pressure maintance

lungs (β2) bronchodilatation improved ventilation

sweat glands (ACh)

sweatthermoregulation

GIT (α, β) inhibition of peristaltic blood redistrubution

eye (α1) mydriasisimproved vision in the dark

penis (α1)uterine (β2)

stimulation of ejaculationtocolytic effect

preservation of tribe/population

Acute sympatoadrenergic activation participates

in maintenance of vital important organs

vasoconstriction – blood pressure - perfusion

increased contractility and frequency – increased heart output

reduction of renal perfusion - blood redistribution

metabol. changes – activation of glycolysis – increased glycaemia

↑A IIacute stress

Chronic sympatoadren. activation participate in harming/damage of vital important organs

ictus

heartfailure

infarctum

renalfeilure

Na+ and water retention

aterogenesis a destabil. platesvasoconstrictionhypertrophy and remodelationligament prolipherationendothelial dysfunctions

hypertroph. a remodel. left ventricledamage of cardiomyocytes

thrombus activation

hypertension

arrhytmias↑A II

-adrenergic stimulatory effect

rec. effector consequences1 Smooth muscles

(vessels, genitourin.) contraction (↑ tension sphincters)

heart ↑ contractility, hyperthrophy

liver glycogenolysis

eye mydriasis, ↑ absorption of intraocular liquid

2 smooth-vessel muscles

contractions

pancreas (-bb.) insuline secretion

α adrenergic stimulation

• Stimulation and maintenance of blood circulation

• glycogenolysis and decrease insuline secretion – increased glucosis and its decreased storage → increased offer of glucose for glycolysis

• increased sphincter tonus

α receptors subtypes

-adrenergic stimulatory effectrec. effector consequences1 myocardium accelerated impuls induction

and conduction, contractility

juxtaglom. apparatus renin secretion

2 smoth musce (bronchial, vessels, genitourin., GIT)

relaxaction (bronchodilatation,uterinere relaxation, vazodilatation)

játra glukoneogenesis,glykogenolysis

eye secretion of the intraocular liquid

skin sweating

3 lipidic tissue lipolysis

β adrenergic stimulation

• blood circulation maintenance

• blood perfusion maintenace

• increased glycaemia → increased offer of glucose for glycolysis

• lipolisis – increased source of adjuvant energy

Dopamin/dopaminergic stimulation

rec. effector consequencesDA vessels (renal, coronary,

brain and splanchnic) dilatation (low doses)

gout decreased motility

Effect na target organs -

• catecholamines have low lipophilicity - low passage into the CNS

• relatively low impact of adrenergic stimulation on brain activity

• tremor, anxiety, euphoria, insomnia, rarely psychosis


• Potenciation of circulation, increased blood pressure, against shock/trauma („anti-shock“ effect), tachycardia, tachyarrythmia, hypertrophy (β1+1)

Effect of sympathetic and parasympathetic NS on the myocardium

sympathetic parasympathetic

noradrenalin acetylcholin

β1 β2 M2

chronotropic eff.dromotropic eff.inotropic eff.bathmtropic eff.


• Vasoconstriction especially in splanchnic circulation –increasing of blood pressure and circulation, vessel spams 1+ 2

• improved sceletal muscles perfusion β2


• stimulation of renin release - β1

• increased blood pressure, Na and water retention, hypertension

• sphyncter contraction, detrusor relaxation - 1 -

• urine retention, prostatic complications


• glycogenolysis - 1

• increased glycaemia,

diabetogenic effect

• reduced insuline secretion - 2

• glucose storage reduction,

diabetogenic effect


• decreased secretion, relaxation, slower passage - dopamine rec. a rec. β2

• blood redistribution, obstipation


• bronchodilatation- β2

• inhibition of mastocytes degranulation, histamine reduction - β2

• vazokonstriction the tissiue - 1

• antiasthmatic effect, antialergic efgect, mucosa decongestion


• increased intraocular fluid secretion - β2

• increased intraocular fluid resorption - 1

• pupil dilatation - 1

• mydriasis, intraocular pressure regulation


• thermoregulatory sweat

glands throughout the body –

release ACH act on M rec.

• stress, anxiety - increased sweating on palms, soles, ampits – release NE – act on mostly α1>β2 rec.

• prevention of hyperthermia, sweating, so called „gous skin“

Pharmacologicalusage - stimulation - inhibition

Adrenergic synapse

Direct and indirect effects

direct effects- on the receptors α (1,2) and β (1,2,3)

indirect effects- precursor for synthesis of the neuromediators (NEP, EP, DOP)- inhibition of degradation (IMAO, ICOMT)– increased release of the neuromediator from the neural ending- re-uptake inhibition- retention inhibition- combinations

SYMPATHOMIMETICS

α and β agonists

α2 α1 β1 β2

adrenaline - inovazodilator

noradrenaline inovasoconstrictor

β2 agonisté bronchodilator

dobutamin inotropic

α2 agonisté centr.

antihypertenzive drug

phenylefrin vasoconstrictor

Sympathomimetics contractility (1)

• vasodilatation (2)

• vasoconstriction (1)

• used only parenteraly for treatment of acute states

• indication: shock, resuscitation, acute heart failure selhání, alergy

• CAVE: proarrhythmic effect + accelerating of ischemia

Sympathomimetics in treatment of chronic heart failure

• inovazodilators - 1,2 mimetcs with inotropic and slight vazodilatory effect - (adrenalin, epinephrine)

• inotropics - 1 mimetics (selective) (dobutamine)

• peripheral and renal vazodilators - DA agonists with renal and peripheral vasodilatation (dopamine)

• inovasoconstrictors - 1 mimet. - contractil., vasoconstr.

- mimetics - vasoconstr. (noradrenaline, norepinephrine)

Myocardial receptores and vessel receptores controlling contractility of vessal tonus

glukagon. receptor

1 - receptor 2 - receptor - receptor dopamin. rec.

adenyl-cyclasis

ATP cAMP

PDE inactivation

1 in

2 in perif.

•inotropic•chronotropic•arrhythmogenic

peripheral vazodilatation

renal and peripheral vazodilatation

vazoconstriction

ADRENALINE (EPINEPHRINE) - inovazodilator

1+2 agonist: contractility, vasodilatation mild heart rate agonist: vasoconstriction

Remarkable contractility increase + mild vasodilatation

increased heart metab. consumption, proarrhythmic effect

indication:increased heart output in heart failure of the left

ventricle

1 - receptor - receptor

ADRENALINE

1 in


vasoconstriction

2 - receptor

2 in periphery

systemic vazodilatation

NORADRENALINE (NOREPINEPHRINE)- inovasoconstrictor

1agonista: contractility, vasoconstriction mild heart rate agonist: vasoconstrictor

signifficant contractility increase + signifficant vasoconstr.

indication: increasing of heart output in heart failure of left ventricle with serious hypotension, shock („peripheral analeptic“)

1 - receptor - receptor

NORADRENALINE

1 in


vasoconstriction

DOBUTAMINE - 1 inotropic

1 agonist (main eff.): contractility,

mild heart rate

agonist (side. effect): vasoconstriction 2 agonist (side. effect): vasodilatation

Secondary effect - increased contractility - increased metab. myocardial requirements - proarrhythmic effect

indication:decreased heart output in acute failure of the left heart ventricle

1 - receptor 2 - receptor - receptor

DOBUTAMINE

1 in 2 in periphery


systemic vasodilatation

vasoconstriction

DOPAMINE - renal vasodilatans • stimul. DA rec. (direct) : renal and peripher. vasodil.

1 agonist (indirectly in doses stimul. NA):

contractility + heart rate

agonist (indirectly increases NA) : vasoconstriction

signifficant vasodilatation (in doses): renal perfsionincreased contractility (in doses - stimul. noradren.)

increases metab. myocardial consumption, proarrhythmic

effectindication: increases heart output in heart failure without

hypotension improves renal perfussion potentiates diuret. effect

1 - receptor - receptor dopaminergicDA1 a 2 rec.

DOPAMINE

renal and peripheral vasodilatation

noradrenaline release

1 in


vasoconstriction

Combination treatment with dopamine and dobutamine

clinical requirements: • increased heart output (periph. vasodilat. + increased

contractility)

• blood presure maintenance (increased contractility + vasoconstriction)

• renal perfussion maintenance (renal vasodilatation)

„golden standard“ – combination with dobutamin (increased contractility + mild vasodilatation) with dopamine (in low doses - increased renal perfusion)

2- sympathomimetics• direct effect on 2 of the bronchial smooth muscles -

bronchodilatation - speed up of sputum outflow - regul. of antiinflammatory mediators,

mastocytes local aplication in the form of aerosol or systematically (p.o. or inj.)

• long-lasting administration induces reduction of the mimetic effects - tolerance due to reduced 2 rec. expression

• glucocorticoids reduce the risk of tolerance (reasonable combination)

2- sympathomimetics

relatively frequent adverse effects :• tachyarrhythmia•tremor, spasms, insomnia •hypocalemia

contraindications:•subvalv. aortal stenosis, hypertr. obst. cardiomyopat. •thyreotoxicosis •tachyarrythmia, repolarisation disturbances (prolonged. QT interval)

-adrenergic effect

1 – receptormyocardium

2 – receptor (bronchial, vessels, urogenit. tract)

adenyl-cyclasis

ATP cAMPin

bronchialvessels

inotropic a chronotropic effect

bronchial relaxation and vazodilatation

General structure of -mimetics

CH CH NH

OH

OH

OH

R

Structure and function of sympathomimetics

adrenalin

isoprenalin

albuterol

salmeterol

Fast and short-acting 2- sympathomimetics (RABA)

• fast onset of short-lasting bronchodilatation after

inhalation, inhalation more safe

• acute use in exacerbation of attack

• onset of effect in 5-10 min (inhal.), 15-90 min (p.o.)

• lasting for 4-6 hod

• salbutamol /Ventolin/

• fenoterol (Berotec)

• terbutalin (Bricanyl)

Long-lasting 2- sympathomimetics (LABA)• bronchodilatation 12 h, onset of effect in one week • not useful for treatment of acute attacks, only

prophylaxis • preference of inhalation (20x higher effect in

comparison to p.o. + systemic side effects• used for combination with inhal. glucocorticoids• medium and serious asthma in comination with

glucocort..

• salmeterol /Serevent/

• formoterol /Oxis/

• procaterol /Lontermin/

2-mimetics – adverse effects

• tremor (in higher doses)

• palpitation (heart), tachycardia, arrhythmias

even sudden death

• headache

• paradoxical bronchospasms (in inhalation)

• rarely allergy

SYMPATHOLYTICS

α and β antagonists

α2 α1 β1 β2

phentolamin - vazodilatation

antag. α1 dilat. prostat.

musc.

β1 blokátory cardioselective

karvedilol nonselective α+β blockernegat. chrono-, dromo-, inotropic, vazodilation, bronchoconstr.

β1+β2 blokátory non-cardioselective

α-BLOCKERS

- treatment of benign hyperplasia of the prostate - treatment of hypertension

α1-adrenergic receptor blockers

• treatment of benign hyperplasia of prostate – reduced sphincter tonus and increased detrusor contraction

• treatment of hypertension - vasodilatation• doxazosin, terazosin – less selective α1 blok. • alfuzosin, tamsulosin – more selective α1A blok.

Adverse eff. - hypotension, disturbed ejaculation, oedema of nasal mucosa

-BLOCKERS- one of the most

important drug groups in treatmant of

cardiovascular diseases

sir James BlackNOBEL PRICE (1958) development of

betablocker (propranolol)

Mechanism of -blocker effects

block of β1 rec.

•slowdown of SA impuls formation

•slowdown of impuls conduction

•reduced myocardial contractility

(reduced heart rate and heart output, myocardial stabilisation – reduced myocardial automacy/irritability)

•reduces renin output (reduced blood pressure)


block of β2 a β3 rec.•increased tonus of arterial vessel smooth muscles (vasoconstriction)

•increased bronchial tonus (bronchoconstriction)

•metabolic effect (lipolysis, hyperglycaemia in diabetics

•diminuation of insuline release)

Mechanism of effect- competitive blockade of postsynaptic activation

noradrenaline

metoprolol

bisoprolol


effect of β1 rec. blockade• Slowdown of impuls formation in the SA nodus • Slowdown of impuls conduction • Reduced myocardial contractility• Reduced myocardial irritability

reduced heart rate and heart output, myocardial stabilisation - reduced fibril. threshold

• Reduced renin output reduced blood pressure


Effect of β2 and β3 blockade

• vasoconstriction

• bronchoconstriction

• lipolysis, hyperglycaemia

Pharmacology of blockade

affinity to the 1 a 2 rec. (selectivity)

possible parcial rec. stimulation (ISA)

lipophylic x hydrophylic

length of the effect

vasodilat. effect (rec. 2 stimulation, rec. blockade , NO release, Ca chanells blockade)

CARDIOSELECTIVITY - influence of 1 and 2 blockade

a) cardioselective

- specifically on myocardial receptors 1

- betaxolol, bisoprolol, metoprolol, esmolol, atenolol...

b) non-selective

- participating of extracardial receptors 2 (or 3)

(broncho- a vasoconstriction, reduced lipolysis and inzuline secretion)

- metipranol, pindolol, bopindolol...

CARDIOSELECTIVITY

greater impact on reduced mortality and morbidity

in the secondary prevention of heart failure

less adverse effects

well tolerated (vaso- and broncho-constriction)

Indexes of selectivity in basic cardioselective -blockers

0,9

1,7

2,4 2,4

0,8

1,6

1,1

0

0,5

1

1,5

2

2,5

acebutolol atenolol betaxolol bisoprolol celiprolol esmolol metoprolol

%

HYDROPHILICITY versus LIPOPHILICITY

a) lipophilic molecules - penetration into the CNS (insomnia, depression) - metabolised in liver ( biol. availability) - variable blood concentrations (polymorfism of CYP) - metoprolol,...

b) hydrophilic molecules - less adverse effects (not central..) - excreted through kidney (prolonged effect,

availability) - atenolol, bisoprolol...

NOT SIGNIFFICANT DIFFERENCES IN THE CLINIC

- BLOCKERS non-specific ANTAGONISING RECEPTORS

rec. blockade :mild vasodilatation

reduced negative metab. impact reduced bronchoconstriction stronger effect in heart failure therapy not sufficient data about secondary preventive

effects karvediol, (labetalol)...

DURATION OF -BLOCKER EFFECTS

it is important to keep sufficient -block. concentration during the maximal sympathicotonia – in the morning i.e. at the time of most acute coronary syndromes occurence

short-lasting non-retarded metoprolol is not suitable

Comparison of T1/2 in basic cardioselective -blockers

7-13

6-9

14-20

12-17

53-4

0

5

10

15

20

25

acebutolol atenolol betaxolol bisoprolol celiprolol metoprolol

%

BETAXOLOL, BISOPROLOL- remarkably cardioselective, withouth ISA, hydrophilic- long T1/2 (15-20 h)- little variability in biodegradation

- remarkably cardioselective, withouth ISA, lipophilic- short and variable T1/2 (drug forms with prolonged effect)- well supported clinical effect

METOPROLOL

NEBIVOLOL• medium cardioselective, hydrophilic, withouth

ISA • T1/2 8-27 h (polymorphic. metabolism)• remarkable vazodilat. effect nitrate-like effect

CELIPROLOL• highly cardioselective, hydrophilic with ISA• longer T1/2 (6-8 h)• vaso-,bronchodilat. effects (2 rec. stimulation)

KARVEDILOL (+β block.)

• mild cardioselective, medium T1/2 (6-8 h)• remarkable vasodialt. effect (-lytic eff.)• does not increase insulin-resistance• most effective drug in heart failure therapy

• prefered in heart failure and always when no hypotension and bronchoconstriction occure

-BLOCKER CARDIOVASCULAR INDICATIONS

• arterial hypertension• ischemic heart disease:

• acute myocardial infarction (IM)• stp IM – secondary prevention• angina pectoris, „mute“ ischemia

• heart failure• arrhythmia (tachyarrhythmia)

select. -BLOCKERS ADVERSE EFECTS

- heart conduction disturbances,

bradycardia

bronchial obstruction

- vasoconstriction

- reduced contractility

- dyslipidemia

- insomnia, depression, hallucination

- obstipation, diarrhoea, flatulency

-BLOCKER ADVERSE EFFECTS

- heart conduction disturbances, bradycardia

- bronchial obstruction - vasoconstriction- reduced contractility - dyslipidemia - insomnia, depression,

hallucination-obstipation, diarrhoea,

flatulency

Contraindication of selective -blokers

valid

• heart conduction

disturbances

• signifficant

bradycardia:< 55 for put on BB, < 45 for stopping BB

• phaeochromocytoma

abandoned• limb ischemia signs• Raynaud´s sy.• diabetes mellitus• depression • dyslipidemia

careful • asthma, chronic bronchitis

VARIOS CHARACTERS OF -BLOCKERS

- IMPACT ON TOLERANCE AND CONTRAINDICATIONS:

in central adverse effects - hydrophilic (e.g. bisoprolol)

in limb ischemic signs - with vazodil. activity and selective

(nebivolol, betaxolol, bisoprolol) in diabetes – non-inducing insuline-resistence

(karvedilol, nebivolol), or highly cardioselective (betaxolol, bisoprolol)

u bronchial obstruction - 2 stimul. (celiprolol) or highly cardioselective (betaxolol, bisoprolol)

-blocker clinical effect and reduction of blood pressure

0

10

20

30

40

50

0 3 6 9 12 15 18 21

pindolol

oxprenolol

practolol

% r

edu

ced

mor

talit

y

heart rate reduction

timolol

metoprolol

propanololpropanolol

sotalol

-blockers are measured according to heart rate (50-60/min)

Thank you for your attention.

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AUTONOMIC PHARMACOLOGY SYMPHATETIC NERVOUS SYSTEM Magdalena Šustková