Download 1 - receptor

AUTONOMIC
PHARMACOLOGY
SYMPHATETIC
NERVOUS SYSTEM
Magdalena Šustková
NERVOUS SYSTEM
CENTRAL
PERIPHERAL
AUTONOMIC NERVOUS SYSTEM
Afferent
part
Efferent part
Sympathetic
Parasympathetic
(adrenergic
nervous
system)
(cholinergic
system)
SOMATIC
NERVOUS
SYSTEM
Senzoric
part
(=efferent)
Motoric
part
(=afferent)
BRAIN
SPINAL
CORD
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 contractility
increased heart rate
increased conduction velocity
increased heart output and
blood circulation
maintenance
vessels
peripheral vasoconstriction α1
/skeletal vasodilatation β2 /
sufficient blood pressure
maintenance
kidneys
stimulation of renin
secretion
homeostasis and sufficient
blood pressure maintance
lungs (β2)
bronchodilatation
improved ventilation
sweat glands
(ACh)
sweat
GIT (α, β)
inhibition of peristaltic
blood redistrubution
eye (α1)
mydriasis
improved vision in the dark
penis (α1)
uterine (β2)
stimulation of ejaculation
tocolytic effect
preservation of
tribe/population
thermoregulation
Acute sympatoadrenergic activation participates
in maintenance of vital important organs
vasoconstriction – blood
pressure - perfusion
acute
stress
↑A II
increased contractility and
frequency – increased heart
output
reduction of renal perfusion
- blood redistribution
metabol. changes – activation
of glycolysis – increased
glycaemia
Chronic sympatoadren. activation participate in
harming/damage of vital important organs
aterogenesis a destabil. plates
vasoconstriction
hypertrophy and remodelation
ligament prolipheration
endothelial dysfunctions
↑A II
hypertension
arrhytmias
hypertroph. a remodel. left
ventricle
damage of cardiomyocytes
thrombus activation
Na+ and water retention
ictus
heart
failure
infarctum
renal
feilure
-adrenergic stimulatory effect
rec. effector
consequences
1
contraction (↑ tension
sphincters)
Smooth muscles
(vessels, genitourin.)
heart
liver
eye
2
smooth-vessel
muscles
pancreas (-bb.)
↑ contractility,
hyperthrophy
glycogenolysis
mydriasis, ↑ absorption of
intraocular liquid
contractions
 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 effect
rec. effector
consequences
1
myocardium
accelerated impuls induction
and conduction,  contractility
2
juxtaglom. apparatus
smoth musce (bronchial,
vessels, genitourin., GIT)
renin secretion
relaxaction (bronchodilatation,
uterinere relaxation,
vazodilatation)
glukoneogenesis,
glykogenolysis
játra
3
eye
secretion of the intraocular
liquid
skin
lipidic tissue
sweating
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
consequences
DA
vessels (renal, coronary,
brain and splanchnic)
gout
dilatation (low
doses)
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
Effect na target organs • Potenciation of circulation, increased blood
pressure, against shock/trauma („antishock“ effect), tachycardia,
tachyarrythmia, hypertrophy (β1+1)
Effect of sympathetic and
parasympathetic NS on the myocardium
sympathetic
noradrenalin
β1
parasympathetic
acetylcholin
β2
M2
chronotropic eff.
dromotropic eff.
inotropic eff.
bathmtropic eff.
Effect na target organs • Vasoconstriction especially in
splanchnic circulation –increasing of
blood pressure and circulation, vessel
spams 1+ 2
• improved sceletal muscles perfusion β2
Effect na target organs • stimulation of renin release - β1
• increased blood pressure, Na and water
retention, hypertension
• sphyncter contraction, detrusor
relaxation - 1
• urine retention, prostatic complications
Effect na target organs • glycogenolysis - 1
• increased glycaemia,
diabetogenic effect
• reduced insuline secretion - 2
• glucose storage reduction,
diabetogenic effect
Effect na target organs • decreased secretion, relaxation, slower
passage - dopamine rec. a rec. β2
• blood redistribution, obstipation
Effect na target organs • bronchodilatation- β2
• inhibition of mastocytes
degranulation, histamine reduction β2
• vazokonstriction the tissiue - 1
• antiasthmatic effect, antialergic
efgect, mucosa decongestion
Effect na target organs • increased intraocular fluid secretion - β2
• increased intraocular fluid resorption 1
• pupil dilatation - 1
• mydriasis, intraocular pressure
regulation
Effect na target organs • 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“
Pharmacological
usage
- 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
dobutamin
inotropic
α2 agonisté
centr.
antihypertenzive
drug
phenylefrin
β2 agonisté
vasoconstrictor
bronchodilator
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.
vazoconstriction
renal and
peripheral
vazodilatation
adenyl-cyclasis
ATP
cAMP
PDE inactivation
1 in 
2
in perif.
•inotropic
•chronotropic
•arrhythmogenic
peripheral
vazodilatation
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
ADRENALINE
1 - receptor
1 in 
•inotropic
•chronotropic
•arrhythmogenic
2 - receptor
 - receptor
2 in periphery
systemic
vazodilatation
vasoconstriction
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“)
NORADRENALINE
1 - receptor
 - receptor
1 in 
•inotropic
•chronotropic
•arrhythmogenic
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
DOBUTAMINE
1 - receptor
1 in 
•inotropic
•chronotropic
•arrhythmogenic
2 - receptor
 - receptor
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 perfsion
increased contractility (in  doses - stimul. noradren.)
increases metab. myocardial consumption, proarrhythmic
effect
indication: increases heart output in heart failure without
hypotension
improves renal perfussion
potentiates diuret. effect
DOPAMINE
noradrenaline release
1 - receptor
 - receptor
1 in 
•inotropic
•chronotropic
•arrhythmogenic
vasoconstriction
dopaminergic
DA1 a 2 rec.
renal and
peripheral
vasodilatation
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 – receptor
2 – receptor
myocardium
(bronchial, vessels, urogenit. tract)
adenyl-cyclasis
in
ATP
cAMP
inotropic
a chronotropic
effect
bronchial
bronchial relaxation
vessels
and vazodilatation
General structure of -mimetics
OH
OH
CH
OH
CH
NH
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.
karvedilol nonselective α+β blocker
negat. chrono-, dromo-, inotropic, vazodilation, bronchoconstr.
β1 blokátory
cardioselective
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 Black
NOBEL 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)
Mechanism of -blocker effects
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
bisoprolol
metoprolol
Mechanism of -blocker effects
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
Mechanism of -blocker effects
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 bronchoconstriction)
Indexes of selectivity in basic
cardioselective -blockers
2,4
2,5
2,4
%
2
1,7
1,6
1,5
1,1
1
0,9
0,8
0,5
0
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
25
%
14-20
20
15
12-17
7-13
6-9
10
5
5
3-4
0
acebutolol
atenolol
betaxolol
bisoprolol
celiprolol metoprolol
BETAXOLOL, BISOPROLOL
- remarkably cardioselective, withouth ISA, hydrophilic
- long T1/2 (15-20 h)
- little variability in biodegradation
METOPROLOL
- remarkably cardioselective, withouth ISA, lipophilic
- short and variable T1/2 (drug forms with
prolonged effect)
- well supported clinical effect
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
% reduced mortality
timolol
50
metoprolol
propanolol
40
propanolol
30
practolol
sotalol
oxprenolol
pindolol
20
10
heart rate reduction
0
0
3
6
9
12
15
18
21
-blockers are measured according to heart rate
(50-60/min)
Thank you for your attention.