Download Autonomní nervový systém

Autonomic nervous system
Main functions:
• contraction and relaxation of smooth
muscles
• function of all exocrine and some
endocrine glands
• heart beat
• some metabolic pathways
parasympaticus
sympaticus
Biosynthesis
of
catecholamines
Dopamine
Receptor-effector system
1 receptor stimulation
• vasoconstriction skin, mucous and splanchnic
vessels, very low in coronary and brain areas,
increasing of periphery vessels resistance, blood
pressure, bradycardia
• mydriasis (contraction of m. dilatator pupilae),
decreasing of intraocular pressure (reabsorption
increasing and decreasing of its production
(vasoconstriction of ciliary body vessels)
• contraction of pregnant uterus
• ejaculation
• contraction of urinary bladder sphincter
2 receptor stimulation
• (presynaptic) decreasing NA release
(especially CNS)
• trombocytes aggregation
• vasoconstriction after local
administration, but after systemic
administration decreasing of symphaetic
transmission (BP)
• hypotensive effect
1 receptor stimulation
heart:
•  heart rate (+ chronotropic) SA nodus
•  automaticity (+ bathmotropic) AV nodus, ventriculs
•  contractions (inotropic)
•  conduction speed (dromotropic)
•  oxygen consumption
kidneys:
•  renin secretion (breaks down angiotensinogene to
angiotensine I)
2 receptor stimulation
• vasodilatation, skeletal muscles (”attack of defence"),
 BP diastolic
• bronchodilatation
• uterus relaxation (abortion prevention)
• relaxation of bowel (+ 2), deceleration of motility
• relaxation of urinary bladder
• glycogenolysis - hyperglycemia, increased insulin
secretion
• tremor of skeletal muscles
3 receptor stimulation
• lipolysis
Receptor activation
receptor
1
2

2
3
D1
D2
tissue
smooth muscles of blood vessels
m. dilatator pupilae
uterus
penis, vesiculae seminales
GIT - sfincters
presynaptic
trombocytes
heart
juxtaglomerular cells
pancreatic B cells
bronchial, vessels, bowel, uterus smooth
muscles
liver
skeletal muscles
lipocytes
smooth muscles
axons
effect
contraction ( resistance of blood vessels)
contraction (mydriasis)
contraction
ejaculation
contraction
inhibition of mediator release
stimulation of aggregation
positively chrono-, dromo- and inotropic
renin release
insulin release
relaxation
glykogenolysis stimulation
tremor ( uptake K+)
lipolysis
relaxation of splanchnic vessels
modification of transmitter release
Receptor selectivity of adrenergic receptors
There is no absolute
selectivity for adrenergic
receptors
Sympathomimetics
Sympathomimetics
direct
-agonists
indirect
-agonists
(1+2) non-selective 1+2)
( selective
1
1
2
2
 transmitter release
reuptake inhibitors
MAO inhibitors
Epinephrine (adrenaline)
• stimulution of , 1 a 2
• affinity mainly to  receptors, in lower concentration stimulates
only -receptors
• Effects
 heart, vessels
 blood pressure
 bronchodilatation
 glykogenolysis - hyperglycemia, increased insulin secretion
 lipolysis
• break down by MAO a COMT, the end products are 3-metoxy,4hydroxyphenylglycol and vanillylmandelic acid
Epinephrine - side effects
 CNS restlessness, anxiety, headache
 intracranial hemorrhagia (phenylpropanolamine)
 cardiac arrhythmia
 hyperthyreosis - increases amount of adrenergic
receptors
 blockers of catecholamines uptake (kokain, tricycl.
antidepressants) and MAO inhibitors increase effect
Epinephrine - indications
• cardiopulmonal resuscitation. 1-2 mg in 5 ml f.sol. i.v. or
intratracheally, intracardial administration is no more used (harm
risk)
• anaphylactic shock
• bronchodilatory
• mucosal decongestion
• inotropic effect
• vasoconstrictive effect
• inhibition of mast cells degranulation
• glaucoma
• local anaesthetic drugs, vasoconstriction elongates anaesthesia
• mucosal decongestion
• antiastmathic drug: today almost 2-selective drugs
Norepinephrine
 a 1 stimulation
• increases systolic and diastolic blood pressure, n.
vagus stimulation can cause bradycardia

• Indications
periphery analeptic drug, therapy of
hypotensive states (spinal anaesthesia,
sympatectomia, hypotensive drug overdosage)
shock therapy is provided by dopamine
Dopamine
  stimulation,  stimulation after high doses admin., Dopamine
receptors in kidneys and bowel. Effect is dose related.
dose 1-2 ug/kg/min: stim. D receptors - increasing of
renal perfusion
dose 2-8 ug/kg/min: stim. beta receptors - pos. inotropic
and chronotropic effect
dose over 8 ug/kg/min: stim. alfa1 receptors vasoconstriction
• Indication
Shock therapy:
– 1 simulation = inotropic and chronotropic effect
– Stim D rec.= increased blood flow in kidneys and
splanchnic area
Heart failure
Dobutamine
• synthetic, 1 stimulation - great inotropic, and
low chronotropic effect, oxygen consumption
is not so affected, I: heart failure, T1/2 =2.5
min, continuous administration
Isoprenaline
• inj., synt., 1 a 2 stimulation - increases heart output,
but 2 vasodilatation in skeletal muscles decreases
diastolic blood pressure.
• Indication
– A-V blocs and heart arrest, when cardiostimulation
is not available
– bradycardia (atropine resistant)
– (former antishock therapy and bronchodilatatory
agent)
Influence of different agonists on
BP
adrenaline
isoprenaline
noradrenaline
Phenylefrine
•
1 stimulation – mydriatic & dekongestant eff.
• EVERCIL and NEOSYNEPHRINE gtt; VIBROCIL gtt
Midodrine
•
1 stimulation – postural hypotension (GUTRON)
Naphasoline, xylometazoline,
oxymetazoline etc.

1 mucous decongestion during 1st phase is a reactive
hyperaemia after chronic use - sanorinismus - (use up to one
week)
2 agonists
Clonidine,  - methyldopa
• I: hypertension (stimulation of 2 central receptors
causes decreasing of periphery adrenergic activity)
• hypotensive agents, treatment of morphine
withdrawal symptoms
 agonists
• non-selective - dopamine
• 1 agonists - dobutamine
• 2 agonists - fenoterol, salbutamol,
terbutaline, formoterol
– bronchodilatatory and tocolytic effect with
minimum cardiovascular effects
– (inhibition of leukotriens, histamine release
and phospholipasis A2 )
Sympathomimetics
Sympathomimetics
direct
-agonists
indirect
-agonists
(1+2) non-selective 1+2)
( selective
1
1
2
2
 transmitter release
reuptake inhibitors
MAO inhibitors
Indirect sympatomimetics
• Inhibitors MAO (antidepressant)
• Amphetamine, metamphetamine,
phenmetrazine, methylphenidate
• increase of transmitter release from presynaptic
vesicles
• cross HEB, CNS stim. effect
– increased psychomot. activity (doping)
– anorectic effect , (hypothalamus stimulation)
• abuse risk
• I: attention deficit hyperactivity disorder (ADHD)
Ephedrine
– nasal decongestion (reactive hyperaemia with
increased secretion)
– bronchodilatans
– metamphetamine synthesis (”pervitin")
Tyramine
• metabolite of tyrosine, eliminated by MAO. But when MAO
are administrated, then food with high tyramine
concentration (cheese, yoghurt, bananas, sausages) can
cause hypertensive reaction
Cocain
• inhibition of neuromediators re-uptake (esp. dopamine)
Side effects
Catecholamines - they do not cross HEB, but
periphery stimulation of  or 1 receptors can cause:
 vasoconstriction
 cardiac arrhythmia
 heart attack
 haemorrhagia or pulmonal oedema
Sympatholytics
indirect
direct
non-selective
selective
Indirect sympatolytics
Reserpine
• alcaloid Rauwolfia serpentina.
• Inhibits transmitter storage in presynaptic vesicles
CNS effects
• antipsychotic effect (D receptor)
• dysphoric effect - reserpine causes depressions that can
induce suicide
• cognitive functions inhibition
Reserpine
Central and peripheral ADRs
gastric HCl hypersecretion, diarrhoea, nasal congestion,
hypotension
Indication
• non responding hypertensive states (combination
with diuretics and ergot alkaloids).
Guanethidine
• peripheral acting sympatolytics (causes hypotensive
states, especially in the morning)
• Blocks exocytosis – release of NE
• Local miotic agent
Sympatholytics
indirect
direct
non-selective
selective
Direct sympatolytics
Reversible -lytics most of sympatolytics, reversible binds to
receptors and acts as agonists or dualists (with intristic
sympatomimetic activity - ISA)
Irreversible a-lytics binds to receptor by covalent binding
phenoxybenzamine (14-48 h).
Prazosin, doxazosin
Reversible 1B-receptor (espec.) blocker. It does not
influence 2-receptors - very low tachycardia.
Relaxation of smooth muscle cells either vascular (I:
hypertension – prazosin, doxazosin) or in prostate (I:
BHP – doxazosin)
Indications of -lytics (synthetic)
Feochromocytome: adrenal medula tumor that produces catecholamines phentolamine and phenoxybenzamin
Mild hypertension: In most cases 1-lytics. Cave postural hypotension after
first dose administration – prazosin
Peripheral vasospastic diseases: (Raynaud´s disease) phenoxybenzamine,
phentolamine, tolazoline. (calcium channel blockers)
Urinary obstruction: tamsulosine, alfuzosine (espec. via 1A-receptors)
Impotency: phentolamine, yohimbine
Natural reversible -lytics
(alkaloids and their derivates)
• Produced by ergot (Secale cornutum), product of
Claviceps purpurea, corn fungus.
• -lytics properties, but they are also NA dualists,
dopamine agonists ( prolactine production) and
serotonin antagonists.
• Secale cornutum (ergot) was ground with meal and
its toxic effect was very well known. Gangrenes of
acral parts of limbs (ergotismus gangrenosus) and
cramp (ergotismus convulsivus).
Saint Anthony the Great (251 - 356)
Ergonovine, ergometrine -
-parcial agonists. Uterotonic
effects (pregnant uterus – more 1 receptors), especially
their methyl- derivatives (methylergometrine). Per os
administration (gtt, tbl) is possible
Ergotoxine, mixture of alkaloids - ergocristine, ergocriptine
and ergocornine - -lytic effect.
Bromocriptine - dopaminergic effect; -lytic effect increase
its dihydroderivatives (DH).
Indications
hypertension - DH-ergocristine:
CRYSTEPIN drg. (clopamide + reserpine + DH-ergocristine)
NEOCRYSTEPIN
drg.
(chlorthalidone
+
reserpine
ergocristine)
vasodilatans - DHergotoxini mesilas
migraine
uterotonic effect - (surgery - prevention of bleeding)
+
DH-
-sympatolytics
• competitive
antagonists
(no
intrinsic
activity),
partial agonists (ISA, intrinsic sympathomimetic
activity)
• Selectivity: non-selective beta-lytics - block 1 and
2 receptors; cardioselective block 1 receptors.
• Lipid solubility - HE barrier penetration
Beta-lytics and their characteristic
Drug
selectivity
ISA
atenolol
metoprolol
esmolol
labetalol
propranolol
metipranol
pindolol
bopindolol
timolol
nadolol
1
1
1
a






0
0
0
+
0
0
+
+
0
0
t1/2
hour
6-9
3-4
l0 min
5
3.5-6
3-6
3-4
3-4
4-5
14-24
bioaviability (%)
lipid solubility
40
50
30
30
40
90-100
90-100
30
33
low
medium
low
medium
high
medium
medium
medium
medium
low
CLASSIFICATION OF
BETA-BLOCKERS (BB)
Non-selective: on 1 and 2
metipranol, sotalol, propranolol, timolol,
Cardioselective: mostly on 1
bisoprolol, metoprolol, atenolol, betaxolol
Non-selective with ISA: partial -agonistic activity
pindolol, bopindolol, oxprenolol,levobunolol
Cardioselective with ISA: acebutol (ACECOR), celiprolol
BB with vasodilatory eff.:
blockage 1 + 2+ 1
carvedilol, labetalol
blockage 1 + 1+ 2 + ISA
celiprolol - TENOLOC
blockage 1 + 2 + ISA
bopindolol - SANDONORM
HYDROPHILICITY x LIPOPHILICITY









a) lipophilic molecules
- cross to CNS (insomnia, depression)
- metabolized in liver ( bioavailability)
- variable level (CYP polymorphism)
- metoprolol,...
b) hydrophilic molecules
- less ADRs (those of CNS origin)
- eliminated via kidneys (longer eff.,  bioavailability)
- atenolol, bisoprolol...
NO DIFFERENCE IN CLINICAL EFF. WAS DEMONSTRATED
Effects
cardiovascular: decrease of BP and CO
negative chronotropic, inotropic, dromotropic effect. Decrease of
rennin production, but due to inhibition of beta-vasodilatation
peripheral vascular resistance can increase - increase of PVR
(peripheral -receptors are not opposed)
bronchopulmonal:
block
bronchoconstriction,
asthma.
of
especially
2-receptors
patients
with
causes
bronchial
Effects II
eye: intraocular pressure decrease local and systemic administration due
to reduction of intraocular liquid production
metabotropic
effects:
glycogenolysis
reduction
hypoglycaemia
Lipolysis inhibition - HDL decrease and VLDL increase
CNS effects: sleep disturbances, depression, nightmare
=>
severe
Indications
Hypertension - monotherapy or combination with other antihypertensive
drugs
Ischemic heart disease - -lytics decrease chest pain frequency,
myocardial output, oxygen consumption, systolic pressure and better
myocardial blood distribution (especially to ischemic parts).
-lytics decreases risk of death (20-30 %) after heart attack at least 3
years after it.
Indications II.
Arrhythmia - supraventricular and ventricular tachycardia
Glaucoma - reduction of intraocular liquid production by corpus cilliare.
(timoptol)
Hyperthyreosis prevents catecholamines effect
Mild anxiolytic effect heart beat, sweating, anxiety
Portal hypertension
Side effects I.
Bronchial asthma
Heart failure: cave! severe heart insufficiency.
Bradycardia, A-V blocks
Hypoglycaemia - diabetes mellitus. (when hypoglycaemia is present,
adrenaline due to its 2-effect increase glucose blood level. -blockers
inhibit this contra-regulation.
Local ischemia - beta receptor inhibition decrease vasodilatation, alpha
receptor stimulation increase vasoconstriction
Side effects II.
 rush, fever
 CNS: sedation, sleep disturbances, depression
 rebound phenomena after breaking the therapy - worsening of
illness => phased lowering therapy is needed