Transcript Parasympathetic nervous system

Parasympathetic nervous
system: textbooks
• Recommended
(possible) literature
1/ Rang and Dale´s
Pharmacology (2012)
2/ Mohr et al.: Color atlas of
pharmacology (2011)
3/ Lippincot´s illustr.
Pharmacology
4/ Simmons: Pharmacology
illustr. review 2012
• Additional (optional)
sources of information
1/ Goodman and
Gilman´s,
Pharmacological basis of
therapeutics (2011)
Nervous System
• Central Nervous System (CNS) - Brain and
spinal cord
• Peripheral Nervous System (PNS)
Autonomic Nervous System (ANS) –
involuntary
Somatic NS – voluntary /you can control e.g.
sceletal muscles/
Autonomic Nervous System
a/ sympathetic (thoracolumbal)
b/ parasympathetic (craniosacral)
Organization of the nervous system
Nervous system
Peripheral Nervous System
Central Nervous System
Efferent Division
Afferent Division
Autonomic System
Somatic System
Enteric
Parasympathetic
Sympathetic
(according to Lippincott´s
Pharmacology, 2006)
Main functions of ANS
• ANS acts on smooth muscles (contraction
or relaxation)
• ANS acts on glands
• ANS controls (regulates) function of the
heart, respiratory system, GI tract, bladder
• ANS: involuntary influencing of physiological
functions - we have little or no control on
functions described above.
• Circulation, breathing, digestion are
regulated automatically, mechanism of
feedback is applied
ANS - 2 types of neurons:
1. Afferent (sensoric) - send impulses to
the CNS for interpretation
2. Efferent - recieve impulses
(information) from the brain & transmit
from the spinal cord to the effector
organ cells
2 branches - sympathetic &
parasympathetic nervous system
Efferent neurons
of the autonomic
system
Cell body
1
Brainstem
or spinal cord
Preganglionic
neuron
Ganglionic transmitter
2
Postganglionic
neuron
Neuroeffector transmitter
(according to Lippincott´s
Pharmacology, 2006)
Effector
organ
CENTRAL NERVOUS SYSTEM
Acetylcholine (ACh) and noradrenaline (NA) as transmitters
in the peripheral nervous system.
ACh
(nic)
Skeletal
muscle
Somatic efferent
system
ACh
(nic)
NA
Blood vessels
etc.
ACh
(nic)
ACh
(mus)
Sweat
glands
ACh
(nic)
Adrenal
medulla
ACh
(mus)
Salivary Parasympathetic
glands etc.
system
ACh
(nic)
Sympathetic
system
(according to Rang HP, Dale
MM et al.: Pharmacology, 2003)
Summary of the neurotransmitters released and the types of receptors
found within the autonomic and somatic nervous system.
(according to Lippincott´s
Pharmacology, 2006)
Preganglionic
neuron
Ganglionic
transmitter
AUTONOMIC
Sympathetic innervation
Parasympathetic
of adrenal medulla
Sympathetic
Acetylcholine
Acetylcholine
Nicotinic
receptor
Adrenal medulla
Neuroeffector
transmitter
SOMATIC
Acetylcholine
Nicotinic
receptor
Nicotinic
receptor
Postganglionic
neurons
Epinephrine release
Acetylcholine
into the blood Norepinephrine
Adrenergic
receptor
No ganglia
Adrenergic
receptor
Effector organs
Muscarinic
receptor
Acetylcholine
Nicotinic receptor
Striated muscle
Somatic and autonomic nervous system
Autonomic nervous system: mediators
• nervous paths (tracts) lead to ganglions
where information is transmitted via
nicotinergic receptors
• parasympathetic nerv. fibres release
acetylcholine, that then acts on
muscarine receptors:
M1: brain, parietal cells of GIT
M2: heart
M3: smooth muscles and glands
• sympathetic nerv. fibres release
noradrenaline (exception sweat glands
where acetylcholine is mediator)
Effects of receptor activation on
contraction of muscles
• cardial inotropy
• chronotropy of
myocardial muscle
(heart rate)
• bronchi
• excitation by beta 1
rcp and inhibition by
M3
• excitation by beta 1 and
inhibition by M2
• contraction M3 and
dilatation by beta 2
Sympathetic and parasympathetic response
of organs
Parasympathetic response
DRUGS INFLUENCING
CHOLINERGIC RECEPTORS
A/ Parasympathomimetics
B/ Parasympatholytic
drugs
Cholinergic agonist drugs are termed
parasympathomimetics,
as they mimic the effects of acetylcholine in
the parasympathetic system
1/ Direct acting parasympathomimetics
bind directly to cholinergic receptors
2/ Indirect acting parasympathomimetics
inhibit enzyme acetylcholinesterase
Direct and indirect
parasympathomimetic drugs
Summary of
cholinergic agonists
Cholinergic agonists
Direct acting
Acetylcholine
Bethanechol
Carbachol
Cevimeline
Pilocarpine
Indirect acting
(reversible)
Ambenomium
Donepezil
Edrophonium
Galantamine
Neostigmine
Physostigmine
Pyridostigmine
Rivastigmine
Tacrine
Indirect acting
(irreversible)
Echothiophate
Isoflurophate
(according to Lippincott´s
Pharmacology, 2006)
Reactivation of
acetyl-choline
esterase
Pralidoxime
Cholinergic agonist drugs
A/ Direct acting - act on the cholinergic
receptors to activate a tissue response
Side effects:
Salivation, lacrimation
Bronchospasm and bradycardia
Diarrhea
Contraindications
Asthma
Cardiac disease
CHOLINERGIC RECEPTORS
2 types of cholinergic receptors
1. Muscarinic (G protein coupled)
M1 in CNS
M2 in heart
M3 in smooth muscle and glands
2. Nicotinic (ligand gated ion channels)
a/ muscle type, b/ neuronal subtypes
• Neuromuscular junction
• Autonomic ganglia and adrenal medulla
(A cholinergic neuroeffector junction)
Mediator acetylcholine - biochemistry
• acts on muscarine and nicotine receptors
• biochemical effect on M receptors:
G protein, phospholipase C, Inositol
triphosphates, increase of intracellular
calcium and then physiological effect
leading to contraction of smooth muscles or
increase of secretion
• degradation of acetylcholine is by enzyme
acetylcholin-esterase
Cholinergic mechanisms: parasympathomimetic drugs
• muscarine agonists pilocarpine and carbachol
1/ pilocarpine is alkaloid that causes contraction
of musculus ciliaris leading to relieving of
Schlemm´s canal
Indications: glaucoma with narrow angle,
glaucoma attack, induction of miosis during
intraocular procedures
2/ carbachol
only for induction of miosis, not
antiglaucomatic drug
[Additional NOTE=not for learning before test about parasympathetic nerv. system :
preferred antiglaucomatic drugs of first choice today are prostanoids (e.g.
latanaprost) or selective betablockers like betaxolol
Pilocarpine
• lipophilic (tertiary nitrogen), central effect, an
alkaloid from tropical American shrubs
• Has effect on M receptors (partial agonist)
and N effect (in ganglions)
Use
ophtalmology – antiglaucomatic
Carbachol
• Hydrophilic (N+), does not pass through the
blood-brain barrier, higher ACHE resistance
• Stimulates excretion + GIT
Use: today as antiglaucomatic (rarely still in
urinary retention and in GIT atonia)
KI – GIT obstruction
Methacholine, bethanechol
Hydrophilic (N+), do not pass through the
blood-brain barrier, higher ACHE resistance
Use – almost not used any more (previously
used for urinary retention, in GIT atonia, for
increase of pancreatic functions, in
glaucoma)
KI – in GIT obstruction
Indications of direct
parasympathomimetic drugs
rather few:
• Rarely glaucoma (carbachol, pilocarpine)
• rarely still in post-operative and neurogennic
ileus, urine retention (bethanechol)
B/ Indirect
acting
parasympathomimetic drugs
inhibit acetylcholinesterase thereby
increasing concentrations of acetylcholine
and enhancing cholinergic function via
activation of nicotinic and muscarinic
receptors
Representatives of reversible blockers of AChE
1/ fysostigmin
2/ neostigmin
3/ pyridostigmin
4/ donepezil, rivastigmine, galantamine
Adverse effects of reversible
inhibitors of cholinesterase
• All of the side effects seen with direct
parasympathomimetics + caused by
increased nicotinic component
• Possible side effects:
1/ Bradycardia and hypotension
2/ Bronchospasm / respiratory
insufficiency = apply atropine that is
parasympatholytic drug
(3/ Convulsions, coma)
Inhibitors of cholinesterase
• Indications:
1/ Myasthenia gravis
Neostigmin, pyridostigmine
2/ Relieving of effect of myorelaxant
drugs used during surgical procedures
(thus means post-operative atonia of GIT
and urinary bladder)
Neostigmine
3/ Atropine poisoning
Physostigmine
Arecoline
misused in „betel“ nuts for its slight stimulatory effects
chewing this stuff results in a red-brown discolouration of the mouth and
staining of the teeth, and can lead to precancerous lesions and subsequently
one or more varieties of oral cancer
Symptoms of intoxication
Extremely increased cholinergic activity,
dependenig on the drug selectivity
M-effects CNS stimulation, myosis, dyspnoe,
bronchial hypersecretion and
bronchoconstriction, diarrhoea, GIT
hypermotility a secretion, hypotension,
vasodilatation, bradycardia…
N-effects – convulsions (CNS), increased
blood pressure (adrenal N rec. stimulation)
Indirect cholinomimetics
- increase of ACH concentration on the
cholinergic synapses (= not specific effect = M
+ N effects)
- substrates for ACH synthesis (lecitine)
- inhibitors of ACHE (= IACHE)
- tertiary ammonium structures (NR3)
- lipophilic – also centrally acting
- quarternary ammonium cations (NR4+)
- lipophilic – only peripherally acting
physostigmine - lipophilic alkaloid from
shrub Physostigma venenosum
edrophonium
5-15 min (peripheral)
physostigmine
0,5 – 2h (central)
neostigmine
0,5 – 3h (peripheral)
pyridostigmine
4-8h (peripheral)
organophosphates
DDT etc. - irreversible
•
Wikipedia
• Reversible
Inhibitors
of Acetyl
Choline
Esterase
Indications of indirect parasympathetics
• Post-operative and neurogennic ileus, urine
retention (neostigmine)
• Myasthenia gravis – neostigmine, pyridostigmine
• Alzheimer´s disease (demention, degeneration of cerebral
cholinergic neurons)
– rivastigmine,
– donezepil – predominantly central effect
– galantamine
Irreversibile Acetyl Cholin
Esterase Inhibitors =
organophosphates
Toxicology of organophosphates
• herbicides, pesticides, DDT
• Parathion primarily as insecticide
• Nerve gas for biological war fare - tabun, sarin,
soman (pass very fast through the skin)
Poisonings!
Use in pharmacotherapy – very rare
scabies (malathione)
Therapy of intoxication by
organophosphates
•
•
•
•
blocking of further absorption
atropine – blocks muscarinic adverse effects
mechanical ventilation
AChE reactivators – pralidoxim, trimedoxim
Parasympatholytic drugs
A/ Tertiary amines (lipophilic):
1/ natural alkaloids in plants - Atropa
belladonna, Datura stramonium, Hyosciamus
niger – atropine, scopolamine…
2/ semi-synthetic analogues – homatropine
B/ Quarternary ammonium structure
(hydrophilic) N-butyl-scopolamine,
Ipratropium, tiotropium
Muscarinic antagonists
direct parasympatholytic drugss
Atropa belladona (nightshade deadly)
Effects of Atropine
Dose
(mg)
<0.5
Atropine effects
reduced heart rate (bradycardia),
reduced salivation, reduces sweating
1.0
increased heart rate, slight mydriasis, complete block of saliva
production
2.0
tachycardia, mydriasis, reduced accomodation ability for near vision
5.0
intensified previous effects, swallowing disorders, tiredness, headache,
urinary retention, constipation, dry and hot skin
>10.0
further intensification of previous effects, rapid and slight pulse, blurred
vision, scarlet red hot and dry skin, ataxia, restlessness,
CNS excitation (hallucinations, delirium), coma
Effects of Atropine
• CNS
1/ antiemetic effect (scopolamine is used in pharmacotherapy of
motion sickness)
2/ toxic doses of atropine - excitation, followed by delirium
and coma
• Eye = mydriasis
- antimuscarinic effect on the sphincter smooth muscle of the
iris - paralysis of the ciliary muscle of the eye resulting in a
loss of accomodation = cycloplegia with accompanying
mydriasis - atropine (5-7 days), homatropine (several hours)
• Cardiovascular system
- the heart rate may be slow initially or following a
low dose (less than 0.5 mg) (result of central vagal
stimulation + block of presynaptic M-autoreceptor
inhibitory effects); as the muscarinic (M2) receptors
on the SA node are blocked by higher concentrations
of atropine, tachycardia results
- at therapeutic doses – atropine has only mild effect
on systemic blood pressure, but it causes
vasodilatation of skin-vessel (red skin) – especially in
high doses
• GIT:
- gastric and gut secretion is reduced at high doses,
GI motility is reduced
Smooth muscle:
- GI contractions are reduced in amplitude and
frequency, muscle tone is also reduced
- biliary tract is relaxed
- urinary bladder and ureter tone are reduced
Respiratory system:
- bronchodilatation occurs in the large bronchi
- reduced secretion
Sweat gland
- secretion is reduced – body temperature is
increased (fever in children)
Possible therapeutic use of Atropine:
1/ Preanesthetic agent
- to reduce salivary and respiratory secretions
- „stabilizes“ n. vagus – prevention of vagal bradycardia
and heart arrest
2/ Bradycardia – induced by antiarrythimcs or rather
digoxine induced bradycardia)
3/ In toxicology - intoxications by organophosphate or
mushroom (if muscarine is the toxic agent)
Atropine is well distributed throughout the body including the CNS (IV=intravenous,
IM=intramuscular, SC=subcutaneous, PO=peroral)
Atropine adverse effects:
-
tachycardia,
dry mouth,
obstipation,
blurred vision (mydriasis)
urinary retention,
increased body temperature (children),
restlessness, desorientation
- „atropine-like adverse effect“ are rather frequently seen
as adverse effects after application of various drugs due to
their insufficient receptor specifity (tricyclic antidepressants,
typical antipsychotics etc.)
Parasympatholytic indications I.
Parkinson´s syndrom –
dopaminergic
drugs
procyclidin)
adjuvant therapy besides
(biperiden,
benzatropin,
Kinetosis. – scolopamine (transcutaneous patch – effective
for 24-48 h)
In bradycardia - atropine
Indications II.
Ophtalmology
Mydriasis for diagnostic purposes – homatropine (with
shorter effect) is more usefull; locally (drops)
Indications III.
Gastrointestinal disturbances.
At these indications quarternary ammonium bases are
predominantly used.
GIT spasmolytics for conservative cholelithiasis and
urolithiasis therapy – N-buthyl-scopolamine,
oxyphenonium, poldine, fenpiverin, otilium
In GIT hypermotility – in diarrhoea (of travelers….) –
mostly combination with non analgetic peripheral
opioids (e.g. atropine with difenoxylate REASEC
Indications IV.
Asthma bronchiale therapy
parasympatholytics induce bronchodilatation and attenuate
lung secretion
ipratropium ATROVENT, or in combination with
sympathomimetic fenoterol (BERODUAL)
Premedication for general anaesthesia – atropine,
scopolamine - prevention of n.vagus stimulation (=
perevention of laryngospasm, bronchospasm, bronchial
hypersecretion – prevention of post-surgical atelectasis).
BUT induces risk of urinary retention and gout hypomotility.
Indications V.
Therapy of IACHE overdose or intoxication (short- and
medium-acting IACHE used in myasthenia gravis etc;
irreversible IACHE –organophosphates). Atropine applied
in high doses (1-2 mg i.v. for 5-15 min) until signs of
antimuscarinic effect occure (dry mouth,mydriasis..)
Mushrooms (Amanita muscaria) poisoning
With fast onset (in 15-30min after consumption) – with
muscarinic signs (nausea, vomiting, bradycardia, salivation,
bronchoconstriction... In Amanita muscaria is an alkaloid –
muscarine). Therapy with atropine (1-2 mg parenteral)
Parasympatholytic intoxication
Intoxication with tertiary amines:
Central – CNS stimulation, excitation - hallucinations,
convulsions, coma, central respiratory depression (coma)
Peripheral – dry, warm/hot scarlatte red skin, dry mouth, no
lacrimation, mydriasis, cycloplegia, tachycardia, low blood
pressure, constipation, increased body temperature (fever
in children)
Therapy of intoxication
- symptomatic (shock prevention, anticolvunsants diazepam)
- IACHE (physostigmine - carefuly, it is rather toxic;
neostigmine)
- cooling of the patient
Intoxication with quarternary ammonium bases:
Peripheral antimuscarinic effects but partly also
antagonism on N (ganglion) receptors (+ orthostatic
hypotension due to the ganglioplegic effect …).
Therapy
- IACHE – neostigmine (=quarternary structure, only
peripheral effects)
- if necessary - possibly α1-sympathomimetic
phenylephrine (against the low BP)
Contraindications of
parasympatholytic drugs
- glaucoma (especially with closed
ancle)
- hyperthrophic prostate, serious
prostatic hyperplasia (increased
risk of urine retention)
- paralytic ileus