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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)
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Nervous System • Central Nervous System (CNS) - Brain and
spinal cord • Peripheral Nervous System (PNS)
Autonomic Nervous System (ANS) –involuntarySomatic NS – voluntary /you can control e.g. sceletal muscles/
Autonomic Nervous Systema/ sympathetic (thoracolumbal)b/ parasympathetic (craniosacral)
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Organization of the nervous system
Nervous system
Peripheral Nervous System
Autonomic System
EntericParasympatheticSympathetic
Central Nervous System
Efferent Division Afferent Division
Somatic System
(according to Lippincott´s Pharmacology, 2006)
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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
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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
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Efferent neurons of the autonomic system
Brainstemor spinal cord
Cell body
Ganglionic transmitter
Neuroeffector transmitter
Preganglionicneuron
Postganglionicneuron
1
2
Effectororgan
(according to Lippincott´s Pharmacology, 2006)
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Acetylcholine (ACh) and noradrenaline (NA) as transmittersAcetylcholine (ACh) and noradrenaline (NA) as transmittersin the peripheral nervous system.in the peripheral nervous system.
CE
NT
RA
L N
ER
VO
US
SY
ST
EM
CE
NT
RA
L N
ER
VO
US
SY
ST
EM
AChACh(nic)(nic)
Skeletal Skeletal musclemuscle
Somatic efferentSomatic efferentsystemsystem
AChACh(nic)(nic)
AChACh(nic)(nic)
AChACh(nic)(nic)
AChACh(nic)(nic)
AChACh(mus)(mus)
AChACh(mus)(mus)
NANABlood vesselsBlood vessels
etc.etc.
SweatSweatglandsglands
AdrenalAdrenalmedullamedulla
SympatheticSympatheticsystemsystem
SalivarySalivaryglands etc.glands etc.
ParasympatheticParasympatheticsystemsystem
(according to Rang HP, Dale MM et al.: Pharmacology, 2003)
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Summary of the neurotransmitters released and the types of receptorsfound within the autonomic and somatic nervous system.
AUTONOMIC SOMATIC
Preganglionic neuron
Ganglionic transmitter
Neuroeffectortransmitter
Sympathetic innervationof adrenal medulla Sympathetic
Parasympathetic
No ganglia
Acetylcholine
Nicotinic receptor
Acetylcholine Acetylcholine Acetylcholine
Nicotinic receptor
Nicotinic receptor
Nicotinic receptor
Adrenal medulla Postganglionicneurons
Epinephrine releaseinto the blood Norepinephrine Acetylcholine
Adrenergicreceptor
Adrenergicreceptor
Muscarinicreceptor
Effector organs Striated muscle
(according to Lippincott´s Pharmacology, 2006)
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Somatic and autonomic nervous system
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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 GITM2: heartM3: smooth muscles and glands• sympathetic nerv. fibres release
noradrenaline (exception sweat glands where acetylcholine is mediator)
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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
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Sympathetic and parasympathetic responseof organs
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Parasympathetic response
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DRUGS INFLUENCING CHOLINERGIC RECEPTORS
A/ Parasympathomimetics
B/ Parasympatholytic drugs
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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
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Direct and indirect parasympathomimetic drugs
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Summary of cholinergic agonists
Cholinergic agonists
Direct acting
Indirect acting (reversible)
Indirect acting (irreversible)
Reactivation of acetyl-choline
esterase
AcetylcholineBethanecholCarbacholCevimelinePilocarpine
AmbenomiumDonepezilEdrophoniumGalantamineNeostigminePhysostigminePyridostigmineRivastigmineTacrine
EchothiophateIsoflurophate
Pralidoxime(according to Lippincott´s Pharmacology, 2006)
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Cholinergic agonist drugsA/ Direct acting - act on the cholinergic
receptors to activate a tissue response
Side effects:
Salivation, lacrimation
Bronchospasm and bradycardia
Diarrhea
Contraindications
Asthma
Cardiac disease
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CHOLINERGIC RECEPTORS2 types of cholinergic receptors1. 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
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(A cholinergic neuroeffector junction)
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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
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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/ carbacholonly 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
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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
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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
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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
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Indications of direct parasympathomimetic drugs
rather few: • Rarely glaucoma (carbachol, pilocarpine)
• rarely still in post-operative and neurogennic ileus, urine retention (bethanechol)
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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
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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)
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Inhibitors of cholinesterase• Indications:1/ Myasthenia gravisNeostigmin, pyridostigmine2/ Relieving of effect of myorelaxant
drugs used during surgical procedures (thus means post-operative atonia of GIT and urinary bladder)
Neostigmine3/ Atropine poisoningPhysostigmine
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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)
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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
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• Reversible Inhibitors
of Acetyl Choline Esterase
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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
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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 rarescabies (malathione)
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Therapy of intoxication by organophosphates
• blocking of further absorption• atropine – blocks muscarinic adverse effects• mechanical ventilation• AChE reactivators – pralidoxim, trimedoxim
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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
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Muscarinic antagonistsdirect parasympatholytic drugss
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Atropa belladona (nightshade deadly)
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Dose(mg)
Atropine effects
<0.5 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
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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)
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• 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
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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)
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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)
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Atropine adverse effects:
- tachycardia,- dry mouth,- obstipation,- blurred vision (mydriasis)- urinary retention,- 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.)
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Parasympatholytic indications I.
Parkinson´s syndrom – adjuvant therapy besides dopaminergic drugs (biperiden, benzatropin)
Kinetosis. – scolopamine (transcutaneous patch – effective for 24-48 h)
In bradycardia - atropine
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Parasympatholytic drugs: indications II.
Ophtalmology
Mydriasis for diagnostic purposes – homatropine (with shorter effect) is more usefull; locally (drops)
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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
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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.
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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)
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Parasympatholytic intoxicationIntoxication 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
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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)
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Contraindications of parasympatholytic drugs
- glaucoma (especially with closed ancle)
- hyperthrophic prostate, serious prostatic hyperplasia (increased risk of urine retention)
- paralytic ileus