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) –involuntarySomatic NS – voluntary /you can control e.g. sceletal muscles/

Autonomic Nervous Systema/ sympathetic (thoracolumbal)b/ parasympathetic (craniosacral)

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)

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

Brainstemor spinal cord

Cell body

Ganglionic transmitter

Neuroeffector transmitter

Preganglionicneuron

Postganglionicneuron

1

2

Effectororgan

(according to Lippincott´s Pharmacology, 2006)

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)

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)

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 GITM2: heartM3: 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 responseof 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

Indirect acting (reversible)

Indirect acting (irreversible)

Reactivation of acetyl-choline

esterase

AcetylcholineBethanecholCarbacholCevimelinePilocarpine

AmbenomiumDonepezilEdrophoniumGalantamineNeostigminePhysostigminePyridostigmineRivastigmineTacrine

EchothiophateIsoflurophate

Pralidoxime(according to Lippincott´s Pharmacology, 2006)

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

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

(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/ 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

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 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

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

• 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 rarescabies (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 antagonistsdirect parasympatholytic drugss

Atropa belladona (nightshade deadly)

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

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,- 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 – adjuvant therapy besides dopaminergic drugs (biperiden, benzatropin)

Kinetosis. – scolopamine (transcutaneous patch – effective for 24-48 h)

In bradycardia - atropine

Parasympatholytic drugs: 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

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 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

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