Parasympathetic nervous system

Dr.asaad

Autonomic nervous system

Autonomic nervous system, which controls involuntary activity (as heart rate, secretion of glands,.), is divided into sympathetic and parasympathetic divisions. Both divisions consist of: 1. pre-ganglionic neurons or nerve cells (with cell bodies in the CNS and ends in the autonomic ganglia) 2. post-ganglionic neurons with cell bodies in the autonomic ganglia and ends in the tissues)
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Classification of neurons (nerve cells) by transmitter released

1. Adrenergic: release
1. norepinephrine (NE) 2. epinephrine (EPI) 3. dopamine (DA)

2. Cholinergic: release acetylcholine (ACh) 3. Other (non-adrenergic, non-cholinergic,

NANC)

Cholinergic - release acetylcholine

1. 2. 3. 4. 5. pre-ganglionic (SNS and PSNS) post-ganglionic (PSNS) post-ganglionic SNS to sweat glands neuromuscular junction (NMJ) CNS (99% muscarinic)

Cholinergic transmission (terminal of the cholinergic neuron)

Synthesis, Storage, Release, and Removal of Acetylcholine

Synthesis and storage: Acetylcholine is synthesized in the cholinergic nerve terminal from acetyl CoA and choline. The formed acetylcholine is stored into vesicles. Release: Conduction of an action potential through the terminal branches of an axon causes entry of calcium into the nerve terminal resulting in the release of acetylcholine molecules outside the nerve terminal. Interaction with cholinergic receptors: Once in the junctional extracellular space , acetylcholine interacts reversibly with cholinoreceptors.
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Termination of action of acetylcholine: The length of time that the molecules of acetylcholine interact with receptors is short because acetylcholinesterase, an enzyme that rapidly hydrolyzes acetylcholine, is highly concentrated on the outer surfaces of both the prejunctional (neuronal) and postjunctional (effector cell) membranes. A rapid hydrolysis of acetylcholine by the enzyme results in a lowering of the concentration of free acetylcholine and a rapid dissociation of receptor-bound acetylcholine from its receptors. Little or no acetylcholine escapes into the circulation. Any acetylcholine that reaches the circulation is immediately inactivated by plasma esterases.
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Cholinergic receptors

Action of acetylcholine at cholinergic receptors

Organ
Eye Circular muscle of the iris Ciliary muscle Sino-atrial node Heart Blood vessels Bronchioles Smooth muscle walls GIT Sphincters Glands Wall Urinary bladder Pregnant uterus Glands Sphincter Myocardium Endothelium

Receptor
M3 M3 M2 M2 M3 M3 M3 M3 M3 M3 M3 M3 M3 Contracts Contracts Slows

Action

Negative inotropic action (more in atria) and negative chronotropic action Vasodilatation Contraction Contraction Relax Secretion Contracts Relax Contracts Secretion
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Modifying Autonomic Nervous System Function

Parasympathomimetics = Cholinoceptor stimulants: bind to acetylcholine receptors and stimulates them.

Parasympatholytics (cholinergic antagonists anticholinergic drugs): bind to acetylcholine receptors and reduce the effects of parasympathetic stimulation by preventing endogenous acetylcholine from binding to them.

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Parasympathomimetics (Cholinoceptor stimulants)

Esters of choline

Direct

Alkaloids Cholinoceptor stimulants

Indirect

Cholinesterase inhibitors

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Cholinoceptor stimulants

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Direct cholinoceptor stimulants

Alkaloids

Esters of choline

Nicotine
Lobeline Muscarine

Acetylcholine
Methacholine Bethanechol

Pilocarpine

Carbachol

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Acetylcholine (ACh) has no therapeutic applications because of its diffuse action and its rapid hydrolysis by both AChE and plasma butyrylcholinesterase. Nicotine
Site of action: A) nicotinic receptors (small doses stimulate and large doses inhibit) 1- NN at autonomic ganglia and adrenal medulla 2- NM at the motor end plate (Affinity is greater for NN sites than NM sites) B) CNS 15

Actions of nicotine
Action at autonomic ganglia (both sympathetic and parasympathetic): 1. Small doses stimulate autonomic ganglia leading to: a) sympathetic effect on the cardiovascular system with tachycardia and hypertension b)parasympathetic effect on the GIT - with nausea, vomiting and diarrhoea and urinary bladder with voiding of urine 2. Large doses or prolonged occupancy at nicotinic receptors inhibit autonomic ganglia
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Actions of nicotine
Action at the neuromuscular junction: 1. Small doses stimulate leading to either fasciculation or strong muscle contraction 2. Large doses inhibit leading to depolarization blockade.

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Actions of nicotine
Action at the CNS:
Small doses (tobacco smoke) Larger doses Very large doses Mild alerting action Tremors Convulsions and death

Used as an insecticide

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Indirect cholinoceptor stimulants (agents that inhibit acetylcholinesterase)

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Cholinesterase inhibitors
Types of cholinesterases:

1- Acetylcholinesterase (true cholinesterase):

Found at: I. Cholinergic neurons II. Cholinergic synapses III. Neuromuscular junction IV. Red blood cells

2- Butyrylcholinesterase (pseudocholinesterase): - Found at: Plasma and liver

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Acetylcholinesterase inhibitors
Three chemical groups:
Alcohols 1- Edrophonium Esters 1- Neostigmine 2- Physostigmine Neostigmine is not absorbed and does not enter CNS Physostigmine is absorbed from all sites including conjunctiva and enters CNS Reversible inhibition after 210 min. Reversible inhibition after 30 min to 6 hours Organophosphates 1- Echothiophate All organophosphorous compounds are well absorbed from all sites of administration and enter the CNS except echothiophate Irreversible inhibition (can be reversed by pralidoxime)

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Action of acetylcholinesterase inhibitors:

Inhibit acetylcholinesterase and to a lesser extent butyrylcholinesterase leading to increase the concentration of endogenous acetylcholine at cholinergic receptors

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Organ system effects of acetylcholinesterase inhibitors

CNS Eye, GIT, Bronchioles and urinary bladder Cardiovascular system Low concentrations cause alertness High concentrations cause convulsions followed by coma Similar to acetylcholine (increase the effect of acetylcholine at muscarinic receptor) Effect is due to : 1- Stimulation of sympathetic and parasympathetic autonomic ganglia 2- Stimulation of cholinergic receptors at the heart and blood vessels Effect on the heart: Similar to acetylcholine leading to decreased cardiac output Effect on the blood vessels: Vasodilatation (less than direct cholinoceptor stimulants) with only little hypotension Therapeutic doses increases strengh of contraction Higher concentrations cause muscle fibrillation Higher concentration cause neuromuscular blockade and paralysis
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Neuromuscular junction

Therapeutic uses of cholinoceptor stimulants

Disease 1- Glaucoma Mechanism of action Contraction of the ciliary muscle and increasing the outflow of the aqueous humor Drug Pilocarpine Physostigmine echothiophate

2- Postoperative ileus 3- Reflux esophagitis Bethanechol or neostigmine neostigmine, pyridostigmine, or ambenonium.

4- Urinary retention
5- Myasthenia gravis

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Myasthenia gravis
Definition: Myasthenia gravis is a disease affecting skeletal muscle neuromuscular junctions. An autoimmune process causes production of antibodies that decrease the number of functional nicotinic receptors on the motor end plates. Frequent findings are ptosis, diplopia, difficulty in speaking and swallowing, and extremity weakness. Severe disease may affect all the muscles, including those necessary for respiration.
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Myasthenia gravis
Diagnosis: Edrophonium test: A dose is injected intravenously. If the patient has myasthenia gravis, an improvement in muscle strength that lasts about 5 minutes will usually be observed. Edrophonium is also used to assess the adequacy of treatment with the longer-acting cholinesterase nhibitors in patients with myasthenia gravis. If excessive amounts of cholinesterase inhibitor have been used, patients may become paradoxically weak because of nicotinic depolarizing blockade of the motor end plate. Small doses of edrophonium (12 mg intravenously) will produce no relief or even worsen weakness if the patient is receiving excessive cholinesterase inhibitor therapy. On the other hand, if the patient improves with edrophonium, an increase in cholinesterase inhibitor dosage may be indicated.

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Myasthenia gravis
Treatment: Long-term therapy for myasthenia gravis is usually accomplished with neostigmine, pyridostigmine, or ambenonium. If muscarinic effects of such therapy are prominent, they can be controlled by the administration of antimuscarinic drugs such as atropine.
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Toxicity of cholinoceptor stimulants

Direct acting muscarinic stimulants (ex. Pilocarpine) meiosis, nausea, vomiting, diarrhea, salivation, sweating, cutaneous vasodilation, and bronchial constriction. These effects are all blocked by atropine. Acute toxicity (treatment symptomatic) (1) central stimulation, which cause convulsions and may progress to coma and respiratory arrest; (2) skeletal muscle paralysis (3) hypertension and cardiac arrhythmias. Acute toxicity: Treated by atropine and pralidoxime) 1- meiosis, nausea, vomiting, diarrhea, salivation, sweating, cutaneous vasodilation, and bronchial constriction 2- These manifestations are followed by: (1) central stimulation, which cause convulsions and may progress to coma and respiratory arrest; (2) skeletal muscle paralysis (3) hypertension and cardiac arrhythmias.
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Direct-Acting Nicotinic Stimulants

Cholinesterase inhibitors