AUTONOMIC NERVOUS SYSTEM AND AUTONOMIC DRUGS

• I. Parasympathetic nervous system drugs:

• 1. The human’s body is made up of systems including nervous system.

• The Nervous system is made up of central nervous system (CNS) and peripheral nervous system.

• The peripheral nervous system is made up of two divisions:

A. Efferent division ( include neurons that leave the CNS and transmit impulses from the CNS to the peripheral parts of the body)

B. Afferent division (Include neurons that bring impulses from the peripheral parts of the body to the CNS)

• The Efferent division of the peripheral nervous system is also divided into:

a) Autonomic nervous system

b) Somatic nervous system

• The autonomic nervous system is subdivided into:

I. Parasympathetic nervous system (PNS)

II. Sympathetic nervous system (SNS)

III. Enteric nervous system (ENS)

• Parasympathetic nervous system:• It is a pathway of impulses from the CNS to

the peripheral parts of the body.• This path consists of two neurons meet each

other in a node called GANGLIA

• The neuron/fibres which is before the ganglia from the CNS side is called PRE-GANGLIONIC Neuron

• The fiber which is in front of ganglia from the organ side is called POST-GANGLIONIC Neuron.

• the preganglionic fibers are long while the post-ganglionic fibers are short

• The parasympathetic preganglionic fibers arise from the cranial nerves (III, VII, IX and X) of brain stem and from 2nd, 3rd and 4th sacral segments of the spinal cord

• The preganglionic fibers run almost to the organ which is innervated and synapse with postganglionic fibers in ganglia near or on the effector organ.

Figure: shows areas on spinal cord from where parasympathetic preganglionic fibers (blue colored lines) arise.

Organs which are innervated by parasympathetic nervous system:

• The cranial nerves III, VII and IX affect :• Pupil• Salivary gland secretion

The vagous nerve X carries fibers to:

• Heart • Lungs• Stomach• Upper intestine• ureter

• The sacral fibers innervate:

• The distal colon• Rectum• Bladder and • reproductive organs.

Function of parasympathetic nervous system

• In physiological terms, the parasympathetic nervous system is concerned with conservation and restoration of energy.

• It causes:• Reduction in heart rate• Reduction in blood pressure• Facilitates digestion and absorption • Facilitates the excretion of waste products.• Usually acts to oppose or balance the actions of

sympathetic system and dominates over it in “rest and digest” situations

• Neurotransmitter:• The chemical transmitter at both pre and

post-ganglionic synapses in the parasympathetic nervous system is Acetylcholine (Ach).

• The drugs acting on these receptors are:

A. Cholinergic agents

B. Anticholinergic agents

A. Cholinergic agents

• These are the agents that bind to the Ach receptors or which inhibit the acetylcholineesterase (AChE) and make Ach available for binding with its receptors.

• Classification of cholinergic agents:

I. Direct acting cholinergic agents:

i. Choline esters:AcetylcholineMethacholine

CarbacholBethanchol

i. Naturally occuring alkaloids:

PilocarpineMuscarineNicotineLobelineArecholine

I. Indirectly acting cholinergics:

i. Reversible:

Physostigmine (tertiary amine)

Neostigmine (quaternary)

Pyridostigmine (-do-)

Edrophonium (-do-)

i. Irreversible:a. Alkyl-phosphate group:TEPP (Tetra-ethyl-pyro-phosphate)HETP (Hexa-ethyl-tetra-phosphate)DFP (DI-isopropyl-fluro-phosphate)OMPA (Octa-methyl-pyrophosphate)

b. Aryl group:ChlorothionMalathionParathionDiazinon

• Miscellaneous :

Tacrine

Rivastigmine

Galantamine

Donepezil

ACETYLCHOLINE

Ach is a cholinergic agent and considered as a prototype of this group.

• Synthesis of Ach:• Its synthesis starts by pumping of choline from extra

cellular space to intra cellular space at nerve ending where the choline will combine with acetyl-coA in the presence of choline-acetyltransferase to form Ach.

• Storage of Ach:

• After synthesis of Ach, it is stored in a synaptic vesicles at the nerve ending as shown in the diagram

• Release of Ach:

• On arrival of nerve impulse, the vesicles come close to nerve ending’s membrane and make pores/channels for the release of Ach.

• Binding of Ach:

• After Ach released from the synaptic vesicles, it diffuses across the synaptic space where it will bind with specific receptors on the postsynaptic neuron/organ as well as presynaptic neuron.

• There are two types of receptors for Ach

a) Muscarinic receptors (M1,M2, M3, M4, M5)b) Nicotinic receptors (Nn, Nm)

• Fate of Ach:

• Ach is very rapidly hydrolyzed in the synaptic cleft by acetylcholinesterase (AChE) to choline and acetate.

• The choline is transported back to the presynaptic nerve ending by a Na+ coupled transportor where it will be acetylated to form another Ach and stored till next impulse occur.

• Pharmacological actions:

• Muscarinic actions:

• Eye(M3):

• Causes constriction of the smooth muscle of iris sphinctor/pupil leading to myosis

• Causes contraction of the ciliary’s muscle leading to accommodation for near vision.

• The iris will be pulled away from the angle of the anterior chamber as a result the trabecular meshwork will be opened leading to drainage of fluid and dec I.O.P.

• CVSHeart(M2) :SA node rate dec Atrial contractility dec AV node rate dec Ventricular contractility slightly decBlood vessels (M3): only skin of face and neck is innervated it cause dilation of vessels causing flushing

• Respiratory system (M3):• Ach stimulates M3 receptors leading to constriction

of bronchial muscles and increase bronchial secretions leading to asthma

• GIT (M3):• It will increase the motility of GIT wall and relaxes

the sphincter and causes defecation and diarrhea

• Genitourinary tract (M3):• It will cause contraction of the urinary bladder and relaxation

of its sphincter leading to maturation• uterus of pregnant will be contracted

• Secretory glands and temperature (M):• Lacrimal, nasopharyngeal, salivary, sweat glands secretions as

well as gastric secretions will be increased skin temperature will increase.• CNS:• both M1 and M3 are available in CNS and present variety of

response for cholinergic agents

• Nicotinic actions:• they will cause stimulation and contraction of

skeletal muscles causing inc in strength of muscle and in high doses they cause paralysis of the muscle

• It will stimulate and activate all the ganglias including adrenal medulla.

• It will stimulate central nervous system leading in high doses to exitation

• Clinical uses:

Clinically Ach is not used due to its rapid metabolism by acetylcholinesterase at the synaptic cleft

But its availability at the synaptic cleft can be increased by indirect acting agents that bind the acetylcholineesterase and thus prevent the degradation of the acetylcholine and make it available for action.

• Alzheimer’s disease:TacrineRivastigmine GalantamineDonepezil

• glaucoma:PilocarpineCarbacholPhysostigmineEchothiophate

• For GIT disorders like Postoperative ileus:• For Urinary disorders like urinary retention that may occur

postoperatively or postpartum

Bethanechol

• Myasthenia gravis:

Edromethonium (diagnosis)NeostigminePyridostigmined-tubocurarine (diagnosis)

• Anticholinergic intoxication:Physostigmine (only in dangerous situation of elevated temperature and

cardiac arrhythmias)

• Smoking cessation: Varenicline• Dryness of mouth associated with sjogren’s syndrome:Pilocarpine (has been used)Cevimeline (newly developed drug)

• Adverse effects:• CNS: excitation• Eye: myosis and lacrimation• Mouth: excessive salivation• Bronchi: excessive secretions and bronchial contraction leading to Asthma• Heart: bradycardia • GIT: increase acidic secretions and may cause peptic ulcer, Increase GIT

motility leading to cramps and diarrhea• Skin: excessive sweating• Urinary system: involuntary urination• Skeletal muscle: excitation and in high dose cause muscle paralysis

• Contraindications:

• Asthmatic patient • Peptic ulcer• Bradycardia• Obstructive urinary bladder

B. ANTICHOLINERGIC AGENTS