Autonomic Nervous SystemLecture 2

Cholinergic Drugs

Parasympathetic Nervous System

• Works to save energy, aids in digestion, and supports restorative, resting body functions.– Decrease in heart rate– Increased gastro intestinal tract tone and

peristalsis– Urinary sphincter relaxation– Vasodilation – decrease in blood pressure

Body Responses – “rest and digest”

• Dilation of blood vessels in skin• Decrease heart rate (bradycardia)• Increase secretion of digestive enzymes• Constriction of smooth muscle of bronchi• Increase in sweat glands - cooling• Contraction of smooth muscles of urinary

bladder• Contraction of smooth muscle of skeletal

system

Cholinergic ReceptorsM1 Secretory glands salivation, stomach acid,

sweating, lacrimation

M2 Heart Decreases heart rate bradycardia

M3 Smooth muscle (GI/GU/Resp)

Contraction of smooth muscles (some) diarrhea, bronchospasm, urination

M3 Pupil and ciliary muscle Contracts MiosisIncreased flow of aqueous humor

Nm Skeletal muscle end plate

Contraction of skeletal muscle

Nn Autonomic ganglia, Adrenal Medulla

Secretion of EpinephrineControls ANS

Cholinergic Drugs• Often called parasympathomimetic drugs, because

their action mimics the action of the PSNS.• Also called as cholinomimetic.• Stimulate parasympathetic nervous system in same

manner as does acetylcholine• May stimulate cholinergic receptors directly or slow

acetylcholine metabolism at synapses (affect the enzyme acetylcholinesterase)

• Cholinergic agonists are two types : 1.Direct acting 2.Indirect acting

Direct acting cholinergic agonist

• They act by binding directly to cholinoceptors. Direct acting cholinergics are lipid insoluble.

• Do not readily enter the CNS so effects are peripheral.• Resistant to metabolism by acetylcholinesterase.• Effects are longer acting than with acetylcholine.

• Acetylcholine

• Methacholine Muscarine

• Carbachol Pilocarpine

• Bethanechol Arecoline

Drug Effects of Cholinergic Agents

• Cardiovascular effects– Decreased heart rate( Bradycardia)– Vasodilation (NO mediated)

• Stimulate intestine and bladder– Increased gastric secretions– Increased gastrointestinal motility– Increased urinary frequency

Drug Effects of Cholinergic Agents

• Stimulate pupil– Constriction (miosis), Spasm of accomodation– Reduced intraocular pressure (increased outflow)

• Respiratory effects– Bronchial constriction, narrowed airways

• Increased salivation and sweating

Drug Effects of Cholinergic Agents

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MiosisSalivationLacrimationUrinationBronchoconstrictionDefaecation Decreased heart rate

Acetylcholine• One of the main neurotransmitters of the ANS is

acetylcholine• Acetylcholine is released at preganglionic fibers of both

the sympathetic and parasympathetic nervous system• Also released from postganglionic sympathetic neurons

that innervate the sweat glands and from motor neurons that innervate the skeletal muscles

• It is a quaternary ammonium compound so cannot penetrate the membrane.

• Does not have any therapeutic importance, because rapid inactivation by acetylcholinesterases.

• It has both Muscarinic & Nicotinic actions .

Bethanechol

• Not hydrolyzed by acetylcholinesterases• Actions• Directly stimulates M receptors causing increased

intestinal motility & tone• It stimulates detrusor muscle of the bladder while trigone

& sphincters are relaxed causing expulsion of urine• Therapeutic Uses:• Paralytic ileus • Urinary retentions• Helpful for postsurgical atony of the bladder

and GI tract

PilocarpineAn alkaloid, lipid soluble & is stable to hydrolysis

by cholinsterases. Actions: When applied locally to cornea Produces rapid

miosis & contraction of ciliary muscle produces spasm of accommodation & vision is fixed at particular distance making it impossible to focus for far situated objects

Therapeutic Use : In Glaucoma it opens trabecular meshwork around schlemm’s canal

• causes drainage of aqueous humor• IOP immediately decreases.

Indirect acting Cholinergic agonists

• They act through inhibition of Acetyl cholinesterase enzyme, so increases Acetylcholine level in the synapse.

• Accumulation of acetylcholine then occurs which enhances the activation of the nicotinic and muscarinic receptors.

• Anticholinesterase drugs are either reversible or irreversible inhibitors of acetylcholinesterase

• Reversible: Irreversible:• Neostigmine Organophosphates • Physostigmine Dyflos, Echothiopate

• Pyridostigmine Parathion,

Malathion• Edrophonium Tabun, Sarin,

Soman• Tacrine Carbamates• Donepezil Carbaryl, Propoxur(baygon)

• Physostigmine - only anticholinesterase capable of crossing the blood brain barrier. Is more lipid soluble. Used as an antidote for overdosage of anticholinergics such as: atropine, antihistamines, TCA, phenothiazines. May also be used in treatment of glaucoma.

• Pyridostigmine - is the maintenance drug of choice for patients with Myasthenia gravis.

• Neostigmine - prototype anticholinesterase agent. Used for long-term treatment of myasthenia gravis and as an antidote for tubocurarine and other non-depolarizing agents in surgery.

• Donepezil - • Used in the treatment of mild to moderate

Alzheimer’s disease.• Helps to increase or maintain memory and

learning capabilities.

Uses of Indirect Cholinergic agonists

• Glaucoma – Pilocarpine, Physostigmine

• Edrophonium to test Myasthenia gravis, Neostigmine and pyridostigmine in treatment of M.gravis.

• Postoperative paralytic ileus - Neostigmine

• Postoperative decurarization – Neostigmine(reverses muscle paralysis)

• Cobra bite – edrophonium (prevent respiratory paralysis.

• atropine poisoning – Physostigmine (antogonizes both central and peripheral effects).

• Alzheimer’s Disease – Donepezil, galantamine, tacrine, rivastigmine.

• TCA, Phenothiazines, overdose – Physostigmine.

Cholinergic Agents: Side EffectsSide effects are a result of overstimulation

of the PSNS.• Cardiovascular:

– Bradycardia, hypotension, conduction abnormalities (AV block and cardiac arrest)

• CNS:– Headache, dizziness, convulsions

• Gastrointestinal:– Abdominal cramps, increased secretions,

nausea, vomiting

Cholinergic Agents: Side Effects• Respiratory:

–Increased bronchial secretions, bronchospasms

• Other:–Lacrimation, sweating, salivation, loss

of binocular accommodation, miosis

Acute toxic effects of irreversible cholinesterase inhibitors (OP poisoning )

• These agents are lipid soluble

• Can enter the body by the eye,skin, respiratory system and GI tract.

• organophosphate insecticides (malathion, parathion) or nerve gases (sarin, tabun, soman)

• These agents cause excessive cholinergic stimulation (muscarinic) and neuromuscular blockade

• Cholinergic crisis occurs because the irreversible anticholinesterase poison binds to the enzyme acetylcholinesterase and inactivates it. Thus, acetylcholine remains in cholinergic synapses causing excessive stimulation of muscarinic and nicotinic receptors.

Treatment of OP poisoningEmergency treatment includes:• Decontamination of clothing• Flushing poison from skin and eyes• Activated charcoal and lavage for GI

ingestion• Atropine to counteract the muscarinic

effects (2mg IV every 10 min till pupil dilates, max 50-100mg)

• To relieve the neuromuscular blockade by nicotinic effects, give pralidoxime, a cholinesterase reactivator.

• Pralidoxime causes the anticholinesterase poison to release the enzyme acetylcholinesterase.

• Give Pralidoxime as soon as possible as if too much time passes, the poison bond becomes too strong (aging) for the pralidoxime to work.

• Other oximes- obidoxime, diacetylmonoxime

Thank you!