Asmah Nasser, M.D.

M1 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 Miosis

Increased flow of aqueous humor

Nm Skeletal muscle end plate

Contraction of skeletal muscle

Nn Autonomic ganglia, Adrenal Medulla

Secretion of Epinephrine

Controls ANS

Classification and examples of direct and indirect acting Cholinergic agonists

Brief discussion of few of the above examples

Pathophysiology, diagnosis, and Management of ◦ Myasthenia gravis and tensilon test◦ Glaucoma◦ Alzheimer's disease◦ Organo Phosphorus compound poisoning

Heart: Cardiac suppressant…Bradycardia, hypotension,

Eye: Miosis, cycloplegia, facilitates aqueous humour drainage, lacrimation

Bronchospasm Excess secretion from glands….salivary,

bronchial, lacrimal glands etc….. GIT /bladder… smooth muscle contraction and

relaxation of sphincters…, increased motility, diarrhea, vomiting , increased micturation (urinary urgency)

Often called parasympathomimetic drugs, because their action mimics the action of the PSNS commonly

Also called as Cholinergic drugs or cholinomimetric

Cholinergic agonists are two types :

1.Direct acting

2.Indirect acting

They act by binding directly to cholinoceptors

Acetylcholine (Synthetic analogue of ACH)

Carbachol

Bethanechol

Pilocarpine (naturally occurring alkaloid)

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

Reversible:◦ Neostigmine◦ Physostigmine ◦ Pyridostigmine◦ Edrophonium◦ Tacrine ◦ Danopezil

•Irreversible :

Ecothiophate

Malathion

Parathion

Sarin

It is a quaternary ammonium compound so Cannot penetrate the membrane

Does not have any therapeutic importance, because of multiplicity of actions & rapid inactivation by acetylcholinesterases

It has both Muscarinic & Nicotinic actions Neurotransmitter for pre-ganglionic

neuron

Not hydrolyzed by acetylcholinesterases It has strong Muscarinic action & no Nicotinic action 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

An alkaloid, lipid soluble & is stable to hydrolysis by cholinsterases It has Muscarinic activity only .

Actions- When applied locally to cornea Produces rapid

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

Therapeutic Use : In GlaucomaIt opens trabecular meshwork around schlemm’s

canal ∴ causes drainage of aqueous humor ∴ IOP immediately decreases.

Cholinesterase inhibitors. Can be reversible or irreversible.

Reversable:◦ Neostigmine ◦ Physostigmine

◦ Edrophonium ◦ Tacrin◦ Danopezil

Irreversible ◦ Malathion and Parathion◦ Sarin◦ Ecothiopate

◦

Neostigmine in M.gravis

Physostigmine in Glaucoma, atropine overdose

Ecothiopate in glaucoma

Edrophonium in M.gravis to test

Tacrin, Danopezil in Alzheimer's

Malathion, Parathion as insecticides

An autoimmune process causes production of antibodies that decrease the number of functional nicotinic receptors on the postjunctional end plates.

Frequent findings are Double vision…. diplopia, Drooping of eyelids…. ptosis, Dysarthria ……Difficulty in speaking Dysphagia …..difficulty swallowing, Difficult in Daily routines Day passes, limb weakness increases. Difficulty in respiration Severe disease may affect all

the muscles, including those necessary for respiration. Death

Immunosuppressant drugs Thymectomy Acetyl Cholinesterase inhibitors

◦ Neostigmine◦ Pyridostigmine ◦ Ambenonium ◦ Edrophonium

Other supportive measures

Neostigmine Has a strong influence at the neuromuscular junction

Pyridostigmine: Has a longer duration of action than neostigmine

Ambenonium :Available only in oral form; cannot be used if patient is unable to swallow tablets

Edrophonium: Diagnostic agent for myasthenia gravis and to diffrentiate myasthenic and cholinergic crisis (Tensilon test )

Clinical situations in which severe myasthenia (myasthenic crisis) must be distinguished from excessive drug therapy (cholinergic crisis) usually occur in very ill myasthenic patients

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 (1–2 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.

A progressive disorder involving neural degeneration in the cortex

Leads to a marked loss of memory and of the ability to carry on activities of daily living

Cause of the disease is not yet known◦ ?????? There is a progressive loss of ACh-

producing neurons and their target neurons

Tacrine

◦ Side effect: HepatoToxicity

◦ First drug to treat Alzheimer’s dementia

Rivastigmine

◦ Available in solution for swallowing ease

Donepezil

◦ Has once-a-day dosing advantage

Only Ecothipate is used clinically in Glaucoma. This is the long acting drug used in glaucoma

◦ Rest of the drugs are used as pesticides or war

gases or poisons: Malathion and Parathion

The dominant initial signs are those of

muscarinic excess: miosis, salivation, sweating,

bronchial constriction, vomiting, and diarrhea.

Central nervous system involvement usually

follows rapidly, accompanied by peripheral

nicotinic effects, especially depolarizing

neuromuscular blockade.

(1) maintenance of vital signs—respiration in particular may

be impaired;

(2) decontamination to prevent further absorption—this may

require removal of all clothing and washing of the skin in

cases of exposure to dusts and sprays; and

(3) Atropine parenterally in large doses, given as often as

required to control signs of muscarinic excess stimulation .

(4)Therapy often also includes treatment with pralidoxime

(Acetylcholinesterase reactivator)

Irreversible cholinesterate inhibitor. LONG acting Used in Glaucoma

Direct/indirect acting cholinergic drugs actions, adverse effects, toxicity features of OP poisoning

In OP poisoning atropine used to reverse only the muscarinic effects..

Pralidoxime used to reactivate the enzyme

Miosis Excessive salivation Bradycardia Bronchospasm Abdominal cramps, vomiting, diarrhea,

urination Sweating

Asmah Nasser, M.D.

About 70 million people are affected Worldwide ◦ 10% of these (~7 million) are blind from

glaucoma US data: > 40 yrs of age, 3 million about 120, 000 Americans are blind from it.

Most common cause of blindness among Black-Americans.

50% of all patients, are not aware they have it, until late

Types of Glaucoma:1. Open Angle Glaucoma – Excessive production of Aqueous Humour2. Closed Angle Glaucoma – Outflow obstruction of Aqueous Humour

Two Therapy aimed at:1. Reduce (Production, Synthesis or Secretion) Dorzolamide, Acetazolamide, Timolol, Betoxolol and

Apraclonidine

2.Facilitate the drainage: Pilocarpine, Carbachol,

Ecothiopate ,Mannitol and Latanoprost

Courtesy : Katzung

Mannitol◦ reduces IOP by reducing vitreous volume by

inhibiting the enzyme carbonic anhydrase Reduces the secretion/synethesis

◦ Timolol topical eye drops Non-selective β blockade

◦ Betaxolol eye drops Selective β1 blockade Reduces the synthesis

◦ Acetazolamide (oral), Dorzolamide (topical ) :

reduces the synthesis of aqueous humour,

inhibits the enzyme carbonic anhydrase

◦ α2 receptor agonist (apraclonidine 1%, topical

drops).

1. Pilocarpine, Carbachol, Ecothiopate and

Physostigmine :Causes Ciliary muscle contraction,

increases Irido-corneal angle and open trabecular

meshwork.

2. Prostaglandins : Latanoprost : increase the outflow

through uveoscleral meshwork

Excessive β adrenergic receptor mediated production and secretion of aqueous humor from the ciliary body epithelium.

Best treated with betablockers

Results from obstruction of canal of Schlemm through which aqueous humor was supposed to be filtrated out .

Caused by1. Mydriatics : Anti-cholinergic drugs2. Antidepressants : SSRI drugs

Treatment: Pilocarpine, Carbachol , ecothiopate and physostigmine