Cholinoceptor-Activating Drugs Definition Classification -- Spectrum of action -- Mode of action Effects -- Ocular, Respiratory Tract, Cardiac, Blood Vessels, GI & Urinary Tract Clinical Uses Representative Drugs: Acetylcholine & Pilocarpine

Mode of Action

Indirect-Acting Drugs

Anticholinesterase Drugs 1.Drugs that inhibit Acetylcholine acetylcholinesterase hydrolyze (AchE) Acetic Acid + Choline Parasympathetic Response 2. Acetylcholine + Receptor

Anticholinesterase Drugs Similar Terminologies Anticholinesterase agents Cholinesterase inhibitor

Classification of Anticholinesterase Drugs Two Types Shorter-acting : reversible -- Edrophonium -- Neostigmine, Physostigmine, Pyridostigmine -- Donepezil Longer-acting: irreversible -- Organophosphates echothiophate, isoflurophate, malathion

Mechanism of Cholinesterase Inhibition

Mechanism of Cholinesterase Inhibition Rapid Acetylcholine Slow Neostigmine Very Slow Isoflurophate

Reversible Inhibitors Edrophonium Quaternary alcohol Not a substrate for the enzyme Binding: reversible Renal excretion: rapid (10 min) Clinical use: Differential diagnosis for suspected Myasthemia Gravis (muscle weakness)

Myasthemia Gravis Autoimmune disease Antibodies bind to N-R Symptoms: -- severe fatigue -- muscle functions

Reversible Inhibitors Neostigmine, Pyridostigmine, Physostigmine Neostigmine & Pyridostigmine -- quatermary amine compound -- less well absorbed from gut -- can not cross BBB Physostigmine -- tertiary amine -- well absorbed from gut -- can penetrate BBB They bind to enzyme, will be hydrolyzed slowly (several hours)

Reversible Inhibitors Clinical Uses: Long-term treatment for myasthemia gravis Counteract curariform drug toxicity -- Neostigmine & Pyridostigmine Counteract atropine overdose & glaucoma -- Physostigmine

Neostigmine Organ system effects Clinical use Myasthenia gravis Skeletal muscle Gastrointestinal tract Neostigmine Organ system effects Clinical use Myasthenia gravis Postoperative ileus and urinary retention Paroxysmal supraventricular tachycardia Overdosage of muscle relaxants intoxication (tubocurarine) ⑤ Atropine intoxication

Neostigmine Adverse reaction large dosage: nausea, vomiting, abdominal pain, tachycardia, fibrillation of muscle fibers, "cholinergic crisis" Contraindication Mechanical intestinal obstruction (ileus) and urinary obstruction Bronchial asthma

Reversible Inhibitors Donepenzil: Centrally acting Ach in CNS Treatment for Alzheimer’s Disease

Irreversible Inhibitors Organophosphates -- echothiophate, isoflurophate, malathion Uses -- Treatment: few -- Pesticide & Chemical warfare agents: most Poisoning -- Accidental -- Intentional

Irreversible Inhibitors Organophosphates Phosphoric acid High lipid-soluble Effectively absorbed from all sites -- Skin -- Mucous membrane -- Gut Oral, ocular, topical

Irreversible Inhibitors Organophosphates Treatment for -- chronic glaucoma (long-term control of IP ) -- strabismus: ocular deviation -- head lice

Irreversible Inhibitors Organophosphates Poisoning -- Decontamination: lavage -- Support of CV and Resp. funtions -- Use Ach-R antagonist (atropine) -- Use Ach E reactivator (ASAP)

Cholinesterase reactivator PAM (pralidoxime iodide) Quaternary nitrogen High affinity to phosphorus

Cholinesterase reactivator Phosphated-PAM PAM

Cholinesterase reactivator Pralidoxime It directly combines with free- organophosphates , prevents them further combine with AChE It has marked action on neuromuscular junctions and promptly inhibits fasciculation. Improves CNS symptoms It can’t directly antagonize the accumulated ACh, therefore, it should be used with atropine

Important Points The direct-acting acetylcholine receptor agonist include choline esters and plant alkaloids. Acetylcholine has limited clinical application (why?) Pilocarpine is used to treat glaucoma and dry mouth. The cholinesterase inhibitors indirectly activate Ach receptors by increasing the synaptic concentration of Ach. These drugs have both parasympathetic and somatic nervous system effects.

Important Points The reversible Ach E inhibitor, Edrophonium , which is used to diagnose myasthemia gravis, and, Neostigmine, which can be used for long-term treatment of myasthemia gravis. The irreversible Ach E inhibitors are organophos- phate compounds that are widely used as pesticides and less commonly used in medical therapy.

Important Points Organophosphates toxicity is treated with atropine and cholinesterase reactivator called pralidoxime.

Question What are the different results between using atropine and PAM for organophosphate poisoning? Why?

What is Glaucoma? increased pressure within the eye. Cells inside the eye produce aqueous humor that maintains the shape of the eye and nourishes the tissues inside the eye. The balance of fluid production and drainage is responsible for maintaining normal pressure within the eye. In glaucoma, the drain becomes clogged but the eye keeps producing fluid. Therefore, the pressure in the eye increases. The increased pressure in the eye actually can cause the eye to stretch and enlarge

How does Glaucoma affect the eye? Vision Loss. Pressure damage to the optic nerve and decreased blood flow to the retina, results in loss of vision. However, if the pressure in the eye remains uncontrolled, the retina degenerates and vision is permanently lost. Permanent blindness can occur within several hours if the pressure is very high and the glaucoma develops rapidly Pain. Humans have normal intraocular pressures between 10 and 20 mmHg. Glaucoma often results in pressures of 20-28 mmHg in humans. The pain persists in the form of a constant headache or migraine. This discomfort can result in decreased activity, less desire to play, irritability, or decreased appetite

What is Myasthemia Gravis Myasthenia gravis (from Greek"muscle",  "weakness", and Latin: gravis "serious"; abbreviated MG) is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatigue. Muscle weakness is caused by circulating antibodies that block acetylcholine receptors at the postsynapticneuromuscular junction, inhibiting the excitatory effects of the neurotransmitter acetylcholine on nicotinic receptors at neuromuscular junctions.

What is Myasthemia Gravis Fatigability: Muscles become progressively weaker during periods of activity and improve after periods of rest. Muscles that control eye and eyelid movement, facial expressions, chewing,talking, and swallowing are especially susceptible. The muscles that control breathing and neck and limb movements can also be affected. Often, the physical examination yields results within normal limits.

What is Myasthemia Gravis The onset of the disorder can be sudden. Often symptoms are intermittent. The diagnosis of myasthenia gravis may be delayed if the symptoms are subtle or variable.

What is Myasthemia Gravis In most cases, the first noticeable symptom is weakness of the eye muscles. In others, difficulty in swallowing and slurred speech may be the first signs. The degree of muscle weakness involved in MG varies greatly among patients, ranging from a localized form that is limited to eye muscles (ocular myasthenia), to a severe and generalized form in which many muscles--sometimes including those that control breathing--are affected. Symptoms, which vary in type and severity, may include asymmetrical ptosis (a drooping of one or both eyelids), diplopia (double vision) due to weakness of the muscles that control eye movements, an unstable or waddling gait, weakness in arms, hands, fingers, legs, and neck, a change in facial expression, dysphagia (difficulty in swallowing), shortness of breath and dysarthria (impaired speech, often nasal due to weakness of the velar muscles).

What is Myasthemia Gravis In myasthenic crisis a paralysis of the respiratory muscles occurs, necessitating assisted ventilation to sustain life. In patients whose respiratory muscles are already weak, crises may be triggered by infection, fever, an adverse reaction to medication, or emotional stress. Myasthenia does not directly affect the heart muscle.