1. 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

2. Mode of Action

3. Indirect-Acting Drugs

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

5. Anticholinesterase Drugs
Similar Terminologies
Anticholinesterase agents
Cholinesterase inhibitor

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

7. Mechanism of Cholinesterase Inhibition

8. Mechanism of Cholinesterase Inhibition
Rapid
Acetylcholine
Slow
Neostigmine
Very Slow
Isoflurophate

9. 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)

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

11. 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)

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

13. 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

14. 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

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

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

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

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

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

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

21. Cholinesterase reactivator
Phosphated-PAM
PAM

22. 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

23. 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.

24. 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.

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

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

28. 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

29. 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 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

30. 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.

31. 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.

32. 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.

33. 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).

34. 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.