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Anticholinesterase Drugs

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Mechanism of Action

1. Stimulates muscarinic receptors at ANS effector organs (heart, smooth muscle, glands)
2. Stimulates then depresses nicotinic receptors at all ANS ganglia and skeletal muscle (NMJ)
3. Stimulates then depresses CNS cholinergic sites (only with lipid-soluble/tertiary amine drugs)

• Lippincott Illustrated Reviews: Pharmacology, p. 159

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Classification

Anticholinesterase Drugs
├── Reversible
│   ├── Short-acting: Edrophonium
│   ├── Intermediate-acting: Physostigmine, Neostigmine, Pyridostigmine, Rivastigmine, Donepezil, Galantamine
│   └── Long-acting (but reversible): Organophosphate-based ophthalmic agents (some)
└── Irreversible
    └── Organophosphates: Echothiophate, Parathion, Malathion, Nerve agents (Sarin, Soman, VX)

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I. Reversible Anticholinesterases

A. Short-Acting: Edrophonium

• Structure: Quaternary amine (cannot cross BBB - peripherally restricted)
• Mechanism: Binds reversibly to the active center of AChE, electrostatically (no covalent bond)
• Duration: 10-20 minutes (rapid renal elimination)
• Uses (historical):
  • Diagnosis of myasthenia gravis (Tensilon test) - IV injection causes rapid, brief improvement in muscle strength in MG patients
  • Assessment of adequacy of treatment with longer-acting cholinesterase inhibitors (distinguishing myasthenic crisis from cholinergic crisis)
  • Note: Edrophonium has been removed from the market due to availability of better diagnostic methods (anti-AChR antibody tests)
• Katzung's Basic and Clinical Pharmacology, 16th Ed., p. 189; Lippincott, p. 160

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B. Intermediate-Acting: Physostigmine

• Structure: Tertiary amine (natural alkaloid from Calabar bean) - crosses the BBB
• Mechanism: Carbamic acid ester; forms a stable carbamoylated intermediate with AChE (reversibly inactivated). Duration: 30 min to 2 hours
• Actions:
  • Stimulates muscarinic + nicotinic sites of ANS
  • Stimulates nicotinic receptors at NMJ (muscle twitches, fasciculations, paralysis at high doses)
  • CNS effects (due to tertiary structure): stimulates central cholinergic sites
• Therapeutic uses:
  • Reversal of anticholinergic (atropine) overdose - can reverse CNS effects (delirium, coma), unlike neostigmine
  • Historically used in glaucoma
• Adverse effects: Convulsions at high doses, bradycardia, decreased cardiac output, skeletal muscle paralysis

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C. Intermediate-Acting: Neostigmine

• Structure: Quaternary amine (synthetic carbamic acid ester) - cannot cross BBB
• Mechanism: Reversible carbamylation of AChE, similar to physostigmine. Duration: 30 min to 2 hours
• Actions: Greater effect on skeletal muscle than physostigmine; can stimulate then paralyze skeletal muscle
• Therapeutic uses:
  • Reversal of non-depolarizing neuromuscular blockade (e.g., post-surgery)
  • Myasthenia gravis (symptomatic management)
  • Paralytic ileus and urinary retention (0.5-1 mg SC)
  • Acute colonic pseudo-obstruction (Ogilvie's syndrome)

• Adverse effects: Salivation, flushing, hypotension, nausea, diarrhea, bronchospasm (generalized cholinergic stimulation). No CNS effects. Contraindicated in mechanical bowel/urinary obstruction
• Lippincott, p. 161; Katzung, p. 187

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D. Pyridostigmine

• Structure: Quaternary amine - peripherally restricted
• Longer duration than neostigmine (~3-6 hours)
• Uses: Chronic management of myasthenia gravis (oral; preferred over neostigmine for long-term use). Also used in nerve agent prophylaxis (military)

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E. CNS-Acting Agents (Alzheimer's Disease)

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II. Irreversible Anticholinesterases

A. Organophosphates (Echothiophate, Parathion, Malathion, Nerve Agents)

• Mechanism: Covalently bind via phosphate group to the serine hydroxyl at the active site of AChE → permanent inactivation
• Recovery requires synthesis of new enzyme molecules

• Aging: After covalent modification, the phosphorylated enzyme slowly loses one alkyl group ("aging") - making it impossible for pralidoxime to reactivate the enzyme
• Faster aging agents: Soman (seconds) > Sarin > VX > Echothiophate
• Echothiophate (historical use): Topical ophthalmic solution for open-angle glaucoma; withdrawn due to risk of cataract formation
• Parathion/Malathion: Agricultural insecticides; major source of accidental poisoning
• Nerve agents (Sarin, Soman, VX, Tabun): Chemical warfare agents; act extremely rapidly at high concentrations
• Lippincott, p. 164-165

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III. Pharmacological Effects (SLUDGE + Nicotinic + CNS)

Muscarinic Effects (SLUDGE / DUMBELS)

Nicotinic Effects (NMJ + Ganglia)

• NMJ: Muscle fasciculations → weakness → paralysis (depolarizing block)
• Ganglia: Tachycardia, hypertension (can counteract some muscarinic effects)

CNS Effects (tertiary amines / lipid-soluble organophosphates)

• Anxiety, restlessness
• Seizures / convulsions
• Loss of consciousness, coma
• Respiratory failure (central + peripheral: bronchospasm + diaphragm paralysis)

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IV. Therapeutic Uses Summary

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V. Treatment of Anticholinesterase Poisoning (Organophosphate Toxicity)

Clinical Presentation (Cholinergic Crisis)

• Dominant signs: bronchospasm, excessive secretions, bradycardia, seizures, miosis, diaphoresis, muscle paralysis

Treatment

1. Pralidoxime (2-PAM) - oxime reactivator of AChE:
   • Must be given before aging occurs (within hours for most agents)
   • Has a charged group that displaces the phosphate from AChE
   • Reverses both peripheral muscarinic and nicotinic effects
   • Does NOT penetrate CNS - cannot reverse central effects
   • Ineffective once aging has occurred, and cannot reverse carbamate (e.g., physostigmine, neostigmine) toxicity
2. Atropine (high doses) - blocks muscarinic effects (bronchospasm, secretions, bradycardia)
3. Diazepam - for persistent convulsions
4. Supportive care: patent airway, oxygen, mechanical ventilation if needed

• Lippincott Illustrated Reviews: Pharmacology, p. 167; Katzung, p. 193

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Key Comparison: Physostigmine vs Neostigmine

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ANTICHOLINESTERASE DRUGS

(KD Tripathi-style | Exam-Ready Notes)

Note: KD Tripathi is not in the digital library, but the following is written in the same concise, point-by-point style KD Tripathi is known for, sourced from Lippincott Pharmacology, Katzung, and Goodman & Gilman.

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DEFINITION / INTRO (Write this first in exams)

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CLASSIFICATION (Most important for exams)

ANTICHOLINESTERASE DRUGS
│
├── A. REVERSIBLE
│   ├── 1. Short-acting (minutes)
│   │       Edrophonium (10–20 min)
│   │
│   ├── 2. Intermediate-acting (hours)
│   │       Physostigmine (30 min – 2 hrs) ← tertiary amine
│   │       Neostigmine (30 min – 2 hrs)   ← quaternary amine
│   │       Pyridostigmine (3–6 hrs)        ← quaternary amine
│   │       Ambenonium
│   │
│   └── 3. Long-acting (used in Alzheimer's)
│           Donepezil, Rivastigmine, Galantamine, Tacrine (withdrawn)
│
└── B. IRREVERSIBLE
        Organophosphates:
        Echothiophate (ophthalmic)
        Parathion, Malathion (insecticides)
        Sarin, Soman, VX, Tabun (nerve agents / chemical warfare)

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MECHANISM OF ACTION

• Edrophonium → binds electrostatically (non-covalent) to the anionic site of AChE. Very brief action.
• Physostigmine, Neostigmine → are carbamic acid esters. They carbamylate the esteratic site of AChE → the enzyme is reversibly inactivated (carbamylated enzyme regenerates slowly over 30 min to 2 hours).

• Covalently phosphorylate the serine-OH at the esteratic (active) site of AChE
• Enzyme is permanently inactivated
• Recovery only by synthesis of new enzyme (takes weeks)
• "Aging" = spontaneous loss of one alkyl group from the phosphorylated enzyme → makes the bond absolutely irreversible, even pralidoxime cannot work after aging

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PHARMACOLOGICAL EFFECTS

1. Muscarinic effects (SLUDGE mnemonic)

• Eye: Miosis + spasm of accommodation (ciliary muscle contracts)
• Heart: Bradycardia, reduced cardiac output, hypotension
• Lung: Bronchoconstriction + increased bronchial secretions
• Skin: Diaphoresis (sweating)

2. Nicotinic effects (NMJ)

• Low dose: Muscle fasciculations, increased muscle strength
• High dose: Depolarizing blockade → muscle weakness → paralysis
• Also: ganglionic stimulation → tachycardia, hypertension (can mask muscarinic bradycardia)

3. CNS effects (only with tertiary amines - physostigmine, organophosphates)

• Low dose: Restlessness, anxiety
• High dose: Tremors, convulsions, coma, respiratory depression

Key exam point: Quaternary amines (neostigmine, pyridostigmine, edrophonium) do NOT cross the BBB → no CNS effects. Tertiary amines (physostigmine) and organophosphates DO cross the BBB → CNS effects occur.

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INDIVIDUAL DRUGS (write these one by one in exams)

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1. EDROPHONIUM

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2. PHYSOSTIGMINE (The most important reversible agent - frequently asked)

• Antidote for anticholinergic (atropine) poisoning - can reverse BOTH peripheral AND central (delirium, coma) anticholinergic effects. This is its KEY use.
• Glaucoma (historically, topical)
• Alzheimer's disease (historical)

• Bradycardia, hypotension
• Convulsions at high doses
• Excessive secretions, bronchospasm
• Skeletal muscle paralysis (at high doses - via NMJ depolarizing block)

Exam tip: "Physostigmine crosses the BBB - so it is used to reverse CNS effects of atropine poisoning. Neostigmine does NOT cross BBB and therefore cannot reverse CNS effects."

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3. NEOSTIGMINE (Most clinically used - MUST know)

1. Reversal of non-depolarizing neuromuscular blockade (post-surgery) - always given WITH atropine/glycopyrrolate to prevent bradycardia
2. Myasthenia gravis - symptomatic treatment
3. Paralytic ileus - 0.5-1 mg SC
4. Urinary retention (post-op, post-partum, non-obstructive)
5. Ogilvie's syndrome (acute colonic pseudo-obstruction) - IV neostigmine

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4. PYRIDOSTIGMINE

• Quaternary amine, similar to neostigmine but longer duration (3-6 hrs)
• Preferred for chronic oral treatment of myasthenia gravis (neostigmine is used acutely)
• Also used as prophylaxis against nerve agent (soman) poisoning in military personnel
• Adverse effects same as neostigmine

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5. DONEPEZIL, RIVASTIGMINE, GALANTAMINE (Alzheimer's group)

Exam tip: "None of these drugs stop the progression of Alzheimer's - they only delay it and give modest symptomatic benefit."

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6. ORGANOPHOSPHATES (Irreversible agents)

• Echothiophate - ophthalmic use (glaucoma), now mostly withdrawn
• Parathion, Malathion - agricultural insecticides
• Sarin, Soman, Tabun, VX - chemical warfare nerve agents

1. Organophosphate covalently phosphorylates serine-OH of AChE → enzyme inactive
2. If left alone → "aging" occurs (loss of one alkyl group)
3. After aging → enzyme is absolutely irreversible - pralidoxime cannot work
4. Rate of aging: Soman > Sarin > Tabun > others (soman ages within seconds!)

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CHOLINERGIC CRISIS (Organophosphate Poisoning) - Very High Yield

Most common cause of death = RESPIRATORY FAILURE (bronchospasm + paralysis of diaphragm + CNS depression)

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TREATMENT OF ORGANOPHOSPHATE POISONING (Very Frequently Asked)

Step 1: Supportive care

• Clear airway, oxygen, mechanical ventilation if needed

Step 2: ATROPINE (given in HIGH doses - life-saving)

• Blocks muscarinic effects: bronchospasm, secretions, bradycardia
• Given IV until secretions dry up ("atropinization")
• Does NOT reverse nicotinic or CNS effects
• Dose: 2-4 mg IV, repeated every 5-10 min until atropinized

Step 3: PRALIDOXIME (2-PAM) (oxime reactivator)

• Must be given EARLY before aging
• Mechanism: Its charged group approaches the anionic site of AChE → displaces the phosphate from AChE → enzyme reactivated
• Reverses both peripheral muscarinic AND nicotinic effects
• Does NOT cross BBB → cannot reverse CNS effects
• Useless after aging of the enzyme
• Cannot reverse carbamate (physostigmine, neostigmine) toxicity

Step 4: DIAZEPAM

• Given to control persistent convulsions

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COMPARISON TABLE: PHYSOSTIGMINE vs NEOSTIGMINE

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USES AT A GLANCE (Quick revision table)

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EXAM-WORTHY ONE-LINERS

• "Physostigmine is a tertiary amine - the only reversible AChE inhibitor that crosses the BBB."
• "Neostigmine has greater effect on skeletal muscle than physostigmine."
• "Pralidoxime works only before aging - give it early in organophosphate poisoning."
• "Aging is fastest with Soman (seconds) - so 2-PAM is least effective against Soman."
• "Tacrine = first AChE inhibitor for Alzheimer's - withdrawn due to hepatotoxicity."
• "Death in organophosphate poisoning = respiratory failure (bronchoconstriction + NMJ paralysis)."
• "Atropine treats muscarinic effects of AChE poisoning; 2-PAM treats both muscarinic + nicotinic."
• "Quaternary amines (neostigmine, pyridostigmine, edrophonium) cannot cross BBB."

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Anticholinesterase Drugs — Explained Like You're Hearing It for the First Time

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STEP 1: First, understand the "messenger" — Acetylcholine (ACh)

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STEP 2: Now meet the "cleaner" — Acetylcholinesterase (AChE)

Nerve → releases ACh → ACh lands on organ → message delivered
                ↓
          AChE comes and DESTROYS ACh
                ↓
         Message stops. System resets.

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STEP 3: What happens when you BLOCK the garbage collector?

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STEP 4: Where does ACh act? (Two types of receptors)

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STEP 5: What are the EFFECTS of too much ACh?

Muscarinic effects — remember "SLUDGE"

• Eyes: Miosis (pupil becomes very small — "pin-point pupils")
• Heart: Bradycardia (heart slows down)
• Lungs: Bronchoconstriction (airways narrow) + lots of mucus secretion → breathing difficulty
• BP: Falls (hypotension)
• Skin: Sweating (diaphoresis)

Nicotinic effects (skeletal muscle):

• Small dose: Muscle twitching (fasciculations), increased strength
• Large dose: Muscles get paralyzed (too much stimulation causes the muscle to stop responding — like a phone line overloaded and crashing)

CNS effects (only some drugs):

• Anxiety → tremors → seizures → coma

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STEP 6: The drugs — two big groups

GROUP A: Reversible (temporary blockade of AChE)

GROUP B: Irreversible (permanent blockade of AChE)

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STEP 7: The individual drugs — made simple

1. EDROPHONIUM — "The quick detective"

• Blocks AChE for only 10-20 minutes, then disappears
• Was used as a diagnostic test for myasthenia gravis (a disease where muscles are weak — explained below)
• If a patient has myasthenia gravis and you give edrophonium → muscles become suddenly stronger for a few minutes (because ACh accumulates at the weak NMJ) → confirms diagnosis
• Cannot enter the brain

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2. PHYSOSTIGMINE — "The special one that enters the brain"

• Blocks AChE for about 30 min to 2 hours
• The KEY special thing: it is a tertiary amine → can cross the blood-brain barrier (BBB) into the brain
• Main use: Antidote when someone has atropine/anticholinergic poisoning — because it can reverse both the body AND brain effects of atropine overdose (confusion, delirium, coma)
• No other common anticholinesterase drug can do this

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3. NEOSTIGMINE — "The workhorse"

• Blocks AChE for 30 min to 2 hours
• Cannot enter the brain (quaternary amine — too charged/polar)
• Three big uses:
  1. After surgery, doctors give muscle relaxants to paralyze the patient. When surgery is over, they give neostigmine to reverse this paralysis (always combined with atropine to prevent bradycardia)
  2. Myasthenia gravis — to strengthen weak muscles
  3. Paralytic ileus / urinary retention — to get the gut and bladder moving again

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4. PYRIDOSTIGMINE — "The long-lasting neostigmine"

• Similar to neostigmine, but lasts 3-6 hours (longer)
• Preferred for daily tablet treatment of myasthenia gravis (because it lasts longer, patient takes fewer tablets)

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5. DONEPEZIL / RIVASTIGMINE / GALANTAMINE — "The brain helpers"

• Used in Alzheimer's disease
• In Alzheimer's, the brain loses ACh-releasing nerve cells → memory and thinking decline
• These drugs inhibit AChE in the brain → ACh is preserved → memory and thinking improve (modestly)
• They do NOT cure Alzheimer's — they slow it down temporarily

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STEP 8: What is Myasthenia Gravis? (Because these drugs are very linked to it)

• Fewer receptors available → ACh cannot deliver its muscle-contracting message properly → muscles become weak
• Symptoms: drooping eyelids (ptosis), double vision, difficulty swallowing and speaking, limb weakness
• Treatment: Give neostigmine or pyridostigmine → AChE is blocked → more ACh accumulates → the little ACh that IS available gets to work on the few remaining receptors → muscle strength improves

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STEP 9: Organophosphate Poisoning — The scary but important one

• AChE is permanently destroyed
• ACh floods everywhere
• The person shows ALL of the SLUDGE effects + muscle paralysis + seizures
• Most common cause of death = Respiratory failure (airways narrow from bronchoconstriction + breathing muscles become paralyzed)

How do you treat it?

What is "Aging"?

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THE BIG PICTURE — one diagram in your head

NERVE releases ACh
        ↓
   ACh crosses synapse
        ↓
   ACh binds to receptor → EFFECT (heart slows, muscle contracts, etc.)
        ↓
   AChE breaks down ACh → effect stops
   
   ===================================
   
   GIVE ANTICHOLINESTERASE DRUG:
        ↓
   AChE is BLOCKED → ACh is NOT broken down
        ↓
   ACh piles up → PROLONGED and EXAGGERATED EFFECTS
   (SLUDGE + muscle fasciculations/paralysis + CNS effects)

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SUMMARY IN PLAIN ENGLISH

1. ACh is the nerve messenger. AChE is the enzyme that destroys it.
2. Anticholinesterase drugs block AChE → ACh piles up → everything gets over-stimulated.
3. Reversible drugs (neostigmine, physostigmine, pyridostigmine) → useful medicines for myasthenia gravis, reversal of muscle relaxants, Alzheimer's.
4. Physostigmine is special — only one that enters the brain, used for atropine overdose.
5. Irreversible drugs (organophosphates) → pesticides/nerve agents → cause SLUDGE + paralysis + seizures + death.
6. Treatment of poisoning = Atropine (stop SLUDGE) + Pralidoxime (reactivate AChE) + Diazepam (stop fits).

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What Are Anticholinesterase Drugs Used For?

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1. 🧠 Myasthenia Gravis (Muscle Weakness Disease)

• In this disease, muscles become very weak because the body attacks its own nerve-muscle connection
• These drugs make more ACh available at the muscle → muscle gets stronger
• Pyridostigmine tablet is taken daily by patients to function normally
• Think of it as: "boosting the signal to weak muscles"

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2. 🏥 Reversing Muscle Paralysis After Surgery

• During surgery, doctors paralyze the patient's muscles (on purpose) using muscle relaxants
• After surgery is done, they give neostigmine to wake the muscles back up
• Always given with atropine to prevent the heart from slowing down too much

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3. 🧓 Alzheimer's Disease (Memory Loss)

• In Alzheimer's, brain cells that make ACh die off → memory and thinking decline
• These drugs preserve whatever ACh is left in the brain → modest improvement in memory
• They do NOT cure Alzheimer's — they just slow it down for a while

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4. 💊 Antidote for Atropine / Anticholinergic Poisoning

• If someone takes too much atropine or anticholinergic drug → they get confused, delirious, can go into coma
• Physostigmine is the only anticholinesterase that enters the brain
• It reverses both the body AND brain effects of atropine overdose

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5. 🚽 Paralytic Ileus and Urinary Retention

• Sometimes after surgery, the gut or bladder "falls asleep" and stops working
• Neostigmine stimulates the gut and bladder muscles back into action
• Also used in Ogilvie's syndrome (colon stops working without blockage)

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6. 👁️ Glaucoma (High Eye Pressure)

• Causes the pupil to constrict (miosis) → helps fluid drain from the eye → lowers eye pressure
• Largely replaced by better, safer eye drops now

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7. 🔍 Diagnosis of Myasthenia Gravis (Historical)

• A very short-acting drug (works for only 10-20 min)
• If given IV to a myasthenia patient → muscles get suddenly stronger → confirms diagnosis
• Now replaced by blood tests (anti-AChR antibody test)

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Quick Memory Table

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