Cholinergic Drugs (00:02 - 10:00)

 Cholinergic drugs mimic acetylcholine's actions in the body

o Classified as direct acting and indirect acting cholinergic drugs

Direct Acting vs. Indirect Acting

 Direct acting cholinergic drugs directly activate cholinergic receptors

o Structurally or functionally similar to acetylcholine
o Bind with nicotinic receptors, muscarinic receptors, or both
 Indirect acting cholinergic drugs enhance cholinergic activity by inhibiting
acetylcholinesterase
o Inhibition of acetylcholinesterase leads to increased accumulation and action of
endogenous acetylcholine
o Do not directly bind to cholinergic receptors

Types of Direct Acting Cholinergic Drugs

 Muscarinic drugs
o Stimulate muscarinic receptors
o Include choline esters and alkaloids derived from plants
o Examples: acetylcholine, methacholine, carbacol, bethanechol

Acetylcholine (10:04 - 20:01)

 Acetylcholine is not commonly used pharmacologically due to its short half-life and
diffuse action.
o It has a very short half-life, lasting in the blood for 5 to 30 seconds.
o It is rapidly destroyed by butyrylcholinesterase in the plasma.
o Its diffuse action activates both nicotinic and muscarinic receptors non-
specifically.
 Acetylcholine cannot effectively cross biological membranes, including the blood-brain
barrier.
o Highly charged and polar compounds like acetylcholine cannot effectively cross
biological membranes.
 It is not commonly used as a pharmacological agent due to these limitations.

Diffuse Action of Acetylcholine

 If acetylcholine is given in heavy doses, it will produce diffuse activation of cholinergic

receptors all over the body.
o It stimulates cholinergic receptors in the central nervous system, ganglia,
neuroeffector sites, and neuromuscular junctions.
o This results in non-selective and diffuse cholinergic activity throughout the body.
 o Acetylcholine stimulates both nicotinic and muscarinic receptors, leading to
widespread cholinergic activation.

Acetylcholine's Non-specific Action (20:06 - 30:06)

 Acetylcholine's non-specific action on the body due to cholinergic stimulation

o Sweating, lacrimation, pupil constriction, nasal secretions, bronchoconstriction,
salivary action, increased gastrointestinal motility, defecation, bradycardia,
massive vasodilation, hypotension, urination

Bethanechol - Drug Analysis

 Bethanechol's muscarinic receptor action

o Strongly stimulates muscarinic receptors on gastrointestinal system and urinary
bladder
o No significant nicotinic action
o Modified acetylcholine with acetate replaced by carbamate and addition of methyl
group
o Longer duration of action compared to acetylcholine (more than 60 minutes)

Bethanechol - Uses and Contraindications

 Uses
o Used for hypoactive gastrointestinal system and urinary bladder
 Contraindications
o Urinary retention due to outlet obstruction (e.g., stones, tumors)
o Benign prostatic hyperplasia with urinary retention

Conditions for Use of Bethenecol (30:09 - 40:07)

 Used to activate the urinary bladder in cases of non-obstructive urinary retention

o Postoperative urinary retention
o Postpartum urinary retention
o Chronic hypotonic, myogenic, or neurogenic bladders

Activation of the Gastrointestinal Tract

 Postoperative adynamic ileus

o Stomach atony or gastroparesis
 Aliasmine paralysis of the gastrointestinal tract due to toxic reasons
o Ensure no obstruction in the gastrointestinal tract

Use for Congenital Mega Colon

 Congenital Mega Colon

 o Absence of ganglia in a segment of the colon
o Results in a dynamic segment leading to mega colon
 Administration of bethenecol for management

Side Effects

 Generalized cholinergic stimulation

o Sweating, salivation, lacrimation, abdominal secretions, peristalsis, abdominal
cramps
o Urgency to urinate
o Flushing and hypertension

Generalized Cholinergic Stimulation (40:09 - 50:07)

 Sweating
o Meiosis
o Spasticity of ciliaris and difficulty to focus the eyes
 Flushing
 Salivation
o Lacrimation
 Bronchoconstriction
o Tightness in the chest
 Bradycardia and hypertension-related complications
 Increased gastrointestinal secretions
o Modality and cramps
o Diarrhea and urinary urgency

Specific Contraindications to the Use of Bethanechol

 Peptic ulcer disease

 Chronic obstructive pulmonary diseases (COPD)
 Ischemic heart disease with coronary problems
 Atrial tachycardia or atrial flutter
 Hyperthyroidism

Contraindication in Parkinson's Disease

 Imbalance between acetylcholine and dopamine

 Nigrostriatal neurons degenerated
 Excessive cholinergic activity causing tremors
 Use of cholinergic drugs exacerbating symptoms

Carbachol

 Not commonly used systemically

  Main use in the eyes for producing meiosis and contraction of ciliary muscle
 Useful for lowering intraocular pressure in glaucoma

Methacholine

 Not systemically used

 Used to challenge bronchial tree for bronchial hyperreactivity
 Inhalation to diagnose hyper reactive bronchial system or asthma

Pilocarpine (50:10 - 00:09)

 Muscarinic drug
o Tertiary amine
o Stable with acetylcholinesterase
 Derived from plants
o Stable to acetylcholinesterase
 Ophthalmic uses
o Used topically for glaucoma
 Absorbed and acts on muscarinic receptors on sphincter pupili and ciliaris
muscle
 Aqueous humor circulation
o Produced by ciliary epithelium
o Moves through posterior and interior chambers
o Drains into canal of schlem
 Open angle glaucoma
o Angle between corneal and iris
o Trabecular meshwork has resistance to flow
o Aqueous humor has difficulty moving through trabecular meshwork due to aging
effects

Open Angle Glaucoma (00:13 - 10:11)

 Contraction of ciliaris muscle pulls the angle posteriorly

o Traction on the meshwork opens the angle for better drainage
 Pilocarpine helps in open angle glaucoma by contracting the ciliaris muscle
o Results in better drainage and decreased intraocular pressure

Narrow Angle Glaucoma

 Some individuals have a shallow anterior chamber or relatively smaller eyeballs

o Pupil dilation causes the root of the iris to accumulate at the angle, making it
narrow
 Pilocarpine is used in emergency cases of narrow angle glaucoma
o Leads to the contraction of sphincter pupili, pulling the iris away from the corner
o Opens the angle for improved drainage and decreased intraocular pressure
Other Uses of Pilocarpine

 Stimulates secretions such as sweat, tears, and saliva

o Can be used to treat dry mouth (xerostomia) resulting from head and neck
irradiation

Pilocarpine Uses (10:13 - 20:11)

 Used for stimulating salivary secretion in conditions such as dry mouth due to residual
gland left or Sjogren syndrome
o Can be administered via pilocarpine spray or tablets
 Used in ophthalmological conditions
o Used in open-angle glaucoma
o Used to reverse mydriasis induced by atropine
o Used to break adhesions between the lens and the iris

Indirectly Acting Cholinergic Drugs

 These drugs bind and inhibit cholinesterase enzymes

o Acetylcholine is rapidly catabolized by cholinesterase enzymes
 Acetylcholine can work on nicotinic or muscarinic receptors
o Catabolized by acetylcholinesterase
o Can work on ion channel receptors (nicotinic) or G protein-coupled receptors
(muscarinic)

Anticholinestrases (20:14 - 30:10)

 Reversible inhibitors of acetylcholinestrases

o Reversible drugs bind with the enzyme but detach over minutes or hours
o Inhibition lasts for a shorter duration
 Irreversible inhibitors of acetylcholinestrases
o Irreversible drugs bind with the enzyme and do not detach
o Enzyme activity is lost for a longer duration, until new enzymes are synthesized
by the tissue

Physostigmine

 Derived from a plant

o Alkaloid
 Tertiary amine structure
o More lipid-soluble
o Better absorption from the gastrointestinal tract
o Crosses the blood-brain barrier effectively
o Can produce toxicity in the central nervous system
Tertiary vs. Quaternary Amine

 Tertiary amine
o Less polar and more lipid-soluble
o Better absorption and can cross biological membranes effectively
o Can produce stronger ganglionic stimulation
 Quaternary amine
o More polar and less lipid-soluble
o Cannot cross blood-brain barrier effectively
o Does not produce CNS toxicity
 Physostigmine (tertiary amine) and other discussed drugs (quaternary amine)
o Differences in lipid solubility, absorption, and potential for CNS effects
 Synthetic drug with a carbamate group
o Others have a carbamate group except for physostigmine, which has an alcohol
group

Importance of Understanding Enzyme Action (30:15 - 40:13)

 Enzyme action determines drug effectiveness

o Different drugs act on acetylcholinesterase in various ways

Types of Drug Action on Acetylcholinesterase

 Adrophonium's weak, non-covalent bond leads to rapid dissociation

o Duration of action: 10-20 minutes
 Physostigmine and neostigmine form labile covalent bonds
o Duration of action: 30 minutes to 4 hours
 Carbamates like neostigmine and pyridostigmine form labile covalent bonds
o Duration of action: Half hour to few hours

Irreversible Anticholinesterases

 Irreversible anticholinesterases form strong, stable covalent bonds

o Examples: Isoflurophate, echothiophate, parathion, malathion
 Complication: Once bound for 30 minutes, removal becomes impossible
o Special alkyl group is key in removal process
 Alkyl group detachment leads to irreversible enzyme loss

Importance of Rapid Intervention with Antidote

 Prompt intervention with pralidoxime can prevent irreversible enzyme loss

o Alkyl group detachment signifies irreversible enzyme damage
 Concept of aging is crucial in understanding irreversible enzyme loss
o Aging process renders antidote ineffective
Irreversible Anticholinestrases (40:17 - 50:16)

 Scientists are working on compounds for military issues, resulting in irreversible

anticholinestrases.
o Exposure to these nerve agents inhibits anticholinestrases, leading to dangerous
accumulation of acetylcholine.
o Complications include convulsions, ganglia stimulation, muscarinic stimulation,
and neuromuscular junction issues.
o Overstimulation of cholinergic system leads to symptoms such as sweating,
lacrimation, salivation, bronchoconstriction, bradycardia, hypotension, abdominal
cramps, diarrhea, and urination.

Management of Irreversible Anticholinestrases

 Treatment involves the administration of atropine to block muscarinic receptors.

o Atropine helps alleviate clinical symptoms caused by overstimulation of
muscarinic receptors.
 Pralidoxime functions by binding and detaching irreversible anticholinestrases, but is
effective only if aging has not occurred.
o Aging occurs when the organophosphate compound binds so strongly with the
enzyme that pralidoxime cannot remove it.

Reversible Anticholinestrases

 Physostigmine is more lipid soluble compared to other reversible anticholinestrases and

can reach the central nervous system.
o It stimulates muscarinic receptors and nicotinic cholinergic receptors at
neuromuscular junctions.
 Therapeutic uses of physostigmine include stimulating gastrointestinal and urinary
bladder motility.
o It can be used for post-operative abdominal distension and non-obstructive
urinary retention.
o Physostigmine can also be used in conditions where neostigmine is used.

Physiostigmine vs Neostigmine (50:18 - 00:15)

 Physiostigmine:
o Stimulates muscarinic receptors
o Used in glaucoma to constrict the pupil and in cases of anticholinergic activity
 Neostigmine:
o Does not enter the CNS
o Less lipid-soluble than physiostigmine
o Better action at neuromuscular junction, directly stimulates cholinergic receptors

Uses of Neostigmine
  Commonly used in Myasthenia gravis
o Disease causing muscle weakness
 Used to stimulate neuromuscular junctions
o Directly stimulates cholinergic receptors
o Not used in atropine toxicity due to inability to enter CNS

Note: Only the first 2 hours of the video were included due to non-unlimited
status.