Anticholinergic Drugs..Pharmacology

• An anticholinergic agent is a substance which blocks the neurotransmitter Acetylcholine in the CNS and PNS. Classic example is Atropine.
• Atropine is specific antagonist for muscarinic receptors. It is competitive inhibitor.
• Atropine is selective for nicotinic and muscarinic receptors.
• Anticholinergics are administered to reduce the effects mediated by acetylcholine on acetylcholine receptors in neurons through competitive inhibition. Therefore, their effects are reversible.
• A parasympatholytic element, also referred to as anticholinergics, reduces the activity of the parasympathetic nervous system.
• The term parasympatholytic typically refers to the effect of a drug, although some poisons, such as organophosphates act to block the parasympathetic nervous system as well.

Parasympathetic Nervous System

• 75% of all parasympathetic nerve fibers are in the vagus nerves
• These nerves supply the thoracic and abdominal organs, which innervate the heart, lungs, esophagus, stomach, and small intestine, proximal half of the colon, liver, gallbladder, pancreas and upper portions of the ureters
• Also supply the muscles of the eyes, lacrimal, nasal, submaxillary, and parotid glands; descending colon and rectum; lower portions of the ureters, bladder and genitalia
• All are regulated by acetylcholine—exerts excitatory effects at nerve synapses and neuromuscular junctions; and inhibitory effects at peripheral sites e.g. heart

Classification of Anticholinergics

• Anticholinergics are classified according to the receptors that are affected:
• Antimuscarinic agents operate on the muscarinic acetylcholine receptors. The majority of anticholinergic drugs are antimuscarinics.
• Antinicotinic agents operate on the nicotinic acetylcholine receptors. The majority of these are non-depolarising skeletal muscle relaxants for surgical use, along with a few of the depolarising agents and drugs of other categories structurally related to curare. These include Ganglionic blocking agents and neuromuscular blocking agents.

Antimuscarinic Agents
Classification
Natural Alkaloids

• Atropine
• Hyoscine (scopolamine)
• Extract of Belladona

Semisynthetic

• Homatropine
• Encatropine
• Methylatropine
• Methscopoline

Synthetic

• Tropicamide
• Glycopyrrolate
• Pirenzeline

Mechanism of Action

• Most anticholinergic drugs interact with the muscarinic receptors in the brain, secretory glands, heart, and smooth muscle
• A few can also affect the nicotinic receptors. Glycopyrrolate (Robinul) is an example
• Act by occupying receptor sites at parasympathetic nerve endings, thereby leaving fewer receptor sites free to respond to acetylcholine
• Distribution of receptors is broad so effects of anticholinergics will be diffuse.

Effects

Effects on CNS

• Scopolamine has greater effects on the CNS than atropine due to its ability to cross the blood-brain barrier.
• Atropine and scopolamine cause CNS depression characterized by amnesia, fatigue and reduction in rapid eye movement sleep.
• Hyoscine has anti-emetic activity, so is used for motion sickness.

Effects on Heart

• Atropine acts on the M2 receptors of the heart and antagonizes the activity of acetylcholine. It causes tachycardia by blocking vagal effects on the sinoatrial node.
• If atropine is given by intramuscular or subcutaneous, it causes initial bradycardia.
• Decreased cardiovascular response to vagal stimulation resulting in tachycardia
• Increases vagal tone Ex. Atropine.

Effects on Body tissues

• Bronchodilation and decreased respiratory tract secretions.
• Antispasmotics of GI tract due to decreased tone and motility
• Mydriasis and cyclopegia Normally do not increase IOP but caution as can precipitate acute glaucoma.
• Can cause decreased oral secretions, decreased sweating, and relaxation of urinary bladder
• Ataxia; loss of coordination
• Decreased mucus production in the nose and throat; consequent dry, sore throat
• Xerostomia or dry-mouth with possible acceleration of dental caries
• Cessation of perspiration; consequent decreased epidermal thermal dissipation leading to warm, blotchy, or red skin
• Increased body temperature
• Pupil dilation (mydriasis); consequent sensitivity to bright light (photophobia)
• Loss of accommodation (loss of focusing ability, blurred vision — cycloplegia)
• Double-vision (diplopia)
• Increased heart rate (tachycardia)
• Tendency to be easily startled
• Urinary retention
• Diminished bowel movement, sometimes ileus - (decreases motility via the vagus nerve)
• Increased intraocular pressure; dangerous for people with narrow-angle glaucoma
• Shaking

Therapeutic Uses

• Uses include GI, GU, ophthalmic and respiratory disorders, bradycardia and in Parkinson’s disease.
• Used preoperatively (preanesthetics)

Use in GI Disorders

• Helpful in treating irritable colon or colitis
• Useful in gastritis, pylorospasm and ulcerative colitis as they slow motility

Use in GU (Genitourinary) disorders

Antispasmotic effects seen in overactive bladder and in urinary incontinence

Urinary Antispasmotics

• Flavoxate (Urispas)—relieves dysuria, urgency, frequency, and pain with GU infections
• Oxybutynin (Ditropan) has direct antispasmodic effects on smooth muscle and anticholinergic effects. Decreases frequency of voiding
• Tolterodine (Detrol) is competitive, antimuscuranic anticholinergic that inhibits contraction. More selective for this area than elsewhere in the body

Ophthalmology

• Mydriatic and cycloplegia for examinations and surgery

Respiratory

• In bronchospasm whether related to asthma or COPD
• Atrovent very useful for its bronchodilating effects

Cardiology

• Atropine is used to increase heart rate in symptomatic bradycardias and higher blocks

Parkinson’s disease

• Useful in those with minimal side effects
• Those who cannot take Levodopa
• Helpful in decreasing salivation, spasticity and tremors

Preoperational

• Help prevent vagal stimulation and potential bradycardia
• Reduce respiratory secretions as well

Antinicotinic Agents

These include;

• Ganglionic Blocking Agents
• Neuromuscular Blocking Agents

Ganglionic Blocking Agents

These are the drugs which inhibit postganglionic transmission by acting as nicotinic antagonists.

These include;

• Hexamethonium
• Pentamethonium
• Trimethophan
• Mecamylamine

Mechanism of Action

• The Ganglionic blocking agents are drugs which act by competiting with Acetyl choline (Ach) from the cholinergic receptors present in the autonomic post ganglionic neurons.
• Since the ganglia of both the sympathetic and parasympathetic nervous systems are cholinergic, these drugs interrupt the outflow through both systems.
• They are used mostly for their interruption of the sympathetic outflow in hypertension, vasopastic disorders and peripheral vascular disease. Thus lowering the B.P and increasing the peripheral blood flow.

Based on the mechanism these are classified as follows.

• By Interfering with Ach release - Triethyl choline, Hemicholinium
• By interference with post synoptic action of Ach - Eg: Hexamethonium
• By prolonged depolarization - E.g.: Nicotine

Effects

Therapeutic Uses

• Trimethaphan is used in case of Increased Blood Pressure (Antihypertensive).
• Mecamylamine is also hypertensive.
• Ganglionic blockers are used less frequently now than they were in the past, because more selective agents are now available. However, they are still used in some emergency situations, such as aortic dissection.

Side Effects

• Cardiovascular: Orthostatic (postural) hypotension, Tachycardia
• GIT: Dry-mouth, GIT atony, urine retention, digestive problems
• Sexual Dysfunction: Failure of erection and ejaculation

Neuromuscular Blocking Agents

Neuromuscular blocking drugs block neuromuscular transmission at the neuromuscular junction causing paralysis of the affected skeletal muscles.

These are of two types;

Competitive Antagonists (Non-depolarizers) - These include;

• D-tubocurarine (prototype drug) is obtained from curare plant. It is also called aerohead poison.
• Gallamine
• Vecuronium
• Pancuronium
• Atracurium

Depolarizers

• Suxamethonium (succinyl choline)
• Decamethonium
• Suxamethonium can be metabolized like acetylchline. So, duration of activity is short. It is metabolized by psuedocholinesterase/butyrylcholinesterase present in plasma.
• Non-ruminants having high concentration of enzyme so shorter duration
• Ruminants having low enzyme so longer duration

Mechanism of Action

• Neuromuscular blocking agents can block the neuromuscular transmission by
• Inhibiting acetyl choline synthesis
• Inhibiting Ach release and inhibit calcium entry have neuromuscular block.
• Interfering with the post synoptic action of Ach
• Non depolarizing blocking agents act by competitive antagonism at Ach receptos of the end plate and these largely accounts for their action.
• Depolarizing blocking agents work by depolarizing the plasma membrane of the muscle fiber, similar to acetylcholine. However, these agents are more resistant to degradation by acetylcholinesterase, the enzyme responsible for degrading acetylcholine, and can thus more persistently depolarize the muscle fibers. This differs from acetylcholine, which is rapidly degraded and only transiently depolarizes the muscle.

Differences b/w depolarizers and non-depolarizers

Therapeutic Uses

• Preoperational
• Fracture cases
• Antihypertensive
• To restrain vicious animals
• As preanesthetic during passing of tracheal tube

Individual Anticholinergic Drugs

Atropine—prototype

• Antidote
• Belladonna alkaloid

Ipratropium (Atrovent).

• Useful in rhinorrhea
• Also excellent bronchodilator

Scopolamine, similar to atropine

• Depresses CNS and causes amnesia, drowsiness, euphoria, relaxation and sleep.
• Also good for motion sickness
•  Given parenterally, orally and transdermally.

Centrally Acting Anticholinergics

Benztropine (Cogentin)

• Temporary use in Parkinson’s disease
• Useful for dystonic reactions caused by antipsychotics

Trihexyphenidyl (Trihexy)

• Also used for txing EPS by some antipsychotics.
• Contraindicated in glaucoma

Toxicity Effects

• Anticholinergic overdose syndrome is characterized by: Hyperthermia, delirium, dry mouth, tacycardia, ileus, and urinary retention. Seizures, coma and respiratory arrest may occur.
• TX—activated charcoal, Antilirium, cooling agents (ice bags, cooling blankets, tepid baths).