Anticholinergic drugs

[SH4:p266-p274; CEACCP 2004 Vol 4(5) "Anticholinesterases and anticholinergic drugs"]

 

Structure

• Atropine and scopolamine are
  * Naturally occurring
  * Esters, formed by tropic acid or mandelic acid combining with an organic base
  * Only the levorotatory forms are active
  * Tertiary amines
  * Alkaloids of belladonna plants
  * Structurally resembles cocaine --> Weak analgesic action
• Glycopyrrolate are
  * Synthetic
  * Quaternary amines
  * Esters, which contain mandelic acid rather than tropic acid
• Scopolamine (hyoscine) = ester of tropic acid and scopine

Pharmacodynamics

Mechanism of action

Anticholinergic drugs act by

• Binding reversibly to muscarinic cholinergic receptors
  --> Compete against ACh
  * Effect can be overcome by increasing ACh concentration
• Does not prevent ACh release
• Does not react with ACh

Selectivity

• Anticholinergic drugs are selective for muscarinic cholinergic receptors
• But at high doses, there is a partial block at nAChRs
  * [CEACCP 2004 Vol 4(5):p167]

Types of muscarinic receptors

Also see [Acetylcholine]

• M1 = CNS and stomach
• M2 = Heart and lung
• M3 = CNS, airway smooth muscles, glandular tissues
• M4 and M5 = CNS

 

Effects other than antagonism at muscarinic cholinergic receptors

Sympathomimetic effects

• Anticholinergic drugs may interfere with normal inhibition on the release of norepinephrine
  --> Increase in NE release
  --> Sympathomimetic effect

Effects by systems

CNS

Sedation

• Scopolamine is about 100 times more potent than atropine in its sedative effect
• Scopolamine may also:
  * Enhance the sedative effect of opioids and benzodiazepines
  * Cause amnesia (so does atropine, though less)
  * Other CNS effects ranging from restlessness to somnolence (more likely in elderly)
• Glycopyrrolate does not cross BBB
  --> Lacks any significant CNS effect

NB:

• Physostigmine is effective in reversing CNS effect due to tertiary amine anticholinergic drugs

Central cholinergic syndrome

[SH4:p273]

• Due to scopolamine, and, to lesser extent, atropine
  * Glycopyrrolate does not cause central cholinergic syndrome
• Symptoms range from restlessness and hallucination to somnolence and coma
• Due to blockade of muscarinic cholinergic receptors in CNS
• Treatment is with physostigmine 15 - 60 mcg/kg IV
  * Not with edrophonium, neostigmine, or pyridostigmine

 

CVS

Treatment of reflex-mediated bradycardia

• Anticholinergic drugs are effective in bradycardia resulting from increased parasympathetic nervous system activity

Paradoxical slowing of HR

• Atropine and glycopyrrolate, and scopolamine (at small doses)
  --> Can cause paradoxical transient slowing of HR
• May be due to blockade of presynaptic inhibitory M1 receptors on vagus nerve endings
  --> Blockade lead to increased ACh release
  --> Initially overcome muscarinic blockade on the M2 receptors in SA node
• NOT due to central vagal stimulation
  * [SH4:p268; CEACCP 2004 Vol 4(5):p168]

NB:

• Atropine has no HR effect on denervated, acutely transplanted heart

Age and heart rate

[SH4:p270]

• In young adults
  --> Vagal tone is enhanced
  --> Anticholinergic drugs have greater effect in increasing HR
• In infants and elderly
  --> Even large doses may not increase HR

Cardiac disease

• Impairment of parasympathetic nervous system activity is associated with
  * Increased incidence of cardiac dysrrhythmia due to IHD
  * Decreased survival after MI
• Glycopyrrolate is preferable to atropine (for use in combination with anticholinesterase)
  * Glycopyrrolate has shorter impairment of parasympathetic nervous system

ECG effect

• Anticholinergic drugs shorten the PR interval

Distribution of muscarinic receptors in CVS

[SH4:p268]

• M3 receptors on luminal surfaces of endothelial cells
  --> Stimulate release of NO from endothelium
  --> Vasodilation in vascular beds
• M3 receptors in the heart
  * Is concentrated around conduction tissues (SA node, AV node, Purkinje fibres)
  * Sparse around myocardium
• Edrophonium (anticholinesterase) may bind to M2 and M3 receptors and act as a competitive antagonist to ACh
  * [SH4:p266]

Respiratory

Bronchodilation

• Bronchial M3 receptors mediate bronchoconstriction (predominately in large and medium sized airways)
• M2 receptors antagonise beta-adrenergic receptor-mediated bronchodilation
  * By inhibition of adenylyl cyclase

Thus,

• Anticholinergic drugs causes bronchodilation
  * By inhibiting M2 and M3 muscarinic receptors on airway smooth muscles
  * May also increase dead space volume
  * Better effect when used as aerosols

NB:

• Anticholinergic drugs can potentially cause inspissation of secretions
  --> Risk of airway obstruction
  * Clinically unlikely after single dose

GIT

Antisialogogue effect

[SH4:p270]

• Scopolamine is approximately 3 times more potent than atropine as an antisialogogue
• Glycopyrrolate is approximately twice as potent as atropine as an antisialogogue

[CEACCP 2004 Vol 4(5):p168]

• Glycopyrrolate is about 5 times more potent than atropine as an antisialogogue

Inhibition of gastric acid secretion

• The high doses required to inhibit gastric acid production are associated with unacceptable cardiac, ocular, and secretory side effects
• H2 receptor antagonists are better in this regard

Inhibition of excessive peristalsis

• Similar to gastric acid inhibition, the doses required to alter GIT motility are associated with unacceptable side effects

Decreased barrier pressure

[SH4:p274]

• Lower oesophageal sphincter pressure is reduced
• But clinical significance is not known

 

Genitourinary tract

• Atropine decreases the smooth muscle tone of biliary tract and ureter
• Atropine is unlikely to overcome opioid-induced spasm of the sphincter of Oddi
• Atropine may prevent spasm of ureter caused by opioids
• Atropine may contribute to urinary retention
  * Increased vesicle sphincter tone
  * Decrease urinary bladder tone

Eye

[SH4:p269,p272]

• Circular muscle of iris
  * Constricts pupil
  * Innervated by cholinergic fibres from CN3
• Ciliary muscle
  * Contraction make lens more convex
  * Also innervated by CN3
• Anticholinergic drugs applied to eyes
  --> Block ACh action at both cicular and ciliary muscles
  --> Mydriasis and cycloplegia
  * Complete recovery may take 7-14 days

Mydriasis

• Mydriatic effect = Scopolamine > Atropine
• Glycopyrrolate has little effect on pupil sizes
• Mydriasis by an anticholinergic drug is blocked by an anticholinesterase drug (e.g. pilocarpine)

Glaucoma

• Relaxation of ciliary muscle
  --> May occlude the angular space
  --> May lead to increased IOP

Others

Prevention of motion-induced nausea

• Transdermal absorption of scopolamine can prevent motion-induced nausea
  * Without much side effects such as sedation, cycloplegia, etc
  * Greatest effect if transdermal application is initiated at least 4 hours before the noxious stimulus
• Oral or IV administration of scopolamine requires a larger dose
  --> Side effects are greater
• Scopolamine blocks transmission to the medulla from overstimulation of vestibular apparatus

NB:

• Contamination of fingers may result in scopolamine being transfer to eye
  --> Anisocoria (unequal pupil size)

Dose-response

• At low doses of anticholinergic drugs
  --> Salivary and bronchial secretions (M3 receptors) are inhibited first
• As doses increase,
  --> Heart and eyes are affected next (M2 receptors)
• At higher doses,
  --> GIT and genitourinary tract are affected next
  * Decreased tone and motility, and inhibition of micturition
• At even higher doses
  --> Gastric acid secretion is inhibited (M1 receptors)

Comparison between atropine, scopolamine, and glycopyrrolate

• Sequence of blockade with increasing dosage is the same for all anticholinergic drugs
• Atropine, scopolamine, and glycopyrrolate do not discriminate among M1, M2, and M3 receptors

Sedation

• Scopolamine >> Atropine
• Glycopyrrolate = 0

Antisialogogue

• Scopolamine > Glycopyrrolate > Atropine [SH4:p268]
• Glycopyrrolate > Scopolamine > Atropine [CEACCP 2004 Vol 4(5):p168]

Increased HR

• Atropine > Glycopyrrolate > Scopolamine [SH4:p268]
• Atropine > Scopolamine > Glycopyrrolate

Relax bronchial smooth muscle

• Atropine = Glycopyrrolate > Scopolamine

Mydriasis and cycloplegia

• Scopolamine >> Atropine
• Glycopyrrolate = 0

Prevention of motion-induced nausea

• Scopolamine >> Atropine
• Glycopyrrolate = 0

Metabolic oxygen consumption

• Glycopyrrolate --> Increase in oxygen consumption
• Atropine --> No effect
• Scopolamine --> Decrease in oxygen consumption

Pharmacokinetics

Absorption

• Oral administration is unpredictable (even for tertiary amine ones)
• IV or IM
• Transdermal (scopolamine)

Distribution

• Atropine and scopolamine are tertiary amines
  --> Easily penetrate BBB
• Glycopyrrolate is a quaternary ammonium compound
  --> Minimal BBB penetration

NB:

According to [Merck's manual: http://www.merck.com/mmpe/lexicomp/scopolamine%20derivatives.html]

• Scopolamine butylbromide is a quaternary salt

Metabolism

Atropine

• Atropine is hydrolysed in liver into tropine and tropic acid
• Minimal amount of atropine is metabolised in plasma

Glycopyrrolate

[CEACCP 2004 Vol 4(5):p168]

• Metabolised in liver by hydroxylation and oxidation

Elimination

Atropine

• Atropine elimination half-time = 2.3 hours
• 18% of atropine is excreted unchanged in urine

Glycopyrrolate

• Glycopyrrolate elimination half-time = 1.25 hours
  * Clearance of glycopyrrolate is more rapid than atropine
  * Significantly prolonged in uremic patients
• 80% of glycopyrrolate is excreted unchanged in urine

Scopolamine

• 1% of scopolamine is excreted unchanged in urine

Action profile

Atropine

• Onset of action for IV atropine = 1 minute
• Duration of action for IV atropine = 30 - 60 minutes

[CEACCP 2004 Vol 4(5):p168]

• Peak action at 1 minute
• Duration of action = 3 hours

Glycopyrrolate

• Onset of action for IV glycopyrrolate = 2 - 3 minutes
• Duration of action for IV glycopyrrolate = approximately the same duration as atropine

[CEACCP 2004 Vol 4(5):p168]

• Onset of action is within 1 minute
• Peak action is at 3 minutes
• Duration of action = 6 hours
• Antisialogogue effect lasts 8 hours
• Vagolytic effect at heart lasts 2-3 hours

Pharmaceutics

Scopolamine

Scopolamine = Hyoscine

Formulation

[Merck's manual: http://www.merck.com/mmpe/lexicomp/scopolamine%20derivatives.html]

• Scopolamine comes as either:
  * Butylbromide, OR
  * Hydrobromide
• The dosages are NOT interchangeable

Hydrobromide vs butylbromide

• Scopolamine hydrobromide = Tertiary salts
  --> Well absorbed orally, better BBB penetration
  --> More CNS activity
  * e.g. Kwells
• Scopolamine butylbromide = Quaternary salts
  --> Poorly absorbed orally, POOR BBB penetration
  * e.g. Setacol, buscopan

NB:

• Some sources do use scopolamine to mean hyoscine hydrobromide, NOT hyoscine butylbromide

Clinical

Usage

Main uses

1. Preoperative medication
2. Treatment of reflex-mediated bradycardia
3. Combination with anticholinesterase during NMBD reversals

Less common uses

1. Bronchodilation
2. Biliary and ureteral smooth muscle relaxation
3. Production of mydriasis and cycloplegia
4. Reduction of gastric acid secretion (by parietal cells)
5. Prevention of motion-induced nusea
6. Part of cold remedies (to dry up airway secretion)
7. Treatment of hiccups
   * Atropine 0.5 mg IV is reported to be effective in hiccups following LMA [SH4:p273]

Preoperative medication

• Therapeutic goals:
  * Produce sedation
  * Antisialogogue
• Doses used will not alter gastric fluid pH
• Caution for use in patients with glaucoma
  * Atropine at low doses and glycopyrrolate has no significant effect

Scopolamine

[CEACCP 2004 Vol 4(5):p168]

• Prophylaxis of motion sickness
• Antispasmodic
• Premedication for its antisialogogue and sedative action

Administration

 

Bronchodilation

• Atropine = 1 - 2 mg via nebuliser

Overdose

Symptoms and signs

• Dry mouth
• Blurred vision
• Photophobia
• Tachycardia
• Dry and flushed skin
• Rash over the face, neck, and upper chest (blush area)
• Increased in body temperature
  * Due to inhibition of sweating
  * Small children particularly vulnerable
• Increased minute ventilation
  * CNS stimulation
  * Increased physiological dead space due to bronchodilation
• Skeletal muscle weakness
  * Due to nAChR blockade
• Orthostatic hypotension
  * Due to nAChR blockade

Fatal events

• Seizures
• Coma
• Medullary ventilatory centre paralysis

Treatment

• Physostigmine is the specific treatment
  --> Short duration of action
  --> May require repeated doses

Other related drugs

Ipratropium

[SH4:p271]

• N-isopropyl derivative of atropine
• Used most commonly as aerosol to produce bronchodilation in COPD (via blocking M3 receptors)
• Dosage:
  * 40 - 80 mcg by metered-dose inhaler
  * 0.25 - 0.50 mg by nebulisation
• Most effective in preventing and treating
  * Bronchospasm due to psychogenic stimuli or beta-blockers
  * COPD (chronic bronchitis or emphysema)
• In bronchial asthma, treatment using ipratropium
  * Slower onset
  * Less effective than beta agonists
• Beta agonists are better in bronchial asthma
  * Beta agonists inhibit the release of mediators such as histamine and leukotrienes
  * Ipratropium is minimally effective in leukotriene-induced bronchoconstriction
  * Adding ipratropium to maximal dose of beta agonists have no benefit [SH4:p272]
• Side effects:
  * No cardiac effect due to minimal systemic absorption (quaternary ammonium)
  * Tolerance does NOT occur

Pirenzepine

[SH4:p267]

• Pirenzepine is selective in blocking M1 receptors
  --> Decrease gastric acid secretion by parietal cells