2.1.2. parasympathetic nervous system - anticholinergic agents

JLDT

atropine

• or hyoscyamine

• Atropa belladona (deadly nightshade)

• Datura stramonium (jimson-weed/sacred Datura thorn apple)

prototype of muscarinic antagonists

• beautiful lade in italian

• cosmetically used to cause dilation of the pupils, according to some references

belladona

• rapid phase t1/2= 2h, slow phase=13h

• 50% excreted unchanged

• effects decline across body rapidly except eyes (persist 72 hours)

2 phase elimination of atropine

Reversible inverse agonism or antagonism

MOA of anticholinergic agents

opposite of DUMBBELSS and CNS ACh effects (+cycloplegia)

• cycloplegia — loss of eye’s ability to focus due to paralysis of ciliary muscle

• low dose: bradycardia → blockage of presynaptic AChR (provides feedback inhibition)

  • presynapse releases NT, postsynapse receives NT

  • ACh (NT) comes from the presynaptic nerve. When this nerve releases ACh but instead of going to the postsynaptic nerve, it binds with the presynaptic AChR where it came from, cholinergic transmission decreases → lowers/inhibit ACh release (negative feedback)

  • if AntiACh binds with presynaptic AChR, cholinergic transmission increases → DUMBBELS

  • thus, first effect of anti ach at low dose is cholinergic in nature (unique instance)

	cholinergics	anticholinergics
D	Diarrhea	Constipation
U	Urination	Urinary Retention
M	Miosis	Mydriasis
B	Bradycardia	Tachycardia
B	Bronchospasm	Bronchodilation
E	Emesis	Antiemetic
L	Lacrimation (increased secretions)	Dry mouth
L	Lethargy
S	Salivation	Decreased secretions
S	Smooth muscle contraction	Smooth muscle relaxation

effect if anticholinergic agents

Umeclidinium

Ipratropium

Tiotropium

Glycopyrronium

Glycopyrrolate

quaternary amines

Atropine

Biperiden

Cyclopentolate

Darifenacin

Solifenacin

Dicycloverine

Homatropine

Oxybutin

Scopalamine / Hyoscine N-butylbromide

Tropicamide

tertiary amines

MOA	Non-selective muscarinic ACh receptor antagonist
SOURCE	Atropa belladonna, Datura stramonium

— indication

1. Symptomatic Bradycardia — 1st line tx (esp for resuscitation), IM/IV

   • important in critical care when hr is too low or when px is experiencing persistent bradyarrhythmia. instead of immediately giving cpr, atropine is given at a maximum dose of 3mg (1mg x 3) to resuscitate patient

     • effect: tachycardia (fast HR)

   • Class IIC anti-arrhythmic (M2 AChR antagonist) → vagolytic effect (improved conduction in SA node) → ↑ heart rate

     • vagus nerve — nerve associated with parasympathetic NS which causes bradycardia to the heart.

     • SA node — natural pacemaker

2. Anesthesia adjuvant — prevent bronchoconstriction, reduce salivation and respiratory secretion = good for airway management during surgery

   • M3 → ↓secretion → improve efficacy of topical anesthetics (prevent anesthetic from being diluted from secretions) + laryngoscopy imaging

     • laryngoscopy — use of small camera to examine larynx.

     • you can decrease dose of anesthesia

   • Neuronal M2 autoreceptor → release ACh → ACh binds to M3 in lungs → bronchoconstriction

   • M1 in brainstem chemoreceptor trigger zone (vomiting center) → reduce nausea, anti-emesis

3. Ophthalmologic — corneal abrasions, eye exam, strabismus and amblyopia

   • eye exam: M3 (in iris smooth muscle) → mydriasis (dilation of pupil) makes it easier to examine eye

   • corneal abrasions, strabismus and ambyopia: M3 (in ciliary) → cycloplegia / loss focus to specific images (opposite of accomodation) → pain relied, encourage use of amblyopic eye

     • 2nd line for strabismus (cross eye) & amblyopia (lazy eye) — due to weak muscles in the eye

atropine

MOA	Non-selective muscarinic ACh receptor antagonism
SOURCE	Hyoscyamus niger
BRAND	Buscopan (Hyoscine N-Butylbromide)

— indication

1. Reduce GI motility — M1 in brainstem chemoreceptor trigger zone → reduce motion sickness

   • tx for motion sickness — can be given as transdermal patch due to adequate lipophilicity

   • genitourinary spasms (dysmenorrhea, gallbladder spasms), irritable bowel syndrome (IBS), Sialorrhea/Hypersalivation

     • dysmenorrhea — pag masyadong contracted yung muscles, brain interprets it as pain → buscopan allows pain relief

hyoscine / scopalamine

MOA	Non-selective muscarinic ACh receptor antagonism

— indication

1. Reduce GI motility

   • tx irritable bowel syndrome, copious respiratory secretions caused by COPDs

dicycloverine / dicyclomine

MOA	Slightly selective antagonist at M3 but no kinetic selectivity (does not bind longer)

— kinetic selectivity: drugs stay longer on M3 receptors vs other receptors

— indication

1. M3R: ↓ secretions — improved efficacy of topical anesthetics + laryngoscopy imaging

2. low affinity for cardiac M2 → less vagolytic than atropine → tachycardia

3. Anesthesia adjuvant (IM/IV) — prevent bradycardia, bronchoconstriction, ↓ salivation and secretion

4. Chronic Obstructive Pulmonary Disease (Inhalation but not used in PH)

5. Sialorrhea (PO)

6. Hyperhidrosis (PO, topical)

glycopyronium / glycopyrrolate

MOA	M3 AChR-selective antagonist with kinetic selectivity (long acting)

— indication

1. Umeclidinium — inhaler for asthma and COPD

   • M3 in lungs → long bronchodilation

Tiotropium, Umeclidinium

MOA	M1, M2, M3 ACh receptor antagonist (short acting)

— indication

1. COPD, Sialorrhea

   • M3 in lungs → bronchodilation

   • Neuronal M2 → release ACh → ACh to m3 in lungs → transient bronchoconstriction

ipratropium

MOA	Slight preference for blocking m3 over m1/m2 (darifenacin more selective)

— indication

1. overactive bladder → lead to urinary retention

— CYP

• Darifenacin - 2D6 inhibitor;

• Solifenacin - 3A4 substrate

solifenacin, darifenacin

MOA	Muscarinic ach blocker (prefer m1/m3/m4)

— indication

1. Hyperhidrosis and overactive bladder (alternative, not available in pnf)

   • M3 in bladder → ↓ bladder tone, sphincter contraction → less urination

oxybutynin

MOA	Non selective muscarinic ach receptor antagonism

— indication

1. eyes — 2nd line for strabismus (crossed eye) and amblyopia (lazy eye), corneal abrasions, eye exams

   1. m3 in iris smooth muscle → mydriasis

   2. m3 in ciliary muscle → cycloplegia → pain relief, encourage use of amblyopic eye

tropicamide, cyclopentolate, homatropine

MOA	Non selective CNS M1-5 ach receptor antagonist

— indication

1. tremors in parkinsons, dystonias, and pseudoparkinsonism from antipsychotics (ineffective for akathisia)

   • block DA blockade → ↑ DA release

biperiden

1. Cholinergic rebound: nausea, diaphoresis (Sweating), hypotension, dizziness, drowsiness, fatigue

   • upregulation

2. cognitive impairment: AEC scale

   • high score = increased risk of cognitive impairment

     1. atropine = 3

     2. hyoscine hydrobromide = 3

     3. hyoscine n-butylbromide = 1

     4. solifenacin = 1

     5. darifenasin, dicycloverine. ipratropium, tiotropium (inhalational) = 0

   • caution with elderly due to being more at risk of cognitive impairment

side effects of anticholinergics

1. additive — anticholinergics, CNS depressants, tachycardics

2. physiologic antagonism — drugs with opposite physiologic effects

3. K salts (oral) — strong anti-ACh may enhance ulcerogenic effect of K salts

4. Nitroglycerin — Anti-ACh decrease dissolution of sublingual tablets

5. Thiazide diuretics — Anti-ACh may increase their concentration

6. Topiramate — Anti-ACh increase its hyperthermia risk

interactions of anticholinergic agents

— Onabotulinumtoxin A, Abobotilunumtoxin A, Incobotulinumtoxin A, Prabotulinumtoxin A

— MOA

• Zn endopeptidase from Clostridium botulinum

• Cleaves certain proteins to stop vesicular fusion and Ca-induced release of ACh from presynaptic neuron in neuromuscular junction → paralysis

— Indication

1. glabellar lines (from lines), forehead lines, lateral canthar lines (crow’s feet)

2. cervical dystonia

3. focal tardive dystonia

4. severe axillary hyperhidrosis

5. refractory conditions (overactive bladder, localized tics, anal fissures, migraine, sialorrhea)

— Side effects

1. injection site swelling/bruising, headache, flu-like sx, hoarseness, UTI, urinary retention, dry mouth

2. BLACK BOX WARNING: muscle weakness further from injection site

botulinum toxin type A

— historical

• hexamethonium — 1st line drug for hypertension (ion channel blocker)

— Rarely used competitive nicotinic ganglionic blockers

• Trimethaphan — hypertensive emergencies due to dissecting aortic aneurysm, pulmonary edema

• mecamylamine — moderately severe to severe htn

ganglionic blockers