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Muscarinic antagonists
  • atropine is the prototypical cholinergic antagonist w/ high affinity for muscarinic receptors (and no affinity for nicotinic)
  • "parasympatholytic" - block actions of parasympathetic system
Muscarinic antagonists
  • structure/function: 3°amines
  • Atropine (and others) are 3° amines: well absorbed in gut, conjunctiva, even skin.
  • after absorption, well distributed in body, incl CNS
  • peak conc usually bw 30m-1hr
Muscarinic antagonists
  • structure/function: 4°amines
  • Some are 4°amines: Ipratropium (atrovent - aeresolized bronchodilator)
  • permanent charge doesn't allow absorption into CNS, used for peripheral applications , not systemic!
Muscarinic antagonists
  • Mechanism of action
  • competetive antagonists: blockade of receptor can be overcome with higher [agonist] (ACh)
  • Different tiss have diff sensitivity to antimuscarinic used
  • most sensitive: salivary, bronchial, sweat glands
  • Least sensitive: Gastric parietal cells
  • Atropine is non-selective (binds all subtypes equally M1-M5)
  • pirenzepine is 5x selective for M1 over M2 receptors

organ system predominant tone
  • Arterioles - sympathetic (adrenergic)
  • Veins - sympathetic (adrenergic)
  • Heart - Parasympathetic (cholinergic)
  • Iris - Parasympathetic (cholinergic)
  • Ciliary muscle - Parasympathetic (cholinergic)
  • GIT - Parasympathetic (cholinergic)
  • Urinary bladder - Parasympathetic (cholinergic)
  • Salivary glands - Parasympathetic (cholinergic)
  • Sweat glands - Sympathetic (cholinergic)
  • Genital tract - symp & parasymp
Muscarinic antagonists: organ system effects
  • CNS
  • cause drowsiness & amnesia
  • Scopolamine is highly absorbed in CNS, causes central SE's - toxic doses of it cause excitement, agitation, hallucinations & coma.
  • tx Parkinson's: decrease cholinergic activit in basal ganglia and striatum.
  • tx vestibular disturbances (motion sick - scopolamine)
Muscarinic antagonists: organ system effects
  • Eye
  • Constrictor m. maintains tone by parasymp muscarinic activity - if tone is removed with an antagonist, sympathetic tone dominates→ mydriasis
  • can ppt acute glaucoma in pt with narrow ant chamber angle
  • anticholinergics block contraction of ciliary muscle→ cycloplegia
  • lacrimation is also blocked → dry eyes
Muscarinic antagonists: Organ system effects
  • CV system: heart
  • mod/high doses: vagal activity in SA node blocked→ tachycardia
  • low doses: bradycardia → presyn muscarinic r's (autor's) on vagal nerve term are blocked...ACh release is more (with agonists, it's reduced) so there's an inc in vagal tone.
  • blockade of atrial M2 is not significant except in atrial flutter/fibrillation.
  • **paraNS has little effect, so musc antagonists don't do much.**
Muscarinic antagonists: Organ system effects
  • CV system: vasculature
  • no parasymp innervation
  • muscarinic activity stim release of NO from endothelial cells→ vasodilation of coronary arteries and symp mediated dilation of sk muscle vessels.  can be blocked by antimuscarinic agents (rel slight effects)
  • **overall effects not dramatic, usu no chg in BP
  • atropine useful to block/reverse effects of cholinergic excess
Muscarinic antagonists: Organ system effects
  • Respiratory system
  • parasymp via vagus of bronchiole sm muscle→ constriction, inc secretions
  • therefore, antagonist causes slight bronchodilation, and ↓secretions.
  • if pt has COPD/asthma, effect is larger (not as good as beta adrenergic agonists)
  • primary use: inhalation anesthesia to reduce secr and prevent laryngospasm
Muscarinic antagonists: Organ system effects 
  • GI tract
  • musc antag causes reduction in Sm muscle motility Stomach to colon.
  • secretions: acid, pepsin, mucin ↓, only at high doses.
  • inhibition of salivation - dry mouth.
  • complete musc block can't abolish GI activity d/t hormones and non-cholinergic neurons of enteric NS
Muscarinic antagonists: Organ system effects 
  • GU tract
  • relax smooth muscle of ureters and bladder
  • reduced voiding (tx spasms, but may worsen urinary retention)
  • no uterus effects
Muscarinic antagonists: Organ system effects 
  • sweat glands
  • suppress sweating - block sympathetic stimulation of sweat glands
  • leads to elevation of body temp in infants & children (atropine fever)
clinical uses of muscarinic antagonists
  • CNS: parkinson's
  • motion sickness
  • ophthalmologic disorders
  • respiratory disorders
  • CV disorders
  • GI disorders
  • GU disorders
  • cholinergic poisoning
Clinical uses of muscarinic antagonists:
  • CNS - Parkinson's
  • extracts from atropa belladona - weak antiparkinsonian effect
  • reduce tremor, used in initial tx (bc L-dopa may worsen the disease) in pt with mild sx
  • in pt with refractory tremor or dystonias, used as adjunct to L-dopa
  • tx drug induced extrapyramidal syndroms
  • agents: benztropine, biperiden, orphenadrine, trihexyphenidyl
Clinical uses of muscarinic antagonists:
  • Motion sickness
  • scopolamine - for motion sickness, with SE's (dry mouth, sedation). Injection, oral, transderm.
  • also used before surgery if pt can't tolerate anesthetics
Clinical uses of muscarinic antagonists:
  • Ophthalmologic Disorders
  • topical - cycloplegia (paralysis of ciliary muscle - loss of accommodation) and mydriasis
  • Cycloplegia aids in measuring refractive error, mydriasis facilitates eye exam of retina
  • DO NOT USE if only want mydriasis (can use alpha adrenoceptor agonist - shorter acting)
Clinical uses of muscarinic antagonists:
  • Drugs used for: Ophthalmologic Disorders
  • Scopolamine (3-7d)
  • Atropine (7-10d)
  • Homatropine (1-3d)
  • Cyclopentolate (1d)
  • Tropicamide (.25d)
  • Tropicamide + hydroxyamphetamine
Clinical uses of muscarinic antagonists:
  • Respiratory Disorders
  • Atropine & Scopolamine - anesthesia to inhibit inc airway secretions and laryngospasm.  SE: exacerbation of postop urinary retention, intestinal hypomotility (not done anymore)
  • 4° antimuscarinic aerosols act as bronchodilators (tx asthma). COPD also responds well.
  • ex: Ipratropium, Ipratropium and albuterol (β2 adrenergic), Tiotropium
Clinical uses of muscarinic antagonists:
  • CV disorders
  • use for increased vagal discharge (intraoperatively, MI, drug induced)
  • Atropine prevents this
  • too little atropine: worsens bradycardia - pre synaptic inhibition
  • too much atropine: causes tachycardia (baroreflex), extends infarct
Clinical uses of muscarinic antagonists:
  • GI Disorders - Peptic ulcer
  • Rarely used bc there are better drugs now.
  • High doses required to reduce gastric secretions, cause SE's (reduce gastric emptying - exacerbates peptic ulcer).
  • atropine, hyoscyamine, glycopyrrolate

Clinical uses of muscarinic antagonists:
  • GI Disorders - Diarrhea
  • relief from mild forms
  • MC usage: additive to opioid antidiarrheals (diphenoxylate - lomotil) to discourage abuse of opioid
Clinical uses of muscarinic antagonists:
  • GI Disorders - Antispasmodics
  • Irritable bowel syndrome & spastic colon
  • dicyclomine (3° amine, less SE than atropine - black box warning <6months), hyoscyamine
Clinical uses of muscarinic antagonists:
  • GU Disorders
  • Relieve urinary urgency and incontinence d/t minor inflammatory bladder disorders & neurologic disorders
  • oxybutynin (ditropan XL - less SE's, better antispazmotic than atropine), tolterodine (detrol LA - more M3 selectivity)
  • enablex and vesicare also target M3 with decreased side effects - these will be "distractors" on the exam
Clinical uses of muscarinic antagonists:
  • Cholinergic poisoning
  • EMERGENCY cause: anticholinesterase insecticides, eating wild mushrooms
  • muscarinic effects treatable with 3° antimusc agent (atropine) given repeatedly in high doses IV (AChE's last longer than atropine)
  • PAM, a cholinesterase regenerator, can be used for organophosphate tox, but doesn't cross BBB.
  • Mushroom poisoning - rapid (15-30min post ingestion - d/t muscarinic XS, tx with IV atropine).  delayed (6-12h post ingestion d/t other mushrooms with amatoxin - kidney and liver damage, atropine is not useful)
Adverse effects of Muscarinic Antagonists
  • therapeutic doses
  • dry mouth w/difficulty swallowing and talking, thirst, reduced bronch secretions
  • mydriasis, cycloplegia, photophobia
  • flushing and dryness of skin
  • transient bradycardia followed by tachycardia, palpitations and arrhythmias
  • difficulty in micturition, reduction in tone/motility of GIT, constipation
Adverse effects of Muscarinic Antagonists
  • Overdosage
  • Peripheral effects become more pronounced
  • hyperthermia, HTN, ↑ resp rate, n/v
  • rash on face/upper trunk
  • CNS stim: restlessness, confusion, excitement, ataxia, incoordination, paranoid, psychotic rxns, hallucinations, delirium, seizures
  • **sever intox** - central stim gives way to CNS depression, coma, circ/resp failure, death.
  • if sx's severe - physostigmine
Anticholinergic toxicity mnemonic
  • Blind as a bat
  • Dry as a bone
  • Red as a beet
  • Mad as a hatter
  • Hot as a hare
  • Can't see
  • Can't pee
Contraindications of antimuscarinics
  • safe in adults, should be used in cholinergic excess
  • CI in pts with glaucoma (esp narrow angly closure)
  • CI in males with prostatic hyperplasia - can ppt urinary retention
Ganglionic blockade
  • agents that block actions of ACh on nicotinic receptors present at both sympathetic and parasympathetic ganglia (ALL receptors at ganglia are Neuronal type Nicotinic receptors)
  • block autonomic outflow, have limited clinical applications
  • prevent reflex activity in the autonomic nervous system!!! (bc ALL autonomic ganglia function is blocked)
  • Mecamylamine is only available agent (good oral absorption)
  • competetive antagonist at Nic ACh recep's at ganglia and at adrenal medulla.
  • blocking ganglionic output will BLOCK DOMINANT TONE!
Organ system effects of ganglionic blockade!
  • CNS
  • Mecamylamine is the only agent that can access CNS (others are 4° amines).
  • Causes sedation, tremor, choreiform mvmts, mental aberrations.
Organ system effects of ganglionic blockade!
  • Eye
  • normal dominant tone is parasympathetic
  • ciliary muscle: cycloplegia
  • iris: pupil dilation
Organ system effects of ganglionic blockade!
  • CV system
  • BV'S: sympathetic dominance; blockade results in arterial/venous dilation↓BP, ↓periph vasc R & venous return, ↓CO.  postural hypotension worse because reflexes to prevent venous pooling are blocked
  • Heart: vagal tone dominates SA node: blockade results in moderate tachycardia
Organ system effects of ganglionic blockade!
  • GI tract
  • Parasymp dominates;
  • gastric & pancreatic secretions are reduced
  • motility is reduced
  • constipation!
Organ system effects of ganglionic blockade!
  • GU system
  • Urinary hesitancy
  • retention in men with prostatic hyperplasia
erection/ejac prevented
Organ system effects of ganglionic blockade!
  • glands
  • Parasymp tone dominates salivary glands: dry mouth
  • Sympathetic (cholinergic) tone dominates sweat glands : anhidrosis
Clinical uses of ganglionic blockade
  • Mecamylamine indicated for moderate-severe HTN
  • orphan drug for Tourette's syndrome
  • useful for ↓ BP in acute dissecting aortic aneurysm.
  • good bc blocks sympathetic reflexes
  • *also creates controlled hypotension for surgical procedures to reduce hemorrhaging in OR
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