Part 3. Cholinergic Receptor Antagonists Flashcards
Cholinergic Receptor Antagonists are broken down into:
Nicotinic antagonists and Muscarinic antagonists
Muscarinic Receptor Antagonists basics:
• High binding affinity for muscarinic receptors but no intrinsic agonist activity
• Cause a conformational change in the receptor different from an agonist
(anticholinergics, antimuscarinics, etc.)
What are the principle targets for muscarinic antagonists?
- M2 – myocardium, smooth muscle organs, prejunctional (presynaptic) receptors
- M3 – glandular and smooth muscle cells
Atropine:
- Prototype muscarinic receptor antagonist
- Naturally occurring compounds
Scopolamine (hycosine):
- Leaves and flowers of Hyoscyamus niger (black henbane) [l(-)-hycosine]
Antimuscarinic Absorption:
- All clinically useful antimuscarinics are effective administered orally or parenterally
- Natural alkaloids and most tertiary amines well absorbed from the gut and conjunctiva
- BUT - Quaternary amines poorly absorbed due to their ionic nature (10 – 30% of dose)
Antimuscarinic Distribution:
- Atropine and other tertiary compounds widely distributed
- Crosses BBB – Significant CNS levels 0.5 – 1hr post-dose
- useful for diseases requiring a central anticholinergic effect (e.g.Parkinson’s)
- but limits dose for peripheral effects
- Quaternary compounds poorly distributed to brain therefore, relatively free from central effects at low doses
Antimuscarinic Metabolism:
- Atropine exhibits TWO-PHASE ELIMINATION:
- Rapid phase t1⁄2 = 2 hrs
- Slow phase t1⁄2 13 hrs
- 50% excreted unchanged in the urine
- Parasympathetic effects decline rapidly except in the eye where persist for ≥ 72 hours
MOA of antimuscarinics:
- atropine - reversible blockade of cholinergic actions at muscarinic receptors
- prevents the normal cascade of biochemical effects – e.g., production of IP3; inhibition adenylyl cyclase
- muscarinic receptors are constitutively active and most muscarinic antagonists are inverse agonists
- E.g., atropine, pirenzepine, ipratropium
MOA of antimuscarinics, cont:
Effectiveness of muscarinic antagonists varies with the tissues and the agonist source
- Most sensitive – salivary, bronchial, and sweat glands
- Least sensitive – acid secretion by gastric parietal cells
• Antimuscarinics generally block exogenous agonists more effectively than endogenous ACh
Atropine Mechanism of Action:
- highly selective for muscarinic receptors
- nonselective for M1, M2, M3
- most synthetic muscarinic antagonist can be less selective for muscarinic receptors than atropine
Effects in the CNS - atropine:
- normal doses - minimal stimulant effects in CNS & slower, longer lasting sedative effect on brain
- Parkinson’s tremor reduced by centrally acting antimuscarinics (atropine one of first drugs used)
- Combination of an antimuscarinic with dopamine precursor sometimes more effective than either drug alone
Effects in the CNS - scopolamine:
- More marked central effects with drowsiness at recommended doses & amnesia in sensitive individuals
- toxic doses - excitement, agitation, hallucinations and coma
- Scopolamine is effective in motion sickness and other vestibular disturbances
- Injection; oral; transdermal patch (significant blood levels up to 72 hrs)
Antimuscarinics - Effects in the Eye:
- Pupillary constrictor muscle depends upon muscarinic cholinergic activation
- Blocked by atropine & other tertiary antimuscarinics
- Result is unopposed sympathetic-mediated dilation — mydriasis
- Antimuscarinics weaken ciliary muscle contraction — cycloplegia
- loss of accommodation and inability to focus for near vision
Antimuscarinics - Effects in the Eye, cont:
- Antimuscarinic effects in the eye can induce acute glaucoma
- Antimuscarinics should not be used unless cycloplegia or prolonged mydriasis is required
- a-adrenergic agonists preferred (e.g., phenylephine) - a shorter duration mydriasis
- Antimuscarinics reduce lacrimal secretion • Dry or “sandy” eyes at high doses
Antimuscarinic effects in the
Cardiovascular System:
- SA node very sensitive to muscarinic receptor blockade
- Moderate to high dose atropine
- tachycardia by blockade of vagal slowing
- at lower doses bradycardia can precede tachycardia
- Blockade of vagal presynaptic M1 (autoreceptors) that would normally limit ACh release in the sinus node and elsewhere
- Atropine can also reduce the PR interval in the EKG via blockade of muscarinic receptors in the AV node
Antimuscarinic effects in the Cardiovascular System, cont:
• Muscarinic effects in atrial muscle are blocked
• Ventricles less affected at normal doses - less vagal
innervation
• Toxic concentrations can cause intraventricular conduction block due to local anesthetic effect
• Vasodilation – blocked by antimuscarinic drugs
• Parasympathetic nerve stimulation dilates coronary
arteries
• Almost all vessels have endothelial muscarinic receptors
Effects in the Respiratory System:
Respiratory smooth muscle and secretory glands receive vagal innervation and have muscarinic receptors
• Atropine causes bronchodilation and reduced secretion
• Effect more significant in patients with airway disease • Not as effective as b-agonists in asthma
• Effectiveness of Non-selective muscarinic blockers for COPD is limited
• M2 autoreceptor inhibitory blockade on postgaglionic parasympathetic nerves works against blockade of M3 receptors on airway smooth muscle
COPD:
• Hyperactive neural bronchoconstrictor reflex is vagally mediated via muscarinic receptors on bronchial smooth muscle
ipratropium bromide (Atrovent):
- atropine analogue
* Inhaled aerosol maximizes concentration at site of action and minimizes systemic effects
tiotropium br (Spiriva):
• Longer duration of bronchodilation
t1/2 = 5-6 days vs 2hrs for ipratropium • Can be dosed once daily
Antimuscarinic Effects in the Genitourinary Tract:
- Relaxation of smooth muscle of ureters and bladder slows voiding
- Rx of spasm induced by inflammation, surgery, and certain neurological conditions
- Can precipitate urinary retention in patients with prostatic hyperplasia
- M2 & M3 receptor subtypes predominate; M3 directly mediate contraction; M2 indirectly via inhibition of the relaxation mediated by NE and E (sympathetic heteroceptor)
Antimuscarinic drugs in urinary disorders:
oxybutynin, darifenacin, solifenacin
oxybutynin (Ditropan):
- Somewhat selective for M3
- Overactive bladder and bladder spasm after urological surgery
- Involuntary voiding in patients with neurological disease (e.g., meningomyelocele)
- Oral or catheter instillation into the bladder improves bladder capacity & continence
darifenacin (Enablex) & solifenacin (Vesicare):
• greater M3 selectivity
• once daily dosing possible due to long t1/2 (≈ 55 hours)
• longer-acting drugs has not improved efficacy or reduced side-effects
like dry mouth
Antimuscarinic drugs in urinary disorders, other:
trospium, tolterodine, fesoterodine, Imipramine
trospium (Sanctura):
• Nonselective; comparable efficacy and safety to oxybutynin
tolterodine (Detrol) & fesoterodine (Toviaz):
- M3-selective
- Adults with urinary incontinence
- available as extended release
imipramine:
- Tricyclic antidepressant with strong antimuscarinic action
- 2nd line therapy of mild to moderate incontinence in institutionalized patients
- cardiac dysrythmias; CNS toxicity
Antimuscarinics in Sweat Glands:
• atropine suppresses thermoregulatory sweating
• Sympathetic cholinergic fibers innervate eccrine sweat
glands
• Adults:
• Body temperature elevated by large doses only
• Children and infants:
• “atropine fever” at normal doses
Antimuscarinic Treatment of cholinergic poisoning
- Tertiary amine must be used
- Large doses of atropine required for extremely potent compounds – e.g., parathion; nerve gases
- 1-2 mg atropine sulfate iv every 5 – 15 minutes until observable effect – (e.g., dry mouth, reversal of miosis)
- Repeated dosing as required due to long duration of anticholinesterase effect (24–48 hrs)
- As much as 1g per day for a month to control symptoms of muscarinic excess
Antimuscarinic Treatment, Pralidoxime (2-PAM):
- i.v. infusion – 1-2g over 15-30 minutes
- Multiple doses over several days in severe poisonings
- Excessive doses can induce muscular weakness
- Not recommended for carbamate intoxication
- Pretreatment
- Pyridostigmine (when potentially lethal poisoning is anticipated) and atropine
Atropine Adverse Effects:
• Antimuscarinic treatment for one organ system almost always has undesirable effects in other organ systems
• High concentrations block all parasympathetic functions
• Relatively safe in adults
• Children, particularly infants, very sensitive to
hyperthermic affect of atropine
Atropine Overdose:
• Supportive, symptomatic treatment
• esp. temperature control; seizure control
(diazepam)
• Quaternary antimuscarinics only associated with peripheral manifestations (few or no CNS effects)
• May cause significant ganglionic blockade and marked orthostatic hypotension
• Antimuscarinic effects can be treated with a quaternary cholinesterase inhibitor
Ganglion-Blocking Drugs:
- Of limited clinical use
- Competitive blockade of ACh and other cholinergic agonists at nicotinic receptors of parasympathetic and sympathetic ganglia
- Used in research because they can block all autonomic outflow
