Part 3. Cholinergic Receptor Antagonists

Question 1

Cholinergic Receptor Antagonists are broken down into:

Answer 1

Nicotinic antagonists and Muscarinic antagonists

Question 2

Muscarinic Receptor Antagonists basics:

Answer 2

• 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.)

Question 3

What are the principle targets for muscarinic antagonists?

Answer 3

• M2 – myocardium, smooth muscle organs, prejunctional (presynaptic) receptors
• M3 – glandular and smooth muscle cells

Question 4

Atropine:

Answer 4

• Prototype muscarinic receptor antagonist

- Naturally occurring compounds

Question 5

Scopolamine (hycosine):

Answer 5

• Leaves and flowers of Hyoscyamus niger (black henbane) [l(-)-hycosine]

Question 6

Antimuscarinic Absorption:

Answer 6

• 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)

Question 7

Antimuscarinic Distribution:

Answer 7

• 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

Question 8

Antimuscarinic Metabolism:

Answer 8

• 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

Question 9

MOA of antimuscarinics:

Answer 9

• 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

Question 10

MOA of antimuscarinics, cont:

Answer 10

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

Question 11

Atropine Mechanism of Action:

Answer 11

• highly selective for muscarinic receptors
• nonselective for M1, M2, M3
• most synthetic muscarinic antagonist can be less selective for muscarinic receptors than atropine

Question 12

Effects in the CNS - atropine:

Answer 12

• 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

Question 13

Effects in the CNS - scopolamine:

Answer 13

• 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)

Question 14

Antimuscarinics - Effects in the Eye:

Answer 14

• 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

Question 15

Antimuscarinics - Effects in the Eye, cont:

Answer 15

• 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

Question 16

Antimuscarinic effects in the

Cardiovascular System:

Answer 16

• 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

Question 17

Antimuscarinic effects in the Cardiovascular System, cont:

Answer 17

• 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

Question 18

Effects in the Respiratory System:

Answer 18

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

Question 19

COPD:

Answer 19

• Hyperactive neural bronchoconstrictor reflex is vagally mediated via muscarinic receptors on bronchial smooth muscle

Question 20

ipratropium bromide (Atrovent):

Answer 20

• atropine analogue

* Inhaled aerosol maximizes concentration at site of action and minimizes systemic effects

Question 21

tiotropium br (Spiriva):

Answer 21

• Longer duration of bronchodilation

t1/2 = 5-6 days vs 2hrs for ipratropium • Can be dosed once daily

Question 22

Antimuscarinic Effects in the Genitourinary Tract:

Answer 22

• 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)

Question 23

Antimuscarinic drugs in urinary disorders:

Answer 23

oxybutynin, darifenacin, solifenacin

Question 24

oxybutynin (Ditropan):

Answer 24

• 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

Question 25

darifenacin (Enablex) & solifenacin (Vesicare):

Answer 25

• 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

Question 26

Antimuscarinic drugs in urinary disorders, other:

Answer 26

trospium, tolterodine, fesoterodine, Imipramine

Question 27

trospium (Sanctura):

Answer 27

• Nonselective; comparable efficacy and safety to oxybutynin

Question 28

tolterodine (Detrol) & fesoterodine (Toviaz):

Answer 28

• M3-selective
• Adults with urinary incontinence
• available as extended release

Question 29

imipramine:

Answer 29

• Tricyclic antidepressant with strong antimuscarinic action
• 2nd line therapy of mild to moderate incontinence in institutionalized patients
• cardiac dysrythmias; CNS toxicity

Question 30

Antimuscarinics in Sweat Glands:

Answer 30

• 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

Question 31

Antimuscarinic Treatment of cholinergic poisoning

Answer 31

• 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

Question 32

Antimuscarinic Treatment, Pralidoxime (2-PAM):

Answer 32

• 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

Question 33

Atropine Adverse Effects:

Answer 33

• 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

Question 34

Atropine Overdose:

Answer 34

• 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

Question 35

Ganglion-Blocking Drugs:

Answer 35

• 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