Part 3. Cholinergic Receptor Antagonists Flashcards

1
Q

Cholinergic Receptor Antagonists are broken down into:

A

Nicotinic antagonists and Muscarinic antagonists

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Muscarinic Receptor Antagonists basics:

A

• 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.)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What are the principle targets for muscarinic antagonists?

A
  • M2 – myocardium, smooth muscle organs, prejunctional (presynaptic) receptors
  • M3 – glandular and smooth muscle cells
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Atropine:

A
  • Prototype muscarinic receptor antagonist

- Naturally occurring compounds

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Scopolamine (hycosine):

A
  • Leaves and flowers of Hyoscyamus niger (black henbane) [l(-)-hycosine]
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Antimuscarinic Absorption:

A
  • 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)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Antimuscarinic Distribution:

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Antimuscarinic Metabolism:

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

MOA of antimuscarinics:

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

MOA of antimuscarinics, cont:

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Atropine Mechanism of Action:

A
  • highly selective for muscarinic receptors
  • nonselective for M1, M2, M3
  • most synthetic muscarinic antagonist can be less selective for muscarinic receptors than atropine
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Effects in the CNS - atropine:

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Effects in the CNS - scopolamine:

A
  • 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)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Antimuscarinics - Effects in the Eye:

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Antimuscarinics - Effects in the Eye, cont:

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Antimuscarinic effects in the

Cardiovascular System:

A
  • 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
17
Q

Antimuscarinic effects in the Cardiovascular System, cont:

A

• 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

18
Q

Effects in the Respiratory System:

A

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

19
Q

COPD:

A

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

20
Q

ipratropium bromide (Atrovent):

A
  • atropine analogue

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

21
Q

tiotropium br (Spiriva):

A

• Longer duration of bronchodilation

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

22
Q

Antimuscarinic Effects in the Genitourinary Tract:

A
  • 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)
23
Q

Antimuscarinic drugs in urinary disorders:

A

oxybutynin, darifenacin, solifenacin

24
Q

oxybutynin (Ditropan):

A
  • 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
25
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
26
Antimuscarinic drugs in urinary disorders, other:
trospium, tolterodine, fesoterodine, Imipramine
27
trospium (Sanctura):
• Nonselective; comparable efficacy and safety to oxybutynin
28
tolterodine (Detrol) & fesoterodine (Toviaz):
* M3-selective * Adults with urinary incontinence * available as extended release
29
imipramine:
* Tricyclic antidepressant with strong antimuscarinic action * 2nd line therapy of mild to moderate incontinence in institutionalized patients * cardiac dysrythmias; CNS toxicity
30
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
31
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
32
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
33
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
34
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
35
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