MUSCARINIC RECEPTOR ANTAGONISTS:

General Uses:
1. To produce mydriasis (dilated pupils).

2.  To treat COPD.

3.  To treat smooth muscle spasma (associated with overactive bladder and urinary incontinence).

Classes:

A. Naturally Occurring alkaloids and smisynthetic derivatives

Drug / Description / Tx Application / Precautions/ Side effects / Duration
1. Atropine – a natural product. S-enantiomer is the active form aka HYOSCAMINE, w/c is a therapeutic agent in itself. / ·  Tropine based.
·  Contains bulky ester grp., which contributes to antagonist action.
·  HYOSCAMINE – the active form. An antidote for AChE inhibitor poisoning.
·  3,tiary amine / ·  Cardiac stimulant effect
·  To treat muscarine (mushroom) poisoning
·  Combined with an opioid (Lomotil) for diarrhea
·  Nerve gas poisoning
·  HOMOTROPINE – shorter duration and is useful in eye exam / ·  0.5 mg - dry mouth & skin
·  1.0 mg - Increased heart rate, thirst.
·  2 mg - pupillary dilation, blurred vision tachycardia
·  5 mg – Reduced peristalsis, urinary retention, hot dry skin, fatigue, flushing
·  10 mg - Rapid and weak pulse, ataxia, hallucinations, delirium, coma / Long: 7-10 days
2. Scopolamine / ·  Greater CNS action than atropine. Easily cross the blood/brain barrier
·  Active S-enantiomer.
·  Contains and epoxide grp.
·  Natural derivative of atropine / ·  Transderm scope for motion sickness / ·  Amnesia
·  Sedation
·  Stupor and hallucinations (Criminally abused to render victims compliant)
3. Ipratropium – similar potency as atropin / ·  Atropine derivative.
·  A 4’nary N which leads to poor absorption of swallowed dose, therefore minimizing the systemic effects. / ·  COPD by inhalation
·  Local axn in the lung / ·  90 % of the drug is swallowed (very inefficient) / Several days
4. Tiotropium / ·  a scopolamine derivative.
·  Same therapeutic /pharmacologic profile as ipatropium
·  contains synthetic ester ( a Thiophene ring) / ·  COPD use once daily
·  Asthma
·  (less effect on lung secretion) / Longer acting than 3.

B. Tertiary Amines Muscarinic Antagonists: functional selectivity for the urinary bladder. All are orally available and are typically absorbed well.

Drug / Description / Tx Application / Precautions/ Side-effects / Metabolism / Duration
1. Oxybutynin / ·  Undergoes CYP3a4-N-deethylation giving an active metabolite (happens at 1st –pass metabolism) / ·  urinary incontinence
·  bladder hyper irritability
·  Overactive Bladder / ·  Ketoconazole is a 3A4 inhibitor – AUC will increase and so as S/E. If this happens, oxybutynin dose should be lowered.
2. Tolderodine / ·  Yields an active metabolite, a hydroxtmethyl metabolite, which have the similar activity as the parent drug.
·  Single R-enantiomer, not racemic / ·  Overactive bladder / Metabolism:
·  Cyp2D6 is the major p/w yielding active metabolite. (genetic polymorphism – 70 % of pop’n are poor metabolizers
·  Cyp3A4 is the minor p/s
·  Active N-dealkylation
3. Solifenacin / ·  Single enantiomer – 2 chiral center / ·  Overactive bladder / Metabolsm:
·  Cyp3a4: Yeilds N-oxide and 4R-hydorxy metabolite but these metabolites don’t contribute to activity. 4R-hydroxy could be active but its [c] is not enough for activity / 45-68 hrs. Dosing is once daily

C: Quaternary Ammonium Muscarinic Antagonists:

Drug / Description / Tx Application / Precautions/ Side-effects / Duration

Glycopyrrolate

/ For pediatric patients / Overactive bladder
Trospium / Overactive bladder / 20 hrs

D. Antimuscarinic Antiparkinsonian Agents: Should be lipophilic, contains 3’tiary amine, and highly polarity to access/penetrate the CNS

Drug / Description / Tx Application / Precautions/ Side-effects / Duration
1. Benztropine / ·  Has 3’tiary amines
·  Highly lipophilic / ·  Duh!!!
2. Procyclidine / ·  Has 3’tiary Alohol
·  Contains aromatic ring (makes the alcohol greasy)

E: Amine Muscarinic Antagonists:

1. Tropicamide / ·  Shorter duration of action than atropine / ·  Use in eye exams for papillary dilation and treatment of iritis / 6 hrs