Download MUSCARINIC RECEPTOR ANTAGONISTS:

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
1. Atropine – a
natural product.
S-enantiomer is
the active form
aka
HYOSCAMINE,
w/c is a
therapeutic
agent in itself.
2. Scopolamine
Description








3. Ipratropium
– similar
potency as
atropin


4. Tiotropium



Tx Application
Tropine based.
Contains bulky ester grp.,
which contributes to antagonist
action.
HYOSCAMINE – the active
form. An antidote for AChE
inhibitor poisoning.
3,tiary amine


Greater CNS action than
atropine. Easily cross the
blood/brain barrier
Active S-enantiomer.
Contains and epoxide grp.
Natural derivative of atropine
Atropine derivative.
A 4’nary N which leads to poor
absorption of swallowed dose,
therefore minimizing the
systemic effects.
a scopolamine derivative.
Same therapeutic
/pharmacologic profile as
ipatropium
contains synthetic ester ( a
Thiophene ring)
Precautions/ Side effects
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




Transderm scope for
motion sickness





COPD by inhalation
Local axn in the lung




COPD use once daily
Asthma
(less effect on lung
secretion)





Duration
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
Amnesia
Sedation
Stupor and hallucinations
(Criminally abused to render
victims compliant)
Long: 7-10 days
90 % of the drug is swallowed
(very inefficient)
Several days
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
1. Oxybutynin

2. Tolderodine


3. Solifenacin

Tx Application
Undergoes CYP3a4-Ndeethylation giving an active
metabolite (happens at 1st –pass
metabolism)
Yields an active metabolite, a
hydroxtmethyl metabolite,
which have the similar activity
as the parent drug.
Single R-enantiomer, not
racemic



urinary incontinence
bladder hyper irritability
Overactive Bladder

Overactive bladder
Single enantiomer – 2 chiral
center

Overactive bladder
Precautions/ Side-effects /
Metabolism
Duration

Ketoconazole is a 3A4 inhibitor –
AUC will increase and so as S/E. If
this happens, oxybutynin dose
should be lowered.
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
Metabolsm:
 Cyp3a4: Yeilds N-oxide and 4Rhydorxy 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
Glycopyrrolate
Trospium
Description
For pediatric patients
Tx Application
Precautions/ Side-effects
Overactive bladder
Overactive bladder
Duration
20 hrs
D. Antimuscarinic Antiparkinsonian Agents: Should be lipophilic, contains 3’tiary amine, and highly polarity to access/penetrate the CNS
Drug
1. Benztropine
2. Procyclidine
Description




Has 3’tiary amines
Highly lipophilic
Has 3’tiary Alohol
Contains aromatic ring (makes
the alcohol greasy)
Tx Application

Duh!!!

Use in eye exams for
papillary dilation and
treatment of iritis
Precautions/ Side-effects
Duration
E: Amine Muscarinic Antagonists:
1. Tropicamide

Shorter duration of action than
atropine
6 hrs