PHAM 3357 – Dr. F.
Ndubi
Devotional thought & prayer:
Lecture outline:
Recap of last lecture.
Introduction to antimuscarinic agents.
Chemistry & pharmacodynamics.
Pharmacokinetic properties.
Introduction:
Muscarinic antagonists are compounds that exhibit
high binding affinity for mAChRs but possess no
intrinsic activity.
Receptor binding by the antagonist has been proposed
to produce a conformational perturbation different
from that produced by an agonist.
These compounds therefore produce the opposite
effect of ACh or cholinergic agonist binding.
Also referred to as anticholinergics, antimuscarinics,
cholinergic blockers, antispasmodics or
parasympatholytics.
Physiological effects:
Decreased GI and urinary tract smooth muscle
contraction.
Pupillary dilation (mydriasis).
Reduced mucosal secretions at the gastric, mucociliary
and salivary glands.
Reduced gastric acid secretion.
Clinical uses:
Treatment of smooth muscle spasm associated with
GI, uterine and bladder sm (overactive bladder).
Ophthalmological examination.
Treatment of gastric ulcers.
Reduction of nasal and URT secretions.
Prophylaxis of motion sickness.
Treatment of Parkinson's disease.
Preventing extrapyramidal s/e of 1st generation
antipsychotics.
Systemic side effects:
Dry mouth.
Blurred vision & photophobia.
Difficulty in swallowing, constipation & abdominal
distension.
Anhydrosis (hot, dry skin).
Urinary retention.
Tachycardia.
Dizziness, nausea & vomiting.
Tremor, fatigue & lack of co-ordination.
Loss of libido & sexual dysfunction.
Classification:
Solanaceous alkaloids and synthetic aminoalcohol
esters – Atropine, Scopolamine.
Aminoalcohols – Procyclidine, Trihexyphenidyl
(Benzhexol).
Aminoethers – Orphenadrine, Benztropine.
Miscellaneous antimuscarinics – Propantheline,
Flavoxate, Solifenacin, Darifenacin.
Chemistry & pharmacodynamics of antimuscarinic agents.
Introduction:
Atropine, the prototypical antimuscarinic, provided
the motif for development of the various synthetic
muscarinic antagonists.
Both Atropine and Scopolamine (Hyoscine) contain
segments which structurally resemble the ACh
molecule.
Even though the ester oxygen and amino group are
separated by more than two carbon atoms, the
conformation assumed by the Tropine ring ensures the
distance between the two functional centers is similar
to that in ACh.
Chemistry:
Portion of Atropine molecule
bearing structural similarity to
ACh molecule.
General structure of synthetic
antimuscarinic agents.
Distinctions in chemistry of
Atropine & Scopolamine..?
Chemistry:
An important difference between Atropine & ACh is
the size of the acyl portion.
From this observation, various substituted acetic acid
esters of aminoalcohols were synthesized and
evaluated for antimuscarinic activity.
The most potent antagonists were those bearing two
lipophilic ring substituents on the carbon α to the
carbonyl ester group.
See chemical structures.
Aminoalcohol esters:
Atropine, Scopolamine,
Homatropine and the
synthetic/semi-synthetic
antimuscarinic esters.
Chemistry..?
Clinical uses of Ipratropium and
Oxybutinin?
Aminoalcohols & aminoethers:
Similarities and differences between
these agents and aminoalcohol esters..?
Chemistry..?
Clinical uses of Trihexyphenidyl?
Miscellaneous agents:
Chemistry..?
SAR:
Substituents R1 and R2 should be heterocyclic or
carbocyclic rings for maximum antagonist activity. The
two rings may be identical, different or fused into a
tricyclic system (Propantheline). Size of the rings is
limited by steric hindrance, as naphthyl substituents
are inactive.
The R3 substituent can be a H, -OH, hydroxymethyl,
carboxamide or part of the ring substituents. Polar
substituents generally afford higher antagonist
potency, presumably by participating in an extra H-
bond interaction at the receptor.
SAR..
The X group is an ester function in the most potent
analogs. However, this is not an absolute necessity for
muscarinic antagonism. The group can be an ether
oxygen or be completely absent, with retention of
activity.
The amino group occurs in quaternary ammonium
form for the most potent antagonists, as in ACh.
However, analogs containing tertiary amine groups are
also active, presumably in their ionized form. Alkyl
substituents are usually methyl, ethyl, propyl or
isopropyl.
SAR..
Distance between the Carbon atom bearing ring
substituents and the Nitrogen atom is not critical. This
may vary from 2-4 Carbons with retention of activity.
Analogs with the highest potency bear two methylene
units in this chain.
Chemistry & antagonist activity:
Requirement of bulky lipophilic groups for antagonist
activity suggests presence of lipophilic binding sites on
the receptor.
Strong binding to these sites prevents agonist binding.
Also, retention of antagonist activity with increased
chain length suggests the lipophilic groups may bind
at hydrophobic binding pockets outside the binding
site of ACh.
Quaternary ammonium compounds are generally used
for local effects while secondary amines are used to
achieve systemic antimuscarinic effects.
Pharmacokinetic properties of Atropine, Scopolamine,
Ipratropium & Oxybutynin.
1. Atropine
The tropic acid ester of Tropine, found naturally in
plants of the Solanaceae family A. belladona, H. niger
and D. stramonium.
Usually marketed as the sulphate salt.
Atropine was the first compound shown to block the
effect of Muscarine, as well as electrical stimulation of
the PNS.
Commonly used for treatment of bradycardia and as
adjunct pre-operative therapy.
Atropine..
When used in symptomatic treatment of OPP,
Atropine only alleviates the symptoms of poisoning,
but does not reverse the underlying AChE inhibition.
Approximately 50% of an administered dose of
Atropine is eliminated in urine unchanged.
Up to 24% is eliminated as Noratropine, 15% as
Atropine N-oxide and less than 5% as products of non-
enzymatic ester hydrolysis.
Elimination half-life is 4 hrs in adults and 6.5 hrs in
children.
Metabolism:
2. Scopolamine (Hyoscine):
Also a Solanaceous alkaloid that is structurally &
pharmacologically related to Atropine.
Scopolamine is the generic name for (-)-Hyoscine, the
naturally-occurring alkaloid.
Usually marketed as the HBr salt which is less
deliquescent than its other salts.
Most commonly used for treatment of motion sickness
and as an antispasmodic.
In management of motion sickness, the preferred
formulation is as a transdermal patch applied to the
skin, usually behind the ear.
Scopolamine..
Though not well characterized, Scopolamine is
extensively metabolized and conjugated in the liver.
Less than 5% of the administered dose appears
unchanged in urine.
3. Ipratropium bromide:
A quaternary ammonium derivative of Atropine,
usually available as the bromide salt.
The free base is soluble in water & ethanol, but
insoluble in ether & chloroform.
The bromide salt is stable in neutral and acidic
solutions, but rapidly hydrolyzed in alkaline solutions.
Ipratropium is used as inhalation therapy to produce
bronchodilation in acute asthmatic attacks. Various
inhaled formulations contain Ipratropium bromide in
combination with Albuterol.
Ipratropium bromide..
The agent causes dilation of bronchial smooth muscle
by competitive inhibition of ACh binding to M2 and
M3 receptors.
Ipratropium has a slow onset of action of 5-15 min,
with peak therapeutic effect observed in 1-2 hrs.
Effects of the drug last for about 6 hrs.
Metabolized by..
4. Oxybutynin:
A synthetic aminoalcohol ester, one of the first agents
specifically developed to exploit the clinical effect of
antimuscarinic activity on the bladder.
It produces spasmolytic effect on bladder sm by
competitive blockade of muscarinic receptors.
The resulting reduction in sm tone allows for greater
volumes of urine to be stored in the bladder.
Used clinically for treating overactive bladder, urinary
incontinence, urinary frequency/urgency and
nocturnal enuresis in children.
Analysis:
Atropine – MP, IR, TLC. Potentiometric titration with
PCA.
Scopolamine – SOR, IR. Potentiometric titration with
NaOH.
Trihexyphenidyl – IR, TLC. Potentiometric titration
with NaOH.
Ipratropium – IR. Potentiometric titration with
AgNO3.
Oxybutynin – MP, IR, TLC. Potentiometric titration
with NaOH.
