Transcript Cimetidine - Clemson University

Cimetidine
Outline of Presentation
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History of Cimetidine
Properties of H2 receptor antagonists
Pharmacokinetics
Mechanism of Action (Pharmacodynamics)
Toxicity
Improvements
History
• H1 receptor antagonists were discovered by
chance. H2 receptor antagonists, however,
resulted from extensive research by Smith,
Kline, and French.
• Cimetidine was first marketed in the United
Kingdom in 1976. It is used for the
treatment of gastric hyperacidity.
• Histamine, a stimulator of allergic reactions,
triggers the release of acid when it binds to
a receptor in the gut lining.
• Existing antihistamines - used to treat hay
fever - did not prevent this acid release.
• Therefore, the histamine was binding to a
new receptor in the gut that was different
from the H1 receptor.
• By modifying histamine, it was confirmed
that a different histamine receptor did exist H2 receptor. So, histamine acts as an H2
receptor agonist (stimulator) in the gut.
• The goal was to find an H2 receptor
antagonist to compete with histamine.
• After four years of research,
guanylhistamine was found to act as an
antagonist of histamine. However, it did
stimulate some acid release as well. The
acid release was due to the ability of the
side chain to ionize and acquire a charge just like histamine!
Structure of Guanylhistamine
• Two years later, another molecule was
created that still acted as a histamine
antagonist. This molecule did not stimulate
acid production. The molecule was made
by replacing the charged guanidine moiety
with a neutral thiourea. The molecule was
called burimamide. However, it could not
be given p.o.
Structure of Burimamide
• To overcome the limits of burimamide, the
electronic effects of influencing the
hydrogen atom attached to one or other
nitrogens in the imidazole ring was
considered and the molecule metiamide was
created. Metiamide was ten times more
effective than burimamide and it could also
be taken orally.
• Metiamide has an electron releasing methyl
group in the C5 position of the ring and an
electron withdrawing sulfur atom in the side
chain.
• Researchers were worried about the
thiourea group in metiamide because it had
been known to produce toxic effects. A
solution to this was to replace this group
with a cyanoguanidine group. Thus,
producing cimetidine.
Structure of Cimetidine
Structures of H2 receptor
antagonists and Histamine
Properties of H2 receptors
• Hydrophilic molecules
• Determined by the imidazole ring
• Have low lipophilicity which limits access
to the CNS
• Unable to mimic the stimulant actions of
histamine because of the uncharged side
chains
Equilibria between the Imidazole
species
Pharmacokinetics
• Cimetidine is rapidly and completely
absorbed in the GI tract.
• First pass metabolism reduces oral
bioavailability to 60-70%.
• After cimetidine is absorbed, it produces
blood and urine concentrations of
unchanged cimetidine that are greater than
the concentrations of any metabolite.
Cimetidine and possible
metabolites
• The rate but not the extent of absorption can
be affected by food.
• The drug distributes throughout body
tissues.
• 48% and 75% of an oral and IV dose,
respectively, is excreted in the urine.
• Half life is roughly 2 hours - with normal
renal function.
Metabolic Pathway
Mechanism of Action
• Cimetidine blocks the effects of histamine
at the receptor located on the basolateral
membrane of the parietal cell.
• This results in reduction of gastric volume
and acidity. It also decreases the amount of
gastric acid released in response to other
stimuli.
Toxicity
• Cimetidine has been shown to have low
acute toxicity.
• In repeated doses in rats studied for 12
months, no important adverse effects were
observed.
• In dogs, having the same treatment, some
tachycardia was observed at high doses.
Acute LD50 values of Cimetidine
Improvements
• Obviously there have been improvements
upon cimetidine because the drugs Zantac,
Axid, and Pepcid have been developed.
• These drugs are among the second
generation of H2 antagonists that were
introduced in the 1980’s.
• These drugs use aromatic groups in place of
the imidazole functionality.
• In Zantac, the methylimidazolyl ring of
cimetidine is replaced by a
dimethylaminomethylfuryl ring. The
cyanoguanidine functionality is replaced by
an isosteric methylnitroethenediamide
moiety. Zantac is 4 to 10 times more potent
than cimetidine.
Production of Zantac from the
substituted form of Cimetidine
• Replacement of the furan ring in Zantac by
a thiazole group gives the drug Axid.
• Axid is 5 to 18 times more potent than
cimetidine.
• In Pepcid, the N-methyl-2-nitro-1,1ethenediamine group of axid is replaced by
the aminosulfonylimidamide function, and
the dimethylaminomethyl group is replaced
by the guanidino functionality.
Structures of Tagamet, Zantac,
Pepcid, and Axid
• There have been more recent improvements
in the field of gastric hyperacidity. The
latest “drug of choice” is Protonix.
• In conclusion, Cimetidine was an excellent
building block for the advancement of H2
antagonists.
Mechanisms regulating the actual
histamine concentration in the vicinity of
the parietal cell and at H2 receptors