AAI Chemistry
Antihistamines, Leukotrienes and Muscarinic Antagonists
Leukotrienes
- Fatty, oily compounds and they cause inflammation in the lungs in people suffering
from asthma and bronchitis
- Two main mechanisms for clinical effect of leukotrienes:
o Leukotriene antagonist – leukast (acts at cysteinyl-leukotriene type 1
receptor), montelukast and zafirlukast – these blocks the action of the
leukotrienes that are overexpressed
o Inhibition of leukotriene synthesis e.g., zileuton and theophylline
Some structures of leukotrienes
- Leukotrienes – alkenes (ene), three
neighbouring double bonds (tri)
Leukotriene antagonist – Montelukast
- “Mont” – discovered by Merck at Montreal site
- “Leukast” – leukotriene antagonist
- The drug is chiral (has chiral centre(s))
- Has carboxyl at the top as well as phenyls
Inhibitors of leukotriene synthesis
- Inhibitor of 5-lipoxygenenase, and this
suppresses leukotriene formation
- The S-Zileuton also has a chiral centre
- R-Zileuton also has chiral centre
- These drugs are used for the prevention
(management) of asthma, not the relief of
asthma
- Theophylline also has this five, and six membered
ring just like the Zileutons
- Theophylline is similar to caffeine
- It is a member of the xanthine family – inhibits
leukotriene synthesis
- Non-selective adenosine receptor antagonist
,AAI Chemistry
- It interacts with other drugs (cimetidine, phenytoin) and has a narrow therapeutic
window
- Theophylline is formulated as
aminophylline
- Two molecules of theophylline
are formulated with
ethylenediamine to give an
improved solubility for
theophylline (from 8.3mg/ml to
50mg/ml)
- Aminophylline is usually found
as solid dihydrate
Muscarinic antagonists
- These antagonists block the activity of
muscarinic ACh receptors
- There are similarities b/w certain
muscarines and ACh such as
o Quaternary amine group with a +ve
charge
- This means that in the receptor, the charged
quaternary amine can bind in the receptor
- Ipratropium bromide (SAMA) is a type of muscarinic antagonist
that is used to treat COPD and asthma.
- It blocks the action of ACh at the muscarinic receptor
- It also has the quaternary amine group at the top, and this links
with the ACh
- Here we have tiotropium bromide (LAMA)
- It is also a muscarinic antagonist that is used to treat COPD and
asthma
- It blocks the action of ACh at the M3 muscarinic receptor i.e., it
specifically binds to the M3 receptor
- It also has the quaternary amine group
Antihistamines
They fall into three categories
- First generation: diphenhydramine, chlorphenamine, promethazine
- Second generation: loratadine, cetirizine
- Third generation: levocetirizine and fexofenadine
, AAI Chemistry
- First generation can cause drowsiness in patients and the effects can last for 24hours
or more
- In second generation antihistamines, drowsiness is less of an issue
- In third generation antihistamines, drowsiness is less of an issue
- Both are diphenhydramine but different formulations
- Left one is gel, right one is dissolving tablet
Third generation – levocetirizine
Antihistamines – Occurrence in the body
- Histamine is an important component in the immune system to protect cells from
infection. Widespread occurrence:
o Smooth muscle contraction
o Vasodilation
o Gastric acid secretion
o Nervous system, NT, sleep regulation
o Male sexual function
o Bone marrow
- L-histidine is an amino acid (comes from
foods)
- Histadine decarboxylase and an enzyme
called PLP convert this L-histadine to
histamine (removes carboxyl group)
- Histamine has 3 nitrogen groups
- The alpha nitrogen – (aliphatic nitrogen), is the amine
group on the right-hand side (NH2)
- The pi nitrogen – (proximal nitrogen) is the nitrogen in the
middle (NH)
- And the Tao nitrogen (far nitrogen) on the left-hand side
(N)
Tautomer – isomers which readily interconvert by atom movement e.g., lactam
lactim or amine imine
- In solution, histamine undergoes isomerisation
Antihistamines, Leukotrienes and Muscarinic Antagonists
Leukotrienes
- Fatty, oily compounds and they cause inflammation in the lungs in people suffering
from asthma and bronchitis
- Two main mechanisms for clinical effect of leukotrienes:
o Leukotriene antagonist – leukast (acts at cysteinyl-leukotriene type 1
receptor), montelukast and zafirlukast – these blocks the action of the
leukotrienes that are overexpressed
o Inhibition of leukotriene synthesis e.g., zileuton and theophylline
Some structures of leukotrienes
- Leukotrienes – alkenes (ene), three
neighbouring double bonds (tri)
Leukotriene antagonist – Montelukast
- “Mont” – discovered by Merck at Montreal site
- “Leukast” – leukotriene antagonist
- The drug is chiral (has chiral centre(s))
- Has carboxyl at the top as well as phenyls
Inhibitors of leukotriene synthesis
- Inhibitor of 5-lipoxygenenase, and this
suppresses leukotriene formation
- The S-Zileuton also has a chiral centre
- R-Zileuton also has chiral centre
- These drugs are used for the prevention
(management) of asthma, not the relief of
asthma
- Theophylline also has this five, and six membered
ring just like the Zileutons
- Theophylline is similar to caffeine
- It is a member of the xanthine family – inhibits
leukotriene synthesis
- Non-selective adenosine receptor antagonist
,AAI Chemistry
- It interacts with other drugs (cimetidine, phenytoin) and has a narrow therapeutic
window
- Theophylline is formulated as
aminophylline
- Two molecules of theophylline
are formulated with
ethylenediamine to give an
improved solubility for
theophylline (from 8.3mg/ml to
50mg/ml)
- Aminophylline is usually found
as solid dihydrate
Muscarinic antagonists
- These antagonists block the activity of
muscarinic ACh receptors
- There are similarities b/w certain
muscarines and ACh such as
o Quaternary amine group with a +ve
charge
- This means that in the receptor, the charged
quaternary amine can bind in the receptor
- Ipratropium bromide (SAMA) is a type of muscarinic antagonist
that is used to treat COPD and asthma.
- It blocks the action of ACh at the muscarinic receptor
- It also has the quaternary amine group at the top, and this links
with the ACh
- Here we have tiotropium bromide (LAMA)
- It is also a muscarinic antagonist that is used to treat COPD and
asthma
- It blocks the action of ACh at the M3 muscarinic receptor i.e., it
specifically binds to the M3 receptor
- It also has the quaternary amine group
Antihistamines
They fall into three categories
- First generation: diphenhydramine, chlorphenamine, promethazine
- Second generation: loratadine, cetirizine
- Third generation: levocetirizine and fexofenadine
, AAI Chemistry
- First generation can cause drowsiness in patients and the effects can last for 24hours
or more
- In second generation antihistamines, drowsiness is less of an issue
- In third generation antihistamines, drowsiness is less of an issue
- Both are diphenhydramine but different formulations
- Left one is gel, right one is dissolving tablet
Third generation – levocetirizine
Antihistamines – Occurrence in the body
- Histamine is an important component in the immune system to protect cells from
infection. Widespread occurrence:
o Smooth muscle contraction
o Vasodilation
o Gastric acid secretion
o Nervous system, NT, sleep regulation
o Male sexual function
o Bone marrow
- L-histidine is an amino acid (comes from
foods)
- Histadine decarboxylase and an enzyme
called PLP convert this L-histadine to
histamine (removes carboxyl group)
- Histamine has 3 nitrogen groups
- The alpha nitrogen – (aliphatic nitrogen), is the amine
group on the right-hand side (NH2)
- The pi nitrogen – (proximal nitrogen) is the nitrogen in the
middle (NH)
- And the Tao nitrogen (far nitrogen) on the left-hand side
(N)
Tautomer – isomers which readily interconvert by atom movement e.g., lactam
lactim or amine imine
- In solution, histamine undergoes isomerisation
