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Antihistamines "lecture 12&13" (:checkered_flag: Acid-Peptic…
Antihistamines "lecture 12&13"
General information
histamine is the main actor in allergy
biogenic amine
Autacoid --> self cure
neurotransmitter
work on:
1- increases the permeability of the capillaries to white blood cells and other proteins, in order to allow them to engage foreign invaders in the affected tissues as part of the immune response.
2- regulate "sleep/awake " physiological function
Allergy
is a local or systemic
inflammatory response to allergens
Symptoms
1- allergic rhinitis
2- conjunctivitis
3- bronchoconstriction
4- atopic urticaria
5- dermatitis
6- anaphylaxis
formation of histamine
1- Derived from L-histidine AA
2- by L- histidine decarboxylase
3- stored in inactive form
4- Once released it becomes active
5- major site of biosynthesis is basophiles, mast cells,
parietal cells of the gastric mucosa
:star:
HISTAMINE
Has two basic centers
-->the aliphatic amino group [pKa = 9.4] and whichever nitrogen atom of the imidazole ring does not already have a proton [pKa = 5.8]
At
physiological pH
, histamine is normally
protonated to a singly-charged cation
.
:green_cross: Pharmacological action of histamine
1- On cardiovascular System
Vasodilation--> reddening at injection site, Increased permeability-->(edema), Systemic hypotension --> fall in blood pressure.
2- On exocrine glands
increase the secretion
from gastric glands, salivary glands, sweat glands, Pancreas, Bronchial glands, Lacrimal gland
3- On vascular Smooth Muscles
increase the contraction
of Bronchial tree, Gastrointestinal tract, Uterus
Histamine Receptors
1- activated only by histamine
2- Activation of histamine receptors produces different biological responses
3- location: varies among peripheral tissues, CNS, GI tract, endothelium
Types of the receptors: :star:
H1
Two nitrogen atoms are required for the activity
Found on smooth muscle, endothelium, and CNS system tissue
Activation results in vasodilation, bronchoconstriction, smooth muscle activation, and separation of endothelial cells
Involved in allergic symptoms and motion sickness
we need
H1 antagonist
to treat
allergy
H2
All three nitrogen atoms are required for activity
Found in the stomach and heart
Regulates gastric acid secretion
we need
H2 antagonist
to treat
peptic ulcer
H3
Found in the central nervous system
Regulates the release of other neurotransmitters, autoreceptors
H4
Found in intestines, basophils, and bone marrow cells.
They facilitate synthesis and release of other pro-inflammatory mediators
They are GPCRs
Antihistamines
H1 Receptor Antagonists
First generation
strong sedatives activity ( cross BBB) & autonomic nervous system blocking
:black_flag: Common structural
2 aromatic rings connected to a central X [ carbon, nitrogen or CO (ether)]
Spacer group between the central X and the amine,
usually 2-3 carbons in length
Linear, ring, branched, saturated or unsaturated
Amine is substituted with small alkyl groups e.g. CH3
Chemically, classified into:
:green_cross: Ethylenediamines
Earliest series
Hydrophobic, planar groups
CNS effects very common (esp. sedation)
Metabolism probably through
N-oxidation
or
glucuronidation
Information on PK data is limited (not well studied)
Not very common nowadays
:green_cross:Ethanolamines ether
The prototype is :check:
diphenhydramine
1- relieves
allergic rhinitis
(seasonal allergy) symptoms
including sneezing, runny nose, itching, watery eyes
Side effect:
Dry mouth, blurry vision
, like other anticholinergic agents
2- Ability to
penetrate the BBB
due to their relative lipophilicity
Used in
treatment of parkinsonism
because of its central
anticholinergic properties
metabolism: by N-demethylation and then by MAO and the last metabolite is by conjugation
Significant
anticholinergic side effects
: dry mouth and sedation
Bulky alkyl groups at
C-2’
increase
anticholinergic activity
and decrease antihistaminic
Bulky substitution at the
C-4’
decrease anticholinergic activity and increase
antihistaminic activity
Arrangement of the aromatic groups of diphenhydramine gave phenyltoloxamine as antihistamine
Changing an
O to an S
dramatically
decrease the antihistamine activity
Antihistamines are structurally similar to SSRIs and to antipsychotics
A retro arrangement of C and O led to SSRI
(Fluoxetine)
:green_cross:Alkylamines
C replaces heteroatom spacer
and can be
chiral
Halogenated varieties have
long duration
and
decreased sedation, anticholinergic effect
Metabolism is by
N-dealkylation
OTC in many cold, allergy preparations
S-enantiomer
has a
greater affinity
than the R-enantiomer
Most selective H-1 antagonist 1st generation
:check: Pheniramine
:check: chlorpheniramine
E- and Z-isomers of the alkenes in this series show very large differences in potency
E-pyrrobutamine is more potent than its z-isomer by 165-fold
5-6 Å distance between the tertiary amine and one of the aromatic ring is required at the site of receptor binding
:green_cross: Piperazines
Structurally related to both the
ethylenediamines
and the
benzhydryl ethers of ethanolamines
Two carbon
separation between the
nitrogen atoms
(piperazine ring)
Diarylmethylene groups are attached to one of the nitrogen atoms and an alkyl or aralkyl substituent is attached to the other nitrogen
Used for motion sickness, vertigo and anti-emetic effects
Have significant anticholinergic and antihistaminic activity
:check: Cetirizine
1- is a metabolite of hydroxyzine (used to treat stress and anxiety)
2- Para-substitution of any aryl group by Cl enhances the antihistaminic activity
3- considered 2nd generation antihistamine because it is less sedative --> Its
amphoteric
nature appears to be associated with decrease, but not absent, sedative side effects
:green_cross:Tricyclics (including phenothiazines)
Phenothiazines (Y=S, X=N) have a
2 [ antihistamines]
or 3 branched carbon chain between the tricyclic N (non basic) and the aliphatic amine
Longer duration of action, pronounced sedative effect
Used for motion sickness, anti-emetic, sedativeshypnotic
:check: promethazine
Side effect :
1- Anticholinergic CNS interactions
2- Gastrointestinal reaction
Common side effect: sedation, dizziness, tinnitus,
blurred vision, euphoria, lack of coordination, anxiety,
insomnia, tremor, nausea and vomiting, constipation,
diarrhea, dry mouth, and dry cough
Second generation
non sedative activity (less lipid soluble and don't cross BBB
selective peripheral H1 antagonism
effects, less anticholinergic effect
Structure similarity to 1st generation antihistamine is not always obvious
:green_cross: Examples
:check: Fexofenadine (Allegra, Telfast, Fenadex)
it is the
active
safe
metabolite
of terfenadine
Terfenadine was discovered accidently while searching for antipsychotics
found to cause rare
cardiac arrhythmia
at high dose in presence of other
CYP3A4 substrates or inhibitors
used with no cardiac side effect
metabolism: oxidation
:check: Loratadine (Claritine, Clarinase, Loraday, Rayon)
Loratadine & its metabolite descarboethoxy-loratadine
(desloratadine) are closely related to the tricyclics
No cardiac toxicity
Does not cross the BBB
Desloratadine
is more potent H-1 antagonist
Metabolic conversion is through
oxidative process
not
direct hydrolysis --> lost of acetaldehyde and CO2
:check: Cetirizine (Zyrtec)
acid metabolite of hydroxazine
highly selective to H-1 receptors
Does not cross BBB
R-enantiomer
; levocetirizine is now marketed with 30 fold higher affinity than S-enantiomer
:check: Mizolastine
:check: Astemizole
Side effects: drowsiness, fatigue, headache,
nausea and dry mouth
Clinical uses
1-
Allergic rhinitis
,
relieves rhinorrhea
, sneezing, and itching of eyes and nasal mucosa
2-
Common cold
: palliative, dries out the nasal mucosa. Often combined with
nasal decongestant and analgesics
3-
Allergic dermatoses
: can control itching associated with insect bites
4- Outpatient procedures for
preanesthetic sedation and prevention of nausea and vomiting
(Promethazine (Phenergan)--> phenothiazines). Phenergan also inhibits salivary and bronchial secretions and can be used as a local anesthetic
5-
Antiemetic
: prevention or treatment of nausea and vomiting
6-
Hypnotics
: limited value
7-
Reduction of tremors and muscle rigidity
in Parkinson's disease
8- Treatment of
migraine headaches
Drug Interactions of H1 Blockers
Antihistamines that produce sedation can potentiate CNS depressants (e.g., barbiturates, opiates, general anesthetics, and alcohol)
Antihistamines that possess anticholinergic actions can produce manifestations of excessive blockade if given with anticholinergic drugs (e.g., dry mouth, constipation, or blurred vision)
Terfenadine (Seldane) taken with grapefruit juice or erythromycin or other drugs that inhibit the enzyme, CYP3A4 can lead to cardiac toxicity. Taken off the market
H2 Receptor Antagonists
1- Competitive Antagonists
2- Inhibits secretory function of gastric mucosa.
3- Reduces gastric acid volume & concentration of pepsin
we need selective H2 antagonist to reduce the gastric acid secretion -->
non-selective will affect H1 --> SE
pregnancy category B
Treat:
treat GERD, peptic ulcers, NSAIDs related ulcers
Available as: OTC, Rx, IV and IM.
:green_cross: EXAMPLES
:check: Cimetidine (Tagamet)
SE:
inhibits CYPs
and thereby increase the levels of a
variety of drugs that are substrates for these enzymes.
:check: Ranitidine (Zantac)
SE:
interacts with hepatic CYPs
, but with an affinity of
only 10% of that of cimetidine
:check: Famotidine (Pepcid) --> safer --> no significant drug interactions mediated.
:check: Nizatidine (Axid) --> safer --> no significant drug interactions mediated.
Side effects are minor and include
diarrhea, headache, drowsiness, fatigue, muscular pain, and constipation
. Less common side effects include those
affecting the CNS (confusion, delirium)
cross the placenta and are excreted in breast milk
Topical antihistamine
use in the eye to relieve
itching, congestion of the conjunctiva --> Mast cells are dense in conjunctiva, histamine concentration
Topical ocular antihistamine such as :check:
pheniramine
, usually in combination with
sympathomimetics vasoconstrictors
:check:
Ketotifen (Zaditen)
is an example of topical antihistamine used for
allergic conjunctivitis
as it
stabilizes the mast cells
H3
an autorecptor that regulates the release of histamine
act as feedback inhibitors in a wide variety of organ
systems in the CNS, agonists cause sedation
GI: agonists down regulate histamine. Thereby decreasing gastrin
Lung: agonists have a bronchodilatory effect
Mechanisms of Action: G-protein coupled receptor, decreases of intracellular Ca++
:red_cross: Gastric acid secretion
The wall of the parietal cell has 3 types of receptors;
Acetylcholine (M3), histamine (H2), and gastrin.
when the parietal cells are stimulated they produce and secrete HCl
To secrete HCI, the cell needs to release
hydrogen ions (H+ions)
in addition to
Cl- ion
which are produced by the proton pump (H+/K+ ATPase pump) of the cell. NEED ATP
H+ and Cl- go out whereas K+ comes in
HOW IS GASTRIC ACID PRODUCED ??
1- by
Gastrin
: stimulate Ca2+ which activate the protein Kinase --> more H+ out by the proton pump
2- by
Histamine
: convert ATP to cAMP which activate the protein kinase
3- by
Ach
which binds to M3 receptors that stimulate Ca2+ --> activate the protein kinase
:no_entry:
NOTE :
PGE2
inhibit the secretion by inhibiting the conversion of ATP to cAMP
Mucosal protective agents
Prostaglandin Analogs:
(
Misoprostol
= Synthetic analog of prostaglandin E1)
Actions: ( both PGE2 & PGI2)
1- Inhibit histamine-stimulated gastric acid secretion
2- Stimulation of mucin and bicarbonate secretion
3- Increase mucosal blood flow
Therapeutic uses
1-
Prevent ion of NSAID
--> induced mucosal injury (rarely
used because it needs frequent administration – 4 times/ daily --> use by people who are both taking
NSAIDs and are at high risk for NSAID-induced ulcers, including the elderly and people with ulcer complications
2-
labor induction
--> BUT it is controversy in pregnant women because it might induce early abortion
:checkered_flag: Acid-Peptic Disorders
1- Indigestion
discomfort in the upper GI tract
2- Acute gastric irritation
Hyperacidity or overproduction of gastric acids
associated with overeating, the consumption of spicy or disagreeable foods, over usage of alcohol, extreme emotions
3- Gastroesophageal Reflux Disease (GERD)
AkA heartburn or sour stomach
Backflow of stomach contents into the esophagus
Occurs most often after a meal
Common during pregnancy
Caused by incompetent lower esophageal sphincter
Food causing relaxation of the lower esophageal sphincter include: alcohol , caffeine, fats, chocolate, cigarette smoking, and certain medications (B blockers)
4- Gastritis
Inflammation of the stomach
caused by
chronic consumption of irritating substances
as alcohol or aspirin. In addition, it might be
associated with
infections or stress
. Bleeding often occur.
5- Peptic Ulcer Disease (PUD)
harmful (esophageal, gastric, duodenal)
Ulcers are erosions (lesions) in the lining of the stomach or in wall of the esophagus or duodenum
An imbalance between mucosal defense (bicarbonate, mucin,
prostaglandin) and injurious factors (acid, pepsin)
6- NSAID-Related Ulcers
Chronic NSAID users have a 2% to 4% risk of developing a
symptomatic ulcer, gastrointestinal bleeding, or perforation
daily dose of 10 mg aspirin may
aggravate ulcer
so NSAIDs should be discontinued in patient with an ulcer
Proton Pump Inhibitors (PPI)
inhibiting the gastric H+, K+-ATPase (proton pump)
these drugs diminish the daily production of acid by 80% to 95%. very powerful
Should be administered 1 hr before meal so that peak serum concentration coincides with maximal activity of proton pumps secretion --> because it is an
irreversible inhibitor
so it need some time to be activated and prevent the gastric secretion
USES:
GERD
peptic ulcers
alone or in combination with antibiotics to eradicate Helicobacter pylori (G-ve bacteria),
stress
related ulcers (IV)
NSAID related ulcers
:green_cross:EXAMPLES :
:check: Omeprazole (Prilosec, losec, Risek)
racemate: contains a tricoordinated sulfur atom in a pyramidal structure and therefore can exist in equal amounts of both the S and R enantiomers
acidic conditions (stomach), it reacts with a cysteine group in H+/K+ ATPase, thereby
inhibiting the ability of the parietal cells to produce gastric acid
undergoes a
chiral shift in vivo
--> converts the
inactive R-enantiomer
to the
active S-enantiomer
doubling the concentration of the active form so it is more potent in vivo than vitro
chiral shift
is accomplished by the
CYP2C19-CYT P450
, which is
not found equally in all human population
--> some are
poor metabolizers
like Asian so we have to give them more dose or directly give them Esomeprazole
At the parietal cell, H+/K+-ATPase, a cysteine residue reacts to form disulfide-attached enzyme inhibitor
:forbidden:metabolism of omeprazole --> hydroxylation , o-demethylation, and sulfoxidation
:check: Esomeprazole (Nexium, Prilosec’s S isomer)
is the
S isomer
of Omeprazole
:check: Pantoprazole (Protonix, Pantazole)
:check: Rabeprazole (Aciphex, Pariet)
:check: Lansoprazole (Prevacid, Zollipak)
