Histamines and Antihistamines Flashcards
name the H2 blockers
cimetidine
ranitidine
famotidine
nizatidine
What is the name of the enzyme responsible for converting histidine to histamine?
L-histidine decarboxylase
Describe the structure of histamine and its important components.
ethylamine chain is important for drug behavior at H1 receptors
imidazole ring is important for action at H2 receptors
Discuss the metabolism of histamine.
oxidative deamination by N-methyltransferase and MAO (and other dehydrogenases)
finally turned into an acetic acid derivative
histaminase (diamine oxidase) is another pathway
diamine oxidase
found in high concentrations in the digestive tract
important for metabolizing ingested histamine
general sites of action of histamine
non-vascular smooth muscle
vascular smooth muscle (and sensory nerve endings in man)
gastric acid secretion
isolated heart peparations
possible neurotransmitter roles
effect of histamine on non-vascular sooth muscle
all are H1 effects
bronchoconstriction - smooth muscle very sensitive
intestinal smooth muscle contracts - high doses can cause diarrhea
effect of histamine on vascular smooth muscle
effects all mediated by H1
triple response of lewis due to skin trauma
triple response of Lewis
redness - direct dilatation
flare - indirect dilatation
wheal - edema
triple response of Lewis - redness
direct dilatation of blood vessels
reflected as a local red spot appearing within seconds after injection or injury
immediate effect mediated by H1 receptors
at higher doses, a sustained H2 component participates in redness
triple response of Lewis - flare
indirect dilatation reflected as an irregular reddish area that develops slowly and extends beyond the original redness by about 1 cm
occurs indirectly via an axon reflex whereby histamine or injury excites sensory nerve terminals from the skin
impulses then travel up sensory nerve into spinal cord and also diverge via an axon collateral, which releases substance P
substance P binds to mast cells and release histamine, causing the flare
triple response of Lewis - wheal
edema at injection site and the area of initial redness becomes raised due to increased permeability of small blood vessels, causing edema
effect of histamine on gastric acid secretion
in very low doses, histamine causes secretion of gastric juice from parietal and chief cells of the mucosa respectively (H2 mediated)
enterochromaffin-like (ECL) cells
paracrine cells that release histamine to induce parietal cells to release HCl
gastrin and ACh are other stimulants that cause these cells to release histamine
effect of histamine on isolated heart preparations
increases the rate and force of cardiac contraction (via H2 receptors) and slows conduction int he AV node (via H1 receptors, this is a minor effect)
may be important in producing arrhythmias during allergic reactions
the effect of histamine on neurons
most important clinical effects of the H1 antihistamines int he CNS are due to blockade of muscarinic receptors
What cells contain histamine?
mast cell and the basophilic leukocyte
What makes up the secretory granules of mas cells?
histamine
proteases
heparin
cytokines
alpha-tryptase
a neutral protease found in the mast cell granule
What cytokines are found in mast cell granules?
ECF-A - eosinophil chemotactic factor of anaphylaxis
TNFs - tumor necrosis factors
anaphylaxis
the physiological stimulus to secretion of mast cells
leads to type I immediate hypersensitivity
Describe the signaling pathway that causes mast cells to release their granules and their contents.
- IgE antibodies become fixed to mast cells
- exposure to antigen triggers binding to antibodies
- phophorylation of interaction leads to activation of phospholipase C
- causes IP3 synthesis and calcium liberation from storage sites in the ER
- CRAC channels open in response to increased calium
- increased cytoplasmic calcium concentrations promote exocitosis and dissociation of the component parts of the granules
urticaria pigmentosa
a disease characterized by huge numbers of mast cells in the skin
when touched, may set of an exaggerated triple response
calcium dependent process, also activating phospholipase A2
detection of alpha-tryptase and histamine metabolites as well as prostaglandin metabolites in the urine
anaphylactoid - not IgE mediated
mechanism of insect stings and bites
poison has a phospholipase A2 component as well as mast-cell degranulating peptides
G-protein induced histamine release
histamine release inhibitors
increases in cAMP inhibit release from human basophils and animal mast cells (epinephrine and theophylline through beta-receptors)
evokers of histamine release
atropine, curare, substance P, morphine, certain antibiotics, ACh, peptides, and other agents in high concentrations
signaling mechanism for H2 receptors
G-protein coupled receptor
increases cAMP and thus PKA phosphorylation
mechanism of H1 receptor antagonists
competitive inhibitors of histamine at the H1 receptor
potently inhibit the effects of histamine if histamine is present at these receptor sites
all are substituted ethylamine derivatives
first generation H1 receptor antagonists (What are some side-effects?)
classical
phenothiazines
piperazines
**CNS effects and thus sedating
**peripheral anti-muscarinic effects
chlorpheniramine
first generation, classical
contained in all OTC anti-allergy preparations (brompheniramine also popular)
useful to treat mild allergic reactions
also contained in cold tablets - relief due to anti-cholinergic effect of drying up secretions
diphenhydramine
*Benadril
first generation, calssical
effective for sleep due to anticholinergic effects
antimuscarinic action like scopolamine
this continues to be an agent of choice for insect bites, poison ivy, and other mild allergic reactions if sedation would not pose a problem
dimenhydrinate
first generation, classical
very powerful anti-ACh action, sleep inducing and also used to combat motion sickness
doxylamine
first generation, classical
another ethanolamine of similar structure
used OTC by itself or witho ther agents as a sedative
hydroxyzine
first generation, classical
used to relieve itching caused by allergies
control the nausea and omiting cause by various condition, including motion sickness
sedative effect can be used to treat anxiety
enhances the euphoric effect of opioids
promethazine
first generation, phenothiazine
strongest anti-ACh action of all antihistamines
used to combat motion sickness and in anti-tussive preparations with codeine
not sold OTC
meclizine
first generation, piperazine
OTC to treat motion sickness
cyclizine
first generation, piperazine
OTC to treat motion sickness
second generation H1 antagonists
agents are used because they have minimal sedative effects as they do not cross the blood-brain barrier
also largeley devoid of muscarinic effects
loratidien
*Claritin
second generation
rapid in onset with no reports of arrhythmias
racemic mixture, made available TOC
useful for hives, itching, and allergic rhinitis
non-sedating and has no anti-muscarinic effects
desloratadine
second generation
a single isomer (active metabolite) of loratadine
no evidence that it is superior
fexofenadine
*Allegra
second generation
a derivative of terfenadine
no cardiac effects
non-sedating and devoid of anti-muscarinic effects
excreted unchanged in the urine
cetirizine
second generation
substantial sedative effects
a metabolite of hydroxyzine
excreted unchanged in the urine
approved for use in children as young as 6 months for the treatment of allergic rhinitis, itching, and hives
effectiveness is enhanced by its ability to inhibit mast cell degranulation - synergy
levocetirizine
second generation
same uses as cetirizine with generally comparable effectiveness
azelastine
second generation
intranasal anti-histamine
recommended as first line therapy for rhinitis
additional anti-inflammatory effect, inhibiting the release of some mast cell mediators - synergy
Doxepin
used clinically as a combined H1 and H2 blocker
appropriate therapeutic uses of H1 blockers
certain mild allergies, insect bites, poison ivy
titrating a suntan or preventing a sunburn - H1 blocker for first hour and cyclooxygenase inhibitor for the next 24 hours
side effects and contrainidications of H1 blockers
dry mouth
constipation
urinary retention
narrow-angle glaucoma
toxicity of H1 blockers at high doses
Dry as a bone
Hot as a stove
Red as a beet
Blind as a bat
Mad as a hatter
treatment of an acute asthmatic attack or anaphylactic shock
for anaphylaxis, epinephrine is required
**diphynhydramine often used as an adjunct to block the H1 effects of release histamine
effects of epinephrine
beta-2 agonist effect opens the airways
alpha-1 effect produces vasoconstriction to oppose the vasodilation associated with anaphylaxis and reduces mucosal edema
inhibits release of mediators from mast cells
Where are the muscarinic vs. adrenergic receptors in the lungs?
adrenergic (beta-2) in the fine branches
muscarinic in the large airways
corticosteroids in asthma treatment
used by themselves for mild to moderate asthma and together with a long-acting beta-agonist such as salmeterol and formoterol for severe asthma
corticosteroid mechanism of action
blocks cyclooxygenase pathway and production of prostaglandins and PGD2
blocks the lipoxygenase pathway, which produces leukotrienes LTC4, LTD4, and LTE4
blocks cytokine release and recruitment of inflammatory cells
blocks PAF, bradykinin, and adenosine production
effects of leukotrienes
bronchoconstriction (LTD4 is 1000x more potent than histamine)
increase vascular permeability
mucus secretion
inflammatory cell infiltration
montelukast
competitive antagonist of the cys-LT1 leukotriene receptor
used for prophylaxis of exercise induced asthma in children
effects of leukotriene B4
causes attraction of neutrophils and subsequent release of damaging factors
not blocked by montelukast
zileuton
inhibits the 5’-LOX enzyme and thus inhibits the synthesis of leukotrienes including LTB4
used for prophylaxis of asthma with a neutrophilic phenotype
cromolyn Na+
stabilizes the mast cell membrane, preventing disease of granules
inhibits eosinophils in airway nerves
used for prophylaxis of exercise induced asthma, and asthma-induced by animal dander
also used for rhinitis and mastocytosis
theophylline
competitive inhibitor of adenosine at adenosine receptors at the lowest doses
at slightly higher doses, inhibits phosphodiesterases (and thus increases cAMP)
suppresses inflammatory genes and proteins
used to treat disorders of the bronchioles - asthma, COPD by relaxing airway smooth muscle, suppressing mediator release, and improving diaphragm contractility
