Antihistamines - Fondell 4/12/16 Flashcards
histamine
- essential mediator of allergic and infl processes
- significant regulator of gastric acid secretion
- important neurotrans in CNS
synthesis from histidine
- His synthesized in 4 major cell types
- mast cells (skin, mucus membranes, lungs, bl vessels)
- basophils (circ blood)
- enterochromaffin-like cells (ECL cells - stomach)
- histaminergic neurons (brain)
decarboxylation of His → histamine
degradation of histamine
- half life of 30-60s, after which degradation by either…
- ring methylation + oxidation [predominant bc key enzyme is widely expressed]
- ox deamination + conj with ribose
storage of histamine
histamine is sequestered and bound in cytoplasmic granules of mast cells and basophils
- contains GAGs (incl -heparin → forms complexes with +histamine), proteases, cytokines
histamine is produced and stored in vesicles of ECL cells of gastric mucosa in stomach and histaminergic neurons of CNS
mechanisms of histamine release
1. immunological release
- antigens/allergens bind to IgE on surface of pre-sensitized mast cells and basophils → aggregation of high-affinity IgE receptors (FCeRI) → degranulation
2. mast cell injury/damage
- rapid degranulation → local release of histamine
3. endocrine or neuronal stimulation
- endocrine stimulation of ECL cells or neuronal stimulation of histaminergic neurons → rapid histamine exocytosis
4. chemical displacement
- drugs/other compounds trigger direct release of histamine from mast cells (no prior sensitization required) → “displacement”
- ex. organic bases or basic peptides (morphine, tubocuranine, some antibiotics, wasp venom, etc.)
IgE mediated histamine release
basic allergic response: sensitization & subsequent exposure/response
type I hypersensitivity
1. sensitization: allergen makes it into blood, B cells recognize (are assisted by Th2 cells) → produce IgE
- IgE binds to FCepsilon receptors on mast cells and basophils = mast cells are now sensitized!
2. subsequent exposure: multivalent antigens can now bind to antibodies on mast cells → crosslinking of IgE → FCepsilon receptors aggregated, activated
- LYN/SYK (beta and gamma subunits of receptor) → phosphorylation of LAT → IP3 and DAG activated → mobilize Ca, activation of PKC
- increase in intracellular Ca → trigger for degranulation → histamine and other infl mediators released → inflammation!
also occuring:
- MAPK pathway → prostaglandins/leukotrienes
- MAPK and CA → transcription and release of cytokines
histamine receptors → signaling (distribution)
- fx
H1
H1 → Galpha q → increased IP3, DAG
(sm muscle, endothelium, periph neurons, brain)
- pruritis, pain, mucosal secretion, NO-mediated vasodil, edema, bronchoconst, contraction of gut
histamine receptors → signaling (distribution)
- fx
H2
H2 → Galpha s → increased cAMP
(gastric mucosa, cardiac muscle, vasc smooth muscle, mast cells, basophils, brain)
- gastric acid secretion, vasodilation (cAMP), heart rate
histamine receptors → signaling (distribution)
- fx
H3
H3 → Galpha i → decreased cAMP
(presynaptic histaminergic neurons in brain, myenteric plexus, other neurons)
- decreased neurotransmitter release
histamine receptors → signaling (distribution)
- fx
H4
H4 → Galpha i → decreased cAMP
(cells of hematopoeitic origin: eosinophils, neutrophils, DCs, basophils, monocytes, T cells)
- differentiation of promyelocytes and myeloblasts, chemotaxis, secretion of cytokines, upreg of adhesion factors
G protein coupled receptor classes
7 alpha helix transmembrane domain
signal through heterotrimeric complex of proteins (alpha, beta, gamma subunits)
4 subtypes of GPCR (alpha s, i, q, 12/13)
- i: H3/H4 → decrease cAMP
- q: H1 → increase IP3, DAG
- s: H2 → increase cAMP
effects of histamine on tissues/organ systems
nervous system
1. peripheral sensory nerve terminals
- induce depol of afferent nerve endings → itch, pain sensation (H1)
- component of urticaria response to stinging instects/plants
2. CNS
- neurotrans for histaminergic neurons (H1, H2, H3)
- modulation of nt release (H3)
- homeostatic and higher brain fx - sleep/wake cycle, circadian, feeding rhythms
- appetite suppression and satiety (H1, H3)
- increased wakefulness (H1, H3)
effects of histamine on tissues/organ systems
cardiovascular system
1. vasodilation
- dilation of terminal arterioles, postcap venules, precap sphincters (H1 - endothelial NO + H2 - cAMP production → max sm muscle dilation)
2. increased cap permeability
- contraction of vascular endothelial cells (H1) → escape of fluid, pl proteins, immune cells from postcap venules
- → edema
- → decrease in local bp
- in some vasc beds, constriction of veins → upstream pressure → edema (H1)
3. heart
- indirect: reflex tachycardia (vasodil + systemic hypotension)
- most pronounced effect of antihists at heart
- direct: stimulation of atrial/ventricular contraction (H2) → increased pacemaker and HR
histamine-mediated vasodilation and cap permeability
causes wheal and flare
- gives immune cells access to site of insult
- gives plasma proteins (clotting factors) access to site of insult
- has chemotactic props (along with other cytokines) → leukocyte recruitment
- action on local afferent neurons → sensation of foreign object
effects of histamine on tissues/organ systems
respiratory system
1. bronchoconstriction
- constriction of bronchial smooth muscle (H1)
- pts with asthma are usually hypersensitive to histamine!
- hist can also have bronchodilation effect via H2, but pretty trivial in humans
effects of histamine on tissues/organ systems
digestive system
1. gastrin-induced acid secretion
- facilitates acid secretion from parietal cells in stomach (H2)
2. contraction of intestinal sm muscle → diarrhea (H1)
3. stimulation of mucus secretion in sm and large intestines (H2)
pathophysio of histamine: allergic rxns
triggers
immediate hypersensitivity rxns
- skin contact
- ingestion
- injection
- inhalation
pathophysio of histamine:
symptoms - reasoning
allergic rhinitis and conjunctivitis
- vasodilation, increased cap permeability, edema in nasal mucosa and surrounding tissues
- increased secretions from nasal/eye mucus membranes
- nasal congestion
allergic bronchospasm
urticaria (hives)
- pruritic, erythematous, edematous plaques on skin
- vasodil, increased cap permeability, edema → wheal and flare
anaphylaxis
- allergen distributed systematically → systemic mast cell/basophil degranulation → explosive release of histamine and other infl mediators
- severe bronchoconst, laryngeal swelling, angioedema
- systemic vasodil and cap permeability → profound drop in bp
- rapid, weak puls
strategies to block histamine action
1. antihistamines
- aimed at H1, H2 receptors
- generally function as inverse agonists
2. inhibition of mast cell degranulation
- prophylactic use of cromolyn and nedocromil → block Ca entry to cell → prevent degranulation
- can be used to prevent asthma attacks (kids)
- lousy solubility, so wont be absorbed across GI tract well → need to be inhaled
- inhaler: prevent bronchospasm
- spray: prevent rhinoconjunctivitis
3. drugs that counteract histamine action
-
epinephrine → agonist of alpha and beta adrenergic receptors
- powerful mediator of bronchodilation, vasoconstriction → increase bp
antihistamines:
two state model of histamine receptor
inactive state ⇔ active state
[exist in equilibrium in absence of histamine; almost 50/50 → histamine receptors are thought to be const active]
- histamine binds preferentially to active state receptors and stabilizes them → shift towards active conformation
***antihistamines do not act as true antagonists → don’t block binding of histamine to receptor***
- instead, act by preferentially binding to inactive conformation and stabilizing it to effect a shift in that direction
- not true antagonists…actually inverse agonists
H1 antihistamines
1st generation
neutral at physiological pH, hydrophobic (lipid-soluble) → readily enter CNS (cross blood/brain barrier)
generally short-acting (4-12h)
effects:
- highly sedative
- strong anti-emetic activity
- component of OTC drugs for insomnia, motion sickness, anti-itch
- nonspecific effects: anticholinergic, anti-alpha-adrenergic, anti-5HT (serotonin)
H1 antihistamines
2nd generation
ionized at physiological pH, hydrophilic → readily enter CNS (cross blood/brain barrier)
generally longer-acting (12-24h)
effects:
- not sedative
- no anti-emetic activity
- v specific: no cross-talk with other receptors
1st generation H1 antihistamines
examples
1. ethanolamines
- diphenhydramine (Benadryl)
2. ethylenediamines
- tripelennamine
3. alkylamines
- chlorpheniramine
4. phenothiazines
- promethazine
5. piperazines
- hydroxyzine
- cyclizine, meclizine
6. piperidines
- cyproheptadine
overall features
- mainly used to treat allergy symptoms (123) and/or nausea (456)
- dizziness, drowsiness side effects → sedative!
-
anticholinergic/antimuscarinic effects indicative of nonspecific receptor crosstalk
- dry mouth, blurry vision, GI upset, constipation/difficulty urinating
- most are metabolized in liver cytochrome P450 system → OD is a real concern, not uncommon
2nd gen H1 antagonists
examples
2gen piperazines
- cetirizine (Zyrtec)
2gen piperidines
- loratadine (Claritin)
- metabolized by liver into active metabolite, so foods/drugs that occupy or inhibit cytP450s can affect its effect
- fexofenadine (Allegra)
general features
- ionized/hydrophilic → do not cross blood/brain barrier easily → few CNS effects!
- not sedative → drugs of choice for daytime antihistamine relief!
- high specificity (few anti-cholinergic/muscarinic effects)
- all are formulated with pseudo-ephedrine (agonist of alpha adrenergic receptors) → side effects of insomnia, restlessness, increased HR
3rd gen H1 antihistamines
levocetirizine
- active R enantiomer of cetirizine
- high potency, can be used at small dosage
desloratadine
- active/major metabolite of loratadine
- inhibitors of CYP dont affect this drug’s action (already active)
- high potency
which H1 antihistamine(s) would you use to treat…
- allergic rxns?
- motion sickness, vertigo, insomnia?
- antiemetics
allergic rxns → 1st, 2nd, 3rd generation H1 antihistamines
- hit hives, rhinitis, allergic conjuctivitis, etopic dermatitis, pruritis
- mostly ineffective to treat asthma or common cold
- can be used prophylactically to treat allergic rxn
- might have adjuvant role in treating systemic anaphylaxis, angioedema; epi is critical in these conditions
which H1 antihistamine(s) would you use to treat…
- allergic rxns?
- motion sickness, vertigo, insomnia?
- antiemetics
motion sickness, vertigo, insomnia → 1st generation H1 antihistamines
- sedative, sleep aid
- vestibular disturbances
- Meniere’s disease
which H1 antihistamine(s) would you use to effect…
- allergic rxns?
- motion sickness, vertigo, insomnia?
- antiemetics
if you want an antiemetic → 1st generation H1 antihistamines
- taken in cases of chemo
adverse effects of H1 antihistamines
CNS toxicity
CNS toxicity (1st gen drugs)
- normal doses → drowsiness, sedation, fatigue, lassitude
- other effects can include: dizziness, tinnitus, impairment of cog fx/memory/psychomotor skills, agitation
- overdose → CNS hyperstimulation → restlessness, tremors, nervousness, anxiety, hallucinations, convulsions (esp infants)
contraindicated for pregnant women, newborns, young infants,
adverse effects of H1 antihistamines
non-CNS effects
anticholinergic/antimuscarinic effects (1st gen drugs)
- dilated pupils, blurry vision, double vision (diplopia), dry eye, dry mouth, dry resp passages
digestive tract
- nausea, loss of appetite, increased appetite, weight gain, constipation, diarrhea
OD of 2nd gen drugs [astemizole, terfenadine] → cardiac arrythmias
adverse effects of H1 antihistamines
drug interactions
1st gen drugs + alcohol/CNS depressants → additive effect that can lead to significantly impaired motor skills
1st gen drugs + drugs that impair hepatic CYP metabolism → increased levels/action of gen1 drugs
- ex. ketoconazole, itracanazole, macrolide antibiotics
H2 antihistamines
mechanism of action (i.e. role of histamine and H2 receptor)
primary site of action: fundus of stomach
H2 functions in regulating gastric acid secretion by parietal cells
- how?*
1. sight/smell of food, distension, etc trigger signals that lead to secretion: - antral G cells: gastrin
- vagal postgang neurons: Ach
- in resp to signals, enterochromaffin cells (ECL cells) → release histamine
- parietal cells respond to…
- Ach, gastrin → increase in intracellular Ca
- histamine → cAMP signaling
- gastric acid secretion from parietal cells, lowering of luminal pH
H2 antihistamines
examples
cimetidine
- inhibits multiple CYP drug metab pathways → potential for drug-drug interactions
ranitidine
- shows some inhibition of CYP pathways (< cimetidine)
famotidine
- most potent H2 antihistamine
- no CYP interference
nizatidine
- no CYP interference
general features
- hydrophilic; do not enter CNS
- high specificity (don’t affect H1 or H3 receptors)
- used to treat GERD, Zollinger-Ellison (hyper-gastrin-secretion); heal ulcers
- can be used prophylactically to treat stress-induced GERD
- being steadily replaced by omeprazole and other proton pump inhibitors (H/K ATPase pump inhibitors) for clinical apps
adverse effects of H2 antihistamines
generally well tolerated - small fraction of users have adverse effects
-
drug interactions (esp cimetidine): interference with hepatic CYP pathways → increased half life of other drugs metabolized in these pathways
- (1st gen antihistamines!!!)
-
neurological effects: can occur in pts with impaired renal or hepatic fx
- confusion, slurred speech, delusions, hallucinations, agitation
- primarily elderly patients receiving IV treatment
-
anti-androgen action, inhibition of estradiol metabolism (cimetidine)
- gynecomastia, impotence [males]
- galactorrhea [females]
other: headaches, diarrhea, fatigue, dizziness, muscle pain, constipation
major drugs:
1st gen H1 antihistamines (8)
2nd gen H1 antihistamines (3)
3rd gen H1 antihistamines (2)
degranulation inhibitors (2)
H2 antihistamines (4)
