Antihistamines Flashcards
H1 receptors
- tissue expression?
- post-receptor mechanism?
- smooth muscle, endothleium, brain, sensory neurons in skin, immune cells
- G_q–> +IP3 –> DAG
H2 receptors
- tissue expression?
- post-receptor mechanism?
- gastric mucosa, cardiac muscle, mast cells, brain vasculature
- G_s –> inc cAMP
H3 receptors
- tissue expression?
- post-receptor mechanism?
- pre-synaptic autoreceptors and heteroreceptors: brain, myenteric plexus and other neurons
- G_i –> dec cAMP
H4 receptors
- tissue expression?
- post-receptor mechanism?
- eosinophils, neutrophils, CD4 T-cells
- G_i –> dec cAMP
H1 inhibitors are used to?
tx:
- allergic rxns
- motion sickness
- nausea
- vomiting
H2 inhibitors are used for?
tx:
-inh acid secretion from parietal cells (GERD & ulcers)
What do H3 inhibitors tx?
-NO approved Tx’s
but H3=allergic rhinitis, Alzheimers, ADHD, epilepsy, narcolepsy, neuropathic pain, obesity
What do H4 inhibitors tx?
NO approved tx’s
-but H4=allergic rhinitis, atopic dermatitis, asthma, and other chronic inflammatory & autoimmune disorders
Histamine in the nervous system:
- His neurons found where?
- His release?
- what effect does histamine have via PNS and CNS receptors?
- histaminergic neuron cell bodies found in part of hypothalamus and go to all parts of the brain
- release is circadian pattern =inc at night and dec at day (regulates wakefulness and appetite/satiety)
- mediates itch
Histamine effects on the vasculature? WHich receptor?
1) H1 and H2 mediated dilation of small blood vessel
- dec TPR – dec systemic BP (reflex tachycardia)
- inc vascular permeability - H1 receptors
Histamine effects on the lungs? Which receptor?
H1 in lungs =elevated secretion of airway fluid and electrolytes + BRONCHOCONSTRICTION
Histamine effects on the heart? Which receptor?
H2 activation = +pacemaker rate and contractility (more calcium in cells)
Histaime effect on the immune system?
- part of response against foreign stuff
- facilitates accumulation of immune cells at site of infection or damage
- -> inc vascular permeability
- ->Immune cell adhesion (inc P-selectin expression)
- -> Chemotaxis of eosinophils and neutrophils
- -> Inc release of inflammatory cytokines
- -> Inc antigen presentation of APC cells
Describe process and role of histamine in an allergic reaction:
1) APC cell expresses allergen to Naive T-cell on MHC class II
2) Naive T-cells acquire the characteristics of TH2 helper cells
3) IL4 and IL3 secreted + other interactions == B-cells secrete allergen specific IgE
4) IgE cross links antigen on mast cell=degranulation of histmine and other stuff ===> airways and smooth muscle vasoconstriction + BV vasodilation + mucous production
Symptoms of histamine release?
- wheal (bumps) & flare (redness)
- pruritus
- nasal conjunctival discharge
- mucous production
- angioedema
- systemic anaphylaxis
- brochoconstriction
Molecular cascade of mast cell histmaine release:
1) Allergen binding to IgE bound FCERI membrane protein
- -> activates tyrosine kinases Lyn and Syk
2) Lyn and Syk phos membrane protein LAT
3) Activated LAT –> helps with PLCy activation –> (–> IP3
- -> DAG) inc intracellular calcium and PKC activation
4a) ==> degranulation of preformed Histamine + activation of transcription factors that inc the synthesis of cytokines
4b) ==> MAPK cascade activated –> ++ expression of eicosanoids and cytokines
MOA for histamine release from mast cells? triggers for each?
1) Cytolytic histamine release
- membrane damage
- high levels (more than therapeutic) phenothiazines, H1 antagonists, opioids
- mechanical damage
2) Noncytolytic histamine release
- immune response from prior sensitization
- non-immune respone from basic polypeptides ex) neuropep substance P (wasp venom) and protamine –> response not through FCERI receptor
- morphine, codine, antibiotic release of histamine
- unexpected anaphylactoid reactions
Anaphylaxis is what and effects on body?
- severe alelrgic rxn
- hypotension - vasodilation
- myocardial depression
- dysrhythmias
- utricaria (hives)
- angioedema
- bronchospasm
Anaphylaxis is partially relieved by inhibiting which receptors?
- partially via H1 and H2
only partial bc leukotrienes, prostaglandins and cytokines are also involved
What is an anaphylactoid response?
cant clinically distinguish from anaphylaxis but this IS NOT CAUSED BY IMMUNE RESPONSE
diseases that inc histamine levels:
1) myelogenous leukemia
- inc in basophils
- high levels of histamine = chronic pruritus
2) gastric carcinoid tumors secrete histamine
- =episodes of vasodilation
3) systemic mast cell diseases
- leukemia –> pruritus, flushing, diarrhea, GERD, anaphylactoid response
3 classes of anti-histamines
1) physiological antagonists
- reverse physiological effects of histamine ex) epinephrine
2) release inhibitors
- prophylactic treatment
ex) cromolym & nedocromil
- monoclonal IgE antibody ex) Omalizumab
3) Receptor antagonists
- drugs competitively block receptors (H1-allergy, H2-gastic acid secretion, H3/H4 nothing clinically yet)
1st gen vs 2nd gen H1-antihistaimnes
- first = effective H1 block but many side effects bc cross BBB - can inh M, alpha1, serotonin, and D2 receptors
- 2nd=non-sedating bc no BBB penetration
Effects of 1st gen H1 antihistamines-
1) dec production of H1 mediated pro-inflammatory cytokines + chemotaxis of immune cells
2) inh vascular permeability and vasodilation (dec edema and wheals)
3) reduce flare and itch
4) cross BBB = sedation, dec alertness & memory
5) antiemetic - reduce motion sickness via CNS cholinergic receptor inhibition
Main uses of first gen antihistaimnes:
- alleric rhinitis
- allergic conjunctivitis
- urticaria
Other: nasuea/vomit, motion sickness, sedative, sleep aid, parkinsons, acute extrapyramidal symptoms, cough, common cold (drying effect)
H1 anti-histamine specific molecular MOA?
INVERSE AGONISTS - so they BIND TO THE transmembrane protein and stabilize the inactive form
Chlorpheniramine
- type?
- sedation effect?
- anti-M effect?
- antiemetic/motion-sickness
- primary tx?
- 1st gen H1 inh
- moderate sedation
- moderate anti-M
- NO antiemetic/antimotion
- tx- allergic rhinitis and other allergies
Diphenhydramine
- type?
- sedation effect?
- anti-M effect?
- antiemetic/motion-sickness
- other effects?
- primary tx?
- 1st gen H1 inh
- significant sedation, anti-M, anti-motion actions
- tx allergic rhinitis, conjunctivitis, utricaria, cough and motion sickness
- tx extrapyramidal reactions from anti-psychotic drugs
- tx parenterally for acute dystonic reactions to antiphsycotics
- local anesthetic effect via Na channel blockade
1st gen H1 anti-histamines?
- chlorpheniramine
- diphenhydramine
- pyrilamine
- hydroxyzine
- meclizine
- promethazine
- cyproheptadine
Pyrilamine
- type?
- sedation effect?
- anti-M effect?
- antiemetic/motion-sickness
- 1st gen H1 inh
- low to mod sedation
- little anti M
- no antimotion
Hydroxyzine
- type?
- sedation effect?
- anti-M effect?
- primary tx?
- 1st gen H1 inh
- much sedation
- much anti-M
- tx- antiemetic, sedative, mild anxiolytic, and for skin allergies
Meclizine
- type?
- sedation effect?
- anti-M effect?
- antiemetic/motion-sickness
- primary tx?
- 1st gen H1 inh
- much sedation but less than hydroxyzine
- minimal anti-M
- tx=motion sickness and vertigo
Patient with benign prostatic hyperplasia with trouble urinating can give?
-meclizine bc minimal anti-M effects = no urinary retention
Promethazine
- type?
- sedation effect?
- anti-M effect?
- antiemetic/motion-sickness
- other effets?
- 1st gen H1 inh
- marked anti-M, antiemetic, and antimotion sickness
- significant sedation
- alpha1 block = hypotension
- local anasthetic effect via Na channel block
- CAN BLOCK D2** (=not good in PD patient on D2 agonists)
Cyproheptadine
- type?
- sedation effect?
- anti-M effect?
- antiemetic/motion-sickness
- tx?
- 1st gen H1 inh
- low-mod sedative and anti-M
- anti-serotonin
- inc weight and appetite (bc of serotonin receptor block)
- tx - serotonin syndrome
Chlorpromazine
- used for?
- blocks what receptors?
- antipsychotic agent
- blcok D2 and H1 (sedation)
Adverse effects of 1st gen H1 blockers:
1) CNS H1 receptors
- dec alertness, cognition, memory…
- impairment w/ or w/out sedation
2) Muscarinic receptors
- inc dry mouth, urinary retention, and sinus tachycardia. mydriasis, constipation
3) Serotonin receptors
- inc appetitite; inc WG
4) alpha1 receptors
- inc dizziness; inc postural hypotension
4) CNS depression
5) glaucoma & prostate hypertrophy due to anticholinergic effects
6) crosses placenta
7) Gi upset
Which H1 blockers have strong effects on D2?
- Promethazine
and Chlorpromazine? an antipsychotic
Do not use H1 blockers with what other drugs?
- other depressants - alcohol, hypnotics/sedatives opioids, neuroleptics
- MAOIs = prolonged and intensified anticholinergic effects
- additive anticholinergic effects with other anticholinergics
- diphenhdramine OD is common
- max dose 300mg/day
2nd generation H1 blockers - the drugs?
- MOA?
- feature?
- fexofenadine
- loratadine
- desloratadine
- citirizine
- non-competitive binding to H1 receptor
- not lipophillic = no BBB crossing = no sedation
MOA of Citirizine? side effect?
- 2nd gen block of H1 receptors
- reduce mast cell degranulation
potential drowsiness (not worse than 1st gen H1 blocekrs
Metabolism of 1st gen vs 2nd gen H1 blocekrs?
- 1st are all highly metabolized in liver
- 2nd varies by drug + age + liver + renal function
1st gen vs 2nd gen MOA comparison?
1st = INVERSE AGONISTS - so the BIND TO THE transmembrane protein and stabilize the inactive form
2nd=non-competitive binding to H1 receptor
1st gen vs 2nd gen
-Drug interactions comparison?
1st gen many
2nd gen low risk of any interactions
Cromolyn and Nedocromil
- MOA?
- administration?
- tx/prophyalxis for?
- stabilize mast cell + inh degranulation of histamine (via inh of Cl channel membranes)
- nasal spray or eye drops
- allergic rhinitis and conjunctivitis
- helps with antigen and exercise induced astma
Omalizumab
- what kind of drug? MOA?
- tx for?
- recomb humanized monoclonal antibody that binds to IgE
- tx for chronic utricaria & asthma
(-very expensive)
- Which tricyclic antidepressant has antihistamine activity?
- which receptors?
- Tx for?
- Doxepin
- H1 and H2 block
- chronic utricaria
Ketotifen
- MOA/
- tx for?
- H1 block + mast cell and basophil stabilization
- chronic utricaria + conjunctivitis-available as ophthalmic solution
Doxepin
- what kind of drug?
- MOA?
- tx?
- tricyclic antidepressant
- Block H1 and H2
- chronic utricaria
