Histamine, 5-HT, and Antagonists Flashcards
autacoids are …
substances produced by neural and non-neural tissues which act locally to modulate activity of smooth muscle, nerves, glands, platelets, etc; regulate aspects of GI, uterine, renal function and involved in pain, fever, inflammation, allergic reactions, asthma, thromboembolic disorders, etc
Where is the largest concentration of histamine found?
skin, lungs, GI, nasal mucosa, blood
Where is histamine stored and synthesized? Ie what types of cells.
storage - bound to proteoglycan in granules in mast cells and basophils
synthesis - rapidly in response to correct stimuli in paracrine cells of gastric fundus and histaminergic neurons
What stimuli cause mast cells to degranulate? Examples?
- antigens and anaphylatoxins (via crosslinking of IgE; Ca mediated)
- certain basic drugs (probably dec GTP; examples codeine, morphine, tubocurarine, Ach)
- chemical or mechanical injury (increased Na; insect, snake venom, cuts)
Distribution and mechanism of H1 receptor.
smooth muscle, endothelium, brain
Gq
Distribution and mechanism of H2 receptor.
gastric mucosa, cardiac muscle, mast cells, brain
Gs
Distribution and mechanism of H3 receptor.
presynaptic: brain, myenteric plexus, other neurons
Gi
Distribution and mechanism of H4 receptor
eosinophils, neutrophils, CD4 T cells
Gi
What’s the really important physiologic effect of histamine in the cardiovascular system?
fall in BP due to vasodilation - pronounced drop, anaphylactic shock
there’s also an increase in vascular permeability and decrease in HR
What effect does histamine have in the lungs? Who does this affect most?
bronchoconstriction; hyperreaction in asthmatics
Effects of histamine in GI tract? Which receptors?
contraction of sm muscle - diarrhea H1
secretion of acid, pepsin, intrinsic factor H2
Effects of histamine on sensory nerve endings in the skin?
pain (dermis) and itching (epidermis) H1
What’s the role of H3 receptors in the brain?
autoreceptors; feedback inhibition on histaminergic neurons to stop synthesis and release
What are the three ways to reduce the effects of histamine?
- physiological antagonists (epi) that have opposite actions (on diff receptors)
- release inhibitors - reduce degranulation of mast cells
- histamine receptor antagonists
Class and action of diphenhydramine.
H1 antagonist; ethanolamine derivative
antimuscarinic effects; sedation
Class and action of tripelennamine.
H1 antagonist; ethylenediamine derivative
moderately sedating, OTC sleep aids
Class and action of cyclizine.
H1 antagonist; piperazine derivative
dramamine; anti-motion sickness
Class and action of promethazine.
H1 antagonist; phenothiazine derivative
antimuscarinic effects, marked sedation, antiemetic
Class and action of chlorpheniramine.
H1 antagonist; alkylamine derivative less sedating (daytime) cold meds
Class and action of loratidine and fexofenadine
H1 antagonist; piperadine derivatives
newest class; 2nd generation
don’t cross BBB - no sedation
longer duration - once a day dosing
Class and action of azelastine
H1 antagonist; 2nd generation
intranasal for allergic rhinitis
ophthalmic solution for allergic conjunctivitis
Class and action of cetirizine.
H1 antagonist; 2nd generation
high grossing - zyrtec
Clinical uses of H1 antagonists.
- allergic reactions - allergic rhinitis, urticaria, conjunctivitis, topically for insect stings
- motion sickness
- nausea and vomiting of pregnancy
- ‘sleep aids’
Adverse effects of H1 antagonists
- sedation (impaired cognitive function)
- anti-muscarinic (blurred vision, dry mouth, urinary retention, constipation)
- poisoning - esp children; convulsions at high doses
- allergy (esp with topical)
- local anesthesia (high conc)
- ventricular tachycardia with high dose of piperadines
What are the H2 antagonists?
cimetidine, ranitidine, famotidine, nizatidine
Mechanism of H2 antagonists?
compete at H2 receptors in parietal cells; block gastric acid secretion (effect more pronounced on nocturnal than post meal)
Clinical use of H2 antagonists?
dyspepsia (OTC)
duodenal and gastric ulcers
hypersecretory conditions (zollinger-ellison syndrome caused by gastrin-secreting tumor)
Adverse effects of H2 antagonists?
very rare (1-3% of pts) CNS dysfunction (slurred speech, confusion; elderly) antiandrogen (cimetidine - gynecomastia, impotence) liver toxicity (ranitidine) P450 inhibition (cimetidine - potentiates action of other drugs; nizatidine doesn't do this!!!)
What amino acid is 5-HT derived from?
tryptophan
Distribution of 5-HT in the body?
GI tract (90% enterochromaffin cells)
platelets (8%)
CNS (2%)
There are a lot of 5-HT receptors. What are most of them? What’s the one exception?
most are GPCRs; 5HT-3 is a ligand-gated cation channel
Actions of 5-HT in GI tract?
contraction of smooth muscle;
not carcinoid syndrome - enterochromaffin tumors release large amounts
Actions of 5-HT in cardiovascular?
vasoconstrictor in smooth muscle, vasodilate in skeletal muscle and heart
reflex bradycardia
platelet aggregation
Actions of 5-HT in nervous system?
peripheral - pain and itching; activator of chemosensitive endings in coronary vascular bed
central - mood, food intake, sleep, regulation of pituitary secretions; presynaptic autoreceptors
Cyproheptadine is both antihistaminic and antiserotinergic. What are its uses and side effects?
Use:
skin allergies, urticaria (anti-H1)
diarrhea of carcinoid (anti-5HT2)
Side effects - sedation, antimuscarinic
Ketanserin isn’t marketed in the US yet, but what is it used for in other countries?
antihypertensive (relaxes vascular and tracheal sm muscle)
antagonizes platelet aggregation
What receptor does ondansetron block? What’s it used for?
5-HT3 antagonist;
prevention of N/V associated with chemo
Ergot alkaloids work at a whole bunch of receptor types - what are they?
agonist and antagonist at serotonin and alpha-adrenergic; some dopamine agonists too
In general, ergot alkaloids have actions in the CNS, vascular sm muscle, and uterine sm muscle. What are these effects?
CNS - powerful hallucinations
Vascular sm muscle - vessel constriction - prolonged and powerful
Uterine sm muscle - prolonged contraction
What ergot alkaloids are used in the Tx of migraines?
ergotamine and methysergide
triptans (not ergot)
When can ergotamine be helpful? Side effects?
given during prodrome of migraine;
side effects - N/V, prolonged vasoconstriction
Methysergide is only used for migrain prophylaxis. What are it’s side effects?
GI disturbances, inflammatory fibrosis fr chronic use, occasional hallucinations
The triptans are also useful for migraine treatment, but aren’t ergot alkaloids. What are the possible mechanisms for how they work?
- activate 5-HT1B,D receptors - vasoconstriction of cerebral vessels, relieving the dilation that contributes to throbbing HA
- stimulate presynaptic receptors (same type) on trigem nerve endings, inhibiting release of pro-inflammatory neuropeptides
What is ergonovine used for?
sustain uterine contraction to treat postpartum hemorrhage
Bromocriptine is an ergot alkaloid that acts as a D2 dopamine agonist in the treatment of what?
hyperprolactinemia - suppresses prolactin secretion from pituitary cells
