Flashcards in Unit 2 - Histamine, Serotonin, and their Antagonists Deck (55):
explain what histamine is
amine formed by decarboxylation of histidine AA
-widely distributed in body, and upon release from storage sites, exserts pharmacological effects of varying intensity (mild irritation/itching to anaphylactic shock/death)
how is histamine metabolized?
1. methylation of the ring followed by oxidative deamination (N-methyltransferase, then MAO)
2. oxidative deamination, then conjugation with ribose (diamine oxidase, then phosphoribosyl transferse)
explain histamine distribution
1. largest concentration of histamine is found in skin, lungs, GI, nasal mucosa, and blood (rich at sites of potential tissue injury)
2. stored in mast cells, bound to proteoglycan inside secretory granules
-synthesized rapidly in response to appropriate stimuli in paracrine cells of gastric fundus and histaminergic neurons
what stimulate mast cell histamine release?
exocytic process that needs ATP and intracellular Ca++
1. antigens and anaphylatoxins (Ag X-link IgE on sensitized mast cells, mediating opening of Ca++ channels, causing enzyme activation)
2. certain basic drugs (increasing GTP)
3. chemical or mechanical injury (degranulation caused by increased Na+)
what are histamine receptors?
GCPRs (7 membrane-spanning regions)
what is the H1 distribution and postreceptor mechanism? effects?
smooth muscle, endothelium, brain
-Gq (increased IP3 --> DAG)
-bronchoconstriction (asthma-like symptoms)
-post-capillary venule dilation (rubor)
-terminal arteriole dilation
-contraction and separation of endothelial cells (edema, wheal response)
-sensitization of afferent nerve terminals (itchiness, pain)
what is the H2 distribution and postreceptor mechanism? effects?
gastric mucosa, cardiac muscle, mast cells, brain
-Gs (increased cAMP)
-minor increase in HR and contractility (minor)
-increased gastric acid secretion (peptic ulcer disease, heartburn)
what is the H3 distribution and postreceptor mechanism? effects?
presynaptic brain, myenteric plexus, other neurons
Gi (decreased cAMP)
-neurotransmitter (circadian rhythms, wakefulness)
what is the H4 distribution and postreceptor mechanism?
eosinophils, neutrophils, CD4 T cells
Gi (decreased cAMP)
what are the physiologic actions of histamine? their general action?
1. cardiovascular system (decrease BP; increase vascular permeability, contractility, HR)
2. bronchiolar smooth muscle (bronchoconstriction)
3. GIT (contraction; stimulates gastric acid, pepsin, IF secretion)
4. nervous system (stimulant of sensory nerve endings)
explain the effects histamine has on the cardiovascular system? the receptors associated with it?
1. immediate fall in BP due to peripheral vasodilation (H1/2)
-most important vascular effect in humans
-extensive systemic release can produce pronounced drop in BP and anaphylactic shock (asthmatics)
2. increase in vascular permeability (endothelial cell contraction) causing edema and loss of plasma from circulation (H1)
3. direct cardiac effects such as increased contractility and HR (H2)
-minor effect in humans
explain the effects histamine has on the bronchiolar smooth muscle? the receptors associated with it?
1. bronchoconstrition (H1)
2. hyperreaction in asthmatics
explain the effects histamine has on the GIT? the receptors associated with it?
1. contraction of intestinal smooth muscle, diarrhea (H1)
2. stimulates gastric acid, pepsin, and IF secretion (H2)
explain the effects histamine has on the nervous system? the receptors associated with it?
1. stimulant of sensory nerve endings (pain/dermis, itching/epidermis) - H1
2. three subtypes have been found in CNS
-H3 receptors are presynaptic autoreceptors on histaminergic neurons that mediate feedback inhibition of synthesis and release of histamine
what are the ways to reduce effects of histamine?
1. physiologic antagonists (smooth muscle actions opposite of histamine, but through different receptors; like E)
2. release inhibitors (reduce degranulation of mast cells)
3. histamine receptor antagonists (competitively antagonize binding of histamine to its receptors; most important class)
what does cromolyn sodium do?
histamine release inhibitor
-for prophylactic treatment of exercise or seasonal asthma
what does methylxanthine do?
histamine release inhibitor
what does albuterol do?
histamine release inhibitor
-B2 selective agonist
what are the types of H1 receptor antagonists?
>40 on the market
1. ethers or ethanolamine derivative
2. ethylenediamine derivative
3. piperazine derivative
4. phenothiazine derivative
5. alkylamine derivative
6. piperidine derivatives
7. 2nd generations
what are general properties of H1 receptor antagonists?
all similar in pharmacokinetics
1. rapidly absorbed following oral administration (1-2 hour peak)
2. widely distributed throughout body
-1st gensreadily enter CNS
3. rapidly metabolized (liver microsomes)
4. many non-prescription
-time release preps in combination with analgesics and decongestants
5. many actions not ascribable to H1 blockade
-due to structural resemblance to drugs with effects at muscarinic cholinoreceptor, a-adrenoceptor, serotonin, and local anesthetic receptor sites
what is diphenhydramine (Benadryl?
1st generation ethanolamine derivatives - H1 receptor antagonist
-antimuscarinic effects (sedation)
-popular antihistamines (Excedrin PM, Tylenol PM, Tavist, Dramamine)
what is tripelennamine (PBZ)?
1st generation ethylenediamine derivatives - H1 receptor antagonist
-moderately sedating OTC sleep aids
what is promethazine (Phenergan)?
1st generation phenothiazine derivative - H1 receptor antagonist
-antimuscarinic effects (marked sedation)
-antiemetic (effective suppressants of chemoreceptor trigger zone)
what is meclizine (Dramamine II, Antivert)?
1st generation piperazine derivative - H1 receptor antagonist
-anti-motion sickness (but others, like promethazine, are better)
what is chlorpheniramine?
1st generation alkylamine derivative - H1 receptor antagonist
-less sedating (daytime); cheap
-component of "cold" emdications (Dristan, Dimetap)
what are loratidine (Claritin) and fexofenadine (Allegra)?
2nd generation piperidine derivatives
-newest class (more specific for H1)
-cross BBB poorly, so fewer central effects (no sedation) and lower incidence of side effects in general
-longer duration of action, so once daily dosing
what is azelastine?
2nd generation H1 antagonist
-intranasal spray for allergic rhinitis
-opthalmic solution for allergic conjunctivitis
what is cetirizine?
Zyrtec - 2nd generation H1 antagonist
-prescribed in combo with decongestant pseudoephedrine hydrocloride
-now available as OTC
what are clinical uses for H1 antagonists?
1. allergic reactions
-can be very effective against allergic rhinitis, urticaria, and conjunctivitis
-can be used as topical application for insect stings
-largely ineffective for bronchial asthma and colds
2. motion sickness, N/V of pregnancy
3. "sleep aids"
what are adverse effects of H1 antagonists?
1. sedation (most common); impairment of cognitive function
2. atropine-like effects (anti-muscarinic) on peripheral muscarinic receptors
-blurred vision, dry mouth, urinary retention, constipation
3. poisoning (especially in children)
-convulsions due to CNS stimulation at very high doses
4. allergy (especially with topical use)
5. local anesthesia (block Na+ channels in excitable membranes, but needs high concentration)
6. rare, serious cardiovascular effects (ventricular tachycardia) with high doses of piperidines
what are H2 receptor antagonists?
cemetidine, ranitidine, famotidine, and nizatidine
what is the mechanism of H2 receptor antagonists?
compete at H2 receptors on basolateral membranes of parietal cells
-blocks gastric acid secretion in response to all stimuli, but reduction in nocturnal acid secretion is much more pronounced than meal-stimulated acid secretion
compare the H2 receptor antagonists in terms of:
-approximate duration of therapeutic effect
-relative effect on P450 activity
-cimetidine has the lowest potency, duration of effect; greatest effect on P450 activity
-famotidine has the lowest bioavailability; highest relative potency, plasma half-life, and duration of therapeutic effect; no effect on P450
-nizatidine has the highest bioavailability; lowest half-life; no effect on P450 activity
-ranitidine has same potency and duration of effect as nizatidine, and same average half-life as cimetidine; very small effect on P450
what are clinical uses for H2 antagonists?
1. dyspepsia (OTC)
2. duodenal and gastric ulcers
3. hypersecretory conditions
what is Zollinger-Ellison syndrome?
gastrin-secreting tumor (hypersecretory)
-treated with H2 antagonists
what are adverse effects of H2 antagonists?
only in 1-3% of patients; cimetidine (oldest) has the most, Nizatidine (newest) has the fewest
1. CNS dysfunction (slurred speech, confusion)
2. antiandrogen (Cimetidine only; gynecomastia in men, impotence)
3. liver toxicity (Ranitidine only)
4. inhibition of P450 oxidative enzymes (Cimetidine only; potentiates actions of other drugs)
what are H3/4 receptor ligands? their antagonists?
none so far
explain the metabolism of serotonin?
tryptophan --trp hydroxylase--> 5-HT --dopa decarboxylase--> serotonin
-can either be broken down by MAO (to 5-HIAA), or by hydroxyindole-O-methyltransferase (to melatonin via pineal gland)
what is the distribution of serotonin receptors in the body?
1. 90% in enterochromaffin cells (GIT)
2. 8% in platelets
3. 2% in raphe nuclei of brain stem/CNS
explain the storage and release of serotonin?
released by mechanical and neuronal stimuli, and reserpine
explain the serotonin receptor family?
at least 7 types of receptors, each with subtypes
-most are GPCR, but one (5HT3) is ligand-gated cation channel
explain what the postreceptor mechanism of the serotonin receptors are?
5HT 1/5: decreased cAMP
5HT 2: increased IP3, DAG
5HT 3: ligand-gated cation channel
5HT 4/6/7: increased cAMP
what are the effects of 5-HT?
1. GIT (contract smooth muscle, carcinoid syndrome)
2. cardiovascular system (vasoconstrictor in smooth muscle, vasodilator in skeletal muscle; platelet aggregation; reflex bradycardia)
3. nervous system (peripheral nociception, central)
what are the effects of 5-HT on GIT?
1. contraction of GI smooth muscle (increase tone and facilitate peristalsis
2. carcinoid syndrome
-enterochromaffin cell tumors that release large amounts of 5-HT and other autacoids
-high level of 5-HIAA in urine is diagnostic (after MAO metabolism)
-probably responsible for severe diarrhea
what are the effects of 5-HT on cardivascular system??
1. powerful vasoconstrictor in smooth muscle; vasodilator in skeletal muscle and heart
2. activation of chemoreceptor nerve endings to cause reflex bradycardia
3. platelet aggregation (5-HT2)
what are the effects of 5-HT on nervous sytem?
-stimulates nociceptive sensory nerve endings (pain, itching)
-activator of chemosensitive endings located in coronary vascular bed (Bezold-Jarisch Reflex)
-receptors in brain involved in mood, food intake, sleep, regulation of pituitary secretions
-presynaptic activation of 5-HT1A/D receptors inhibit raphe cell firing or serotonin release
what is cyproheptadine? uses? side effects?
antihistamine and antiserotinergic (resembles phenothiazne H1 blocker)
-use for skin allergies (urticaria - anti H1) and carcinoid diarrhea (anti-5HT2)
-side effects: sedation, antimuscarinic effects
what is ketanserin? uses? side effects?
selective antagonist of 5-HT2A/C, a1, and H1 receptors
-use for antihypertensive (relaxes vascular/tracheal smooth muscle), antagonizes platelet aggregation
what is odansetron? uses? side effects?
5-HT 3 antagonist
-used to prevent N/V associated with chemotherapy
explain the basic pharmacology of ergot alkaloids?
2 structural classes: amino acid alkaloids and amine alkaloids, both which tetracyclic eroline nucleus
-both have agonist and antagonist actions at serotonin and a1 receptors; some are dopamine receptor agonists
what are the actions of ergot alkaloids?
1. CNS (powerful hallucinogens)
-action on dopamine receptor suppresses PRL secretion from pituitary cells (Bromocriptine)
--used for hyperprolactinemia
2. vascular smooth muscle (blood vessel constriction is powerful and prolonged)
-used for migraines somehow
3. uterine smooth muscle (prolonged contracture at high doses)
-used for postpartum hemorrhage
what does ergotamine do? side effects?
non-specific partial agonist at 5-HT1/2 receptors and a-adrenergic receptors
-given during prodrome of migraine
-toxicities include N/V and cumulative, prolonged vasoconstrition with fibroblastic changes
(combined with caffeine as cafergot)
what does methysergidedo? side effects?
partial agonist at all 5-HT1 receptors, but 5-HT2 receptor antagonist
-for prophylaxis of migraines only
-ASE: GI disturbances, inflammatory fibrosis from chronic use, and occasional hallucinations (must take "drug holidays")
what are triptans?
non-ergot serotonin analogs that are very selective 5-Ht1B/D agonists
-effective for acute migraine (1-2 hours for effect)
include sumatriptan, naratriptan, rizatriptan, and zolmitriptan