Exam 2: Lecture X, Histamines Flashcards
Histamine and serotonin are synthesized from…..
amino acids
also antacids
Histamine made from…
histidine
stored in high conc in mast cells
Important in pathophysiological reactions (inflammation)
Released in response to IGE-mediated (immediate) allergy
Histamine in mast cells….
bound form is biologically inactive, stored in granules in mast/basophils
stimuli can trigger release
mast cells numbers at sites of potential tissue injury
Non-mast cell Histamine….
found in several tissues and brain
function as NT in brain…sleep + arousal, thermal/body weight regulation, neuroendocrine control and cardiovascular regulation
Ergot Alkaloids Toxicity Brain
Hallucinations resembling psychosis are common with the LSD
Methysergide is occasionally used as a “recreational drug” (an LSD substitute)
Ergot Alkaloids Toxicity Uterus
Powerful contractions may be produced during pregnancy
Uterus is progressively more sensitive to ergot alkaloids
Abortions are rare, however better to avoid ergot alkaloids
Avoid migraine treatment with ergot alkaloids during pregnancy
Ergot Alkaloids Toxicity Blood Vessels
Strong and prolonged vasoconstriction
An overdose may cause severe ischemia and gangrene
Release of Histamine (immunologic)
Immunologic response the important mechanism of mast cell/basophil histamine release
Cells sensitized by IgE attached antibodies degranulate explosively exposed to antigen
Degranulation leads to the release of histamine,ATP, and other stored mediators
Histamine released by this mechanism is a mediator in immediate (type I) allergic reaction
Chemical and Mechanical Release of Histamine
Drugs (morphineand tubocurarine) can displace bound histamine from the cells
Loss of granules from the mast cell also releases histamine
Chemical/Mechanical mast cell injury causes degranulation and histamine release
Histamine Effects
Flushing
Hypotension
Tachycardia
Bronchoconstriction
H1
Tissue:Smooth muscles, endothelium, brain
Signal Transduction:Gq; ↑IP3, DAG
H2
Tissue:Stomach, heart, mast cells, brain
Signal Transduction:Gs; ↑cAMP
H3
Tissue:Nerve endings, CNS, plexuses
Signal Transduction:Gi; ↓cAMP
H4
Tissue:Eosinophils, neutrophils, CD4 T-cells
Signal Transduction:Gi; ↓cAMP
H1 effects
Important in processes caused by IgE-mediated allergic responses
Typical responses – bronchoconstriction, and vasodilation
Vasodilation occurs due to release of NO
Capillary endothelium permeability increases with edema formation
H2 effects
Mediates gastric acid secretion by parietal cells
Cardiac stimulant effect.
By a negative feedback reduces histamine release from mast cells
H3 effects
Operates in presynaptic neurons in the CNS
Modulation of histamine neurotransmission in the CNS
H4 effects:
Operates in chronic inflammatory conditions
H1 antagonists:
Histamine solo = no therapeutic application
Histamine aerosol used as provocative test of bronchial hyperactivity
drug that block histamine effect = v important
Competitive antagonists at the H1 receptor in the periphery
Do not affect the release of histamine from storage sites
H1 antagonists resemble muscarinic antagonists and alpha-adrenergic blockers
H1 antagonists are pharmacological antagonists at muscarinic receptors and alpha-receptors
H1 antagonists may block serotonin receptors
H1 antagonists are characterized by extensive liver metabolism
1st vs 2nd Gen H1 antagonists
1st = strong sedative effects
more likely to block autonomic receptors
2nd = less sedating
h1 blockers less distributed into CNS
H1 antagonist Typical Effects
Sedation Antinausea and antiemetic effect Antiparkinsonism effects Anticholinoceptors effects Antiadrenoreceptor effects Antiserotonin effects Local anesthesia
1st gen antihistamines
Ethanolamines: Carbinoxamine (Clistin), Diphenhydramine (Benadryl)
Piperazine derivatives: Hydroxyzine (Atarax), Meclizine (Bonine)
Alkylamines: Brompheniramine (Dimetane), Chlorpheniramine (Chlor-Trimeton )
Phenothiazine derivatives: Promethazine (Phenergan)
Miscellaneous agents: Cyproheptadine (Periactin)
2nd gen antihistamines
Piperidine: Fexofenadine (Allegra)
Miscellaneous agents: Loratadine (Claritin), Cetirizine (Zyrtec)
Diphenhydramine (Benadryl)
Treatment of Allergic reactions:
H1 receptors blockers are used for allergic conditions
Hay fever, urticaria, drug-sensitivity rashes, insect bite and stings
Agents are not effective in asthma.
CNS effects: Sedation, motion sickness, nausea, and vomiting
Anesthetic effect: Many H1 blockers are potent local anesthetics
Diphenhydramine (Benadryl) Toxicity
Toxicity: Common
Highly sedative (diphenhydramine and promethazine)
Antimuscarinic effect: Dry mouth and blurred vision
Alpha-blocking effect: Orthostatic hypotension
Less common toxicity:
Excitation and convulsion in children
Allergic responses (topical application of H1 antagonists)
H2 antagonists
Selectively block H2 receptors
Structurally do not resemble H1 blockers
No effect upon H1 receptors, 5-HT receptors, or α-receptors
Active orally
Relatively non-toxic
Possible to use in large doses (single dose for 12-24 hours)
H2 antagonists Clinical Uses
Reduction of gastric acid secretion
Acid-peptic disease - especially duodenal ulcer
Effective in healing and preventing recurrences in gastric peptic ulcer
Effective in acid hypersecretion, GI bleedings, and diarrhea
Acute ulcer is treated with 2 doses/day
Accelerate healing
Prevent recurrences
Recurrence can often be prevented with 1 single bedtime dose
Very useful agents!
H2 prototype antagonist
Cimetidine (Tagamet)
Relatively selective and have no effect upon H1 receptors
Relatively non-toxic - can be given in large doses
Main application in acid-peptic disease - especially duodenal ulcer
Accelerates healing and prevents recurrences
Recurrences may be prevented by a single bedtime dose
Also effective in healing and preventing severe gastric peptic ulcers
Very helpful in controlling acid hypersecretion
Very helpful in treatment of GI bleeding and diarrhea
May be used to treat gastroesophageal efflux disease (GERD)
Cimetidine (Tagamet) Toxicity
Relatively non-toxic
Potent inhibitor of hepatic enzymes
May reduces hepatic blood flow
Antiandrogen effect in many patients
(Newer H2 blockers do not have endocrine effects)
** Alcohol: Very serious drug interaction may occur
Serotonin Syndorme
skeletal muscle contraction precipitated when MAO inhibitors are given together with SSRI antidepressants. Two mechanisms are discussed – hyperthermia caused by muscle contraction, or by the effect of drugs upon the CNS
Serotonin is produced from amino acid….
tryptophan
potent pain stimulant
Ondansetron (Zofran, Zuplenz)
5-HT3 blocker
Prevention of nausea and vomiting caused by chemotherapy and radiotherapy
Cyproheptadine (Periactin)
5-HT2 blocker and H1 blocker
Treatment of allergy symptoms – sneezing, watery eyes, and itching
Ketanserin ( Sufrexal )
5-HT2 and alpha adrenoreceptor blocker
An antihypertensive agent, and a scientific tool to study 5-HT2 receptors
Dexfenfluramine (Redux)
serotonin uptake inhibitor
Inhibits the reuptake carrier for 5-HT
Characterized by a pronounced and effective appetite-reducing effect
Toxicity:
Related to serious cardiac disease in patients – was withdrawn (2010)
Sumatriptan (Imitrex)
5-HT1d and 5-HT1B agonist.
Effective in the treatment of acute migraine and cluster headaches
Available for oral, nasal, and parenteral administration
5-HT3 Distribution
CNS sensory system. Chemoreceptors, vomiting center,
and enteric system
5-HT2 Distribution
CNS excitation system, smooth muscles, gut, bronchi,
uterus, vessels, and platelets
5-HT1d Distribution
Brain
5-HT6,7 Mechanism
Gs, increase cAMP
5-HT2 Mechnism
Gq, increase IP3/DAG
All other 5-HT receptors mechanism….
Gi, decrease cAMP
5-HT3 Mechanism
Gated channels, resembles Ach at nicotinic channels
Ergot Alkaloids
Ergot alkaloids are complex molecules
Produced by a fungus in wet or spoiled grain
Fungus also synthetize histamine, Ach, and tyramine
Were responsible for the epidemics of “St. Anthony’s Fire”
These epidemics were frequent during the Middle Ages
Ergot Alkaloids Receptors
Partial agonists at alpha-adrenoreceptors and 5-HT receptors
Some ergot alkaloids are strong agonists at dopamine receptors
Ergot Alkaloids Classification base on….
organ or tissue involved
Bromocriptine (Parlodel, Barlolin, Brocriptin, and Butin )
for Parkinsonism
extremely effective in reducing the high levels of prolactin from pituitary tumors
associated with regression of the tumor, in some cases
Ergotamine used to treat….
acute migraine
Methysergide (Deseril) used for…..
migraine prophylaxis….not frequently prescribed
Ergot Alkaloid effect on blood vessel
OD can cause ischemia and gangrene
Strong/prolonged a receptor mediated vasoconstriction
Migraine treatment
Ergot derivatives are highly specific for migraine pain
Preferred by clinicians and patients
Ergotaminetartrate for oral, sublingual, rectal, and inhaler use
Often combined withcaffeine
Vasoconstriction is long-lasting and cumulative
Patient: careful with the oral preparation (10 mg per week)
Ergotaminetartrate may be given intravenously or intramuscularly
Ergot Alkaloid effect on Brain
Hallucinations – more prominent with naturally occurring substances and LSD
Hallucinations – less prominent with therapeutic agents
Ergot Alkaloid effect on Uterus
Powerful contraction near term
Early in pregnancy high doses may cause abortion or miscarriage
Useful contraction after placenta delivery (postpartum bleeding)
Postpartum contractions reduce blood loss
- **Ergonovine (Ergotrate)
- *** Ergotamine
Preferred agent for control of postpartum hemorrhage…..
Oxytocin
Ergonovine use….
only for control for postpartum uterine bleeding
should never be given before delivery
Vasoselective Ergot
Ergotamine
used: Migraine/cluster headache
Duration: 12–24 h
Toxicity:Prolonged vasospasm causing angina, gangrene; uterine spasm
Uteroselective Ergot
Ergonovine
Used: postpartum bleeding/migraine headache
Duration: 2-4 h
Toxicity:Prolonged vasospasm causing angina, gangrene; uterine spasm
CNS selective Ergot
LSD
uses: none
Duration: hours
Toxicity: prolonged psychotic state/flashbacks
