• Decarboxylation of L-Histadine
• Inactivated by monoamine oxidase and diamine oxidase.

• Mast cell secretory granules
• Enterochromaffin-like (ECL) cells. (Stomach)
• Presynaptic vesicles in neurons

• Injury-physiologic
• Immunologic stimulated release:
• Antigen binds mast cell
• Complement cascade activation
• Regulated by feedback inhib H2R on mast cells
• Release by displacement bound to heparin, displaced by morphine.

THP: Histamine released in response to IgE immediate allergic rxns and is impt physiologically in seasonal rhinitis, urticaria, angioedma

• Test of pulmonary fct.
• Potential ADR with this
• Contraindications: Asthmatics, active ulcer, GI bleeding

• Physiologic antagonist of histamine action.
• Ex.: Vasoconstrictors, Bronchodilators
• Epinephrine: for anaphylactic shock
• Release Inhibitors:
• Cromolyn, nedocromil: Block activation of mast cells.
• These are exteremly insoluble - inhalers, nasal spray, eyedrops
• Histamine Receptor antagonists:
• H1: Used in allergic rxns
• H2: Used in gastric secretion
• Very selective - no cross activity b/w H1 & H2 antagonists.

• Second generation H1 antagonists.

• Meclizine
• 12-24 hours

• Muscarinic Cholinergic receptor:
• Sedation
• Anti-nausea (motionsickness, morning sickness, chemotherapy nausea)
• Atropine-like effects on peripheral muscarinic receptors (Dry mouth, blurred vision, non-allerginic rhinorrhea)
• Adrenoceptor (α):
• Orthostatic hypotension
• Serotonin receptor
• Sodium channel:
• Local anesthesia

• Diphenhydramine, dimenhydrinate/doxylamine

• Brompheniramine
• Chlorpheniramine
• Cyclizine
• Meclizine

• Dimenhydrinate, cyclizine, meclizine, promethazine
• Muscarinic cholinergic receptors

• Promethazine

• Diphenhydramine

• Promethazine
• Effects on Adrenoceptor (α)

• Diphenhydramine and promethazine
• Effects on sodium channel

• Allergic rhinitis/Hay fever
• Urticaria (hives)
• Angioedema (swelling) [prevention only]
• Atopic dermatitis (eczema)
• Non-bronchial asthma
• Motion sickness
• Morning sickness
• Sleep aid
• Chemotherapy

• Anticholinergic activity: dry mouth, blurred vision
• Sedation
• Orthostatic hypotension

• Terfenadine and astemizole:
• Ventricular arrhythmias when taken w/ antimicrobials that inhibit CYP3A4, esp. ketoconazole.
• Accumulate and block heart K channels
• Removed from market
• Sedative effects additive:
• Eg., with benzodiazepines, alcohool
• Autonomic effects additive
• w/ muscarinic and α blockers.

• Uses:
• Acid-peptic disease (ulcer)
• Gastro-esophageal reflux disease
• Cimetidine

• 5-hydroxytryptamine (5-HT)
• Regulates:
• Mood, sleep, appetite, pain perception, blood pressure, vomiting, depression, anxiety, migraine.

• Generated from L-tryptophan by hydroxylation and decarboxylation.
• Inactivated by monoamine oxidase:
• In the pineal gland, serotonin serves as a precursor to melatonin.

• Cell bodies from teh mid brain and pons innervate most brain regions.
• Generally strongly inhibitory <5HT₁> <5HT₂→excita>
• Regulation of sleep, temperature, appetite, and neuroendocrine control.
• Stimulates pain and itch sensory nerve endings <5HT₃>.
• 5-HT3 receptors in GI and medulla mediate vomiting reflex: "Chemoreceptor trigger zone"
• 5-HT3 receptors on afferent vagal nerve ending: "chemoreceptor reflex" -- bradycardia and hypotension.

• Facilitates release of ACh from bronchial vagal nerve. <5HT₂>.
• Mild bronchoconstriction. <ACh release → this effect>

• Contraction of vascular smooth muscle <phase 2>:
• Peripheral <5HT2>
• Cerebral vessels <5HT1>
• Dilation of vessels in skeletal and heart muscle <phase 3> <5HT2>
• Triphasic blood pressure response to 5-HT injection:
1. Decrease in heart rate, cardiac output, BP
2. BP ↑ due to vasoconstriction
3. BP ↓ due to vasodilation in skeletal muscle
• Constricts veins, increased capillary load.          <→ Flushing>
• Platelet aggregation:
• Prolonged 5-HT elevation: valvular malformation <5HT2>

• Stimulant of GI smooth muscle: Peristalisis
• Direct effect on smooth muscle <5HT₂>
• Indirect effect via ACh <5HT₄→Prokinetic>
• Serotonin overload: diarrhea

• Serotonin syndrome:
• SSRI + MAOI = too mch serotonin
• Skeletal muscle contractions, hypertension, hyperthermia, diarrhea, agitation, coma.
• Tx: Sedation, ventilation, 5HT₂ antagonist

• Carcinoid tumors produce excessive amounts of serotinin. Results in:
• Bronchoconstriction
• Valve/electric cardiac malfunctions
• Diarrhea
• 5-hydroxylindoleactetic acid (5-HIAA) is diagnostic
• Metabolite, in urine
• Treat w/ 5-HT₂ inhibitor

• Classic: Brief aura, visual disturbances, nausea, throbbing unilateral headache, 1-2 days.
• Also common: headache only

• Vasodilation:
• Trigeminal nerve → Calcitonin gene related peptide "CGRP → Vasodilation of intracranial arteries
• Perivascular edema:
• Vasodilation → leakage → edema → activation of pain nerve endings

• Inhibition of CGRP (calcitonin gene related peptide) release:
• <Presynaptic 5HT₁ →Gi →βγ—|Ca⁺⁺ in trigeminal nerve>
• Counteract vasodilation by direct vasoconstriction:
• <5-HT₁ in cerebral vessels>

• 5-HT1D agonists:
• Triptan drugs: Sumatriptan
• These are all 5-HT1D agonists
• Differ by PK and contraindications
• Anti-inflammatory analgesics also helpful
• As effective as ergot alkaloids, but short lasting and expensive.

• Altered sensations, dizziness, muscle weakness, neck pain.
• Contraindicated in pts w/ coronary artery disease/angina.

Naratriptan and frovatriptan

• Buspirone:
• A 5-HT_1A agonist
• Also activates D₂

• (Dex)Fenfluramine
• Multiple mechanisms
• Taken in combo w/ Phenteramine (Fen-phen)
• Fatal pulmonary hypertension, valvular lesions
• Toxicity associated w/ 5-HT agonist activity.

• Cyproheptadine
• Also cold-induced uticaria

• The 5-HT3 antagonists:
• "-setrons": Ondansetron, granisetron, dolasetron, alosetron
• Used for chemotherapy and pregnancy associated nausea

• Irritable bowel

• Reflux, irritable bowel:
• Toxic, compassionate use only

• Affect α-adrenergic, dopamine, and 5-HT receptors
• Results in dementia w/ hallucinations, vasospasm, spontaneous abortion

• 5-HT1A/D agonist → migraine
• 5HT2 → Uterine stimulant

• Agonist/partial agonist activity:
• Useful for pituitary tumors, parkinson's

• Vasoconstriction, variable
• Ergotamine and methylsergide <no longer used>, potent partial agonists, multiple targets.
• Toxicity: Severe vasospasm, ~irrevresible→gangrene

• Ergonovine-- Contractions
• Via α and 5-HT receptors, sensitivity increases during prenancy

• Ergot Alkaloid
• Effects the brain:
• 5-HT antagonist peripherally, agonist in CNS, strong D2 agonist
• Causes hallucinations

• Ergot alkaloids
• Effects brain as D₂ agonists
• Inhibit prolactin, motor control

• Ergots are longer lasting and less expensive than -triptans.
• Ergotamine: Acute migraine attack (effective early in attack)
• Ergonovine: Prophylactic against migraine
• Dihydroergotamine
• Methylsergine: Toxic and not used.

• Bromocriptine: Reduces prolactin secretion, improves motor function.
• Pergolide: No longer used.

• Ergonovine
• Used to stop post-partum bleeding <Cause contractions which helps w/ bleeding>
• Dangerous to use before delievery
• Used as back-up; oxytocin is tried first

• Obstructive vascular disease
• Collagen disease
• Pregnancy