PM 719 Pharmacology II Chapter 16 Histamine, Serotonin, & Ergot Alkaloids PDF

PM 719 Pharmacology II Lecture Notes (LN) Chapter 16 Histamine, Serotonin, & The Ergot Alkaloids **Histamine** An amino acid product that is a neurotransmitter (NT). This chapter also covers the role of histamine that is released by non-neuronal tissue and is responsible for causing allergic re...

PM 719 Pharmacology II Lecture Notes (LN) Chapter 16 Histamine, Serotonin, & The Ergot Alkaloids **Histamine** An amino acid product that is a neurotransmitter (NT). This chapter also covers the role of histamine that is released by non-neuronal tissue and is responsible for causing allergic reactions (urticaria, reddening of the skin, pain, itching, bronchospasm) and the general inflammatory response. So, with that said, histamine is not a drug but drugs used to block histamine are at the core of this chapter. This chapter will cover the role of histamine as a NT in the CNS or histamine's role in the stomach where it causes release of hydrochloric acid from parietal cells. Both topics are covered in other chapters but are introduced here in this chapter. Synthesis in the body from the amino acid L-histidine L-histidine histidine decarboxylase histamine Most histamine is stored in granules (storage vesicles) within mast cells and basophils. Basophils are a type of circulating white cell and mast cells are found in tissues throughout the body. **Triggers that cause release of histamine from mast cells and basophil cel**ls: Immunological Release of Histamine IgE antibodies made by the patient to an antigen (food, peanuts, drugs, pollen, cat hair etc. etc.) binds to mast cells. When exposed to the antigen again, Chemical Release of Histamine Some drugs like **morphine** can cause mast cells to release histamine. Many patients demonstrate an allergic reaction after receiving morphine or similar opiate drugs (drugs derived from opium, the plant). Much more on this in the Opioid chapter. Opioid = drugs found in the opium plant and drugs that are produced in a test tube and which act like opium (OxyContin etc. etc.) **Histamine Receptors:** Histamine binds to histamine receptors in the cell wall of many different tissues. There are four different histamine receptors H~1~ smooth muscle, endothelium, brain H~2~ gastric mucosa, cardiac muscle, mast cells, brain H~3~ presynaptic autoreceptors, neurons, brain H~4~ eosinophils, neutrophils, CD T white cells All of these receptors are G-protein coupled (serpentine) receptors. Some drugs are **antagonists** at some histamine receptor types and **inverse agonists** at other histamine receptors. **Tissue and Organ System Effects of Histamine:** Nervous System: Cardiovascular System: variable and mixed, edema can result from increased histamine levels Bronchiolar Smooth Muscle: bronchoconstriction, especially in asthma patients with over reactive airways GI: contraction of intestinal smooth muscle (diarrhea) Secretory Tissue: release of hydrochloric acid by parietal cells in stomach (a separate chapter coming up) Histamine **Triple Response** (**This is important**): Following intradermal injection of histamine, it causes, 1\. Red Spot at the site of dermal injection due to dilation of small blood vessels 2\. Edema an edema wheal at the injection site 3\. Flare red irregular flare surrounding the wheal caused by an axon reflex reaction This is often used to screen patients for allergies to specific compounds, for example, inject a very small amount of morphine following an intradermal injection and look for **Histamine As A Drug:** Almost never. **Histamine** aerosol given to patients to check and see if they have an exaggerated lung response consistent with asthma. Used as a provocative diagnostic test under very careful observation. Also, histamine from spoiled fish causing **scombroid fish poisoning.** Discussed in Katzung and discussed in more detail in the Lecture Slide (well worth knowing) and the basis of the attached Case Study. **Histamine Antagonists (Blockers):** Physiological Antagonist: **epinephrine** reverses the bronchoconstriction caused by histamine, this is a case of reversing the effect of drug or ligand A with drug B. Release Inhibitors: block the ability of the mast cell to release histamine drugs used in asthma coming up in asthma chapter, beta~2~ agonists can block histamine release also Histamine Blockers: 1957 first drugs used to block histamine (antihistamines) 1972 first H~2~ receptor blockers (used for heart burn) These will be covered in detail in the chapter on GI drugs coming up. **H~1~ Histamine Receptor Antagonists:** (trade names for information only, most are OTC) All are reversible competitive inhibitors (antagonists) First Generation (enter the CNS and induce sedation, not good if you have surgery to perform in the morning) **diphenhydramine** (Benadryl^^) **hydroxyzine** (Atarax^^) **brompheniramine** (Dimetane^^) **promethazine** (Phenergan^^) Second Generation (do not readily enter the CNS, less sedating to mostly non-sedating) **fexofenadine** (Allegra^^) **loratadine** (Claritin^^) **cetirizine** (Zyrtec^^) ADRs (some good and some bad) **Sedation**: mostly first generation, some are sold OTC as "sleep-aids." **Anti-nausea and antiemetic**: sold to prevent motion sickness, **doxylamine** sold for many years to prevent the nausea of the first trimester of pregnancy. Discussed in the Lecture Slides. **Anti-Parkinsonism** **Effects:** some first generation like **diphenhydramine** used to treat the motor disorders induced by some drugs, more coming up in another chapter on Parkinson's and motor disorders. **Anti-muscarinic Actions**: some first generation have an atropine like side effect, can cause urinary retention and blurred vision. **Adrenoceptor-Blocking Actions**: first generation, **promethazine**, can block alpha receptors and cause orthostatic hypotension. **Local Anesthetics:** first generations can act like local anesthetics through block of sodium axonal channels, **diphenhydramine** is a more potent local anesthetic compare to procaine. Lidocaine, coming up, works by blocking sodium channels in he axon. **Clinical Use of Anti-Histamines:** **Allergic Reactions:** to treat allergic rhinitis (hay fever), urticarial eruptions **Motion Sickness:** first generations, they enter the CNS, **diphenhydramine** and **promethazine** mostly used **Nausea and Vomiting of Pregnancy:** the **doxylamine** story, teratogenic effects and story in drug withdrawal from the market is discussed in the lecture slides. Think it is worth knowing? **ADRs: mostly covered above** **Serotonin (5HT): The next topic in this chapter** serotonin = 5-hydroxytryptamine (5-HT) serotonin is a neurotransmitter, a local hormone in the gut, component in the platelet clotting process, and may have an important role in migraine In the CNS, 5-HT is involved in mood, sleep, appetite, and temperature regulation, anxiety, migraine etc. Seven different 5-HT receptors, with too numerous sub-types to remember. **Tissue and Organ System Effects:** Nervous System: stimulates itch and pain in nerve endings (like histamine) following insect bite and dermal plant contact Respiratory System: stimulates bronchiolar smooth muscle Cardiovascular System: contracts vascular smooth muscle, except in the heart GI Tract: facilitates peristalsis Serotonin Syndrome: in the box on pg 298, discussed at length in the Lecture **Serotonin Agonists:** **buspirone**, a sedative drug used to treat anxiety **lorcaserin**, used to treat obesity **sumatriptan**, used to treat migraine, which may be caused by vasodilation (vessels **Serotonin Antagonists:** (Related Note: carcinoid tumors produce large amounts of 5-HT and must be blocked) **phenoxybenzamine**, already discussed in a previous chapter, used to block NE, EP, 5-HT in patients with adrenal tumors (pheochromocytomia). **ondansetron**, used to treat nausea and vomiting especially after gas anesthesia and cancer chemotherapy **The Ergot Alkaloids: (the last topic in this chapter)** The fungus *Claviceps purpurea* grows on grains, corn and grasses and secretes ergots. These ergots interact with a wide range of receptor types, they produce a potentially lethal condition called ergotism. Subjects who ingest grains (bread, tacos etc.) that contain ergots present with severe vasoconstriction of the digits (gangrene), hallucinations, stimulation of uterine smooth muscle (abortion). Book mentions St. Anthony's Fire and this was discussed in the Lecture Slides. (Sorry, but this is a topic of great interest to your teacher.) MOA of ergot alkaloids, wide range of actions at numerous different receptors that have already been covered (alpha, serotonin and dopamine receptors). Also keep in mind that there too many different ergots found on fungus infected plants to list them here. Only specific ones of clinical interest are discussed. **Organ System Effects:** CNS, **lysergic acid diethylamide (LSD)** is derived from ergot alkaloids, major hallucinations. **bromocriptine, cabergoline, pergolide,** all ergot derivatives, all act on dopamine receptors as agonists. A big deal coming up in the motor disease Parkinson Syndrome chapter. Vascular Smooth Muscle, **ergotamine** a potent vasoconstrictor which can lead to gangrene of toes and fingers. Uterine Smooth Muscle, induce prolonged contraction, **ergonovine**. **Clinical Uses:** Used mostly for treating migraine headaches and pituitary dysfunction. Migraine, **ergotamine** for its vasoconstrictive effects in the CNS Hypoprolactinemia, increased tumor production of prolactin by the pituitary can lead to serious metabolic problems (amenorrhea and infertility). **Bromocriptine** reduces prolactin levels Postpartum Hemorrhage, postpartum uterine bleeding can be stopped with the vasoconstriction induced by **ergonovine**. ADRs. include CNS hallucinations and vasoconstriction that can lead to gangrene in the digits. Usually high doses are required to achieve these effects. [Drugs Required in **Bold along with any drugs in bold in this Lecture Note.**] H1 Antihistamines First Generation **diphenhydramine** **chlorpheniramine** **doxylamine** Second Generation **cetirizine** **loratadine** **fexofenadine** H2 Antihistamines **cimetidine** (see in Chapter 62 p 1155 ff) Serotonin Agonists **sumatriptan** **lorcaserin** **almotriptan** Ergot Alkaloids Vasoselective **ergotamine** Uteroselective **ergonovine** CNS Selective **LSD**