Histamine, Serotonin and the Ergot Alkaloids

Histamine and 5-HT Histamine and Serotonin (5-HT) are biologically active amines that function as neurotransmitters They are often used in non-neural tissues

The Autocoids Histamine, serotonin and endogenous peptides, prostaglandins, leukotrienes, and cytokines are called autocoids, meaning “self-remedy” in Greek

Histamine Histamine is an important mediator of immediate allergic and inflammatory reactions Histamine also plays an important role in gastric acid secretions

Histamine Histamine also functions as a neurotransmitter and neuromodulator Histamine also plays an important role in chemotaxis of white blood cells

Histamine Histamine is formed from the amino acid histadine Immunologic processes account for the most important pathophysiologic mechanism of mast cell and basophil histamine release

Histamine Histamine and mast cells release histamine explosively when antigens come in contact with the cells IgE antibodies This degranulation of the mast cells and basophils require calcium and energy

Histamine Histamine is also released by damaged tissues Histamine causes vasodilation and capillary leakage, allowing plasma immune mediators to enter the area

Histamine Pharmacodynamics Histamine activates specific cellular receptors on surface membranes We know of 4 types of histamine receptors

Histamine Pharmacodynamics H1 receptors are found on smooth muscle and endothelium H2 are found on gastric mucosa

Histamine Pharmacodynamics H3 receptors are found in nerves in the gut responsible for peristalsis H4 receptors are found on white blood cells

Histamine Neural Action Histamine is a powerful stimulant of sensory nerve endings, especially those that mediate pain and itching

Histamine Vascular Action Histamine causes vasodilation and lowers blood pressure

Histamine Bronchiole Action Histamine causes bronchoconstriction because of bronchial smooth muscle constriction People with asthma are especially sensitive to histamine

Histamine Gut Action Histamine causes contraction of intestinal smooth muscle

Histamine Stomach Acid Secretion Histamine causes secretion of stomach acid secretion

Histamine Scombroid Poisoning Scombroid fish poisoning (scombrotoxism, scromboid ichthyotoxicosis) is a food-related illness typically associated with the consumption of fish Originally the illness was associated with scombroidea fish (e.g. large dark meat marine tuna, albacore, mackerel), however, we have identified the largest vector to be nonscombroid fish, such as mahi-mahi and amberjack

Histamine Scombroid Poisoning The principal agent in scombroid poisoning is histamine, along with other biologically active amines

Histamine Scombroid Poisoning Scombroid toxicity is usually self-limited but may cause significant discomfort. The onset of symptoms is usually 10-30 minutes after ingestion of the implicated fish, which is said to have a characteristic peppery bitter taste. The symptoms are nonspecific and may include the following:

Histamine Scombroid Poisoning Flushing Palpitations Headache Diarrhea Sense of anxiety or unease Prostration (complete physical or mental exhaustion) Loss of vision (rare) Diffuse, macular blanching erythema (most common) Tachycardia Wheezing (generally only in histamine-sensitive asthmatics) Hypotension or hypertension

Histamine Pharmacology Histamine is used clinically as a provocative test in pulmonary function tests It has no clinical use otherwise

Histamine Antagonism Histamine actions are the opposite effect of epinephrine, although different receptors and physiologic processes are involved Epinephrine is the physiologic antagonist of histamine

Histamine Antagonists Several histamine receptor antagonists or “blockers” have clinical usefullness H1 Antagonists – “Antihistamines” H2 Antagonists – “H2 Blockers”

Antihistamines H1 Antagonists Antihistamines exert their “antiallergy” properties by antagonizing histamine at the H1 receptor However, many of the actions of antihistamines have nothing to do with H1 receptor blockade

Antihistamines H1 Antagonists Sedation Anxiolytic effect Antinausea and motion sickness Antiparkinsonian effect Anticholinergic effect None of these effects are due to H1 antagonism

Antihistamines H1 Antagonists Serotonin Blockade Adrenergic Blockade None of these effects are due to H1 antagonism

Antihistamines H1 Antagonists Diphenhydramine (Benadryl) Antiallergy Antiparkinsonian Sedative

Antihistamines H1 Antagonists Hydroxyzine (Atarax) Antipruritic Anxiolytic

Antihistamines H1 Antagonists Meclizine (Bonine) Motion sickness Vertigo

Antihistamines H1 Antagonists Cyproheptadine (Periactin) H1 antagonist that also prevent serotonin production Indicated for allergy Indicated for serotonin syndrome

Antihistamines H1 Antagonist Newer generation H1 blockers have a more selective effect on H1 blockade - fexofenadine (Allegra) - Loratadine (Claritin) - Ceririzine (Zyrtec)

H2 Blockers H2 histamine receptor antagonists are used to prevent excess stomach acid Cimetidine (Tagamet) Famotidine (Pepcid) Nizatidine (Axid) Ranitidine (Zantac)

Serotonin 5-Hydroxytryptophan (5-HT) It has been known that when blood is allowed to clot, a vasoconstrictive substance is released from the clot This substance was called “serotonin”

Serotonin (5-HT) This substance was later found to have many other properties Serotonin is an important neurotransmitter, a local hormone in the gut, and is involved in migraine headaches

Serotonin (5-HT) Serotonin is synthesized from the amino acid tryptophan 5-HT is metabolized to 5-HIAA (5-hydroxyindoleacetic acid) by monoamine oxidase (MAO)

Carcinoid About 10% of carcinoid tumors secrete excessive serotonin (5-HT) Flushing Diarrhea Wheezing Abdominal cramping Peripheral edema

5-HIAA Carcinoid tumors can secrete excessive amounts of serotonin 24-hour urine secretion of 5-HIAA is a diagnostic test for carcinoid tumors

Serotonin (5-HT) There are many serotonin receptor subtypes mostly in the brain There are subtypes of serotonin receptors in the gut, smooth muscle, and platelets as well

Serotonin (5-HT) Serotonin has no clinical application as a drug But many serotonin agonists and antagonists have extensive clinical value

Serotonin (5-HT) Agonist Buspirone (Buspar) is a 5-HT1A agonist - nonbenzodiazepine anxiolytic

Serotonin (5-HT) Agonists Sumatriptan (Immitrex) is a 5-HT1D/1B agonist - migraine headache

Serotonin (5-HT) Agonists There are many “triptans” on the market for migraine headaches - sumatriptan (Immitrex) Naratriptan (Amerge) Almotriptan (Axert) Zolmitriptan (Zomig) Nizatriptan (Maxalt) Eletriptan (Relpax)

Serotonin (5-HT) SSRI are commonly prescribed for depression, anxiety, and obsessive compulsive disorders

Serotonin (5-HT) There are many SSRI’s in the markey - fluoxetine (Prozac) - sertraline (Zoloft) - paroxetine (Paxil) - citalopram (Celexa) - escitalopram (Lexapro)

Serotonin (5-HT) Antagonists Ondansetron (Zofran) is a 5-HT antagonist used for nausea and vomiting of cancer chemotherapy

Serotonin Syndrome Is a potentially fatal complication of excess synaptic serotonin by the use of one or more serotonin increasing drugs such as: - SSRI - MAOi - the migraine “triptans” - ondasetron (Zofran)

Serotonin Syndrome Presents clinically as: - Hypertension - hyperreflexia - tremor - hyperthermia - diarrhea - mydriasis - agitation - coma

Serotonin Syndrome Serotonin syndrome is treated with: - benzodiazepines Diazepam (Valium) crproheptadine (Periactin) An antihistamine that blocks serotonin production

The Ergot Alkaloids Are produced by a fungus that infects grains. This fungus claviceps purpurea, synthesizes histamine, acetylcholine, tyramine, and other biologically active products, in addition to a wide range of ergot alkaloids

Ergot Alkaloids These ergot alkaloids affect alpha adrenoreceptors, dopamine receptors, and serotonin receptors

Ergot Alkaloids Accidental ingestion of ergot alkaloids from moldy grain can be traced back over 2000 years Ergotism

Ergot Alkaloids The most dramatic effect being dementia, hallucinations, prolonged vasospasm, gangrene, and spontaneous abortion, one can imagine the social chaos and accusations of witchcraft and satanism associated with outbreaks of ergotism

Ergot Alkaloids But now we know that certain naturally occuring ergot alkaloids have hallucinatory properties LSD (lysergic acid diethylamide) is a synthetic ergot alkaloid with 5-HT2 properties

Ergot Alkaloids Bromocriptine is an ergot alkaloid with an agonist effect on dopamine receptors Bromocriptine (Parlodel) is used to treat Parkinson’s disease and treat pituitary adenomas that secrete prolactin

Ergot Alkaloids Ergotamine (Cafergot) is especially effective for migraine headache during the prodrome or “aura” phase