1. Histamine, Serotonin and the Ergot Alkaloids

2. 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

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

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

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

6. 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

7. 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

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

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

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

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

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

14. Histamine Vascular Action
Histamine causes vasodilation and lowers blood pressure

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

16. Histamine Gut Action
Histamine causes contraction of intestinal smooth muscle

17. Histamine Stomach Acid Secretion
Histamine causes secretion of stomach acid secretion

18. 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

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

20. Histamine Scombroid Poisoning
Scombroid toxicity is usually self-limited but may cause significant discomfort. The onset of symptoms is usually 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:

21. 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

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

24. 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

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

26. 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

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

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

29. Antihistamines H1 Antagonists
Diphenhydramine (Benadryl)
Antiallergy
Antiparkinsonian
Sedative

30. Antihistamines H1 Antagonists
Hydroxyzine (Atarax)
Antipruritic
Anxiolytic

31. Antihistamines H1 Antagonists
Meclizine (Bonine)
Motion sickness
Vertigo

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

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

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

36. 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”

37. 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

38. 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)

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

40. 5-HIAA Carcinoid tumors can secrete excessive amounts of serotonin
24-hour urine secretion of 5-HIAA is a diagnostic test for carcinoid tumors

41. 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

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

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

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

45. 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)

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

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

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

49. 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)

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

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

52. 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

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

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

55. 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

56. 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

57. 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

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