1. Stinging Nettle (Urtica dioica) Defense mechanism: The nettle is covered with hairs that resemble syringes. When contact is made with the hairs, they break off and inject a chemical mixture onto the skin which causes severe inflammation and irritation. This mixture is composed of histamine, acetylcholine, 5-hydroxytryptamine, and small amounts of formic acid.

2. Histamine:  Histamine:  synthesized in 1907 and  later isolated from mammalian tissues;  In humans,  important mediator of immediate allergic and inflammatory reactions,  has an important role in gastric acid secretion;  functions as neurotransmitter  T cell neutrophil and eosinophil chemotaxis

3. Histamine:  Sources:  Plants  Animals  Component of some venoms and stinging secretions  Formed by  decarboxylation of the amino acid L-histidine,  catalyzed in mammalian tissues by enzyme histidine decarboxylase  Destiny  either stored or rapidly inactivated

4. Histamine:  Most histamine is sequestered in tissue and bound in granules (vesicles) in mast cells or basophils; and blood  The histamine content of many tissues is directly related to their mast cell content (such as skin, bronchial mucosa, and intestinal mucosa.)  Bound form is biologically inactive, but many stimuli triggers the release of histamine, allowing the free histamine to exert actions on surrounding tissues

5. Mast cells degranulating and releasing vasoactive amines.

6. Histamine:  Non-mast cell histamine is found in  brain, functions as a neurotransmitter  Skin  Intestinal mucosa  Entero-chromaffin-like cells (ECL) fundus of the stomach; release histamine,  acid-producing parietal cells of mucosa

7. Food containing histamine  Result of microbial enzymes  Histidine (present in all proteins) to histamine. All foods subjected to microbial fermentation cheeses, fermented soy products, other fermented foods, alcoholic beverages, and vinegars;  Tomatoes,  Eggplant,  Spinach,  Tuna  Avocado

8. Histamine Releasing Foods Include:  Alcohol  Bananas  Chocolate  Eggs  Fish  Milk  Papayas  Pineapple  Shellfish  Strawberries  Tomatoes

9. Histamine (mechanism of action)  Histamine exerts its action by combining with specific cellular serpentine receptors located on the surface membrane (H 1 -H 4 );  In the brain, H 1 and H 2 receptors are located on postsynaptic membranes, while H 3 receptors are predominantly presynaptic

10. Histamine (mechanism of action)  H1 receptor play an important role in inflammation and allergic reactions  H2 receptors are important in gastric acid secretion  H3 receptors are involved in the feedback control of histamine synthesis and release  H 4 receptors are associated with induction chemotaxis, secretion of cytokines and upregulation of adhesion molecules

11. Tissue and organ system effects of Histamine 1. Nervous system: powerful stimulant of sensory nerve endings, especially those mediating pain and itching 2. CVS: decrease in systolic and diastolic BP (indirect vasodilation, NO) and an increase in HR 3. Bronchiolar smooth muscle: bronchoconstriction mediated by H1 receptors 4. GIT smooth muscle: contraction, may cause diarrhea 5. Secretory tissue: powerful stimulant of gastric acid secretion 6. The “ triple response ” :

12. The “ Wheal-and-Flare ” response  Intradermal injection of histamine causes a characteristic weal-and-flare response that was first described over 60 years ago 1. At site of injection, a reddening appears owing to dilation of small vessels, followed by; 2. An edematous wheal at the injection site and 3. A red irregular flare surrounding the wheal;

13. Histamine Toxicity from Ingestion  Food poisoning….from spoiled scombroid fish (as tuna)  The high histidine content combines with a large bacterial capacity to decarboxylate histidine, generating a lot of histamine  Causes severe nausea, vomiting, headache, flushing, and sweating  Can also follow red wine consumption in persons with a diminished ability to degrade histamine  Suppressed by H 1 antagonists

14. Clinical use of histamine:  NO other current clinical applications  In pulmonary function laboratories, histamine aerosol is sometimes used as a provocative test of bronchial hyperreactivity;  Antihistamines are among the most commonly used medications in the world  2 main categories: H1 receptor blocking agent and H2 receptor blocking agent

15. Classification  H 1 antagonists are divided into 1 st and 2 nd generation;  1 st generation has strong sedative effects (enter the CNS) and can block autonomic receptors  2 nd generation: incomplete distribution to CNS  less sedation

17. H 1 Receptor Antagonists  Competitive antagonists of H1 receptor found in many OTC and prescription medication alone or in combined formulation  Major therapeutic uses: 1. motion sickness, 2. control of allergy-related itching, 3. cough and cold palliation 4. and used as sleep aids

18. Pharmacokinetics  Drug absorption may be delayed due to the pharmacologic effects of these agents on the GI tract  Volumes of distribution are generally large (3–20 L/kg)  Elimination half-lives are highly variable, ranging from 1–4 hours for diphenhydramine to 7–24 hours for many of the others  Converted to active or inactive metabolite in the liver and then excreted in the urine  Drugs that inhibit CytP450 may lead to its accumulation (ketoconazole)

19. Toxicity:  H1 antagonists are rarely ingested for suicidal purposes and have a high therapeutic/toxic ratio  Wide spectrum of side effects  Sedation, antimuscarinic action  most common undesirable actions

20. Toxicity:  Toxic dose. The estimated fatal oral dose of diphenhydramine is 20–40 mg/kg  In general, toxicity occurs after ingestion of 3–5 times the usual daily dose  Children are more sensitive to the toxic effects of antihistamines than are adults  The non-sedating agents are associated with less toxicity

21. Toxicity:  CNS: sedation (most common with 1 st generation), coma, delirium, hallucinations, psychomotor agitation (myoclonic or choreoathetoid movements), or convulsions  Anticholinergic effects: hyperpyrexia, tachycardia, HTN, urinary retention, dilated pupils, dry mouth  Reports of cholinergic toxicity upon stopping taking the drug

22. Toxicity:  CV effects: massive diphenhydramine overdose has been reported to cause myocardial depression and QRS widening….similar to TCAs overdose  Overdosage of astemizole or terfenadine may induce cardiac arrhythmias through QT prolongation (removed from the US market)

23. Drug Interactions:  Arrhythmia occur particularly when taken with P450 inhibitor (erythromycin, ketoconazole, grapefruit juice….)  Significant sedation when taken with alcohol, benzodiazepines  C/I while driving or operating machinery

24. Treatment  Treatment is supportive…. stabilization and reduce amount absorbable 1. Maintain an open airway and assist ventilation if necessary 2. Treat coma, seizures, hyperthermia, and atypical ventricular tachycardia if they occur 3. Monitor the patient for at least 6–8 hours after ingestion.

25. Treatment  Decontamination:  Administer activated charcoal orally  Gastric lavage not necessary  N.B: GI decontamination helpful even in late-presenting patients because of slowed GI motility  Enhanced elimination  Hemodialysis, hemoperfusion, peritoneal dialysis, and repeat-dose activated charcoal are not effective in removing antihistamines

26. Treatment  There is no specific antidote for antihistamine overdose  Physostigmine used for the treatment of severe delirium or tachycardia  Not recommended routinely! may cause toxic effects as seizures, bronchoconstriction, bradycardia, asystole (may need to be reversed by atropine)