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Home , Antiemetic, Antihistamine, Autacoid, Azatadine, Decongestant, Doxylamine

Learning Objectives

I Pharmacological effects Histamine and Sites of action Conditions which cause release Aron H. Lichtman, Ph.D. Diagnostic uses Associate Professor II Antihistamines acting at the H1 and H2 and Pharmacological effects Mechanisms of action Therapeutic uses Side effects and interactions Be familiar with the existence of the H3 receptor III Be able to describe the main of cromolyn sodium and its clinical uses

Histamine Pharmacology First to be discovered. (Greek: autos=self; Histamine Formation akos=cure) Synthesized in 1907 Synthesized in mammalian tissues by Demonstrated to be a natural constituent of of the l- mammalian tissues (1927) Involved in inflammatory and anaphylactic reactions. Local application causes swelling redness, and , mimicking a mild inflammatory reaction. Large systemic doses leads to profound vascular changes similar to those seen after or anaphylactic origin

Histamine Stored in complex with:

Heparin Chondroitin Sulfate Eosinophilic Chemotactic Factor Neutrophilic Chemotactic Factor Proteases

1 Conditions That Release Histamine 1. injury: Any physical or chemical agent that injures tissue, skin or mucosa are particularly sensitive to injury and will cause the immediate release of histamine from mast cells.

2. Allergic reactions: exposure of an to a previously sensitized (exposed) subject can immediately trigger allergic reactions. If sensitized by IgE attached to their surface membranes will degranulate when exposed to the appropriate antigen and release histamine, ATP and other mediators.

3. and other foreign compounds: , dextran, antimalarial drugs, dyes, bases, , amides, quaternary ammonium compounds, (phospholipase C). Penicillins, Tetracyclines, Basic drugs- amides, amidines, diamidines, Toxins, venoms, Proteolytic enzymes, , , &

3 Types of Histamine Receptors Pharmacological Effects of Histamine 1. Cardiovascular system. 1. H1 receptors: mediate effects on a) triple effect on terminal vasculature (itching & ): leading to , increased vascular i. reddening at site due to vasodilation permeability, and contraction of nonvascular ii. wheal or disk of edema within 1 to 2 min iii. a large, bright crimson flare or halo surrounding the wheal smooth muscle. b) i.v. histamine: fall in pressure, cutaneous , over the face and upper trunk, rise in skin temperature, intense . 2. H receptors: mediate histamine stimulation of 2. Smooth muscle of ; causes contraction of nonvascular 2 smooth muscle. Asthmatics may experience marked bronchial and may be involved in constriction compared with normal subjects. cardiac stimulation. 3. Exocrine glands: potent stimulator of gastric secretion (HCl & ), enhances salivary and lacrimal gland secretion (minimal unless large doses are given), stimulates chromaffin cells in adrenal 3. H3 receptors: feedback inhibitors in CNS, medulla to secrete . , lung, . 4. Peripheral : itching and pain

Pharmacological Effects: Pharmacological Effects: Exocrine Glands Arterioles, & Venules

Gastric glands Salivary glands Vasodilation Sweat glands Pancreas Secretion Increased permeability, (edema) Bronchial glands Lacrimal glands Systemic

2 Pharmacological Effects Effects: Vascular Smooth Muscles Antihistamines Background

Daniel Bovet, Nobel Prize 1944 Bronchial tree Synthesized first antihistamines Compounds appeared to prevent the binding of histamine to H receptors through their Gastrointestinal tract Contraction 1 structural similarities

Uterus

General Mechanism of Action of Histamine vs. Antihistamines Cardiovascular Effects

Blocks action of histamine at receptor Histamine dilation of small blood vessels / increased Competes with histamine for binding permeability

Displaces histamine from receptor Antihistamine Most beneficial when given early prevents dilation / prevents increased permeability

Histamine Decreases Histamine vs. Antihistamine: Smooth Muscle Effects

Histamine Stimulates exocrine glands (salivary, gastric, lacrimal, & bronchial )

Antihistamine prevents: salivary, gastric, lacrimal, & bronchial secretions

3 Histamine vs. Antihistamine: Diagnostic Uses of Histamine Immune Effects

Histamine 1. Sampling gastric acid content, 1 mg histamine mast release: histamine & other substances released subcutaneously to stimulate gastric secretion (no major effects on blood vessels).

Antihistamine 2. Pulmonary (for diagnosing ). bind to receptors and prevents histamine from eliciting a response 3. Sensory function.

Therapeutic Uses of H1 Blockers Actions Not Caused by H1 Receptor Blockade 1. Allergic , relieves , sneezing, and itching of eyes and nasal mucosa. 1. antinausea and effects 2. : palliative, dries out the nasal mucosa. Often combined with nasal and . (antimuscarinic effects) 3. Allergic dermatoses: can control itching associated with insect bites. 2. antiparkinsonism effects (antimuscarinic 4. Outpatient procedures for preanesthetic sedation and prevention of effects) and ( (Phenergan)). Phenergan also inhibits salivary and bronchial secretions and can be used as a local 3. peripheral antimuscarinic effects . 4. adrenoceptor-blocking actions 5. Antiemetic: prevention or treatment of nausea and vomiting () (Bendectin, with ). 6. : limited value. 5. manifested as orthostatic hypotension 7. Other uses: 6. -blocking action () a. Reduction of tremors and muscle rigidity in Parkinson's disease 7. , blockade of sodium channels b. Treatment of ( and promethazine)

Toxic Reactions & Side Effects of Mechanism of Action: H1 Antagonists H1 Blockers 1. CNS depression (mainly in first generation agents). Displaces histamine from the H1 receptor, which is a G- coupled receptor 2. Allergic reactions (topical application). 3. loss, nausea and vomiting, or Histamine leads to formation of IP3 and a release . of stored Ca++, followed by a cascade of other 4. , tremors, nervousness, irritability, events. tachycardia, dry mouth, blurred vision, , constipation (1st generation). 5. CNS stimulation with hallucinations, motor H1 receptor blockade prevents this activity and leads to a decrease in Ca++ inside of the cell disturbances (tremors and convulsions), and death. 6. Secreted in breast milk and can cross the placenta.

4 Drug Interactions of H1 Blockers First Generation Antihistamines 1. Antihistamines that produce sedation can potentiate CNS (e.g., , opiates, general Side Effects , and ) Sedating 2. Antihistamines that possess actions can produce manifestations of excessive blockade if Anticholinergic given with anticholinergic drugs (e.g., dry mouth, Many available Over- the- Counter (OTC) constipation, or blurred vision) Inexpensive (Average $4.50/pack) 3. (Seldane) taken with grapefruit juice or or other drugs that inhibit the , 56% of sufferers use OTC, but only CYP3A4 can lead to cardiac . Taken off the $325 million in sales market.

First Generation Antihistamines First Generation Antihistamines (Alkylamines) 1. Alkylamines Chlorpheniramine maleate 2. (Chlor Trimeton®) 3. Schering (1949) 4. Currently sold OTC by 5. Phenothiazines Schering-Plough 6. Piperadines Healthcare Products

First Generation Antihistamines (Ethanolamines) First Generation Antihistamines (Piperadines)

Diphenhydramine HCl (®) Parke Davis (1946) (Optimine®) Currently sold OTC by , Schering (1977) Inc., Warner -Lambert Available only by Consumer Healthcare prescription

5 First Generation Antihistamines First Generation Antihistimines (Piperazines) (Phenothiazines) HCl (Atarax®) Promethazine HCl (Phenergan®) Pfizer (1956) (1951) Available only by prescription Available only by prescription

Second Generation Antihistamines: Second Generation Antihistamines Terfenadine (Seldane®) Non-sedating Generally do not cause the sedation and drying seen Caused fatal heartbeat irregularities when taken with in first generation antihistamines certain drugs and foods Do not cross the blood- barrier as readily as Ketoconozole, erithromycin, grapefruit juice First Generation compounds interfered with drug increasing the concentration of terfenadine in bloodstream Lipophobicity Removed from the market (1992) Large molecular size Electrostatic charge

Second Generation Antihistamines: Second Generation Antihistamines: HCl(Allegra®) (Claritin®) Safe of Terfenadine FDA approved on July 25, 1996 Schering-Plough, Inc. FDA approved 1993 Non-sedating (FAA, Air force, Navy approved) Developed from Azatadine Clinical studies showed no cardiac side effects Non-sedating (FAA, Air force, Navy approved) No reported cardiac side effects up to 160 mg

6 Second Generation Antihistamines: Specificity of Selected H Blockers (Zyrtec®) 1

Pfizer, Inc and UCB Pharma Inc. FDA approved 1995 Metabolite of hydroxyzine Effective against / No reported cardiac side effects Potential for sedation

H2 Antagonist Pharmacological Effects 1. Competitive antagonists at the H receptors OTC Available H Antagonists 2 2 2. Inhibits secretory function of . 3. Few other effects than those on gastric secretion. 4. Reduces gastric acid volume & concentration of pepsin 1. (Tagamet) associated with most side effects Most Common Adverse Effects 1. Diarrhea 2. rantidine (Zantac) 2. Dizziness 3. (Pepcid) 3. 4. (Axid) 4. Headache 5. Rash 6. Constipation 7. Vomiting 8. Arthralgia

H2 Blockers Decrease Gastric Acid H Antagonist Therapeutic Uses Release 2 1. Duodenal ulcer 2. Gastric ulcer 3. Zollinger-Ellison syndrome (a pathological hypersecretory state resulting in excessive gastric pepsin & HCl) 4. Gastroesophageal reflux disease 5. Used prior to surgery in patients with GI obstruction to elevate gastric pH 6. Reflux 7.

7 Toxic Reactions (Mostly Associated With Cimetidine (Tagamet)) H2 Antagonists: Mechanisms of Action 1. Most common (seen in only 1-2% of patients): diarrhea, dizziness, somnolence, headache, and rash. Displaces histamine from the H receptor, a Also constipation, vomiting and arthralgia. 2 2. CNS effects: slurred speech, delirium, confusion. G-protein coupled receptor Most commonly seen in older patients or those with Because histamine activates cAMP, H2 or kidney impairment blockers lead to a decrease in cAMP and 3. Endocrine function (minor and reversible): a concomitant decrease in Ca++ effects, e.g., loss of libido, impotence, reduced sperm count 4. Blood dyscrasias. 5. Liver: reversible cholestasis.

H2 Antagonist H3 Receptor Drugs Cimetidine: increased activity of drugs that are metabolized through pathway and also reduces Believed to act as feedback inhibitors in a wide variety of systems in the CNS, cause sedation blood flow through the liver including. e.g., , , propanolol, , , , GI: agonists down regulate histamine. Thereby decreasing , , , , , and calcium channel blockers. Lung: agonists have a bronchodilatory effect

All H2 blockers except famotidine (Pepcid) increase the of ethanol. Clinical Uses Agents that inhibit gastric secretion alter the bioavailability None (Drugs are available only for research purposes) and rate of absorption of many other drugs Mechanisms of Action G-protein coupled receptor, decreases of intracellular Ca++

Inhibitors of Histamine Release Histamine Release Inhibitors: Cromolyn sodium (Intal, Nasalcrom) Therapeutic Uses Sodium mild to moderate bronchial asthma to prevent asthma attacks. in vitro studies : Reduces the release of histamine, other granular contents & production. effective in children Devoid of bronchodilating capability reduces need of or Inhibits pulmonary in response to a ineffective for an acute attack variety of stimuli including the interaction between cell- becomes effective over time (e.g. 2-3 weeks) bound IgE and specific antigen. Does not relax bronchial or other smooth muscle in vitro or, atopic diseases of the eye in the short term, in vivo. However, long term giant papillary conjuctivitis administration diminishes bronchial hyperactivity.

8 Histamine Release Inhibitors Learning Objectives I Histamine Dosage form Pharmacological effects aerosol powder (Intal) and solution - asthma Sites of action (Nasalcrom) - allergic rhinitis Conditions which cause release Diagnostic uses optic solution 4% - (Opticrom) - allergic II Antihistamines acting at the H1 and H2 receptor Pharmacological effects Toxicity Mechanisms of action well tolerated, few adverse reactions Therapeutic uses irritation due to powder inhalation Side effects and drug interactions Be familiar with the existence of the H3 receptor Stinging, Burning, Bad Taste III Be able to describe the main mechanism of action of Coughing, sneezing, allergic reactions cromolyn sodium and its clinical uses

Practice Questions Practice Questions 1) Which of the following antihistamines is most likely to 3) Which of the following statements about antihistamines are correct? potentiate the CNS effects of alcohol? A. antihistamines prevent histamine release A. Promethazine (Phenergan) B. antihistamines produce their effects through competition at the B. Loratadine (Claritin) receptor C. Rantidine (Zantac) C. antihistamines promote histamine degradation D. Chlorpheniramine (Chlor-Trimeton) D. antihistamines prevent histamine synthesis E. none of the above E. all of the above statements are correct

2) Rantidine (Zantac), an H2 , is most likely to 4) Which of the following effects is NOT associated with histamine? produce which of the following effects? A. triple effect A. inhibition of the "triple effect" of histamine B. progressive fall in blood pressure B. inhibition of gastric secretions C. headache C. inhibition of nausea and vomiting D. secretion of catecholamines from chromaffin cells in adrenal D. sedation medulla E. inhibition of salivary and bronchial secretions E. sedation

Practice Questions Practice Questions 5) Which of the following drugs would be the best treatment for 7) Antihistamines acting at the ______receptor are most likely to allergic rhinitis if you operated heavy machinery? ______.

A. diphenhydramine (Benadryl) A. H1 receptor; inhibit the "triple effect" of histamine B. nizatidine (Axid) B. H2 receptor; inhibit the "triple effect" of histamine C. promethazine (Phenergan) C. H1 receptor; reverse D. fexofenadine (Allegra) D. H2 receptor; reverse anaphylaxis E. rantidine (Zantac) E. H1 receptor; block gastric secretions

6) Nizatidine (Axid) an H2 antagonist, can be effectively used for 8) Which of the following effects is most commonly associated with the control of _____. histamine? A. itching associated with insect bites A. progressive increase in blood pressure B. asthma B. progressive decrease in blood pressure C. C. decrease in gastric secretions D. the triple effect D. triple effect E. insomnia E. sedation

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