pharmolacology and toxicology
pharmolacology and toxicology Pharmacology and Toxicology
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Pharmacology and Toxicology
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This 9 page Study Guide was uploaded by Jren0330 on Friday March 4, 2016. The Study Guide belongs to Pharmacology and Toxicology at Republic Polytechnic taught by - in Spring 2016. Since its upload, it has received 37 views. For similar materials see Science in Science at Republic Polytechnic.
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Date Created: 03/04/16
Learning Objectives I Histamine Pharmacological effects Sites of action Histamine and Antihistamines Conditions which cause release Aron H. Lichtman, Ph.D. Diagnostic uses Associate Professor II Antihistamines acting at the H1 and H2 receptor Pharmacological effects Pharmacology and Toxicology Mechanisms of action Therapeutic uses Side effects and drug interactions Be familiar with the existence of the H3 receptor III Be able to describe the main mechanism of action of cromolyn sodium and its clinical uses Histamine Pharmacology First autacoid 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 mammalian tissues (1927) decarboxylation of the amino acid l-histidine Involved in inflammatory and anaphylactic reactions. Local application causes swelling redness, and edema, mimicking a mild inflammatory reaction. Large systemic doses leads to profound vascular changes similar to those seen after shock or anaphylactic origin Histamine Stored in complex with: Heparin Chondroitin Sulfate Eosinophilic Chemotactic Factor Neutrophilic Chemotactic Factor Proteases 1 Conditions That Release Histamine 1. Tissue 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 antigen to a previously sensitized (exposed) subject can immediately trigger allergic reactions. If sensitized by IgE antibodies attached to their surface membranes will degranulate when exposed to the appropriate antigen and release histamine, ATP and other mediators. 3. Drugs and other foreign compounds: morphine, dextran, antimalarial drugs, dyes, antibiotic bases, alkaloids, amides, quaternary ammonium compounds, enzymes (phospholipase C). Penicillins, Tetracyclines, Basic drugs- amides, amidines, diamidines, Toxins, venoms, Proteolytic enzymes, Bradykinin, Kallidin, & Substance P Pharmacological Effects of Histamine 3 Types of Histamine Receptors 1. Cardiovascular system. 1. H 1eceptors: mediate effects on smooth muscle a) triple effect on terminal vasculature (itching & pain): leading to vasodilation, increased vascular i. reddening at injection 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 blood pressure, cutaneous flushing, over the face and upper trunk, rise in skin temperature, intense headache. 2. Smooth muscle of bronchioles; causes contraction of nonvascular 2. H 2 receptors: mediate histamine stimulation of smooth muscle. Asthmatics may experience marked bronchial gastric acid secretion and may be involved in constriction compared with normal subjects. cardiac stimulation. 3. Exocrine glands: potent stimulator of gastric secretion (HCl & pepsin), enhances salivary and lacrimal gland secretion (minimal 3. H receptors: feedback inhibitors in CNS, unless large doses are given), stimulates chromaffin cells in adrenal 3 medulla to secrete catecholamines. gastrointestinal tract, lung, heart. 4. Peripheral Nervous system: itching and pain Pharmacological Effects: Pharmacological Effects: Arterioles, Capillaries & Venules Exocrine Glands Gastric glands Vasodilation Salivary glands Sweat glands Pancreas Secretion Increased permeability, (edema) Bronchial glands Lacrimal glands Systemic hypotension 2 Pharmacological Effects Effects: Antihistamines Background Vascular Smooth Muscles Daniel Bovet, Nobel Prize 1944 Synthesized first antihistamines Bronchial tree Compounds appeared to prevent the binding Gastrointestinal tract of histamine to 1 receptors through their Contraction structural similarities Uterus General Mechanism of Action of Histamine vs. Antihistamine 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 Blood Pressure Histamine vs. Antihistamine: Smooth Muscle Effects Histamine Stimulates exocrine glands (salivary, gastric, lacrimal, & bronchial secretions) Antihistamine prevents: salivary, gastric, lacrimal, & bronchial secretions 3 Histamine vs. Antihistamine: Immune Effects Diagnostic Uses of Histamine Histamine mast cell release: histamine & other substances 1. Sampling gastric acid content, 1 mg histamine released subcutaneously to stimulate gastric secretion (no major effects on blood vessels). Antihistamine 2. Pulmonary function (for diagnosing asthma). bind to receptors and prevents histamine from eliciting a response 3. Sensory nerve function. Therapeutic Uses of H Blockers 1 Actions Not Caused by H Recepto1 Blockade 1. Allergic rhinitis, relieves rhinorrhea, sneezing, and itching of eyes and nasal mucosa. 1. antinausea and antiemetic effects 2. Common cold: palliative, dries out the nasal mucosa. Often (antimuscarinic effects) combined with nasal decongestant and analgesics. 3. Allergic dermatoses: can control itching associated with insect bites2. antiparkinsonism effects (antimuscarinic 4. Outpatient procedures for preanesthetic sedation and prevention of effects) nausea and vomiting (Promethazine (Phenergan)). Phenergan also 3. peripheral antimuscarinic effects inhibits salivary and bronchial secretions and can be used as a local anesthetic. 4. adrenoceptor-blocking actions 5. Antiemetic: prevention or treatment of nausea and vomiting (phenothiazines) (Bendectin, doxylamine with pyridoxine). 6. Hypnotics: limited value. 5. manifested as orthostatic hypotension 7. Other uses: 6. serotonin-blocking action (cyproheptadine) a. Reduction of tremors and muscle rigidity in Parkinson's disease 7. local anesthesia, blockade of sodium channels b. Treatment of migraine headaches (diphenhydramine and promethazine) Toxic Reactions & Side Effects of Mechanism of Action: H Antagonists1 H Blockers 1 Displaces histamine from the H re1eptor, which 1. CNS depression (mainly in first generation agents). is a G-protein coupled receptor 2. Allergic reactions (topical application). 3. Appetite loss, nausea and vomiting, constipation or Histamine leads to formation of IP3 and a release diarrhea. ++ 4. Insomnia, tremors, nervousness, irritability, of stored Ca , followed by a cascade of other tachycardia, dry mouth, blurred vision, urinary events. st retention, constipation (1neration). H 1eceptor blockade prevents this activity and 5. CNS stimulation with hallucinations, motor 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 H Blocker1 First Generation Antihistamines 1. Antihistamines that produce sedation can potentiate CNS depressants (e.g., barbiturates, opiates, general Side Effects anesthetics, and alcohol) Sedating 2. Antihistamines that possess anticholinergic 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) 3. Terfenadine (Seldane) taken with grapefruit juice or Inexpensive (Average $4.50/pack) erythromycin or other drugs that inhibit the enzyme, 56% of allergy sufferers use OTC, but only CYP3A4 can lead to cardiac toxicity. Taken off the $325 million in sales market. First Generation Antihistamines First Generation Antihistamines (Alkylamines) 1. Alkylamines Chlorpheniramine maleate 2. Ethanolamines (Chlor Trimeton®) 3. Ethylenediamines Schering (1949) 4. Piperazines Currently sold OTC by 5. Phenothiazines Schering-Plough 6. Piperadines Healthcare Products First Generation Antihistamines (Ethanolamines) First Generation Antihistamines (Piperadines) Diphenhydramine HCl (Benadryl®) Parke Davis (1946) Azatadine (Optimine®) Schering (1977) Currently sold OTC by Pfizer, Inc., Warner -Lambert Available only by Consumer Healthcare prescription 5 First Generation Antihistamines First Generation Antihistimines (Piperazines) (Phenothiazines) Hydroxyzine HCl (Atarax®) Promethazine HCl (Phenergan®) Pfizer (1956) Wyeth (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 certain drugs and foods in first generation antihistamines Ketoconozole, erithromycin, grapefruit juice Do not cross the blood-brain barrier as readily as interfered with drug metabolism increasing the First Generation compounds Lipophobicity concentration of terfenadine in bloodstream Large molecular size Removed from the market (1992) Electrostatic charge Second Generation Antihistamines: Second Generation Antihistamines: Fexofenadine HCl(Allegra®) Loratadine (Claritin®) Safe metabolite 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 Cetirizine (Zyrtec®) 1 Pfizer, Inc and UCB Pharma Inc. FDA approved 1995 Metabolite of hydroxyzine Effective against rash/hives No reported cardiac side effects Potential for sedation H A2tagonist Pharmacological Effects 1. Competitive antagonists at the H receptors OTC Available H Antagon2sts 2. Inhibits secretory function of gastric mucosa. 3. Few other effects than those on gastric secretion. 4. Reduces gastric acid volume & concentration of pepsin 1. cimetidine (Tagamet) associated with Most Common Adverse Effects most side effects 2. rantidine (Zantac) 1. Diarrhea 2. Dizziness 3. famotidine (Pepcid) 3. Somnolence 4. nizatidine (Axid) 4. Headache 5. Rash 6. Constipation 7. Vomiting 8. Arthralgia H 2lockers 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 esophagitis 7. Antacid 7 Toxic Reactions (Mostly Associated H 2ntagonists: Mechanisms of Action With Cimetidine (Tagamet)) 1. Most common (seen in only 1-2% of patients): diarrhea, dizziness, somnolence, headache, and rash. Also constipation, vomiting and arthralgia. Displaces histamine from the H rec2ptor, a 2. CNS effects: slurred speech, delirium, confusion. G-protein coupled receptor Most commonly seen in older patients or those with Because histamine activates cAMP, H 2 liver or kidney impairment blockers lead to a decrease in cAMP and 3. Endocrine function (minor and reversible): a concomitant decrease in Ca ++ antiandrogen effects, e.g., loss of libido, impotence, reduced sperm count 4. Blood dyscrasias. 5. Liver: reversible cholestasis. H A2tagonist Drug Interaction H 3eceptor Drugs Cimetidine: increased activity of drugs that are metabolized through cytochrome P450 pathway and also reduces Believed to act as feedback inhibitors in a wide variety of blood flow through the liverincluding. e.g., warfarin, organ systems in the CNS, agonists cause sedation GI: agonists down regulate histamine. Thereby decreasing phenytoin, propanolol, metoprolol, quinidine, caffeine, gastrin lidocaine, theophylline, benzodiazepines, ethanol, Lung: agonists have a bronchodilatory effect tricyclic antidepressants, and calcium channel blockers. All H blockers except famotidine (Pepcid) increase the bioavailability 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 Nedocromil Sodium mild to moderate bronchial asthma to prevent asthma attacks. in vitro studies : Reduces the release of histamine, other effective in children granular contents & leukotriene production. Devoid of bronchodilating capability reduces need of steroid or bronchodilators Inhibits pulmonary mast cell degranulation 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. allergic rhinitis Does not relax bronchial or other smooth muscle in vitro or, atopic diseases of the eye in the short terin vivo. However, long term giant papillary conjuctivitis administration diminishesbronchial hyperactivity. 8 Histamine Release Inhibitors Learning Objectives I Histamine Dosage form Pharmacological effects Sites of action aerosol powder (Intal) and solution - asthma nasal spray (Nasalcrom) - allergic rhinitis Conditions which cause release Diagnostic uses optic solution 4% - (Opticrom) - allergic conjunctivitis II Antihistamines acting at the H1 and H2 receptor Pharmacological effects Toxicity Mechanisms of action well tolerated, few adverse reactions Therapeutic uses Side effects and drug interactions irritation due to powder inhalation 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 depressant 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), an2Hreceptor antagonist, 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. H receptor; inhibit the "triple effect" of histamine 1 B. nizatidine (Axid) B. H 2eceptor; inhibit the "triple effect" of histamine C. promethazine (Phenergan) C. H 1eceptor; reverse anaphylaxis D. fexofenadine (Allegra) D. H 2eceptor; reverse anaphylaxis E. rantidine (Zantac) E. H 1eceptor; block gastric secretions 6) Nizatidine (Axid) an 2 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. indigestion C. decrease in gastric secretions D. the triple effect D. triple effect E. insomnia E. sedation 9
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