Ebook Essentials of pharmacology for anesthesia, pain medicine and critical care: Part 2

(BQ) Part 2 book Essentials of pharmacology for anesthesia, pain medicine and critical care presents the following contents: Histamine modulators, central nervous system stimulants, antiepileptic agents, chemotherapeutic agents, minerals and electrolytes, psychopharmacologic agents and psychiatric drug considerations,...

Chapter 22 Histamine Modulators Michael Yarborough and Judy G Johnson Contents Introduction Drug Class and Mechanism of Action Indications and Clinical Pearls Drug Interactions/Side Effects/Black Box Warnings Cardiac Effects CNS Effects Summary Chemical Structures References 365 366 367 374 374 375 377 377 378 Introduction Discovery of certain chemicals to counteract the effects of histamine occurred in the early twentieth century The development of a drug that would alleviate allergic reactions such as itchy, watery eyes, and a runny nose from a cold or hay fever had an astronomical effect on the medical community By the 1950s, antihistamines were being mass-produced in the USA and prescribed extensively as the drug of choice for those suffering from allergies The public perceived antihistamines as the “wonder drug” and with the misconception that it was a “cure all” to the common cold Eventually, scientist began to discover additional indications for the use of antihistamines These compounds continue to be one of the most universal drugs lining the shelves of local pharmacies However, the plethora of roles that antihistamines play in the treatment of the human condition is much more extensive, including suppression of allergy symptoms, sedative agents, and antiemetic actions to name a few M Yarborough, MD Department of Anesthesiology, Tulane Medical Center, New Orleans, LA, USA e-mail: myarboro@tulane.edu J.G Johnson, MD (*) Department of Anesthesiology, Louisiana State University, New Orleans, LA, USA A.D Kaye et al (eds.), Essentials of Pharmacology for Anesthesia, Pain Medicine, and Critical Care, DOI 10.1007/978-1-4614-8948-1_22, © Springer Science+Business Media New York 2015 365 366 M Yarborough and J.G Johnson Drug Class and Mechanism of Action Histamine is involved in local immune responses as well as regulation of physiologic functions in the gut It can also act as a neurotransmitter Histamine is made and released by different cells, i.e., basophils, mast cells, platelets, histaminergic neurons, lymphocytes, and enterochromaffin cells It is stored in vesicles or granules awaiting release upon stimulation [1] As part of an immune response to foreign pathogens, histamine increases the permeability of capillaries to white blood cells and other proteins in order to allow them to engage foreign invaders in the infected tissues Clinical effects of histamine result in increased vascular permeability and leakage of plasma proteins, causing fluid to escape from capillaries into the tissues [2] This leads to the classic symptoms of an allergic reaction such as a localized rash, itching, puffy and watery eyes, nasal congestion, and rhinorrhea There are four known human histamine receptors that have been identified (Table 22.1) These receptors belong to the G-protein-coupled receptors family They are signified as H1, H2, H3, and H4 Stimulation of the H1 receptor can activate intracellular signaling pathways leading to the development of classic allergic symptoms [1] Historically, antihistamines were noted to cause a parallel displacement in the histamine concentration/response This behavior was consistent with a competitive inhibition for histamine receptors, lending to the classification as the H1 receptor antagonists With further research, it was found that the antihistamines are in the class that are now called inverse agonists Table 22.1 Histamine receptors classification Receptor type Tissue location H1 Airway and vascular smooth muscles, endothelial, central nervous system (nerve cells), neutrophils, eosinophils, monocytes H2 H3 H4 Nerve cells, vascular smooth muscles and parietal cells, hepatocytes, endothelial cells, epithelial cells, neutrophils, eosinophils, monocytes Histaminergic neurons, eosinophils Found primarily in the central nervous system, low expression in peripheral tissues High expression in bone marrow and peripheral hematopoietic cells Low expression in nerve cells, hepatocytes, spleen, thymus, small intestine, colon, heart Intracellular function Cause bronchial smooth muscle contraction, separation of endothelial cells causing hives, pain, and itching Allergic reaction symptoms, motion sickness, and regulation of sleep Vasodilation and stimulation of gastric acid secretion Inhibits histamine release and synthesis Decreases release of serotonin, acetylcholine, and norepinephrine Stimulates chemotaxis of eosinophils and mast cells 22 Histamine Modulators 367 Table 22.2 Chemical classifications of antihistamines Alkylamines Ethanolamines Ethylenediamines Phenothiazines Piperidines Piperazines Brompheniramine, chlorpheniramine, dexchlorpheniramine, pheniramine, triprolidine Carbinoxamine, clemastine, dimenhydrinate, diphenhydramine, doxylamine, orphenadrine Pyrilamine, tripelennamine Methdilazine, promethazine, trimeprazine Cyproheptadine, fexofenadine, desloratadine, loratadine Terfenadine and astemizole recalled by FDA Cetirizine, cyclizine, hydroxyzine, levocetirizine, meclizine Modified from Nicolas [5] As an inverse agonist, the compound preferably binds to the inactive state of the histamine receptor, stabilizing the receptor in the inactive conformation, and moves the equilibrium shift in the direction of the inactive state Since H1 antihistamines have been discovered as inverse agonist, the adoption of the term “H1 antihistamines” has been contemplated [1, 3] The chemical structure of antihistamines can be varied (Table 22.2) Indications and Clinical Pearls H1 antihistamines are used to relieve or prevent allergy symptoms Suppression of allergic inflammation in the mucous membranes and reduction of the size of wheal (swelling) and flare (vasodilation) response will help alleviate symptoms such as itching, rhinorrhea, sneezing, urticaria, and congestion [4] The effect on airway smooth muscle is that of bronchodilation H1 antihistamines can be grouped into two classifications: First-generation (sedative) antihistamines and second-generation (nonsedating) antihistamines First-generation H1 antihistamines include chlorpheniramine (Chlor-Trimeton), clemastine (Tavist), dexchlorpheniramine (Polaramine), dimenhydrinate (Dramamine), dimetindene (Fenistil), doxylamine (Unisom – used as the sedative in NyQuil), diphenhydramine (Benadryl), hydroxyzine (Vistaril), meclizine (Antivert), orphenadrine (Norflex), pheniramine (Avil), and promethazine (Phenergan) First-generation H1 antihistamines cross the blood-brain barrier due to their lipophilic molecular structure leading to the possible unwarranted effect of sedation Adverse reactions may be due to their inhibition on muscarinic, serotonergic, and adrenergic receptors (Table 22.3) Reports of toxicity with overdose, whether intentional or accidental, have been reported Antiemetic effects may be elicited due to blockade of the histaminergic signal from the vestibular nucleus to the vomiting center in the medulla [6] Clinical uses can extend beyond the treatment of allergic symptoms to the treatment of vestibular disorders, sedatives, sleeping aids, and antiemetics These agents are usually administered in three to four daily doses (Table 22.4) 368 M Yarborough and J.G Johnson Table 22.3 H1 antihistamine adverse effects on various receptors Adverse effect of first-generation H1 antihistamines H1 receptor CNS neurotransmission reduction, sedation, cognitive and neuropsychomotor performance reduction, appetite↑ Muscarinic Tachycardia, urinary retention receptor Hypotension, dizziness, reflex tachycardia α-adrenergic receptor Appetite increase Serotonin receptor Cardiac channels Prolongation of the QT interval, ventricular arrhythmia Modified from [1, 5] Second-generation antihistamines include acrivastine (Semprex), cetirizine (Zyrtec), desloratadine (Clarinex), ebastine (Kestine), fexofenadine (Allegra), levocetirizine (Xyzal), and loratadine (Claritin) The Food and Drug Administration (FDA) removed terfenadine (Seldane) and astemizole (Hismanal) from the US market With development over the last two decades of the newer second-generation H1 antihistamines, advantages over the earlier drugs have been seen Less sedation and fewer anticholinergic side effects have lead to their significant advance in the pharmacologic treatment of allergic symptoms Second-generation H1 antihistamines differ from the first generation because of their high specificity and affinity for peripheral H1 receptors [5] These newer advanced drugs have much less effect on the central nervous system and not have sedating effects (Table 22.5) They are rapidly absorbed and peak plasma concentrations are reached after 1–3 h Once- to possibly twice-daily dosing administration schedules are recommended Of note, most show significant renal clearance lending to the need to adjust dosing in patients with renal impairment Suppression of stomach acid secretion occurs due to prevention of histamine action on the H2 receptor found in the gastric mucosa parietal cells Like the H1 antihistamines, the H2 antihistamines are inverse agonist rather that true receptor antagonists Their uses are for treatment of acid-related gastrointestinal conditions, i.e., dyspepsia, gastroesophageal reflux, and peptic ulcer disease Prevention of stress ulcers has also been described along with a decrease in vascular permeability H2 receptors are also found in smooth muscle, cardiac cells, and the central nervous system [6] All four H2 blockers, including cimetidine, ranitidine, famotidine, and nizatidine, are available over the counter in the USA Most are well tolerated due to the selectivity They not block H1 receptors or have antimuscarinic activity (Table 22.6) © Norflex © Orphenadrine Vistaril © Hydroxyzine Diphenhydramine Benadryl Drug Dosage 25–50 mg PO q4–6 h; 10–50 mg IV/IM (total of 400 mg/day) (Tabs, capsules, liquid, rapidly dissolving tab or strip, IV) 25 mg po TID–QID 25–100 mg IM q 4–6 h (Capsules, oral suspension, IM) 60–100 mg PO q h, 60 mg PO, IM, IV for Parkinson’s disease (Tabs, oral solution, IM/IV) Treatment usage Allergy symptoms Motion sickness Insomnia Dystonia in early Parkinson’s disease Allergy symptoms Nausea/vomiting Motion sickness Anxiety Alcohol withdrawal Pain (muscle spasms), headache Migraines Parkinson’s disease Table 22.4 First-generation H1 antihistamines Special precautions Normal Normal Special diet Normal Drowsiness Dizziness Restlessness Constipation Increase in chest congestion Urinary retention Euphoria Side effects Dry mouth Drowsiness Dizziness Nausea/vomiting Constipation Increase in chest congestion Headaches photosensitivity Urinary retention Dry mouth drowsiness Dizziness Chest congestion Headache Muscle weakness Increased anxiety Dry mouth (continued) Prescribed Prescribed Availability Over the counter 22 Histamine Modulators 369 Modified from Lin [6] Phenergan Motion sickness Insomnia Promethazine © 6.25–12.5 mg PO qd, 12.5–25 mg IV Precaution q 4–6 h (tabs, rectal supp, IV) in the elderly and children Not to be given to children under years of age Allergy symptoms Special precautions Dosage Treatment usage Drug Table 22.4 (continued) Normal Special diet Side effects Drowsiness Nausea/vomiting Blurred vision Nightmares Nervousness Restless, hyperactivity Respiratory depression Confusion Dry mouth Availability Prescribed 370 M Yarborough and J.G Johnson Xyzal © Levocetirizine Allegra © Fexofenadine Clarinex © Desloratadine Zyrtec © Cetirizine Drug mg PO q day (Tablets, orally disintegrating tabs, syrup) Seasonal allergic rhinitis 60 mg PO BID or 180 mg PO q day (Tablet, orally disintegrating tabs, suspension) mg PO q day (Tablet, oral solution) Seasonal allergic rhinitis Chronic idiopathic urticaria Motion sickness Insomnia Seasonal allergic rhinitis Chronic idiopathic urticaria Chronic idiopathic urticaria Dosage 5–10 mg PO q day (tablets, chewable tabs, syrup) Treatment usage Seasonal allergic rhinitis Chronic idiopathic urticaria Table 22.5 Second-generation H1 antihistamines Dosing adjustment for renal impairment Dosing adjustment for renal impairment Dosing adjustment for renal or hepatic impairment Special precautions Dosing adjustment for renal, hepatic impairment and the elderly Normal Decreased absorption from fruit juices: grapefruit, orange, and apple Normal Special diet Normal Side effects Somnolence Fatigue Dry mouth Pharyngitis Stomach pain Diarrhea Vomiting Pharyngitis Dry mouth Myalgia Fatigue Somnolence Headache Dry mouth Nausea Dizziness Weakness Headache Aggression Dry mouth Pharyngitis Somnolence Fatigue Nasopharyngitis (continued) Prescribed Over the counter Prescribed Availability Over the counter 22 Histamine Modulators 371 Dosage 10 mg PO q day (Tablet, orally disintegrating tabs, syrup) Treatment usage Seasonal allergic rhinitis Chronic idiopathic urticaria Modified from Lin [6] Claritin © Loratadine Drug Table 22.5 (continued) Dosing adjustment for hepatic and renal impairment Special precautions Increased plasma levels noted with CYP inhibitors Special diet Headache Dry mouth Somnolence Blurred vision Fatigue Side effects Over the counter Availability 372 M Yarborough and J.G Johnson Dyspepsia PUD GERD Prevention of stress ulcers (Experimental use with weight gain) Dyspepsia PUD GERD Prevention of stress ulcers Dyspepsia PUD GERD Prevention of stress ulcers Treatment usage Dyspepsia Peptic ulcer disease (PUD) Gastroesophageal reflux (GERD) Prevention of stress ulcers Modified from Lin [6] Axid © Nizatidine Zantac © Ranitidine Pepcid © Famotidine Tagamet © Cimetidine Drug Table 22.6 H2 antihistamines Dosage 300 mg PO q day – twice daily for OTC, 300 mg q 6–8 h PO or maximum 2.4 g/ day (Tablet, liquid, IV/ IM) 20 mg PO q day, twice daily for OTC, 20 mg up to four times/day (tablet, chewable tabs, capsule, liquid, IV) 150 mg PO twice daily, 50 mg IV/ IM q 6–8 h (tablet, effervescent tabs, granules, syrup, capsule, IV) 150 mg PO q day, twice daily (tablets, capsule) 30–60 prior to meals and bedtime 15–60 prior to meals and bedtime Special diet 30 prior to meals and bedtime Does not interfere 30–60 with hepatic prior to oxidation, meals and increase in liver bedtime enzymes noted in some patients Does not interfere with hepatic oxidation Does not interfere with hepatic oxidation Special precautions Inhibits hepatic oxidative metabolism by most cytochrome P450 enzymes leading to drug interactions Headache Dizziness Constipation Diarrhea Sweating Stomach pain Headache Diarrhea Constipation Nausea/vomiting Stomach pain Headache Dizziness Constipation Diarrhea Dizziness Drowsiness Depression Side effects Confusion Headache Diarrhea Over the counter, some prescribed formulations, last H2 antihistamine before “proton pump inhibitors” Over the counter, some prescribed formulations Over the counter, some prescribed formulations Availability Over the counter, some prescribed formulations 22 Histamine Modulators 373 374 M Yarborough and J.G Johnson Drug Interactions/Side Effects/Black Box Warnings Cardiac Effects Concerns over the development of ventricular arrhythmias have been reported, and the metabolic profile and susceptibility with other drug interactions among some of these second-generation compounds exist Potassium channels in the heart may be blocked by various substrates lending to a prolongation of the QT interval of the electrocardiogram resulting in lethal arrhythmias [7] Metabolism is emerging as an important part of second-generation antihistamines In order to understand the risk of cardiac arrhythmias, an understanding of CYP3A4 antihistamine metabolism and other drug interactions, i.e., inhibitors, substrates, and inducers, must be understood Compounds such as the second-generation antihistamines have very low plasma levels secondary to high tissue uptake and first-pass liver metabolism These compounds are metabolized to pharmacologically active agents The metabolic pathway is mediated primarily by CYP3A4, an isoenzyme belonging to the cytochrome P450 (CYP) superfamily CYP3A4 is responsible for 30 % of total CYP metabolism in the liver and 70 % in the intestine Besides antihistamines, CYP3A4 can accommodate a large variety of structurally diverse exogenous and endogenous compounds It should be noted the CYP3A4 can be inhibited or induced by a number of drugs; hence it is implicated in many drug interactions [1, 5] An example of potential risk is found in the concomitant usage of erythromycin and ketoconazole with terfenadine These compounds hinder the metabolic clearance of terfenadine, thereby inducing its accumulation triggering a cardiac response These effects are thought to be due to the potency of terfenadine to block cardiac potassium channels leading to QT interval prolongation and possible fatal arrhythmias Subsequent investigations have shown other substrates and/or inhibitors have lead to cardiac events with terfenadine The FDA removed this drug from the US market in 1997 Astemizole also has been shown to have arrhythmogenic potential [5] resulting in its withdrawal from the US market in 1999 In contrast, cetirizine, epinastine, and fexofenadine are on the other side of the metabolic hurdle, and most of the dose is eliminated as unchanged drug No active metabolites have been reported for these agents [1] Grapefruit juice and tonic water containing quinine may interfere with antihistamine metabolism by inhibition of CYP3A4-dependent first-pass metabolism at the intestinal level FDA warnings about interactions with astemizole and quinine have been established As for grapefruit juice, the magnitude of the interaction may be unpredictable and dependent on factors of individual susceptibility, type and amount of juice consumed, and timing of administration [1, 5, 6] In addition, variability among humans with the lowest CYP activities may be at risk for development of high concentrations of antihistamines even with recommended dosing and no interfering drugs Metabolic pathways and concomitant drug usage may affect the safety of these drugs Terfenadine and astemizole are examples ... (eds.), Essentials of Pharmacology for Anesthesia, Pain Medicine, and Critical Care, DOI 10.1007/978-1-4614-8948-1 _23 , © Springer Science+Business Media New York 20 15 381 3 82 E.S Hsu wakefulness... once daily at 20 0 mg/day for days followed by 400 mg/day for 21 days Coadministration of methylphenidate (20 mg/day) during days 22 28 of modafinil treatment h after the daily dose of modafinil did... of 5, 10, and 20 mg for oral administration Ritalin-SR is available as sustained-release tablets of 20 mg for oral administration The chemical formula for methylphenidate is methyl α-phenyl -2- piperidineacetate