Antihistamine. JI HYUN LEE, M.D., Ph.D. Department of Dermatology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea

Transcription

1 Antihistamine JI HYUN LEE, M.D., Ph.D. Department of Dermatology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea

2 micromedex2/librarian/

3 Objectives To understand the mechanisms of action of antihistamines To know when it is appropriate to use antihistamines To list the adverse effect of antihistamines

4 J Allergy Clin Immunol. 2011;128:

5 Histamine (2-[4-imidazolyl]ethylamine) Low-molecular-weight amine derived from L-histidine By means of four types of receptors Affects cellular growth and proliferation Modulates inflammation Acts as a neurotransmitter

6 Brenner & Stevens. Pharmacology. Saunders 2013

7 Seven membrane-spanning regions and coupled with G proteins An Bras Dermatol. 2010;85:

8 Histamine H 1 and H 2 receptor : widely expressed H 1 receptor: neuron, smooth muscle, epithelium, endothelium, many other cells H 2 receptor: gastric mucosa parietal cell, smooth muscle, epithelium, endothelium, heart, other cells H 3 and H 4 receptor : limited expression H 3 receptor: histaminergic neurons H 4 receptor: bone marrow, hematopoietic cells

9 J Allergy Clin Immunol. 2011;128:

10 J Allergy Clin Immunol. 2011;128:

11 J Allergy Clin Immunol. 2003;112:15-22

12 Eur J Pharmacol. 2006;533:69-76

13 J Allergy Clin Immunol. 2011;128:

14 H 1 ANTIHISTAMINE

15 H1 antihistamine 1 st generation H1 antihistamines - Chlorpheniramine, hydroxyzine, tripelennamine, cyproheptadine, diphenhydramine 2 st generation H1 antihistamines - cetirizine/ levocetirizine, ebastine, loratadine, fexofenadine

16 H 1 - and H 2 - antihistamines act as inverse agonists that combine with and stabilize the inactive conformation of the H-receptor, shifting the equilibrium toward the inactive state J Allergy Clin Immunol. 2011;128:

17 J Allergy Clin Immunol. 2011;128:

18 Mechanism of Action Inverse agonists : reversibly bind and stabilize the inactive form of the H 1 receptor

19 Mechanism of Action 1 st generation H1 antihistamines Can also act on muscarinic, α-adrenergic, and serotonin receptors and cardiac ion channels Serious adverse effects (urinary retention, hypotension, cardiac arrhythmia) 1 st generation antihistamines are divided into six groups on the basis of chemical structure ethylenediamines, ethanolamines, alkylamines, phenothiazines, piperazines, piperidines Aromatic or heterocyclic ring + alkyl substitutient Lipophilicity, allow penetration of the blood-brain barrier

20 Katzung BG et al. Basic & Clinical pharmacology. The McGraw-Hill companies 2012

21 Chemical class Alkylamines Functional class First generation Chlorpheniramine Functional class Second generation Piperazines Hydroxyzine Cetirizine, levocetirizine Piperidines Cyproheptadine, ketotifen Bepotastine, desloratadine, ebastine, fexofenadine, loratadine, terfenadine Ethanolamines Ethylenediamines Phenothiazines Dimenhydrinate, diphenhydramine Tripelennamine Others Doxepin Azelastine J Allergy Clin Immunol. 2011;128:

22 Mechanism of Action Low-sedating or 2 nd generation H 1 antihistamines Mostly chemically derived from 1 st generation agents Binding noncompetitively to the H 1 receptor Not easily displaced by histamine Dissociate slowly Have a longer duration of action Selectivity for the H 1 receptor and their reduced lipophilicity Less likely to cause sedation and have different safety profiles

23 Mechanism of Action Low sedating H 1 antihistamines affect trafficking of cells in the skin and other tissue In a skin, cetirizine reduced eosinophil influx after allergen challenge In vitro, cetirizine inhibits eosinophil, monocyte, T- lymphocyte chemotaxis to N-formyl-methionyl-leucylphenylalanine and platelet activating factor H 1 antihistamines modulate the expression of cellular adhesion molecules and influence the release mediators from leukocytes Desloratadine and emedastine Inhibit platelet-activating factor-induced eosinophil chemotaxis, TNF-α-induced eosinophil adhesion, phorbol myristate-induced superoxide generation

24 Pharmacokinetics Sedating 1 st Generation H 1 Antihistamines Oral administration Effects can be observed within 30min ~ 1hr Persist for 4~6hr, some agents last for 24 hr or longer Metabolized by hepatic cytochrome P450(CYP) enzyme 3A4 Form glucuronides before excretion in urine Potency and relative concentration in the skin can be compared by inhibition of the cutaneous wheal and erythema response to histamine injected cutaneously Double-blind, placebo-controlled trials, no evidence of the development of tolerance or tachyphylaxis in the suppression of skin test reactivity by H 1 Suppression of skin test reactivity may be observed for up to 7 days after discontinuation of a regularly used sedating H 1 antihistamines

25 Pharmacokinetics Sedating 1 st Generation H 1 Antihistamines Oral administration Divided doses at intervals of 4~8h Topical formulations for dermatology Available, less effective Development of delayed contact dermatitis

26 Pharmacokinetics Low-sedating 2 nd Generation H 1 Antihistamines Administration once or twice daily Achieve peak plasma concentrations within two half-lives Generally achieve higher concentration in the skin than sedating H1 antihistamine Single does can suppress the wheal-and-erythema reaction from 1 to 24h

27 Pharmacokinetics Low-sedating 2 nd Generation H 1 Antihistamines Metabolized by hepatic enzyme CYP 3A4 Terfenadine, astemizole, ebastine, oxatomide Minimal hepatic metabolized drug Cetirizine, fexofenadine, levocabastine, deloratadine Less interaction with other drug

28 J Allergy Clin Immunol. 2011;128:

29 Second-generation H1-antihistamines, confirm that they decrease symptoms and improve quality of life. Orally administered first (old) generation H 1 -antihistamines are no longer medications of choice in patients with allergic rhinitis, allergic conjunctivitis, and chronic urticaria. J Allergy Clin Immunol. 2011;128:

30 In patients with chronic urticaria, second-generation H 1 - antihistamines are the medications of choice. With some of these medications, such as levocetirizine, increasing the dose up to 4-fold significantly improves efficacy without compromising safety. H 1 -antihistamines are not medications of choice for atopic dermatitis, asthma, anaphylaxis, nonallergic angioedema, colds, otitis media, sinusitis, nasal polyps, nonspecific cough, or nonallergic, nonspecific itch, in which their efficacy and safety have not been documented in highquality randomized controlled trials. J Allergy Clin Immunol. 2011;128:

31 Indications Used to treat pruritus of various etiologies, urticaria, angioedema More effective in treating physical urticaria and dermatographism, chronic idiopathic urticaria Less effective for hereditary and acquired angioedema syndromes and urticarial vasculitis Both 1 st, 2 nd generation drug are used to treat pruritus in patients with atopic dermatitis, although their efficacy has not been proved by rigorous clinical trials

32 Indications Commonly used to treat cutaneous and systemic mastocytosis Pruritus associated with other conditions may be relieved by H1 antihistamine - allergic contact dermatitis, lichen planus, mosquito bites, infestations, secondary pruritus 1 st generation agents may be favored for permitting more restful sleep Pre-treatment before certain procedures for patients with a history of radiocontrast media and transfusion reaction

33 Initiation of Therapy Lowest effective dosage is preferred to minimize doserelated side effects Gradual escalation of dosing permits the development of tolerance to sedation Higher dosage to be used to treat certain conditions, such as refractory chronic urticaria Patient with renal or hepatic disease, require lower dosage Some situation may call for more careful assessment

34 Table Dosing regimens for H 1 antihistamines B Drug Formulation Dosage First-generation H 1 Chlorpheniramine 2-, 4-, 8-, 12-mg tablet 2 mg/5 ml syrup Adult: 4 mg tid, qid; 8 12 mg bid Age 6 11 years: 2 mg q4 6h Cyproheptadine 4-mg tablet Adult: 4 mg tid, qid Diphenhydramine Hydroxyzine 2 mg/5 ml syrup Age 7 14 years: 4 mg bid, tid 25-, 50-mg tablet 12.5 mg/5 ml syrup 50 mg/15 ml syrup 6.25 mg/5 ml syrup 12.5 mg/5 ml syrup 10-, 25-, 50-, 100-mg tab let 10 mg/5 ml syrup Adult: mg q4 6h Age 6 12 years: mg q4 6h Age <6 years: mg q4 6h Age 6 years: mg q6 8h or qhs Age <6 years: mg qd Tripelennamine 25-, 50-, 100-mg tablets Adult: mg q4 6h Conditions requiring dosage adjustment Hepatic impairment Hepatic impairment Hepatic impairment Hepatic impairment Hepatic impairment

35 Second-generation H 1 antihistamines Acrivastine 8-mg tablet Adult: 8 mg tid Renal impairment B B B Azelastine Cetirizine Desloratadine Ebastine Fexofenadine 2-mg tablet b 0.1% nasal spray 5-, 10-mg tablet 5 mg/ml syrup 2.5-, 5-mg tablet 5 mg/ml syrup 10-mg tablet 30-, 60-, 120-, 180-mg tablet Adult: 2 4 mg bid Age 6 12 years: 1 2 mg bid 2 sprays/nostril bid Age 6 years: 5 10 mg qd Age 2 6 years: 5 mg qd Age 6 months 2 years: 2.5 mg qd Age 12 years: 5 mg qd Age 6 12 years: 2.5 mg qd Age 1 6 years: 1.25 mg qd Age 6 12 months: 1 mg qd Age 6 years: mg qd Age 6 12 years: 5 mg qd Age 2 5 years: 2.5 mg qd Age 12 years: 60 mg qd, bid; mg qd Age 6 12 years: 30 mg qd, bid Levocetirizine 5-mg tablet Age 6 years: 5 mg qd Loratadine 10-mg tablet 5 mg/ml suspension Age 6 years: 10 mg qd Age 2 9 years: 5 mg qd Mizolastine 10-mg tablet Adult: 10 mg qd Renal and hepatic impairment Renal and hepatic impairment Renal and hepatic impairment Renal impairment Renal impairment Renal and hepatic impairment Renal and hepatic impairment Hepatic impairment

36 Factors for Risk-Benefit Assessment of H1 Antihistamine Therapy Risk Contraindications History of cardiac arrhythmias, particularly ventricular arrhythmias First trimester of pregnancy Prostatic hypertrophy Narrow-angle glaucoma Concomitant use of monoamine oxidase inhibitors

37 Monitoring of Therapy Therapeutic endpoints are evaluated by observation of clinical signs and symptoms No particular monitoring beyond the usual surveillance for adverse effects Patients with impaired metabolism or co-morbid condition and taking other drug require closer monitoring

38 Risk and Precautions J Allergy Clin Immunol. 2011;128:

39 Risk and Precautions Most commonly reported problem : primarily with 1 st -generation H 1 antihistamines Associated with an increase in occupational injuries and automobile accidents. Impair alertness, cognition, learning, and rapid response/waking memory, car driving Increasing the latency to onset of restful rapid eye movement sleep (REM), reducing the duration of the REM sleep

40 Risk and Precautions Minimal or no adverse effects are reported with 5 mg of cetirizine, 5 mg of desloratadine, 360 mg of fexofenadine (off-label), 5 mg of levocetirizine, 10 mg of loratadine, or 10 mg of rupatadine. At higher doses, with the exception of fexofenadine, 2 nd generation H 1 - antihistamines might cause doserelated CNS effects in some adults with some allergic diseases.

41 Risk and Precautions Stimulatory CNS effects, which occur with the alkylamine group (chlorpheniramine), include nervousness, irritability, insomnia, tremor

42 Risk and Precautions Another frequent side effect Especially with the ethylenediamine group Administration with food may reduce these manifestations

43 Risk and Precautions Often associated with ethanolamine, phenothiazine, and piperazine (hydroxyzine, cetirizine, levocetirizine) groups Preclude drug use in patients with narrow-angle glaucoma Require close monitoring in patients with prostatic hypertrophy First generation H 1 -antihistamines are contraindicated in persons with glaucoma or prostatic hypertrophy. Anti α-adrenergic effects include peripheral vasodilation, orthostatic hypotension, and dizziness.

44 Risk and Precautions Most serious cardiac toxicity Dose-dependent effects Mediated through blockade of potassium channels Transient hypotension may develop after intravenous therapy Concerns are minimal in countries in which regulatory agencies scrutinize secondgeneration H 1 -antihistamines for potential cardiac toxicity and do not approve them for use if this is identified.

45 Risk and Precautions May be secondary to excipients in the drug Both first- and secondgeneration H1 antihistamines are reported to cause rare adverse effects for which the mechanisms are incomletely understood. These include agranulocytosis, anaphylaxis, fever, fixed drug eruption, liver enzyme elevation/hepatitis, photosensitivity, and urticaria. Rhabdomyolysis has been reported after overdose.

46 Risk and Precautions 2 nd generation antihistamine Selectivity for peripheral H 1 receptor Less both the sedative and anticholinergic effect Sedation is most often reported in a subset of patients taking cetirizine and acrivastine Terfenadine and astemizole, have been removed from the US market due to risk of QT interval prolongation and torsade de pointes.

47 Drug Interactions May interact with other drugs metabolized by the hepatic CYP system Imidazole antifungals, cimetidine, and macrolide antibiotics Contraindicated for patients receiving monoamine oxidase(mao) inhibitors Central depressive effects may be accentuated when 1 st generation antihistamines are combined with alcohol or other CNS depressants Antihistamines of the phenothiazine group may block and reverse the vasopressor effect of epinephrine use norepinephrine of phenylephrine

48 Special Patients Population Children Safely used in children with appropriate dosing More susceptible to certain side effects such as excitation and insomnia. Acute poisoning may develop, but is rare Regulatory agencies in the United States and other countries have mandated that more than 500 pediatric oral formulations containin g first-generation H 1 -antihistamines be withdrawn from the market. The long-term safety of cetirizine, desloratadine, fexofenadine, levo cetirizine, and loratadine has been confirmed in young children. Eldery Caution about decreased Cr clearance, co-morbid condition, potential drug interaction More susceptible to anticholinergic effect

49 Special Patients Population Pregnant Women FDA pregnancy category B or category C 1 st, FDA Pregnancy Category B (chlorpheniramine and diphenhydramine) or C (hydroxyzine and ketotifen 2 nd, FDA Pregnancy Category B (alcaftadine, cetirizine, emedastine, and loratadine) or C (azelastine, bepotastine, desloratadine, epinastine, fexofenadine, levocetirizine, and olopatadine) In early reports: Linked to fetal malformations, particularly cleft palate defects avoid in the first trimester More recent studies Do not indicate any increased risk of congenital malformations associated with H antihistamine use

50 Special Patients Population Breastfeeding Women No formal studies have been performed on the safety during breastfeeding. Theoretically, 1 st -generation drugs may diminish milk supply via anticholinergic effects. Many H 1 antihistamines are known to be excreted in breast milk Effects on the nursing infant are not known First-generation, in nursing infants they potentially cause irritability or drowsiness. Second-generation, no CNS adverse effects have been reported in nursing infants.

51 Chlorpheniramine (Pheniramine ) Chlorpheniramine 2-, 4-, 8-, 12-mg tablet 2 mg/5 ml syrup 4mg/2ml inj. Adult: 4 mg tid, qid; 8 12 mg bid Age 6 11 years: 2 mg q4 6h Adult 5-10mg qd~bid IM, SC, IV Hepatic impairment Pheniramine drugs, such as chlorpheniramine, are less sedating than other first-generation drugs and are used primarily in the treatment of allergic reactions to pollen, mold spores, and other environmental allergens Used orally for symptomatic relief of hay fever and urticaria and by slow intravenous injection as an adjunct to adrenaline (epinephrine) for the emergency treatment of anaphylaxis and angioedema

52 Hydroxyzine (Ucerax ) Hydroxyzine 10-, 25-, 50-, 100-mg tablet 10 mg/5 ml syrup 30-60mg #2 or #3 Age 6 years: mg q6 8h or qhs Age <6 years: mg qd Hepatic impairment Primary biliary cirrhosis, Qd or less Used for pruritus and for the short-term treatment of anxiety

53 Azelastine (Azeptin ) Azelastine 1mg tablet 0.1% nasal spray 1mg bid Adult: 2 4 mg bid Age 6 12 years: 1 2 mg bid 2 sprays/nostril bid marketed as a nasal spray for the treatment of allergic rhinitis Renal and hepatic impairment Azelastine is metabolized by cytochrome P450 enzymes to an active metabolite, desmethylazelastine, a substance whose plasma concentrations are 20% to 30% of azelastine concentrations. Azelastine and its principal metabolite are both H 1 receptor antagonists. The unchanged drug and its active metabolite are excreted primarily in the feces

54 Cetirizine /Levocetirizine (Xyzal ) Levocetirizine 5-mg tablet 0.5 mg/ml syrup Age 6 years: 5 mg qd Age 2-6 years 2.5ml bid Age 1 2 years: 2.5ml qd Renal and hepatic impairment Clcr <50ml/min: Adult 5mg EOD Clcr <30ml/min: Adult 5mg ETD Cetirizine is the metabolite of the hydroxyzine Levocetirizine: the levo-isomer of cetirizine Cetirizine, dose-dependent CNS H1-receptor occupancy Cetirizine, levocetirizine Peak concentration : 1hr after administration Half -life : 8hr Renal or hepatic function impairment lower dose

55 Ebastine (Ebastel ) Ebastine 10-mg tablet Age 6 years: mg qd Age 6 12 years: 5 mg qd Age 2 5 years: 2.5 mg qd Renal impairment Clcr <50% 50% of the usual dose Ebastine Half -life : 15hr No dose adjustment is necessary for patients with hepatic impairment. Precautions A) Untoward effects during use of other H1-receptor antagonist agents (loratadine, azelastine, cetirizine, astemizole, terfenadine) B) Cardiovascular disease (particularly arrhythmias/established QTc interval prolongation) C) Asthma/upper respiratory tract infection D) Liver disease E) Renal insufficiency F) Combined use with cytochrome P450 enzyme inhibitors (eg, ketoconazole, macrolide)

56 Fexofenadine (Allegra ) Fexofenadine 30-, 60-, 120-, 180-mg tablet Age 12 years: 60 mg qd, bid; mg qd Age 6 12 years: 30 mg qd, bid Renal impairment Clcr <80ml/min: Adult 60mg qd Fexofenadine Peak concentraion : 2~3hr after administration Half-life : 14hr Decreased creatinine clearance : lower dose Hepatic function is not concerned Fexofenadine is the active metabolite of the now-banned terfenadine. Unlike terfenadine, fexofenadine does not prolong the QT interval or cause torsades de pointes. Has the lowest sedative effect, choice for airline pilots

57 Loratadine(Clarityne ) Loratadine 10-mg tablet 5 mg/ml suspension Adult, Age 12 years: 10 mg qd Age 6-12: 5mg qd Age 6 years: 10 mg qd Age 2 9 years: 5 mg qd Renal and hepatic impairment - CrCl(mL/min) 30 1 Age 2-5 : 5mg EOD 2 Age 6 years: : 10mg EOD Prodrug of desloratadine Loratadine Half-life : 8-24hr, depending on hepatic function Cetirizine, desloratadine, and loratadine also lack cardiac effects Concurrent use of amiodarone and loratadine may result in increased risk of QT interval prolongation and torsade de pointes

58 H 2 ANTIHISTAMINE

59 Antigen presentation Mechanism of action Inverse agonist Bind H2 receptors throughout the body including epithelial and endothelial cells H2 receptor are expressed on mast cells and dermal dendritic cells Mediation Cutaneous vascular permeability Local release of inflammatory mediators Cellular recruitment

60 Pharmacokinetics Rapidly absorbed from GI tract Peak level : 1~2h after administration Extensive hepatic metabolism with renal clearance Relatively lipophilic with limited penetration of the BBB

61 Indications in dermatology Dermatologic condition Acute allergic reactions Chronic urticaria Urticaria pigmentosa and systemic mastocytosis Pruritus associated with other conditions H2 antihistamine used in addition to H1 antihistamines in refractory cases of chronic urticaria and angioedema In a study, hydroxyizine + cimetidine caused more reduction in pruritus and wheal number, size, severity than hydroxyizine alone Similar with chlorpheniramine combined with cimetidine helpful in systemic mastocytosis and urticaria pigmentosa

62 Indications in dermatology Anecdotal report of using cimetidine to treat pruritus secondary to various medical condition such as polycythemia vera and carcinoid flush High doses of cimetidine are successful treatment in verruca vulgaris in some patients

63 Dosing regimens B Drug Formulation Dosage Cimetidine 100-, 200-, 300-, 400-, 800-mg tablet 300 mg/5 ml syrup 200 mg/20 ml syrup Adult: mg bid Conditions requiring dosage adjustment Renal or hepatic impairment B Ranitidine 75-, 150-, 300-mg tablet 15 mg/ml syrup 150-mg granules Adult: mg bid Pediatric: 5 10 mg/kg/day divided in two doses Renal impairment B Famotidine 10-, 20-, 40-mg tablet 40 mg/5 ml syrup Adult: mg bid Age 1 16 years: 1 mg/kg/day divided in two doses, up to 40 mg bid Renal impairment B Nizatidine 150-, 300-mg capsule 15-mg/5-mL syrup Age 12 years: 150 mg qd, bid Renal impairment

64 Initiation of therapy Generally used in conjunction with H1 antihistamines following an unsuccessful trial of H1 antihistamine alone No need of any particular lab. screening Patients medication list reviewed carefully inhibition of hepatic CYP450 system and drug interaction Ranitidine is less inhibitory of CYP system than cimetidine

65 Initiation of therapy Patients with decreased creatinine clearance require dosage adjustment In patients taking the cardiac drug dofetilide, cimetidine is absolutely contraindicated risk of prolongation of the QT, life-threatening cardiac arrhythmias

66 Monitoring of therapy Therapeutic endpoints Clinical signs & symptoms (eg. Severity of pruritus; wheal number, size, and frequency) No particular monitoring beyond the usual surveillance is required. In patients with a history of thrombocytopenia, a complete blood count may be warranted Thrombocytopenia has been reported as an idiosyncratic effect of drugs in few individuals

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68 Risks and precautions Cimetidine Gynecomastia with or without elevated prolactin levels in men, galactorrhea with elevated prolactin levels in women, loss of libido, impotence, reduction of sperm counts in young men Elevation in serum creatinine levels and hepatic transaminase levels Reverse after drug is withdrawn Dermatologic adverse effects Rare alopecia and urticarial vasculitis

69 Risks and precautions Ranitidine Does not bind to androgen receptors Does not enhance cell-mediated immune response Altering parasympathetic and sympathetic control function Affect physiologic autonomic control of the cardiovascular system lead to susceptibility to arrhythmia Famotidine and nizatidine Are associated with few side effects Less inhibition of the hepatic CYP450 system fewer drug interaction

70 Drug interactions Cimetidine Inhibition of CYP system, increase the serum levels of numerous drugs Serum level of warfarin PT, risk of bleeding Interaction with many cardiac drug(β-blocker, CCB, amiodarone, antiarrhythmic agents) Contraindication dofetilide because of the risk of prolongation of the QT interval and life-threatening cardiac arrhythmias Other interaction drug phenytoin, benzodiazepine, metformin, sulfonylurea, SSRI

71 Drug interactions Ranitidine Interaction less frequently than cimetidine Significant interactions with fentanyl, metoprolol, midazolam, nifedipine, theophyllin, warfarin Decrease absorption of diazepam, reduce plasma level by 25% Famotidine and nizatidine Fewer drug interactions

72 Special patient populations Children Ranitidine, famotidine safety with appropriate dose Cimetidine, nizatidine not recommend other than reducing gastric acidity. Risk of necrotizing enterocolitis in neonates Elderly Decreased Creatinine clearance Downward adjustment of dosage Careful review of medication lists More susceptible to CNS disturbances, confusion and dizziness

73 Special patient populations Pregnancy women FDA pregnancy category B Cimetidine, ranitidine, famotidine, nizatidine excreted in breast milk

74 Cimetidine (cimet ) Cimetidine 100-, 200-, 300-, 400-, 800-mg tablet 300 mg/5 ml syrup 200 mg/20 ml syrup Only small proportion absorbed from the stomach Mostly absorbed from small intestine Half life : 2hr Adult: 1000mg #4 (hs 400mg) or hs 800mg Child: 20-40mg/kg/D Adult: mg bid 69% is excretion unchanged in the urine Cimetidine has weak antiandrogenic activity and can cause gynecomastia in elderly men, but this reaction is uncommon with other H 2 blockers. Renal or hepatic Impairment Clcr <50ml/min 75% of the usual dose Clcr <10ml/min 50% of the usual dose

75 Cimetidine (cimet ) Cimetidine 100-, 200-, 300-, 400-, 800-mg tablet 300 mg/5 ml syrup 200 mg/20 ml syrup Adult: 1000mg #4 (hs 400mg) or hs 800mg Child: 20-40mg/kg/D Adult: mg bid Renal or hepatic Impairment Clcr <50ml/min 75% of the usual dose Clcr <10ml/min 50% of the usual dose Cimetidine is a well-known inhibitor of cytochrome P450 isozymes CYP2C9, CYP2D6, and CYP3A4. These isozymes are involved in the metabolism of numerous drugs, including alprazolam, carbamazepine, cisapride, disopyramide, felodipine, lovastatin, phenytoin, saquinavir, triazolam, and warfarin. The dosage of these drugs may need to be reduced in patients taking cimetidine. Other H 2 blockers do not inhibit P450 enzymes significantly and are preferred for patients receiving concomitant drug therapy. Limited data in children show that cimetidine 25 to 40 mg/kg is effective in treating multiple recalcitrant common or plantar warts

76 CYP 450 inhibitor Acute alcohol use Sulfonamides Isoniazid Cimetidine Ciprofloxacin Ketoconazole (antifungals) Erythromycin (macrolide antibiotics) Grapefruit juice Amiodarone Trimethoprim Ritonavir (protease inhibitor) CYP 450 inducer Chronic alcohol use Carbamazepine (anticonvulsants) Phenytoin (anticonvulsants) Phenobarbital (anticonvulsants) Rifampin Isoniazid Terfenafine St. John s Wort Statins (atorvostatin, simvastatin) Warfarin

77 Ranitidine (Albis, Curan inj ) Ranitidine 84-mg tablet 75-, 150-, 300-mg tablet 50mg/2ml inj. 15 mg/ml syrup 150-mg granules Adult 2T bid Age 8 years: 2mg/kg bid 50mg tid or qid IM, IV Adult: mg bid Pediatric: 5 10 mg/kg/day divided in two doses Renal impairment Clcr <50ml/min 150mg orally qd Half life : 2~3h. Longer in individuals with liver or kidney disease and in the elderly Metabolites excreted in the urine Ranitidine is less inhibitory of CYP system than cimetidine

78 Famotidine (Gaster ) Famotidine 10-, 20-, 40-mg tablet 40 mg/5 ml syrup Adult: mg bid Age 1 16 years: 1 mg/kg/day divided in two doses, up to 40 mg bid Renal impairment Clcr <50ml/min 50% of dose or increase dosing interval to hrs Half life : 3~8h. Over 20h in renal failure patients

79 Nizatidine Half life : 1~2h. Duration of action : up to 10h Primarily eliminated by kidney within 16h Oral bioavailability is not affected by food

80 OTHER THERAPEUTIC AGENTS WITH ANTIHISTAMINIC ACTIVITY

81 not established Doxepin Tricyclic Antidepressant Bind both H 1 and H 2 receptors Refractory chronic idiopathic urticaria, physical urticaria, and pruritus associated with systemic conditions For preventing and relieving insomnia, when given in low doses, 1 to 3 mg of doxepin once daily at bedtime Use of both oral and topical forms is contraindicated during breast feeding Under age 12, the safety and efficacy of doxepin are

82 Doxepin Tricyclic Antidepressant Used with caution in elderly people more susceptible to anticholinergic effects(urinary retention, blurred vision) Not be used concurrently with monoamine oxidase inhibitor All patients with depression should be closely monitored for the signs of suicidal ideation Can cause systemic contact dermatitis, allergic contact dermatitis Not be used in patients with glaucoma sudden increase in intraocular pressure

83 Ketotifen (Zaditen) C Ketotifen 0.2mg/mL syrup Adult: 5-10 ml bid Age 6months 3 years: 2.5ml bid H1-type antihistamine with additional mast cell and basophil stabilizing properties Success in the treatment of Chronic idiopathic urticaria More effective than clemastine Physical urticaria Urticaria pigmentosa

84 Ketotifen Results of one open-label trial for Neurofibromatosis Reduce pruritus and pain Slows the growth of neurofibromas But, not confirmed by other investigators Common side effect sedation, atropin like effects Antiserotonin effects include appetite stimulation and weight gain (especially ketotifen) No study about safety in pregnant or breast feeding woman Available only as an ophthalmic solution in US

85 Mirtazapine (Mirtax) C Mirtazapine 15mg-, 30mg- tablet Adult: 15mg qd-bid Renal impairment TCA antidepressant with H1 antihistamine property Success in reducing pruritus attributable to Uremia Cholestasis Various cancer Require monitoring of blood counts and lipid levels Hyperlipidemia Agranulocytosis (rare) Neutropenia (rare)

86 Mirtazapine FDA Black-box warning Possible increased risk of suicide Concomitant use MAO inhibitor is contraindicated FDA pregnancy category C Safety of breast-feeding woman and children is not established

87 Take Home message Histamine receptor 임신중? chlorpheniramine, cetirizine, levocetirizine, loratadine 수유중? 모유수유를통해이행 소아? 2세대 H 1, ranitidine, famotidine 노인? 신장질환? 용량조절 간질환? fexofenadine 진정작용이가장적은? fexofenadine

88 감사합니다