Systemic Medication in Dermatological Therapy 皮肤病的系统治疗

1. Systemic Medication in Dermatological Therapy皮肤病的系统治疗 Professor Zheng Min 郑 敏 教授

2. Systemic Medication in Dermatology • We list here only preparations we use commonly for our patients with skin disease. • Antihistamines drugs(sedative and non-sedative) • The Retinoids • Oral Antifungal Agents • Systemic Glucocorticoids • Antimalarial drugs • Cytotoxic (immunosuppressants) drugs • Immunoloregulation agents • Thalidomide

3. Systemic Medication in Dermatology • Following medication also very important in skin disorders therapy: • Antibacterials • Erythromycin, Metronidazole…… • Antivirals • Acyclovir, Famciclovir • Anti-androgens

4. ANTIHISTAMINES IN DERMATOLOGY

5. Antihistamines have been used in dermatology primarily for the relief of pruritus and the treatment of urticaria and angioedema. • Not all H1-type antihistamines have similar beneficial therapeutic effects, and nonresponders to one drug may respond favorably to another.

6. Antihistamines are effective in blocking experimental pruritus induced by histamine; • They are of limited use in many pruritic cutaneous diseases. • It has been suggested that the soporific side effect of the traditional H1-type antihistamines plays a role in the treatment of pruritus.

7. Histamine which is present in mast cells, basophils, and platelets in association with their granules, • in gastric parietal cells • and in nerve endings • is formed by the enzymatic decarboxylation of the amino acid histidine by histidine decarboxylase.

8. The biologic effects of histamine • The biologic effects of histamine result from its interactions with tissue receptors, designated H1, H2, and H3.

9. The biologic functions mediated by H1 receptors • The biologic functions mediated by H1 receptors include • contraction of endothelial cells and smooth muscle; • increases in venular permeability • increases airways resistance; • stimulation of cutaneous nerves and nasal mucus secretion; • enhancement of chemotaxis of eosinophils and neutrophils.

10. The biologic functions mediated by H2 receptors • The biologic functions mediated by H2 receptors include • dilation of vascular smooth muscle and bronchial smooth muscle; • increases in venular permeability, cardiac rate and force of contraction, and airways mucus production; • increases secretion of parietal cell acid; • stimulation of CD8+ T lymphocytes with delayed-type hypersensitivity suppression; • inhibition of chemotaxis of neutrophils and eosinophils.

11. Traditional, Classic, or First-Generation H1-Type Antihistamines • The traditional, classic, or first-generation H1-type antihistamines have in common with histamine a substituted ethylamine moiety as an integral part of the molecule

12. The activity of an H1-type antihistamine is increased by the substitution of a halogen in the para position of the phenyl or benzyl group of R1 Ethylamine moiety present in H1 antihistamines R1, aromatic and/or heterocyclic groups; X, linkage such as nitrogen, oxygen, or carbon.

13. First Generation H1-type Antihistamines • Traditional H1-type antihistamines have been divided into • six groups based on substitution at the X position with nitrogen, oxygen, or carbon.

14. Antihistamines have a number of effects • In addition to their antihistamine actions, the H1-type antihistamines have a number of effects that include • sedation, • anticholinergic activity, • local anesthesia, • antiemetic activity, • anti-motion-sickness effects.

15. Moreover, they have a variety of • Antiinflammatory • antiallergic properties that are independent of H1 blockade. • Some H1-type antihistamines possess a-adrenergic receptor or cholinergic muscarinic receptor blocking properties, • while others possess antiserotonin effects.

16. The side effects of antihistamines • The central nervous system (CNS) effects • Sedation is the most common • Other CNS effects include • dizziness, tinnitus, disturbed coordination, inability to concentrate, blurred vision, and diplopia.

17. The side effects of antihistamines • Anticholinergic effects, including • dry mucous membranes, • difficulty in micturition, • urinary retention, • dysuria, • urinary frequency, • and impotence.

18. The side effects of antihistamines • Infrequent side effects of H1-type antihistamines include • headache, • a sensation of tightness in the throat, • tingling, • numbness

19. CONTRAINDICATIONS AND DRUG INTERACTIONS • When H1-type antihistamines are consumed in combination withalcohol or other therapeutic agents with CNS depressant effects, such as diazepam, there may be an accentuation of the central depressive effects. • There are limited guidelines for the use of H1-type antihistamines in pregnant women. • Most drugs are classified as FDA category B, which is defined as no risk to the human fetus despite possible animal risks, or category C, in which risk cannot be ruled out.

20. Low-Sedating or Second-Generation H1-Type Antihistamines • Certain low-sedating H1-type antihistamines affect the trafficking of cells in the skin and other tissues, the release or generation and release of inflammatory mediators, and the expression of adhesion molecules.7 • Cetirizine • Loratadine • Fexofenadine • Acrivastine • Azelastine • Ebastine • Levocabastine

21. Second-Generation H1-Type Antihistamines

22. ANTIHISTAMINES IN DERMATOLOGY • Antihistamines have been used in dermatology primarily for the relief of pruritus and the treatment of urticaria and angioedema. • Not all H1-type antihistamines have similar beneficial therapeutic effects, and nonresponders to one drug may respond favorably to another. • Antihistamines are effective in blocking experimental pruritus induced by histamine; • It has been suggested that the soporific side effect of the traditional H1-type antihistamines plays a role in the treatment of pruritus

23. ANTIHISTAMINES IN DERMATOLOGY • Urticaria/Angioedema • Other Dermatologic Disorders • atopic dermatitis • systemic mastocytosis and urticaria pigmentosa • Pruritus associated with other conditions • allergic contact dermatitis • other forms of eczematous dermatitis • lichen planus • mosquito bites • Infestations • pruritus secondary to underlying medical disorders or of an idiopathic nature

24. The Retinoidsin Dermatology

25. The Retinoids • Retinoids have diverse biologic effects. • They affect cell growth and differentiation, morphogenesis, • inhibition of tumor promotion and malignant cell growth, • immunomodulatory actions, and • alterations in cellular cohesiveness

26. The Retinoids • Two classes of nuclear retinoid receptors have been identified • retinoic acid receptors (RARs) • retinoid X receptors (RXRs) • The RARs and RXRs are complex classes of receptors • each composed of a, b, and g subtypes • In adult skin, most of the RAR is RAR-g subtype.

27. The Retinoids in skin disorders • CYSTIC ACNE • Cystic acne is unique among the retinoid-responsive diseases in that most cases of even the greatest severity can be successfully treated with only one 4- or 5-month course of isotretinoin at a dosage of 0.5 to 2.0 mg/kg body weight per day Severe cystic acne in a female before (A) and after (B) treatment with oral isotretinoin.

28. The Retinoids • The most likely mechanism by which isotretinoin leads to clinical improvement in acne is inhibition of sebaceous gland function with a reduced rate of sebum excretion and alterations in skin-surface lipid film chemistry.In addition, other mechanisms include anti-inflammatory effects, antibacterial effects, inhibitory effects of microbial enzyme activity, and desquamative effects on poral occlusion.

29. PSORIASIS • When retinoids are used as monotherapy for psoriasis vulgaris, etretinate at a dosage of 0.5 to 1.0 mg/kg per day is superior to isotretinoin Generalized chronic plaque-type psoriasis before (A) and after (B) treatment with etretinate

30. Combining retinoids with other effective therapies • Combining retinoids with other effective therapies increases effectiveness and minimizes toxicity. • Etretinate at lower doses has been used in combination with • photochemotherapy (PUVA), • anthralin, • ultraviolet radiation (UVB, 280 to 320 nm), • and topical glucocorticoids.

31. CUTANEOUS DISORDERS OF CORNIFICATION • Darier's disease • pityriasis rubra pilaris Darier's disease before (A) and after (B) treatment with isotretinoin. Chronic pityriasis rubra pilaris before (A) and after (B) treatment with isotretinoin.

32. CANCER • nevoid basal cell carcinoma syndrome • xeroderma pigmentosum • Low-Dose Isotretinoin for Basal Cell Carcinoma

33. ACUTE TOXICITY • Mucocutaneous Toxicities • Cheilitis • Conjunctivitis • Hair Loss

34. SYSTEMIC TOXICITY • Teratogenicity • It is currently recommended that women who have taken etretinate avoid pregnancy for at least 2 years after the discontinuation of therapy. • Arthralgias and Myalgias • Pseudotumor Cerebri

35. LABORATORY ABNORMALITIES • Hyperlipidemia • Liver Toxicity • Renal Toxicity

36. FACTORS IN THE DECISION TO USE RETINOIDS • As with other medications, a risk/benefit ratio should be used to determine whether or not to treat a dermatologic patient with synthetic retinoids • Factors to be considered include the following:

37. FACTORS IN THE DECISION TO USE RETINOIDS • Responsiveness of the disorder to retinoids. The treatment of cystic acne with isotretinoin is optimal, with short-term exposure leading to long-term remission. • Dose of retinoid required. The use of retinoids in combination with other effective treatments, such as RePUVA (combination photochemotherapy) for psoriasis, may allow dose reduction with fewer side effects.

38. FACTORS IN THE DECISION TO USE RETINOIDS • Availability of alternative treatments. In some diseases (severe Darier's disease, epidermolytic hyperkeratosis) synthetic retinoids may be the only effective treatment. • Chronicity of retinoid therapy. Diseases that relapse rapidly on withdrawal of synthetic retinoids require continuous retinoid administration and, therefore, are associated with increased risk of chronic skeletal toxicity.

39. FACTORS IN THE DECISION TO USE RETINOIDS • Severity of the disease. Disease-induced limitations on educational, psychological, or physical development should be considered. For example, early retinoid treatment of lamellar ichthyosis may prevent the development of ectropion.

40. FACTORS IN THE DECISION TO USE RETINOIDS • Age of the patient. Children with disorders of cornification requiring chronic moderate- to high-dose retinoid therapy are at highest risk of developing bone toxicity. They are at risk of premature epiphyseal closure and, because of longer lifetime exposure to the drug, they are at higher risk for future development of the vertebral changes resembling diffuse idiopathic skeletal hyperostosis.

41. FACTORS IN THE DECISION TO USE RETINOIDS • Sex of the patient. Retinoid teratogenicity entails special risks for the female patient of childbearing potential. Although isotretinoin and acitretin are rapidly cleared from the body within days, etretinate can be detected in the serum for months or even years after the discontinuation of therapy. • Presence of other disorders that may be aggravated by retinoid use. Renal or hepatic compromise, preexisting hyperlipidemia, or a family history of hyperlipidemia or premature atherosclerotic cardiovascular disease should be considered in the therapeutic assessment.

42. FACTORS IN THE DECISION TO USE RETINOIDS • Concomitant use of other drugs with similar toxicities. Other drugs that are hepatotoxic (methotrexate), elevate serum lipids (estrogens, glucocorticoids), or rarely produce benign intracranial hypertension (tetracycline) should be avoided, if possible, or the patient must be carefully monitored during the clinical course.

43. Oral Antifungal Agents in Dermatology

44. Oral Antifungal Agents • In order to eliminate refractory dermatomycoses and onychomycosis, physicians must familiarize themselves with the systemic antifungal agents available

45. Three new oral antifungal agents that have been released are • the first oral allylamine, terbinafine (Lamisil) • the triazoles fluconazole (Diflucan) • itraconazole (Sporanox)

46. Rational selection of therapy • Rational selection of therapy depends on • the mechanism of action of each agent • an understanding of • tissue pharmacokinetics, • spectrum of clinical activity, • potential adverse reactions, • significant drug interactions, • efficacy, • optimal dosage protocols.

47. Systemic GlucocorticoidsAgents in Dermatology

48. Systemic Glucocorticoids • Glucocorticoids are a mainstay of dermatologic therapy because of their potent immunosuppressive and anti-inflammatory properties.

49. BIOLOGY of Glucocorticoids • The major naturally occurring glucocorticoid is cortisol (hydrocortisone). • The daily secretion of cortisol ranges between 10 and 20 mg, with a diurnal peak around 8 A.M. • Cortisol has a plasma half-life of 90 min. • It is metabolized primarily by the liver, although it exerts hormonal effects on virtually every tissue in the body. • The metabolites are excreted by the kidney and the liver.

50. BIOLOGY of Glucocorticoids • Glucocorticoids profoundly affect the replication and movement of cells • Glucocorticoids affect cell activation, proliferation, and differentiation • They modulate the levels of mediators of inflammation and immune reactions, • as seen with the inhibition of • IL-1, IL-2, IL-6, and TNF synthesis (or release)