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1、Chapter 20 Drugs affecting endocrine system【Learning points】Part I.Thyroid and anti-thyroid drugs 1.Thyroid hormones Thyroid hormones,T4 and T3,are synthesized in thyroid follicular epithelial cells.idodine and tyrosine are materials for synthesis of thyroid hormones.Under the action of peroxidase,i
2、odine is transformed to active iodine.Active iodine binds to tyrosine residues on thyroglobulin to form moniodine tyrosine(MIT)and bisiodine tyrosine(DIT).MIT or DIT coupled to DIT to form T4 and T3.Synthesis and secretion of thyroid hormones are regulated by thyrotropin(TSH)and thyrotropin releasin
3、g hormone(TRH).Thyroid hormones maintain the normal growth and development of the human body,and promote metabolism.Moreover,thyroid hormones improve the reactivity of the sympathetic nervous system.Thyroid hormones are mainly used in hypothyroidism and simple goiter.Excess thyroid hormones cause hy
4、perthyroidism.2.Anti-thyroid drugs 2.1 Thiourea drugs Thiourea drugs are classified into thiouracil and imidazoles,thiouracil includes methoxan and propoxan,imidazoles includes methimazole and carbimazole.They inhibit the synthesis of thyroid hormones via inhibition of thyroid peroxidase,the couplin
5、g of tyrosine to iodine,the transformation of T4 into T3.Additionally,thiourea drugs show immuno-suppression.Thiourea drugs are commonly used for paitients with hyperthyroidism.Thiourea drugs are often used in preoperative preparation of hyperthyroidism for four weeks before surgery.They are used fo
6、r children and adolescents with hyperthyroidism,for patients with postoperative recurrence of hyperthyroidism,and patients with unresectable hyperthyroidism and resistance to radioactive iodine treatment.The patient with hyperthyroidism who has severe heart,liver,kidney,hemorrhagic diseases.Thiourea
7、 drugs controlled the thyroid crisis as well as hyperthyroidism.Their adverse effects include skin pruritus,drug rash,a few with fever;anorexia,vomiting,abdominal pain,diarrhea,etc.granulocytosis(hemogram should be monitored),goiter and hypothyroidism.Pregnant women with caution or not,breast-feedin
8、g women prohibited.2.2 Iodine and iodide Iodide and iodine serve as materials for synthesis of thyroid hormones.iodine or iodide at low dose prevents simple goiter via increase of thyroid hormones systhesis.While iodine or iodide at large dose inhibits thyroid hormones release.Iodine or iodide is co
9、mmonly used in hyperthyroidism and crisis to decrease T3 and T4 release via inhibiton of TSH or TRH release.Iodine or iodide at large dose is also used in preoperative preparation of hyperthyrodism for two weeks before surgery(Thiourea drugs 4w+Iodine 2w)to reduce bleeding and thyroid crisis during
10、surgery.Iodine or iodide shows weak adverse effects,such as throat discomfort,intraoral metallic taste,respiratory irritation,etc.fever,rash,dermatitis,vascular neuroedema,severe laryngeal edema;iodine or iodide may induce thyroid dysfunction such as hyperthyroidism,hypothyroidism and goiter when it
11、 is used at large dose over two weeks.2.3 receptor blockers Propranololol is an adjuvant therapy for hyperthyroidism and thyroid crisis to reduce sympathetic activation.They are commonly used in combination with antithyroid drugs in hyperthyroidism and thyroid crisis.2.4 Radioiodine iodine Radioiodi
12、ne(131I)produce rays,resulting in acinar epithelium damage,atrophy,reduce secretion.It could be used in unresectable hypothyroidism,allergy to thioureas,postoperative recurrence.131I overdose leads to hypothyroidism Part II Insulin and other glucose-lowering drugs Diabetes can be mainly classified i
13、nto insulin-dependent diabetes(IDDM,type1)and noninsulin-dependent diabetes mellitus(NIDDM,type2).IDDM depends on insulin injection.NIDDM is usually controlled by sulfonylurea,biguanidine,-glucosidase inhibitors,insulin sensitizers and postprandial blood glucose regulators.1.Insulin Insulin is an ac
14、idic protein composed of two polypeptide chains.Insulin reduces blood glucose,promotes fat synthesis,protein and glycogen synthesis and storage,accelerates glucose uptake and oxidation.Insulin activate the receptor protein kinase in the insulin receptor.Insulin is commonly used in diabetes,including
15、 type1 diabetes(NIDDM),poorly controlled type2 diabetes;diabetes with acute or severe complications,such as ketoacidosis and hyperosmotic coma,severe infection,trauma,surgery,pregnancy,etc.;potassium deficiency in cells.Insulin can be divided into four types according to the effect rate,activity pea
16、k time and action duration:(1)quick-acting insulin;(2)moderate-acting insulin;(3)long-acting insulin;(4)single-component insulin.Insulin leads to hypoglycemia,the most common adverse reaction,should be treated with glucose.As a xenogenic peptide,insulin may induce mild allergic reaction,it could be
17、avoided by using the human recombinated insulin.For repeated administration,insulin resisitance may be induced because of insulin antibody production,insulin receptor down-regualtion,attenuation of signal transduction of insulin receptor,and other.Fat atrophy is often seen at the injection site.2.Or
18、al glucose-lowering drugs 2.1 Insulin sensitizer Thiazolidinediones:rosiglitazone,pioglitazone,traglitazone,cycloglitazone,englitazone,etc.are commonly used for insulin resistance.They improve insulin resistance,reduce hyperglycemia,and enhance islet cell function.They improve the disorder of fat me
19、tabolism,and prevent vascular complications in type 2 diabetes mellitus.This may benefit the cardiovascular functions.They are mainly used in the treatment of insulin resistance and type 2 diabetes.Low incidence of hypoglycemia occurrs.Side effects include muscle and skeletal pain,headache,digestive
20、 tract symptoms and so on.Traglitazone has obvious hepatotoxicity,such as liver failure or death,to few sensitive patients.2.2 sulfonylureas Sulfonylureas are commonly used drugs for type2 diabetes:toluene sulfobutylurea,chlorosulfopropylurea,glibenclamide,glipizide,glimepiride,glizide,etc.They redu
21、ce blood glucose via modulation of insulin release from cells,and they enhance the insulin actions,such as binding to receptor,decrease of insulin metabolism.Among them,chlorosulfopropylurea and glibenclamide show effects on diabetes insipidus but only chlorosulfopropylurea is used in diabetes insip
22、idus.The third generation sulfonylureas have anti-coagulation,it benefits the cardiovascular complications in diabetes.Common adverse reactions of sulfonylureas are skin allergy,gastrointestinal discomfort,lethargy and neuralgia,which can also cause liver damage,especially chloropropylurea.The diabe
23、tic patients,particularly the old patients,with poor kidney functionmay have the higher incidence of liver and kidney dysfunction.2.3 Biguanides Biguanides include phenethylfuming and methylfuming(metformin).Biguanides promote the hepatic glucoeogenesis but not the release of insulin.They are mainly
24、 used in mild but not severe diabetes.They may cause lactic acidemia in higher blood glucose.2.4-glucosidase inhibitors Acarbose,an-glucosidase inhibitor,reduces the hydrolysis of carbohydrates in gastrointestine and the absorption of glucose.It is effective in patients with type1 and type2 diabetes
25、.The main adverse reaction is gastrointestinal reaction.2.5 Other glucose-lowering drugs Reglinide stimulates insulin release from cells and is used in type 2 diabetes,and the diabetic complications such as diabetic nephropathy.Analogs of Glucagon-like peptide-1(GLP-1),such as incretin,activated lon
26、g-acting GLP-1 receptor.They are used in metformin,sulfonylurea resistance diabetes.The most common side effects are gastrointestinal reactions.DPP-IV inhibitors,including sitagliptin and saxagliptin,block dipeptidyl peptidase-IV.They are used in type II diabetes monotherapy or in combination with s
27、ulfonylurea,metformin or insulin.Part III adreanal hormones 1.Glucocorticoids 1.1 Pharmacological effects of glucocorticoids Glucocorticoids are commonly used in cilinic for several diseases or emergency.Glucocorticoids,such as cortisone,dexamethasone,beclometasone etc.,show pharmacological effects
28、on inflammatory reaction,immune reaction and metabolism etc.1.1.1 Glucocorticoids modulate the metabolism Glucocorticoids modulate the metabolism,this may bring the adverse effects when they are used chronically at large dose.Glucocorticoids elevate gluconeogenesis,reduce glucose uptake and utilizat
29、ion in tissue,resulting in blood glucose increase.Glucocorticoids enhance protein metabolism,especially the catabolism of protein,and increase the excretion of serum amino acids,resulting in negative nitrogen balance.Glucocorticoids at large dose inhibit protein synthesis.Glucocorticoids also stimul
30、ate subcutaneous fat redistribution,leading to central obesity.Besides glucose,protein and fat metabolism,glucocorticoids show effects on water and electrolyte,increase Na+reabsorption and K+secretion of renal tubules,resulting in water retention and electrolyte disturbance.Moreover,glucocorticoids
31、induce mRNA and tRNA synthesis,resulting in inhibition of cell synthesis and metabolism.1.1.2 anti-inflammatory effects and immunosuppression Glucocorticoids inhibit chemistry-,radio-or biology-induced inflammatory reaction,Glucocorticoids relieve the symptoms of inflammatory,such as red,swelling,he
32、at,pain,scars and other symptoms.Glucocorticoids decrease capillary permeability,leukocyte infiltration and phagocytosis,the release of inflammatory mediators.In the late stage of inflammation,glucocorticoids reduce fibroblast proliferation and collagen synthesis and inhibit scar formation.The mecha
33、nisms underlying anti-inflammatory effects assoicate with the gene expression.Glucocorticoids bind to the corresponding intracellular receptor,the compound is translocated into nuclear to initiate the gene expression via GRE,and then some proteins,such as cytokinesNOS and COX-2 are expressed.Glucoco
34、rticoids also modulate inflammatory reaction via HSP90.Glucocorticoids depress the immune system function,including antigen presentation,antibody production and antigen-antibody induced reaction,decrease functions of monocytes and macrophages,etc.Thus,glucocorticoids show strong anti inflammatory an
35、d immunosuppression.1.1.3 anti-shock Glucocorticoids often are used in severe shock.Glucocorticoids stabilize the lysosomal membrane and reduce the formation of myocardial inhibitory factors,and glucocorticoids inhibit the production of certain inflammatory factors.Glucocorticoids enhance the tolera
36、nce to bacterial endotoxin and elevate cardiac contractility and vasoconstriction.1.1.4 permissive action There is no direct effect on some tissue cells,but it can create favorable conditions for other drugs to exert pharmacological effects,which is called permissive action.1.1.5 other roles There a
37、re other pharmacological effects,such as antipyretic effect;increase of central excitability,osteoporosis,reduction of lymphocytes while elevation of platelets,red blood cells and neutrophils in the blood.1.2 Clinical applications 1.2.1 Glucocorticoids are often used in severe infection or inflammat
38、ory diseases.For severe infections,such as infectious shock,glucocorticoids must be combined with sufficient effective antibiotics or anti-virus.Glucocorticoids also used to prevent or reduce inflammatory sequelae,such as scar and adhesion.1.2.2 Glucocorticoids are used in autoimmune diseases,organ
39、transplant rejection and allergic diseases,severe rheumatic fever,systemic lupus erythematosus and nephrotic syndrome;urticaria,vascular neuroedema,bronchial asthma and anaphylactic shock;Organ transplant rejection.1.2.3.Glucocorticoids are used to treat hematopathy.It has certain therapeutic effect
40、 on acute lymphoblastic leukemia,aplastic anemia,granulocytopenia,thrombocytopenia and Henoch-Schonlein purpura.1.2.4.Glucocorticoids are used in eczema,contact dermatitis,psoriasis and inflammation in front of the effect.1.2.5 replacement therapy.1.3.Adverse effects 1.3.1.Glucocorticoids show many
41、adverse effects,especially at large dose,long-term use or abuse,including(1)gastric and duodenal ulcers;(2)induction or aggravation of an infection;(3)Iatrogenic adrenocortical hyperfunction;(4)Cardiovascular complications:atherosclerosis and hypertension;(5)Osteoporosis,muscular atrophy,slow wound
42、healing,etc.;(6)Diabetes;(7)Other:Persons with history of epilepsy or psychosis are forbidden or used with caution.1.3.2.Withdrawal symptom:(1)Iatrogenic adrenocortical insufficiency.(2)Rebound phenomenon:the recurrence or deterioration of the original disease caused by the sudden withdrawal of drug
43、s or excessive reduction.Both can be controlled via stopped the drug gradually.1.3.3.Contraindications for severe psychosis(past or present)and epilepsy,corneal ulcers,active peptic ulcer disease,recent gastrointestinal anastomosis,fractures,acute trauma,adrenocortical hyperfunction,diabetes,severe
44、hypertension,pregnant women,infections beyond the control of antimicrobial agents such as measles,mold infection,etc.1.3.4.Usage and duration of treatment:(1)strong glucocorticoids with shorten half life are suggested for acute or emergency at large dose,such as infectious shock;(2)For most of immun
45、e diseases,transplantation and inflammatory diseases,glucocorticoids are commonly used at general dose with long-term therapy;(3)Cortisol replacement therapy at small dose 2.Salt corticosteroids There are aldosterone and oxycarbazone.Aldosterone mainly acts on the distal kidney tubules,promoted reab
46、sorption of Na+and Cl-and excretion of K+,H+.It is combined with hydrocortisone to treat chronic adrenocortical dysfunction.3.Corticotrophin and corticosteroid inhibitors 3.1 Corticotrophin Corticotrophin stimulates the secretion of corticosteroids from adreanal gland.It can be used to evaluate the
47、function of anterior pituitary-adrenocortical cortex and monitor the adreanal cortical function before glucocorticoids withdrawal after chronic administration.3.2 Corticosteroids inhibitors 3.2.1 Mitotan selectively induces in atrophy and necrosis of adrenocortical fascicular and reticular cells.It
48、is mainly used for unresectable cortical carcinoma,resected recurrent carcinoma and adjuvant therapy after operation of cortical carcinoma.3.2.2 Methadone inhibits 11-hydroxylase.It is used incortical cancer and hypercortisolism caused by adrenal cortical tumors and ACTH tumors.3.2.3 Amlumit inhibit
49、s cholesterol conversion to 20-hydroxycholesterol,it is commonly used in cushing syndrome that caused by ACTH over-secretion.Part IV estrogens and androgens Sex hormones,including the estrogens and androgens,are produced by the gonads.They are necessary for conception,embryonic maturation,and develo
50、pment of primary and secondary sexual characteristics at puberty.They are used in contraception,supplementary therapy,etc.Estrogen receptor modulators,are used in breast cancer,osteoporosis.1.Estrogens Estrogens are produced and released from ovary.Estrogens bind to the corresponding receptors,or su