Thyroid hormones and antithyroid drugs

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Thyroid hormones and antithyroid drugs
Dept of Pharmacology Shi-Hong Zhang
(???) shzhang713_at_zju.edu.cn
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Thyroid gland
Front view
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Thyroid hormones
1. Uptake of iodide 2. Oxidation of iodide
(peroxidase) and iodination and coupling of
tyrosine 3. Formation of thyroxine (T4) and
triiodothyronine (T3) from iodotyrosine 4.
Secretion of thyroid hormones (proteolytic
enzymes) 5. Regulation by thyroid stimulating
hormone (TSH), T4, T3
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Hyperthyroidism
??
??,????
?????
????????
?????,??,????
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Hypothyroidism
simple goiter (???????)

• cretinism (???)

?
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Therapeutic drugs on thyroid dysfunction

• Hyperthyroidism
• antithyroid drugs
• thiourea derivatives ???
• iodine and iodides ?????
• ? receptor antagonists
• Radioiodines ???? 131I
• Hypothyroidism
• thyroid hormones
• iodine and iodides

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Antithyroid drugs

• Thiourea derivatives

?????
????
????
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Antithyroid drugs

• Thiourea derivatives
• 1. Pharmacological effects
• (1) Inhibiting the formation of thyroid hormones
  by interfering with iodination inhibiting
  peroxidation, then the iodination and coupling
• Symptom relieving 2-3 weeks
• Basic metabolic rate returning 1-2 months
• (2) Inhibiting peripheral deiodination of T4 T4
  ? T3 ? (propylthiouracil ?????)

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Antithyroid drugs

• Thiourea derivatives
• 1. Pharmacological effects
• (3) Inhibiting glucose metabolism by
  down-regulating ßreceptor
• (4) Immunosuppression TSI?

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Mechanism of inhibition of thyroid hormone
synthesis by thioureas Thioureas are oxidized by
oxidized thyroid peroxidase (TPO)
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Thiourea derivatives

• 2. Clinical uses
• (1) Non-operative therapy of hyperthyroidism
  latent period
• (2) Preoperative therapy of hyperthyroidism
  combined with iodide
• (3) Thyrotoxic crisis combined with larger dose
  of iodide, propylthiouracil
•  3. Adverse effects
• (1) Agranulocytosis (0.2)
• (2) Hypersensitivity
• (3) GI reactions
• (5) Goitrogenic action (goiter) TSH?

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Antithyroid drugs

• Iodine and iodides
• 1. Pharmacological effects
• (1) Small doses simple goiter
• (2) Larger doses inhibiting the release of
  thyroid hormones (proteolysis ?) and synthesis
• After iodide use, the thyroid vascularity is
  reduced, and the gland becomes much firmer, the
  cells become smaller.

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Mechanism of iodides
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Antithyroid drugs

• 2. Clinical uses
• (1) Simple goiter
• (2) Preoperative therapy of hyperthyroidism
  combined with thiourea derivatives
• (2) Thyrotoxic crisis combined with thiourea
  derivatives (propylthiouracil)
• Lugols solution ???? 5 iodine and 10
  potassium iodide

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Antithyroid drugs

• 3. Adverse effects
• (1) Acute effects hypersensitivity, angioedema,
  swelling of the larynx
• (2) Chronic intoxication (iodism)
• (3) Thyroid dysfunction exacerbation of
  hyperthyroidism, goiter

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Antithyroid drugs

• Radioiodines
• 131I, 125I, 123I
• Destroying thyroid tissue ßray
• Careful use for hyperthyroidism and
  differentiated thyroid carcinoma
• Radioactive iodine uptake test

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Antithyroid drugs

• ? receptor antagonists
• 1. Pharmacological effects
• (1) Heart ?1 block
• (2) CNS relieving anxiety
• (3) Presynaptic ?2 receptor NE release ?
• 2. Clinical uses
• Adjuvant therapeutic drug

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Pancreatic hormones antidiabetic drugs
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????? ??? ????
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Overview of Glucose Regulation by insulin
Glucose absorption
lipolysis
Insulin secretion
lipogenesis
Persistent Hepatic Glucose Output
Glucose disposal
Glycogenesis
Amended from Dinneen SF. Diabetes Med.
199714(suppl 3)S19-24.
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Different forms of diabetes mellitus
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prediabetic metabolic syndrome
Beta-cell failure
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Complications of diabetes mellitus

• Acute complications
• Diabetic ketoacidosis (?????)
• Hyperosmotic nonketotic coma(?????????)
• Chronic complications
• Cardiovascular diseases
• Renal damage
• Retinal damage
• Nerve degeneration
• Infection
• Myopathy
• etc.

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Pharmacological therapy

• Insulin
• Oral hypoglycemic drugs
• Insulin secretagogues (???????)
• Sulfonylureas ????
• Meglitinides (Non-SU) ????
• GLP-1 agonists and DPP-4 inhibitors
• Insulin sensitizers ??????
• Thiazolidinediones (TDs,??????)
• Biguanides ???
• a-glucosidase inhibitors a-????????
• Amylin analogue ?????????
• Aldose reductase inhibitor ?????

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A. Insulin
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Frederick Sanger (1918- )
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A. Insulin
1. Pharmacological effects (1) Carbohydrate
metabolism reducing blood glucose levels by
glycogenolysis ?, glycogen synthesis ?,
gluconeogenesis ? (ketone bodies ?), glucose
transport ?. (2) lipid metabolism fat synthesis
?, lipolysis ?, plasma free fatty acids ? (3)
Protein metabolism active transport of amino
acids ?, incorporation of amino acids into
protein ?, protein catabolism ? (4) Mechanism of
insulin actions Interacting with insulin
receptor
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A. Insulin
2. Clinical uses (1) Insulin-dependent patients
with diabetes mellitus (type 1 diabetes mellitus)
(2) Insulin-independent patients failure to
other drugs (3) Diabetic complications diabetic
ketoacidosis (?????), hyperosmotic nonketotic
coma(?????????) (4) Critical situations of
diabetic patients fever, severe infection,
pregnancy, trauma, operation (5) Others
promotion of K uptake into the cells
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A. Insulin

• 3. Preparations
• Fast-acting insulin
• Regular insulin ?????
• Monocomponent insulin ??????
• Start working 0.5-1h after injection, reach peak
  2-4h, and last 5-7h.

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A. Insulin

• 3. Preparations
• Intermediate-acting insulin
• Neurtral protamine hagedorn (NPH) ?????????
• Isophane insulin ????????
• Globin zinc insulin ???????
• Start working 1-1.5h after injection, reach peak
  8-12h, and last 24h.

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A. Insulin

• 3. Preparations
• Long-acting insulin
• Protamine zinc insulin(PZI) ????????
• Start working 4-8h after injection, reach peak
  14-20h, and last 24-36h.

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A. Insulin

• 3. Preparations
• Mixed insulin
• Human insulin isophane ????????
• Human insulin ????
• Start working 0.5h after injection, reach peak
  2-12h, and last 16-24h.

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A. Insulin

• 3. Preparations
• Fast-acting insulin analogs
• Insulin aspart ?????
• Insulin lispro ?????
• Start working 5-15 minutes after injection,
  reach peak at 1h, and last 4 hours.

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A. Insulin

• 3. Preparations
• Super-long acting insulin analogs
• Insulin glargine ?????
• Onsets 1-2 h after injection and continues to
  work for as long as 24 hours.
• Used to treat type 1 or type 2 diabetes
  mellitus.
• Less soluble than native human insulin at
  physiological pH, and precipitates in skin
  following subcutaneous injection, resulting in
  delayed absorption.

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• For patients who eat meals out, may consider use
  of an insulin pen.
• Most insulins now available as pen

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Insulin Pump and Glucose Monitoring
Insulin Pump Open Loop Patient sets basal
infusion rate and superimposed boluses
Continuous Glucose Monitor
Closed Loop insulin pump system is ultimate
goal infusion rate adjusted based on input from
continuous glucose monitor.
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A. Insulin
4. Adverse effects (1) Hypersensitivity treated
with H1 receptor antagonist, glucocorticoids (2)
Hypoglycemia adrenaline secretion (sweating,
hunger, weakness, tachycardia, blurred vision,
headache, etc.), treated with 50 glucose (3)
Insulin resistance acute, chronic (4)
Lipoatrophy and lipohypertrophy (5) Weight
gain (6) Refractive errors (7) Edema
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B. Oral hypoglycemic drugs

• Insulin secretagogues (???????)
• Sulfonylureas ????
• Meglitinides (Non-SU) ????(???????)
• GLP-1 agonists and DPP-4 inhibitors
• Insulin sensitizers ??????
• Thiazolidinediones (TDs,??????)
• Biguanides ???
• a-glucosidase inhibitors a-????????
• Amylin analogue ?????????
• Aldose reductase inhibitor ?????

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B. Oral hypoglycemic drugs
Sulfonylureas(????) Tolbutamide (D860)
????? Chlorpropamide ???? Glibenclamide ????
(???) Glipizide ????(???) Gliclazide ????
(???)
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Sulfonylureas
1. Pharmacological effects 1) Increase insulin
release blocking ATP sensitive K channel, Ca2
inflow ?
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Sulfonylureas
1. Pharmacological effects 2) Increase receptor
affinity to insulin (long-term use) 3) Promote
glucose uses 4) Increase sensitivity of ßcells
to glucose 5) Anti-uretic effect (Chlorpropamide
????) 6) Anti-platelet effect (Gliclazide????)
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Sulfonylureas
2. Clinical uses (1) Insulin-independent diabetic
patients (type 2) alone or combined with
insulin (2) Diabetes insipidus (???)
Chlorpropamide (????) anti-uretic hormone (ADH)
?
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Sulfonylureas
3. Adverse effects (1) GI reactions (2) CNS
reactions (3) Hypoglycemia especially in
elderly, hepatic or renal insufficiencies (4)
Others leukopenia (?????), cholestatic jaundice
(???????), hepatic damage
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Sulfonylureas
4. Drug interactions (1) Potentiation of
hypoglycemic effects replacement in plasma
protein binding salicylic acid, sulfates,
indomethacin, penicillin, warfarin, etc.
inhibition of hepatic microsomal enzymes
chloramphenicol, warfarin (2) Attenuation of
hypoglycemic effects induction of hepatic
microsomal enzymes phenytoin, phenobarbital,
etc. interactions in pharmacodynamics
glucagon, thiazides, etc.
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Non-SU Insulin Secretagogues

• Act by binding to SUR1 on beta cells to promote
  insulin secretion.
• Repaglinide (????) and Nateglinide (????) are
  current agents in class.
• Major advantage is rapid onset and offset
• Can dose just prior to meals with better
  post-prandial control
• Fewer overnight lows
• Ability to skip the dose if skip the meal.
• Efficacy for repaglinide appears to be similar to
  SUs

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Non-SU Insulin Secretagogues

• Hepatic metabolism permits use in patients with
  impaired renal function.
• Major side effect is hypoglycemia.
• Many drug interactions. Most concerning is
  gemfibrozil (????) which increases repaglinide
  (????) concentration and may result in prolonged
  effect.
• Cost may be an issue (1 or 2 mg tabs
  122.09/month at drugstore.com)

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GLP-1 agonists and DPP-4 inhibitors

• Exenatide (????) only available as injection
• Sitagliptin (????)

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B. Oral hypoglycemic drugs
Insulin sensitizers Thiazolidinediones (TZDs)
???????? Rosiglitazone ????
Pioglitazone ???? Biguanides (???)
Metformin ????
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Thiazolidinediones
1. Pharmacological effects Selective agonists
for nuclear peroxisome proliferator activated
receptor-? (PPAR ?, ?????????????), increasing
glucose transport into muscle and adipose
tissue. (1) Lowering insulin resistance (2) Lipid
metabolism regulation TG, free fatty acid ? (3)
Preventive effects on diabetic complications (4)
Improve ? cell function
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Thiazolidinediones
2. Clinical uses Used for treatment of
insulin-resistant diabetic patients or type 2
patients Delayed onset of action takes
8-12 weeks to achieve maximal effect Absence
of hypoglycemia when used as monotherapy No
reliance on renal excretion
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Thiazolidinediones
3. Adverse effects Edema at higher doses
and used with insulin, in older patients,
patients with multiple medical problems, patients
with underlying CAD or CHF Headache Myalgia
(??) GI reactions Hepatic damage
(troglitazone). Contraindicated with Class III or
IV heart failure or significant liver disease.
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Biguanides
1. Pharmacological effects Increasing glucose
uptake in fat tissues and anaerobic glycolysis in
skeletal muscles Decreasing glucose
absorption in gut and glucagon release  2.
Clinical uses Mild insulin-independent
patients with obesity Major advantages Lack
of weight gain Absence of hypoglycemia Low cost
with generic prep. 3. Adverse effects Severe
lactic acidosis, malabsorption of vitamin B12 and
folic acid 
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B. Oral hypoglycemic drugs
Alpha-Glucosidase inhibitors
Acarbose-Precose ???? Miglitol-Glyset
???? Voglibose ?????
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Alpha-Glucosidase inhibitors

• Acarbose is an oligosaccharide, whereas miglitol
  resembles a monosaccharide.
• Miglitol is fairly well-absorbed by the body, as
  opposed to acarbose.
• Reducing intestinal absorption of starch (??),
  dextrin (??), and disaccharides (??) by
  inhibiting the action of intestinal brush border
  ?-glucosidase.
• Acarbose also blocks pancreatic alpha-amylase
  (???).
• Used for diabetes mellitus type 2, particularly
  with regard to postprandial hyperglycemia.

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Alpha-Glucosidase inhibitors

• Must be taken at the start of main meals to have
  maximal effect.
• Efficacy will depend on the amount of complex
  carbohydrates in the meal.
• Absence of hypoglycemia when used as monotherapy.
  
• Side effects gastrointestinal side effects such
  as flatulence and diarrhea voglibose, in
  contrast to acarbose, has less of GI side effects
  and more economical.

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Amylin analogues
B. Oral hypoglycemic drugs

• Mechanism of action
• Inhibits postprandial glucagon secretion, thereby
  reducing hepatic glucose production
• Slows gastric emptying
• Promotes satiety? reduces caloric intake
• Pramlintide (Symlin????) is the only amylin
  analog on the market
• As adjunct therapy for patients with type 1 or 2
  diabetes to control postprandial glucose
• Increases the risk of severe hypoglycemia
• Main side effect is nausea.

Riddle and Drucker. Diabetes Care 2006 29435-49.
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Alsose reductase
B. Oral hypoglycemic drugs

• Aldose reductase activity increases in those
  tissues that are not insulin sensitive, including
  lenses, peripheral nerves and glomerulus.
• Epalrestat (????) inhibits aldose reductase.
• Delay the progression of diabetic neuropathy and
  ameliorate the associated symptoms of the
  disease.

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B. Oral hypoglycemic drugs
Mechanism of Action Class of Agent Indications for Use
Stimulators of insulin secretion Sulfonylureas Glinides Primary
Insulin sensitizers Thiazolidinediones (PPAR agonists) Primary or Secondary
Suppressors of hepatic glucose production Biguanides Primary or Secondary
Reduces postprandial glucose excursion Alpha-glucosidase Inhibitors Glinides Secondary
Enhance incretin/GLP1 action GLP1 analogs DPPIV inhibitors Secondary
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Type II Diabetic Medications
Medication Site of Action/Mechanism Side-Effects
Sulfonylurea (eg. glyburide) Augments insulin secretion, binds SUR Hypoglycemia, caution renal insufficiency, elderly
Thiazolidinediones (eg. rosiglitazone) PPARg receptor/increased insulin sensitivity Liver, LE edema, congestive heart failure, MI
Biguanide (metformin) Reduced hepatic gluconeogenesis GI upset, Lactic acidosis (very rare), only use if creatininelt1.5 mg/dl
Glinides (repaglinide) Bind SUR, short action Hypoglycemia, caution in renal insufficiency
Alpha-glucosidase inhibitors (acarbose) Inhibits brush border enzyme/Reduce glucose absorption Flatulence, diarrhea
Incretins/GLP-1 (exenatide) Stimulates insulin, delays gastric emptying, satiety Nausea, vomiting (given by injection)
DPP4 Inhibitors (vildagliptin) Inhibits GLP1 breakdown GI side effects
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Adrenocorticoids adrenocortical antagonists
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• Adrenocortical hormones
• Glucocorticoids
• (Glucocorticosteroids)
• Mineralocorticoids
• Sex hormones

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Zona Faseciculata
Zona Reticularis
Androgens
Adrenaline
Structure and function of adrenal cortex
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ACTH
Regulation of glucocorticoids
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A. Glucocorticoid drugs
Basic structure of glucocorticoid drugs
18
H
12
C
D
13
16
19
15
14
1
9
2
8
10
A
B
????
3
5
7
4
6
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A. Glucocorticoid drugs
Structure
(1) 1??2???????????? cortisone ?
prednisone hydrocortisone ?
prednisolone. (2) 16????? triamcinolone(????)
. (3) 6????? 6?-methylprednisone
(6??????). (4) 9?????? fludrocortosone
(?????).
????
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H
12
16
18
13
D
C
14
15
1
9
2
8
10
A
B
3
5
7
4
6
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Hydrocortisone (?????, Cortisol)
Cortisone (???)
H
Prednisone (???)
Prednisolone (????)
Fluocinolone (???)
(????)
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A. Glucocorticoid drugs
2. ADME and properties of commonly used
drugs Cortisone and prednisone are reduced and
transformed to hydrocortisone and prednisolone
(active forms) in the liver Metabolism will be
increased by hepatic enzyme inductors
(phenobarbital, phenytoin, rifampine, etc.)
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A. Glucocorticoid drugs
Commonly used drugs Short-acting hydrocortisone
(cortisol) ?????
cortisone ??? Intermediate-acting prednisone
???, ???
prednisolone ????, ???? Long-acting
dexamethasone ???? Topical
fluocinolone ???
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A. Glucocorticoid drugs
binding to glucocorticoid receptor (GR)
nuclear translocation binding to
GRE or nGRE regulating related gene
transcription biological effects (usually
slow)
Mechanisms of glucocorticoid actions
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Genetic action mode of glucocorticoid drugs
CBG corticosteroid binding globulin S
glucocorticoid steroids GR glucocorticoid
receptor HSP heat shock protein IP
immunophilin GRE glucocorticoid-response element
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Dexamethasone
Nuclear translocation of glucocorticoid receptors
(GR)
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Examples of glucocorticoid actions Inhibition
of proinflammatory gene transcription (AP-1 and
NF?B)
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A. Glucocorticoid drugs
1. Pharmacological effects (1) Effects on
metabolism (2) Permissive action (3)
Anti-inflammatory effects (4) Effects on immune
and allergy (5) Anti-shock (6) Other effects
antipyretic effects effects on blood and
blood-forming organs skeletal system
CNS effects
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A. Glucocorticoid drugs

• (1) Effects on metabolism
• ?Glucose metabolism
• gluconeogenesis?, glucose oxidation and
  utilization?
• ? blood glucose?.
• ?Protein metabolism
• synthesis?, degradation?.
• ?Lipid metabolism
• plasma cholesterol?, fat redistribution
  (central obesity moon face, buffalo hump,
  etc.).
• ?Water and electrolytic metabolism
• Na excretion?, K excretion?, Ca2
  excretion? and absorption?.

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Weaker action of glucocorticoid drugs
(cortisol?????) on mineralocorticoid receptor
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A. Glucocorticoid drugs
 (2) Anti-inflammatory effects 1) Acute a)
Increasing anti-inflammatory proteins and
enzymes inducing lipocortin (???), inhibiting
phospholipase A2 activity, decreasing mediators
PGs, LTs, PAF inducing vasocortin (?????),
decreasing microvascular permeability
inhibiting the expression of COX-2, inducible
NOS, etc. b) Inhibiting cytokines decreasing the
transcription and activities of TNFa, IL-1, IL-2,
IL-5, IL-6, IL-8, etc. c) Inhibiting adhesion
molecules d) Inducing apoptosis of inflammatory
cells
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A. Glucocorticoid drugs
 (2) Anti-inflammatory effects Chronic
inhibiting fibroblast proliferation
deposition of
collagen
cicatrization (????)
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Inhibition of proinflammatory gene transcription
(AP-1 and NF?B)
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A. Glucocorticoid drugs
(3) Suppressive effects on immune and allergy a)
inducing apoptosis of T and B lymphocytes b)
inducing DNA degradation of T and B
lymphocytes c) Inhibiting DNA and protein
synthesis of T and B lymphocytes d) inhibiting
transcription factor activity (eg. AP-1,
NF-?B e) Inhibiting mast cells (anti-allergic) (4)
Permissive action Potentiating the effects of
catecholamines and glucagon
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A. Glucocorticoid drugs
(5) anti-shock a) improving cardiovascular
functions b) inhibiting the production of
inflammatory factors c) stabilizing lysosome
membrane decreasing the release of myocardial
depressant factor (MDF) d) increasing the
tolerance to endotoxin from bacteria
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A. Glucocorticoid drugs
(6) Other effects a) antipyretic effects b)
effects on blood and blood-forming organs red
cell ? lymphocytes ? neutrophils ?
(function ?) eosinophils ? platelets ? c)
skeletal system osteoporosis d) CNS increasing
excitability (elevated mood, euphoria, insomnia,
restlessness, increased motor activity)
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A. Glucocorticoid drugs
3. Clinical uses (1) Immune diseases a)
autoimmune disorders rheumatic fever, rheumatic
carditis, rheumatic arthritis, rheumatoid
arthritis, osteoarthritis, systemic lupus
erythematosus, polyarthritis nodosa, nephritic
syndrome, etc. b) rejection of organ
transplantation c) allergic diseases urticaria
(??), serum sickness, contact dermatitis, drug
allergic reactions, chronic severe asthma, status
asthmaticus, angioneurotic edema, etc.
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A. Glucocorticoid drugs
3. Clinical uses (2) Severe infection and
inflammation a) acute severe infections merely
suppressing inflammatory manifestations but at
times lifesaving Caution ?combination with
effective anti-microbial drugs ?Large dose
?short term administration ! Usually be not used
in viral and fungal infections except for those
with cerebral edema or severe systemic
symptoms b) prevention of sequelae (???) of some
types of inflammation, such as in brain, heart,
eye, joint, etc.
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A. Glucocorticoid drugs
3. Clinical uses (3) Septic shock Caution
larger dose, short-term, and combined with
antimicrobial drugs.  (4) Hemological diseases
acute lymphocytic leukemia, lymphomas, aplastic
anemia (???????), hemolytic anemia,
leukocytopenia, thrombocytopenia, etc. (5)
Topical applications skin, eye, respiratory
tract, joint (local injection) (6) Some types of
tumors breast and prostatic cancers, acute
lymphocytic leukemia, etc.
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A. Glucocorticoid drugs
4. Adverse effects (1) Effects resulting from
continued used of large doses a)
Hypercorticism-like syndrome central obesity
(moon face, buffalo hump, etc.) hypertension
glycosuria, hypokalemia etc. b) Increasing
susceptibility to infections Caution
specific antimicrobial drugs should be
administered with GCs c) Ingestive system peptic
ulcers, etc.
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A. Glucocorticoid drugs
4. Adverse effects d) Cardiovascular system
hypertension, arteriosclerosis e) Myopathy and
osteoporosis vertebral compression fractures,
spontaneous fractures, especially in
postmenopausal women f) CNS behavioral
disturbances, induction of epileptic seizures g)
Inhibition or arrest of growth in children
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?
ACTH
Suppression of hypothalamic-pituitary-adrenal axis
and glucocorticoid drugs
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A. Glucocorticoid drugs
4. Adverse effects (2) Withdrawal syndrome
a) Suppression of hypothalamic-pituitary-adrenal
axis b) Exacerbation of the underlying
diseases (rebound)  (3) Contraindications
psychiatric disorders epilepsy active peptic
ulcers fractures hypercorticism severe
hypertension diabetes mellitus viral or fungal
infections, etc.
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Balance the ratio of benefit/risk before the use
of GCs !
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A. Glucocorticoid drugs
5. Applications (1) Replacement therapy usually
using hydrocortisone (2) Prompt intensive
treatment i.v. gtt hydrocortisone,
dexamethasone (3) Long-term therapy oral
prednisone or prednisolone morning single
dose alternate-day therapy Notes for
less severe and less sustained patients
less suppression on hypothalamic-pituitar
y-adrenal (HPA) axis (4) Typical applications
skin eye respiratory tract
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Some indications for the use of glucocorticoids
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B. Mineralocorticoid drugs

• Aldosterone ???
• Roles
• Na excretion ?, K excretion ?
• edema
• hypertension
• hypokalemia, etc.
• Used for adrenocortical dysfunction with
  imbalance of water and electrolytes

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Action of aldosterone on mineralocorticoid
receptor
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AIP

• Mineralocorticoid receptor signal transduction.
• MR mineralocorticoid receptor
• HRE hormone responsive element.
• AIP Aldosterone induced protein

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C. Adrenocorticotropic hormone and corticosteroid
synthetase inhibitors

• Adrenocorticotropic hormone (ACTH)
• Used for diagnosis of adrenocortical function
• inhibition of secretion of adrenocortical
  hormones after long-term glucocorticoid drug use
• Easily inducing allergy to ACTH

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C. Adrenocorticotropic hormone and corticosteroid
synthetase inhibitors

• 2. Corticosteroid synthetase inhibitors
• Mitotane ???
• Metyrapone ????
• Aminoglutethimide ????
• Used for adrenocortical tumors or
• hypercorticism