Transcript Glucocorticoid drugs

Drugs affecting endocrine
system
Weiwei Hu
[email protected]
88208226
Dept. Pharmacology,
Medical School,
Zhejiang University
 Drugs related to adrenocortical hormones
 Thyroid hormones and antithyroid drugs
 Insulin and oral hypoglycemic drugs
Cortex:adrenocorticoid
Glucocorticoids
(Glucocorticosteroids)
Mineralocorticoids
Sex hormones
Medulla:epinephrine
norepinepherine
Adrenocorticoid
 Glucocorticoids :
hydrocortisone, cortisone
 Mineralocorticoids：
aldosterone，desoxycortone
 Sex hormones
黄山药
穿地龙
薯蓣属植物（黄山药、穿地龙）
提取薯蓣皂苷元合成皮质激素
Basic structure of adrenocorticoid drugs
甾核结构
Cortisone
(可的松)
aldosterone
(醛固酮)
Hydrocortisone
(氢化可的松)
Structure and Activity Relationship
(1) 1位和2位碳之间改成不饱和的双键:
cortisone  prednisone
hydrocortisone  prednisolone
基本结构
Cortisone
(可的松)
Hydrocortisone
(氢化可的松,
Cortisol)
Prednisone
(泼尼松)
Prednisolone
(泼尼松龙)
Structure and Activity Relationship
(2) 9引入氟原子:
fludrocortosone (氟氢可的松).
基本结构
(3)引入甲基:
6-methylprednisolone,dexamethasone
(6甲泼尼龙, 地塞米松).
(4) 16引入羟基:
triamcinolone(曲安西龙).
Fludrocortisone
(氟氢可的松)
(地塞米松)
Triamcinolone
(曲安西龙)
Non-gene modulation
Gene modulation (GCS, TH)
Mechanisms of glucocorticoid actions
binding to glucocorticoid receptor (GR)
nuclear translocation
binding to GRE or nGRE
regulating related gene transcription
biological effects (usually slow)
Action mode of
glucocorticoid drugs
CBG: corticosteroid binding
globulin
S: glucocorticoid steroids
GR: glucocorticoid receptor
HSP: heat shock protein
IP: immunophilin
GRE: glucocorticoidresponse element
Nuclear
translocation of
glucocorticoid
receptors (GR)
Dexamethasone was used
GR was labeled with
green fluorescent protein
 1. Pharmacological effects
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Mechanisms of glucocorticoid actions
(1) Effects on metabolisms
(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
Glucocorticoid drugs
 (1) Effects on metabolisms
 a) Carbohydrate: blood glucose ↑: gluconeogenesis ↑,
glycolysis↓, glucose utilization↓
 b) Protein: synthesis ↓, degradation ↑
 c) Lipid: long term use: plasma cholesterol ↑, fat redistribution
(central obesity: moon face, buffalo hump)
 d) Water and electrolytic: Na+ excretion ↓, K+ excretion ↑,
Ca2+ excretion↑and absorption↓
Glucocorticoid drugs
 (2) Permissive action
 Potentiating the effects of catecholamines and
glucagon
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 (3) Anti-inflammatory effects
 Acute: inhibiting microvascular leakage
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leukocyte infiltration
 Chronic: inhibiting fibroblast proliferation
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deposition of collagen

cicatrization (瘢痕形成)
Glucocorticoid drugs
 a) Inhibiting inflammation related proteins or enzymes
 inducing lipocortin, inhibiting phospholipase A2 activity,
decreasing mediators: PGs, LTs, PAF
 inhibiting the expression of PLA2, COX-2, inducible NOS, etc.
 inducing ACE, degrade bradykinin.
PAF
Lipid-derived
autocoids and
related drugs
Glucocorticoid drugs
a) Inhibiting inflammation related proteins or enzymes
inducing lipocortin, inhibiting phospholipase A2 activity,
decreasing mediators: PGs, LTs, PAF
inhibiting the expression of COX-2, inducible NOS, etc.
inducing ACE, degrade bradykinin.
b) Inhibiting cytokines: decreasing the transcription and
activities of TNF, IL-1, IL-2, IL-5, IL-6, IL-8, etc.
c) Inhibiting adhesion molecules
d) Inducing the apoptosis of inflammatory cells
Glucocorticoid drugs
 (4) Effects on immune and allergy
 Suppressing immunological functions and allergy
 a) inhibit DNA, RNA and protein synthesis, and induce
the DNA degradation of lymphocytes
 b) inducing apoptosis of lymphocytes
 c) inhibiting transcription factor nuclear factor B (NFB) and increase expression of I B a
 d) inhibit the allergic mediator production
(4) Effects on immune and allergy
Glucocorticoid drugs
 (4) Effects on immune and allergy
 Suppressing immuneological functions and allergy
 a) inhibit DNA, RNA and protein synthesis, and induce
the DNA degeneration of lymphocytes
 b) inducing apoptosis of lymphocytes
 c) inhibiting transcription factor nuclear factor B (NFB) activity and increase expression of I B 
 d) inhibit the allergic mediator production
Examples of glucocorticoid actions:
Inhibition of proinflammatory factors (AP-1 and NFB)
Glucocorticoid drugs
 (4) Effects on immune and allergy
 Suppressing immuneological functions and allergy
 a) inhibit DNA, RNA and protein synthesis, and induce
the DNA degeneration of lymphocytes
 b) inducing apoptosis of T and B lymphocytes
 c) inhibiting transcription factor － such as nuclear
factor B (NF-B) or activating protein-1 (AP-1) activity
 d) inhibit the allergic mediator production
Glucocorticoid drugs
 (5) Anti-shock
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Septic 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
Glucocorticoid drugs
 (6) Other effects
 a) antipyretic effects
 b) effects on blood and blood-forming organs
 red blood cells ; lymphocytes ; neutrophils  (function );
eosinophils ; platelets 
 c) skeletal system: osteoporosis
 d) CNS: increasing excitability (elevated mood, euphoria,
insomnia, restlessness, increased motor activity)
Glucocorticoid drugs
 2. ADME and properties of commonly used
drugs
 Binding to corticosteroid-binding globulin (CBG, 皮质激
素运载蛋白) in the plasma
 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.)
Glucocorticoid drugs
Commonly used drugs
 Short-acting: hydrocortisone (cortisol)
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cortisone 可的松
氢化可的松
 Intermediate-acting: prednisone 泼尼松, 强的松
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prednisolone 泼尼松龙, 强的松龙
 Long-acting: dexamethasone
 Topical:
fluocinolone
地塞米松
氟轻松
PK – Administration and Absorption
 Intravenous
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conjugated with phosphate or hemisuccinate to increase solubility
 Oral
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Prednisolone and prednisone are the most common
Others include methylprednisolone, dexamethasone
 Inhalation
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Increase local effective dose and decrease systemic toxicity
Glucocorticoid drugs
 3. Clinical uses
 (1) Immune diseases
 a) autoimmune disorders: rheumatic fever, rheumatic
carditis, rheumatic arthritis, osteoarthritis, systemic lupus
erythematosus, polyarteritis 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.
Glucocorticoid drugs
 (2) Severe infection and inflammation
 a) acute severe infections: merely suppressing inflammatory
manifestations but at times lifesaving
 Causion: combination with effective antimicrobial
drugs !
 Usually not used in viral 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.
Glucocorticoid drugs
 (3) Septic shock: larger dose, short-term, combined with
antimicrobial drugs
 (4) Hemological diseases: acute lymphocytic leukemia,
lymphomas, aplastic anemia, hemolytic anemia,
leukocytopenia, thrombocytopenia, etc.
 (5) Replacement therapy
 (6) Topical applications: skin, eye, respiratory tract,
joint (local injection)
Glucocorticoid drugs
 4. Adverse effects
 (1) Effects resulting from continued used of large
doses
 a) Hypercorticism-like syndrome (医源性肾上腺皮质功能
亢进): central obesity (moon face, buffalo hump, etc.);
hypertension; glycosuria, hypokalemia; muscular atrophy, etc.
 b) Increasing susceptibility to infections:
 specific antimicrobial drugs
should be administered with GCs
 c) Digestive system: peptic ulcers, etc.
Glucocorticoid drugs
 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
 h) skin
Adverse effects of
glucocorticoid drugs
Effects resulting from
continued used of large doses
Glucocorticoid drugs
 (2) Withdrawal syndrome
 a) iatrogenic adrenocortical insufficiency: suppression
of hypothalamic-pituitary-adrenal axis
 b) Exacerbation of the underlying diseases (rebound)
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 (3) Contraindications
 psychiatric disorders; epilepsy; active peptic ulcers;
fractures; hypercorticism; severe hypertension;
diabetes mellitus; viral or fungal infections, etc.
Feedback inhibition of
CRH and ACTH by
plasma cortisol
Circadian rhythm of the secretion of
ACTH and cortisol
Plasma cortisol
Glucocorticoid drugs
 (2) Withdrawal syndrome
 a) iatrogenic adrenocortical insufficiency: suppression
of hypothalamic-pituitary-adrenal axis
 b) Exacerbation of the underlying diseases (rebound)
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 (3) Contraindications
 psychiatric disorders; epilepsy; active peptic ulcers;
fractures; hypercorticism; severe hypertension;
diabetes mellitus; viral or fungal infections, etc.
糖皮质激素利弊对比
Glucocorticoid drugs
Balance the ratio of
benefit / risk before
the use of GCs !!!
Glucocorticoid drugs
 5. Applications
 (1) Low dose－replacement therapy: usually using
hydrocortisone, cortisone
 (2) Prompt intensive treatment: i.v. gtt hydrocortisone,
dexamethasone
 (3) Long-term therapy: oral
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morning single dose (hydrocortisone, cortisone);
alternate-day therapy (prednisone or prednisolone)
for less severe and sustained patients;
less suppression on hypothalamic-pituitary-adrenal (HPA) axis
 (4) Topical applications: skin; eye; respiratory tract
Case A: Part 1
A 55-year-old male immigrant with no significant past
medical history came to the emergency department
for evaluation of a 3-day history of dyspnea, nonproductive cough, and fever. Physical examination
revealed tachypnea(心悸), diffuse end expiratory
wheezes. The patient was started empirically on a
cephalosporin(头孢菌素) and a macrolide(大环内酯)
for community-acquired pneumonia. Given the diffuse
wheezing on exam, he was also treated with
intravenous corticosteroids.
Case: Part 2
Over subsequent days, the patient deteriorated,
developing respiratory failure and requiring transfer to
the intensive care unit. Diffuse wheezing persisted.
Subsequent chest radiographs and CT scans revealed
progressive bilateral diffuse granular opacities. More
extensive work-up pursued to evaluate for atypical
and fungal pneumonia revealed no culprit organism.
Bronchoscopy revealed thick yellow mucus and
cultures were sent. Ultimately, bronchial washings
demonstrated the larvae of strongyloides stercoralis
(粪类圆线虫).
What will you do then?
What do you learn from this case?
The Presented Case
 Proper therapeutic regimen would have
included discontinuing glucocorticoids, and
providing appropriate anti-infectives for S.
stercoralis: thiabendazole(噻苯咪唑) and
ivermectin(伊维菌素)
Glucocorticoids
 Glucocorticoids not helpful in Strongyloides
stercoralis
 Should be considered essentially for acute
use, with plans to taper or replace with other
medications
 Exceptions are chronic or prolonged
diseases for which there are no more
therapeutic options
Glucocorticoid drugs
Balance the ratio of
benefit / risk before
the use of GCs !!!
Future developments
 Further separation of their anti-inflammatory effects from the toxicity
associated with their metabolic effect, e.g. Deflazacort, a predinisolone
derivative with lower lipid solubility, has less activity on bone,
carbohydrate and lipid metabolism
 Concurrent administration of other drugs to diminish the side effects:
e.g. Ca++ and vitamin D supplementation; growth hormone treatment to
reverse glucocorticoid-induced growth retardation in children.
 Elucidation of downstream pathways may allow the design of new
drugs which mimic corticosteroid action, e.g. screening of small
molecules that can interact with co regulator proteins or NF-kB
transcription factors may represent a promising approach in this effort.
Mineralocorticoid drugs
Aldosterone 醛固酮
 Na+ excretion , K+ excretion :
edema, hypertension,
hypokalemia, etc.
Effects of Aldosterone
Cardiac Myocyte
Fibroblast
Peripheral Artery
Hypertrophy
Hyperplasia
Vasoconstriction
Potassium Loss
Norepinephrine Release
Collagen Synthesis
Endothelial Dysfunction
Sodium Retention
Fibrosis
Hypertrophy
Decreased Compliance
Kidney
Mineralocorticoid drugs
Replacement therapy for chronic adrenocortical
hypofunction (desoxycortone)

Aldosterone antagonists
Drugs Without Positive Inotropic Effects Used in Heart Failure
Spironolactone and Eplerenone get additional
function to decrease morbidity and mortality in
patients with severe heart failure who are also
receiving ACE inhibitors and other standard therapy.
Probability of Survival (%)
RALES: Aldosterone Antagonist Reduces
All-Cause Mortality in Chronic HF
1.00
0.95
0.90
0.85
0.80
0.75
0.70
0.65
0.60
0.55
0.50
0.45
Spironolactone (25 mg) + standard care (n = 822)
Placebo + standard care (n = 841)
HR = 0.70 (95% CI, 0.60 to 0.82)
P<.001
0
0
3
6
9
12
HR = hazard ratio; RR = risk reduction.
15
18
21
24
27
30
33
36
Months
*Ejection fraction ≤35% Class III or IV symptoms at some point in prior 2 months.
Pitt B et al. N Engl J Med. 1999;341:709-717.
Cumulative Incidence (%)
EPHESUS Co-Primary Endpoint:
Total Mortality
22
20
18
(16.7%)
Eplerenone + standard care
(n = 3319)
(14.4%)
Placebo + standard care
(n = 3313)
16
14
12
10
8
6
HR = 0.85 (95% CI, 0.75 to 0.96)
P = .008
4
2
0
0
3
6
9
12
15
18
21
Months Since Randomization
HR = hazard ratio.
Adapted from Pitt B et al. N Engl J Med. 2003;348:1309-1321.
24
27
Adrenocorticotropic hormone and corticosteroid
synthetase inhibitors
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1. Adrenocorticotropic hormone (ACTH)
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Used for diagnosis of pituitary-adrenocortical
function
Used for diagnosis of adrenocortical function
after long-term glucocorticoid drug use
Use after glucocorticoid withdrawal to prevent
adrenocortical insufficiency
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Case2 part1
A 35-year-old woman with a 6-year history of Hashimoto’s thyroiditis
(甲状腺炎) (autoimmune thyroiditis) with hypothyroidism, who had been
well and stable on treatment with levothyoxine(左旋甲状腺素) 0.125 mg
daily, came to see her physician with complaints of fatigue, lethargy(嗜
睡), and loss of appetite over the preceding 3-4 months. She also
complained of intermittent nausea and dizziness on standing up from a
recumbent position. Physical examination revealed a lean (瘦弱) and
rather frail person with a BP of 115/70 in the supine(仰卧) position and
90/60 when she stoop up. She said that she had not been in the sun for
at least a year, yet her skin was tanned and there was increased
pigmentation in the creases of her palms and on the gum margins. The
thyroid gland was at the upper range of normal size, and she was
clinically euthyroid(甲状腺功能正常) on her usual dose of levothyroxine.
Addison’s disease
Use ACTH for diagnosis of pituitary-adrenocortical function
Detect base level of serum ACTH
Case 2 part2

Laboratory investigations revealed a mild normochromic
normocytic anemia, normal T4 and T3 levels, but elevated
serum K+. A random plasma sample showed a cortisol level of
200 nmol/L(normal range 170-660) and an ACTH level of 330
pmol/L(normal<22). A presumptive diagnosis of Addison’s
disease was made. The patient was quickly stabilized with
intravenous hydrocortisone hemisuccinate and rehydration with
intravenous saline. Subsequently , a 3-day infusion of ACTH
was given to test adrenal cortical function, but no adrenal
response to ACTH was found.

She was therefore started on long-term replacement
therapy with prednisone 5 mg each morning and 2.5 mg each
evening, together with fludrocortisone acetate 0.1 mg twice
daily . She has felt well and completely symptom-free on this
therapy.
Adrenocorticotropic hormone and
corticosteroid synthetase inhibitors
 2. Corticosteroid synthetase inhibitors
 Mitotane
米托坦 damaging cells in zones of fasciculate & reticularis
in the adrenal cortex
 Metyrapone
美替拉酮
inhibiting 11-hydroxylation
 Aminoglutethimide
氨鲁米特 inhibiting production
(hydrocortisone and aldosterone) of 20-hydroxyl cholesterol from
cholesterol
 Used for adrenocortical tumors or hypercorticism