adrenocorticosteroids and adrenocortical antagonists
DESCRIPTION
Adrenocorticosteroids And Adrenocortical antagonists. DR.Dr. Endang Isbandiati Soediono, MS, SpFK Dept.PharmacologyTherapy,MedicalFaculty,AirlanggaUniversit Dept.Clinical Pharmacology,Dr.Soetomo-Teaching Hospital, SURABAYA. ADRENAL CORTEX STEROID. Glucocorticoids Mineralocorticoids - PowerPoint PPT PresentationTRANSCRIPT
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ADRENOCORTICOSTEROIDSAND
ADRENOCORTICAL ANTAGONISTS
DR.Dr. Endang Isbandiati Soediono, MS, SpFKDept.PharmacologyTherapy,MedicalFaculty,AirlanggaUni
versitDept.Clinical Pharmacology,Dr.Soetomo-Teaching
Hospital,SURABAYA
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ADRENAL CORTEX STEROID
Glucocorticoids Mineralocorticoids Sex Steroids ( Androgen & Estrogen)
Human glucocorticoid : cortisol mineralocorticoid : aldosterone
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HPA - AXIS
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CIRCADIAN RHYTM
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Aldosterone Cortisol TestosteroneADRENALSTEROID
BIOSYNTHESIS
Mineralocorticoid Glucocorticoid Androgen
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CORTISOL Pharmacokinetic
very sensitive to negative feedback cyrcadian rhythm (peak : early morning &
after meal)
Protein Binding (saturable) : CBG ( α2 – globulin 90%) albumin (5%)
Pregnancy Hypothyroidism Estrogen CBG Genetic defect
CBG Hyperthyroidism Protein deficiency
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Cortisol continued
Pharmacodynamic
MOA : family of nuclear receptors (steroid, sterol, thyroid, retinoid acid) Physiological Effects: direct actions homeostatic responses “ permissive “ effects
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C. Metabolic Effects
Dose- related: carbohydrate, protein, fat fasted state muscle catabolism
amino acid
gluconeogenesis glycogen synthesis
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glucocorticoid
glucose
insulin lipolysis lipogenesis
fat deposition
fatty acid glycerol
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D. Catabolic Effects Hepar : protein & RNA synthesis Catabolic: lymphoid, connective tissue, muscle, fat, and skin Cushing’s syndrome bone
osteoporosis Hi.Do. : muscle mass weakness
Children : reduce growth
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E. Anti-inflammatory & Immunosuppressive Effects
Glucocorticoid
Leukocytes PG Leukotriene PAF Mediators of
inflammation (cytokine, chemokine, lipid,
glucolipid)
Anti-inflammation
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F. Other Effects:
. adrenal insufficiency
psychiatric depression
. glucocorticoid >>>
insomnia, euphoria intracranial pressure
depression
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Chronic glucocorticoid :
suppress the pituitary
ACTH, GH, TSH, LH
Hi.Do. : peptic ulcerFat redis. : visceral, facial, nuchal &
supraclav.Antagonize : Ca2+ absorptionIncrease : platelet and red blood
cellsCortisol (-) : impaired GFR,
vasopressin Development of fetal lungs (surfactant)
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CLINICAL PHARMACOLOGYA. Dx & Tx of Disturbed Adrenal Function
1. Adrenocortical Insufficiency2. Adrenocortical Hypo- and
Hyperfunction3. Diagnostic purposes
B. Stimulation of Lung Maturation Hi.do. : prevent resp. distress in premature infant
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C. Nonadrenal Disorders . Rheumatic Disorders . Hepatic
disease . Noninflammatory joint dis . Malignancies . Renal diseases . Cerebral
edema . Alergic disease . Sarcoidosis . Bronchial asthma .
Thrombocytopenia . Infectious disease . Autoimmune
destr. . Ocular disease of
erythrocytes . Skin disease . Organ transpl.
. Gastrointestinal disease . Spinal cord
injury
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Corticosteroid !!!!!
…to prevent damage from an inflammatory Should not stopped abruptly
The shorter-acting glucocorticoid (Prednisone , Methylprednisolone)
preferred to facilitate drug tapering and/or conversion to alternate-day therapy
Considered :
diet rich in potassium and low in sodium
high protein intake antacid pts. epigastric distress Ca and vit. D
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Toxicity Metabolic Effects
. fat tends to be redistributed to the trunk
Other Complication peptic ulcer masking bacterial and mycotic infection proximal myopathy hypomania or acute psychosis increase intraocular pressure
pts heart dis. : sodium retention lead to
CHF
Adrenal Suppression : tapering off
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Contraindication & Caution
A. Special precaution Monitore : hyperglycemia, glycosuria,
sodium retention with edema/ HT, hypokalemia, peptic ulcer, osteoporosis
B. Contraindications Peptic ulcer, heart disease / HT with CHF,
infections, psychosis, diabetes, osteoporosis, glaucoma, herpes simplex infection
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MINERALOCORTICOIDS(Aldosterone, Deoxycorticosterone,
Fludrocortisone)
Aldosterone Promote the reabsorption of sodium Overdosage : hypernatremia, hypokalemia,
metabolic alkalosis, increased plasma volume, HT
Deoxycorticosterone (DOC)A precursor of aldosteroneSecretion is primarily under the control of ACTH
FludrocortisoneBoth glucocorticoid and mineralocorticoid activity
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ANTAGONIST OF ADRENOCORTICAL
METYRAPONE Inhibit 11- hydroxylation : cortisol &
corticosterone Tx. : severe cortisol excess AE : salt & water retention, hirsutism
AMINOGLUTETHIMIDE Tx. : (+) Dexamethasone or Hydrocortisone
to < E (+) Metyrapone or Ketoconazole to <
steroid Increase clearance of Dexamethasone
KETOCONAZOLE Inhibitor of adrenal and gonadal steroid
synthesis Tx. use : Cushing’s syndrome
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ANTAGONIST OF ADRENOCORTICAL ( continued)
MIFEPRISTONE (RU 486) Blocks the glucocorticoid receptors Tx. : inoperable ectopic ACTH secretion adrenal Ca Progesterone antagonist
MITOTANE adrenolytic toxic effects : n, v, d, depression,
somnolence
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MINERALOCORTICOID ANTAGONIST
SPIRONOLACTONE Interfere aldosterone synthesis Tx. use : primary aldosteronism hirsutism in women diuretic CHF AE : hyperkalemia, Cardia arr., menstrual abnorm., gynecomastia,
sedation, GIT
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PANCREATIC HORMONEAND
ANTIDIABETIC DRUGS
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INSULIN
Secretion : low basal rate higher rate
glucose sugar ( mannose) amino acids (leucine,
arginine) vagal activity
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Insulin lowers the concentration of BG
a. inhibiting hepatic glucose production EC50 : ± 20 μU/ml
b. stimulating the uptake and metabolism
by muscle and adipose tissue
EC50 : ± 50 μU/ml
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The Insulin Receptors
Affinity : . hydrocortisone . Growth Hormone . insulin
desensitization (obese; insulinoma)
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Diabetes Mellitus
Type 1 absolute deficiency of insulin immune-mediated idiopathic Environmental : infections, chemical,
dietary
Type 2
Heterogenous disorders : Insulin resistance & relative insulin deficiency or β - cell dysfunction
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Blood Glucose Level
. excessive glucagon . defect of somatostatin; excess of GH, cortisol, epinephrine . Drugs : corticosteroids, diazoxide, phenytoin, glucagon, caffein, cyclophosphamide, lithium, epinephrine,
estrogens, furosemide, thiazide, thyroid prep., and sugar containing medication
. sulfonylureas, disopyramide, ethanol, MAO-inhibitors, propranolol, and salicylates
. Cushing’s disease, phaeochromocytoma, aldosteronism, hyperthyroidism, pancreatitis, cirrhosis, pregnancy,
emotional stress, and infection
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DM : Treatment Non Pharmacologic Therapy: Diet & Activity
Pharmacologic Therapy Insulin (as monotherapy in Type 1 DM) Oral Anti Diabetic Agents:
. Sulfonylurea . Meglitinide . Biguanide .
Thiazolidinedione . Alpha- Glucosidase Inhibitor . Pramlintide
. Exenatide . Sitagliptin
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Insulin : available preparations
(1) Ultra-short –acting (Insulin Lispro)
(2) Short- acting (Regular Insulin) Rapid onset of action (sc 30 min.
and last 5 – 7 h) DOA; OOA : intensity of peak action > : dose > Short- acting soluble insulin :
intravenous adm. (3) Intermediate and Long-acting (4) Mixtures
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Complications of Insulin Therapy
A. Hypoglycemia: Autonomic hyperactivity; Impaired CNS Treatment : . glucose . Uncosciousness or stupor : 50% glucose iv/
2-3 min 1mg glucagon
sc/im
B. Allergy and Resistance
C. Lipoatrophy and lipohypertrophy
D. Edema; abdominal bloating, and blurred vision.
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Drug Interactions
Drug induced hypoglycemic states :
ethanol, β - adrenergic receptor antagonists, salicylates, (pentamidine).
Drugs cause hyperglycemia :
epinephrine, glucocorticoids phenytoin, clonidine, Ca channel-blocker K+ depletion
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Oral Antidiabetic Agents
. Insulin secretagogues :
Sulfonylureas; Meglitinides; D-phenylalanine derv. . Biguanides. Thiazolidinediones. Alpha-glucosidase
inhibitors. Pramlintide. Exenatide. Sitagliptin
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Sulfonylurea
MOA A. Major action : increase insulin
releaseB. Reduction of glucagon levelC. Extrapancreatic effect
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First Generation of Sulfonylurea
TolbutamideProlonged hypoglycemia : (+) inhibition
metabolism Dicumarol, Phenylbutazone, or
Sulfonamide
ChlorpropamideCI : hepatic and renal insufficiencyAntidiuretic effect : (+)
Tolazamide Doa shorter than chlorpropamideOOA : several hours
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Second Generation of Sulfonylurea
Glyburide, Glipizide, and Glimepiride
potent sulfonylurea
caution :
CV DISEASESELDERLY
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GLYBURIDEMetabolite : very low hypoglycemic activityCI : hepatic impairment and renal
insufficiency
GlipizideAbsorption delayed when taken with foodLess serious hypoglycemiaCI : hepatic and renal insufficiency
GlimepirideThe lowest dose blood glucose lowering
effect
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Meglitinide
MOA modulate β - cell insulin release
( potassium efflux )Repaglinide : very fast ooaAdverse Effect : weight gain &
hypoglycemiaInteractions:Ketoconazole, Miconazole, Erythromycin:
metabolismCarbamazepine, Barbiturates :
metabolism
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BIGUANIDE
MOA Blood glucose lowering effect does not
depend on the presence of functioning pancreatic β – cells
…. “euglycemic “ / antihyperglycemic agent (1) direct stimulation of tissues glycolysis glucose removal from blood (2) Hepatic & renal gluconeogenesis (3) Slowing glucose absorption from GIT (4) Plasma glucagon levels
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Metabolism and Excretion
Gluconeogenesis blockade: impair hepatic uptake of
lactic ac. Renal insufficiency : lactic acidosis
Clinical UseRefractory obesity, “insulin resistance syndrome”Combination with sulfonylurea
CI : renal disease, alcoholism, hepatic disease, predisposing
to tissue anoxia Adverse effects: abdom. bloating, diarrhea, nausea
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THIAZOLIDINEDIONE
Rosiglitazone and PioglitazoneMOA Glucose uptake and metabolism in muscle
and adipose tissues Restrain gluconeogenesis, lipid metabolism,
ovarian steroidogenesis, systemic blood pressure, and the fibrinolytic system
… an “euglycemic”Chronic therapy : TG ; HDL and LDL Metabolized: cytochrome P450Common AE : mild anemia
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ALPHA- GLUCOSIDASE INHIBITOR
Acarbose and Miglitol : competitive inhibitors of
α – glucosidase
. minimize upper intestinal digestion
. defer digestion and absorption
lowering postmeal glycemic
excursion ( insulin – sparing effect)
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Adverse EffectsFlatulence, diarrhea and abdominal painTolerance to the side effects : (+)Hypoglycemia : (+) insulin or sulfonylurea
Treatment : glucose (dextrose) but not sucroseCI : serum creatinine > 2,0 mg/dL chronic or inflammatory bowel diseaseCaution : hepatic diseaseInteraction : intestinal adsorbent (charcoal)
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Pramlintide Antihyperglycemic (injectable) preprandial use Postprandial glucose (type 1 and type 2 DM )MOA : suppresses glucagon release, delays gastric
emptying, CNS anorecticAbsorption : abdomen, thighInjection : separate syringe
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Exenatide MOA : potensiated glucose-mediated insulin
secretion, suppresseion of glucagon release, slowed gastric emptying, and CNS loss of appetite
Sitagliptin
Renal impairment : dose adjustment Hypoglycemic : rare Facilitated weight loss
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GLUCAGON
Regulation of secretion :
. glucose, insulin, amino acid, fatty acid, keton
. Autonomic innervation DM : plasma glucagon
gluconeogenesis & glycogenolysis
hyperglycemia
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