adrenocorticosteroids and adrenocortical antagonists

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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


E. Anti-inflammatory & Immunosuppressive Effects

Glucocorticoid

Leukocytes PG Leukotriene PAF Mediators of

inflammation (cytokine, chemokine, lipid,

glucolipid)

Anti-inflammation


F. Other Effects:

. adrenal insufficiency

psychiatric depression

. glucocorticoid >>>

insomnia, euphoria intracranial pressure

depression


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)


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


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


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


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


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


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


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


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


MINERALOCORTICOID ANTAGONIST

SPIRONOLACTONE Interfere aldosterone synthesis Tx. use : primary aldosteronism hirsutism in women diuretic CHF AE : hyperkalemia, Cardia arr., menstrual abnorm., gynecomastia,

sedation, GIT


PANCREATIC HORMONEAND

ANTIDIABETIC DRUGS


INSULIN

Secretion : low basal rate higher rate

glucose sugar ( mannose) amino acids (leucine,

arginine) vagal activity


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


The Insulin Receptors

Affinity : . hydrocortisone . Growth Hormone . insulin

desensitization (obese; insulinoma)


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


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


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


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


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.


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


Oral Antidiabetic Agents

. Insulin secretagogues :

Sulfonylureas; Meglitinides; D-phenylalanine derv. . Biguanides. Thiazolidinediones. Alpha-glucosidase

inhibitors. Pramlintide. Exenatide. Sitagliptin


Sulfonylurea

MOA A. Major action : increase insulin

releaseB. Reduction of glucagon levelC. Extrapancreatic effect


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


Second Generation of Sulfonylurea

Glyburide, Glipizide, and Glimepiride

potent sulfonylurea

caution :

CV DISEASESELDERLY


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


Meglitinide

MOA modulate β - cell insulin release

( potassium efflux )Repaglinide : very fast ooaAdverse Effect : weight gain &

hypoglycemiaInteractions:Ketoconazole, Miconazole, Erythromycin:

metabolismCarbamazepine, Barbiturates :

metabolism


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


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


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


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)


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)


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


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


GLUCAGON

Regulation of secretion :

. glucose, insulin, amino acid, fatty acid, keton

. Autonomic innervation DM : plasma glucagon

gluconeogenesis & glycogenolysis

hyperglycemia


THANK YOU

adrenocorticosteroids and adrenocortical antagonists

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