Download CORTICOSTEROID

DR.Dr. Endang Isbandiati Soediono, MS, SpFK
Dept.PharmacologyTherapy,MedicalFaculty,AirlanggaUniversit
Dept.Clinical Pharmacology,Dr.Soetomo-Teaching Hospital,
SURABAYA
FKMPcoCorOADEIS09
1
Glucocorticoids
Mineralocorticoids
Sex Steroids ( Androgen & Estrogen)
Human
glucocorticoid
: cortisol
mineralocorticoid : aldosterone
FKMPcoCorOADEIS09
2
HPA - AXIS
FKMPcoCorOADEIS09
3
CIRCADIAN RHYTM
FKMPcoCorOADEIS09
4
Mineralocorticoid
Aldosterone
Glucocorticoid
Cortisol
Androgen
ADRENALSTEROID
Testosterone BIOSYNTHESIS
FKMPcoCorOADEIS09
5
Pharmacokinetic
very sensitive to negative feedback
cyrcadian rhythm (peak : early morning & after meal)
Protein Binding (saturable) :
CBG ( α2 – globulin 90%)
albumin (5%)
Pregnancy
Estrogen
CBG
Hyperthyroidism
Hypothyroidism
Genetic defect
CBG
Protein deficiency
FKMPcoCorOADEIS09
6
Pharmacodynamic
MOA : family of nuclear receptors
(steroid, sterol, thyroid, retinoid acid)
Physiological Effects:
direct actions
homeostatic responses
“ permissive “ effects
FKMPcoCorOADEIS09
7
Dose- related: carbohydrate, protein, fat
fasted state
muscle catabolism
amino acid
gluconeogenesis
glycogen synthesis
FKMPcoCorOADEIS09
8
insulin
lipolysis
lipogenesis
fat deposition
fatty acid
glycerol
FKMPcoCorOADEIS09
9
Hepar : protein & RNA synthesis
Catabolic: lymphoid, connective tissue,
muscle, fat, and skin
Cushing’s syndrome
bone
Hi.Do. :
osteoporosis
muscle mass
weakness
Children : reduce growth
FKMPcoCorOADEIS09
10
Glucocorticoid
Leukocytes
PG
Leukotriene
PAF
Mediators of inflammation
(cytokine, chemokine, lipid, glucolipid)
FKMPcoCorOADEIS09
11
. adrenal insufficiency
psychiatric depression
. glucocorticoid >>>
insomnia, euphoria
intracranial pressure
depression
FKMPcoCorOADEIS09
12
ACTH, GH, TSH, LH
Hi.Do. : peptic ulcer
Fat redis. : visceral, facial, nuchal & supraclav.
Antagonize : Ca2+ absorption
Increase
: platelet and red blood cells
Cortisol (-) : impaired GFR, vasopressin
Development of fetal lungs (surfactant)
FKMPcoCorOADEIS09
13
Adrenocortical Insufficiency
2. Adrenocortical Hypo- and
Hyperfunction
3. Diagnostic purposes
1.
B. Stimulation of Lung Maturation
Hi.do. : prevent resp. distress in premature infant
FKMPcoCorOADEIS09
14
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
FKMPcoCorOADEIS09
15
…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
FKMPcoCorOADEIS09
16
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
FKMPcoCorOADEIS09
17
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
FKMPcoCorOADEIS09
18
Aldosterone
Promote the reabsorption of sodium
Overdosage : hypernatremia, hypokalemia, metabolic
alkalosis, increased plasma volume, HT
Deoxycorticosterone (DOC)
A precursor of aldosterone
Secretion is primarily under the control of ACTH
Fludrocortisone
Both glucocorticoid and mineralocorticoid activity
FKMPcoCorOADEIS09
19
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
FKMPcoCorOADEIS09
20
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
FKMPcoCorOADEIS09
21
SPIRONOLACTONE
Interfere aldosterone synthesis
Tx. use : primary aldosteronism
hirsutism in women
diuretic
CHF
AE : hyperkalemia, Cardia arr.,
menstrual abnorm., gynecomastia, sedation,
GIT
FKMPcoCorOADEIS09
22
FKMPcoCorOADEIS09
23

Secretion :
low basal rate
higher rate
glucose
sugar ( mannose)
amino acids (leucine, arginine)
vagal activity
FKMPcoCorOADEIS09
24
a. inhibiting hepatic glucose production
EC50 : ± 20 μU/ml
b. stimulating the uptake and metabolism
by muscle and adipose tissue
EC50 : ± 50 μU/ml
FKMPcoCorOADEIS09
25
Affinity :
. hydrocortisone
. Growth Hormone
. insulin
desensitization
(obese; insulinoma)
FKMPcoCorOADEIS09
26
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
FKMPcoCorOADEIS09
27
. 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
FKMPcoCorOADEIS09
28
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
FKMPcoCorOADEIS09
29
(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
FKMPcoCorOADEIS09
30
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; abdominalFKMPcoCorOADEIS09
bloating, and blurred vision. 31
Drug induced hypoglycemic states :
ethanol, β - adrenergic receptor antagonists,
salicylates, (pentamidine).
Drugs cause hyperglycemia :
epinephrine, glucocorticoids
phenytoin, clonidine, Ca channel-blocker
K+ depletion
FKMPcoCorOADEIS09
32
. Insulin secretagogues :
.
.
.
.
.
.
Sulfonylureas; Meglitinides;
D-phenylalanine derv.
Biguanides
Thiazolidinediones
Alpha-glucosidase
inhibitors
Pramlintide
Exenatide
Sitagliptin
FKMPcoCorOADEIS09
33
MOA
A. Major action : increase insulin release
B. Reduction of glucagon level
C. Extrapancreatic effect
FKMPcoCorOADEIS09
34
Tolbutamide
Prolonged hypoglycemia : (+) inhibition metabolism
Dicumarol, Phenylbutazone, or Sulfonamide
Chlorpropamide
CI : hepatic and renal insufficiency
Antidiuretic effect : (+)
Tolazamide
Doa shorter than chlorpropamide
OOA : several hours
FKMPcoCorOADEIS09
35
Glyburide, Glipizide, and Glimepiride
potent sulfonylurea
caution :
FKMPcoCorOADEIS09
36
GLYBURIDE
Metabolite : very low hypoglycemic activity
CI : hepatic impairment and renal insufficiency
Glipizide
Absorption delayed when taken with food
Less serious hypoglycemia
CI : hepatic and renal insufficiency
Glimepiride
The lowest dose blood glucose lowering effect
FKMPcoCorOADEIS09
37
MOA
modulate β - cell insulin release ( potassium
efflux )
Repaglinide : very fast ooa
Adverse Effect : weight gain & hypoglycemia
Interactions:
Ketoconazole, Miconazole, Erythromycin:
metabolism
Carbamazepine, Barbiturates : metabolism
FKMPcoCorOADEIS09
38
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
FKMPcoCorOADEIS09
39
Gluconeogenesis blockade: impair hepatic uptake of lactic ac.
Renal insufficiency :
lactic acidosis
Clinical Use
Refractory obesity, “insulin resistance syndrome”
Combination with sulfonylurea
CI : renal disease, alcoholism, hepatic disease, predisposing
to tissue anoxia
Adverse effects: abdom. bloating, diarrhea, nausea
FKMPcoCorOADEIS09
40
Rosiglitazone and Pioglitazone
MOA
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 P450
Common AE : mild anemia
FKMPcoCorOADEIS09
41
Acarbose and Miglitol : competitive inhibitors of
α – glucosidase
. minimize upper intestinal digestion
. defer digestion and absorption
lowering postmeal glycemic excursion
( insulin – sparing effect)
FKMPcoCorOADEIS09
42
Adverse Effects
Flatulence, diarrhea and abdominal pain
Tolerance to the side effects : (+)
Hypoglycemia : (+) insulin or sulfonylurea
Treatment : glucose (dextrose) but not
sucrose
CI : serum creatinine > 2,0 mg/dL
chronic or inflammatory bowel disease
Caution : hepatic disease
Interaction : intestinal adsorbent (charcoal)
FKMPcoCorOADEIS09
43
Antihyperglycemic
(injectable)
preprandial use
Postprandial glucose
(type 1 and type 2 DM )
MOA :
suppresses glucagon release, delays gastric
emptying, CNS anorectic
Absorption : abdomen, thigh
Injection : separate syringe

FKMPcoCorOADEIS09
44




MOA :
potensiated glucose-mediated insulin secretion,
suppresseion of glucagon release, slowed
gastric emptying, and CNS loss of appetite
Renal impairment : dose adjustment
Hypoglycemic : rare
Facilitated weightFKMPcoCorOADEIS09
loss
45
Regulation of secretion :
. glucose, insulin, amino acid, fatty acid, keton
. Autonomic innervation
DM : plasma glucagon
gluconeogenesis & glycogenolysis
hyperglycemia
FKMPcoCorOADEIS09
46
FKMPcoCorOADEIS09
47