department of pharmacology and therapeutics faculty of...
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![Page 1: Department of Pharmacology and Therapeutics Faculty of ...ocw.usu.ac.id/course/download/1110000095... · ROZAIMAH ZAIN-HAMID Department of Pharmacology and Therapeutics Faculty of](https://reader030.vdocuments.us/reader030/viewer/2022040622/5d324c6e88c9931a3d8d704e/html5/thumbnails/1.jpg)
ROZAIMAH ZAIN-HAMID
Department of Pharmacology and Therapeutics
Faculty of Medicine
Universitas Sumatera Utara
Medan, Indonesia
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ADRENOCORTICOSTEROID
♦♦♦♦Glucocorticoid
(hydrocortisone)
intermediate in
metabolism
♦♦♦♦ Mineralocorticoid
(aldosterone)
Na & water
retention &metabolism
process
retention &
Influenced by
angiotensin
♦♦♦♦ Testosterone &
estrogen secretion
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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ADRENOCORTICOSTEROIDADRENOCORTICOSTEROID
DIAGNOSTIC:Adrenal gland disfunction
THERAPY:♦♦♦♦ Inflammation process
♦♦♦♦ Disturbancies of
immunologic process
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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PHARMACOKINETICSGLUCOCORTICOIDGLUCOCORTICOID
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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GLUCOCORTICOIDGLUCOCORTICOIDCortisol (hydrocotisone)
Pharmacokinetic :Pharmacokinetic :Pharmacokinetic :Pharmacokinetic :
���� Synthesized from cholesterol
���� 75 % : Corticosteroid-binding globulin (αααα2-globulin)25 % : free form & 5 %: loosely bound to albumin
(effect on target cells )
���� Cortisol is secreted 10-20 mg daily (“Circadian rhythm” )
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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PharmacokinetPharmacokinetPharmacokinetPharmacokineticicicic ::::
GLUCOCORTICOIDGLUCOCORTICOID(Cortisol : hydrocotisone) (Cortisol : hydrocotisone)
���� Synthetic corticosteroid (dexamethasone) :>>> bound to albumin
���� Only 1 % of cortisol is secreted unchanged in the urine
>>> bound to albumin
���� t ½ : 60 – 90 minutes, could be longer : >>> cortisol administration,
stress, hypothyroidsm & liver disease
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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PHARMACODYNAMICSGLUCOCORTICOIDGLUCOCORTICOID
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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Steroid
Cell membrane
Steroid:receptor
Nuclear membrane
Steroid:Acceptor
Mechanism of action of steroid hormone
SteroidSteroid:receptor complex
Receptor
Steroid:receptor complex
Chromatin
Acceptor
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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GLUCOCORTICOIDGLUCOCORTICOID(Cortisol : hydrocotisone)(Cortisol : hydrocotisone)
Pharmacodynamic :Pharmacodynamic :Pharmacodynamic :Pharmacodynamic :
� Physiologic effects (homeostasis)(homeostasis)
���� Metabolic effects
���� Catabolic effects
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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GLUCOCORTICOIDGLUCOCORTICOID(Cortisol : hydrocotisone)(Cortisol : hydrocotisone)
Pharmacodynamic :Pharmacodynamic :Pharmacodynamic :Pharmacodynamic :
���� Anti-inflammatory
���� Immunosuppresant
� Effects on the development ofthe fetus
���� Immunosuppresant
���� Effects on the nervous system
� Increase platelets & red blood cells
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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Ig E
Ag
YYmethyl
transferasePhospho-lipid
Phosphatidylethanolamine
Phosphatidyl choline
phospholipase A2
Ca++
Histamin
Ca++
HistaminArachidonic acid
Cascade in inflammation reaction
Glucocorticoid
HistaminECF, NCF
Arachidonic acid
lypoxygenase cyclooxygenase
5-HETE LeucotrienesLTB4LTC4LTD4LTE4
ThromboxanesTXA2
ProstaglandinsPGD
PGF2αααα
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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CLINICAL PHARMACOLOGYGLUCOCORTICOIDGLUCOCORTICOID
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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� Diagnosis & treatment of disturbed adrenal function
GLUCOCORTICOIDGLUCOCORTICOID
Clinical Clinical Clinical Clinical pharmacology pharmacology pharmacology pharmacology
� Stimulation of lung maturation in the fetus
� Autoimmune disease : LE, rheumatoid arthritis etc
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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� Inflammatory condition of bones & joint :
arthritis, bursitis etc
GLUCOCORTICOID GLUCOCORTICOID
Clinical Clinical Clinical Clinical pharmacology pharmacology pharmacology pharmacology
� Pulmonary diseases : Asthma,
aspiration pneumonia, prevention IRDS etc
� G.I.T diseases : Inflammatory bowel disease, subacute hepatic necrosis etc
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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� Hematologic diseases : ITP, leukemia,acquired hemolytic anemia, etc
GLUCOCORTICOIDGLUCOCORTICOID
Clinical pharmacology Clinical pharmacology Clinical pharmacology Clinical pharmacology
acquired hemolytic anemia, etc
� Neurologic disease: Cerebral edema,multiple sclerosis
���� Renal disease : Nephrotic syndrome
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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���� Skin & eye diseases: Atopic dermatitis,
GLUCOCORTICOID GLUCOCORTICOID
Clinical pharmacology Clinical pharmacology Clinical pharmacology Clinical pharmacology
� Organ transplantation:
Prevention & treatment of rejection(immunosuppression)
seborrheic dermatitis, optic neuritis,allergic conjunctivitis, choroiditis, etc
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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Glucocorticosteroid cessation
Tappering-off
Withdrawal syndrome
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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NATURAL & SYNTHETICGLUCOCORTICOIDSGLUCOCORTICOIDS
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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SHORT TO MEDIUM ACTING GLUCOCORTICOIDS
Activity
Agent Anti-inflam. Topical Salt-retain. Eq. oral Forms
dose (mg) available
Cortisol 1 1 1 20 oral. inj, tpcl
Cortisone 0.8 0 0.8 25 oral, inj, tpcl
Prednisone 4 0 0.3 5 oral
Prednisolone 5 4 0.3 5 oral, inj, tpcl
Flurocortolone 5 oral, tpcl
M.prednisolone 5 5 0 4 oral, inj, tpcl
Meprednisone 5 0 4 oral, inj
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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INTERMEDIATE - ACTING GLUCOCORTICOIDS
Activity
Agent Anti-inflam. Topical Salt-retain. Eq. oral Forms
dose (mg) available
Triamcinolone 5 53 0 4 oral. inj, tpcl
Paramethasone 10 0 2 oral, inj.
Fluprednisolone 15 7 0 1.5 oral
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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LONG - ACTING GLUCOCORTICOIDS
Activity
Agent Anti-inflam. Topical Salt-retain. Eq. oral Forms
dose (mg) available
Betamethasone 25-40 10 0 0.6 oral. inj, tpcl
Dexamethasone 30 10 0 0.75 oral, inj, tpcl
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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Bila hendak menuai yang baik, tanam yang baik
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TOXICITYGLUCOCORTICOIDSGLUCOCORTICOIDS
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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GLUCOCORTICOID
Toxicity :Toxicity :Toxicity :Toxicity :
* Metabolic effect : Cushing’s syndrome
* Peptic ulcers & their complication* Peptic ulcers & their complication
* Myopathy (triamcinolone)
* Nausea, dizziness (methylprednisolone)
* Psychosis
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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GLUCOCORTICOID
Toxicity :Toxicity :Toxicity :Toxicity :
* Post. subcapsular cataract & glaucoma
* Adrenal suppression
* Intracranial hypertension
* Hypokalemic, hypochloremic & hypertension
* OsteoporosisZain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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SPECIAL PRECAUTIONGLUCOCORTICOIDGLUCOCORTICOID
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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GLUCOCORTICOID
Special precaution :Special precaution :Special precaution :Special precaution :
Development of hyperglycemia, glycosuria,Development of hyperglycemia, glycosuria,
sodium retention with edema &
hypertension, hypokalemia, peptic ulcer,
osteoporosis, and hidden infection
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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CONTRA-INDICATIONGLUCOCORTICOIDGLUCOCORTICOID
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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Peptic ulcers, heart disease or
Contraindication :Contraindication :Contraindication :Contraindication :
GLUCOCORTICOID
Peptic ulcers, heart disease or
hypertension with CHF, psychosis,
diabetes, glaucoma, osteoporosis &
herpes simplex infection
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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ANTAGONIST OFGLUCOCORTICOIDSGLUCOCORTICOIDS
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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ANTAGONIST OF GLUCOCORTICOID
Mitotane, amphenone B, metyrapone,
aminoglutethimide, ketoconazole,
mifepristone (RU 486)
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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Mitotane:
�orally in divided dose
� 1/3 adrenal carcinoma patient,
ANTAGONIST OF GLUCOCORTICOID
� 1/3 adrenal carcinoma patient, ���� in tumor mass
� 2/3 of patients, ���� steroid production
�Side effects: nausea, vomiting diarrhea, depression, skin problems
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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Amphenone B
���� More potent inhibitor of synthesis than
mitotane
ANTAGONIST OF GLUCOCORTICOID
mitotane
� Too toxic for use in human
� Side effects: CNS depression,
g.i.t & skin disorders,impairs liver & thyroid function
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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Metyrapone:���� More selective effect at lower dose
than mitotane & amphenone B
� Inhibits 11-hydroxylation, interfering with
ANTAGONIST OF GLUCOCORTICOID
� Inhibits 11-hydroxylation, interfering with cortisol & corticosterone synthesis &
leading to secretion of 11-deoxycortisol
� Most commonly used in test of adrenal function
�Toxicity << the above agents, transient dizziness, g.i.t disturbancies
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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Aminogluthetimide:� Blocks convers. cholesterol ���� pregnonolone
� ���� synthesis of all hormonally active steroids
� Conjunction with dexamethasone to
ANTAGONIST OF GLUCOCORTICOID
� Conjunction with dexamethasone to
���� estrogen & androgen production in
breast carcinoma
� Conjunction with ketoconazole to ���� steroid
secretion in Cushing’s syndrome
� ���� metabolism of dexamethasone & ���� its T ½ by an half
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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Ketoconazole:
� Potent & rather non-selective inhibitor of
ANTAGONIST OF GLUCOCORTICOID
� Potent & rather non-selective inhibitor of adrenal & gonadal steroid synthesis
� Inhibitory effects are seen only at high doses
� Treatment of Cushing’s due to several causes
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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Mifepristone:
� May be useful in treatment of endometriosis,
Cushing’s syndrome, breast cancer & other
ANTAGONIST OF GLUCOCORTICOID
Cushing’s syndrome, breast cancer & other
neoplasma that contain glucocorticoid or
progesterone receptors
� Has been used to terminate early pregnancy
� Side effects: vomiting, diarrhea, pain, vaginal
bleeding requiring intervention
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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MINERALOCORTICOIDMINERALOCORTICOID
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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MINERALOCORTICOID
ALDOSTERONE :
Synthesized mainly in Synthesized mainly in
the zona glomerulosa
of the adrenal cortex
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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� Act by binding to
the mineralocorticoid receptor in
the cytoplasma of target cell
ALDOSTERONE :
����
collecting tubules of the kidney; specificity →→→→ by presence of the enzyme
11 ß hydroxysteroid dehydrogenase
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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Metabolism is similar to that cortisol,
appearing in the urine as conjugated tetrahydroaldosterone
ALDOSTERONE :
tetrahydroaldosterone
&
small part is excreted free or as the 3-oxoglucoronide
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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ALDOSTERONE :
���� Promote reabsorption of sodium fromurine by distal renal tubule
�Overdosage of mineralocorticoid
����
����Antagonist of aldosterone →→→→spironolactone
����hypernatremia, hypokalemia,
metabolic alkalosis, ↑↑↑↑ plasma volume,
hypertension.
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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MINERALOCORTICOIDS
Activity
Agent Anti-inflam. Topical Salt-retain. Eq. oral Forms
dose (mg) available
Fludrocortisone 10 10 250 2 oral. inj, tpcl
Desoxycortico- 0 0 20 inj, pellets
sterone
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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MINERALOCORTICOIDANTAGONISTANTAGONIST
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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MINERALOCORTICOID ANTAGONIST
Spironolactone:� May be useful in treatment of primary
aldosteronism, hirsutism in womenaldosteronism, hirsutism in women
� Potassium-sparing diuretic
� Side effects: hyperkalemia, menstrual
abnormalities, gynecomastia, sedation,
headache, g.i.t disturbancies, skin rash
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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Like a solid rock is not shaken by the wind,
so the wise are not moved by praise or
blame (Dhammapada)
Zain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.
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THANK YOUTHANK YOUTHANK YOUTHANK YOUZain-Hamid, R; Faculty of Medicine, Universitas Sumatera Utara.