Download Adreno-cortico-steroids, Inhibitors, and Antagonists

Adreno-cortico-steroids,
Inhibitors, and Antagonists
Kaukab Azim, MBBS, PhD
Drug List
Glucocorticoids
Mineralocorticoids
Inhibitors / Antagonists
Inhibitors of Corticosteroids
Short-acting
➨ Ketoconazole
➨ Metyrapone
➨ Aminoglutethimide
➨ Mitotane
➨ Hydrocortisone (cortisol)
➨ Cortisone
Intermediate-acting
➨ Prednisolone
➨ Prednisone
➨ Methyprednisolone
➨ Triamcinolone
Long-acting
➨ Betamethasone
➨ Dexamethasone
➨ Aldosterone
➨ Fludrocortisone
➨ Desoxycorticosterone
(DOC)
Glucocorticoid receptor
antagonist
➨ Mifepristone (RU 486)
Mineralocorticoid receptor
antagonists
➨ Spironolactone
➨ Eplerenone
Learning Outcomes
By the end of the course the students should be able to
➨ Explain the molecular mechanism of action of corticosteroids
➨ Describe the pharmacological and permissive effects of glucocorticoids upon different organ
systems
➨ Explain the mechanism of the anti-inflammatory, immunosuppressive and antineoplastic action
of glucocorticoids
➨ Describe the factors that regulate aldosterone secretion.
➨ Describe the main features of the pharmacokinetics of corticosteroids.
➨ List the routes of administration of corticosteroids.
➨ Describe the adverse effects of glucocorticoids after acute or long-term administration.
➨ List the main microorganisms that can cause an infection in patients receiving glucocorticoids.
➨ Describe the clinically relevant interactions between glucocorticoids and other drugs
➨ List the main contraindications to the use of glucocorticoids.
➨ Outline the therapeutic uses of corticosteroids in adrenal and in non-adrenal disorders.
➨ Describe the mechanism of action and therapeutic uses of the antagonists of glucocorticoids.
Hypothalamic-Pituitary-Adrenal Axis
+
-
Stress
Adrenal Gland Histology
Adrenal Medulla
Adrenal Cortex
➨ Zona Glomerulosa
➨ Zona Fasciculata
➨ Zona Reticularis
Androgens
Adrenal Cortex Hormones
1.
Mineralocorticoid: Aldosterone
2.
Glucocorticoid: cortisol
3.
Adrenal androgens: Dehydroepiandrosterone (DHEA), Androstenidione:
these are converted into testosterone and estrogen. Adrenal androgens
constitute the major endogenous precursors of estrogens in women
after menopause.
Regulation:
• The secretion of adrenal steroids is regulated by corticotropin-releasing
hormone (CRH) and adrenocorticotropic hormone (ACTH). The secretion
of CRH and ACTH is affected by physical and mental stress. Cortisol
regulates CRH and ACTH secretion by a feedback mechanism. The
secretion of aldosterone is chiefly regulated by renin-angiotensin system.
Mechanism of action:
• All are steroidal hormones. They enter the cell and bind to cytosolic
receptors. The hormone-receptor complex translocates into the nucleus,
and alter the gene expression by binding to the glucocorticoid-response
element (GRE) or mineralocorticoid response element.
What would be the
consequence of
genetic deficiency
of 21β/11β
hydroxylase?
Mechanism of Action of Glucocorticoids
Diffusion of glucocorticoid across the
membrane of the target cell to bind to a
glucocorticoid receptor-heat-shock
protein complex in the cytoplasm
Decreased or increased accumulation of
mRNA within the target cell
Release of the heat-shock protein and
transport of the hormone receptor
complex into the nucleus
Decreased or increased transcription of
genes coding for specific proteins
Binding of the hormone-receptor complex
to specific nucleotide sequences along
the DNA, called Glucocorticoid response
elements (GREs)
☞
Changes in the rate of synthesis of specific
proteins that carry out the biologic
actions of the hormones
Glucocorticoid receptor is a member of the nuclear hormone receptor superfamily that include the receptors for
steroid hormones, thyroid hormone, Vit D and retinoic acid
Pharmacodynamics of Glucocorticoids
The effects of glucocorticoids can be subdivided into:
1. Direct: the effects are due to direct actions of these
hormone in the cells.
2. Indirect: the effects are the result of homeostatic
responses (e.g. by insulin, glucagon, PTH, etc.).
They can also be subdivided into:
1. Physiologic (or pharmacologic): the effects are dosedependent.
2. "Permissive": the effects take place at a significant
rate only in the presence of glucocorticoids, but they
are not further stimulated when larger doses are
given.
Pharmacodynamics of Glucocorticoids
Metabolic effects
a) Carbohydrate metabolism
➨Increased gluconeogenesis (in liver and kidney).
➨Increased glycogen synthesis and storage (in liver).
➨Inhibition of glucose uptake and utilization by both adipose
tissue and skeletal muscle. (the hyperglycemia stimulates
insulin secretion)
b) Lipid metabolism
➨Increased lipolysis, which leads to an increased plasma
levels of free fatty acids (but insulin secretion stimulates
lipogenesis leading to a net increase in fat deposition)
➨Increased fat absorption from intestine.
Pharmacodynamics of Glucocorticoids
Metabolic effects
c) Protein metabolism
➨ Increased protein synthesis in the liver.
➨ Decreased synthesis and increased breakdown
of proteins in lymphoid and connective tissue,
muscle, fat and skin.
d) Salt and water metabolism
➨ The effect is less pronounced than those of
mineralocorticoids (for some synthetic
compounds these effects are negligible).
Pharmacodynamics of Glucocorticoids
Cardiovascular Effects
➨Hypertension (mechanisms are still uncertain: they may
include blockade of prostaglandin synthesis, Na+ retention,
etc.).
Renal effects
Maintenance of:
➨a normal water permeability in the distal collecting tubules
(due to inhibition of vasopressin secretion) (the above
mentioned effects are "permissive")
➨Increased excretion of calcium.
Pharmacodynamics of Glucocorticoids
Gastrointestinal effects
➨Increased production of gastric acid and pepsin.
➨Decreased cytoprotection of gastric mucosa.
➨Decreased calcium absorption from the
intestine (also due to blockade of Vit D action).
➨Antiemetic effects (mechanism is unknown).
Endocrine effects
➨Decreased release of CRH, ACTH, GH, TSH, FSH
and ADH.
➨Increases release of PTH and glucagon.
Pharmacodynamics of Glucocorticoids
Central nervous system effects
➨ Decreased cortical threshold for convulsions.
➨ Behavioral disturbances (after high doses).
➨ Increased intracranial pressure (after high doses).
Hematopoietic effects
➨ Decreased concentration of lymphocytes, monocytes,
eosinophils, and basophils (due to increased efflux from blood
to the lymphoid tissue)
➨ Increased concentration of neutrophils (due both to increase
efflux from bone marrow and to decreased migration from
the blood vessels).
➨ Increased concentration of red blood cells and platelets.
Pharmacodynamics of Glucocorticoids
Locomotor system effects
➨ Decreased muscle mass (after high doses).
➨ Decreased bone formation (direct effect due to inhibition of
osteoblasts).
➨ Increased bone reabsorption (indirect effect due to increased
secretion of PTH and decreased secretion of calcitonin).
Antineoplastic action
➨ It is mainly due to:
a.
b.
Dissolution of pathologic lymphocytes and lymphoid tissue
(lympholythic action).
Inhibition of growth of mesenchymal cancer tissue.
➨ In many tumors glucocorticoids exert a non-specific effect which is
mainly the consequence of their anti-inflammatory action.
The Anti-Inflammatory Action of
Glucocorticoids
Features
☛ All type of inflammatory reactions are affected
☛ Both early and late phases of inflammation are
inhibited
The Anti-Inflammatory Action of Glucocorticoids
Mechanisms
Main mechanisms of anti-inflammatory action are:
1.
Alteration of number, distribution and function of
peripheral leukocytes and tissue macrophages.
It includes:
a. For leukocytes:
➨ Decreased migration of neutrophils from the blood vessels (but
phagocytic activity of neutrophils is not affected)
➨ Decreased production of interleukins (mainly IL-2).
➨ Inhibition of histamine release from basophils and mast cells.
➨ Inhibition of fibroblast proliferation (due to the decrease in growth
factors and IL-2).
➨ Increased movement of lymphocytes, monocytes, eosinophils and
basophils from the vascular bed to the lymphoid tissue
The Anti-Inflammatory Action of Glucocorticoids
Mechanisms
Main mechanisms of anti-inflammatory action are:
1.
Alteration of number, distribution and function of
peripheral leukocytes and tissue macrophages.
It includes:
b.
For macrophages:
➨ Decreased accumulation of macrophages at the site of inflammation
➨ Decreased macrophage ability to phagocytize and kill
microorganisms
➨ Decreased production of interleukins (mainly IL-1), TNF , interferon
gamma and pyrogens .
➨ Decreased activation of T cells (due to decreased production of IL-1)
The Anti-Inflammatory Action of Glucocorticoids
Mechanisms
Main mechanisms of anti-inflammatory action
are:
2.
Inhibition of PG and leukotriene synthesis
➨ Inhibition of phospholipase A2 production (through induction of
lipocortin the synthesis of lipocortin, an enzyme the acts as an
inhibitor of phospholipase A2)
➨ Decreased Transcription of genes coding for cyclooxygenase 2
Additional Mechanisms:
Decrease in capillary permeability (due to inhibition of histamine
release and kinin activity) and inhibition of the effects of
complement system
The Immuno-suppressive Action
of Glucocorticoids
Features
☛ Humoral immunity is slightly affected (antibody
production is reduced only after high doses)
☛ Cellular immunity is strongly inhibited (distribution and
function of immune cells are deeply modified)
The Immunosuppressive Action of Glucocorticoids
Mode of Action
1.
Most actions of glucocorticoids on leukocytes and
macrophages can impair immunity. Especially
important in this regard are:
➨ The inhibition of macrophage-mediated production of
interleukin-1 and interleukin-6 (which in turn decreases
T cells activation and B cells proliferation) and of TNF
➨ The inhibition of T cell-mediated production of
interleukin-2 (which in turn decreases T cells
proliferation and impairs the activation of NK cells
➨ The direct lympholythic effect on certain subset of T
cells, including cytotoxic T cells.
The Immunosuppressive Action of Glucocorticoids
Mode of Action
2. Additional mechanisms are:
➨ Inhibition of other cytokines (glucocorticoids inhibit the
synthesis of almost all known cytokines).
➨ Inhibition of antigen release from grafted tissue.
➨ Stimulation of the catabolism of IgG (thus lowering the
effective concentration of specific antibodies).
3. The antiinflammatory effect of glucocorticoids
Is due to decreased synthesis of prostaglandins, leukotrienes, PAF,
TNF, histamine and kinins, and increased transcription of genes
coding from anti-inflammatory proteins such as IL-10, IL-12.
In fact the anti-inflammatory and immunosuppressive effects of
glucocorticoids are inextricably linked, perhaps because both
involve inhibition of leukocyte functions.
Relative Potencies of Corticosteroids
Relative Potency
Drug
Equivalent Oral
Dose (mg)
Anti-inflammatory
activity
Salt-retaining
activity
Cortisol*
1
1
20
Prednisone
4
0.3
5
Triamcinolone
5
0
4
Betamethasone
25-40
0
0.6
Dexamethasone
30
0
0.7
Fludrocortisone
10
250
2
Desoxycorticosterone
0
20
-
* Potencies relative to cortisone (taken as 1)
Pharmacokinetics of Glucocorticoids
ABSORPTION
➨ Oral bioavailability: 60-90%
➨ Rectal bioavailability: generally quite good.
➨ Absorption also occurs easily through the skin.
DISTRIBUTION
➨ Vd (70 Kg): cortisone 20 L; betamethasone 90 L
➨ Distributed in all tissues, including brain.
BIOTRANSFORMATION
➨ > 95% by the liver and other organs.
EXCRETION
➨ < 5% by the kidney.
Half-lives: 1-6 hours
BIOLOGICAL HALF-LIVES (DURATION
OF ACTION) OF CORTICOSTEROIDS
SHORT ACTING
Plasma t½:
0.5 – 2 hours
Biological t½: 8 – 12 hours
Cortisol
Cortisone
Fludrocortisone
INTERMEDIATE ACTING
Plasma t½:
2 – 5 hours
Biological t½: 18 – 36 hours
Prednisone
Prednisolone
LONG ACTING
Plasma t½:
3 – 6 hours
Biological t½: 36 – 54 hours
Dexamethasone
Betamethasone
Routes of Administration for
Corticosteroids
➨ Oral (tablets, syrups, etc.)
➨ Rectal (suppositories, enemas)
➨ Intramuscular (solutions, suspensions)
➨ Intra-articular, intralesional (solutions, suspensions)
➨ Intravenous (solutions)
➨ Respiratory (oral aerosol)
➨ Topical (cream, lotions, sprays, eye drops)
Absorption rate of various preparations depends on drug
formulation (salts, esters, excipients)
Some absorption of topical preparations always occurs and
may be high.
Toxicity of Glucocorticoids
Adrenal suppression
➨ The degree and duration of suppression depends on the dose and
duration of therapy.
➨ It takes at least 2-3 months for the pituitary and adrenals to become
responsive, after chronic steroid therapy is discontinued.
➨ If therapy is to be stopped corticoid dosage should be tapered slowly
(ACTH administration is not useful)
➨ If the dose is reduced too rapidly acute or chronic adrenal
insufficiency could ensue (nausea and vomiting, weight loss, lethargy,
fever, muscle pain, circulatory collapse, renal failure).
Iatrogenic Cushing's syndrome
(treatment with high dose for more than 2-3 weeks)
➨ Rounding and puffiness of the face ("moon face"), redistribution of fat
to the face and trunk ("buffalo hump"), thin limbs, thin and atrophic
skin, acne, hypertrichosis, purple striae.
(additional effects may be present)
Toxicity of Glucocorticoids
Other effects
a.
Early effects (days, weeks)
➨
➨
➨
➨
➨
Weight gain
Mood changes (hypomania or depression)
Glucose intolerance
Retarded wound healing
Allergic contact dermatitis (when given topically)
Toxicity of Glucocorticoids
Other effects
b. Long-term effects (months, years)
➨ Central obesity, cutaneous fragility
➨ Osteoporosis
➨ Opportunistic infections
➨ Growth failure (in children)
➨ Raised intracranial pressure
➨ Diabetes mellitus (in risk patients)
➨ Increased intraocular pressure (common)
Diabetogenic Effect of Glucocorticoids
Glucocorticoids may cause diabetes mellitus in risk patients by:
1. Stimulation of gluconeogenesis due to;
➨ increased transcription of enzymes that convert amino acids into
glucose in liver and kidney cells.
➨ increased mobilization of amino acids from extrahepatic tissues
(thereby providing amino acids for gluconeogenesis).
➨ increased lipolysis (thereby providing glycerol for gluconeogenesis).
2. Decreased glucose utilization by the cells.
Mechanism is uncertain
3. Increased glucagon secretion
Most Common Infections Occurring in
Patients Receiving Glucocorticoids
Infection
Causative Agent
Bacterial
➨ Mycobacterium tuberculosis
➨ Staphylococcus Species
Viral
➨ Herpes simplex virus
➨ Varicella-zoster virus
Fungal
➨ Candida albicans
➨ Cryptococcus neoformans
Parasitic
➨ Toxoplasma gondii
➨ Entemoeba histolytica
Glucocorticoid Contraindications and Precautions
➨ Cushing’s syndrome
➨ Diabetes mellitus
➨ Heart failure
➨ Renal failure
➨ Peptic ulcer
➨ Hypertension
➨ Osteoporosis
➨ Glaucoma, cataracts
➨ Herpes simplex infection
➨ Varicella, measles, acute viral hepatitis
➨ Bacterial and fungal infections
➨ Hypothyroidism (sensitivity to GC is increased)
➨ Schizophrenic or depressive psychoses
➨ Seizures
➨ Children
➨ Pregnancy
Drugs Interacting with Corticosteroids
Drug
Interaction
Clinical Relevance
Ethacrynic acid
Increased K+ loss and risk for
gastric hemorrhage
High
Cyclosporine
Decreased cyclosporine
metobolism
High
Estrogens
Decreased metabolism of
corticosteroids
High
Clinical Uses of Glucocorticoids
Diagnostic uses
The dexamethasone suppression test is used for:
The differential diagnosis in patients with Cushing's
syndrome (cortisol levels are reduced in the
presence of Cushing’s disease).
Clinical Uses of Glucocorticoids
Therapeutic uses
a. Endocrine disorders
1.
Replacement or supplementation therapy
➨ Acute and chronic adrenocortical insufficiency
➨ During and after surgical removal of a pituitary or adrenal adenoma.
2.
Feed-back inhibition of ACTH
➨ Congenital adrenal hyperplasia
b. Non-endocrine disorders
☛ Musculoskeletal and connective tissue diseases
➨Arthritis (rheumatoid arthritis, gouty arthritis, etc.)
➨Bursitis, tenosynovitis
➨Lupus erythematosus
➨Polyarteritis nodosa
➨Myasthenia gravis
Clinical Uses of Glucocorticoids
Therapeutic uses
b. Non-endocrine disorders (....contd.)
☛ Neoplastic diseases
➨ Leukemias, lymphomas, multiple myeloma
➨ Complications of malignancy
☛ Hematologic diseases
➨
➨
➨
➨
Autoimmune hemolytic anemia
Acute allergic purpura
Immunologic thrombocytopenic purpura
Transfusion reactions
Clinical Uses of Glucocorticoids
Therapeutic uses
☛ Gastrointestinal diseases
➨
➨
Inflammatory bowel diseases (ulcerative colitis, Crohn's
disease)
Nontropical sprue
☛ Pulmonary diseases
➨
➨
➨
➨
➨
➨
Bronchial asthma
Aspiration pneumonia
Prevention of infant respiratory distress syndrome
(administered to the mother during pregnancy)
Idiopathic pulmonary fibrosis
Sarcoidosis
Eosinophilic pneumonia
Clinical Uses of Glucocorticoids
Therapeutic uses
☛ Cardiovascular diseases
➨ Rheumatic carditis
☛ Renal diseases
➨ Nephrotic Syndrome
☛ Neurologic diseases
➨
➨
➨
➨
Acute cerebral edema
Multiple sclerosis
Mysathenia gravis
Spinal cord injury
Clinical Uses of Glucocorticoids
Therapeutic uses
☛ Allergic and immune diseases
➨
➨
➨
➨
➨
➨
Subacute thyroiditis
Allergic rhinitis
Angioneurotic edema
Insect venom allergy
Drug reactions
Transplantation rejection (host-versus-graft
disease and graft-versushost disease)
➨ Most immunologically mediated diseases
Clinical Uses of Glucocorticoids
Therapeutic uses
☛ Eye diseases
➨
Scleritis and
episcleritis
➨
Uveitis
➨
Ophthalmic herper
zoster
➨
Malignant thyroid
exophthalmos
☛ Skin diseases
➨
Urticaria
➨
Various dermatitis
(seborrheic, exfoliative, atopic)
➨
Pruritis ani
➨
Psoriasis
➨
Pemphigus
Guidelines for Glucocorticoid Therapy
1.
For any disease, in any patient, the appropriate dose to achieve
a given therapeutic effect must be determined by trial and
error.
2.
The dosage should be kept flexible, being raised or lowered
according to the status of the disease or the appearance of
unwanted effects.
3.
The synthetic analogs are generally preferable to natural
steroids because of their negligible sodium-retaining effects.
4.
A single dose of corticosteroids, even if very large, is virtually
without harmful effects.
Guidelines for Glucocorticoid Therapy
5. A few days of glucocorticoid therapy, in the absence of specific
contraindications, are unlike to produce harmful results.
6. When glucocorticoid therapy is prolonged over periods of weeks
or months, with doses exceeding the equivalent of substitution
therapy, the incidence of adverse effects is greatly increased.
7. A long-term corticosteroid therapy should be considered only
when there is either an undisputed therapeutic indication or
after other therapeutic measures have failed.
8. The lowest effective dose should be prescribed for the shortest
possible time. Moderation of symptoms with minimal untoward
effects is preferable to complete palliation with major
complications.
Regulation of Aldosterone Secretion
Aldosterone secretion can be stimulated by 4
main factors:
1. The increased concentration of K+ in the
extracellular fluid. (small changes in K+
concentration can increase aldosterone
secretion several folds).
2. The activation of the renin-angiotensin
system. (the system can be activated by a
decrease of mean arterial pressure, renal
blood flow, or plasma Na+ concentration)
Pharmacology of Mineralocorticoids
Mechanism of action
➨ A mineralocorticoid receptor (quite similar to the glucocorticoid
receptor) is present in the cytoplasm of target cells.
➨ Regulation of gene expression is the same as described for
glucocorticoids.
Pharmacological effects
➨ Stimulation of absorption of Na+ in:
a.
b.
c.
d.
Distal renal tubules (the main effect).
Salivary glands
Gastrointestinal mucosa
Across cell membranes in general.
➨ Increased renal secretion of K+.
➨ Increased renal secretion of H+.
Pharmacology of Mineralocorticoids
Pharmacokinetics and administration
➨ Plasma t½: aldosterone: . 20 min; DOC and fludrocortisone: .
1.5 hrs.
➨ Administration: fludrocortisone, by oral route.
Adverse effects
➨
➨
➨
➨
Hypernatremia
Hypervolemia
Hypokalemic alkalosis (weakness, paralytic ileus and tetany)
Hypertension
Therapeutic uses
➨ Acute adrenal insufficiency
➨ Chronic adrenal insufficiency (Addison's disease)
(in both cases cortisol must always be given concomitantly)
CORTICOSTEROID INHIBITORS AND ANTAGONIST
Drug
Mechanism of Action
Clinical Use
Corticosteroid synthesis inhibitors
Aminoglutethimide
Reversible blockade of the
➨ Cushing’s syndrome
conversion of cholesterol to
➨ Ovariectomized women
pregnenolone (production of
with metastatic breast
all adrenal steroids is
cancer (to eliminate adrenal
inhibited)
estrogen production)
Ketoconazole
(high doses)
Reversible blockade of
several steps of
steroidogenesis requiring
cytochrome P450 enzymes
Cushing’s syndrome
Receptor antagonists
Mifepristone
(high doses)
Blockade cytoplasmic
glucocorticoid receptor
Inoperable patients with
ectopic ACTH secretions or
adrenal carcinoma (it is also an
antiprogestin)
Spironolactone
Blockade of cytoplasmic
mineralocorticoid receptor
➨ Hyperaldostronism
➨ Hirsutism in women