steroidal anti-inflammatory compounds 343

7/28/2019 Steroidal Anti-Inflammatory Compounds 343

1/18

VII. STEROIDAL ANTI-INFLAMMATORY

COMPOUNDS

Classification of adrenocorticosteroids:

1. Natural and synthetic.

2. Glucocorticoids and mineralocorticoids.

Glucocorticoids: concerned with CH metabolism and may include

natural glucocorticoid as Hydrocortisone (cortisol) and Cortisone

and synthetic ones including Prednisone, Prednisolone, Methyl-

prednisolone,Triamcinolone, Betamethasone and Dexamethasone.

Mineralocorticoids: concerned with salt and water metabolism and

may include natural mineralocorticoid as Aldosterone and

Desoxycorticosterone (DOC) and synthetic ones including

Fludrocortisone.

Mechanism of Action of Glucocorticoids:

1) Diffusion of glucocorticoid across the membrane of the target

cell to bind to a glucocorticoid receptor-heat-shock protein

complex in the cytoplasm.

2) Release of the heat-shock protein and transport of the hormone-

receptor complex into the nucleus.

3) Binding of the hormone-receptor complex to specific nucleotide

sequence along the DNA called glucocorticoid response elements

(GREs).

4) Decreased or increased accumulation of mRNA within the target

cell (alteration of transcription).

5) Changes in the rate of synthesis of specific proteins that carry

the biological actions of the hormones.


2/18

Mechanism of action (some details)

1. Enter cells where they combine with steroid receptors in

cytoplasm.

2. Combination enters nucleus where it controls synthesis of

protein, including enzymes that regulate vital cell activities over a

wide range of metabolic functions including all aspects of

inflammation.

3. Formation of a protein that inhibits the enzyme phospholipase

A2 which is needed to allow the supply of arachidonic acid. The

latter is essential for the formation of inflammatory mediators.

4. Also act on cell membranes to alter ion permeability

5. Also modify the production of neurohormones

Effects of glucocorticoids may be:

A) Direct effects: Direct actions in the cell.

B) Indirect effects: the results of the homeostatic responses (e.g. by

insulin, glucagon, PTH).

A) Physiologic (or pharmacologic) effect: dose-dependent effect.

B) Permissive effect: dose-independent effect

Important to distinguish between physiological effects

(replacement therapy) and pharmacological effects (occur at

higher doses).


3/18

1. Metabolic Effects:

A) Carbohydrate Metabolism

1. Increased gluconeogenesis in liver and kidney.2. Increased glycogen synthesis and storage.

3. Inhibition of glucose uptake and utilization by both adipose

tissue and skeletal muscle.

4. The hyperglycemia stimulates insulin secretion

B) Lipid Metabolism:

1. Increased lipolysis which leads to an increased in plasma levels

offree fatty acids.

2. Insulin secretion stimulates lipogenesis leading to a net increase

in fat deposition.

3. Increased fat absorption from the intestine.

4. Redistribution of body fat (increased in the back of the neck and

face, decreased in the extremities).

C) Protein Metabolism

1. Increased protein synthesis in the liver.

2. Decreased synthesis (anabolism is decreased).

3. Increased breakdown of proteins in lymphoid and connective

tissue, muscle, fat and skin. Catabolism continues unabated or is

increased resulting in negative N balance and muscle wasting.

Osteoporosis occurs, growth slows in children, skin atrophies

(together with increased fragility leads to brusing and striae),

healing and fibrosis delayed.


4/18

D) Salt and Water Metabolism:

1. Salt and water retention

2. Less than mineralocorticoids.

3. Negligible with some synthetic glucocorticoids.

4. Mineralocorticoids cause:

A) Na retention by renal tubule

B) Increased K excretion in urine

2. Cardiovascular Effects:

A. Permissive Effects: maintenance of:

1. A normal capillary permeability.

2. A normal vasomotor response to CAs.

3. A normal heart contractility.

4. A normal cardiac output.

B. Direct effect:

1. Direct vasoconstriction on small vessels.

2. Hypertension.

3. Renal Effects:

A) Permissive Effects: maintenance of:

1. A normal glomerular filtration.

2. A normal water permeability in the distal collecting tubules due

to inhibition of vasopressin secretion.

B) Increased excretion of Ca++.

C) Renal urate excretion increased

4. Gastrointestinal Effects:

1. Maintenance of normal function of visceral smooth muscle

(permissive Effect).

2. Increased production of gastric acid and pepsin.

3. Decreased cytoprotection of gastric mucosa.

4. Decreaed Ca++ absorption from the intestine (also, due to

blockade of vitamin D action).

5. Antiemetic effects.

6. General depressive effects on intestinal functions after high

doses.


5/18

5. Central Nervous System Effects:

1. Decreased cortical threshold for convulsions.

2. Behavioural disturbances after high doses.

3. Increased intracranial pressure after high doses.

Euophoria or psychotic states may occur probably due to CNS

electrolyte changes

6. Endocrine Effects:

1. Decreaed release of CRH, ACTH and beta-lipotropin, TSH,

FSH, and ADH.

2. Increased release of GH.

7. Hematopoietic Effects:

1. Decreased concentration of lymphocytes, monocytes, basophils

and eosinophils in blood due to increased efflux of these cells from

blood to the lymphoid tissue.

2. Increaed concentration of neutrophils in blood due both to 1)

increased efflux from bone marrow and to decreased migration

from the blood vessels.

3. Increased concentration of red blood cells and platelets.

8. Locomotor System Effects:

1. Permissive effect: Maintenance of normal function of striatal

muscle (Permissive effect).

2. Decreased muscle mass after high doses.

3. Decreased bone formation (direct effect due to iinhibition of

osteoblasts.4. Increased bone resorption (indirect effect due to increased

secretion of PTH and decreased secretion of calcitonin.

5. Negative total body Ca++ balance.

9. Antineoplastic action due to:

1. Dissolution of pathologic lymphocytes and lymphoid tissue

(lympholythic action).

2. Inhibition of growth of mesenchymal cancer tissue.


6/18

3. In many tumors, the effect is the consequence of their anti-

inflammatory action.

10. Anti-Inflammatory action:Have two important characters:

1. All types of inflammatory reactions are affected.

2. Both early and late phases of inflammation are inhibited.

Inlammatory response depressed

Main mechanisms of anti-inflammatory actions are:

1) Alteration of number, distribution and function of peripheral

leukocytes and tissue macrophages.2. Inhibition of PG and leukotriene synthesis.

3) Additional mechanisms.

Alteration of number, distribution and function of peripheral

leukocytes and tissue macrophages includes:

For leukocytes:1. Decreased migration of neutrophils from the blood vessels.

2. Increased movements of lymphocytes, monocytes, basphils and

eosinophils from vascular bed to the lymphoid tissue.

3. Decreased production of Interleukins (mainly I 2). TNF, and

interferon gamma.

4. Inhibition of histamine release from basophils and mast cells.

5. Inhibition of fibroblast proliferation both due to the decrease in

growth factor production and the decreae in interleukin 1.

For macrophages:

1. Decreased accumulation of macrophages at the site of

inflammation.

2. Decreased macrophage ability to phagocytose and kill

microorganisms.

3. Decreased production of interleukins (mainly I 1), TNF,

interferon gamma and pyrogens.4. Decreased activation of T cells.


7/18

Inhibition of PG and leukotriene synthesis.

1. Inhibition of phospholipase A2 production.

2. Inhibition of COX-II production.

Additional mechanisms of anti-inflammatory action include

Decrease in postcapillary permeability due to

1. Inhibition of histamine release and kinin activity.

2. Inhibition of the effects of complement system.

11. Immunosuppressive action:

Have two important characters:

1. Humoral immunity is slightly affected as the antibodyproduction is reduced only after high doses.

2. Cellular immunity is strongly inhibited as the distribution and

function of immune cells are deeply modified.

Mechanisms of immunosuppressive action are:

A) Most of the effects on leukocytes and macrophages mentioned

above can impair immunity. Especially in this regard are:

1. Inhibition of interlekin 1 production which in turn decreases theproliferation of T cells and impairs the responses of both T and B

cell to antigen.

2. The direct lympholythic effect on certain subset of T cells

(cytotoxic T cells and inflammatory T cells).

B) Additional mechanisms include:

1. Inhibition of antigen release from grafted tissue.

2. Stimulation of the catabolism of IgG antibodies thus loweringthe effective concentration of specificantibodies.


8/18

Relative potencies of corticosteroids

Drug AI SR EOD(mg)

Hydrocortisone 1 1 20

Prednisone 4 0.3 5

Prednisolone 5 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 -

AI: Antiinflammatory activity

SR: Salt-retaining activity.

EOD: Equivalent oral dose (mg)

Duration of action of corticosteroids

Group Plasma t1/2 Biological t1/2 Examples

Short-Acting 0.5-2 hrs 8-12 hrs Hydrocortisone,

cortisone,

Fludrocortisone

Intermediate

Acting

2-5 hrs 12-36 hrs Prednisone,

prednisolone,

Triamcinolone

Long Acting 3-6 hrs 36-72 hrs Betamethasone,

Dexamethasone


9/18

Routes of administration of corticosteroids

Route Dosage form

Oral Tablets, syrups, etc.

Rectal Suppositories, enemas

Intramuscular Solutions, suspensions

Intra-articular Solutions, suspensions

Intravenous Solutions

Respiratory Oral aerosol

Topical Cream, lotions, sprays, eye

drops

Note: Some absorption of topical preparations always occurs

and may be high.


10/18

Toxicity of glucocorticoids

1. Adrenal suppression

2. Iatrogenic Cushings syndrome

3. Other toxic effects: subdivided into:

A) Early toxic effects (days, weeks)

B) Later toxic effects (months, years)

Adrenal suppression:

1. The degree and duration of adrenal suppression

depend

on the dose and duration of glucocorticoid therapy

2. It takes at least 2-3 months for the pituitary and

adrenals to become responsive, after chronic steroid

therapy is discontinued

3. If therapy is to be stopped, corticosteroid dosage

should

be tapered slowly.

4. If the dose of glucocorticoid is reduced too rapidly,

acute

or chronic adrenal insufficiency could ensue.

What are the symptoms of acute or chronic adrenal

insufficiency?

A) Nausea and vomiting

B) Weight loss

C) Lethargy

D) Fever

E) Muscle pain

F) Circulatory collapse

G) Renal failure

N.B. Steroid suppressed adrenal continues to secrete

aldosterone.


11/18

Iatrogenic Cushings syndrome:

Treatment with high dose for more than 2-3 weeks

Symptoms of Cushings syndrome include:

1. Moon face: rounding and puffiness of the face

2. Buffalo hump: Redistribution of fat to the face andtrunk

3. Thin limbs

4. Thin and atrophic skin

5. Acne

6. Hypertrichosis

Early Toxic effects (days or weeks after administration)

1. Weight gain

2. Mood changes

3. Retarded wound healing

4. Glucose intolerance

5. Allergic contact dermatitis when given

6. Rare early toxic effects:

- Hypertriglyceridemia

- Peptic ulcer

- Acute pancreatitis

Later toxic effects (months or years after administration)

1. Central obesity2. Cutaneous fragility

3. Ecchymosis

4. Osteoporosis

5. Myopathy

6. Opportunistic infections

7. Growth failure in children (Growth reduction occurs

where new cells are being added (as in children) but not

where they are replacing cells as in adult tissues.

8. Raised intracranial pressure (pseudotumor cerebri)


12/18

9. Diabetes mellitus in risk patients

10. Hypertension (rare with synthetic glucocorticoids)

11. Rare late toxic effects:

12. Aseptic necrosis in bone

13. Posterior subcapsular cataracts, glaucoma

Infections occurring with increased frequency and severity

in patients receiving glucocorticoids

Bacterial infection caused by:

Mycobacterium tuberculosis

Proteus VulgarisPseudomonas aeruginosa

Staphylococcus species

Viral infection caused by:

Herpes simplex virus

Varicella-Zoster virus

Fungal infection caused by:

Aspergillus fumigatus

Candida albicans

Parasitic infection caused by;

Entamoeba histolytica, Toxoplasma gondii

Contraindications and Cautions of Glucocorticoids

1. Diabetes mellitus

2. Hypertension

3. Heart failure

4. Renal failure5. Osteoporosis

6. Osteoarthritis

7. Glaucoma

8. Bacterial infections

9. Herpes simplex infection

10. Acute viral hepatitis

11. Schizophrenic or depressive psychosis

12. Pregnancy


13/18

Drug interactions with corticosteroids:

1. with ethacrynic acid (high clinical relevance)

Increased K+ loss

Increased risk of gastric hemorrhage

2. with cyclosporine (high clinical relevance)

Decreased metabolism of cyclosporine

3. with estrogens (high clinical relevance):

Decreased metabolism of corticosteroids

4. with enzyme inducers as barbiturates, phenytoin.

Rifampin and carbamazepine (medium clinical relevance):

Increased metabolism of corticosteroids

5. with salicylates (medium clinical relevance):

Increased salicylate excretion

Enhancement of gastric effects

6. Among the drugs that interact with corticosteroids are:

* Insulin and diabetes medicines

* Heart medicines such as digitalis

* Diuretics

* Medicines containing potassium or sodium

* Immunization (vaccination)

* Blood thinners such as warfarin

Clinical uses of glucocorticoids:

1. Diagnostic uses

2. Therapeutic uses

A. Endocrine disorders

B. Non-endocrine disorders


14/18

Diagnostic uses:

Dexamethazone suppression test is used for:

A) Differential diagnosis in patients with Cushings

syndrome

B) Differential diagnosis of psychiatric states (the test is

abnormal in the presence of severe mental disorder)

Uses of glucocorticoids in endocrine disorders:

1. Replacement or supplementation therapy in:

A. Acute and chronic adrenal insufficiency

B. During and after surgical removal of a pituitary or

adrenal adenomaC. Feed-back inhibition of ACTH as in congenital adrenal

hyperplasia

Uses of glucocorticoids in non-endocrine disorders:

1. Musculoskeletal and connective tissue diseases

* Rheumatoid arthritis* Gout arthritis

* Bursitis

* Polymyalgia rheumatica

* Polymyositis

* Polyarteritis nodosa

* Lupus erythematosus

Neoplastic diseases*n Leukemias

*n Lymphomas

* Multiple myeloma

* Complications of malignancy

Hematologic diseases:

* Acquired hemolytic anemia

* Autoimmune hemolytic anemia* Some forms of aplastic anemias


15/18

* Idiopathic thrombocytopenic purpura

* Acute allergic purpura

* Transfusion reactions

Gastrointestinal diseases

* Ulcerative colitis

* Crohns disease

* Chronic active hepatitis

* Subacute hepatic necrosis

Pulmonary diseases

* Bronchial asthma* Aspiration pneumonia

* Prevention of infant respiratory distress syndrome

(administered to the mother during pregnancy)

* Idiopathic pulmonary fibrosis

Cardiovascular diseases

* Myocarditis and pericarditis

* Rheumatic carditis* Temporal arteritis

Renal disease

*Nephrotic syndrome

Neurologic diseases

* Acute cerebral edema

* Meningitis* Multiple sclerosis

* Myasthenia gravis

* Spinal cord injury

Eye diseases

*Anterior uveitis

* Posterior uveitis

* Optic neuritis


16/18

* Malignant thyroid exophthalmos

Allergic and immune diseases

*Subacute thyroiditis* Allergic conjunctivitis

* Allergic rhinitis

* Angioneurotic edema

* Serum sickness

* Insect venom allergy

* Drug reactions

* Anaphylaxis

* Transplantation rejection (host-versus-graft diseaseand graft-versus-host disease)

Skin diseases

* Urticaria

* Various types of dermatitis

* Erythema multiforme

* Psoriasis

**Normal daily secretion of hydrocortisone is 10-30 mg.

exogenous daily dose that completely suppresses cortex is 40-

80 mg (or prednisolone 10-20 mg).

**Prednisolone is standard choice for anti-inflammatory

therapy and can be given orally or IM

**Methylprednisolone used for IV pulsed therapy

**Dexamethazone longer acting

**Fludrocortisone used to replace aldosterone where the

adrenal cortex has been destroyed

**Beclomethazone and budesonide used by inhalation for

asthma.


17/18

Principles for using glucocorticoids

1. for any disease, in any patient, the appropriate dose to

achieve a given therapeutic effect must be determined bytrial and error

2. The dosage should be kept flexible, being raises or

lowered according to the activity of the disease or the

development 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

5. in the absence of specific contraindications, a few days of

corticosteroid therapy are unlike to produce harmful effects,

except at the most extreme dosage

6. as corticosteroid 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. Committing a patient to long-term corticosteroid therapy

should be considered only when there is 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

9. in stable treatment programs, use of the alternate day

dosage schedule should be considered. With this regimen,

unwanted effects are fewer and less severe


18/18

10. Abrupt cessation of prolonged, high dosage

corticosteroid therapy is associated with significant risk of

adrenal insufficiency that can be threatening to life

11. Patients who have received cortisone 50 mg or more per

day (or equivalent amount of other corticosteroids) for more

than one month should be considered to have some degree of

pituitary adrenal suppression for at least one year after

corticosteroid withdrawal

12. except in adrenal insufficiency, the administration of

corticosteroids is neither an etiological nor a curative

therapy but only a symptomatic one

END OF THE LECTURE

steroidal anti-inflammatory compounds 343

Documents