Download Glucocorticoids

Corticosteroids
 The term ‘corticosteroid’ or ‘corticoid’ includes natural
gluco- and mineralo-corticoids and their synthetic
analogues.
Simplified depiction of the pathways of adrenal steroid hormone biosynthesis
Mineralocorticoid actions
 Mineralocorticoid affects on Na+, K+ and fluid balance.
 The principal mineralocorticoid action is enhancement of
Na+ reabsorption in the distal convoluted tubule in
kidney. There is an associated increase in K+ and H+
excretion.
Side effects:
 edema
 progressive rise in BP
 Hypokalemia
 Alkalosis
Glucocorticoid actions
Carbohydrate metabolism
 Inducing hepatic glycogen
synthase (increased glucose
release from liver)
 Promoting gluconeogenesis
 They inhibit glucose
utilization by peripheral
tissues.
Protein metabolism
 Catabolic action (Protein
breakdown)
This results in:
 hyperglycaemia,
 resistance to
insulin
 diabetes-like state
This results in:
•Muscle wasting
•Lympholysis
•Loss of osteoid from
bone
•Thinning of skin
Glucocorticoid actions
Fat metabolism
 Redistribution of body fat occurs:
 Subcutaneous tissue over extremities loses fat
 Body fat is deposited over face, neck and shoulder
producing ‘moon face’, ‘fish mouth’ and ‘buffalo
hump’.
Glucocorticoid actions
Calcium metabolism
 Glucocorticoids inhibit intestinal absorption and
enhance renal excretion of Ca2+.
 Loss of osteoid (decreased formation and increased
resorption) indirectly results in loss of Ca2+ from
bone, producing negative calcium balance.
Stomach
 Secretion of gastric acid and pepsin is increased—may
aggravate peptic ulcer.
Glucocorticoid actions
CVS
 Glucocorticoids cause cutaneous vasoconstriction.
Skeletal muscles
 Weakness occurs in both hypo- and hypercorticism.


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Hypocorticism: diminished work capacity and weakness are primarily due to hypodynamic
circulation.
Hypercorticism: excess mineralocorticoid action → hypokalaemia → weakness;
Excess glucocorticoid action → muscle wasting and myopathy → weakness.
CNS
 Mild euphoria, increased motor activity, insomnia,
hypomania or depression, occasionally psychosis..
Glucocorticoid actions
Inflammatory responses
 Inflammation (redness, heat, swelling and pain) is suppressed by
glucocorticoids
 Strong antiinflammatory actions
 Corticoids are only palliative; do not remove the cause of
inflammation.
Immunological responses
 Glucocorticoids suppress all types of hypersensitization/
immunological responses
 Strong immunosuppressant actions
 This is the basis of their use in autoimmune diseases and organ transplantation, e.g. delayed
hypersensitivity and graft rejection
Allergic responses
 Glucocorticoids suppress all types of allergic phenomena
 Strong antiallergic actions
Relative activity of systemic
corticosteroids
Hydrocortisone (cortisol)
 Acts rapidly but has short duration of action.
 In addition to primary glucocorticoid, it has significant
mineralocorticoid activity as well.
Uses :
 Replacement therapy
 Shock
 status asthmaticus
 acute adrenal insufficiency
Prednisolone
 It is 4 times more potent than hydrocortisone, also
more selective glucocorticoid.
 Causes less pituitary-adrenal suppression when a
single morning dose is given.
Used for:
 allergic, inflammatory, autoimmune diseases and in
malignancies(oral, i.m., intraarticular; also topically).
Methylprednisolone
 Slightly more potent and more selective than
prednisolone
Uses
 ulcerative colitis.
 nonresponsive active rheumatoid arthritis,
 renal transplant,
 pemphigus, etc.
Triamcinolone
 Slightly more potent than prednisolone but highly
selective glucocorticoid:
 oral, i.m., intraarticular injection. Also used topically.
Dexamethasone
 Very potent and highly selective glucocorticoid.
 Causes marked pituitary-adrenal suppression.
It is used for:
 inflammatory and allergic conditions
 shock
 Cerebral edema
Betamethasone
 Similar to dexamethasone.
 Dexamethasone or betamethasone are preferred in
cerebral edema and other states in which fluid
retention must be avoided.
Deflazacort
 The glucocorticoid potency of this newer steroid is less
than of prednisolone, but it lacks mineralocorticoid
activity.
 It has been recommended for pediatric patients.
 It is used mainly for inflammatory and immunological
disorders.
USES
Replacement therapy
 1. Acute adrenal insufficiency
 2. Chronic adrenal insufficiency (Addison’s disease)
Pharmacotherapy (for nonendocrine diseases)
 Rheumatoid arthritis
 Collagen diseases (lupus, polyarteritis nodosa, ermatomyositis, nephrotic
syndrome, glomerulonephritis)
 Severe allergic reactions (anaphylaxis, angioneurotic edema)
 Autoimmune diseases (Autoimmune haemolytic anaemia, idiopathic
thrombocytopenic purpura, active chronic hepatitis)
 Bronchial asthma
 Inflammatory diseases
 Skin diseases (pemphigus vulgaris, exfoliative dermatitis, Stevens-Johnson
syndrome)
 Intestinal diseases (Ulcerative colitis, Crohn’s disease, coeliac disease are
inflammatory bowel diseases)
 Organ transplantation and skin allograft
 Septic shock
ADVERSE EFFECTS
Mineralocorticoid
 Sodium and water retention,
 edema
 hypokalaemic alkalosis
 progressive rise in BP.
Glucocorticoid ADR
Cushing’s habitus: characteristic appearance with rounded face, narrow
mouth, supraclavicular hump, obesity of trunk with relatively thin limbs.
2. Fragile skin: purple striae—typically on thighs and lower abdomen, easy
bruising, telangiectasis, hirsutism. Cutaneous atrophy localized to the
site occurs with topical application as well.
3. Hyperglycaemia, may be glycosuria, precipitation of diabetes.
4. Muscular weakness
5. Susceptibility (tendency) to infection: this is nonspecific for all types of
pathogenic organisms. Latent tuberculosis may flare; opportunistic
infections with low grade pathogens (Candida, etc.) set in.
6. Delayed healing: of wounds and surgical incisions.
7. Peptic ulceration: bleeding and silent perforation of ulcers may occur.
8. Osteoporosis → fractures
9. Glaucoma
10. Growth retardation: in children occurs even with small doses
11. Foetal abnormalities
12. Psychiatric disturbances: manic psychosis, nervousness, decreased sleep
and mood changes, depressive illness)
1.
CONTRAINDICATIONS
The following diseases are aggravated by corticosteroids.
 Peptic ulcer
 Diabetes mellitus
 Hypertension
 Viral and fungal infections
 Tuberculosis and other infections
 Osteoporosis
 Herpes simplex keratitis
 Psychosis
 Epilepsy
 CHF
 Renal failure
Antihistaminics
a type of pharmaceutical drug that opposes the activity of
histamine receptors (H1 antagonists/ H1 blockers)
 Antihistamines that target the histamine H1-receptor are
used to treat:
 allergic reactions (Allergic rhinitis, conjunctivitis,
dermatological conditions (contact dermatitis),
rhinorrhea (Runny nose), angioedema, anaphylactic or
anaphylactoid reactions)
 for insomnia (1 generation H1-antihistamines)
 motion sickness or vertigo caused by problems with
the inner ear (1 generation H1-antihistamines)
H1-antihistamines
Histamine, acting on H1 While H1-antihistamines help
receptors, produces:
against these effects, they work
only if taken before contact with
 pruritus (Itch),
the allergen.
 vasodilation,
 hypotension,
 Additional administration of
 flushing,
epinephrine is required by people
 headache,
with severe allergies, such as
 tachycardia,
anaphylaxis or angioedema
 bronchoconstriction,
 increase in vascular
permeability,
 potentiation of pain, and
more.
First-generation (non-selective, classical)


These are the oldest H1-antihistaminergic drugs.
They are effective in the relief of allergic symptoms, but have action at α-adrenergic receptors, 5-HT receptors, muscarinic
receptor (anticholinergic).
I. HIGHLY SEDATIVE (strong hypnotic effect)
 Diphenhydramine (Benadryl)
 Dimenhydrinate (Dramamine,Vomex)
 Promethazine
 Hydroxyzine
 Chloropyramine (Suprastin)
II. MODERATELY SEDATIVE
 Pheniramine
 Cyproheptadine
 Cinnarizine
III. MILD SEDATIVE
 Chlorpheniramine
 Dexchlorpheniramine
 Clemastine (Tavegyl)
First-generation H1-antihistamines
Adverse drug reactions
Due to:
 relative lack of selectivity for the H1-receptor
 ability to cross the blood-brain barrier.
 The most common ADR is sedation; this "side-effect" is
utilized in many sleeping-aid preparations.
 Other common ADR:
 dizziness, tinnitus, blurred vision, euphoria,
uncoordination, anxiety, increased appetite leading to
weight gain, insomnia, tremor, nausea and vomiting,
constipation, diarrhea, dry mouth, and dry cough.
Second-generation (selective, non-sedating)
 2-generation H1-antihistamines are newer → more
selective → significantly reducing of the occurrence of
ADR, such as sedation.
 They are very polar → do not cross the blood–brain
barrier and act mainly outside the CNS.
 Loratadine
The most common ADR:
 Cetirizine
drowsiness, fatigue, headache, nausea and dry mouth
 Ketotifen
!!!Prolongation QT interval → polymorphic ventricular
 Acrivastine
tachyarrithmia (Torsades de pointes)!!!!
 Terfenadine
 Quifenadine
Third-generation H1-antihistamines
 Active metabolites of second-generation drugs are
informally labeled as third-generation because they
are intended to have:
 increased efficacy
 decreased risk of cardiac arrhythmia
 Levocetirizine
 Desloratadine
 Fexofenadine
Immunosuppressant Drugs
Immunosuppressants are drugs which:
 inhibit cellular/humoral or both types of immune
responses,
 have their major use in organ transplantation and
autoimmune diseases.
Immunosuppressants
 Specific T-cell inhibitors:
 Cyclosporine (Ciclosporin),
 Tacrolimus
 Cytotoxic drugs (Antiproliferative drugs):
 Azathioprine,
 Methotrexate,
 Cyclophosphamide
 Glucocorticoids:
 Prednisolone and others
 Biological agents
 TNFα inhibitors:
 Infliximab
 Adalimumab
 IL-2 receptor antagonists:
 Basiliximab
 Polyclonal antibodies:
Antithymocyte antibody (ATG),
Rho (D) immune globulin.
Sites of action of immunosuppressant drugs
The antigen (Ag) is processed by macrophages or
other antigen presenting cells (APC), coupled
with class II major histocompatibility complex
(MHC) and presented to the CD4 helper T-cell
which are activated by interleukin-I (IL-1),
proliferate and secrete cytokines—these in turn
promote proliferation and differentiation of
antigen activated B cells into antibody (Ab)
secreting plasma cells.
Antibodies finally bind and inactivate the
antigen.
In cell-mediated immunity—foreign antigen is
processed and presented to CD4 helper T cell
which elaborate IL-2 and other cytokines that in
turn stimulate proliferation and maturation of
precursor cytotoxic lymphocytes (CTL) that have
been activated by antigen presented with class I
MHC.
The mature CTL (Killer cells) recognize cells
carrying the antigen and lyse them.
1. Glucocorticoids
2. Cytotoxic drugs
3 Specific T-cell inhibitors.
4. Antibodies
Mechanism of action
 Cytotoxic drugs block proliferation and
differentiation of T and B cells.
 Specific T-cell inhibitors (Cyclosporine,
tacrolimus) inhibit antigen stimulated activation
and proliferation of helper T cells as well as
expression of IL-2 and other cytokines by them.
 Glucocorticoids inhibit IL-1, IL-2, IL-6 production
so that helper T-cells are not activated..
 Antibodies (antithymocyte globulin) specifically
bind to helper T cells, prevent their response and
deplete them.
Adverse effects
The two general ADR of immunosuppressant therapy are:
 Increased risk of bacterial, fungal, viral (especially
CMV) as well as opportunistic infections.
 Development of lymphomas and related malignancies
after a long latency.