3. What are the functions of each
product ?
How synthesis & release of each
product is regulated ?
How they are now in pharmacological
practice ?
Why GCs more public ?
4. Functions of Cortisol
Protein Metabolism
It inhibits amino acid uptake & protein synthesis in extrahepatic tissues
Catabolic in Muscle , Skin & Bone
Excess cortisol Severe Muscle Wasting
5. Functions of Cortisol
CHO Metabolism
Reduce tissue uptake of glucose
Reduce conversion of glucose to glucose-6- phosphate
( Anti-insulin action )
Increase Gluconeogenesis in liver
Excess cortisol Diabetogenic
6. Functions of Cortisol
Fat Metabolism
Mobilization of fat from fat depots to supply energy
( Lipolytic Ketogenic )
Excess Cortisol Ketosis
DM + Cortisol = Possible Ketosis
7. Functions of Cortisol
Cortisol impedes development of
Cartilage & Bone :
It reduces absorption of Ca++ from GIT by antagonizing effect of vitamin-D
Increase Ca++ loss in urine
Excess Cortisol OP of bones especially vertebrae
8.
9. Functions of Cortisol
Anti-Stress :
Activate Energy Metabolism
In severe mental & Physical Stress ,
Cortisol plasma concentration remains at a very high level
( up to 10 times the normal value ) throughout the day
10. Functions of Cortisol
Cardiovascular function :
Increase Myocardial contractility
Vasoconstriction
How GC causing vasoconstriction ?
By enhancement of catecholamines effects
( permissive effects of cortisol )
11.
12.
13. Functions of Cortisol
Anti-allergic :
It inhibits allergic responses
Reduce Histamine Synthesis in mast cells & basophils
Reduce Kinin Synthesis
14. Functions of Cortisol
Anti-inflammatory :
It inhibits all stages of inflammatory process
It has a stabilizing action on Lysosomal membranes of Leucocytes
Reduce inflammatory chemical mediators as PG.s & IL.s
It suppresses migration of Neutrophils
It inhibits proliferation of Fibroblasts in wound repair
Abscess
18. Functions of Cortisol
Immunosuppressive :
It inhibits normal immune response
Reduce circulating Lymphocytes , Basophils & Eosinophils
Reduce Antibody production
Disadvantages : It causes spread of infection ( as TB )
Advantages : it is used in treatment of autoimmune disorders
19.
20.
21. GC effects on the immune system
Inhibt Adhesion molecules
Inhibit Complement pathway proteins
Inhibit NO
Supraphysiologic GCs : Suppress
Fibroblast proliferation
IL-1
TNF-alpha – induced MMPs
They inhibit most of the proinflammatory ,
T-helper type 1 ( TH1 ) cytokines , including :
IL-1B , IL-2 , IL-3 , IL-6 , TNF-alpha ,Interferon-@ & GM-CSF
Conversely :
They stimulate ( or not affect ) production of Th2 cytokines as
IL-4 , IL-10 & IL-13
Suppress lipoxygenase , Prostanois , Arachidonic , PGs
They decrease Cytokines .. Decrease inducible form of NO synthetase .. Decrease NO production in inflammatory sites … Decrease Blood flow … Decrease
exudation & probably decrease amplification of the inflammatory response
Suppress Bone destruction & erosions
Potentially DMAOSDs
26. Patients taking even low-dose GC therapy report a slight increase in their overall
sense of well-being,
which appears to be independent
of improvement in disease activity.
Neuropsychiatric effects
27. Symptoms of
Akathisia (motor restlessness),
Insomnia, and
Depression
are also occasionally observed in patients taking
low-dose therapy.
Neuropsychiatric effects
28. Memory impairment
can occur even at low doses, particularly in older patients.
Daily split-dose therapy,
in particular, tends to be troublesome because
the evening dose promotes sleep disturbances.
True GC psychosis
is distinctly uncommon at dosages of less than
20 mg/day of prednisone.
Neuropsychiatric effects
29. Excess & frequent stresses
are showers of
Catecholamines & GCs
Adrenal Fatigue Syndrome
The 21st Century Stress
Syndrome
32. GENOMIC
GCs at any therapeutic dosage
do its effects :
via classic genomic mechanisms
The main mechanism whereby GCs
deliver their anti-inflammatory action
33. . GENOMIC ACTION
Because of this, the genomic action of GCs
takes at least 4 hours
to start showing an effect
Less frequent dosing
the duration of action is also prolonged
and may exceed 24 hours
34. Non-genomic action of GCs includes all actions that do
Not directly alter gene expression & are
Not blunted by inhibitors of gene transcription
This mode is characterized by its
Rapid onset (seconds to minutes) &
Short duration (60-90 min).
These actions are dose dependent
With high doses :
NON-GENOMIC ACTION
35. NON-GENOMIC ACTION
Therefore :
The response to high dose may be biphasic
with an early rapid non-genomic effects
and :
delayed & more sustained
classic genomic effect
Clinically ,,, both effects cannot be separated
40. Relative potencies of various GCs to produce genomic & nonspecific nongenomic effects
(A)Data for classic genomic effects relative to control
(B)Data for nongenomic effects relative to prednisone
N.B. Nonspecific nongenomic effects are especially relevant in higher doses
Calculate for prednisone equivalent for Genomic effect but
not for non-genomic non-specific effects
