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Lecture 22 Athsma Iii Notes

Pharmacology Notes > Drug Development (BIOL10822) Notes

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Anti-Asthma Drugs III - (Lecture 22)
ADRENCORTICOSTERIOIDS:The corticosteroids can be divided into two classes - the mineralocorticoids such as aldosterone and the glucocorticoids e.g. hydrocortisone.
Both types are synthesised in the adrenal cortex using cholesterol as a starting point.
The glucocorticoidss are amongst the body's most important hormones, involved in regulation of many metabolic processes as well as the immune system.

MINERALOCORTICOSTERIOIDS:
- E.g. aldosterone
- Water and electrolyte balance
GLUCOCORTICOSTEROIDS:E.g. hydrocortisone
Low concentrations - modulation of protein and carbohydrate metabolism
High concentrations - suppression of inflammation and immune responses

NUCLEAR HORMONE RECEPTORS (NHR):--

The corticosteriods act via nuclear hormone receptors.
Nuclear hormone receptors are one of the major receptor superfamilies. For lipophilic substances such as steroid hormones, corticosteroids, sex hormones, thyroid hormones and fat soluble vitamins A and D
They all have a similar structure
They bind agonist and regulate transcription of
DNA to mRNA.
The evolutionary relationships of some of the members of the Homo sapiens steroid receptor family are shown here GR=glucocorticoid receptor; MR= mineralocorticoid receptor; PR=
progesterone receptor; AR= androgen receptor;
ER= estrogen receptor.
Because NHR drugs such as adrenal steroids all alter cell function by changing the expression of proteins, they tend to have a long lag period before their effects are seen.
This can range from several hours to more than a day.
Therefore there are situations such as asthma where the anti-inflammatory actions of the
GC drugs are very useful in preventing attacks, but in which they cannot be used for acute, life-threatening emergencies. NHR STRUCTURE:The sequence of nuclear hormone receptors can be divided into a number of regions or domains.
At the N-terminal end of the protein is a loosely folded region.
This is followed by the DNA binding domain (DBD) which is linked to the ligand binding domain (LBD) by a hinge region.
Finally we have the C terminal tail. This general structure is common to all NHRs.
The lower panel shows the three dimensional structure of the two major domains.

NATURAL STEROIDS:The endogenous (produced by the body) steroids are hydrocortisone and corticosterone,
which act on both GCRs and MCRs produced by the adrenal cortex
Also, aldosterone, which has purely mineralocorticoid effects.

ANTI-INFLAMMATORY EFFECTS OF GLUCOCORTICOSTEROIDS IN THE LUNGS:-

Actions of the glucocorticoids in asthma are quite complex
Two actions include
à Up regulation of the antiinflammatory protein annexin 1
(also known as lipocortin),
inhibits phospholipase A2
à Down regulation of the enzyme cyclo-oxygenase,
reduced number of prostaglandins made
These effects decrease inflammatory eicosanoid signalling.

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