LOCAL HORMONES, INFLAMMATION AND IMMUNE REACTIONS 1st of February, 2012

Overview All living creatures face a constant challenge to their physical well being and survival In order to overcome this challenge, evolution has provided us with: Homeostatic systems to maintain a stable environment Mechanisms for combating the ever-present threat of infection (immune responses) Mechanisms for promoting healing and restoration of normal function in the event of injury (inflammatory reaction)

Overview In mammals, the vital function of protection from infection and /or injury is subserved by the innate and adaptive immune responses, working together with a variety of mediators and mechanisms that give rise to inflammation

Introduction A mammalian organism facing an invasion by a disease-causing organism (pathogen) can call on a prodigious array of powerful defensive responses: the deployment of these constitutes the acute inflammatory/immune reaction. When these defenses are lacking (e.g. in AIDS) or are suppressed by drugs, organisms that are not normally pathogens can cause disease (opportunistic infections).

However, in some circumstances, these defensive responses may be brought into play in response to other sorts of injury caused by chemicals, ultraviolet, heat etc In other circumstances they may be inappropriately deployed against innocuous substances from outside the body (e.g. pollen) or against the tissues of the body itself ( in autoimmune conditions)

Note: (Autoimmune diseases are caused by the host’s immune system attacking the host’s own tissue, i.e. they result from inappropriately deployed immune responses)

When this happens, the responses themselves can produce damage and may indeed constitute part of the disease process-either acutely, as e.g. anaphylaxis, or chronically as e.g. in asthma, rheumatoid arthritis, or atherosclerosis

It is for this sorts of conditions that anti-inflammatory or immunosuppressive drugs are used.

An impressive variety of chemical mediators control or modulate these defensive responses of the host, and an understanding of the action, mechanism of action and clinical use of drugs that affect the inflammatory and immune responses depends on an appreciation of the way in which the cells and the mediators interact with each other.

Inflammation Inflammation can be defined as a localised physical condition in which part of the body becomes reddened, swollen, hot and often painful especially as a reaction to injury or infection It is an active defensive response from the body to injury of any kind.

The inflammatory stimuli include chemical or physical trauma, infestation with helminthes, infection with protozoa, fungi, bacteria, rickettsia or viruses and antigen/antibody interaction. Cardinal signs of inflammation include redness, swelling, heat, pain and loss of function

General principles of inflammation In the skin an inflammatory stimulus results in the area becoming warm and red due to increased blood flow, swollen due to leakage of plasma protein, followed by salt and water, into the interstitial space as a result of increased protein permeability of microcirculatory vessel walls, and painful due to stimulation of sensory pain fibres.

Loss of function may consequently occur. Similar inflammatory processes occur at all other sites

In acute inflammation, a succession of changes takes place over a short period minutes to days), which ends either by return of tissue to normal or by conversion to chronic inflammation. Chronic inflammation may last months to years and is characterized by periods of regression and repair, which may be punctuated by further acute inflammatory changes

Components of the Acute Inflammatory Reaction The acute inflammatory reaction has two components: the innate and the adaptive responses Some aspects of the innate response are non-immunological but the adaptive response is mainly immunological being an exquisitely pathogen-specific response However, the adaptive response also boosts the cells and mediators of the innate response

Many of the diseases that need drug treatment involve inflammatory processes. Understanding of the action and, therefore, the use of anti-inflammatory and immunosuppressive drugs necessitates an understanding of the inflammatory reaction

H/W-Read on the following: Components of the acute inflammatory reaction i.e. -innate non-adaptive immune response -adaptive immune response Systemic responses in inflammation Unwanted inflammatory reactions and immune responses

H/W-Read on the following: Unwanted immune responses are termed allergic or hypersensitivity reactions and have been classified into 4 types: i. e. Type I, II, III and IV ( further reading) NB: the term allergy is now generally restricted to Type I hypersensitivity The outcome of the inflammatory response

H/W-Read on the following: Mediators of inflammation and immune reactions includes: Histamine-(Revision) Eicossanoids Prostanoids- (Prostaglandins and thromboxanes) Leukotirenes Lipoxins Platelet-activating factor(PAF) Bradykinin (Revision)

Nitric oxide-(Revision) Neuropeptides (Revision) Cytokines Chemokines Interferons Note in each: Biosynthesis, catabolism, receptors, actions, role in inflammation and clinical uses

ANTI-INFLAMMATORY AND IMMUNOSUPPRESSANT DRUGS

Overview We will discuss on the drugs used to treat inflammatory and immune disorders. Inappropriate inflammatory or immune reactions are involved in most of the diseases that you as clinicians will meet, and the drugs used to treat this conditions are very extensively used in medical practice

Anti-inflammatory Agents Include the following: Glucocorticoids- common drugs used are hydrocortisone, prednisolone, betamethasone and dexamethasone ( will be discussed in detail later, in drugs affecting the pituitary and adrenal cortex) Non-steroidal anti-inflammatory drugs-(NSAIDs)

Other anti-inflammatory drugs include; Anti-rheumatoid agents Drugs used to treat gout Histamine H1 receptor antagonists ( though not strictly anti-inflammatory agents)

Immunosuppressant Drugs The main drugs affecting the immune response are the immunosuppressants