Chronic inflammation

What is Chronic Inflammation:

Inflmmation of prolonged duration in which inflmmation, tissuue injury and attempts at repair coexist, in varying combinations.

1. Chronic Suppurative on acute: 
2. Chronic granulomatus: (Initiates without an acute phase)

Suppurative in type:

Abscesses

• Inadequate or delayed drain leads to thick fibrous wall    formation.                                         
• The residual bacteria get reactivated
• Pus formation.   
• Presence of foreign material or indigestible dead tissue.

Eg: Osteomyelitis, damaged Collagen

Chronic inflammation

Follow acute inflammation

Persistence of the stimulus

Disturbance to the healing process

ŸRepeated bouts of acute inflammation and healing in between.

Low grade persistent infection.    

Causes

• Microorganisms where body can mount limited immune reactions
• Impaired Sequelae of an acute inflammation
• Foreign bodies
• body defense
• Immune reactions

Chronic inflammation without an acute phase

Infection: TB, Leprosy, Syphilis

Immunological: Rheumatoid arthritis Ulcerative colitis Crohn’s disease

Poor blood supply (leg ulcer)

Chronic inflammatory lesions

May vary histologically according to causative agent

However there is a set of morphological features in common.  

Histologically

• Infiltration by mononuclear cells
• Macrophages
• lymphocytes
• plasma cells
• Proliferation of blood vessels/fibrosis (angiogenesis)
• Fibrosis
• Tissue destruction (induce by inflammatory cells)  

 

Mononuclear phagocytic system

Blood monocyte:

Macrophages (at extra vascular tissue) 

Tissue macrophages (Scattered in connective tissue or concentrated in organs)

Eg: Kupffer cells in Liver                                                                                                   

Sinus histiocytes in lymph nodes

Alveolar macrophages in lung

Osteoclasts in bones

Microglia (CNS)

Monocytes

Migration

Morphological transformation (macrophages and giant cells)

Activation

Secretion of biologically active products

Cells types present

• Macrophages            Ÿ 
• Eosenophils
• Mast cells                 
• ŸLymphocytes

Existence of CI, AI and repair

• Macrophages persist at the site (Due to the influence of chemical mediators)
• Destruction of invading microorganisms /normal tissues
• Secretion of chemical mediators by macrophages
• Functions of them,
• Proliferation of fibroblasts, Laying down of collagen
• Angiogenesis, Activation of lympho macrophages
• ŸDead and dieing leukocytes/necrotic tissues helps in developing acute inflammation  

Granulomas /Granulomatus infection

• Chronic inflammatory lesion in the form of mass.
• Collection of macrophages or modified macrophages (epitheliod / giant cells)
• Granulomas /Granulomatus infection
• A granuloma is a focal area of granulomatus inflammation.
• Consist of macrophage aggregation
• Epithelial cell transformation
• Collar of lymphocytes
• Appearance giant cells and of fibrosis can see with the time 

    

Eg: 

• TB
• Sarcoidosis
• Cat scratch disease
• Leprosy
• Syphilis
• Mycotic infections

Two types of granulomas: Base on pathogenesis

Foreign body type:

Form around foreign bodies

Immune type: When the foreign practical are capable of induce cell mediate immune responses

(but not always granulomas will develop)

Definition

Granulomas is a result of chronic inflammatory reaction containing a collection of cells of monocytic series arrange in a compact mass.

Cells

Macrophages

Epithelioid cells

Giant cells: Langhans giant cells

Foreign body type giant cells  

Accumulation of macrophages

Under the influence of chemotaxis

C5a, fibrinopeptides, cationic proteins

Lymphokines :

PDGF, TGF(beta)

products of collagen brake down

By mitotic division 

Immobilization and prolong survival  (if the irritants are low virulent )

Tuberculosis:

Chronic disease common worldwide.

Causes a characteristic granulomatous inflammation

Inability of the neutrophils to kill the micro organisms due to lipoprotein coating.

Mycobacterium tuberculosis.

Hominis (lungs)                                                

Bovis (Tonsils, Intestine) 

Spread

• Droplet from patients (weeks or months)
• Conjunctiva
• Punctures
• However need sustain contact than casual contact.

Tissue damage 

MT has no Endotoxins

Exotoxins 

Histiolitic enzymes

Development of immune response against outer coat of the organism.

Tuberculin test

2 to 4 weeks after infection : + Tuberculin test

PPD (purified protein derivative)

(Culture in which TB is grown)

Induration More that 5.mm within 48 hours.

Positivity indicates infection but not the disease.

Primary Tuberculosis

Occurs in individuals who have never previously been infected with M. tuberculosis (childhood infection if TB is common, adult life if uncommon)

Usually caused by inhalation of the organisms or rarely by ingestion of the organism.

Primary infection

Lungs             Hilum

Tonsils           neck nodes

Intestine         mesentery

Primary Tuberculosis

In respiratory system, inhalation of the organisms cause a subpleural lesion usually in the lower part of the upper lobe or upper part of the lower lobe. This is called Ghon focus.

Location is in these sites is because bacterium is a strict aerobe and prefers these well oxygenated regions

Ghon’s focus

When the tissue is invaded by the mycobacteria there is no hypersensitivity reaction. Instead there is acute, non specific inflammatory response with predominant neutrophils.

This is followed by macrophages which ingest the bacilli and present Ags to to T lymphocytes leading to proliferation of a clone of T cells .

The emergence of specific hypersensitivity lead to release of lymphokines,that attract more macrophages.

These accumulate to form the characteristic granuloma.

Ghon focus

Usually single

1 to 2 cm

Location –Beneath pleura- mid zone of the lung 

Microscopic appearance

Primary complex

Tubercle bacilli, either free or contained in macrophages, may drain to the  regional lymph nodes and set up granulomatous inflammation, causing massive lymph node enlargement.

The combination of the Ghon focus, draining lymphatics and the regional lymph nodes is called the primary complex.

Calcification of the lymph nodes

Sequelae of primary complex

Healing  with small fibrous scar replacing caseous necrosis. Lesion will be walled off.

Calcification

Reactivation of infection later when host defences become lowered.

plural effusion

Enlarged caseous nodes can obstruct bronchi, leading to collapse, retention of secretion and inflammatory consolidation

Caseous node erodes into a bronchi  with satellite lesions in lungs (TB bronchopneumonia).

Eroding into a pulmonary vein causing generalised milliary TB.

Erosion into pulmonary artery leads to miliary TB of lungs

TB bronchopneumonia

Opening of the caseous node to a bronchus.

Air bone infection

TB bronchopneumonia

(Multiple pneumonic patches arrangeed in and around terminal bronchi)

The lesions spread rapidly and accumulate macrophages and lymphocytes followed by necrosis 

Necrotic patches get enlarged and discharged which will lead to dissemination and cavitations. (no fibrous walls)

Pneumothorax

TB bronchopneumonia can happen after both 1ry and 2ry TB.  

Rapidly spreading tuberculous bronchopneumonia: debilitated by intercurrent disease, diabetes, malnutrition etc.

Acute miliary tuberculosis of the lungs due to blood stream spread to lungs. Grey tubercles visible to naked eye 3mm in diameter. More numerous and larger in upper lobes than lower lobes. Microscopically these are ill formed and often giant cells are absent. Usually these lesions do not cavitate

Effects on the other organs of the body

Miliary tuberculosis due to systemic spread to kineys, spleen, brain, liver etc.

Tuberculous ulcers in the intestine  due swallowed sputum.

Tuberculosis of larynx due to direct spread from sputum.

Secondary amyloidosis.

Miliary TB

Common with 1ry TB

Due to involvement of veins

Multiple scatted tubercles

Not well developed/uniform in size

1-2 mm

Some times without giant cells (necrosis)

Secondary  Tuberculosis (Post primary)

Infection may me exogenous or endogenous

After active primary infection

Reactivation asymptomatic primary lesions:

Malnutrition,

Severe illness,

Intercurrent lung infection,

Systemic immunosuppression

Exogenous: caused by inhaled organisms

Immunity

During primary tuberculosis or during BCG immunisation, the patient develops cell mediated immunity to antigens of tubercle bacillus.

This is demonstrated by skin test (Mantoux) test

Immunity is associated with increased resistance to subsequent infection.

Re infected lesions:

Apex of the lungs

Endogenous infections (swallowing sputum) 

Metastatic lesions are similar to re-infected

Lesions

Large in size (spread locally) no lymph node involvement

Cavity formation

Caseous material discharge gradually leaving a small cavity.

Cavities can become very large with overgrowth of fibrous tissue.

Cavity walls are irregular with raised bands representing obliterated blood vessels.

The surface is lined by caseous material or by pus and debris mixed with blood.

If the disease is inactive the wall becomes very smooth

In early cases the lesions are often in the apices of the lungs

In advanced cases there may be more than one cavitatory lesion.

All the lesions are distributed in the upper part of the lungs

Caseation may involve the wall of a bronchus leading to obstruction of the lumen.

Sequelae of tuberculous cavities
Local effects

Due to fibrosis lung tissue shrinks causing bronchiectasis (upper lobe bronchiectasis)

Blood vessels  can become weaken and rupture leading to haemoptysis

Aneurysm formation- called Rasmoussen’s aneurism leading to fatal haemorhage.

Fungal infections can be localized in these cavities.

Tuberculosis                 
Primary

Seen in non immune people.

Usually childhood cases

Subpleural mid zone

Lymph nodes are always involved

Seen in immune people

Secondary

Often adults

Lung apices

Lymph nodes are not always involvecd

Adverse Drug Reactions and Drug Interactions.

ADVERSE DRUG REACTIONS:

Definition : Adverse Reaction:

“Any response that is noxious and unintended that occur at the doses used for diagnosis, prevention and treatment of disease.”

Drug toxicity may come in many forms:

1. Acute versus chronic,
2. Mild versus severe,
3. Predictable versus unpredictable,
4. Local versus systemic.

Administration of drug may result in:

•          Side effects.

•          Untoward effects.

•          Toxic effects.

Definition:

Pharmacological effects of drug produced at therapeutic doses that depending upon the condition; may be desirable or undesirable.

For example :

Atropine produces dryness of mouth.

•          Dryness of mouth is side effect when atropine is used for treatment of sinus bradycardia,

•          but it is desirable when atropine is used as preanesthetic medication.

UNTOWARD EFFECTS:

Undesirable effects produced at therapeutic doses, when severe enough, necessitate cessation of drug therapy.

For example: Hypokalemia produced by loop diuretics.

TOXIC EFFECTS:

•          produced when drug is repeatedly administered or given in large doses.

               

For example :

Respiratory depression produced by morphine.

Important systemic adverse effects:

DRUG INTOLERANCE:

Inability to tolerate the drug.

Drug intolerance may be:

A. Quantitative.                       

B. Qualitative

                a) Idiosyncrasy.

                b) Hypersensitivity (Allergy).

QUANITATIVE INTOLERANCE:

•          Some persons show increased response to therapeutic or even smaller doses of the drugs such people are called “HYPER REACTORS.”      

For example:

      G.I bleeding and vomiting with single dose of salicylates.

QUALITATIVE INTOLERANCE:

IDIOSYNCRASY:

•          Unusual individual response to certain drugs due to deficiency or complete lack of certain enzymes in drug recipient.

                                                                                OR

•          Genetically controlled abnormal reaction to a drug..

For example:

     Hemolysis produced by Primaquine and Sulfonamides in patients with G.6.P.D deficiency.

HYPERSENSITIVITY (ALLERGY):

•          Exaggerated sensitivity to certain foreign substances which are harmless to great majority of population. It has an immunological basis.

•          Allergy can be distinguished from other forms of drug toxicity in some respects

First, prior exposure to drug or closely  related compound.

Second, intensity of response is  usually dose independent.

Third usually similar signs and symptoms produced irrespective  of the drug used .

Drugs commonly producing allergic reactions are:

•                          Penicillins,

•                          Sulfonamides,

•                          Quinidine,

•                          Insulin,

•                          Dextran.

  
4 groups of allergic reactions:

TYPE-I:

•          Immediate form of allergy

•          disturbances appear within minutes or hours.

•          Immune reaction is initiated by attachment of antigen to IgE antibodies to surface of mast cells and basophils.

•         Rupture of these cells liberates histamine and other mediators of inflammation.

•          Major signs and symptoms are erythema, urticaria, itching, broncho-constriction, edema, abdominal cramps and diarrhea.

Anaphylaxis:

Severe form of type-I reaction.

•          Life threatening reactions are common with parenteral drug injection than oral or topical drug application.

•          Epinephrine reverse the manifestation of severe reactions;

•          Antihistamines and Corticosteroids are also useful.

TYPE-II Reactions:

•          Mediated by circulating IgG.

•          usually delayed responses from several hours to days after drug exposure.

Examples:

•          Drug induced hemolysis,

•          leukopenia and

•           thrombocytopenia.

TYPE-III:

•          immune complexes are formed between antigen & antibody.

•          deposited in small blood vessels or within interstitial spaces resulting in activation of complement cascade that attract neutrophils.

•          lysosomal enzymes liberated by neutrophils cause local tissue damage and promote thrombosis of affected blood vessels.

TYPE-IV:

•          mediated by sensitized T lymphocytes.

•          usually delayed .

G.I.T DISTURBANCES:

•          Many drugs produce gastrointestinal disturbances. Like;

•          Nausea and vomiting by digitalis, morphine, anticancer drugs.

•          Constipation by opioids, verapamil and antidiarrheal agents

Diarrhea by colchicine and purgatives.

HEMOPOETIC TOXICITY:

ANEMIA:

•          Chloramphenicol,

•          Primaquine,

•          Methyldopa,

•          Sulfonamides.   

LEUKOPENIA:

•          Phenylbutazone,

•          Thiouracil,

•          Chlorpromazine,

•          Imipramine

•          Chloramphenicol.

•           

THROMBOCYTOPENIA.

•          Quinidine,

•          Tolbutamide,

•          Digitalis

•          Rifampin.

BLEEDING:

•          Aspirin,

•          Corticosteroids,

•          Heparin

•          Warfarin.

HEPATOTOXICITY:

                Direct:

•          Isoniazid,

•          Tetracycline and Halothane.   

Immunological:

•          Isoniazid,

•          Rifampin,

•          Pyrazinamide,

•          Methyldopa,

•          Indomethacin and chlorpromazine.

NEPHROTOXICITY:

•          Aminoglycosides,

•          Amphotericin B,

•          Vancomycin,

•          Bacitracin,

•          Polymyxins,

•          Sulfonamides,

•          Hydralazine,

•          Pencillamine,

•          Phenacetin and Acetaminophen.

BEHAVORIAL TOXICITY:

Reserpine:           Suicidal tendencies.
Amphetamine:     Disorientation, Confusion
Glucocorticoids:  Euphoria.

ELECTROLYTE DISTURBANCES:

•          Hypokalemia:                   

                               Diuretics.

•          Hypernatremia:               

          Carbenoxolone,                    

          Corticosteroids.

ENDOCRINE DISTURBANCES:

Chlorpromazine:               Menstrual irregularities.

Oral contraceptives:         Suppression of  lactation.

Corticosteroids:                Hyperglycemia

Cimetidine:                        Gynecomastia.

Ketoconazole:                   Gynecomastia.

Lithium carbonate:           Goiter.

SKIN TOXICITY:

                Skin rashes (Urticaria) by

•          PENICILLINS,

•          CEPHALOSPORINS,

•          AMIODARONE

•          CLOFAZEMINE,

•          SULFONAMIDES AND TETRACYCLINES.

CARCINOGENESIS:

•          Estrogens produce breast and endometrial cancer;

•          reserpine produces breast cancer,

•          metronidazole is mutagenic and produces tumors.

TERATOGENICITY:

•          Some drugs produce developmental abnormalities in fetus (teratogenic effect) like phocomalia by thalidomide, cleft palate by phenytoin.when these drugs administered during pregnancy.

DRUG DEPENDENCE:

•          Certain drugs when used repeatedly may make the individual psychologically and physiologically dependent upon the drug i.e. discontinuation of drug may produce withdrawal syndrome.

•          Morphine alcohol and cocaine can produce drug dependence.

UNMASKING OF DISEASE:

•          Thiazides and corticosteroids unmask diabetes mellitus, and epilepsy is unmasked by isoniazid.

IATROGENIC EFFECT:

•          Disease produced physician through the use of certain drugs is called iatrogenic effect.

                For example:

•          Parkinson’s disease produced by antipsychotic drugs,

•          peptic ulcer by NSAIDs.

DEFINITION;

               

It is the modification of the effect of one drug (the object drug ) by the prior concomitant administration of another (precipitant drug).

OUTCOMES OF DRUG INTERACTIONS

1. Loss of therapeutic effect
2. Toxicity
3. Unexpected increase in pharmacological activity
4. Beneficial effects  e.g additive  & potentiation (intended) or antagonism (unintended).
5. Chemical or physical interaction e.g I.V incompatibility in fluid or syringes mixture

STORAGE CONDITIONS:

Pharmacokinitics

involve the effect of a drug interaction from point of view that includes absorption ,distribution , metabolism and excretion.

Pharmacodynamics

are related to the pharmacological activity of the interacting drugs e.g synergism.antagonism, altered cellular transport, effect on the receptor site. 

Drug interactions: Pharmacodynamic and Pharmacokinetic

Pharmacodynamic Interaction

Drug A alters the effect of Drug B without a change in the concentration of Drug B Pharmacokinetic Interaction

Drug A alters the effect of Drug B by changing the plasma concentration of Drug B

Pharmacokinetic interactions

1) Altered GIT absorption.

•          Altered pH, Altered bacterial flora, formation of drug chelates or complexes, drug induced mucosal damage and altered GIT motility.

•          Altered pH;

•          The non-ionized form of a drug is more lipid

•          soluble and more readily absorbed from GIT

•          than the ionized form does.  

ENZYME INHIBITION:

It is the decrease of the rate of metabolism of a drug by another one.This will lead to the increase of the concentration of the target drug and leading to the increase of its toxicity

Inhibition of the enzyme may be due to the competition on its binding sites , so the onset of action is short may be within 24h.

First-pass metabolism

Oral administration increases the chance for liver and GIT metabolism of drugs leading to the loss of a part of the drug dose decreasing its action. This is more clear when such drug is an enzyme inducer or inhibitor

RENAL EXCRETION

•          Active tubular secretion;

It occurs in the proximal tubules (a portion of renal tubules). The drug combines with a specific protein to pass through the proximal tubules.

PREVENTION OF DRUG INTERACTION

1)      Monitoring therapy and making adjustments

2)      Monitoring blood level of some drugs with narrow

                 therapeutic index e.g., digoxin, anticancer agents…etc

3) Monitoring some parameters that may help to

                characterize the the early events of interaction

                or toxicity e.g., with warffarin administration, it

                is recommended to monitor the prothrombin time

                to detect any change in  the drug activity.

Main offenders :

Light  (sodium nitroprusside)

water  (aspirin)

Air  (oxidation of drug)

drug Interactions: Outside Body

Mechanisms of drug interactions

Things to Remember

• Interactions are easily forgotten when prescribing
• Interactions are difficult to remember
• Pharmacodynamic interactions can often be predicted across drug classes
• Pharmacokinetic interactions can not be predicted – experiments needed
• Many interactions probably remain undescribed – so look out for them
• The chances of interaction are 60 times higher in a patient taking 5 drugs than in one taking 2. 

USE OF DRUGS IN PREGNANCY:

·         The FDA to indicate the Potential of  systemically absorbed  drugs for causing birth defects; establishes five pregnancy categories:

CATEGORY A:

·         Controlled studies in the pregnant women fail to demonstrate a risk to the fetus in first trimester with no evidence of risk in later trimesters.

·         The possibility of fetal harm is remote

o   Examples:

o   INSULIN,

o   VITAMIN B,

o   VITAMIN D,

o   PARACETAMOL..

CATEGORY B:

·         Either animal reproduction studies have not demonstrated fetal risk but there are no controlled studies in pregnant women OR animal reproduction.

·         Studies shown an adverse effect (Not Teratogenic) that was not confirmed in controlled studies in women, in the first trimester and there is no evidence of risk in later trimesters.

o   Example:

o   RABEPRAZOLE, AMOXICILLIN, METOPROLOL, METHYLDOPA.

CATEGORY C:

·         Either studies in animals have revealed adverse effects on fetus (Teratogentic) and there are no controlled studies in women,                                                                          OR

o   Studies in women and animals are not available.

·         Drug should be given only if the potential benefits justify the potential risk to the fetus.

o   Examples:

o   ACETAZOLAMIDE,

o   OMEPRAZOLE,

o   ACYCLOVIR.

CATEGORY D:

·         There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk e.g. if the drug is needed in the life-threatening situations or for a serious disease for which safer drugs are ineffective.

·         Examples:

o   DIAZEPAM,

o   METHOTREXATE,

o   PHENYTOIN.

CATEGORY X:

·         Studies in animals or human beings have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience, or both, and the risk of use of drug in pregnant women clearly outweighs any possible benefit. The drug is strictly contraindicated in women who are pregnant.

o   Examples:

o   DOXORUBICIN,

o   SIMVASTATIN,

o   TESTOSTERONE.