Biol22111: Pathop/pharm Of Cells/tissues

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WHAT IS INFLAMMATION

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Physiological Response to Infection or Injury which is above a Minimum Threshold without being immediately Lethal, mobilising the bodies Defense system in a locilased area.

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Acute, Sub-Acute and Chronic Inflammation

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Acute - Few hours to 6 weeks
Sub-Acute - 6 weeks to 3 months
Chronic - 3 months to decades

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Adverse Effects of Inflammation

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Allergic Reactions - Urticarial Rashes, Asthma, Anaphyalactic Shock, Oedema
Degradative - Dermatitis, Rheumatoid Artharitis
Fibrotic (Scarring) - Aspestosis, Silicosis, Sepsis (Septic Shock, MRSA)

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Urticarial Rash

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Alergen -> Production of Antibodies (IgE) -> Bind to mast Cells -> Mast Cells release granules containing Histamine -> Histamine travel to effected area

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Systematic Responses to Injury (Acute Phase) - Fever

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Destruction of bacteria releases Pyrogens.
Pyrogens increase hypothalamus max temp to 41*C
Improves efficency of immune and innate response

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Systematic Responses to Injury (Acute Phase)

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Fatigue
Lack of appetite
Nausea
Wasting of skeletal muscle
Low blood pressure/hypotension
High white blood cell count (selective leucocytes)
Acute phase proteins APPs

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APPs

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Local injury/Infection causes changes in levels of plasma proteins.
Produced by liver and white blood cells
Promotes Phagocytosis and bacteria lysis
Binding of iron (needed by bacteria)
Inhibit protease release from damaged cells and phagocytes

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3 Types of APPs

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Major APPs increase 100-1000 times
Moderate APPs increase 3-20 times
Negative change APPs that decrease

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Major APPs

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C-reactive Protein - Binds to foreign cells and proteins promoting phagocytosis and initiating the complement system which lysis foreign cells
Serum Amyloid - Pink staining in interstital space of inflammed tissue
Cysteine Protease Inhibitor - reduces damage of protease enzymes released by damaged cells and phagocytes

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Outward Signs of Inflammation

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Heat at injury area
Reddening
Swelling
Pain
Loss of function

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Local Vascular Events After Injury

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Vasodilation
Increased Permeability for exudate
Flare reaction by an axon reflex
Delivery of defensive components of immune and innate response as well as soluble components first followed by cellular components

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Local Enzymatic Events After Injury

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Coagulation Cascade - Blood Clot
Kinin Cascade - Bradykinin
Complement Cascade - Lysis and release of mediators
Fibrinolytic Cascade - Removal of fibrin

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Local Cellular Events After Injury

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Mast Cells - Histamine
Neutrophils, Macrophages, Monocytes - Phagocytosis and release of mediators
T-lymphocytes - Killing

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Repair of Injury

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Cell Division
Regrowth of blood vessels and nerves fibres
Fibroblasts: synthesis of collagen
Removal of white blood cells

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Pain

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Imediate and lasting pain directly caused by stimulated pain nerve endings nociceptors and indirectly caused by inflammatory mediators histamine, bradykinin and prostaglandin E

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Wheal and Flare/Triple Response

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Injury -10 seconds-> red dotting -1min-> flaring -10 min-> swelling
message sent to CNS, Vasodilatory peptides released due to sensoyr nerves

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Response to Injury

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Person A -> Acute Injury -> Acute Local Consequences -> May Radiate out to other Organs and Tissues -> Chronic Long Term Effects -> Organ Failure -> Survival Comprimised -> Take Medical Intervention to get Healthy or Death

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Negative Feedback

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Low B.P -> Pressure Receptors -> Cardiovascular Centre in Hindbrain -> Signals sent via Symathetic Nerves -> increase Blood Pressure

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Changes In Living Cell Numbers

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Conception -> Growth -> Maturity -~> Old Aging -> Death
Cell Turnover - replacement of same number of cells and same type

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Normal Function of Cells

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Change in Stimuli -> signal to brain -> brain sends signal to effector to correct the change.

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3 Types of work load

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Physicial, Secretort and Metabolic

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Physical Workload

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targets skeletal, cardiac and smooth muscle

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Secretory

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Intestinal gland stimulated by presence of foods

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Metabolic

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Induction of enzymes in liver

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Atrophy

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Decrease in cells size but not number during low workload

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Hypertrophy

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Increase in cell size - response to increase time of workload (opposite of Atrophy) Certain degree of adaption is normal (physiological) however can be driven outside of normal range (Pathological), e.g. excess hypertrophy on heart muscles causes work exceeding maximum oxygen intake so cels become damaged by hypoxia - heart failure

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Hyperplasia

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Increase in cell number only in tissues of continuous stem cell division (not muscles or neurons) onset by increase in metabolism or endocrine stimuli.
is reversable in normal physiological range

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Hypoplasia

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Opposite of Hyperplasia

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Metaplasia

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The trasformation of normal cells to an abnormal cell, the stage leading to Dysplasia

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Dysplasia

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The enlargment of Tissues or organs by the proliferation of cells in an abnormal state.

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example of adaptation long term changes to metabolic work load

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barbiturate is used as sleeping pills where cytochrome P450 oxidases them. constant dosage causes increased production of cytochrome P450 so stronger dose is required

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Gout

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Acute or Chronic Artharitis, high uric acid in your blood and Synovial Fluid.
Is an inflammatory response attacking synovial membrane causing pain and swelling.

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Normal and Gout Purine Removal

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Oxidation of dietry and breakdown DNA. broken down to uric acid which is carried to kidney by the blood and filtered and secreted by the nephrons.
Excess dietry DNA, Excellerated breakdown of cells making excess uric acid in body.

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Bodies Response to Gout

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Deposit Uric acid within tissue aswell as phagocytes moving to joints to try to remove excess uric acid causing swelling.

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Risky foods for Gout

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Sardines Mushroom and Alcohol
Asprin competes with uric acid to be removed.

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Treatment of Gout

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Dietry modification
Drugs to reduce production
Drugs for promoting uric acid secretion
Inhibition of Phagocytosis stopping oxidising enzymes to reduce swelling

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Allopurinol

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inhibits the production of uric acid by inhibiting the enzyme xanthine oxidase which is required for the reaction:
Hypoxanthine -> xanthine -> uric acid

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Pathophysiology of Acute Gout

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Hypouricimiea - precipitation of urate crystals in joints

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Left Ventricular Hypertrophy

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Resulted by chronic hypertension. this is when the cells of the left ventricule are increased in size causing higher blood pressure

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Nerve Injury

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Can cause Atrophy of normal skeletal cells

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Formation of Cellular Exudate

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Migration - Nuetrophils, Monocytes and Eosinophils move to damaged tissue
Margination - WBC move to margins of blood vessels
Adhesion - stick to endothelium
Diapedesis - WBC move through wall of capilary
Selectins and Intergrins are proteins which hell in the formation of Exudate

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Neutrophils and Macrophages

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Neutrophils recognise non-self cells
Phagocytic vesicle fuses with lysosome where bacteria is exposed to oxidising agents H2O2, O2 and HO-
Neutrophil release proteases and Inflammatory response mediators

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Type 1,2 and 3 Immune responses

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Type 1 - IgE, Soluble Antigen, Mast Cell Activation, Allergic Rhinitis, systemic anaphylaxis, asthma
Type 2 - IgG, Cell or matrix associated antigen, phagocytes and NK cells, some drug allergies
Type 3 - IgG, Soluble Antigen, FcR+ cell compnent, Serum sickness and arthum reaction

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Type 4 immune response with TH1, TH2 and CTL cells

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TH1, Soluble Antigen, Macrophage Activation, Contact Dermatitis and tuberculin reaction
TH2, Soluble Antigen, Eosinophil activation, Chronic asthma and Chronic allergic rhinitis
CTL, Cell associated antigen, cytotoxicity, contact dermatitis

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Anti Inflamatory Drugs

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Steroid, Asprin like, Disease modifying, Anti Gout

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Steroid Drugs - Adrenal Cortex - corticosteroids - anti inflammatory effects

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Glucocorticoids - increase in Glycogenolysis, Gluconeogenisis (Fuel Metabolism) and Immunosupression. slow down synthesis of histamine in mast cells.
Minaralocorticoids - increased Na+ Retention, K+ loss and Fluid Accumulation

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Hydrocortisone and aldosterone

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Hydrocortisone - All four effects (Fuel metabolism, Na+ retention and K+ loss, Anti-inflammatory and immunosuppression
Aldosterone - mineralocorticoid only (Na+ Retention + K+ Loss)

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Structural Modification of Modern Anti-inflammatory Steroid Drugs

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High anti-inflammatory action without minaralocorticoid activity but with glucocorticoid and immunosupression activity

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Steroid Anti-inflammatory Drugs

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Hydrocortisone, Cortisone, Betamethasone

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Mechanism of Action of Steroid drugs

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Inhibits Vasodilation, Vasopermeability, Migration of white blood cells, release of enzymes and oxidants from neutrophils and macrophages, cytotoxic action of T-lymphocytes, Fibroblast collagen formation, repair proccesses. doesnt inhibit analgesic nor antipyretic

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Inhibition of Leukotrines and Prostaglandins

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Steroid anti-inflammatory drugs inhibit the release of arachidonic acid from laeving the cell membrane.
Leukotrines and prostaglandin are inflammatory mediators oxidised by lipoxygenase and cyclo-oxygenase respectively

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Beta receptors

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Steroid drugs cause increase in beta receptor numbers and response to beta agonists. these cause relaxation in smooth muscle in places like airway spaces.

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Adverse effects of prolonged therapy with high doeses of anti inflammatory steroids

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Salt Retention, Increase blood volume causing hypertension
Metabolic effects - Insulin resistance, redistribution of body fat to face and shoulders, osteoprosis (osteocytes in bones)
Thinning of skin
Depression
Pituitary/adrenal insufficiency

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Adverse effects of prolonged therapy

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Reversible effects - increased libido, low sperm count, scrotal pain, gynaecomastia, acne, oedema, hirsutism
Psychological effects - Euphoria, Nervousness and aggression
Other effects - Nausea, increased urination and tremor

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Asprin-like Drugs - Non Steroidal anti inflammatory drugs (NSAIDS)

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Saligenin (willow bark), Salicylate and aspirin (acetyl salicyclic acid)

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Theraputic effects of NSAIDS

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Anti-inflammatory, Analgesic, anti-pyretic, anti-coagulant and anti cancer

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Mechanisms of NSAIDS

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Inhibit release of arachidonic acid from cells
Inhibit cyclo-oxygenase
Inhibit action of prostanoids
Displace ligands from plasma proteins

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Adverse effects of NSAIDS

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Gastric bleeding, ulceration and erosion
Mefanemic Acid and asprin can cause rashes and photosensitivity
Liver damage - Paracetamol overdose
Kernicterus

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Cyclo-oxygenase independant adverse effects

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Allergy - Acetylation of plasma proteins in immune response
Irritation - Acid action
Kernicterus - displacement of bilirubin from plasma proteins allowing free bilirubin to flow into brain of children damaging Basal Ganglia

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Cyclo-oxygenase dependant adverse effects

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Gastric erosion and Ulceration due to inhibition of prostanoids which normally produce mucus reducing acid production
Prolonged blood clotting time
Renal Damage

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Features of COX1 and COX2

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COX1 inhibited by NSAIDS, produce a Prostaglandin and Thromboxane, required for renal, gastric and platelet function
COX2 Inhibited by NSAIDS and COX2 inhibitors (Meloxicam, Diclofenac, Piroxicam), Induced by Cytokines (TNF), Endotoxins and mitogens, produce prostaglandin and prostacyclin

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Functions of COX and COX2

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COX1 - Normally active in most cells and involved in normal physiological functions, Prostaglandins produced responsible for protection of stomach
COX2 - not normally active in most cells and induced for inflammatory responses by injury, Prostaglandins produced responsible for inflammatory regulation, Down regulated by IL-10

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Advantages and Disadvantages of COX Inhibitors

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COX2 produces Prostaglandins which cause inflammation, inhibitors would reduce inflammation and reduce pain
COX2 Produces Prostacyclins which relax muscles to stop platelet aggregation, inhibitors would cause this to happen.

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What is Tuberculosis

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A Lethal Disease and Infection which effect mainly the lungs and sometimes other parts of the body. it is transmitted in the air when a carrier coughs or sneezes. 9/10 cases the bacteria mycobacterium tuberculosis lays dormant

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Symptoms of Active TB

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Chronic Coughing with blood in mucus, Fever, Night sweats and Weight loss

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Transmission of TB

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Cough/Sneeze -> Bacteria expelled into air -> Droplet Inhaled -> Bacteria lodged in alveoli stimulating immune reaction -> Activates macrophages and neutrophils -> some TB multiply and survive within macrophages

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Pathophysiology of TB bacteria

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Gram-Positive thin rod
Slow growing obligate aerobe
Possesses a type of lipid called mycosides which give it its virulence

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Inflammation of affected alveoli

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Macrophages and Th1 cells come to inffected are and release inflammatory chemicalls such as TNF and IFN-gamma to kill the bacteria. A granuloma is produced made of calcium from the dead tissue from TNF killing host cells.

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Formation of Granulomas

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Epithelial cells are multi nuclear giant differentiated macrophages containing mycobacteria. This is then surrounded in T cells, mainly T helper cells. people with bad immune response will allow the mycobacterium to break through this barrier

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Pharmacotherapy

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Kill the bacteria without killing host cells
Target the Differences:
- Cell wall
- DNA Replication
- RNA Synthesis
- Protein Production

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Cell Wall Syntehsis Inhibition

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Inhibitors - Isoniasid (INH), Ethambutol, Cycloserine
Peptidoglycan cell wall is introduced to INH which causes pores in the cell wall allowing exposure to hypertonic environment and eventually cell lysis

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Inhibitors of DNA Replication and RNA Transcription

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DNA - Flouroqunolones and PAS
RNA - Rifampicin and aminoglycosides

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Uric Acid Production

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Adenine or Guanine -> Xanthine -> Uric acid via Xanthine Oxidase

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Uric acid from AMP

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AMP -> Adenosine -> Adenine -> hypoxanthene -> xanthene -> uric acid
AMP -> IMP -> Inosine -> Hypoxanthene -> Xanthene -> uric acid

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Uric acid from XMP

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XMP -(Nucleotidase)-> xanthosine -(Purine nucleotide phosphorylase)-> xanthine -> uric acid
XMP -(Deaminase)-> GMP -(Nucleotidase)-> Guanosine -> Guanine -> Xanthine -> uric acid

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Inhibition of Phagocytosis

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Phagocytosis of uric acid in synovial fluid releases oxidising agents and hydrolytic enzymes. colchicine disrupt vessicles that transport phagocytes. reduction of oxidising agents and enzymes reduce attack on synovial membrane

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Probenecid

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Induces uric acid excretion but has other actions