9/20 Flashcards by Andrew Vidalis

Cardinal Signs of Inflammation explained by Chemicals

1-2. Rubor/calor: vasodilation increases blood flow

Histamine, prostaglandins, and bradykinin relax arteriolar smooth muscle

Tumor: fluid leakage from venules into interstitium (exudate)

Histamine causes endothelial cell contraction

Dolor: bradykinin and PGE2, sensitive nerve endings
Fever: pyrogens (LPS) cause IL-1 and TNF-alpha release from macrophage, increased cyclooxygenase activity in hypothalamus

Increased PGE2 raises temp. set point

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Mediators of Endothelial Cell Activation

Early activators: histamine, bradykinin, PAF, thrombin

Promote vasodilation and permeability

Late Activators: IL-1beta, TNFalpha, IFNgamma
Other mediators: Complement, bacterial products, hypoxia, viruses, prostaglandins, leukotrienes

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Consequences of Endothelial Cell Activation

Transient vasoconstriction from endothelins, thromboxane, and angiotensin II

Vasodilation of precapillary arterioles that is caused by NO, PAF, bradykinin, PGI2

Increased vascular permeability, fluid and cells leave circulation

Release cytokines like IL-8 that promote neutrophil activation

Contraction of cytoplasmic myosin occurs early due to histamine, bradykinin, and leukotrienes, increase vascular permeability by increasing gap between endothelial cells

Retraction of cytoskeletal elements occurs later due to IL-1, INF-gamma, TNF-alpha

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Transudate vs. Exudate

Transudate: low protein content, essentially no leukocytes, no endothelial cell damage, clear liquid

Due to decreased protein synthesis like liver disease or increased protein loss like kidney disease

Allergic dermatitis, herpes

Exudate: high protein content, has some WBCS and RBCs

Due to inflammation that causes vasodilation and increases interendothelial spaces, has Endothelial Cell damage

Cloudy liquid, fibrin rich, purulent, sanguineous

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Starling’s Law and how Inflammation Impacts it

Increased vascular permeability: slight increase in K
Interendothelial gap formation: slight increase in K

Involves early contraction of cytoplasmic myosin that is then balanced later by a late retraction of cytoskeletal elements

Direct Endothelial Cell Injury: large increase in K, severe monophasic increase in permeability

May be direct injury to vessel and can be fast/long lived

May be leukocyte-dependent injury, mostly venules/pulmonary capillaries, late response and is long lived

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Steps in Neutrophil Arrival

Margination: hemoconcentration where RBCs group in middle of vessel, WBC margination, vasodilation slows blood flow
Rolling- Selectins (speed bumps) upregulated
P-selectin: Weibel-Palade bodies store them on ECs, released by histamine
E-selectin: induced by TNF and IL-1
Adhesion: cellular adhesion molecules upregulated on endothelial cells by TNF and IL-1, integrins upregulated on leukocytes by C5a, CAM-Integrin interaction results in firm adhesion of leukocytes to endothelial cells
Transmigration and chemotaxisneutrophils attracted by bacterial products, IL-8, C5a, LTB4
Phagocytosis
Resolution: neutrophils do apoptosis and die within a day of inflammation resolution

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Cell Adhesion Molecules

P selectin on EC binds to leukocyte mucin carbs like sialyl-Lewis X residues, activated by histamine, PAF, and thrombin

E-selectin upregulated due to TNFalpha and IL-1beta

Integrins on leukocytes bind to ECM, VCAM-1, fibronectin, and fibrinogen

CAMs from immunoglobulin superfamily stimulated by TNFalpha and IL-1beta

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Chemokines Dependent Leukocyte Activation

Low avidity integrins on Leukocyte bind to receptors on endothelial cell with chemokines on proteoglycans on cell surface

Activated ECs from TNF and IL-1 express new CAMs that bind to the high avidity integrins on activated leukocytes

Integrins are heterodimeric proteins

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Leukocyte Paracellular Transmigration

Intracellular Adhesion molecule 1 (ICAM1) on EC binds macrophage antigen 1 (MAC1)

Triggers increased intracellular Ca2+, RHO, and p38 MAPK to increase myosin contractility and EC contractility

Beta-1 integrin and other proteases on Leukocyte help transmigrated between cells

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Leukocyte transcellular transmigration

Go through thin parts of EC with actin and caveolae-rich regions, ICAM1 containing caveolae link together to form vesiculo-vacuolar organelles to form an intracellular channel, ERM proteins provide structural support between ICAM1 and EC actin

Go through pericyte gaps, may need MMP and neutrophil elastase activity to help move through basement membrane

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Chemotaxis

Go along conc. gradient of chemotactic factors like C5a, IL-8, and PAF

Rapid actin polymerization at leading edge of leukocyte’s filopodia, integrins on surface help facilitate movement

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NSAIDs basics

2 types: non-selective and selective/COX-2 inhibitors

Inhibition of COX-1 causes GIT toxicity, PGE has protective effects on gastric mucosa

COX-1: prostaglandins and thromboxanes

Gastroprotectiin, platelet aggregation, renal function

COX-2: prostaglandins

Pain, fever, renal function, tissue repair, reproduction, development

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NSAIDs Types

COX-1/2 Inhibitors-
Aspirin

Ibuprofen: Motrin, Advil, osteoarthritis, rheumatoid arthritis

COX-2 Inhibitors-
Celecoxib: Celebrex, inflammation, osteoarthritis, rheumatoid arthritis

Meloxicam

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Patent Ductus Arteriosus

Congenital heart disorder where neonate’s ductus arteriosus fails to close after birth

PDA remains open (patent), have improper mixing between oxygenated aorta blood and deoxygenated pulmonary artery blood

Congestive heart failure if untreated

Prostaglandin E1 keeps the ductus patent, use NSAIDs like indomethacin to help close

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NSAIDs Pharmacological Effects

Analgesic

Antipyretic

Anti-inflammatory

Some are uricosuric

GIT damage like ulcers/gastritis (lack PGE1)

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Aspirin

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Acetylsalicylic acid, normally converted to salicylic acid by esterase

Aspirin irreversibly inhibits COX (1 and 2) by acetylation, most other NSAIDs are reversible inhibitors

Decrease synthesis of thromboxane A2 and prostaglandins, increase bleeding time, used for anti-platelet effects

Clinical Uses:
Anti-inflammmatory
Analgesic
Antipyretic
Anti-coagulant

Adverse Reactions-
GI: nausea, vomit, ulcers
CNS: tinnitus, hearing loss
Hematologic: increase bleeding time, thrombocytopenia (low platelet count)
Reye’s Syndrome: children problem
Pulmonary: asthma if aspirin hypersensitivity

Reye’s Syndrome

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Acute encephalopathy and fatty degenerative liver failure (microvesicular fatty change)

Seen in children after viral infections

Symptoms: nausea, vomit, mental status change, encephalopathy, altered liver function

Aspirin shouldn’t be used in children

Kawasaki Syndrome

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Autoimmune disease seen in kids under 5

Inflammation in walls of medium sized arteries including coronary arteries

Symptoms: fever, skin rashes, red eyes, strawberry tongue, sore throat, swollen palm/feet/lymph nodes

Treatment: high aspirin dose and IV gamma globulin, only time give kids aspirin

NSAIDs: Selective COX-2 Inhibitors

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Analgesic, antipyretic, anti-inflammatory, doesn’t affect platelet aggregation

Preferred in patients with gastritis or ulcers, doesn’t inhibit PGE1

Higher risk of cardiovascular thrombotic events: decrease PGI2 (reduces platelet aggregation) and no effect on thromboxane (increase platelet aggregation)

Celecoxib: cardiovascular black box warning, sulfonamide so rashes

Meloxicam: treats osteoarthritis

Rofecoxib: selective COX-2 inhibitor that was withdrawn over safety concerns, heart attack and stroke from long term high doses, widely used

Acetaminophen (Tylenol)

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Weak COX-1/2 inhibitor in peripheral tissues, not very good anti-inflammatory

Analgesic, antipyretic, use for moderate pain when don’t need anti-inflammatory, no effect on platelet function and no gastric problems

Give to kids instead of aspirin

Adverse Reactions: 15 g may be fatal due to severe hepatotoxicity

Antidote: N-Acetylcysteine, Tylenol broken down to toxic intermediate that needs glutathione intervention, high conc. of intermediate binds to liver proteins and causes hepatic cell death, antidote is glutathione substitute

Glucocorticoids

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Most powerful anti-inflammatory

Cortisone, hydrocortisone, prednisone

Inhibits Phospholipase A2 and expression of COX-2

Anti-inflammatory and immunosuppressant, chronic use causes Cushing Syndrome

Side effects: hypertension, obesity, muscle weakness, moon fancies, skin ulcers, buffalo hump

Methotrexate

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DMARD of choice to treat rheumatoid arthritis

Folic acid analog that inhibits dihydrofolate reductase and get less THF, less dTMP and then DNA synthesis

Clinical Use-

Non-neoplastic: rheumatoid arthritis, abortion, ectopic pregnancy, psoriasis
Cancer: leukemia, lymphoma, sarcomas

Toxicity-

Myelosuppression, reversible with leucovorin
Macrovesicular fatty change in liver
Mucositis
Teratogenic

Increased Hydrostatic Pressure

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Value for capillary hydrostatic pressure increases, get edema from backup of venous blood, push more blood into interstitium

Impaired venous return: hepaticncirrhosis, pulmonary edema due to congestive heart failure

Venous Obstruction: lower limb inactivity (gravity), thrombosis, mass

Problems: ascites, pulmonary/peripheral/pitting edema

Ascites

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Fluid accumulation in the abdominal cavity

Transudate fluid accumulation due to liver cirrhosis, compression of portal vein due to destruction of liver architecture, venous blood entering liver is backed into microvasculature

Liver cirrhosis: cobblestone appearance for gross anatomy, see blue stained CT on histology

Pulmonary Edema

Fluid accumulation in the alveoli See white frothy transudate when lungs are pressed, clear air spaces of alveoli have pink fluid in them Left heart failure: left heart can't pump out normal amount of blood with each contraction due to aortic/mitral valve disease or damage to cardiac muscles by infarction/infection Blood backs up in pulmonary veins, increases hydrostatic pressure on thin walls of alveoli

Peripheral Edema

Gravity causes increased venous hydrostatic pressure by ankles Due to standing/sitting all day with little activity, venous blood pools

Pitting Edema (cutaneous edema)

Accumulation of interstitial fluid in the extremities, leaves pit after pressing Causes: kidney disease, thrombosis in vein, inflammation of a vein, mass obstruction of a vein from pregnancy, congestive heart failure in right heart causes backup of blood returning to the heart from the lower limbs

Decreased Oncotic Pressure

Decreased oncotic pressure in the capillary, causes edema Causes- 1. Increased protein (albumin) loss: nephrotic syndrome leads to proteinuria, gastroenteropathy like diarrhea 2. Decreased protein (albumin) synthesis: hepatic cirrhosis, malnutrition 3. Excessive IV fluid during resuscitation from shock Problem: anasarca

Anasarca

Decreased plasma oncotic pressure from low serum protein conc. Malnutrition from Kwashiorkor, older baby stopped getting breastfed and switched to carb gruel diet

Altered Lymph Drainage

Amount of edema in the interstitial tissue exceeds ability of lymphatic System to drain it Etiologies- 1. Primary: congenital, hereditary 2. Secondary: infection/inflammation, surgical dissection (lymphadenectomy), chronic venous insufficiency Obstruction/fibrosis from trauma, surgery, tumors, radiation therapy

Lymphedema

Clinical Features- 1. Usually unilateral, upper/lower limbs 2. Made worse by prolonged dependency (gravity) 3. Physical exam: increased limb diameter, sensory/ROM problems, edema may be pitting, brawny, or weeping 4. Increased risk for infections Can be from surgical trauma that destroys inguinal lymph node, axillary lymph node dissection due to breast cancer, lymphatic filariasis or elaphantiasis of scrotum

Hyperemia

Increased blood flow in an organ or tissue Active hyperemia: increased blood flow in tissue/organ due to exercise or inflammation Passive hyperemia (congestion): pooling of venous blood Opening of precapillary sphincters in hypoxia, decreased pH, increased CO2, increased temperature, increased K+

Venous Congestion

Venous blood engorgement of an organ, increase in organ weight/size Organ/tissue may appear cyanotic Congestion often accompanies edema and may precede it Pump failure or clogged pipes

Pump Failure

1. Right side heart failure: congestion of spleen, liver, lower limbs Enlarged right ventricle that looks like tennis shoe in X-ray Cyanosis, dissension of jugular vein, hepatomegaly, splenomegaly Hepatic congestion: nutmeg liver, expansion of hepatic sinuses 2. Left side: pulmonary congestion Cloudiness in chest X-ray, respiratory problems like dyspnea, orthopnea (can't lie flat in bed) Lungs appear blueish, acute congestion has edema filling in alveoli and alveolar Capillaries engorged with erythrocytes, chronic has widening of alveolar septa and alveolar macrophages with hemosiderin pigment (Prussian blue staining)

Clogged Pipes

Causes congestion Venous thrombosis: blue leg, prevents venous drainage from lower limb, rare Venous stasis: defective valves in large veins of the lower limb that lead to high venous pressure

5 steps to EBP

1. Ask: a good question 2. Acquire: get literature 3. Appraise: see strengths/weakness of article 4. Apply: make a decision based on what you've found and evaluated 5. Adjust: evaluate the impact of the decision and start the process again

PICO

Patient, Problem, or Population: describe patient's condition or disease state Intervention: could be therapeutic, diagnostic, or etiologic Comparison Intervention: other therapy, gold standard, or none Outcome of interest: whether patient lives or dies, pop. has fewer strokes

Background vs. Foreground Questions

Background: general questions without comparisons Foreground: specific questions that compare interventions

Cohort Study

Follow group of individuals forward through time to capture outcome Why do it- 1. Examine incidence 2. Look at natural history of disease 3. Assess temporality of an exposure/disease relation (when a RCT is not feasible) Only way other than a RCT to ensure that exposure preceded disease Disadvantages: costs a lot, not good for rare disease or if long latent periods, loss to follow up

9/20 Flashcards

(39 cards)