Module 5 Overall Flashcards

Typical cascade of acute inflammation

Movement of fluid out of vessels (oedema) → movement of neutrophils → movement of macrophages → vasoactive and chemotactic mediators activate → cytokine and chemokines activate

Vasoactive mediators

acts of the vessels

Chemotactic mediators

trigger chemotaxis for cell migration

Types of inflammatory mediators

• amines

• prostaglandins

• leukotrines

• cytokines

• chemokines

• complement cascade

Where can mediators be produced

1. plasma

2. local

3. cell

Plasma-derived mediators

circulating inactive precursors that are activated into mediators at the site of inflammation

Locally-derived mediators

are produced by various cells at the site of inflammation and act directly on target tissues

Cell-derived mediators

Released from intracellular granules (histamine, serotonin)

Synthesized de novo (PGs, leukotrines, cytokines)

What cells produce mediators

• macrophages

• dendritic cells

• mast cells

• platelets

• neutrophils

• endothelial cells

• epithelial cells

Features of mediators

1. short-lived

2. built-in self regulatory mechanisms

3. propagate effects → one mediator can stimulate the release of other mediators

Two type of vasoactive amine mediators

1. histamine

2. serotonin

Histamine

• 1st mediator released

• formed intracellularly

• Sources of histamine:

  • mast cells

  • basophils

  • platelets

Release of histamine

Degranulation in response to:

• Physical injury

• binding of cell surface receptors

Histamine effect on blood vessels

• hypersensitivity

• allergic reaction

• dilation of arterioles and increase permeability of venules

  • via H1 and H2/3/4 receptors

• Contraction of bronchial smooth muscle

Serotonin (5-hydroxytryptaine, 5-HT)

• similar to histamine

• vasoactive mediator stored in mast cells and basophils

• primarily produced by platelets and neuroendocrine cells

• potent vasoconstrictor via 5HT2 receptor

• small vasodilation via 5HT1 receptor (low conc.)

Two types of Lipid derived mediators

1. Prostaglandins

2. leukotrines

Formation of lipid derived mediators

Membrane phospholipids activated by phospholipase A2 → arachidonic acid → PGs and Leukotrines (via cyclooxygenases [PG] and lipoxygenases [leuko])

Drug that blocks Phospholipase A2

corticosteroids

Drug that blocks cyclooxygenase

NSAIDs

Drug that block lipoxygenase

zileuton

Cytokines

• molecules that give signals between cells

• produced by effector cells

• one cytokine can produce many effects and many cytokines can produce one effect

Main types of cytokines

• Interferons

• Tumor necrosis factor

• Colony stimulating factors

• Platelet derived growth factor

Properties of cytokines

• present everywhere

• released quickly

• produced in various amounts

• have potent effects

• can act in autocrine, paracrine, endocrine mechanism

Tumor necrosis factor (TNF) and Interleukin 1 (IL-1)

• Produced by activated macrophages, dendritic cells, T cells, Mast cells

• critical in leukocyte recruitment

  • via increase endothelial activation and expression of adhesion molecules

Leukocyte activation

1. IL-1 activates fibroblasts to increase collagen synthesis, synovial cell and mesenchymal cell production

2. IL-1 + IL-6 = increase proinflammatory TH17

3. IL-1a activated in nucleus of endo and epithelial cells -- functions as alarmin

Side effects of cytokines

can cause sickness following a cytokine storm

What can TNF antagonists treat

• chronic inflammatory diseases

• ulcerative colitis

• rheumatoid arthritis

• psoriasis

Chemokines

bind to 7-transmembrane g-protein coupled receptors and induce acute inflammation and maintain tissue architecture

Chemokine role in acute inflammation

• guide leukocytes along a chemoattractant gradient to the site of infection/inflammation

• increase affinity of integrins for leukocyte attachment to endothelium

Chemokine role in maintaining tissue architecture

• homeostasis

  • homeostatic chemokines guide organization of various cell types in tissues

The complement system

• more than 20 soluble proteins and receptors that function in immune response

• functions in both innate and adaptive immunity

• proteins are inactive in plasma and activated through 3 main pathways:

  • classic

  • alternative

  • lectin

Other mediators of inflammation

• platelet activating factor (PAF)

• Kinins (bradykinin)

• lipoxins

Platelet activating factor

• phospholipid derived

• sourced from some mast cells

• causes:

  • vasoconstrcition

    • (will cause vasodilation at low conc.)

  • bronchoconstriction

  • increase permeability

Bradykinin

• increase vascular permeability

  • increase contraction of smooth muscle in vessels

• vasodilation

• similar effect to histamine with shorter half life

Lipoxins

• generated by the lipoxygenase pathway

• suppresses inflammation:

  • decrease leukocyte recruitment

  • decrease neutrophil adhesion to endothelium

  • decrease neutrophil chemotaxis

• lipoxins are a regulatory mechanism

Chronic inflammation

a delayed, prolonged response to injury/infection, characterized by presence of large number of macrophages, lymphocytes, neutrophils in tissue

can also be continuous destruction and repair of normal tissue

Causes of chronic inflammation

1. Persistent infection

2. hypersensitivity diseases

3. prolonged exposure

Persistent infection in chronic inflammation

Involves mycobacteria, viruses, fungi, parasites that multiply very slowly leading to a persisting infection and chronic inflammation

Hypersensitivity diseases in chronic inflammation

Autoimmune or allergic diseases

1. Autoimmune disease: self antigens evoke chronic inflammation and tissue damage (ex,, rheumatoid arthritis, MS, rheumatic heart disease)

2. Allergic disease: an environmental substance triggers excessive immune response leading to acute and chronic inflammation (ex,, bronchial asthma)

Prolonged exposure in chronic inflammation

Exogenous/endogenous agents or non-conventional inflammatory disorders

1. exogenous agents are materials outside the body that cause disorders when introduced (ex,, silica → silicosis)

2. endogenous agents are materials in the body that lead to disorder when they build-up (ex,, cholesterol build-up → atherosclerosis)

3. non-conventional inflammatory disorders are disorders that are now considered to be inflammatory disorders (ex,, alzheimer’s disease, metabolic syndrome, type II diabetes, tumor development)

Cell components of chronic inflammation

1. Macrophages

   • dominant cell type with persistent infections (slow replication and inability to fully phagocytose infections)

   • originate from haemopoietically-derived stem cells in bone marrow or from progenitor cells in the yolk sac

   • secrete cytokines to activate B and T cells

2. Lymphocytes (T and B cells)

   • dominant cell type in autoimmune and hypersensitivity diseases

   • chronic inflammation involving B and T cells tends to be persistent and severe

T cell and Macrophage interaction

• T cells produce gamma interferons (IFN-G) which activates macrophages (macrophages are still recruited first)

• active macrophages secrete potent cytokines for leukocyte recruitment:

  • TNF

  • IL1

  • chemokines

3 patterns of chronic inflammation

1. Granulomatous

2. Suppuration

3. Mixed/Diffuse

Granulomatous inflammation

• characterized by the accumulation of macrophages and T cells

  • sometimes involved with central necrosis (only tuberculosis)

• Granuloma is formed which contains the foreign body to prevent its spreading

  • granuloma formation is facilitated by TNF

Granuloma formation

1. invasion of foreign particles

2. phagocyte inability to contain the pathogens

3. cytokines activate cell-mediated immunity (adaptive)

4. chemokines recruit monocytes

5. monocytes → macrophages via cytokines

6. two macrophages fuse

7. growth factors initiate fibrosis and forms fibrous tissue

8. granuloma is formed

3 types of granulomatous inflammation

1. Immune type

2. Foreign body

3. Unknown origin

Granulation tissue vs Granuloma

Granulation tissue

• formed with loos matrix with numerous blood vessel and fibroblasts with numerous leukocytes

Granuloma

• organized collection of macrophages and lymphocytes in response to chronic inflammation that results from a failed attempt at containing the foreign agent

Suppuration

a condition where purulent exudate (pus) is formed

• chronic pus often forms in dental abscesses

Examples:

• chronic periapical periodontitis

• osteomyelitis

Chronic periapical periodontitis

bacteria penetrate the small canaliculi of haversion canals in bone

• bacteria multiply and causes necrosis of the bone

Osteomyelitis

• bacteria enter bone through canaliculi and cause necrosis of osteocytes

• leukocytes and other antimicrobials cannot enter canaliculi

• leads to constant re-infection and build-up of pus in the bone

Mixed/Diffuse

Mix of cells involved in both acute (PMNs) and chronic (macrophages, B, T cells) inflammation

• Usually has specific immune response

• associated with fibrotic granulation tissues

• may undergo acute flare-ups

• initiating agent unknown

Ex,,

• Rheumatoid arthritis

• Crohn’s disease

Rheumatoid Arthritis

• Mixed/Diffuse condition

• Free floating neutrophils in the synovial fluid of joints

• Pannus (tissue) grows inside the synovial fluid that contains macrophages, B cells, T cells, dendritic cells

Crohn’s Disease

• Mixed/Diffuse condition

• maturation of chronic inflammatory granulation tissue into scar tissue which leaves skin tags and mucosal folds

Regeneration

replacement of injured tissue by parenchymal cells of same type (less severe)

Repair

replacement of injured tissue by fibrous tissue - leads to scar formation (more severe)

Healing

regeneration, repair, or combo of the two

3 cell types of regeneration

1. Labile cells

2. Stable cells

3. Permanent cells

Labile cells

• normally proliferate to replace cells that are continually being lost

• ex,, gut epithelium, bone marrow stem cells

Stable cells

• do not normally proliferate but have the capability

• initiated by growth factors and cytokines

• ex,, fibroblasts, endothelial cells, hepatocytes

Permanent cells

• rarely proliferate, but may be able if given enough growth factors

• ex,, CNS neurons, cardiac myocytes

Signals that drive regeneration and cell proliferation

1. From cells:

   • growth factors

   • Sources:

     • macrophages

     • endothelial

     • epithelial

     • stromal cells

   • Actions:

     • bind to ECM proteins → accumulate in injury site → signal gene expression for cell division

2. From ECM:

   • integrins

     • signal for cell proliferation and stem cell activation +maturation

First intention of healing

Margins can attach

Margins are sutured and no infection

Second intention of healing

Margins are not ready to attach - infection and margins are devitalized → bruising and necrosis of tissue

Most common wound healing process

Steps of healing by first intention

1. platelets and fibrin (minutes)

2. neutrophils and macrophages (hours)

3. fibroblasts (secrete collagen within days-weeks)

4. death of fibroblasts and angiogenesis (months-years)

Steps of healing by second intention

1. Haemostasis: Stops the bleeding

2. Inflammation: Ward off bacteria

3. Proliferation: Granulation tissue (soft callus) become scar tissue (fibrous/hard callus)

4. Remodelling: wound contraction and maturation of scar

Haemostasis in healing by second intention

STOP THE BLEEDING

1. arteriole vasoconstriction

   • decreases blood flow allowing for accumulation of platelets and fibrin in the wounded area

2. forming of blood clots

   • accumulation of platelets releases growth factors (PDGF, IGF, EGF, TGF-beta)

3. forming a meshwork of fibrin filaments

   • important for trapping neutrophils, macrophages, fibroblasts in the area

Inflammation in healing second intention

WARD OFF BACTERIA

• recruit neutrophils then monocytes (become macrophages) via chemoattractants from complement system and chemokines

• Two types of macrophages begin their repair:

  • M1: clear microbes, necrotic tissue and promote inflammation in a positive feedback loop and scavenge debris

  • M2: produce growth factors that stimulate proliferation of cell types

Proliferation in healing by second intention

Granulation tissue (soft callus) becomes scar tissue (fibrous hard callus)

Several cells proliferate adn migrate to collectively form “granulation tissue”:

• macrophages: responsible for proliferating growth factors

• epithelial cells: migrate to the sides/edges to cover wounds

• endothelial cells: involved in angiogenesis

• fibroblasts: ECM collagen formation

Remodelling in healing by second intention

Wound contraction and maturation of scar

• collagen fibers are deposited and organized to form stable fibrotic scar

  • controlled via matrix metalloproteinases (MMPs)

• A scar is only 70% of normal skin even after fully healing

Scar maturation

1. Progressive vascular regression:

   • goes back to normal form vascular (red) tissue to pale avascular tissue

2. Wound contraction:

   • fibroblasts → myofibroblasts (contractile cells) that cause wound to shrink

Matrix Metalloproteinases (MMPs) and Scar shrinkage

MMPs regulate scar through degradation of collagen and ECM materials

MMPs produce:

• fibroblasts

• macrophages

• neutrophils

• synovial cells

• endothelial/epithelial cells

MMPs regulated by:

• growth factors

• cytokines

• ROS

• tissue inhibitors of metalloproteinases (TIMPs)

Balance of MMPs and TIMPs regulates size and nature of scar

Systemic factors that affect healing

• Nutrition

• Vitamin deficiency

• Age

• Immune status

• Disease

Local factors that affect healing

• necrosis

• infection

• apposition

• blood supply

• mobility

• foreign bodies

Immunological network of the gingiva

• neutrophils continuously transmigrate through the junctional epithelium

• resident lymphocytes are predominantly T cells, some B cells and ILCs

• diverse mononuclear phagocytes

Oral Epithelium

• first barrier of defence against pathogens in the oral cavity

Pathogen Recognizing Receptors (PRRs) of the oral epithelium

Toll-like receptors

Functions:

1. Recognizing and identifying pathogens

2. Preventing excessive host response

3. regulates tolerance of oral cells

Resident cells of the oral epithelium

Provide rapid and localized response to infection

• mast cells

• macrophages

• dendritic cells

• natural killers

• langerhan cells

M1 Macrophages in the oral cavity

(Classic activated) - activated by pro-inflammatory signals (IFN-G, LPS)

act against infections and tissue damage

Functions:

• pathogen desturction

• inflammation promotion

• antigen presentation

• tissue remodeling

Drawbacks:

• alveolar bone loss

• disease progression

• microbiota dysbiosis

• potential tumor development

M2 Macrophages in the oral cavity

(alternatively activated) - activated by anti-inflammatory signal (IL-4, IL-13)

Functions:

• anti-inflammatory

• tissue repair

• immune regulation

Drawbacks:

• tumor promotion

Neutropenia

a deficiency of neutrophils - linked to periodontal disease

Dendritic cells

master regulators of the immune system - remain immature until activated

Roles:

1. migrate lymphoid tissue and activate T cells/T helper cells

2. Induce IgM to become IgA

Th17

a subset of CD4+ T helper cells that is activated at mucosal sites

Functions:

• defence against foreign pathogens

• produce pro-inflammatory cytokine (IL-17)

• recruit immune cells

• amplify inflammation

• tissue repair

• contributes to autoimmune disease

Defects lead to periodontal inflammation and bone loss

Quality of Medicines definition

• selecting management options wisely;

• choosing suitable medicines;

• ensuring medicine is considered necessary;

• using medicines safely and effectively

Concepts of pharmacokinetics

Absorption

Distribution

Metabolism

Excretion

Factors that determine route of administration

• time to onset of drug effect

• most convenient

• physiochemical properties of drug

• expense

• local action

Different routes of administration for Lignocaine

• intravenous

• ophthalmic

• oral (for local action)

• topical (for local action)

• subdermal

• transdermal

• rectal (for local action)

Routes of elimination

1. metabolic biotransformation

   • liver, intestine, kidney, lung

2. renal elimination (urine)

3. biliary elimination (feces)

4. exhalation

5. other methods (ie, sweat, lactation)

Metabolic biotransformation

• oxidation, reduction, or conjugation of drug

• chemical conversion/conjugation makes metabolite more soluble for excretion

Drug metabolizing enzymes

Phase I enzymes: Cytochrome P450 (CYP)

Phase II enzymes: Uridine 5’-diphospho-glucuronosyltransferase (UGT)

Clearance

Efficiency of drug elimination from the body

Volume of blood cleared of drug per unit time

• used to estimate maintenance dose rate

Calculation:

• after single dose:

  • CL = F x Dose / AUC

• for steady-state dosing:

  • CL = F x Dose / Conc. @ steady-state

• Units: L/hour

Volume of distribution (V)

(L or L/kg)

• extent of drug distribution

• Determine the loading dose

Bioavailability (F)

• fraction of dose absorbed after oral dose

• determine dose adjustments between routes of administration

Half-life (t 1/2)

• describes how lone a drug/metabolite stays in the body

• determines frequency of dosing

List al routes of administration

• Intraocular/Ocular

• Otic

• Intranasal

• Oral

• Sublingual/Buccal

• Intramuscular

• Inhaled

• Subcutaneous

• Topical/Transdermal

• Intravenous

• Vaginal/Rectal

Pharmacokinetic considerations of dose route

• how quick will it work

• where will it work

• will the drug be absorbed

• what metabolism occurs after being administrated

Formulation considerations of dose route

• how expensive is it

• can the drug be formulated for that route

• is it practical to use the formulation

• does the formulation affect stability

  • what is the appropriate dosage form

Patient consideration of dose route

• is dosage form acceptable to patient

• is taste an issue

• does the patient have swallowing issue

• any systemic adverse effects or DDIs

• how expensive

Oral route of administration

Swallowed

• most common route

• generally accepted by patients

• non-invasive and inexpensive

• can be self-administered

• metabolized by first pass

Other

• sublingual/buccal

• less common and generally most expensive

• rapid absorption

• avoids first pass metabolism

• must be kept in contact with absorption

• taste is important

Topical route of administration

• useful to minimize systemic exposure

• targets effects of drugs to specific site

• can be self-administered

• taste/texture if used in mouth

Inhaled route of administration

• absorbed through alveolar membrane in lungs

• rapid absorption

• relatively non-invasive