Seminar 1 :

Systemic effect of Inflammation

GROUP A
SYSTEMIX EFFECT OF
INFLAMMATION
• PHYSIOLOGY

• BIOCHEMISTRY

• PATHOLOGY

• PHARMACOLOGY
 What is running inside your
mind when you think about

Infection – bacteria, virusss

or toxic chemicals Sign and symptoms of
inflammation – cardinal
Immune system activation signs of inflammation

Acute or chronic
inflammation
 What about in inflammatory events occurring in
dental practice?
Examples :
• Dental trauma
• Dental abscess
• Facial cellulitis 2' to
odontogenic infection
• Periodontal abcess
• Immunodeficiency patient This Photo by Unknown author is licensed under CC BY-SA-NC.
Systemic Effect of
Inflammation
( Physiology )

ASHIATUN NAIM BT ZAMAILI | 2023448378 |

MScD 20234/2024
SLO 1. Describe complete
( Physiology ) and differential
blood count​
2. State the possible
changes in complete
and differential
blood count
during inflammation​

This Photo by Unknown author is licensed under CC BY-SA.

Full blood count (FBC) or complete blood
count (CBC) is a haematological test used to
evaluate the health of a patient
• detection of a wide range of disorders,
including anaemia, thrombocytopenia,
infection and leukaemia.
• Most routine lab test

Introduction
 Why we do CBC & differential test?
The CBC is not a single test and has numerous parameters.
• Provide basic information about your health
• Detect a health condition before you have any symptoms
• Confirm that a health condition exists
• Identify the causes of your symptoms
• Find out if your medicine is working
• Rule out a disease
• Establish a baseline that can be used for comparison with
future test results
 Familiar?
PARAMETERSOF MEASURED
WITH VALUE INCLUDING UNIT
AND REFERENCE RANGE

RED – ABNORMAL VALUES

EITHER HIGH OR LOW

The CBC test evaluates your whole blood

counts value, including RBC (Red blood cells),
WBC (White blood cells), and Platelets.
COMPLETE BLOOD COUNT PARAMATERS ( Roshan 2009 ) & The complete blood count and white blood cell differential by Alisha Ware )

Parameter Normal range Normal range Man Normal value Woman

RBC count - measures the number of red blood cells in a specific 3.8-4.6 4.5–6×10¹²/L 4–5×10¹²/L
volume of blood.
WBC count – body immune and defense system 4.0-10.0 3.78–9.7 3.37–10.09
Platelet count – involves in blood clotting mechanism 150–450×10⁹/L.
PCV (Pack cell volume) or Hematocrit - percentage of blood 36-46% 40 to 54% 36 to 48%
volume occupied by red blood cells.

Haemoglobin concentration - indicates the blood's oxygen- 14–17.5 g/dL 12–15 g/dL
carrying capacity.

Mean Corpuscular Volume (MCV) - measures the average size 80 to 96

of red blood cells. It's useful in diagnosing anemia and other femtoliters (fL).
blood disorders.
Mean Corpuscular Hemoglobin (MCH) - measures the average 27 to 33
amount of hemoglobin in a single red blood cell. picograms (pg)
per cell.
Mean Corpuscular Hemoglobin Concentration (MCHC) 33–35 g/dL
- assesses the concentration of hemoglobin in a red blood cell.

Red Cell Distribution Width (RDW) - measures the variation in 11% to 15%
size of red blood cells. It can help diagnose different types of
anemia.
DIFFERENTIAL BLOOD COUNT PARAMATERS
A differential blood count is a part of the CBC that specifically analyzes the types and percentages of white blood cells (WBCs) in the blood.
Parameter
Neutrophils: These are the most abundant
type of white blood cells and play a crucial
role in fighting bacterial infections.
Lymphocytes: Lymphocytes are responsible
for the body's immune responses and are
involved in fighting viral infections and
certain types of cancer.
Monocytes: Monocytes are involved in the
body's immune response to various
infections and also participate in tissue
repair.
Eosinophils: These cells are primarily
Normal
Description
range
40 to 75% If count is higher > 75% = Neutrophilia.
Neutrophils count gets an increase in recent onset inflammation for a short duration.
Neutrophilia can also be seen in infection, which produces pus like staphylococcus and
streptococcus infection in sore throat, pharyngitis tonsilitis, etc.
If lower than 40%, that indicates Neutropenia. It commonly happens in viral infections.
15 to 40% Lymphocytes are the main army of the immune system.
When any microbes or foreign particles enter the body, these cells fight with them and
protect the body
Lymphocytes have two main types –
• T-Lymphocytes (also called T cells or Natural killer cells), and
• B-Lymphocytes (also called B cells)
B- Cells help produce antibodies, while T-cells directly kill the micro-organism
An increase (more than 40%) in lymphocyte count = Lymphocytosis. It is mostly seen in
viral infections and chronic infections.
Low lymphocyte count (less than 15%) = Lymphocytopenia. It is mostly seen in HIV,
autoimmune disorders and undernutrition conditions.
2 to 10%. Monocytes are just like a type of phagocyte. These cells find the germs (or micro-
organisms) and destroy them.
More than 10 % of monocytes indicate Monocytosis. It is classically seen in chronic
infections (or long-term infections) like tuberculosis, HIV etc.
1-6 %. > 6% in your CBC = Eosinophilia.
 State the possible changes in complete blood count during
inflammation

Red Blood Cell (RBC) Count, Hemoglobin (Hb), and Hematocrit (Hct): Inflammation can
lead to mild decreases in RBC count, hemoglobin, and hematocrit. This is known as inflammation-
induced anemia.

Platelet Count: Platelet count may increase (thrombocytosis) during inflammation, primarily to
help with the blood clotting process in response to tissue damage.

White Blood Cell (WBC) Count: During inflammation, there is often an increase in the total
WBC count, a condition known as leukocytosis. This is because the body mobilizes more white
blood cells to the site of infection or injury to combat pathogens and aid in the inflammatory
response.
 State the possible changes in differential blood count during
inflammation

Neutrophils are the most responsive to bacterial infections and are often elevated during inflammation to
combat invading bacteria

Lymphocytes: The percentage of lymphocytes may initially decrease in the blood due to their migration to
the site of inflammation, but in later stages, especially in viral infections, lymphocyte counts can increase

Monocyte, which can differentiate into macrophages, are also recruited to the site of inflammation. Their
numbers in the blood may increase during inflammation.

Eosinophils and Basophils: These are generally less affected by inflammation, and their percentages may
remain relatively stable. However, in certain allergic or parasitic inflammatory conditions, eosinophils may
increase.
Biochemistry
Systemic
Effect of
Inflammation
(Biochemistry
Perspective)
Siti Zakiyah binti Muharam
2023887376
SPECIFIC LEARNING OUTCOMES

a) List the biomarkers involved in inflammation

b) Discuss the inflammatory cytokines,proteins and
enzyme
Biomarker

 A parameter (chemical, physical, or biological) that can be

applied to detect and compute the progress of disease or
the results of treatment in preclinical research and clinical
diagnosis

(Mayeux 2004; Kumar and Sarin 2009)

 Inflammatory Marker

 A disparate set of biomarkers that are used clinically to assess patient for:

 Presence or absence of an active inflammatory disease process

 Activity of known disease revenue growth

Bell, D., Knipe, H. Inflammatory markers. Reference

article,Radiopaedia.org. (accessed on 22 Oct 2021)
https://radiopaedia.org/articles/75869
Biomarkers for inflammation

C-Reactive Erythrocytes Sedimentation Leukocytes counts

Protein(CRP) Rate (ESR)
 1)C-Reactive Protein (CRP)
 It named because it binds to the C-polysaccharide of the pneumococcus. It was later found
that the protein appeared in plasma during many infectious or inflammatory conditions.
 CRP is synthesized in the liver.
 Its physiologic role is to bind to phosphocholine expressed on the surface of dead or dying
(apoptosis) cells in order to activate the complement/immune system, which enhances
phagocytosis by macrophages.
 Levels of CRP begin to rise within 2 hours of an insult, and has a half-life of about 18 hours.
 The rapid action of CRP makes it a participant in the acute or first phase of the inflammatory
process, which is why it is often called an "acute-phase protein."
 Rapid, marked increases in CRP occur with a wide variety of disorders including infection,
trauma, tissue necrosis, malignancies, and autoimmune disorders.

Erythrocyte Sedimentation Rate and C-Reactive Protein: Old But Useful Biomarkers for Pain Treatment
Biology of C Reactive Protein in Health and Disease pp 67-107
2.Erythrocyte Sedimentation Rate (ESR)
 The ESR rate increases as a result of any cause or focus of
inflammation.
 When an inflammatory process is present, fibrinogen
enters the blood in high amounts and causes red cells to
stick to each other, which raises the ESR.
 Moderate elevations are common in active inflammatory
diseases.
 But because the test is often normal in patients with
neoplasm, connective tissue disease, and infection, a
normal ESR cannot be used to exclude these diagnostic
possibilities.
 3)Leukocytes Count
 Leukocytosis – often defined as an elevated white blood
cell (WBC) count greater than 11.0 x 109 /L in non pregnant
adult
 Is a common feature of inflammatory reactions, especially
those induced by bacterial infections.
 The peripheral white blood cell count can double within
hours after certain stimuli because of the large bone
marrow storage and intravascularly marginated pools of
neutrophils.
 Stressors capable of causing an acute leukocytosis include
surgery, exercise, trauma, and emotional stress
1.Hoffman R, Benz EJ Jr, Silberstein LE, Heslop H, Weitz J, Anastasi
J. Hematology: Basic Principles and Practice. 6th ed. Philadelphia, Pa.:
Elsevier/Saunders; 2013:table 164–20.
Where does the mediators came from?
 Cytokines
 Are small secreted proteins released by cells have a specific effect
on the interactions and communications between cells.
 Cytokine is a general name; other names include:
 lymphokine (cytokines made by lymphocytes),
 monokine (cytokines made by monocytes),
 chemokine (cytokines with chemotactic activities),
 and interleukin (cytokines made by one leukocyte and acting on
other leukocytes).

Jun-Ming Zhang, MSc, MD1 and Jianxiong An, MSc,

MD2
34

Presentation title
35

Presentation title
Chain of cytokine action:
Stimulus > Cytokine-producing cell >Cytokine >Target cell > Receptor
>Biological effect(s)
- Cytokines bind to specific
receptors on the membrane of
target cells, triggering signal-
transduction pathways that
ultimately alter gene
expression in the target cells.

- The cytokine and their fully

assembled receptors exhibit
very high affinity for each
other and deliver intrcellular
signals.
 - A particular cytokine may bind to
receptors on the membrane of the same
cell that secreted it, exerting autocrine
action.
Actions of cytokines: - It may bind to receptor on a target cell
Autocrine: Affects the
in close proximity to the producer cell,
generating cell (self)
exerting paracrine action
Paracrine: Affects cells
in the immediate - In few cases, it may bind to taget cells
vicinity
in distant parts of the body, exerting
Endocrine: Affects cells
endocrine action.
remote from the
secreting cell.
Cytokine
family

Presentation title
 The role of cytokines in acute myeloid leukemia: A systematic review. T. Kupsa, J. Milos Horacek, L. Jebavy
 Biomedical Papers(2012)
1)Interleukins
- They are numbered in order
they were discovered. So the
numbers don’t actually tell us
anything about what they do.
- Interleukins are released & act
on both leukocytes (wbc) as
well as non-leukocytes.
- Vast majority are produced by
T-helper cells
2)Chemokines
• Chemokines are a family of
chemoattractant cytokines
(small proteins secreted by
cells that influence the immune
system) which play a vital role
in cell migration through
venules from blood into tissue
and vice versa, and
• in the induction of cell
movement in response to a
chemical (chemokine) gradient
by a process known as
chemotaxis (Figure 1). I

Mackay CR. Nat Immunol. 2001 Feb;2(2):95-

101.
 3)Interferon
General functions:

•Antiviral proteins (so named

because they were found to
interfere with viral replication)

3)Interferons •Important immunoregulatory

proteins affecting cell growth,
(IFNs) differentiation, gene transcription,
and translation
- As the name implies, they interfere
with process like viral replication.
4)Tumor Necrosis Factors (TNFs)

• TNF has ability to kill tumor cells.

• They elicit inflammation and then
the inflammatory cell (neutrophils &
macrophages) do the killing.
• TNF-a,TNF-b & lymphotoxin –b
have wide variety biological effects
in the inflammatory response
including activate endothelial cells
to upregulate expression of
adhesion molecules & increase
vascular permeability.
5)COLONY STIMULATING FACTORS
 These cytokines bind to surface receptors on hematopoietic stem cell
causing them to proliferate and differentiate.
 Eg: GM-CSF secreted by wide variety of immune & non-immune cells
that stimulate development of granulocytes and macrophages.
 Granulocyte–macrophage colony-stimulating factor (GM-CSF) is often
used to treat leucopenia.
 Other haematopoietins may increase the number of circulating
leucocytes with higher efficiency, but GM-CSF has additional effects
that may be far more relevant than its haematopoietic activity.
 GM-CSF induces differentiation, proliferation and activation of
macrophages and dendritic cells which are necessary for the
subsequent T helper cell type 1 and cytotoxic T lymphocyte
activation.
6)Transforming Growth Factors

FIGURE 1. Activation of TGF-

β signaling by dimerization of
respective receptors followed
by phosphorylation and
translocation of Smads into the
nucleus to regulate transcription
of genes involved in cell
proliferation, apoptosis and
differentiation

Kit Leng Lui, S., Iyengar, P. V., Jaynes, P., Isa, Z. F. B. A., Pang, B., Tan, T. Z.,
et al. (2017). USP26 Regulates TGF-β Signaling by Deubiquitinating and
Stabilizing SMAD7. EMBO Rep. 18, 797–808. doi:10.15252/embr.201643270
Clinical significant of cytokine
W. Ansar, S. Ghosh, Biology of C Reactive Protein in
Health and Disease, DOI 10.1007/978-81-322-2680-2_4
 References
1. Forest Tennant, MD, DrPH Erythrocyte Sedimentation Rate and C-Reactive
Protein: Old But Useful Biomarkers for Pain Treatment 11 Articles in Volume 13,
Issue #2 Practical Pain Management
2. Bell, D., Knipe, H. Inflammatory markers. Reference article,Radiopaedia.org.
(accessed on 22 Oct 2021) https://radiopaedia.org/articles/75869
3. (Review on inflammation Biomarkers)
https://cebp.aacrjournals.org/content/23/9/1729.short
4. Lyrad K.Riley, Evaluation of Patients with Leukocytosis AFP Journal 2015 Dec
1;92(11):1004-1011.
https://www.aafp.org/afp/2015/1201/p1004.html#afp20151201p1004-b3
5. Giuseppe Novelli, Genetic tests and genomic biomarkers: regulation,
qualification and validation. Clin Cases Miner Bone Metab. 2008 May-Aug;
5(2): 149–154. PMID: 22460999
6. Kuby Immunology. 8th edition
7. Kit Leng Lui, S., Iyengar, P. V., Jaynes, P., Isa, Z. F. B. A., Pang, B., Tan, T. Z., et
al. (2017). USP26 Regulates TGF-β Signaling by Deubiquitinating and
Stabilizing SMAD7. EMBO Rep. 18, 797–808. doi:10.15252/embr.201643270
8. W. Ansar, S. Ghosh, Biology of C Reactive Protein in Health and Disease, DOI
10.1007/978-81-322-2680-2_4
SYSTEMIC EFFECT
OF
INFLAMMATION
BIOCHEMISTR
Y
List the biomakers involved
in inflammation.

Discuss the inflammatory

cytokines, proteins and enzymes.

Discuss the metabolic response

to injury.
 10. 1.Increased
M odulation energy
of metabolic expenditure
pathways
9. 2.
Oxidativ Glycolysis
e stress COMPONENTS OF THE
METABOLIC RESPONSE 3. Glucose
8. Immune
TO INFLAMMATION redistribution
cell
activation
4. P rotein
7.
metabolism
Cytokine
signaling
6. Acute-phase 5. Lipid
protein metabolism
synthesis
 1.INCREASED ENERGY
EXPENDITURE

Immune
response
Inflammation Energy
spending Tissue
repair

primarily met through increased glucose

metabolism
2.
GLYCOLYSIS

Inflammation

Inflammatory
mediators

Glucose

Glycolysis

Pyruvate
 3. GLUCOSE
REDISTRIBUTION

Gluconeogenesis

Increases glucose production

Maintain adequate Ensuring a constant

blood glucose supply of energy to
levels cells
 4. PROTEIN
METABOLISM

Inflammation

Protein
Proteolysis
Amino acids

Energy Acute-phase Tissue

production protein repair
synthesis
 5. LIPID
METABOLISM

Inflammation

Inflammatory signals

Lipid/Fats

Lipolysis

Fatty acids

Provide additional energy for healing

process
6. ACUTE-PHASE PROTEIN
SYNTHESIS

Inflammation

Liver

Produces acute-phase proteins

(c-reactive protein, fibrinogen, serum Amyloid
A
Acute-
phase
response
Blood Tissue
clotting repair
 7. CYTOKINE
SIGNALING
Cytokines
(Interleukins and tumor necrosis factor-alpha(TNF-
α)

INFLUENC
E
Protein Glucos Lipid
synthesis e metabolism
 8. IMMUNE CELL
ACTIVATION
Immune cells
(macrophages, neutrophils)

Inflammat
ory
response

Undergo metabolic changes

-increrase glucose uptake
-shift to aerobic glycolysis

Trap bacteria or other offending agents Healing injured tissue

9. OXIDATIVE
STRESS

Inflammation
Generate reactive oxygen
species (ROS)

Im
balan
ce
betwe
en
produ
ction
and
elimin
DNA damage Neoplastic
ation Apoptosis
transformation
Cronic
inflammation
Pathology
Discuss the acute-
phase response of
clinical changes
in acute
inflammation
PATHOLOGY –SYSTEMIC EFFECTS OF
INFLAMATION
Clinical • General • Local symptoms
Changes in symptoms Calor (heat)
Acute Fever Rubor(redness)
Inflammation Increased heart Dolor(Pain)
rate
Tumor(swelling)
Hyperventilation
Funtio laesa(Loss
Tiredness of function)
Loss of appetite
 • Immune response
• Macrophages,
GENERA endothelial cell and
reticuloendothelial Increase core body

L system
temperature
• Vasoconstriction – to

SYMPTO • Releasing pyrogenic

cytokines: IL-1, IL-6,
prevent heat loss
• Thermogenesis of fat and
M: TNF muscle- produce heat

• Induce
FEVER prostaglandin E2 in
hypothalamus
• Increase core body
temperature
 INCREASE BODY
CORE
TEMPERATURE

Generalized
Increase oxygen Increase
Loss of apetite weakness,
demand – sweating
tiredness
Increase HR,
Respiratory rate
hyperventilate
LOCAL SYMPTOMS

RUBOR (REDNESS) CALOR (HEAT)

• Vasodilation of small blood
vessel •
LOCAL SYMPTOMS

TUMOR (SWELLING)
• Exudation – escape of fluid,
protein and blood cell to
interstitial tissue or body cavity
• Exudate: inflammatory
extravascular fluid ( high protein
content, cellular debris)
• Transudate: ultra filtrate blood
(albumin-low protein content)
• Edema
LOCAL SYMPTOMS
DOLOR (PAIN)
• Stretching and distortion of
tissue due to edema
• Chemical mediators: bradykinin,
serotonin, prostaglandin
LOSS OF FUNCTION
• Well known sign of acute
inflammation
• Movement restriction at the
inflamed area due to pain
• Severe swelling may physically
immobilize the tissues
SYSTEMIC EFFECTS OF INFLAMMATION

PATHOLOGY

• Discuss the acute-phase response of clinical changes in acute

inflammation
• Discuss the acute-phase response of pathologic changes in acute
inflammation
 SYSTEMIC EFFECTS OF INFLAMMATION
PATHOLOGY

ACUTE-PHASE RESPONSE:

-Is a coordinated series of events that takes place in

response to infection, inflammation, or trauma.

- Cytokines stimulates the synthesis of plasma proteins in

the liver & their level in the blood increase up to several
hundred fold during inflammation

-This response can be seen as the host's means of creating

an inhospitable environment for the invading microbe.
 SYSTEMIC EFFECTS OF INFLAMMATION
PATHOLOGIC CHANGES IN ACUTE-PHASE RESPONSE OF INFLAMMATION
BENEFICIAL EFFECTS:
Elevated levels of acute-phase proteins
-inflammation will release various cytokines.
-these cytokines stimulate plasma protein synthesis in the liver
as a response to the inflammatory stimuli
These cytokines are responsible for systemic effects:
a. IL- 1 and TNF Serum Amyloid Protein (SAA)
-bind to microbial cell wall & act as
opsonin
-bind to chromatin to clear necrotic
nuclei
b. IL-6 C- Reactive Protein (CRP)
-bind to microbial cell wall & act as opsonin
-bind to chromatin to clear necrotic nuclei
Fibrinogen
-bind to RBC and form stack (rouleaux) that will
increase Erythrocyte Sedimentation Rate (ESR)
 SYSTEMIC EFFECTS OF INFLAMMATION
PATHOLOGIC CHANGES IN ACUTE-PHASE RESPONSE OF INFLAMMATION
BENEFICIAL EFFECTS: HARMFUL EFFECTS:
Elevated levels of acute-phase proteins
Hepcidin: reduce iron availability ->
-increase plasma protein synthesis in the liver as response from anemia in chronic inflammation
inflammatory stimuli
-inflammation will release various cytokines.
Thrombopoietin -> thrombocytosis
These cytokines are responsible for systemic effects:
a. IL- 1 and TNF Serum Amyloid Protein (SAA)
-bind to microbial cell wall & act as opsonin Secondary Amyloidosis
-bind to chromatin to clear necrotic nuclei
b. IL-6 C- Reactive Protein (CRP)
Risk of MI for pt with coronary heart
-bind to microbial cell wall & act as opsonin
-bind to chromatin to clear necrotic nuclei disease
Fibrinogen
-bind to RBC and form rouleaux that will increase
Erythrocyte Sedimentation Rate (ESR) Leukocytosis & leukemoid reaction
 SYSTEMIC EFFECTS OF INFLAMMATION
PATHOLOGIC CHANGES IN ACUTE-PHASE RESPONSE OF INFLAMMATION

CAUSE OF INFECTION PRESENTATION

Bacteria Neutrophilia ( increase in the blood neutrophils count)
Viral Lymphocytosis (increase number of lymphocytes)
Allergies Eosinophilia (increase in number of eosinophils)
Certain infection: typhoid fever, certain viral Leukopenia ( decreased number of circulating white cells)
infection, certain protozoa)

• In severe bacterial infections (sepsis), the large amounts of bacteria and their
products in the blood stimulate the production of enormous cytokines (especially
TNF and IL-1).

• High blood levels of cytokines cause various clinical manifestations such as : This clinical triad is known as septic
• disseminated intravascular coagulation, shock (severe, often fatal disorder
• hypotensive shock referred to as SIRS : systemic
• metabolic disturbances, including insulin resistance and hyperglycemia. inflammatory response syndrome)
pharmacology
By : Dr Wan Salmah & Dr Fatin
Group A
SLO
• Discuss the classification and the mechanism of action of important
anti-inflammatory drugs
• Explain the clinical uses and important adverse effects of non-
steroidal anti-inflammatory drugs (NSAIDS), acetaminophen and
corticosteroids
Classification of Anti-Inflammatory Drugs

Steroid Anti- Non-steroidal anti-

Inflammatory drugs Inflammatory drug

- cortisone - Acetaminophen
- hydrocortisone - Aspirin
Anti-inflammatory drugs
• Drugs that relieve pain or discomfort by blocking or reducing the
inflammatory process
 Steroidal anti-inflammatory drugs (corticosteroids)
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Not considered to be true analgesics :
- Opioids work on CNS and reduce perception of pain
Analgesia and pain pathway

Processes of nociception: NSAIDs

Transduction: C and A-delta fibres of COX-2 inhibitors

primary afferent neurones respond to

noxious stimuli (depolarisation )

Transmission: Transfer information

to  dorsal horn neurons 
brainstem, thalamus and
somatosensory cortex

Perception: pain becomes a

conscious experience, cortical areas
activated and elicit responses include
reticular system, somatosensory
cortex and limbic system
NSAIDs
Modulation: changes or inhibits COX-2 inhibitors
(endogenous opioids) transmission of Kehlet H, Dahl JB., Anesth. Analg.
1993;77:1049
Pain
• Pain: "unpleasant sensory and emotional experience associated with
actual or potential tissue damage or described in terms of such damage“
(International Association for the Study of Pain (IASP) definition).

• Nociception: sensory process that provides the signals that trigger pain

• Pain can be (1) acute, (2) chronic and associated with malignant disease,
or (3) chronic and not associated with malignant disease.

• Pain is known to affect physical and mental functioning, and uncontrolled

pain can have a significant impact on a patient’s quality of life.

• Pain is provoked when a variety of inflammatory mediators such as

bradykinin, histamine, leukotrienes, and prostaglandin E2 are released into
the tissues.
Dental pain
• The majority of dental pain is an acute response to inflammation. The
acute pain associated with dental trauma, infection, or surgery

• Oral pain is associated with trauma, pulpitis, periodontitis, pericoronitis,

abscesses (endodontic/periodontal), temporomandibular disorders
(TMDs) and masticatory muscle disorders.

• Pain management remains an important consideration in dental care

and patient management.

• Part of the successful management of pain requires blocking or managing

the development of inflammation.
 Non-Steroidal Anti-Inflammatory
Drugs (NSAIDs)
• NSAIDs: effective against pain associated with inflammation / tissue damage
(mild or moderate pain)
• Useful in treating acute pain (toothache), chronic pain (arthritis)
• Reduce inflammation (oedema and vasodilation by decreasing PG synthesis)
which causes pain

• Therapeutic effects of NSAIDs:

1. Analgesic
Antipyretic
2. Anti-inflammatory

3. Antipyretic (fever reducing) Analgesic

4. Antiplatelet (inhibition of thrombocyte aggregation). Anti-inflammatory

Classification of NSAIDs based on
chemical structures

Propionic acids
Salicylates Arylalkanoic acids
Ibuprofen
Aspirin Diclofenac sodium
Ketoprofen
Diflunisal Diclofenac potassium
Naproxen
Salsalate Indomethacin
Oxaprozin

Oxicams COX-2 inhibitors

Fenamates
Piroxicam Celecoxib
Mefenamic acid
Meloxicam Etoricoxib
Lornoxicam Meclofenamate Parecoxib
 NSAIDs
Mechanism of action
• NSAIDs block prostaglandin production by inhibiting COX enzymes in the
arachidonic acid pathway. COX is needed to convert arachidonic acid to
prostaglandin E2 in the body.
 Cyclooxygenase enzymes
(COX)
NSAIDs act by inhibiting cyclooxygenase (COX), a key enzyme responsible
for the biosynthesis of prostanoids in the arachidonic acid pathway

COX-1
- Constitutive enzyme  concentration of
the enzyme is not altered and remains at a
constant rate to regulates homeostasis
- Expressed in: Kidney, gastric mucosa and
platelets
-Inhibition of COX-1 responsible for gastric
complications, depression of renal function
and inhibition of platelet aggregation
COX-2
- Inducible enzyme  induced by IL-1
and TNF- at sites of inflammation
- Responsible for production of
prostaglandins mediators of
inflammation, pain and fever
-Inhibition of COX-2 responsible for the
anti-inflammatory effects of NSAIDs
and mediate pain and fever

Bleeding Gastric ulcer Renal failure Reduced inflammation and pain

 Classification of NSAIDs based on
selectivity to cyclooxygenase
• Non-selective NSAIDs: NSAIDs that Types NSAIDs
inhibit both COX-1 and COX-2 Non-selectivity COX- Aspirin
enzymes. Each NSAID inhibits COX-1 1 & COX-2 inhibitors Indomethacin
and COX-2 to varying degrees. Ketoprofen
Piroxicam
Diclofenac
Ibuprofen
• Naproxen
COX-2 inhibitors: NSAIDs that mainly
inhibit COX-2 enzymes (Celecoxib).
Preferable COX-2 Meloxicam
inhibitors
Nimesulide
Highly selectivity Celecoxib
towards COX-2
inhibitors Etoricoxib

Parecoxib
 Clinical uses of NSAIDs

Acute pain: short-term (including toothache) / post-operative

Chronic pain: longer-acting:

Also in conjunction with opioids

Other uses:
- Anti-inflammation: (rheumatoid arthritis, osteoarthritis, gout)
- Antipyretic: through inhibition of PG production in the hypothalamus
(paracetamol)
CLINICAL USES AND
IMPORTANT ADVERSE EFFECTS
OF NSAIDS, ACETAMINOPHEN
& CORTICOSTEROIDS
FATIN NADHIRAH BINTI KAMALUDIN LATIFI
2023464058
 CLINICAL USES
THREE MAIN THERAPEUTIC EFFECTS OF ALL NSAIDS,
INCLUDING SELECTIVE COX-2 INHIBITORS ARE:

 anti-inflammatory effect: modification of the inflammatory

reaction

 analgesic effect: reduction of certain types of (especially

inflammatory) pain

 antipyretic effect: lowering of body temperature when this is

raised in disease (i.e. fever).

11
 Fetal Circulatory System: Indomethacin and ibuprofen
have been used in neonates to close the inappropriately
patent ductus arteriosus.

 Cardioprotection: Aspirin reduces the risk of serious vascular

events in high risk patients.

• Irreversible acetylation of platelet COX → inhibition of platelet

function until sufficient numbers of new platelets are
released.

• Permanent and complete suppression of platelet COX-1–

dependent TxA2 formation → cardioprotective effect of aspirin.
12
OTHER CLINICAL
USES
Systemic Mastocytosis:
⚫ In patients with systemic mastocytosis, PGD2, released
from mast cells in large amounts is the major mediator of
severe episodes of flushing, vasodilation, and hypotension.
⚫ This PGD2 effect is resistant to antihistamines.
⚫ The addition of aspirin or ketoprofen provides relief.
 Niacin Intolerability: Aspirin inhibits PGD2 mediated flushing by
niacin.
 Bartter Syndrome:

⚫ Caused by mutations in a Na+-K+-2Cl− co-transporter.

⚫ Treatment with indomethacin, combined with potassium
repletion and spironolactone, is associated with
improvement in the biochemical derangements and 14

symptoms.
ADVERSE EFFECTS OF NSAIDS
Gastrointestinal:
 Abdominal pain

 Nausea

 Diarrhea

 Anorexia

 Gastric erosions/ulcers

 Anemia

 GI hemorrhage

Platelets:
 Inhibited platelet activation

 Propensity for bruising

 Increased risk of hemorrhage 15

Renal:
 Salt and water retention
 Edema, worsening of renal function in renal/cardiac and

cirrhotic patients
 Decreased effectiveness of antihypertensive medications

 Decreased effectiveness of diuretic medications

 Decreased urate excretion (especially with aspirin)

 Hyperkalemia

Cardiovascular:
 Closure of ductus arteriosus

 Myocardial infarction*
* With the exception
 Stroke* of low-dose aspirin
16
 Thrombosis*
CNS:
Headache


 Vertigo

 Dizziness

 Confusion

 Hyperventilation (salicylates)

Uterus:
 Prolongation of gestation

 Inhibition of labor

93
Hypersensitivity:
 Vasomotor rhinitis

 Angioneurotic

edema
 Asthma

 Urticaria

 Flushing

 Hypotension

 Shock

94
NON-SELECTIVE COX
INHIBITORS
 SALICYLATES
(ASPIRIN)
• Traditional NSAIDs
Actions-
⚫ reduces inflammation
⚫ antiinflammatory action is exerted at high doses (3–6 g/day or
100 mg/kg/ day).
⚫ analgesic(0.3–1.5 g/day) for inflammatory pain
⚫ antipyretic (i.e. reduces raised temperature)
⚫ At low doses (40-325mg) it acts as antiplatelet drug

MOA- Irreversibly inactivating both cyclo-oxygenase (COX-1 20

and COX-2).
 CLINICAL USES

• As analgesic
• By inhibiting platelet aggregation aspirin lowers the
incidence of reinfarction in Postmyocardial infarction
• As antipyretic
and poststroke patients.

• Acute rheumatic fever  Aspirin 6–1000 mg/day reduces the incidence of

myocardial infarction (MI)
• Rheumatoid arthritis
 Aspirin reduces ‘transient ischaemic attacks’
• Osteoarthritis and lowers incidence of stroke in such
patients
97
ADVERSE EFFECTS
Gastrointestinal disturbances, especially gastric bleeding.

 In high dosage can cause ‘salicylism’ (tinnitus, vertigo, reduced

hearing); allergic reactions occasionally; renal toxicity rarely.

 Can cause the potentially fatal Reye’s syndrome

(encephalopathy & liver disorder) in children after a viral
infection.

 At therapeutic dose it can cause hyperuricemia.

 Prolongs bleeding time. 23

 PRECAUTIONS AND
CONTRAINDICATIONS
 Aspirin is contraindicated in patients who are sensitive to it and in peptic ulcer,
bleeding tendencies, in children suffering from chicken pox or influenza.

 Liver disease: can cause hepatic necrosis.

 It should be avoided in diabetics, in those with low cardiac

reserve or frank CHF and in juvenile rheumatoid arthritis.

 Pregnancy & lactation

 G-6PD deficiency
24
 ASPIRIN TOXICITY -
T R E AT M E N T

 Decrease absorpti on - activated charcoal,

emetics, gastric lavage

 Enhance excreti on - alkalinize urine, forced

diuresis, hemodialysis

 Supporti ve measures - fluids, decrease

temperature, bicarbonate, electrolytes & glucose

25
 PHENYLACETIC ACID
(DICLOFENAC)
 Preferential COX-2 inhibitors

 Diclofenac reduces inflammation, acts as an analgesic, reducing

pain in conditions such as arthritis or acute injury.

 The action of one single dose is much longer (6 to 8 hours) than the
very short half-life that the drug indicates.

 This could be partly because it persists for over 11 hours in

synovial fluids.
28
DICLOFENAC IS
USED FOR:
musculoskeletal complaints:
 arthritis

 rheumatoid arthritis

 polymyositis

 osteoarthritis

 dental pain

 Ankylosing spondylitis

 Gout attacks

Pain management in kidney stones and gallstones.

Additional indication is: acute migraines.

Usedcommonly to treat : mild to moderate post-operative or post-

traumatic pain, particularly when inflammation is also present. 29

 Is effective against: menstrual pain and endometriosis.

 PROPIONIC ACIDS DERIVATIVES
(IBUPROFEN)
• Ibuprofen is a N S A I D originally marketed as Brufen.

• It is used for relief of symptoms of

• Arthriti s
• Primary dysmenorrhea
• Fever
• As an analgesic especially where there is an
infl ammatory components.

• Ibuprofen is known to have an antiplatelet effect, though it is relatively mild

and short-lived when compared with aspirin or other better-known
antiplatelet drugs. 10
4
OTHER PROPIONIC ACID DERIVATIVES

Naproxen, Ketoprofen, Flurbiprofen and Oxaprozin.

Mechanism of action:
•These drugs are reversible inhibitors of the cyclooxygenases, and
thus, inhibit the synthesis of prostaglandins.

Uses:

•All these drugs possess anti-inflammatory, analgesic, and

antipyretic activity.

•Used in the chronic treatment of rheumatoid arthritis and

osteoarthritis, because their gastrointestinal effects are
10
generally
less intense than that of aspirin. 5
 FENAMATES (MEFENAMIC
ACID)
 Used to treat pain, including menstrual pain. It is typically
prescribed for oral administration.

 Decreases inflammation(swelling) and uterine contractions by

inhibiting prostaglandin synthesis.

 Used for premenstrual migraine headache prophylaxis, with

treatment starting 2 days prior to the onset of flow or 1 day
prior to the expected onset of the headache and continuing for
the duration of menstruation.
10
6
 Since hepatic metabolism plays a significant role in mefenamic
acid elimination, patients with known liver deficiency may be
prescribed lower doses.

 Kidney deficiency may also cause accumulation of the drug

and its metabolites in the excretory system. Therefore
patients suffering from renal conditions should not be
prescribed mefenamic acid.

10
7
 ACETIC ACID DERIVATES
(INDOMETHACIN)
 Indomethacin, is a potent nonselective COX inhibitor and
may also inhibit phospholipase A and C, reduce neutrophil
migration, and decrease T cell and B cell proliferation.

 Probenecid prolongs indomethacin's half-life by inhibiting both

renal and biliary clearance.

Clinical Uses:
 Gout and ankylosing spondylitis. In addition, it has been used
to treat patent ductus arteriosus.
10
8
CLINICAL
USES:
 An ophthalmic preparation for conjunctival inflammation
to reduce pain after traumatic corneal abrasion.

 Gingival inflammation is reduced after administration of

indomethacin oral rinse.

 Epidural injections produce a degree of pain relief similar to

that achieved with methylprednisolone in post laminectomy
syndrome.

10
9
ACETIC ACID DERIVATIVES
(KETOROLAC)
 Ketorolac is an NSAID promoted for systemic use mainly as an
analgesic, not as an antiinflammatory drug (though it has typical
NSAID properties).

 Rapidaly absorbed after oral and IM administration.

 It is most often given intramuscularly or intravenously, but an

oral dose formulation is available.

 Higly plasma protien bound and 60% excreted unchanged in

urine. 37
 The drug has been used successfully to replace morphine in
some situations involving mild to moderate postsurgical pain.

 When used with an opioid, it may decrease the opioid

requirement by 25–50%.

 An ophthalmic preparation is available for anti-inflammatory

applications.

 Toxicities are similar to those of other NSAIDs, although renal

toxicity may be more common with chronic use.

38
ENOLIC ACID DERIVATIVES
(PIROXICAM)
 Piroxicam, an oxicam is a nonselective COX inhibitor but at high
concentrations also inhibits polymorphonuclear leukocyte
migration, decreases IgM rheumatoid factor and inhibits
lymphocyte function.

 Suitable for use as long-term antiinflammatorydrug in

rheumatoid and osteo-arthritis, ankylosing spondylitis.

 Toxicity includes gastrointestinal symptoms (20% of

patients),
dizziness, tinnitus, headache, and rash.
 When piroxicam is used in dosages higher than 20 mg/d, an
increased incidence of peptic ulcer and bleeding is
encountered. 39
 ACETAMINOPHEN
(PARACETAMOL)
Actions:
Paracetamol has potent analgesic and antipyretic actions but
rather weaker anti inflammatory effects than other NSAIDs.

MOA:
Inhibition of COX-1, COX-2 and also the recently identified COX-3
which occurs predominantly in the CNS.

Absorption/Metabolism:
It is given orally and metabolised in the liver (half-life 2-4 hours).
Metabolized to N-acetyl paraaminobenzo qunonimine (NAPQ) by
microsomal enzyme. 26
ADVERSE
EFFECTS:
o Hepatotoxicity due to NPAQ

o Glutathione produced by liver detoxifies NPAQ

o Chronic alcoholics are predisposed to toxicity due to

 Reduced glutathione

 Alcohol induces production of NPAQ from acetaminophen.

o Antidote of choice is N - acetylcysteine 27

SELECTIVE COX-2
INHIBITORS
 COX-2 SELECTIVE
INHIBITORS
 These drugs have advantage of very little GI toxicity.

 Renal toxicity is similar to traditional NSAIDs and chances of

thrombosis (acute MI and stroke) are increased on prolonged
use.

 Celecoxib, rofecoxib and valdecoxib are sulphonamide

derivatives (can cause hypersensitivity reactions)

 Etoricoxib is longest acting and requires hepatic function

monitoring during its use.
 Lumiracoxib is a newer COX- 2 inhibitor that has more activity 41

in the acidic medium.

 COX-2 SELECTIVE
INHIBITORS

 COX-2 inhibitors have been recommended mainly for treatment

of osteoarthritis and rheumatoid arthritis.

 Other indications include primary familial adenomatous

polyposis, dysmenorrhea, acute gouty arthritis & acute
musculoskeletal pain.

11
7
CORTICOSTEROIDS
 Clinical Uses: synthetic drugs with corticosteroid-like effect are used in a variety of

conditions, ranging from brain tumors to skin diseases.

 Dexamethasone and its derivatives are almost pure glucocorticoids, while

prednisone and its derivatives have some mineralocorticoid action in addition to the
glucocorticoid effect.

 Fludrocortisone (Florinef) is a synthetic mineralocorticoid.

 Hydrocortisone (cortisol) is available for replacement therapy, example in adrenal

insufficiency and congenital adrenal hyperplasia.

 CLINICAL USES OF GLUCOCORTICOIDS

Adrenal disorders

 Addison’s disease (chronic adrenal cortical insufficiency)

 Acute adrenal insufficiency associated with life threatening shock, infections or

trauma.

 Congenital adrenal hyperplasia (in which synthesis of abnormal forms of

corticosteroids are stimulated by ACTH).

Non-adrenal disorders

• Allergic reactions (e.g; bronchial asthma, angioneurotic edema -

swelling in larynx and respiratory system-, drugs reactions, urticaria,

allergic rhinitis)

• Collagen vascular disorders: Auto-immune diseases against

connective tissues (e.g; rheumatoid arthritis, systemic lupus

erythematous, giant cell arteritis, poly myositis, mixed connective

• Organ transplant: prevention and treatment of rejection- immunosuppression.

• GIT disorders: inflammatory bowel disease, non-tropical sprue.

• Hematologic disorders: leukemia, multiple myeloma, acquired hemolytic anemia,

acute allergic purpura ‘auto-immune disease cause destruction in the RBCs’.

 Natural Cortisol (hydrocortisone) synthetic Glucocorticoids
• It’s the major natural glucocorticoid.
• The physiologic secretion of cortisol is regulated by adrenocorticotropic (ACTH) &
secretion rate varies during the day (Circadian rhythm). Peaks in the morning and
information
General

trough (declines) in midnight.

• Beclomethasone & budesonide Have been developed for use in asthma and
other condition in which good surface activity on mucous membrane or skin is
Uses

needed and systemic effects are to be avoided.

• Rapidly penetrate the airway mucosa but have very short half lives after they
enter the blood, so that systemic effects and toxicity are greatly reduced.

The cortisol molecule also has a small but significant salt-retaining (mineralocorticoid)
effect. This is an important cause of hypertension in patients with cortisol secreting
adrenal tumor or a pituitary ACTH secreting tumor (Cushing's syndrome)

• Cushing’s syndrome (iatrogenic, by higher doses more than 100mg hydrocortisone daily for more than 2 weeks characterized by moon shape face
and buffalo hump)
ADRs (toxicity)

• Increase growth of fine hair on face, thighs and trunk.

• Myopathy, muscle wasting, thinning of skin, Diabetes Mellitus (because of its effect on blood glucose levels).
• Osteoporosis and aseptic necrosis of the hip. (because of its catabolic effects on protiens)
• Wound healing impaired.
• In general patients treated with corticosteroids should be on high protein and potassium enriched diet
• Peptic ulcer
• Adrenal suppression (high cortisol leads to low ACTH levels by negative feedback therefore the body will depend on the drug instead of the natural cortisol secreted by
the adrenal glands, so the gland will be atrophied)
• Acute psychosis, depression
• Sub-capsular cataracts (loss of lens transparency)
• Growth suppression
Adverse Effects:

 Typical mineralocorticoid side effects are Hypertension, Hypokalemia, Hypernatremia without

causing peripheral edema, metabolic alkalosis and connective tissue weakness.
 Corticosteroids can cause permanent eye damage by inducing central serous retinopathy.
 A variety of steroid medications, from anti-allergy nasal sprays (Nasonex, Flonase) to topical
skin creams, to eye drops (Tobradex), to Prednisone  CSR
Quiz
Physiology
1. what are the type of WBC that elevate due to the response to parasitic infections?

2. When the neutrophils falls below 40%, what is the condition called?
Biochemistry
1. What cause RBC to sink in erthyrocyte sedimentation rate?

2. What is the term used for metabolic process of glucose that is formed from
noncarbohydrated sources?
Pathology
1. What mechanism increase the core body temperature?

2. What is the local symptom of acute inflammation?

3. What are the cytokines involve in systemic effects of inflammation?

Pharmacology
• 1. What is the mechanism of action of nsaids and steroid anti-inflammatory drugs?

2. Which NSAIDS has antiplatelet effects?

3. What is the 3 main clinical uses of NSAIDS?

4. What is the common adverse effect of prolong used of corticosteroid?