PHARMACOLOGY:

PAIN AND
INFLAMMATION

REFERENCES:
Pharmacology in Rehabilitation, 4th ed. by Charles D. Ciccone (2007)
OBJECTIVES
1. Explain how injury/infection/trauma can cause
inflammation and pain.
2. Give examples of non-opioid analgesics.
3. Define the terms:
- analgesic
- anti-inflammatory
- anti-pyretic
- anti-platelet
4. Explain the 4 actions of NSAIDs.
5. Compare aspirin from acetaminophen in terms of
use.
6. Define eicosanoids.
OBJECTIVES
7. Illustrate how eicosanoids are produced in
inflammation.
8. Identify the enzyme responsible for the production
of leukotrienes.
9. Identify the enzyme responsible for the production
of prostaglandins and thromboxanes.
10. Explain the effects of eicosanoids on the different
organs:
- PGE2
- PGI2
- TXA2
- LTC4 and LTD4
11. Give examples of NSAIDs that are non-selective
inhibitors of COX enzymes (generic and brand names)
OBJECTIVES
12. Give examples of NSAIDs that are selective
inhibitors of COX enzymes (generic and brand names).
13. Explain the advantage of COX2 selective NSAIDs
over non-selective NSAIDs.
14. Explain the role of prostaglandins in causing pain,
fever, and inflammation.
15. Explain the physiologic effects of glucocorticoids.
16. Explain how glucocorticoids achieve its anti-
inflammatory effects.
17. Give examples of conditions treated with
glucocorticoids.
18. Tabulate the adverse effects of glucocorticoids using
the acronym GLUCOCORTICOIDS.
YOUTUBE VIDEOS must watch
https://www.youtube.com/watch?v=I1uHkbocRCw&list=PLqOJveLKwrzeShfqIxk5oQeX
Oc9UdeorQ&index=17
Pharmacology - NSAIDs & PROSTAGLANDIN ANALOGS (MADE EASY) (11min) 6:18 STOP
Speed Pharmacology

https://www.youtube.com/watch?v=qhiMmNZjHRg
Pharmacology - Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)(12:10min)
Armando Hasudungan

https://www.youtube.com/watch?v=XL7yduSbjOw
Pharmacology of Inflammation – Pharmacology | Lecturio (7:49 min)
Lecturio Medical
 Injury/infection/trauma

Attacks the cell membrane of the cell

Cell membrane contains phospholipids

Activation of phospholipase occurs

It causes formation of arachidonic acid

Arachidonic acid is further metabolized by….

Cyclooxygenase pathway Lipoxygenase pathway 6
 Physical/chemical stimuli

Transmission from Nerve fibers

Tactile sensations from L fibers Pain from S fibers

Reaches spinal cord (DRG)

1st transmission cells Collateral cells in Subst.Gelatinosa

SG inhibits the upwards propagation

When strong stimuli→ SG cells are inhibited→ HIGHER Out Put is released

2nd order neurons → transmission crosses over to

other side and form spinothalamic tract

Tract ends in thalamus

Relays fibers to 7
Sensory cortex Frontal lobes Hypothalamus Limbic system
ANALGESICS – pain relievers

1. OPIOIDs- for chronic pain

(narcotics) codeine, morphine

2. NON-OPIOIDs-
NON-OPIOID ANALGESICS
Aspirin
Acetaminophen
NSAIDs
 NSAIDs
NON-STEROIDAL ANTI-
INFLAMMATORY DRUGS
 4 actions of NSAIDs
1. decrease inflammation (anti-inflammatory)
2. relieve mild-to-moderate pain (analgesia),
3. decrease elevated body temperature
associated with fever (antipyresis), and
4. decrease blood clotting by inhibiting platelet
aggregation (anticoagulation). anti-platelet
aggregant
• The best representative of an
NSAID is aspirin acetylsalicylic acid
(ASA)
• Acetaminophen or paracetamol is
similar to aspirin and other NSAIDs
in its ability to decrease pain
(analgesic) and fever (anti-pyretic)
• However, acetaminophen lacks
anti-inflammatory and
anticoagulant properties
• prostaglandins, thromboxanes, and
leukotrienes are eicosanoids
derived from arachidonic acid
which are ingested in the diet and
stored as phospholipid in the cell
membrane.
 EFFECTS OF
EICOSANOIDS ON
THE DIFFERENT
SYSTEMS
 Pharmacological/Physiological Effects
EFFECTS ON CARDIOVASCULAR SYSTEM

TXA2:
vasoconstrictor.

PGE2 and PGI2:

vasodilators.

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 EFFECTS ON GI TRACT

PGE2+ PGI2:
PGE2: inhibit gastric
watery acid secretion;
PGE2 + LT’s Cytoprotective
diarrhea, effects (↑ mucosal
contract blood flow;
vomiting ↑cAMP;
smooth
and ↑ mucus
muscle
cramps secretion;
(↑cAMP) ↑ protein
synthesis)

17
 PGI2 & PGE2 have protective
effects on GIT

PGI2 & PGE2

ACTIONS

Inhibits leucocyte- Inhibits the

Inhibits acid Has cytoprotective
secretion & action endothelial activation of
increase mucus interaction neutrophils
production.

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 PGI2 & PGE2 have protective
effects on GIT
PGI2 & PGE2
ACTIONS

Inhibits acid Has Inhibits leucocyte- Inhibits the

secretion & cytoprotective endothelial activation of
increase mucus action interaction neutrophils
production. So interaction of Protease and
leucocyte with oxygen radicals
endothelial cells
Endothelial
Capillary injury
CONSEQUENCES
obstruction
OF BLOCKING
PGI2 & PGE2 Ischemic
injury
FROM NSAID INTAKE

Mucosal
ulceration

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EFFECTS ON RESPIRATORY SYSTEM

LTC4 AND LTD4 cause

bronchoconstriction + increased mucus
secretion +Increased vascular
permeability

PGI2 AND PGE2 cause

bronchodilatation..

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EFFECTS ON REPRODUCTIVE ORGANS

Role in
PGE2: and promoting Role in
PGF2: Both labor; in maintaining
miscarriages
contract (premature
patent
pregnant labor); ductus
uterus. inducing arteriosus.
abortions.

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 Pharmacological/Physiological Effects
EFFECTS ON PAIN AND INFLAMMATION
1. PGE2, PGI2, LTB4: sensitize nerve endings to
painful stimuli.
2. Hyperemia, edema, hotness due to
increased eicosanoids at inflammation sites.
3. LTB4: chemotactic factor for neutrophils and
mononuclear cells. Promotes aggregation
and degranulation of polymorphonuclear
WBCs adhesion to vessel wall and migration

22
 • vasodilatation
PGD2

• Affect the hypothalamus temperature regulating system produces fever

PGE2 • Increases water electrolytes and mucus secretion in GIT.

• Produces contraction of uterine smooth muscles.

PGF2α

• Vasodilatation and inhibition of platelet aggregation.

PGI2
They are
opposite!
• Vasoconstriction and stimulates platelet aggregation
TXA2

• Bronchoconstriction
LTC4 AND • Increased capillary permeability
LTD4

23
• the cyclooxygenase enzymes that
synthesize prostaglandins:
COX-1 and COX-2
• Aspirin and most other NSAIDs are
nonselective cyclooxygenase
inhibitors; they inhibit both the
COX-1 and COX-2 enzymes
• This is nonselective inhibition
• COX-2 inhibitors or COX-2 selective
drugs – EX: celecoxib (Celebrex)-
inhibit synthesis of inflammatory
prostaglandins, while sparing
synthesis of beneficial
prostaglandins that help regulate
normal physiologic function
• decrease pain and inflammation
with minimal or no adverse effects
on the stomach and other tissues
ROLE OF PROSTAGLANDINS
IN PAIN, FEVER AND
INFLAMMATION AND HOW
DRUGS FUNCTION
Prostaglandins produce PAIN…
how ?
PERIPHERALLY :
PGs sensitize the
nerve endings to
bradykinin and
histamine

PAIN
CENTRALLY :
PGs lower the
threshold for
central pain
circuits
27
 REDUCES THE
PERIPHERALLY : INTENSITY OF
PGS sensitize
PAIN
the nerve
endings to
bradykinin and
histamine

NSAIDS
block PAIN
CENTRALLY :
PGs lower the
threshold for
central pain
circuits
28
 PGs produce FEVER….. How ?
• Hypothalamus contains
thermoregulatory center
• Maintains balance between heat
production and heat loss
• It regulates heat dissipating mechanisms

29
 Hypothalamus
Normally activates heat
When
hypothalamus losing So This set point
temperature
is adjusted mechanisms temperature is elevated in
is elevated like sweating is normalized FEVER
to a set
beyond level and
point vasodilatation

PGE2 has two

When there is mechanisms :
tissue Increased
damage/inflam Stimulates 1. Increases
Neutrophil PGE2 Raised body
mation/antigen heat
releases COX-2 synthesis temperature
-antibody production.
IL-1 enzymes in → FEVER
reaction/ hypothalamus 2.shuts down
infection HEAT LOSING
MECHANISM

30
 ANTIPYRETIC ACTIVITY
• Hypothalamus contains thermoregulatory center
• Maintains balance between heat production and heat
loss
• It regulates heat dissipating mechanisms
PGE2 has two
When there is mechanisms :
tissue
Increased 1. Increases
damage/infla Stimulates Raised body
Neutrophil PGE2 heat
mmation/AG: COX-2 temperature
releases IL-1 synthesis in production.
AB enzymes → FEVER
hypothalamus 2.shuts down
reaction/infec
tion HEAT LOSING
MECHANISM

Reduces fever due to inflammation. But not due to…

1. Heat stroke NSAIDS inhibits
2. Exercise induced/Physiological diurnal variation in PGE2 synthesis and
temperature reduces fever 31
PGs CAUSE INFLAMMATION … HOW ?

Increased
capillary
permeability

INFLAMMATION

32
Anti-inflammatory mechanism of action of NSAIDS
Inhibits the cyclooxygenase enzyme & reduces
prostaglandin biosynthesis
Reduce production of superoxide radicals
Induce apoptosis MOST
IMPORTANT
Inhibit the expression of adhesion molecules MECHANISM

Decrease nitric oxide synthase,

Decrease proinflammatory cytokines (e.g., TNF-, interleukin-1)
Modify lymphocyte activity
Alter cellular membrane functions.
Stabilize lysosomal enzymes
33
 ANTI-INFLAMMATORY ACTION
Decrease
activation
and
function of
neutrophils

Reduce edema, Stabilization of

pain and Anti-inflammatory
inflammation action lysosomal
membranes

Inhibits
mucopoly
saccharide
biosynthesis

34
 ANTIPLATELET ACTION
• Platelets aggregate that lead to thrombus
formation.
• Platelet aggregation is prevented by PGI2
and promoted by TXA2.
• Inhibition of TXA2 by Aspirin at LOWER
DOSES (75-150 mg) → reduce platelet
aggregation.

35
Cyclooxygenase: COX-1 & COX-2

COX-1 COX-2

▪ Physiologic, normal ▪ Present if there is

inflammation
▪ Present in most tissues
▪ Induced mainly at sites of
▪ Synthesizes PGs
inflammation by cytokines
that regulate physiologic
processes ▪ Synthesizes PGs that
mediate inflammation, pain,
▪ Especially important in
and fever
▪ gastric mucosa
▪ kidneys ▪ Constitutive expression
▪ platelets primarily in
▪ vascular endothelium ▪ brain
▪ kidneys
Needleman P, Isakson PC. J Rheumatol. 1997;24(suppl 49):6–8.
DuBois RN et al. FASEB J. 1998;12:1063–1073.
 PAIN DUE TO INFLAMMATION

Peripheral Central
Trauma/inflammation Central sensitization
IL-6?

Release of arachidonic acid

IL-1ß Pain
COX-2

 Prostaglandins E2  Prostaglandins

Pain COX-2

Peripheral sensitization
ACETAMINOPHEN
 ACETAMINOPHEN
• known also as paracetamol
• advantage of acetaminophen - not associated
with upper gastrointestinal tract irritation.
• Not an NSAID
• Has no anti-inflammatory nor anticoagulant effects
• Has anti-pyretic and analgesic effects
• important and useful medication in the treatment
of fever and mild to moderate pain (without
inflammation)
Glucocorticoids
 Physiologic Effects of Glucocorticoids
Effects on Glucose, Protein, and Lipid Metabolism
• Cortisol and other glucocorticoids increase blood glucose
and liver glycogen.
• Cortisol facilitates the breakdown of muscle into amino
acids and lipids into free fatty acids, which can be
transported to the liver to form glucose
(gluconeogenesis).
• Glucose that is synthesized in the liver can either be
stored as glycogen or released back into the
bloodstream to increase blood glucose levels.
Effects of cortisol on muscle, fat, and liver cells. Cortisol causes the breakdown of muscle and
fat into amino acids and free fatty acids, which can be used by the liver to produce glucose.
Glucocorticoids are effective and potent
anti-inflammatory agents.
Anti-inflammatory Effects of Corticosteroids
▪ Suppress the transcription of genes involved in
inflammation
▪ Inhibit the phospholipase A2 which release AA from
the cell membrane
• Stabilize lysosomal membranes, thereby making
them less fragile and susceptible to rupture.
Lysosomes are organelles that contain degradative
enzymes. When lysosomes are ruptured, these
enzymes begin to digest cellular components
contributing to inflammation.
• Decrease vascular permeability that helps control
swelling and erythema at the site of inflammation.
 General Principal Action Desired Examples of Specific
Indication of Glucocorticoids Disorders
Allergic Decreased inflammation Anaphylactic reactions, drug-
disorders induced allergic
reactions, severe hay fever,
serum
sickness
Collagen Immunosuppression Acute rheumatic carditis,
disorders dermatomyositis,
systemic lupus
erythematosus
Dermatologic Decreased inflammation Alopecia areata, dermatitis
disorders (various forms),
keloids, lichens, mycosis
fungoides, pemphigus,
psoriasis
 General Principal Action Examples of Specific
Indication Desired of Disorders
Glucocorticoids
Gastrointestinal Decreased Crohn disease, ulcerative
disorders inflammation colitis

Hematologic Immunosuppression Autoimmune hemolytic

disorders anemia, congenital
hypoplastic anemia,
erythroblastopenia,
thrombocytopenia
Nonrheumatic Decreased Bursitis, tenosynovitis
inflammation inflammation
 General Principal Action Examples of Specific
Indication Desired of Disorders
Glucocorticoids
Neoplastic Antilymphocytic Leukemias, lymphomas,
disease effects nasal polyps, cystic
tumors

Neurologic Decreased Tuberculous meningitis,

disease inflammation and multiple sclerosis,
myasthenia gravis

Neurotrauma immunosuppression Brain surgery, closed head

injury, certain
brain tumors, spinal cord
injury
 General Principal Action Examples of Specific
Indication Desired of Disorders
Glucocorticoids
Ophthalmic Decreased Chorioretinitis,
disorders edema;* inhibit conjunctivitis, herpes
free radical- zoster
ophthalmicus,
iridocyclitis, keratitis,
optic
neuritis
Organ induced neuronal Transplantation of liver,
transplant damage kidney, heart, and so
forth
Renal diseases Decreased Nephrotic syndrome,
inflammation membranous
glomerulonephritis
 General Principal Action Examples of Specific
Indication Desired of Disorders
Glucocorticoids
Respiratory Immunosuppression Bronchial asthma,
disorders berylliosis, aspiration
pneumonitis, symptomatic
sarcoidosis,
pulmonary tuberculosis

Rheumatic Decreased Ankylosing spondylitis,

disorders inflammation psoriatic arthritis,
rheumatoid arthritis, gouty
arthritis,
osteoarthritis
Adverse Effects of
Glucocorticoids
 SIDE EFFECTS OF GLUCOCORTICOIDS
G GLAUCOMA On TOPICAL use
L LIMB MUSCLE ATROPHY Proximal myopathy
U ULCER PEPTIC
C CATARACT On SYSTEMATIC use; Posterior Subcapsular
cataract kind.
O OSTEOPOROSIS Dose/Duration Dependent; ribs/ vertebra
C CUSHING SYNDROME Cushingoid features; Moon facies
O OSTEONECROSIS Aseptic necrosis, Femur head MC inv.
R RETARDATION OF GROWTH Also stands for retention of NA+ / H20
T THINNING OF SKIN Easily bruising
I INFECTIONS Immunosuppression
C CHANGES IN MOODPSYCHE Behavioral Disturbances
O OEDEMA Mineralocorticoid action
I IMPAIRED HEALING of wounds
D DIABETES MELLITUS Hyperglycemic action
S SUPPRESSION OF hypothalamus, Serious; may cause Acute Adrenal
pituitary gland, and adrenal glands Insufficiency
THE END