PHARMACOLOGY OF
INFLAMMATION
David J. Mokler, Ph.D.
October 29, 2009
OBJECTIVES
After studying this material the student should;
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Describe the role of prostaglandins in the
inflammatory response.
Describe the mechanism of action of non-steroidal
drugs used in the treatment of inflammation.
Describe the pharmacology and toxicology of the
non-steroidal anti-inflammatory agents.
Discuss the toxicity of acetaminophen
OBJECTIVES
After studying this material the student should;
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Discuss the proper and rational use of
corticosteroids in the treatment of inflammation.
Discuss the toxic effects of the corticosteroids used
in chronic therapy.
NSAIDs – COX INHIBITORS
Aspirin
Indomethacin (INDOCIN)
Proprionic Acid Derivatives
 Ibuprofen (MOTRIN, RUFEN, ADVIL,
NUPRIN)
 Naproxen (NAPROSYN)
 Piroxicam (FELDENE)
 Nabumetone (RELAFEN)
Ketorolac (TORADOL)
Acetominophen (TYLENOL, TEMPRA, others)
NSAIDs – COX INHIBITORS
COX2 Inhibitors
Celecoxib (CELEBREX)
PROSTAGLANDINS
History
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1930 - Kurzrok and Lieb
1930s - Goldblatt, Euler
"prostaglandin"- lipid- soluble acid
1962 - isolation of PGE1 and PGF1
1964 - synthesis from arachadonic acid
Arachadonic acid metabolites via cyclooxygenase
Released by mechanical, thermal, chemical,
bacterial and other trauma
PROSTAGLANDINS
PROSTAGLANDINS
Effects
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produce blood flow in injured region, vascular
permeability, enhance lymphocytic infiltration
may modulate release of histamine from mast
cells - PGD2 stimulates, PGE2 and PGI2 inhibits
oxygen radicals produced as byproduct of
synthesis ® inflammation
potentiate pain-producing effects of kinins
produce fever in hypothalamus
PGE1 and PGE2 stimulate osteoclasts ® bone
resorbtion
Fever
PROSTAGLANDINS
Effects
PGE1 and PGD2 inhibit platelet
aggregation
 TXA2 induces aggregation
 PGA2, PGE1 and PGE2 induce
erythroporesis
 PGFs contract, PGEs relax bronchial
smooth muscle, non-pregnant and
pregnant uterus

Two Forms of
Cyclo-oxygenase (COX)
COX-1
COX-2
 Produces prostanoids
that mediate homeostatic
functions
 Produces prostanoids that
mediate inflammation, pain, and
fever
 Constitutively expressed
 Induced mainly at sites of
inflammation by cytokines
 Especially important in:
– Gastric mucosa; smalland large-bowel mucosa
– Kidney
– Platelets
– Vascular endothelium
DuBois RN, et al. FASEB J. 1998;12:1063–1073.
 Constitutive expression in:
– Brain
– Kidney (mainly animal data)
– Female reproductive tract
Mechanism of Action of
Anti-inflammatory Agents
Arachidonic acid
COX-2–targeted
agents
X
COX-1
COX-2
X
Prostaglandins
Protect
gastroduodenal
mucosa
Traditional
NSAIDs
X
Thromboxane
Prostaglandins
Supports
platelet
function
Mediate
inflammation,
pain, and fever
LEUKOTRIENES
arachidonic acid metabolites from
lipoxygenase
may be inhibited by some NSAIDs,
inhibited by steroids
LEUKOTRIENES
LEUKOTRIENES
Effects
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LTB4 potent chemotaxic substance
act on endothelium of postcapillary venules to
cause exudation of plasma
5-HPETE and 5-HETE induce release of
histamine from basophils
LTC4 and LTD4 potent bronchoconstrictors
LTD4 is the slow reacting substance of
anaphylaxis (SRSA) ® bronchoconstriction,
histamine release, vasopermeability
OTHER MEDIATORS OF
INFLAMMATION
Histamine
5-hydroxytryptamine (Serotonin)
Bradykinins
Vasopermeability
 histamine release
 prostaglandin synthesis
 Pain

NSAIDs
SALICYLATES
Aspirin – acetylsalicylic acid (ASA)
NSAIDs
ASPIRIN (ASA)
Mechanism of action

inhibits prostaglandin synthesis by
acetylation of cyclooxygenase
Pharmacological actions
Analgesia
 Anti-inflammatory
 Antipyretic action
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NSAIDs
SALICYLATES
Pharmacokinetics
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rapid absorption- low pH increases absorption- high
pH increases solubility, enhances absorption
peak blood levels: 2 hours
up to 90% protein bound in plasma
metabolism in liver-glycine or glucuronide conjugates;
10% is free salicylate
excretion in urine
free salicylate excretion (not metabolites) may be
enhanced by making the urine more alkaline
NSAIDs
SALICYLATES
Toxicity
large doses will increase depth of
respiration
 nausea and vomiting
 salicylism - chronic treatment of high
doses- confusion-delerium- tinnitus –
dizziness
 increased bleeding time
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gastric ulceration (especially with alcohol)
 hemorrhage
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may alter uric acid excretion (dose
dependent)
Toxicity
Overdose
acid-base changes - usually acidosis,
metabolic & respiratory
 High doses suppress respiration →
respiratory acidosis
 Uncouple oxidative phosphorylation in
cells → metabolic acidosis

PROPRIONIC ACID
DERIVATIVES
Ibuprofen (MOTRIN, ADVIL, NUPRIN)
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rapidly absorbed after oral administration, peak
concentration 1 to 2 hours
extensively (99%) protein bound, 90% excreted
as metabolites in urine
Naproxen (NAPROSYN)
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longer half life, therefore 2 x day dosing
inhibits PMN migration
Piroxicam (FELDENE)
Nabumetone (RELAFEN)
PROPRIONIC ACID
DERIVATIVES
anti-inflammatory, anti-pyretic,
analgesic
inhibit cyclooxygenase, inhibit
leukocyte migration possibly by
inhibition of lipoxygenase
Better anti-inflammatory than
aspirin?
PROPRIONIC ACID
DERIVATIVES
Toxicity – this relates to all NSAIDs
Increased bleeding time
 Gastric bleeds
 Long term may cause liver toxicity
 Hypertension and renal failure especially in
the elderly
 Edema
 CNS – dizziness, confusion, drowsiness,
anxiety

Ketorolac (TORADOL)
High potency, analgesia equivalent to
morphine
Used for moderate to severe pain
Not for mild pain
Short term peri-operative use
Similar side effects to other
NSAIDs
Indomethecin (INDOCIN)
Potent inhibitor of cyclooxygenase, inhibits PMN migration
Analgesic, anti-inflammatory and anti-pyretic - similar to
aspirin
Rapidly and completely absorbed following oral administration,
90% protein bound, low concentrations in CSF but plasma
levels in synovial fluid
Toxicity - 35 to 50% of patients receiving therapeutic doses
report side effects: GI - anorexia, nausea, abdominal pain,
ulceration of upper GI tract: CNS - severe frontal headache
most common (25-50%), dizziness, vertigo, light-headedness,
mental confusion: hematopoietic reactions, hypersensitivity
(cross-sensitivity with aspirin)
Mean Plasma half-lives of different NSAIDS
Drug
Half-life (hr)
Short
Aspirin
0.25
Diclofenac
1.1
Etolodac
3.0
Ibuprofen
2.1
Indomethacin
4.6
Ketoprofen
1.8
Long
Diflunisal
Naproxen
Phenylbutazone
Piroxicam
Sulindac
15
14
68
57
14
Acetaminophen (TYLENOL)
Actions
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Analgesic, antipyretic properties comparable to
salicylates
Weak inhibitor of prostaglandin biosynthesis in
periphery, more activity in CNS
Identification in 2002 of COX-3 in brain that has
a higher affinity for acetaminophen – now thought
to be a splice variant of COX-1
Weak anti-inflammatory action
No effect on respiration
No effect on platelets
No effect on uric acid excretion
Acetaminophen (TYLENOL)
Pharmokinetics
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rapid absorption
peak blood levels: 1-2 hours
acetaminophen to glucuronide conjugation
excreted in urine
Acetaminophen (TYLENOL)
Toxicity
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Allergic reactions (rare)
Toxicity at therapeutic doses
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2 extra strengths = 1000 mg
FDA panel recommends no more than 650 mg per dose
Recommends total daily dose less than 4000 mg
Evidence of long term hepatic toxicity with long term
use
Use of acetaminophen in many combination
products
Acetaminophen (TYLENOL)
Toxicity in overdose
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No acute signs but
medical emergency
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Hepatic necrosis, renal
tubular necrosis
emerges over days
Hypoglycemic coma
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Treatment
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acetylcysteine
COX2 inhibitor
Celecoxib (CELBREX)
Selectively inhibit COX2 – inducible
cyclo-oxygenase
May be no better than non-selective
inhibitors
Gastrointestinal Toxicity With Celecoxib vs
Nonsteroidal Anti-inflammatory Drugs
for Osteoarthritis and Rheumatoid Arthritis
The CLASS Study: A Randomized Controlled Trial
JAMA 284(10): 1247, 2000
http://jama.amaassn.org/issues/v284n10/rfull/joc01227.html
Figure 2. Annualized
Incidence of Upper
Gastrointestinal Tract Ulcer
Complications Alone and
With Symptomatic
Gastroduodenal Ulcers
Figure 3. Patients With Decreases in
Hematocrit and/or Hemoglobin at 6 Months
Figure 4. Patients With Increases in Serum Creatinine
and/or Serum Urea Nitrogen and With Elevations in
ALT and AST at 6 Months
What happened to the COX-2
inhibitors??
Rofecoxib (VIOXX) withdrawn
In APPROVe trial
Designed to evaluate the efficacy of rofecoxib, 25 mg, in
preventing recurrence of colorectal polyps in 2,600
patients with a history of colorectal adenomas
The increased cardiovascular risk began after 18 months
of treatment with rofecoxib and persisted. At three
years, cumulative incidence of cardiovascular events was
7.5 per 1,000 patients receiving placebo compared with
15 per 1,000 patients receiving rofecoxib
Mechanisms of cardiovascular
toxicity
COX-1 helps promote thrombosis and
COX-2 helps inhibit it, blocking COX2 but not COX-1 could theoretically
increase the risk of myocardial
infarction and other thrombotic
events.
Mechanisms of cardiovascular
toxicity (con’t)
Depression of prostaglandin I2 formation
by coxibs might be expected to elevate
blood pressure, accelerate atherogenesis,
and increase the thrombotic response to
rupture of an atherosclerotic plaque. In
patients at higher cardiovascular risk,
coxibs would be more likely to predispose
to a clinical event early in the course of
treatment
CONSIDERATIONS OF
THERAPY WITH NSAIDs
Most NSAIDs are similar in efficacy
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Patient variability in efficacy and toxicity
Classification by duration of action
Side effects serve as the basis for
therapeutic choice
Inhibition of cyclooxygenase varies as to
distribution in body fluids
Aspirin and para-aminophenol toxicity
Blood dyscrasias
TREATMENT OF ARTHRITIS
WITH NSAIDs
Reduced inflammation slows progress
of disease
High dose therapy
Aged population
monitor renal function
 monitor blood for dyscrasias
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Use best tolerated agent and lowest
cost
ANTI-INFLAMMATORY
STEROIDS
David J. Mokler, Ph.D.
October 29, 2009
CORTISOL
Chemistry & Metabolism
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major glucocorticoid in humans
synthesized from cholesterol in cells of the zona
fasiculata and zona reticularis of the adrenal cortex
released under the influence of ACTH
20 mg secreted per day in adult in the absence of
stress
95% bound in blood to corticosteroid binding
globulin
T½ 90-110 min; increased with large amounts or
hypothyroidism
reduced and conjugated in liver, excreted in urine
as 11-oxy 17-ketosteroids
Physiologic and Pharmacological
Effects
Widespread effects - homeostasis
Dose-related and "permissive" effects
Effects on metabolism
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Protects glucose-dependent tissue (brain and
heart)
In periphery decreases glucose utilization
Increases blood glucose
Stimulates gluconeogenesis
glycogen stores
Anti-insulin effects
Physiologic and Pharmacological
Effects
Cardiovascular
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decrease capillary permeability, incr in Na+
retention
Blood elements
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↑ hemoglobin and red blood cells, ↑ PMN
leukocytes
↓ lymphocytes, eosinophils, monocytes,
basophils
↓ lymphoid tissue and immune response
Mechanisms of Action
Glucocorticoid Receptor Signaling
SIGMA-ALDRICH
STEROIDS FOR THOUGHT
Anti-Inflammatory
Properties
Inhibit early phase (edema, fibrin
deposition, capillary dilatation, migration of
leukocytes and phagocytic activity)
Inhibit late phase (capillary proliferation,
fibroblast proliferation, deposition of
collagen and cicatrization)
Inhibit inflammatory response regardless
of inciting agent - palliative therapy
Inhibit recruitment of neutrophils and
monocyte - macrophages
SYNTHETIC
CORTICOSTEROIDS
Structure for ↑ glucocorticoid activity
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1, 2 double bond - prednisone, prednisolone - enhances
glucocorticoid effects
6α -methylation - unpredictable - 6α- methyl-prednisolo
ne - increased anti-inflammatory
9-fluoridation - increases all activity - paramethasone,
betamethasone, dexamethasone
16-methylation eliminates Na+ retaining effect with
slight change in metabolic and anti-inflammatory effect
17 α-hydroxy - maximizes carbohydrate and
anti-inflammatory potency
SAR and parallel activity of glucose metabolic and
anti-inflammatory activity suggests similar receptor
mechanisms
Relative Potencies
Anti-inflammatory
Cortisol
1
Prednisone
4
(Δ1-Cortisone)
Prednisolone
4
Fludrocortisone
10
Corticosterone
0.35
Triamcinalone
5
(9α-Fluoro-16α-hydroprednisolone)
Paramethasone
10
(6α-Fluoro-16α-methylprednisolone)
Betamethasone
25
(9α-Fluoro-16β-methylprednisolone)
Dexamethasone
25
(9α-Fluoro-16α-methylprednisolone)
Na+
1
0.8
0.8
125
15
0
0
0
0
PHARMACOKINETICS
Well absorbed after oral administration
Also available for i.v, i.m., intrasynovial and
topical administration
90% protein bound to
corticosteroid-binding globulin - increases
during pregnancy and administration of
estrogens and cortisol
Hepatic and extra-hepatic metabolism
TOXICITY OF STEROIDS
Acute and Subacute
days or a few weeks
 few adverse effects
 behavioral changes
 acute peptic ulcers
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TOXICITY OF STEROIDS
Chronic Therapy – Withdrawal
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acute adrenal insufficiency
withdrawal syndrome - fever, myalgia,
arthralgia, malaise
Chronic Therapy - Continued High Dose
Therapy
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Adrenal suppression
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supplementary therapy at times of severe stress
accidental trauma, surgery
recovery following withdrawal, may take 6-9 months
following chronic treatment
TOXICITY OF STEROIDS
Chronic Therapy - High Dose Therapy
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Iatrogenic Cushing's syndrome
 redistribution of body fat from extremities to trunk and
face
 striae, ecchymoses, acne and hirsutism
Increased susceptibility to infection
 Nonspecific
 aggressive treatment with drugs specific for pathogen
Hypokalemia, hypochloremia, edema - not seen with
16-substituted compounds
Behavioral disturbances, psychoses - nervousness, insomnia,
changes in mood, manic-depressive or schizophrenic
symptoms, suicidal tendencies
TOXICITY OF STEROIDS
Chronic Therapy - High Dose
Therapy
Cataracts
 Osteoporosis
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in all ages
inhibition of osteoblasts and Ca++ uptake,
secretion PTH  (+) osteoclasts, therefore 
formation and  resorbtion
indication for withdrawal from therapy
Growth retardation in children - not
reversible by exogenous HGH
THERAPEUTIC USES
Substitution therapy
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acute - cortisol in dose equivalent to maximum
daily rate of secretion in stress - with
intravenous isotonic saline
chronic - cortisol in twice daily dosing to mimic
diurnal cycle - with mineralocorticoid
Arthritis
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rheumatoid
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lowest dose to alleviate symptoms
continue NSAIDs, rest, physical therapy
osteoarthritis - intra-articular injection controversial
THERAPEUTIC USES
Rheumatic carditis - non-responsive to
salicylates -in combination with salicylates
Renal diseases - in some cases of acute and
chronic glomerulonephritis with nephrotic
syndrome
Collagen diseases - most diseases associated
with collagen except scleroderma - life
threatening, fulminating SLE
Allergic disorders - manifestations of short
duration controlled - used in combination with
other agents - not effective for severe acute
reactions - Why?
THERAPEUTIC USES
Ocular diseases - contraindicated in herpes
simplex, mechanical lacerations, or fungal, viral
or bacterial infections
Skin diseases - topical steroids - psoriasis,
vitiligo, seborrhea
Liver diseases - only certain patients with
chronic active hepatitis
Cerebral edema - neoplasia, no strong evidence
for value in edema due to trauma, cerebrovascular accident or shock
THERAPEUTIC
CONSIDERATIONS
Empirical use - 6 principles
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Careful titration of dose
A single dose of steroid, even large, has very
little harmful effect
A few days of therapy at moderate doses and in
the absence of contraindications is unlikely to
produce harmful effects
Increased toxicity with increased dose and
increased duration of therapy
Not curative except for adrenal insufficiency
Abrupt withdrawal following high-dose therapy
may be life-threatening