Anti-Inflammatory &
Immunosuppressive Drugs 1
I-3 Fall 2011
Susan Masters, Ph.D.
Pharmacology in I-3
Week 2
Week 4
Week 5
Anti-inflammatory
and immunosuppressive
drugs 1 & 2
Antibacterial drugs 1
Antibacterial drugs 2
Antibacterial drugs 3
Drugs for mycobacterial
infections
Week 6
Week 7
Week 8
Antifungal drugs
Antiviral drugs 1
Antiviral drugs 2
Antiparasitic drugs
The Inflammatory Cascade
Perceived threat
Tissue injury
Adaptive immune
system
Infection
2
Leukocyte & endothelial cell activation
1
Inflammatory mediators
Inflammation (redness, edema,
warmth, pain, tissue destruction)
Innate immune
system
Anti-inflammatory & Immunosuppressant
Drugs
1
2
NSAIDS
Acetaminophen
Antihistamines
Corticosteroids
Immunosuppressants
Newer biologic agents
Drugs for gout
Inhibitors of Eicosanoid Production
Zileuton
montelukast,
zafirlukast
Phospholipase A2
NSAIDS (including
aspirin)
Arachidonic acid
Lipoxygenase
Lipoxygenase products
(leukotrienes)
Inflammatory effects
(esp. in asthma)
5-ASA (IBD)
Cyclooxygenase (COX)
Prostaglandins & thromboxanes
Inflammatory effects
IBD, inflammatory bowel disease; 5-ASA, 5-amino salicylic acid
Homeostatic
functions
Notable NSAIDS
aspirin
naproxen (Naprosyn, Aleve)
ibuprofen (Motrin, Advil)
indomethacin (Indocin)
ketorolac (Toradol)
- parenteral (IM)
celecoxib (Celebrex)
NSAID Therapeutic Effects
Antipyretic,
Analgesic
Antithrombotic
(aspirin only)
0
1
2
Anti-inflammatory
3
4
5
Daily dose of aspirin (g)
N-acetyl--aminophenol
Acetaminophen (Tylenol; AKA paracetamol)
antipyretic, analgesic NOT anti-inflammatory
NSAID & Acetaminophen Toxicity
NSAIDS: Disruption of
homeostatic function
GI upset & ulcers (esp. COX-1)
Acute renal failure (COX-1 & 2)
Thrombosis (COX-2)
Aspirin: Reye syndrome
Syndrome of hepatic injury &
encephalopathy in kids treated
with aspirin after a viral illness
Bleeding (COX-1, esp. aspirin)
Impaired labor (COX-1 & 2)
Aspirin & acetaminophen:
very dangerous in overdose
Aspirin: salicylate poisoning
Acetaminophen: liver failure
NSAIDS: Rare
hypersensitivity reaction
Excessive shunting of
arachidonic acid products
to lipoxygenase pathway when
COX is blocked
Acetaminophen Toxicity
Acetaminophen
UDP glucuronosyltransferase
Sulfotransferase
glucuronide
sulfate
CYP2E1
Acetylcysteine
(antidote)
Glutathione-Stransferase
glutathione
Live r failure
protein
The Inflammatory Cascade
Perceived threat
Adaptive immune
system
Tissue injury
Leukocyte & endothelial cell activation
NSAIDS, acetaminophen
Antihistamines
Inflammatory mediators
Inflammation (redness, edema,
warmth, pain, tissue destruction)
Infection
Innate immune
system
IgE-Mediated Mast Cell Degranulation
Resting Mast Cell
Activated Mast Cell
Histamine
Proteases
Heparin
Histamine
Histidine
Histidine
decarboxylase
Histamine
H receptor
1
-vascular permeability
venule vasodilation
pruritus
Cimetidine,
ranitidine
H2 receptor
- gastric acid secretion
H1 Histamine Antagonists (Antihistamines)
Prototype
Properties
Low affinity for
Loratadine (Claritin)
muscarinic receptors,
Fexofenadine (Allegra) doesn’t cross BBB
Diphenhydramine
(Benadryl)
Clinical Uses
Allergic reactions
Allergic reactions, dystonic
Muscarinic antagonist,
rxtn to dopamine blockers,
crosses BBB
OTC sleep aid, antiemetic
However, in the case of severe hypersensitivity reactions, including
anaphylaxis, drugs of choice are: Epinephrine (need 1
vasoconstriction and 2 bronchodilation) and corticosteroids!
The Mighty Corticosteroids
Perceived threat
Infection
Corticosteroids
Adaptive immune
system
Tissue injury
Innate immune
system
Corticosteroids
Leukocyte & endothelial cell activation
Corticosteroids
Corticosteroids
Inflammatory mediators
Inflammation (redness, edema,
warmth, pain, tissue destruction)
Glucocorticoids Regulate Transcription
Cortisol
Cortisol
Cortisol
GR
NUCLEUS
­ transcription (eg, lipocortin)
IP
HS P
GR
HSP
Cortisol Cortisol
GR
GR
or
¯transcription (IL-1, IL-2,
TNF- a, IF-g)
GRE
mRN A
Proteins
mRN A
GR, glucocorticoid receptor; HSP, heat shock protein; IP, immunophilin;GRE, glucocorticoid receptor
Corticosteroids Inhibit Eicosanoid
Production
Corticosteroids
Lipocortin
Phospholipase A2
Corticosteroids
inhibit induction
of COX-2 expression
Arachidonic acid
Lipoxygenase
Lipoxygenase products
(leukotrienes)
Cyclooxygenase (COX)
Prostaglandins & thromboxanes
Glucocorticoids Are Powerful Immunosuppressants
Corticosteroids affect nearly every facet of immune function,
although less inhibition of humoral arm than cell-mediated arm;
they also induce apoptosis in rapidly-dividing leukocytes
Clinical Use of Glucocorticoids
Self-limited reaction
(eg, poison oak)
Acute flare of a
chronic inflammatory
condition or organ
rejection reaction
Toxicity of Chronic Systemic
Glucocorticoids
Cushing’s
syndrome
• Fat redistribution
• Hypertension
• Glucose intolerance
• Impaired wound healing
• Osteoporosis (prevent with bisphosphonates)
• Cataracts
• Gastric ulcers (prevent with omeprazole, misoprostol)
• Risk of infection
• CNS effects, including psychosis
• Growth inhibition in children
www.sd-neurosurgeon.com/diseases/pit_tumors.html
Adrenal Suppression with Chronic
Systemic Glucocorticoids
Hypothalamus
CRH
prednisone
Anterior
pituitary
ACTH
Adrenal cortex
cortisol,
aldosterone
Some Corticosteroids
Relative AntiInflammatory
Activity
Relative SaltRetaining
Activity
Oral, parenteral,
topical
1
1
Cortisone
Oral
0.8
0.8
Prednisone
Oral
4
0.3
Triamcinolone
Oral, injectable,
topical, inhaled
5
0
Dexamethasone
Oral, injectable,
topical
30
0
Oral
0
250
Agent
Cortisol (hydrocortisone)
Fludrocortisone
(mineralocorticoid)
Forms Available
Summary
• Inhibitors of the production or action of inflammatory
mediators (NSAIDS, antihistamines, presumably
acetaminophen) provide symptomatic relief with reasonable
safety in most people but do not ameliorate ongoing immune
reaction;
• Corticosteroids have powerful anti-inflammatory and
immunosuppressant actions but chronic use produces much
toxicity
Reminder - Studying Pharmacology
• Drug names (focus on prototypes; use flash cards, tables)
• Unusual chemical structures (eg, antibody, receptor, cytokine)
•Mechanisms of action
• Clinical uses
• Pharmacokinetics (eg, notable route administration, elimination)
• Adverse effects (predictable, unusual, teratogens)
• Drug interactions (eg, CYP450 inducers, inhibitors, narrow
therapeutic window AND a CYP substrate)
Eicosanoids As Drugs
(Additional info that will NOT be tested in I-3)
Drug Name
Analog Of
Clinical Use
Epoprostenol
PGI2
Pulmonary hypertension
Dinoprostone
PGE2
Medical abortion, relax uterine cervix in
preparation for induction of labor
Misoprostol
PGE1
Peptic ulcer, medical abortion
Alprostadil
PGE1
Maintain a patent (open) ductus arteriosus
in neonates with certain cardiac
malformations until emergency surgery;
erectile dysfunction
Carboprost
PGF2
Labor induction
Latanoprost
PGF2
Glaucoma