Anti-Inflammatory &
Immunosuppressive Drugs 1
I-3 Fall 2012
Marieke Kruidering, Ph.D.
Pharmacology in I-3
Week 2
Week 4
Week 5
Anti-inflammatory
and immunosuppressive
drugs 1 & 2
TBL
Antibacterial drugs 1
Antibacterial drugs 2
Antibacterial drugs 3
Drugs for mycobacterial
infections
Week 6
Week 7
Week 8
Antifungal drugs
Antiviral drugs 1 & 2
Antiviral drugs 3
Week 9
Antiparasitic drugs
Reminder - Studying
Pharmacology
• Drug names (focus on prototypes; use flash cards,
tables)
• Unusual chemical structures (eg, antibody, receptor,
cytokine)
• Mechanisms of action
• Clinical uses (aka “spectrum of activity”)
• Pharmacokinetics (eg, notable route administration,
elimination)
• Adverse effects (predictable, unusual, teratogens)
• Drug interactions (eg, CYP450 inducers, inhibitors,
narrow therapeutic window AND a CYP substrate)
Anti-inflammatory &
Immunosuppressant Drugs
1
2
NSAIDS
Acetaminophen
Immunosuppressants
Newer biologic agents
Drugs for gout (TBL)
(tylenol)
Antihistamines
Corticosteroids
Inflammatory cascade: Triggers
Infection
Immune response
Tissue and/or
vessel damage
Inflammatory
Mediators
Acute Inflammatory Response
Note this is a common & non-specific response
- Redness
- Heat
- Swelling
- Pain (allodynia)
- Loss of function
Drugs block production or effect of
inflammatory mediators
Tissue and/or
vessel damage
Infection
Inflammatory Mediators
o
o
o
o
o
Vasoactive peptides:
Histamine,serotonin
The kinin system
Coagulation cascade
The complement system
Arachidonic Acid
metabolites
Anti-histamines
NSAIDS
Corticosteroids
Inflammatory Enzymes: PLA2 & COX
3. Zileuton
Montelukast,
zafirlukast
1. Steroids Phospholipase A
2
2.NSAIDS (including
aspirin)
Arachidonic acid (AA)
Lipoxygenase
Lipoxygenase products
(leukotrienes)
Inflammatory effects
(esp. in asthma)
Cyclooxygenase (COX)
Prostaglandins & thromboxanes
Inflammatory effects Homeostatic
(inducible)
Functions
(stomach mucus)
Eicosanoids: PGs & TXA Effects
AA
Cyclooxygenase (COX)
Lipoxygenase
NSAIDS
PGH2,PGG2 unstable)
Leukotrienes)
• Chemotaxis
• Vasodilation
Thromboxane A2
Stable prostaglandins
PGD2,PGE2,PGF2
Prostacyclin
PGI2
1.
1. Vasoconstriction
2. Stimulate platelet aggregation
Vasodilation
1. Vasodilation
2. Inhibition of platelet aggregation
Notable NSAIDS
Aspirin
ibuprofen (Motrin, Advil)
naproxen (Naprosyn, Aleve)
etodolac
(Lodine)
cox 2 >cox1
indomethacin
(Indocin)
ketorolac (Toradol)
- parenteral (IM)
celecoxib (Celebrex)
NSAID Dose Dependent
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)
Bleeding (COX-1, esp. aspirin)
Aspirin: Reye syndrome
Syndrome of hepatic injury &
encephalopathy in kids treated
with aspirin after a viral illness
Impaired labor (COX-1 & 2)
Aspirin & acetaminophen:
Dangerous in overdose
(OTC: Can be fatal)
Aspirin: salicylate poisoning
(respiratory alkalosis followed by metabolic acidosis)
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
induces
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
Clinical Uses
Loratadine (Claritin)
Fexofenadine
(Allegra)
Low affinity for
muscarinic
receptors, doesn’t
cross BBB
Allergic reactions
Diphenhydramine
(Benadryl)
Muscarinic
antagonist, crosses
BBB
Allergic reactions,
dystonic rxtn to dopamine
blockers, 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
cortisol,
aldosterone
Adrenal cortex
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;
Even though aspirin and acetaminophen are OTC
overdoses can be fatal.
Corticosteroids have powerful anti-inflammatory and
immunosuppressant actions but chronic use produces
much toxicity
FYI: Eicosanoids As Drugs
(Additional info that will NOT be tested in I-3)
Tip: recognize the “prost” in the drug name so you know it is a
prostaglandin analog
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
FYI. ASPIRIN: Antiplatelet effect
Adverse effects: bleeding due to longer cox -1
inhibition in platelets than in endothelium (why?)
Platelets have no nucleus thus cannot resynthesize COX-1 once it is inhibited by aspirin,
while endothelial cells can regenerate COX-2. Net result: selective COX 1 inhibition &
reduced platelet aggregation.