NSAIDS n o n-salicylates
Sandra P. Welch, Ph.D.
Professor
Pharmacology & Toxicology
Learning Objectives:
1.
Learn the main differentiating
property, use or side effect for the nonsteroidal aspirin substitutes.
S m i t h 7 3 4 , 8 2 8- 8 4 2 4 , s w e l c h @ h s c . v c u . e d u
2.
Understand concerns for toxicity of
NSAIDs in those with compromised renal
or liver function.
I.
General Use
A.
1.
2.
3.
4.
Similarities to aspirin
a n t i-i n f l a m m a t o r y ( i n h i b i t P G s y n t h e s i s )
analgesic,
antipyretic
antithrombotic
B. T h e y d i f f e r f r o m a s p i r i n i n t h a t
they m a y
1.
produce fewer or more side effects,
2.
have greater tissue distribution,
3.
be more potent and
4.
have a longer duration.
Unlike aspirin, they are reversible
i n h i b i t o r s o f c y c l o o x y g e n a s e.
TOXICITY CONCERNS
Individuals who are allergic to aspirin
will be allergic to other NSAIDs that
inhibit cyclooxygenase.
Some NSAID aspirin substitutes produce
fewer side effects compared to ASA (e.g.
selective COX- 2 inhibitors - less stomach
upset).
N S A I D s c a n decrease G F R i n t h o s e w i t h
renal failure, congestive heart disease or
cirrhosis of the liver.
NSAIDs can produce idiosyncratic interstitial
nephritis in a small population who are simply
“allergic” to the NSAID.
NSAIDs should be used with caution in
individuals with reduced renal or liver
function.
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Older patients may also have fluid retention
Also NSAIDs can complicate antihypertensive therapy;
exacerbating heart failure and hypertension.
The elderly also have a significantly higher rate of
in some patients they can decrease renal
function and excretion, which tends to
increase blood pressure.
N S A I D -i n d u c e d G I b l e e d i n g c o m p a r e d t o a g ematched controls not receiving NSAIDs, and often
are asymptomatic.
Additionally, memory loss
The elderly may quickly develop impaired
renal function from NSAIDs.
and other cognitive impairments
occasionally occur in the elderly.
Ranking of NSAIDs on Basis of Adverse
MORTALITY DATA FOR SEVEN SELECTED DISORDERS IN 1997.
A TOTAL OF 16,500 PATIENTS WITH RHEUMATOID ARTHRITIS OR OSTEOARTHRITIS
DIED FROM THE GASTRO INTESTINAL TOXIC AFFECTS OF NSAIDS. DATA ARE FROM
THE NATIONAL CENTER FOR HEALTH STATISTICS AND THE ARTHRITIS,
RHEUMATISM, AND AGING MEDICAL INFORMATION SYSTEM.
(N. ENGL. J. MED 340: 1888-1899, 1999)
Reaction and Deaths per Million Prescriptions
Serious reactions/million prescriptions during the first
years of marketing.
Azopropazone
87.9
Fenbufen
69.4
Piroxicam
68.1
Sulindac
54.3
Diflunisal
47.2
Fenoprofen
43.7
Naproxen
41.1
Diclofenac
39.4
Ketoprofen
38.6
Flurbiprofen
35.8
Ibuprofen
(CSM Update)
13.2
R e f : B M J 292 May 1996
PHENYLBUTAZONE (BUTAZOLIDIN)
Learning Resources:
•
An older effective anti- i n f l a m m a t o r y a g e n t
(available since 1949)
•
Was once widely used to treat inflammation
associated with rheumatoid arthritis
•
L o n g- term use is limited due to significant
side effects such as: gastric distress,
allergies, skin rashes, ulcer formation, liver
and renal dysfunction, and severe
abnormalities in various types of blood cells
7. Oxaproxin
•
Half- life is quite long (~ 2 days)
8. Ketorolac
•
Rarely used in USA, more use in veterinary
medicine (horses) and in Europe
•
Use from theft from veterinary offices
Drugs to Remember:
1. Indomethacin
2. Sulindac
3. Diclofenac
9. Celecoxib
10. Rofecoxib
4. Ibuprofen
5. Naproxen
6. Piroxicam
2
I b u p r o f e n (Motrin) (O T C - Advil, Nuprin,
M e d i p r e n, etc.
Indomethacin (Indocin)
L e s s a n t i -i n f l a m m a t o r y a c t i v i t y ( A I A ) t h a n
Potent AIA, anti-pyretic, some analgesic effect.
indomethacin,
analgesic, antipyretic, well absorbed,
99% plasma protein bound, t 1/2=2 hrs.
d y s m e n o r r h e a, r h e u m a t o i d a r t h r i t i s
( R A ) , o s t e o - a r t h r o s i s - for m i l d - m o d e r a t e
p a i n . w e l l t o l e r a t e d, f e w G I e f f e c t s .
Inhibits motility of PMNs ,
uncouples oxid. phos. in cartilage and hepatic
mitochondria. Readily absorbed, 90% plasma
protein bound,t 1/2=4 -12 hrs.
F o r R A w h e n A S A ineffect ., ankylosing
spon., acute gout, patent ductus art., Barrters
Syndrome
frontal headache,GI and hematopoetic probs., antag.
furosemide
Sulindac (Clinoril)
Diclofenac
AIA, analges, anti-pyr. Deriv. of indo
(1/2 as potent), well absorbed
Sulfoxide
Sulphone (no AIA) urine + bile
(Sulindac, Sulphide (active (t 1/ 2 =18 hrs)
pro-drug
t 1/2=7 hrs, weak)
feces
(Voltaren)
P o t e n t A I A, t 1 / 2 = 1 - 2 h r s b u t e f f e c t i v e
l o n g e r b e c a u s e a c c u m u l a t e s i n synovial fluid
RA, osteoarthritis, ankylosing
spondylitis
RA, osteoarthrosis
occasional GI effect, few headaches,
GI effects common
compared to indomethacin
Naproxen (Naprosyn
Anaprox, O T C - Aleve )
Piroxicam (Feldene)
S l i g h t l y l e s s A I A t h a n i n d o . , a n a l g e s . , a n t i - p y r. , w e l l
absorbed, absorb. ↑
↑
by NaHCO3, ↓
↓ b y A l ( O H )3 a n d
antacids .
9 8 % plas. p r o t . bound,
t 1 / 2 = 1 0 - 17 hrs .
Good AIA, long plasma t 1/2=20 - 40 hrs.
RA, osteoarthrosis
Excreted in urine unchanged, demethylated or as
glucuronide conj.
RA
better tolerated than ASA or indo. Some GI
probs.
occasional GI effect
3
Ketorolac(Toradol)
Cyclooxygenase inhibitor with strong analgesic properties
Oxaproxin
which are likely not due to CO inhibition
(Daypro)
but rather
another mechanism, perhaps at opioid receptors?
G o o d A I A , l o n g p l a s m a t 1 / 2 = 5 0 -6 0 h r s ,
1/dayRA, osteoarthritis, ankylosing spondylitis
Can replace or reduce morphine and
meperidine use which, unlike ketorolac, cause
respiratory depression.
oral and injectable (IM) for acute pain, postoperative analgesia, adjunct use in surgery. Also
good for those who cannot or should not be given
opioids. Not used for chronic inflammation
relatively minor, same as other CO inhibitors, not
for obstetrical use
O T H E R Side effects: excessive bleeding (due to platelet inhibition),
and renal failure (minimized by limiting the use of the drug to 24 -48
hrs after surgery)
Celecoxib (Celebrex) Rofecoxib (Vioxx)
Selective COX- 2 inhibitor at normal
therapeutic doses .
Celebrex®
December 30, 1998
N D A 2 0 - 9 9 8 ( C e l e c o x i b)
C O X -2 is expressed constitutively in brain
and kidney and induced in other tissues
during inflammation.
Minimal activity on COX-1, which forms
cytoprotective GI PGs and forms the
p r e c u r s o r t o t h r o m b o x a n e A2 , w h i c h i n d u c e s
platelet aggregation.
Plasma t 1/2 = 11 hrs. Metabolized by
cytochrome P2C9.
FDA approved for osteoarthritis and RA
Like other NSAIDs except less GI ulcers and
452 volumes x 400 pages/volume = 180,800 pages !!!
little/no effect on bleeding time
Pain Control - Acetaminophen
Learning Objectives:
1. Understand the therapeutic uses for
acetaminophen and how they differ from aspirin and
aspirin substitutes.
2 . K n o w t h e m a i n t o x i c s i d e-effects of
acetaminophen overdose and the antidote for
acetaminophen overdose
NSAIDs
To use or not to use?
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Pain Control - Acetaminophen
I.
Pain Control - Acetaminophen
Table 29-2. STRUCTURAL FORMULAS
OF MAJOR PARA-AMINOPHENOL
DERIVATIVES, AND THEIR
INTERRELATIONS
Acetaminophen
A c e t a m i n o p h e n i s n o t a n a n t i -i n f l a m m a t o r y o r a n t i -
NHCOCH
NHCOCH
3
NHCOCH
3
3
t h r o m b o t i c a g e n t, b e c a u s e i t d o e s n o t i n h i b i t s y s t e m i c
cyclooxygenase.
It is however equal to aspirin in
analgesic and antipyretic properties.
Acetaminophen
OH
Acetaminophen
Acetanilid
( T y l e n o l ®, T e m p r a ® )
NH
NHCOCH
2
OC H2 5
Phenacetin
NH
3
2
Phenacetin - chemically related to acetaminophen and
once prevalent in many OTC agents.
Its use is no
longer advised since phenacetin is believed to cause
Aniline
analgesic nephropathy.
O R
Conjugated Acetaminophen
R = glucuronate (major)
sulfate (minor)
OC H2 5
Para-Phenetidin
Methemoglobin-Forming and Other Toxic Metabolites
C.
B.
Acetaminophen Absorption, Distribution
and Excretion
Pharmacological Effects
Analgesic and antipyretic,
equals aspirin,
1.
a b s o r p t i o n - r a p i d a n d c o m p l e t e i n 1/2 – 1 h r
2.
p l a s m a t 1 / 2 =1 - 3 h r s
3.
metabolized by liver microsomal enzymes
4.
80% excreted in urine after liver
MOA - unknown
Doesn’t inhibit platelet aggregation, therefore is not
useful for prevention of vascular clotting or for
prophylaxis against heart attacks or stroke
conjugation predominantly with
glucuronic acid
D.
Toxicity - Very well tolerated in recommended
doses, although elderly people may experience
ACETAMINOPHEN
toxicity at lower doses than younger adults.
However, overdose effects serious, including hepatic
necrosis a n d d e a t h d u e t o f o r m a t i o n o f t o x i c
metabolite by liver P450 metabolism of
acetaminophen.
A n t i d o t e - N- a c e t y l c y s t e i n e ( M u c o m y s t ® ) w h i c h i s a n
oxygen free radical scavenger and promotes
formation of glutathione. Glutathione promotes
detoxification and elimination of P450 metabolite.
glucuronide or
sulfate metabolite
P450 mixed
function oxidase
overdose
N -acetyl
cysteine
normally
toxic intermediate
hepatic
glutathione
glutathione
intermediate
covalent bonding to
hepatic protein
mercapturic acid
cell death
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There has been some concern about the simultaneous use of
acetaminophen and alcohol.
Regular use of alcohol may lower
the threshold for acetaminophen induced liver damage because it
induces the enzymes that catalyze
oxidative metabolism of
acetaminophen and
thus may more readily form the toxic P450
m e t a b o l i t e N- a c e t y l - b e n z o q u i n o n e i m i n e .
In addition, alcoholics may have depleted stores of
glutathione and an already damaged liver.
However
the risk of regular or sporadic use of acetaminophen in
patients who regularly drink moderate amounts of
alcohol is not clear.
E.
Therapeutic use -
ASA substitute for analgesic and antipyretic effects only.
LEAR NING RE SOURCES :
Drugs to Re member:
1.
2.
Acetaminophen
N-acetyl cysteine
Recommended Reading:
1.
2.
Basic and Clinical Pharmaco logy, B.G. Katzung (ed.), 8th ed., 2001.
Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Hardma n
and Limbir d (eds.), 10th ed., 2001.
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