NSAIDS n o n-salicylates

Sandra P. Welch, Ph.D. Professor Pharmacology & Toxicology 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

Learning Objectives:

1. Learn the main differentiating property, use or side effect for the nonsteroidal aspirin substitutes. 2. Understand concerns for toxicity of NSAIDs in those with compromised renal or liver function.

I. A. 1. 2. 3. 4.

General Use 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). NSAIDs should be used with caution in individuals with reduced renal or liver function. 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.

Also NSAIDs can complicate antihypertensive therapy;

Older patients may also have fluid retention 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.

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)

Ranking of NSAIDs on Basis of Adverse Reaction and Deaths per Million Prescriptions
Serious reactions/million prescriptions during the first years of marketing. Azopropazone Fenbufen Piroxicam Sulindac Diflunisal Fenoprofen Naproxen Diclofenac Ketoprofen Flurbiprofen Ibuprofen (CSM Update) 87.9 69.4 68.1 54.3 47.2 43.7 41.1 39.4 38.6 35.8 13.2 R e f : B M J 292 May 1996

Learning Resources: Drugs to Remember: 1. Indomethacin 2. Sulindac 3. Diclofenac 4. Ibuprofen 5. Naproxen 6. Piroxicam 7. Oxaproxin 8. Ketorolac 9. Celecoxib 10. Rofecoxib

PHENYLBUTAZONE (BUTAZOLIDIN)
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 Half- life is quite long (~ 2 days) Rarely used in USA, more use in veterinary medicine (horses) and in Europe Use from theft from veterinary offices

I b u p r o f e n (Motrin) (O T C - Advil, Nuprin, M e d i p r e n, etc. 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 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 .

Indomethacin (Indocin)
Potent AIA, anti-pyretic, some analgesic effect. 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 (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 GI effects common

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
RA, osteoarthrosis occasional GI effect, few headaches, 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. antacids . 9 8 % plas. p r o t . bound, t 1 / 2 = 1 0 - 17 hrs . Excreted in urine unchanged, demethylated or as glucuronide conj. RA occasional GI effect b y N a H C O 3 , b y A l ( O H )3 a n d

Good AIA, long plasma t 1/2=20 - 40 hrs. RA, osteoarthrosis

better tolerated than ASA or indo. Some GI probs.

Ketorolac(Toradol) Oxaproxin (Daypro) 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

Cyclooxygenase inhibitor with strong analgesic properties which are likely not due to CO inhibition but rather another mechanism, perhaps at opioid receptors?

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?

Pain Control - Acetaminophen

I. Acetaminophen

Pain Control - Acetaminophen

Table 29-2. STRUCTURAL FORMULAS OF MAJOR PARA-AMINOPHENOL DERIVATIVES, AND THEIR INTERRELATIONS NHCOCH NHCOCH NHCOCH

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 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 ( T y l e n o l , T e m p r a ) Its use is no

Acetanilid

OH Acetaminophen

OC H 2 5 Phenacetin

NH

NHCOCH

NH

Phenacetin - chemically related to acetaminophen and once prevalent in many OTC agents. analgesic nephropathy. longer advised since phenacetin is believed to cause
Aniline

O R Conjugated Acetaminophen R = glucuronate (major) sulfate (minor)

OC H 2 5 Para-Phenetidin

Methemoglobin-Forming and Other Toxic Metabolites

C. B. Acetaminophen Absorption, Distribution and Excretion

1. 2. 3. 4. 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 p l a s m a t 1 / 2 =1 - 3 h r s metabolized by liver microsomal enzymes 80% excreted in urine after liver conjugation predominantly with glucuronic acid

Pharmacological Effects

Analgesic and antipyretic, equals aspirin, MOA - unknown

Doesnt inhibit platelet aggregation, therefore is not useful for prevention of vascular clotting or for prophylaxis against heart attacks or stroke

D.

Toxicity - Very well tolerated in recommended

ACETAMINOPHEN normally glucuronide or sulfate metabolite

doses, although elderly people may experience 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.

overdose

P450 mixed function oxidase

N -acetyl cysteine

toxic intermediate

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.

hepatic glutathione

glutathione intermediate

covalent bonding to hepatic protein

mercapturic acid

cell death

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 R member: e 1. 2. Acetaminoph en N-acetyl cysteine

Recommended Reading: 1. 2. Basic and Clinical Pharmaco logy, B.G. Katzung (ed.), 8th ed., 2001 . Good man and G ilmans The Pharmacological Basis of The rapeutics, Hardma n and Limbir d (eds.), 10th ed., 2001.