NSAIDS = Non-steroidal anti-inflammatory drugsNSAIDS = Non-steroidal anti-inflammatory drugs

Dr. Christine PrattCellular and Molecular MedicineRoom 3107 RGNcpratt@uottawa.ca

Increased platelet aggregration Reduced platelet aggregation

leukotrienes

Renal effects

Blood pressureBlood pressure& platelet agg& platelet agg

Plateletaggregation

NSAIDs

*

VasoconstrictionBronchconstriction

1) Carboxylic Acids         a) Salicylic Acids & Esters                    acetylsalicylic acid/ASA (Aspirin®)                    Diflunisal         b) Acetic Acids                    i) Phenylacetic Acids                            Diclofenac- topical                    ii) Carbo- and Hetero-Cyclic Acetic Acids                           Indomethacin (Indocin®)                           Ketorolac-parenteral formluation                           Sulindac                           Tolmetin         c) Propionic Acids                           Flurbiprofen                           Ketoprofen                           Tiaprofenic Acid                           Ibuprofen (generic/Motrin®)                           Naproxen (Alleve®)                           Fenoprofen         2) Enolic Acids

 a) Pyrazolones                           Phenylbutazone b) Oxicams                           Piroxicam (Feldene®) 

Propionic Acids:

Ibuprofen

•Indicated for rheumatoid arthritis and dysmenorrhea•Tends to accumulate in synovial fluid

• Indicated for numerous inflammatory conditions including rheumatoid arthritis and gout

• 10-20X more potent than ASA

Naproxen

Oxicams:

Piroxicam•prolonged half-life (30-85hrs) due to active entero-

hepatic circulation•as effective as indomethacin in treatment of

rheumatoid diseases but very goodpatient compliance

NSAIDs are non-Cox-selective

Salicylate

-first recognized medicinal properties ofwillow bark (salicin) ~1750- purified in 1829- also found in other plants including spirea, wintergreen

Dr. Hoffman, a chemist employed by Bayer was the first to synthesizeacetylsalicylic acid (ASA/aspirin) 1897

St. Aspirinia- the patron saint of “headaches”

Mechanism of action of Aspirin

Serine 530 in COX-1/Serine 516 in COX-2

Arg120 Arg 120

Val 523Iso 523

NSAIDs block the opening of both COX-1 and COX-2 byinteracting with Arg 120 in both enzymes in a reversible manner

COXibs block only the opening of the COX-2 enzyme inan irreversible manner

Cox-2 selective (COXibs)

Non-selective NSAIDs

Celebrex(Pfizer)

Vioxx(Merck)

Valdecoxib(Bextra)Not shown

UK

Prostaglandins in acute/chronic inflammation:

Hallmarks- heat, redness, edema, pain

PGE1PGE2PGI2

Induce or augment 4 signs of inflammation

PGs are involved in the late phase of inflammation

-local heat, vasodilation in most compartments-increase vasopermeability, platelet aggregation at siteof injury

So it would seem that the Coxibs would make fabulousanti-inflammatory drugs but….

All is not wonderful for big pharma…..

Merck to Pay $950 Million Over VioxxBy DUFF WILSON

Merck has agreed to pay $950 million and has pleaded guilty to a criminal charge over the marketing and sales of the painkiller Vioxx, the company and the Justice Department said Tuesday. The negotiated settlement, which includes resolution of civil cases, was the latest of a series of fraud cases brought by federal and state prosecutors against major pharmaceutical companies. By the time Vioxx, which was approved by the Food and Drug Administration in 1999, was pulled off the market in 2004 because evidence showed that it posed a substantial heart risk, about 25 million Americans had taken the drug. In a statement on Tuesday, Merck said that it had previously disclosed the seven-year investigation by the United States attorney in Massachusetts and had charged $950 million against its earnings in October 2010. Merck agreed to pay a $321 million criminal fine and plead guilty to one misdemeanor count of illegally introducing a drug into interstate commerce, the Justice Department said in a news release. The charge arose from Merck’s promotion of Vioxx to treat rheumatoid arthritis before the Food and Drug Administration approved it for that purpose in 2002. Merck also is paying $426 million to the federal government and $202 million to state Medicaid agencies. Those payments will settle civil claims that its illegal marketing caused doctors to prescribe and bill the government for Vioxx they otherwise would not have prescribed. Physicians are free to prescribe drugs for any purpose they see fit, but pharmaceutical companies are prohibited from marketing them for any uses except those that the Food and Drug Administration has determined are safe and beneficial. “When a pharmaceutical company ignores F.D.A. rules aimed at keeping our medicines safe and effective, that company undermines the ability of health care providers to make the best medical decisions on behalf of their patients,” Tony West, assistant attorney general of the Justice Department’s civil division, said in a statement. Merck, based in Whitehouse Station, N.J., withdrew Vioxx from the market in more than 80 countries in 2004 after a clinical trial showed it doubled the risk of heart attack, stroke and death. In 2007, Merck agreed to pay $4.85 billion to settle 27,000 lawsuits by people who had claimed they or their relatives had suffered injury or death after taking the drug. Merck has also signed a corporate integrity agreement in connection with the settlement, promising to monitor future promotional activity and report back regularly to the government. Merck joins Pfizer and most other major drug companies in settling long investigations with prosecutors. No person was held liable for Merck’s conduct. “It’s just a cost of doing business until a pharmaceutical executive does a perp walk,” said Erik Gordon, a pharmaceutical analyst and clinical assistant professor at the Ross School of Business at the University of Michigan. Investors are also suing Merck, saying it played down the risks of Vioxx and cost them billions of dollars in stock value after the drug was removed from the market. Merck shares declined most of the day on Tuesday, dropping 0.97 percent to $33.81.

A version of this article appeared in print on November 23, 2011, on page B1 of the New York edition with the headline: Merck to Pay $950 Million Over Vioxx.

PGI2 (prostacyclin) is anti-thromboticTXA2 (thromboxane) is pro-thrombotic

Why????

Aspirin, NSAIDS, COXibs and Stroke:

TxA2 –platelets contain COX-1which is inhibited by low dose aspirin without effecting COX-2 (anti-thrombotic effect)

COXib inhibition of COX-2 only results in reduced PGI2 (mostly from endothelium) therefore preventing its anti-thrombotic activity (pro-thrombotic effect)

NSAIDS inhibit both COX-1 and COX-2 therefore the pro and anti-thrombotic effects are balanced.

Cox-2Cox-2

Cox-2

Cox-2 Cox-2 Cox-2

Cox-2 Cox-2Cox-2 Cox-2

Cox-2

Cox-2

Cox-1 PGI2TXA2PGI2PGI2

TXA2 TXA2

TXA2PGI2 Cox-1

endothelial cells

platelets

Both coxibs and non-selective NSAIDs can produce acuteBoth coxibs and non-selective NSAIDs can produce acuterenal failure and renal hypertension by 2 mechanismsrenal failure and renal hypertension by 2 mechanisms

i) Decreasing renal blood flow by inducing leukotriene production

ii)ii) Prostaglandins reduce Na+ retention in the kidney Prostaglandins reduce Na+ retention in the kidney and thus increase Na+ excretion in the urineand thus increase Na+ excretion in the urine -since H-since H22O follows that Na+ out of the body thisO follows that Na+ out of the body this

maintains normal blood volume and therefore normalmaintains normal blood volume and therefore normalblood pressureblood pressure

- blood pressure helps determine the glomerular filtration rate- blood pressure helps determine the glomerular filtration rate(GFR)(GFR)

So NSAIDs and COXibs can:So NSAIDs and COXibs can:

1- Increase [Na+] and blood pressure-peripheral edema1- Increase [Na+] and blood pressure-peripheral edema

2- reduce GFR 2- reduce GFR (NB.(NB. GFR is a function of hydrostatic & osmoticGFR is a function of hydrostatic & osmotic pressures and vessel permeability)pressures and vessel permeability)

Celecoxib should not be prescribed to patients with cardiovascular disease or diabetes or those at increased risk of cardiovascular events.

Celecoxib should be used in the lowest effective doses for short periods (weeks) only. A risk–benefit discussion is necessary for those requiring the drug for a longer period.

AA PGE2 PG receptor on acid-secreting parietal cell

COX1

Signals activatingproton (acid) pumps

NSAIDs/aspirin

Effects of NSAIDs on the stomach mucosaEffects of NSAIDs on the stomach mucosa

H+

Stomach lumen

Mesoprostol

Risk of GI complications with various NSAIDs

(relative to Ibuprofen ,risk= 1)

Ibuprofen

Aspirin-induced asthma and urticaria

-in up to 10% of people with bronchial asthma ASA (and otherNSAIDs) induce asthma attacks

COX-1 and -2 expressed in respiratory epithelium:- COX-1 inhibition most potently induces bronchospasm but COX-2 inhibitors are well tolerated- asthmatic response most likely related to inhibition of PGE2 production

- NSAIDs also result in production and release of Cys-leukotriene resulting in bronchoconstriction- skin reaction may have a similar etiology

Potential Side Effects of NSAIDsPotential Side Effects of NSAIDsand COXIBsand COXIBs

AA- GI upset- GI upsetBB- Aspirin/ NSAIDs-induced asthma- Aspirin/ NSAIDs-induced asthmaCC- Reyes syndrome- Reyes syndromeDD- Dose-dependent urate- Dose-dependent urate accumulationaccumulationEE- high BP/ renal failure/ stroke- high BP/ renal failure/ strokeFF- bleeding- bleeding

FEVER

+ +

Partial depolarization (sensitization)

2-arachidonoylglycerol

In brain, liver, and lung……in relatively low levels

monoacylglycerol lipase

arachidonic acid

PGs

COX-1/2

WHY??? In brain, liver, and lung:

•therapeutic concentrations of acetaminophen inhibit COX-1/2 activity when the levels of arachidonic acid and peroxide are low

•little effect when the levels of arachidonic acid or peroxide are high ie. severe inflammatory conditions such as RA

•acetaminophen also inhibits prostaglandin synthesis by scavenging peroxynitrite, an activator of COX

Acetaminophen (a para-aminophenolAcetaminophen (a para-aminophenol) )

• Originally derived from coal tar• NOT an anti-inflammatory drug but great for headaches

Max 4 g/day Max pediatric : 65 mg/kg/dayMax geriatric: 2-3g/day??

Mechanism of long term high dose liver toxicity

NSAID case

E.J. is a 73 year old man who has been admitted to hospital because of a fractured hip that occurred after he tripped on a carpet at home. The orthopaedic surgeon has booked him for surgical repair. The patient’s past medical history is significant for hypertension (high blood pressure), myocardial infarction (heart attack), type II diabetes mellitus and chronic renal insufficiency (kidney failure). His current medications include: acetylsalicylic acid (ASA), ramipril (angiotensin converting enzyme inhibitor) and glyburide (oral hypoglycemic agent). The orthopaedic surgeon has ordered naproxen (NSAID) in addition to hydromorphone (opioid) for pain management.

1. Does this patient have any contraindications to the use of naproxen? If so, what is the mechanism by which a NSAID drug could make his condition(s) worse? What are the contraindications to using NSAIDs? Use a diagram showing conversion of arachidonic acid to its various metabolites to explain the rationale for these contraindications.

2. After speaking to the orthopaedic surgeon, you convince him that the patient is not a good candidate for NSAIDs. The surgeon prescribes acetaminophen (Tylenol) instead. Does acetaminophen have the same contraindications as NSAIDs. Why/why not? Is acetaminophen safe to administer to this patient?

3. The patient complains of stomach upset after taking naproxen. What is the mechanism of stomach upset with NSAIDs? Is there any way to treat or prevent this side effect? What other adverse effects must you watch for in a patient on NSAIDs?

DMARDsDMARDs = disease modifying anti-rheumatic drugs= disease modifying anti-rheumatic drugs

Cell processes and secreted products are therapeutic targetsin inflammation/RA

Monocytes are attracted to the rheumatoid arthritis (RA) joint, where they differentiate into macrophages and become activated.

Macrophages play a central role in arthritic disease.

Dendritic cells process and present synovial proteoglycan (aggrecan ) to T cells to stimulate them to make cytokines and develop into cytotoxic cells.

Dendritic cells (APCs)

T cell

Immune Cells involved in Rheumatoid arthritisImmune Cells involved in Rheumatoid arthritis

IL-2IL-1

macrophage

1-Macrophages make and secreteTNFα and Interleukin 1 (IL-1)

2-Fibroblasts and bone cells in the jointhave TNFα receptors that respond to TNFα and ( and IL-1) to secretemediators of tissue destruction

3-endothelial cells respond to TNF andIL-1 by promoting the adhesion andretention of white blood cells at the site

4-IL-1 stimulates IL-2 production by T cells to further promote T-cellexpansion and maturation.

In rheumatoid arthritis:

1

2

3

IL-2

T-cellexpansion

4

& otherInflammatoryconditions

“decoy receptor”

Golimumab “Simponi” is similar to Humira

“Remicade”

“Enbrel”

“Humira”

Certolizumab   ’Cimzia’

Not available(TNFRII)

(TNFRI)

Infliximab: IV every 4-12 weeks Adalimumab: 40mg s.c. 2X per day

Etanercept: s.c. 2X per week $$$

Clinical Applications:

RA, Crohn’s, IBDankylosing spondylitispsoriasis

Mostly used for RArefractory to other DMARDs

All are often used together with methotrexate or sulfasalazine.

Complications: serious infections/sepsis and some unexplainedmalignancies including lymphomas and cutaneous(squamous cell) cancers

Kineret® (anakinra) is a recombinant proteinthat mimics the body’s own antagonist of IL-1(IL-1a) -inhibits binding of IL-1 to the IL-1 receptor-often used in combination with MTX-daily s.c. injections-side effects: Injection site reaction, infection headache,nausea

Other DMARDs

Cyclosporin (also tacrolimus)

Functions of IL-2:-maturation and expansion ofantigen-stimulated T cells

-activates macrophages

Transcription of the interleukin-2(IL-2 gene)

CyclosporinCyclosporin

Tolypocladium inflatum

-derived from mold

Methotrexate’s therapeutic and toxic effects are a result of its ability to limitDNA and RNA synthesis by inhibiting dihydrofolate reductase and thymidylatesynthetase. Dihydrofolate reductase reduces folic acid to tetrahydrofolate, an essentialco-factor in the synthesis of purine nucleotides.

MethotrexateMethotrexate

-reduction of nucleic acid synthesis prevents T cell expansion

-usually well tolerated but can cause adverse GI, hematologic, hepatic reactions-benefits within 3-4 weeks

……Methotrexate (MTX)

LeflunomideLeflunomide

-newer drug-active metabolite formed in intestine and liver-inhibits pyrimidine biosynthesis-marketed as an alternative to MTX

HydroxychloroquineHydroxychloroquine

• Hydroxychloroquine is a 4-aminoquinoline antimalarial with actions similar to those of chloroquine but is mainly used in the treatment of SLE and rheumatoid arthritis

• increases cellular pH and thereby interferes with proteolysis and proper antigen presentation by APCs (macrophages)

• inhibits Ca2+ signaling in T cells necessary for activation

SulfasalazineSulfasalazine

-is a combination of 5-amino salicylic acid with theantibacterial drug sulfapyridine-is a prodrug, that is broken down by bacteria in the colon into 5-ASA and sulfapyridine

-mechanism not really known….although sulfapyridinecan cause folate deficiency….hmmm..as a “side effect”

AzathioprineAzathioprine

• Metabolized to mercaptopurine (a purine analogue) which inhibits DNA synthesis

• inhibits clonal expansion (cell division) of both B and T cells during the induction phase of the immune response

• also used as immunosuppressant during transplantation

• quite well tolerated however- rare skin diseases, “Stevens-Johnson” syndrome and toxic epidermal necrolysis, can occur

Stevens-Johnson Syndrome

Therapeutic gold compounds:Therapeutic gold compounds:

●Gold sodium thio-malate (GST), which contains almost 50 percent gold in a water-based solution and is administered by intramuscular (IM) injection every one to four weeks.

●Auranofin, which is a gold triethylphosphine compound taken orally each day.

Cox-2hyaluronansynthase

Cytokines(ie. IL-1)

NF-kB NF-kB

Au Au

X X

Synovial fibroblasts

Canadian Rheumatology Association

-joint damage occurs early in RA-aggressive therapy with DMARDs has a lasting effecton prevention of damage and long term outcome

DMARD case

F.S. is a 63 year old woman who has been diagnosed with rheumatoid arthritis. It has affected many of the joints in her hands and is quite painful. Her past medical history is unremarkable. She has been taking acetaminophen (Tylenol) for the pain but does not find it very effective. Her rheumatologist has prescribed celecoxib (a COX-2 inhibitor) and methotrexate.

1. What are possible reasons her rheumatologist has ordered celecoxib over other NSAIDs?

2. Why do you think celecoxib would be more effective at treating her pain than acetaminophen?

3. Why did the rheumatologist order both celecoxib and methotrexate?

4. Methotrexate is only one of a broad class of drugs called ‘DMARDs’. What does the term DMARD stand for?

5. Name 5 drugs, other than methotrexate, that belong to this category (please refer to the Lange Basic and Clinical Pharmacology textbook, Chapter 36 in the 10th and 11th editions). What is the mechanism of action of each of these drugs? What do all these drugs have in common with respect to mechanismof action?

6. What are side effects or potential issues common to all DMARD drugs?

What is Gout?What is Gout?

• Metabolic disease involving increased plasma urate concentration

• Can be precipitated by various factors including alcoholic beverages (beer lovers beware!!), increased cellular turnover and defects in urate excretion.

• Intermittent attacks of gouty arthritis as a result of deposition of urate crystals in synovial space

• Strong neutrophil response

Treatment of Gout:

Often a combination of NSAIDs and disease modifying drugs

100% of serum urate isfiltered through glomerulusthen secreted into tubule

PROXIMALTUBULE

excretion

URAT1transporter

Probenecid& high doseAspirin

XLow Dose Aspirin

X90% readsorption

GLOMERULUS

Allopurinol prevents urate synthesis (used for over-production of urate)- drug interaction with azathiaprine (prevents catabolism)

Probenicid prevent resorption of urate in the kidney (usedfor under-excretion of urate

Drugs for the treatment of Gout with different Mechanisms of action

Colchicine….. another optionColchicine….. another option

• derived from crocus

• prevents migration of neutrophils by binding to and depolymerizing microtubules

• can be used therapeutically as an acute treatment in gouty arthritis

•can cause nausea, vomiting, diarrhea, cramps.

Gout case

Y.C. is a 39 year old man who presents to your office complaining of severe pain in his left great toe. This had occurred once before, he was told it was gout, and he said he was given a prescription for some kind of medicine which worked well for the pain. He said he was also given another prescription to take every day after the pain went away, but he never got the prescription filled. He is otherwise healthy. His daily urate excretion rate was determined to be 950mg/day (~800mg is normal).

1. What class of medication do you suspect he was given for pain? Why? Are there any other medications that can be used for acute gouty arthritis? What are the mechanisms of action of these two classes of medications?

2. What medication/class of medication should be used to prevent further attacks of gout? How does this medication work? Are there any significant side effects that you need to warn the patient about?