Pharmacology of NSAIDs

What are the 4 main classes of effects NSAIDs have?

What was the original NSAID? How do NSAIDs differ from one another?

How can NSAIDs be classified?

1) Anti-inflam

- used for gout, RA, and OA

2) Analgesic

- used for headache, dental pain, joint pain, and in combo with opioids (which allows for reduced dose of opioid)

- typically secondary effect to anti-inflam

3) Anti-pyretic

- used for fever

- typically secondary effect to anti-inflam

4) CV

- anti-plt activity

Aspirin (ASA) was OG NSAID... now there have been many mods but ASA is still the best anti-plt NSAID

- in general, NSAIDS are chemically diverse

- They share very similar mechanisms of action (very similar to ASA)

- Due to their different chemical structures their P.Kinetics are different (but they still target the same enzymes)

Can be classified according to: chemical similarity, COX selectivity, and PK properties

-Objective was to design COX-2 selective drugs for a while to target inflam while keeping housekeeping role in tact (i.e., celecoxib)

What is inflam?

What are the 5 characteristics of inflam?

What are mediators of inflam?

What are the two main consequences of inflam?

A response by living, vascularized tissue designed to remove some injurious agent (including mechanical, chemical, thermal, radioactive etc.)

--> Reaction to injurious agent almost always involves a change in blood flow so that more WBC, RBC, and macrophages get to the area of injury and repair it

- Inflam is essentially a mechanism to restore tissue to normal

- Inflammation involves a reaction of the vasculature that is characterized by the movement of leukocytes and fluid from the blood into tissue

Characteristics:

Redness: Caused by increased blood flow

Swelling: Caused by fluid retention/edema

Heat: Caused by increased blood flow

Pain: Caused by impingement/pressure on local nerves

Loss of function: excess of all of the above

Mediators:

1)Histamine

- Released by mast cells in tissue and platelets in blood

2)Prostaglandins

- The initial cause of the injury is thought to increase arachidonic acid availability with a subsequent increase in prostaglandin production

-Prostaglandins cause peripheral vasodilation with redness and edema (partly due to bradykinin activation)

3)Bradykinin

4)Serotonin

--> these mediators are important to know because we can target them with drugs

--> they also lead to a super coordinated and robust response

Pain (often) and fever (sometimes)

What modulates pain?

How do NSAIDs restore body temp when fever occurs? Illustrate by explaining the mechanism of fever in the body

How do we treat inflam?

Activation of nociceptors (pain receptors)

- Either mechanical or chemical induction

--> Inflammatory mediators can directly induce pain (histamine, kinins) or can decrease pain threshold (histamine, PGE2 and PGI2)

How NSAIDs restore body temp:

- when there is an infection where you have microorg invasion, the immune sys recognizes it and phagocytizes that organism...

- when this happens there is a signal to release lymphokines and cytokines

- these molecules activate leukocytes which are amazing at secreting other signalling factors including IL-1

-IL-1 then travels through the body goes to brain, hypothal (temp control region) responds to this by release PGE2 which is impt for controlling temp regulatory center in brainstem, regulatory center then causes characteristic responses with fever (vasoC of the skin, decreased heat loss, increased heat generation (shivering), increased body temp

-NSAID inhibits production of PGE2 and then as a result restores temp to normal

TWO MAJOR GOALS OF ANTI-INFLAMMATORY THERAPY:

1.Relief of pain and other symptoms

2. Slowing or arrest of tissue damaging process (especially in chronic inflammatory condition)

-->Key is to avoid side effects

Describe the PK and PD (MOA) NSAIDs.

T or F? NSAIDs are superior to GCs in terms of anti-inflam activity

PK:

-Very high oral bioavailability

-Well absorbed (bc they are almost always weak acids)

-Highly metabolized; phase I + phase II enzymes

-Primarily renally eliminated

-Some biliary excretion/enterohepatic circulation

-Very highly protein-bound (principally albumin)

--> Because they are highly protein bound they can displace other proteins that are protein bound and thereby increase AUC of those other drugs

PD:

- Competitive inhibitors of the binding of cyclooxygenase to AA (in contrast to ASA which acts irreversibly)

--> AKA COX inhibitors

- Inhibit the production of prostaglandins

--> this is good when it comes to inflam but not good for house keeping PGs from COX1

- Thus drugs have been developed (coxibs) that selectively inhibit COX2

**Mechanisms of anti-inflam goes beyond inhibiting COX although this is the main MOA

-Bradykinin and histamine have vasoactive effects so NSAIDs decrease vessel sensitivity to these agents and reverse vasoD

-Have effect directly on inflam cells: they are able to inhibit the release of lymphokines (inflammatory agents) from those cells

False!

-Good anti-inflam drugs... not as good as glucocorticoids but they come with less AEs than them

How are PGs synthesized? Which PG is mostly involved in inflam?

What are the main therapeutic uses of NSAIDs?

How does aspirin have cardioprotective effects? Similarly, how does ASA differ from other NSAIDs?

Arachidonic acid acted on by COX 1 and 2 to produce PGs.

--> PGE2 is the predominant PG involved in inflam... this isn't well validated with experiments however

Therapeutic Uses of NSAIDs:

1) Anti-Inflammatory Drugs

-Arthritis, Gout

2) Antipyretics

-inhibit effect of PGs in hypothalamus

3) Analgesics

-very effective for low to moderate pain (dental pain)

-when used in combination may reduce the concentration of opioids

4) Fetal Circulation

-used to close patent ductus

5) Cardioprotection

-aspirin is an antiplatelet drug and offers protection from cardiovascular disease

6) Niacin Tolerability

- niacin is an effective LDL- and triglyceride-lowering medication but its use is associated with a flushing reaction; NSAIDS reduce the flushing

7) Cancer Prevention

aspirin significantly reduces risk of colon cancer

-Plts are cell fragments important in coagulation... they need to get activated

-They circulate around and their job is to respond to injury in BV so if there is injury plts become activated and after this their job is to recruit other platelets and block the injury

-Plts become sticky and release proactivating chemicals of which thromboxin is a part of

-Thromboxin is activated and recruits and activates oteher plts

-So thromboxin is also produced from COX activity

-If we inhibit COX with NSAIDs thromboxin doesn't get produced and thus anti-plt effects

-This is useful therapeutically to reduce thrombotic events in those susceptible to this (reduces stickiness of platelets)... usually use asa in this case

-Asa is diff from other nsaids especially in use with plts because its irreversible... irreversibly inhibits COX and this is important because plts aren't proteins and they don't have a nucleus and thus cant produce new proteins

-So if you irreversibly inhibit the enzyme that makes them theres no way more can be fromed

-Eliminate function of that plt forever

-ASA is thus successful anti-plt agent

What are NSAID AEs due to reduce PGs?

What are the CV and Renal AEs?

PGs are very protective in the stomach so if we take chronic NSAIDs we reduce that protection and increase risk of ulcers (reversible erosive gastritis)

Thus we want cox-2 selectivity because cox1 is what leads to protective PGs (and we don't want to block those)

Renal:

- PGs have an important role in controlling renal perfusion and ion reabsorption (maintenance of kidney dynamics)

- if we decrease PGs there will be changes in GFR and chronic increase in risk of irreversible kidney damage

- concerning in elderly who already have kidney damage

- in other words, NSAIDS have effects on renal blood flow so will have long term toxicities and changes in fluid dynamics

- in patients with CHF, hypovolemia (low ECF vol), and chronic kidney disease, inhibition of PGs can lead to altered renal blood flow and salt retention

CV:

-associated with COX-2 selective drugs; likely due to decreased PGI2 (prostacyclin) which is protective against thrombotic events

- known to have interactions with anti-hypertensives like ACEIs

- hypertension because of fluid retention and fluid retention because of renal effects

List common NSAID AEs in the following systems:

1) GI

2) Plts

3) Renal

4) CV

5) CNS

6) Uterus

What are common contraindications or drug interactions fro NSAIDs?

1) GI

- Abdominal pain, nausea, diarrhea, anorexia, ulcers

2) Platelets

- Inhibited platelet activation, increased bruising, increase hemorrhage

3) Renal

- Salt and water retention, edema, decrease effectiveness of antihypertensive drugs including diuretics and ACE inhibitors,

- Hyperkalemia, decreased urate excretion

4) CV

- Closure of ductus arteriosus, (MI, stroke, thrombosis for COX2 selective)

- potential to increase stroke and MI

5) CNS

- Headache, vertigo, dizziness, confusion, hyperventilation

Uterus

Prolongation of gestation, inhibition of labor

Contraindications/ Drug Interactions

-due to anti-platelet effects ASA should not be used in hemophiliacs (bleeding disorder where blood doesn't clot properly)

-All NSAIDS may enhance the anticoagulant effect of Warfarin (NSAIDs inhibit cyp2C9 which is how warfarin is metab)

-NSAIDS may reduce antihypertensive effects of ACE inhibitors/caution with hypertensive individuals particularly if individual is being maintained on ACE inhibitors, ARBs and diuretics

-not to be used during pregnancy

-aspirin should not to be used in children after viral infection (due to danger of Reye's)

-High protein binding may result in the displacement of other drugs and therefore toxicity

Describe the PK of aspirin

Describe diclofenac.

Describe Indomethacin

Pharmacokinetics of Aspirin

-organic acid; pKa 3.5 (highly acidic)

-Rapidly absorbed from stomach and upper small intestine

-Peak plasma salicylate levels are reached in 1-2 hours

-Rapidly hydrolyzed to acetic acid and salicylate (half-life 15 minutes)

-Highly bound (saturable) to albumin (may displace other drugs)

-Metabolic pathways for salicylate disposition saturate at 600 mg; beyond this, dosage increases increase salicylate concentration

--> not used for anti-inflam effects as much, moreso as anti-plt

--> narrow therapeutic window and elevations can lead to CNS effects... if enough elevation can get resp and renal failure

Diclofenac

- phenylacetic acid derivative

- Very potent anti-inflammatory agent , also has analgesic, antipyretic action

- Used in the treatment of acute gout, severe osteoarthritis and rheumatoid arthritis

--> mostly used topically for joint pain

- COX-2 selective

- Very short half-life (one of the shortest of the NSAIDs)

- Due to selective COX-2 targeting diclofenac offers some GI protection compared to non-selective NSAIDS

-Associated with reversible increase in liver transaminase levels (can be problematic for those with some sort of hepatic dysfunction

Indomethacin:

- indol class

- Very potent anti-inflammatory drug

-Well absorbed (oral route)

-Substantial plasma protein binding

-Hepatic metabolism

- Causes serious gastrointestinal complications therefore should only be used for rheumatoid arthritis, ankylosing spondylitis (arthritis of the back) and acute bouts of gout

- Headache common: frequency = 15%-25% (including dizziness, depression, confusion)

--> causes highest frequency of CNS effects and one of the worst on renal function as well...

--> so very harsh drug but its also quite effective

Describe Ibuprofen, naproxen, and ketorolac

Ibuprofen:

- Phenylpropionic Acid Derivative

- Very well tolerated for long-term use in individuals who can't tolerate ASA because it causes gastrointestinal irritation/bleeding much less frequently than with aspirin

- Used often in children (flavoured chewable tablets, suspensions)

- Very high oral bioavailability

- Extensive protein binding

- Serum half-life: 2 hours

- Adverse Effects: Headache, GI irritability, Tinnitus

--> has been associated with CNS effects as well

Naproxen:

- Phenylpropionic Acid Derivative

- Naproxen is generally safe but it can cause GI disturbances (20-30%)

- Naproxen can compete with ASA for albumin binding sites

- Antacids containing Magnesium oxide or aluminum hydroxide can reduce rate of absorption

- Extensive plasma protein binding, excellent bioavailability and longer half-life than most other NSAIDS

- Available as both a topical and ophthalmic solution

- generally well tolerated (considered one of the safest NSAIDs)

Ketorolac (***not super relevant):

- acetic acid derivative

-Potent analgesic with moderate anti-inflammatory effects

-Rapid onset and short duration of action

-Often used post-operatively

Adverse Effects

-Risk of serious GI irritation, renal complications and bleeding

Compare and contrast COX1 and COX2

Detail the mechanism of COX2-selective NSAIDs increasing CV risk

Why were COX2 selective drugs developed? What is the prototype of these drugs? Describe it

COX1: Housekeeping function in GI tract, kidneys and platelets

COX2: Induced at site of inflammation

In the past, cox-2 selectors interrupted an important balance for CV function between cox-1 and cox-2

- Cox-2 should normally be associated with inflam but in endothelial cells there is additional role- responsible for producing prostacyclin

- PC is important vasodilator... important for regulating prothrombotic effects carried out by COX-1 and vasoD effects (As well as some plt inhibition)

--> it protects from prothrombotic effects of COX1

- When you use cox2 inhibitor you are removing that protection by inhibiting PC... but cox-1 path intact

-So in plts because cox-1 is intact thromboxin is produced like it normally would be and now you have imbalance

-Thromboxane accumulates and you don't have protection from PC and you leave patient vulnerable to thrombotic events

-- found with earlier examples of COX-2 inhibitors

COX 2 selective NSAIDS: Developed to inhibit prostaglandin synthesis by the COX 2 isozyme at sites of inflammation without affecting COX 1 (especially in GI tract)

- Prototype is celecoxib (15-20X more selective for COX 2)

- Only one of its kind at the moment

Celecoxib

- As effective as other NSAIDS in treating rheumatoid arthritis

- Causes fewer endoscopic ulcers compared to other NSAIDS

--> so protective against both GI and renal symptoms

- Reduction of Prostacyclin (PGI2) synthesis in endothelium increases risk of thrombosis (as previously mentioned)

- Significant drug interaction with warfarin (CYP2C9)

- Although has fewer GI side effects than other NSAIDS they have a number of other adverse effects including increased risk of cardiovascular events

Describe acetaminophen. What is its PK like?

- A non anti-inflammatory analgesic (not considered an NSAID although does target COX); Predominantly antipyretic and analgesic

- Not useful as anti-rheumatic therapy

- Mechanism of action is unclear

- No anti-platelet effects

- Ideal analgesic for individuals who are susceptible to the gastric irritation of NSAIDS (doesn't cause GI effects)

- Analgesic and Antipyretic of choice for children and infants

- Very well tolerated at therapeutic doses

Pk of Acetaminophen:

•Oral administration

•Peak plasma levels: 30-60 minutes

• At large toxic doses may deplete glutathione in the liver which results in hepatotoxicity (antidote is N- acetylcysteine if delivered within 10 hrs of overdose)

What are the dietary considerations of gout?

What is the acute treatment for gout? What about chronic treatment?

- Increasing unsaturated fatty acids such as eicosopentanoic acid (marine fish) can compete with arachadonic acid and alter the metabolites (good for other inflammatory diseases too)

- Avoid alcohol (wine and beer) and foods high in purines: meat, fish, dry beans, mushrooms, spinach, cured or pickled products

Acute treatment:

•NSAIDS (indomethacin)

•Corticosteroids

--> If more than two attacks a year, chronic treatments should be considered

Chronic treatment:

Uricosuric agents

•- e.g. probenecid, sulfinpyrazone

•- inhibit proximal tubular reabsorption of uric acid

•- secretion of other weak acid drugs may be

affected

Colchicine

-natural compound derived from the autumn crocus

- decreases the mobilization of granulocytes and leukocytes by inhibiting microtubule polymerization

Allopurinol

Inhibits xanthine oxidase to decrease uric acid synthesis