L23-24 NSAIDS Flashcards
(70 cards)
1
Q
NSAIDS indications
A
Reduce inflammation - chronic inflammatory disease
Pain Relief
Fever reduction
promotes closure of a patent ductus arterius
2
Q
Aspirin specific indications
A
stroke/MI prevention
Inhibition of platelet activation
3
Q
Mechanism of action of NSAIDS
A
inhibit Cyclooxygenase enzymes (cox enzymes) which block prostaglandin and thromboxane production which mediates the inflammatory response (pain, inflammation, fever)
4
Q
how do NSAIDS inactivate COX
A
NSAIDs inhibit cyclooxygenase enzyme activity by preventing the binding of the arachidonic acid substrate to the active site of the enzyme. Via competitive inhibition except Aspirin (non-competitive/irreversable)
5
Q
COX 1 and 2 activity
A
both catalyze the rate-limiting conversion of membrane derived Arachidonic acid into prostaglandins and thromboxane
COX1: constant low level of PG production
COX2: acute high level of PG production
6
Q
COX1 and 2 expression
A
Cox1: constitutive
Cox2: Inducible in many cell types in response to pro-inflammatory mitogenic stimuli
7
Q
Tissue location of COX1 and 2
A
COX1: most tissues
COX2: induced in macrophage and monocytes
low level of constitutive expression: kidney, endothelium
8
Q
physiological role of COX1 and COX2
A
COX1: general housekeeping, protection and maintenance
COX2: pro-inflammatory response, signaling and mitogenesis
9
Q
Inhibitors of COX1 and COX2
A
Aspirin, tNSAIDS for both
not celecoxib for COX1
10
Q
prostaglandins affect on pain
A
increased PG synthesis acts on primary afferent neurons to decrease the activation for pain stimuli which decreases peripheral pain sensation
increased cytokines activate COX2 in the dorsol horn neurons increasing PG production which enhances depolarization and secondary sensory neurons leading to central pain sensitization
11
Q
what causes fever
A
inflammatory mediators (IL-1 and TNF) produced in the periphery act on endotheial cells lining the hypothalamus to induce COX2 resulting in the production of PGE2 which acts in the CNS to cause fever
12
Q
housekeeping function of COX-1
A
COX1 activity is involved in regulating:
A) The GI Tract
B) The Cardiovascular system C) The Kidney D) Female Reproduction E) The Ductus Arteriosus interfering with COX-1 effects causes the negative side effects
13
Q
how do PGs help to protect the stomach
A
inhibit gastric acid secretion
increase bicarb and mucus production
increase vasodilation and GI blood flow
loss of these affects leads to gastric toxicity
14
Q
platelets
A
express only COX-1 and produce mostly TXA2(thromboxane)
15
Q
Thromboxane (TXA2)
A
vasoconstrictor
promotes platelet aggregation and activation
16
Q
endothelial cells expression and production
A
express both COX-1 and COX2 but lack TXA2 synthase so they primarily produce PGI2 which is a vasodilator that inhibits platelet aggregation
17
Q
why is TXA2 and PGI2 balance important
A
regulates BP and thrombogenesis
imbalance can lead to vasoconstriction and platelet aggregation causing hypertension, ischemia, thrombosis MI, stroke
18
Q
kidney function
A
expresses both COX1 and COX2
- PGs promote vasodilation in the kidney, thereby increasing renal blood flow and preventing renal ischemia
- PGs also increase: - glomerular filtration rate
- water and sodium excretion
- PGs also increase: - glomerular filtration rate
- especially important in disease states (e.g. HF and renal disease) to counteract the presence of vasoconstrictors
19
Q
Female Reproduction
A
PGE2/PGF2α production stimulates uterine contraction and plays a role in birth
- hence NSAIDs use may delay labor
20
Q
Fetal opening of the Ductus Arteriosus
A
Fetal structure that allows blood to shunt from the pulmonary artery to the aorta thereby bypassing circulation to the lungs
N.B. fetus receives oxygen from the placenta not the lungs
kept open by PGs
NSAIDS promote closing
21
Q
3 types of NSAIDs
A
- Aspirin and salicylates
- traditional non-selective NSAIDs
- Coxibs: selective COX-2 inhibitors
22
Q
Aspirin is more selective for
A
COX-1 but inhibits both
23
Q
Aspirin chemical characteristics
A
Acetylsalicylic Acid is a weak acid with pKa = 3.5
- In the acidic environment of the stomach Aspirin will be predominantly in its protonated, neutral form that can readily cross the plasma membrane
- Rapidly absorbed in stomach and upper small intestine
- Short serum half life - ~15-20 mins
- Metabolized by serum esterases to Salicylic acid + acetic acid (both aspirin and salicylic acid inhibit COX enzymes)
24
Q
Aspirin mechanism of action
A
Aspirin acts as an irreversible inhibitor of COX1 by acetylating Ser530 in the active site thereby preventing access to arachidonic acid substrate
Aspirin also acetylates COX-2, but is a less potent inhibitor,
as the COX2 active site is larger and can still partially bind arachidonic acid
25
Aspirin indications
1. Treatment of mild to moderate pain
e.g muscle/joints
dental surgery
headaches
2. Inflammatory diseases
e. g. Rheumatoid Arthritis
3. Fever reduction
4. Prophylactic prevention of cardiovascular events i.e. MI and stroke
- Unique Indication for low dose Aspirin
5. Cancer chemoprevention: frequent use of aspirin associated with a 50% decrease in the risk of colon cancer
- EXPERIMENTAL
26
Aspirin Dosages and Indications
Anti-platelet activity: 81 mg/day
Analgesic/Anti-pyretic: ~ 2, 400 mg/day
Anti-inflammatory: 4, 000-6,000 mg/day
27
Aspirins use in CVD prevention
a) as a treatment in acute occlusive stroke
b) as secondary prevention of CVD after either a prior MI, STROKE or TIA
c) prophylactic treatment for the primary prevention of stroke and myocardial infarction in individuals at moderate to high risk of CVD
Extensive clinical studies have shown that this treatment has a significant effect on reducing future cardiovascular events, as well as decreasing overall mortality
28
Mechanism of Action of low-dose Aspirin in the
| treatment of cardiovascular disease
Aspirin acetylates COX-1 in platelets, permanently inhibiting its activity and thereby preventing the production of the platelet-derived pro-thrombogenic agent TXA2. (irreversible = more effective than other NSAIDs)
Because platelets lack the ability (no nucleus) to re-synthesize COX-1 this inhibition is long lasting and acts for the lifetime of the platelet (7-10 days). (longer lasting than other NSAIDs)
Since endothelial cells are able to re-synthesize COX-1 (and also express COX-2) this low level of Aspirin does not affect the production of endothelium-derived PGI2 (an inhibitor of platelet aggregation) (at higher doses PGI2 decreases will counteract decreases in TXA2)
By inhibiting TXA2 production and sparing the synthesis of PGI2, low-dose aspirin treatment promotes a strongly anti-thrombogenic environment
29
Other Salicylates
Salsalate
Diflusinal
Magnesium salicylate
Sodium thiosalicylate
Methyl salicylate
30
aspirin vs other salicylates
Unlike Aspirin, other salicylates are non-acetylated and consequently are unable to irreversibly inhibit COX-1
Consequently: - less potent COX inhibitors
- lower risk of adverse effects
May be preferable to Aspirin for use in patients with:
- increased risk of GI complications (e.g. gastric ulcers)
- increased risk of bleeding (e.g. hemophiliacs).
All salicylates are 50-90% protein bound- high potential for drug interactions
e.g. warfarin, sulfonylureas
aspirin is the only one with CV protective effects
31
Salicylate toxicity
```
SALICYLATE INTOXICATION
hyperventilation, metabolic acidosis,
hypoglycemia, confusion, tremors,
seizure, cerebral edema, delerium
hyperthermia, respiratory depression
COMA and DEATH
Mortality: Acute ~2%/Chronic ~25%
```
low doses metabolized via 1st order kinetics in liver
high doses saturate metabolism enzymes - zero order kinetics
32
treatment of salicylate toxicity
alkalinization of the urine with bicarbonate
- increases relative amount of ionized form in urine
- prevents reabsorption of drug in the renal tubule
- increases the rate of salicylate excretion
33
traditional NSAIDs
```
Examples
Ibuprofen (Advil®/Motrin®/Nuprin®)
Naproxen (Aleve®/Anaprox®/Naprosyn®)
Indomethacin (Indocin®)
Diclofenac (Cataflam®)
Keterolac (Toradol®)
Oxaprozin (Daypro®)
Meloxicam (Mobic®)
```
34
what is an indication of tNSAIDs that is not an indication for aspirin/salicylates?
treatment of acute gout
35
characteristics of tNSAIDs
All Traditional NSAIDs are competitive inhibitors of COX activity
non-selective inhibitors of both COX-1 and COX-2
All exhibit anti-inflammatory, anti-pyretic and analgesic effects
36
indications of tNSAIDs
```
Indications include:
- Mild to moderate pain
- Fever
- Inflammation associated with Rheumatoid Arthritis,
osteoarthritis and related diseases
- Treatment of acute Gout
```
37
ibuprofen unique features
- Equipotent with Aspirin and better tolerated
- potent analgesic and anti-inflammatory properties
* **- Rapid onset of action 15-30 mins- ideal for treatment of fever and acute pain
- GI and bleeding occurs less than with Aspirin
- often prescribed in lower OTC doses (
38
Naproxen
- 20X more potent than aspirin
* ** - rapid onset of action 60 mins -ideal for anti-pyretic use ***- long serum half life of 14 hrs- allows for twice daily dosing
- low incidence of GI bleeding
- Considered to be one of the safest NSAIDs
39
Oxaprozin
- Slow onset of action ~6hrs
* ** - v. long serum half life of 50-60 hrs allows for once daily dosing
- mildly uricosuric (i.e. increases excretion of uric acid) therefore potentially more useful in treatment of gout
40
indomethacin
* *- 10-40X more potent than Aspirin as an anti-inflammatory
- also inhibits neutrophil mobility
* ** - not tolerated as well as ibuprofen- toxicity limits use
* ** - ~50% of users experience side effects, ~20% discontinue esp. CNS i.e. dizziness, anxiety & confusion
- can delay labor by suppressing uterine contractions
* ** - used to promote closure of patent ductus arteriosus
41
ketorolac ***
- relatively weak anti-inflammatory activity
* ** - used mainly as an IV analgesic for post-surgical pain
* ** - can be used as a replacement for opioid analgesics e.g. morphine
42
Diclofenac
- more potent anti-inflammatory than indomethacin and naproxen
- somewhat better tolerated
* ** - relatively selective for COX-2
* ** - Increased heart/stroke risk similar to coxibs (↑40%)
- somewhat better tolerated
43
Adverse effects of Aspirin and tNSAIDs
1. GI Toxicity***
2. Kidney impairment***
3. Cardiovascular
4. Anti-platelet effect/Increased risk of bleeding
5. NSAID Hypersensitivity
6. Pregnancy-related adverse effects
Aspirin specific 7. Reye’s Syndrome
Aspirin specific 8. Increased risk of gout
44
GI side effects can be ameliorated by
Effects can be ameliorated by co-administration of:
Misprostol- a PGE1 analog (Note: Caution in women/Abortifacient)
Omeprazole- proton pump inhibitor (inhibits gastric acid production)
45
Most common adverse effect of all NSAIDs
GI toxicity
Epigastric distress, nausea & vomiting, GI bleeding (5-10% mortality rate)
Aggravates & promotes development of Gastric and Duodenal Ulcers
46
causes of GI toxicity
Causes
direct damage to gastric epithelial cells caused by ion-trapping of aspirin/NSAIDs
inhibition of COX1 in the stomach blocks the gastric protective effect of prostaglandins
- not caused by celecoxib due to lack of COX1 inhibition
47
adverse effects of NSAIDs on the kidneys
(A) Hemodynamically-mediated acute renal failure
(B) Acute interstitial nephritis and the nephrotic syndrome
(C) Analgesic Nephropathy / Chronic Interstitial Nephritis
48
Acute interstitial nephritis and the nephrotic syndrome
Rare, but clinically important (~15% of patients with renal failure) additional side effect of NSAIDs on the kidney
- Drug-induced kidney failure associated with inflammatory cell infiltration
- Typically occurs after several months of exposure - Mechanism unknown
- More common in the elderly and in women
Symptoms include: Nausea, vomiting, malaise , WBC in the urine and proteinuria
- Spontaneous recovery typically occurs weeks after drug discontinuation
49
Hemodynamically-mediated acute renal failure
Caused primarily in patients with underlying kidney disease or conditions of volume depletion e.g. heart failure or cirrhosis
- Especially problematic in the elderly
Due to NSAIDs blocking the production of vasodilatory PGs that normally act to prevent renal ischemia in diseased states
Usually reversible following discontinuation of the drug
Not typically seen in normal individuals because PG do not play a major role in renal hemodynamics under normal non-pathological conditions
50
(C) Analgesic Nephropathy / Chronic Interstitial Nephritis
Associated with chronic daily overuse of drug over many years
- Slowly progressive renal failure leading to end-stage renal disease caused by prolonged renal ischemia
51
Adverse effects of NSAIDs on Cardiovascular system
1. increased risk of heart attack and stroke (all except aspirin, risk is small)
2. worsening of hypertenstion and HF (not with low dose aspirin) (may worsen HF due to increased BP increasing afterload on the heart)
52
antiplatelet effect
- all NSAIDs (except celecoxib) inhibit platelet COX-1 production of pro-thrombogenic TXA2 ⇒ ↓clotting ⇒ ↑risk of bleeding
- avoid NSAID use in patients with pre-existing platelet deficiency
- avoid NSAID use prior to surgery for > 4-5x drug t1/2
53
NSAID HYPERSENSITIVITY
~15% of patients taking Aspirin exhibit an airway hypersensitivity reaction (present in ~20% of asthmatics)
Exposure leads to a rapid often severe asthma attack within 30-60 mins
Symptoms can include: - Wheezing and Severe airway obstruction
- Ocular and Nasal congestion
- Facial flushing
- Angioneurotic edema
- fatal anaphylatic shock is rare
Aspirin-sensitive patients are also reactive to other NSAIDs
e.g. indomethacin, naproxen and ibuprofen
Not caused by an immunological hypersensitivity reaction, but is thought to result from increased production of leukotrienes due to build up of Arachidonic Acid
54
PREGNANCY-RELATED ADVERSE EFFECTS
- NSAID use during pregnancy associated with increased rate of miscarriage
NSAID use after 30 weeks of pregnancy can promote premature closure of the ductus arteriosus
- can cause serious heart defects and fetal death
NSAID use can can delay labor
PGE2/PGF2α production play an important role at birth by stimulating uterine contraction
- NSAID use late in pregnancy associated with increased risk of post-partum hemorrhage due to decreased blood clotting
55
Reye’s Syndrome
Reye’s Syndrome is a rare, often fatal, liver degenerative disease with associated encephalitis
It is associated with ASPIRIN given to young children and adolescents during a febrile viral infection (e.g. chickenpox or influenza)
Use an NSAID or acetaminophen instead of aspirin
56
Coxibs
Selective COX-2 inhibitors
| Celecoxib - only one currently on the market
57
Celecoxib mechanism
Selective competitive inhibitor of COX-2, minimal effects on COX-1
anti-inflammatory, anti-pyretic and analgesic properties
similar to other NSAIDs
58
indications of celecoxibs
1. Mainly for the treatment of rheumatoid arthritis & osteoarthritis
2. May be specifically indicated in patients with increased risk of GI complications
- due to poor inhibition of COX-1 in the stomach
3. May be specifically indicated in patients with increased risk of bleeding (e.g. hemophiliacs)
- due to poor inhibition of COX-1 in platelets
59
adverse effects of celecoxibs
Associated with fewer GI side effects than tNSAIDs/Aspirin
(does not effectively inhibit COX-1 in the stomach)
No effect on platelet aggregation
(does not effectively inhibit COX-1 in platelets)
Exhibits similar renal toxicities to traditional NSAIDs
(due to constitutive expression of COX-2 in the kidney)
***Potentially associated with increased risk of developing cardiovascular events, especially at higher doses
*- Due to potentially increased CVD risk celecoxib is NOT recommended as a 1st choice NSAID, especially in
patients with pre-existing CVD or at increased risk of CVD
60
cause of increased CV risk with coxibs
Believed to be caused by the selective inhibitory effect of the COX-2 inhibitors on the endothelial cell production of PGI2 (prostacyclin)
- N.B. COX-2 is constitutively expressed in the endothelium
- reduced anti-thrombotic and vasodilatory affects
61
NSAID contraindications
* 1. History of GI ulcers (not celecoxib)
* 2. Patients with Renal disorders
3. Patients with bleeding disorders or on anti-coagulants
- ↓platelet aggregation may prolong bleeding time (not celecoxib)
- drug interaction with warfarin -serum protein displacement
- discontinue prior to surgery
4. Patients with a history of CVD/hypertension/heart failure
- especially celecoxib
5. Patients with hypersensitivity to an NSAID
6. Pregnancy
- NSAIDs may delay the onset of labor - not given 6-8 days prior to birth
- premature closure of the ductus arteriosus
- Increase risk of post-partum hemorrhage
Aspirin/Salicylate-specific
*7. Patients with prior history of GOUT
* 8. Children with febrile viral infections
- risk of developing Reye’s syndrome
62
drug interaction with lithium
all NSAIDs, NSAIDs impair renal function, decreased renal lithium clearence, increasing the chance of lithium toxicity (lithium has a narrow window of toxicity)
63
methotrexate (chemotherapy)
All NSAIDS decrease renal function associated with less clearence, and displacement from proteins leads to increased MTX toxicity
64
Aminoglycosides
NSAIDs decrease renal clearance increasing toxicity
65
Acetaminophen effects
An important drug used for the treatment of mild to moderate pain & Fever
- Anti-Pyretic and Analgesic activity (equivalent to Aspirin)
- No anti-Inflammatory activity (Does not inhibit peripheral COX-2)
- No anti-platelet activity (Does not inhibit Platelet COX-1)
66
mechanism of acetaminophen
A. Only a very weak inhibitor of COX-1 and COX-2 in peripheral tissues
- due to inhibitory effects of high concentrations of hydroperoxides
- However, acetaminophen inhibits COX-1/COX-2 in the CNS
Most potent effects are on the pain & thermoregulatory centers of the CNS
- selectively metabolized in the brain to an “active metabolite” AM404
- AM404 can inhibit COX-2 in the brain
- AM404 also acts on the cannabinoid system to decrease Pain/Fever
67
peripheral effects of acetaminophen
No anti-inflammatory
No Anti-platelet effect
Reduced Adverse effects
No GI Toxicity/Renal effects
very weak COX-1/COX-2 inhibitor due to high concentrations of hydroperoxides in periphery
68
CNS affects of acetaminophen
Potent inhibitor of COX-2 in CNS
| leads to decreased pain and fever
69
indications of acetaminophen
1. Mild to moderate pain not associated with inflammation
- does not inhibit COX2 in the periphery
2. Preferred ANALGESIC/ANTI-PYRETIC for:
a) Children with febrile viral infections
- to avoid Reye’s Syndrome
b) Patients with Peptic Ulcer disease
- does not inhibit peripheral COX-1- NO GI TOXICITY
c) Patients with hemophilia or increased risk of bleeding
- does not inhibit platelet COX-1
d) Patients with HYPERSENSITIVITY to Aspirin or other NSAIDs
FEWER ADVERSE EFFECTS COMPARED TO ASPIRIN or NSAIDs
70
acetaminophen toxicity
Acetaminophen is generally well tolerated with few adverse effects
However, acetaminophen overdose can be FATAL
at high concentrations metabolic enzymes are overwhelmed leads to build up of toxic metabolite (NAPQI) that depletes hepatic glutathione and causes hepatic toxicity due to formation of hepatic protein adducts
kills the liver especially in people who drink alot
