5 - NSAIDs Flashcards
1
Q
NSAIDS:
- define, fxns,*
- prototype*
A
- def: nonsteroidal anti-inflammatory drugs
- fxn
- anti-inflammatory
- analgesic (reduce pain)
- anti-pyretic (reduce fever)
- prototype: aspirin
2
Q
types of inflammation
A
acute
(immune response)
chronic
3
Q
mediators of acute inflammation, and the effects on:
vasodilation, vascular perm, chemotaxis, pain
A
4
Q
mediatros of CHRONIC inflammation:
& primary effects
A
5
Q
where in the process do NSAIDs act? and what do they do?
A
Prevent arachidonic acid from being converted into PG, thromboxane, prostacyclin
*INHIBIT COX enzymes
6
Q
where in the body is the NSAID working?
A
occurs locally at the site of action in the periphery
blocks competitively or non-competitively
7
Q
what are autacoids, and how are they involved in inflammation?
A
- biological factors (molecules) which act like local hormones, have a brief duration, and act near their site of synthesis after binding to nerve fiber receptors in the periphery
- function to block pain and inflammation response in the periphery at the site of action (blocking the production of prostaglandins)
8
Q
which have more adverse side effects and why?
corticosteroids, or NSAIDs?
A
*corticosteroids, because these act higher up in the process –> more downstream side effects
9
Q
what are the therapeutic strategies of drugs?
A
- relief of pain
- slowing or arresting of the tissue damaging process
10
Q
NSAIDs:
chief clinical use?
A
- anti-inflammatory agent in tx of musculoskeletal disorders (OA and RA)
- these DO NOT arrest the progression of pathological injury to tissue
11
Q
- what is the current gold standard to which anti-inflammatory drugs are compared?
- which drug was historically the gold standard (prior to 1960s)
A
- current gold standard: IBUPROFEN
- previously/historically: aspirin
12
Q
REVIEW: pharmacokinetics categories?
A
ADME
- absorption
- distribution
- metabolism
- excretion
13
Q
Aspirin:
pharmacokinetics (ADME)
A
- A - rapidly absorbed
- D - found in synovial fluid
- M - metabolized by cytochrome p450
- E - renally excreted
14
Q
Aspirin:
pharmacodynamics
A
- IRREVERSIBLY inhibits COX activity
- esp affects platelets
15
Q
Aspirin:
clinical uses
A
- analgesia: pain of mild-mod intensity
- antipyretic: little effects on normal Tb
- anti-inflammatory: inflammatory joint conditions
Other uses: prevention of ischemic attacks, unstable angina, thrombotic conditions
16
Q
Aspirin:
adverse effects
A
- GI upset; (intolerance) –> upper GI bleeding from erosive gastritis
- Salicylism –> vomiting, tinnitus, dec. hearing, vertigo
- Inc. serum uric acid levels
- Inhibition of platelet function –> blocks (noncompetitively) COX-1 platelets –> change conformation and inactivate platelet (7-11 days) –> won’t function in coagulation response (bad for pt with bleeding disorder)
- Renal BF alterations
- Reye’s syndrome –> causes brain and liver damage
17
Q
how common are the side effects of Aspirin?
A
very common!
- Dyspepsia: 15-40%
- Duodenal ulcers: 5-8%
- Gastric ulcers: 15-20%
- GI bleed: more rare, 1-2%
For every $1 spent on NSAIDs –> $0.66 spent on side effects
18
Q
Can we prevent NSAID- induced adverse events?
A
Yes! There are some drugs that prevent these:
-
**Proton pump inhibitor:
- reduces chances of damaging gastric mucosa
- cheapest and most effective
- e.g. omeprazole, prilosec, nexium –> dec. liklihood of damaging mucosa
-
Misoprostol: prostoglandin E1 analogue –> protects gastric mucosa from chemical irritation
- PG is important for protection of the GI tract
- replaces the PG that you’re blocking w/ the NSAID
- but can cause diarrhea/ due to contraction of smooth muscles
-
Cox-2 inhibitor
- allows COX 1 to function
19
Q
these are in which family of drugs?
- diclofenac
- flurbiprofen
- ibuprofen
- indomethacin
- ketoralac
- naproxen
- piroxicam
A
NSAIDs
20
Q
diclofenac:
characteristics, use
A
- developed as a “super-aspirin” to be gentler on the stomach;
- formulations:
- diclofenac alone
- diclofenac + PG analogue
- Tx: dysmenorrhea and gout
- Type of NSAID
21
Q
flurbiprofen:
characteristics, tx for what
A
- developed as ocular eye drop
- pre-analgesic prior to eye surgery; or after to tx pain
22
Q
Ibuprofen:
characteristics, fxn
A
- **gold standard NSAID; works as antipyretic, anti-inflammatory, analgesic
- thought to be safer than aspirin
- ibuprofen is a COMPETITIVE inhibitor, so it doesn’t have the same effect on bleeding or platelets
23
Q
Indomethacin:
characteristics, fxn, tx
A
- works as antipyretic, anti-inflammatory, analgesic
- 5-7 hour half-life
- fxn: works as antipyretic, anti-inflammatory, analgesic
- tx: HA, migraine, gout (more so than diclofenac)
- (NSAID)
24
Q
Ketorolac:
characteristics, fxn, tx
A
- only NSAID that is indicated for moderate to severe pain (all others are mild-moderate pain)
- more potent –> more side effects
- Administration –
- developed as an injectible; used for parenteral use
- IV drug or intramuscular injection
- •ONLY INDICATED FOR ACUTE SETTING (up to 5 days)
25
**naproxen:**
*characteristics, fxn*
* available OTC; half-life is longer like 13 hours (BID) whereas ibuprofen is 4-6 hour half life
* patients respond differently to the drugs
* looks like Ibuprofen (but half-life is different)
26
**Piroxicam:**
*characteristics*
* drug has half-life of **45-55 hours**; so it would last longer in the patients' system
* **higher adverse event rate -**-\> so blood levels are higher --\> higher incidence of side effects, esp GI
* NSAID
27
NSAIDs in general:
mechanism and duration
* Acts as reversible, competitive inhibitors of COX activity (in contrast to aspirin)
* Duration of action is primarily related to the pharmacokinetic clearance of the drug from the body
28
what are the COX types, and what are the key differences?
29
which type of COX inhibitors do we want to block during **acute** injury?
Want to block COX-2, NOT COX-1
(because COX-2 is thought to be the one that produces the prostanoid mediators of inflammation)
30
COX-2 inhibitors target what, and prevent which symptoms?
* targets: COX-2, an inducible enzyme
* Prevents conversion of Arachidonic acid --\>
* preventing pain and inflammation response
31
when considering the COX-2 inhibitors, how does the affinity for COX-1 and COX-2 relate?
* Diclofenac, for example -- high affinity for COX-2 and low affinity for COX-1 (desirable)
* Ibuprofen and Naproxen have comparatively high affinity for COX-1 --\> can cause GI ulceration at a higher rate
32
COX-2 inhibitors:
## Footnote
*key characteristics*
* Efficacy is EQUAL to that of NSAIDs
* Rapid onset (\<30min)
* Adverse events: variable
* Mechanism: COX-1 and COX-2 selectivity
33
**Celecoxib**:
## Footnote
*family, characteristics, tx*
* COX-2 inhibitor
* No known higher rates of adverse CV events
* Tx: used in patients that you want to avoid GI side effects
34
**Acetominophen:**
*family, characteristics, tx, hx*
* COX-2 inhibitor
* \*\*ONE OF THE MOST IMPORTANT DRUGS for tx when anti-inflammatory is NOT needed
* Tx for mild-mod pain w/o anti-inflammatory effect
* Hx:
* active metabolite of **phenacetin** (prodrug, but no longer used due to toxicities)
35
**Acetaminophen:**
*pharmacoKINETICS (adme)*
* A - **rapidly** & completely absorbed
* D - **most body fluids** (uniformly distributed)
* M - by **hepatic microsomal enzymes**
* E - **90-100%** excreted
36
What is the major difference b/w Acetaminophen and NSAIDs?
Their METABOLISM!
* Acetaminophen uses **hepatic microsomal enzymes**
* NSAIDs uses **cytochrome p450**
37
**Acetaminophen:**
*pharmacoDYNAMICs*
* a **weak inhibitor** of COX activity
* antipyretic effects of CNS-mediated COX inhibition?
* UKNOWN MECHANISMS OF ACTION
38
**Acetaminophen:**
*therapeutic use, and adverse effects*
* Therapeutic use: for pts whome **aspirin is contraindicated**
* *bc there's no effect on peptic ulcers*
* *no platelet-inhibiting properties*
* *can be used in pregnancy*
* Adverse effects:
* Skin rash/ allergic rxn
* Hepatic necrosis due ot overdose
* *minor metabolite --\> can cause oxidative stress injury to hepatocytes*
* *therefore, contraindicated in patients w/ compromised liver fxn*
39
Why would a patient use Acetaminophen over Aspirin?
* If pregnant
* If has GI issues like peptic ulcer
* or Bleeding concern (bc there's no platelet inhibiting properties)
40
Tx for Acetaminophen overdose?
* Needs vigorous supportive therapy
* Gastric lavage --\> to flush out of bloodstream
* Administer N-acetylcysteine --\> replenish hepatic stores of glutathione
* Protects against further liver damage by mopping up electrophiles
41
What are DMARDs and SAARDs?
* **DMARD:** disease-modifying anti-rheumatic drug
* **SAARD:** slow-acting anti-rheumatic drug
42
**Methotrexate:**
*family, fxn, structure, adverse effects*
* immunosuppressive
* potent immunosuppressive drug at anti-cancer doses; works non-specifically
* structure:
* related to folic acid
* dihydrofolase reductase inhibitor
* adverse effects: (*opportunistic infections)*
* N/V/rash urticaria
* Renal damage, dec hepatic function
43
**Leflunomide (Arava)**:
## Footnote
*family, fxn, adverse effects*
* immunosppressive
* pyrimidine synthesis inhibitor; used as a 3rd line therapy as non-specific immunosuppresive drug
* AE:
* liver damage
* lung dissease
* immunosuppression
44
**Sulfasalazine (Azulfidine)**:
## Footnote
*family, fxn, adverse effects*
* immunosuppressive
* Second-line therapy for non-specific immune modulator drugs; **metabolized by bacteria in the colon (into sulfapyridine and mesalazine)**
* AEs: hemolytic anemia, orange skin, and urine
45
List the Anti-TNFalpha drugs;
what's a short-cut for identifying them based on their name?
* Most end in -**mab** (monoclonal antibody)
* Etanercept (Enbrel)
* Anti-Tumor Necrosis Factor Alpha --\> Blocks cytokine (TNF-alpha) to prevent inflammation
46
other agents for RA;
* binds to diff't immune cells; antibody (soluble receptor)
* drugs
* Tocilizumab (Actemra) - *anti-IL-6*
* Abatacept (Orencia) - *T cell co-stim modulator*
* Rituximab (Rituxan) - *anti-CD20*
* Tofacitinib (Xeljanz) - *JAK inhibitor*
47
TNFalpha mechanism:
* can bind to surface receptors --\> causing damage to joints
* So the soluble TNF receptor "mops up the TNF", preventing inflammation
48
**Etanercept (Embrel):**
* *define/structure,*
* *pharmacoKINETICS (A,D),*
* *pharmacodynamics*
* A recombinant fusion protein that consists of 2 soluble TNF p75 receptor moieties linked to the Fc portion of human IgG1
* Binds two TNF-alpha molecules
* PK
* A - **slowly** absorbed after subQ injection
* D - **serum** peak conc in 72 hrs
* PD
* captures and inactivates some TNF molecules --\> prevent triggering inflammation
49
**Etanercept (Embrel)**:
## Footnote
*adverse effects*
* injection site rxns & headache
* etanercept dosing should be discontinued in pts w/ serious infxn
* possible reports of CNS disorders such as MS, seizures, inflammation of nerves of eyes
50
**Infliximab (Remicade):**
*structure/mech, admin, tx*
* struc: **chimeric** (25% mouse/75% human) monoclonal Antibody --\> binds w/ high affinity and specificity to human TNF-a
* admin by IV dosing intervals of 4-8 wks
* Tx: for reducing signs/sxs of **moderately to severely active rheumatoid arthritis** in pt's who have had an inadequate reponse to methotrexate
* used in combination w/ methotrexate
51
**Infliximab (Remicade)**:
## Footnote
*adverse effects*
* sxs
* upper respiratory infection
* nausea, headaches, sinusitus, rash
* incidences of this is the same as methotrexate
* some opportunistic infections
* a chimeric biologic therapy --\> can lead to formation of human antichimeric antibodies in up to 50% of patients
* concurrent therapy w/ methotrexate greatly reduces the prevalence of HACAs and in the basis for the recommendation of the combined administration
52
what are the other agents to treat rheumatoid arthritis?
(in addition to methotrexate, infliximab)
* These are 4th adn 5th line treatments for RA
* **gold salts**
* **antimalarials**
* **penicillamine**
53
**Gold Salts:**
*tx, mech, types, adverse effects*
* tx for rheumatoid arthritis
* mech: unknown mechanism; slows the progression of bone and articular destruction
* types
* aurothio-malate; and aurothio-glucose: *parenterally admin; water-soluble gold salts*
* auranofin: *orally administered, gold-thioglucose derivative*
* adverse effects:
* GI disturbances (diarrhea)
* dermatitis
* hematological abnormalities, stomatitis (*metal taste in mouth*), peripheral neuropathy
54
**Antimalarials**:
## Footnote
*example, mech, tx*
* Ex: Hydroxychloroquine
* Mech: mech of anti-inflammatory action is unclear; --\> suppresses responsiveness of T-lymphocytes
* inhibits DNA and RNA synthesis
* Trap free radicals
* Tx: used in tx of Rheumatoid Arthritis
55
**Penicillamine:**
*tx, structure, mech*
* Tx: reserved for patients w/ progressive, erosive rheumatoid arthritis not controlled by conservative therapy
* Struc: metabolite of penicillin w/ some anti-infective properties
* Mech: unclear, but may interfere w/ synthesis of DNA, collagen, and mucopolysaccharides
