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219 Cards in this Set

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What is MSM similar to?
DSMO
What class are glucosamine and chondroitin sulfate in?
Nutraceuticals
What does glucosamine inhibit? Increase?
Inhibit: MMP, NO production, and stops IL-1's from inducing aggrecanase activity
Increase: GAGs, PG's, Hyaluronic acid, and aggrecan synthesis
Chondrotin sulfate inhibits translocation of ____ into chondrocytes.
NFkB
Name 4 areas that are hindered in patients taking Nutraceuticals for Inflammation (OA).
1. NO
2. Proteases
3. IL-1
4. TNF
What does chondroitin sulfate do to NFkB?
inhibits its translocation of NFkB into chondrocytes and synovial membrane
Do glucocorticoids have mineralcorticoidal activity? How or how not?
Yes, bc affect Na and K+
What is the flow of the HPA axis?
Ceberal cortex stimulated (via stress) --> triggers hypothalamus --> releases CRH ---> anterior pituitary lobe --> releases ACTH --> adrenal gland --> steroids are made (cortisol)
What is CRH?
Corticotropin releasing hormone
What are the 2 negative feedback mechanisms of the HPA axis?
Coritsol (long ) and ACTH (short)
too much of either will stop the production of CRH
What receptor does ACTH act on in the adrenal glands?
Melanocortin-2 receptor
How many weeks does it take to get suppression/atrophy of the HPA axis? How long to recover?
2 weeks;
9-12 months
What is the normal release of cortisol? Under stress?
10-25 mg/day
300mg/day
The genomic theory of steroids is that it enters the ____ of the cell and either synthesizes ___ or interferes with ____.
cytoplasm/nucleus; proteins; transcription
How do steroids stop NFkB activation?
By surrounding the complex with IkB's so IKK cannot remove the one for activation
What two items are transported from the periphery to the liver as a result of steroids?
amino acids and glucose
In regards to metabolism, Steriods promote ___ and ___ ____.
gluconegenesis
lipid breakdown
What disease can be induced by steriods? How?
Diabetes (How...)
Liver increases gluconeogenesis; increases blood glucose and glycogen storage (deposition)
Steroids promote lipid breakdown increasing FFA. They also decrease insulin sensitivity except what two areas of the body? What does this cause?
Face and shoulders
lipid deposition --> moon face and buffalo hump
Concerning electrolytes, while on steroids you get ___ reabsorption and ___ loss.
Na
K
While on steroids, what is one cell that is increased in the plasma but the function is not?
neutrophils
With steroids many blood cells are decreased. What can this cause an increase in?
infections
Why are steroids so good of a drug?
Bc they are anti-inflammatory and immunomodulators (which is vital with chronic inflammation)
What happens to fibroblasts while on steroids?
dec synthesis of cytokines and MMP
What happens to cartilage while on steroids?
inc glycosaminoglycan synthesis
What happens to bone while on steroids?
Inhibits bone formation; increase osteoCLAST activity by inc RANK/RANKLY and dec OPG
What happens to endothelial cells while on steroids?
inhibits expression of adhesion molecules, NO, PG's, complement, and angiogenesis
Which type of immunity is most affected by steroids?
cellular
What two key mechanisms are blocked with steroids in SLE?
1. cytokines
2. antigen processing

(SLE = Type III - so immune cells are also not working as well)
Can you get HTN while on steroids?
Yes

HOW?
Bc of Na+ retention
While on steroids, what happens to protein synthesis? What conditions can occur
It is decreased
Myopathy, skin thinning, delayed wound healing, fetal growth retardation, negative Ca2+ balance, osteoporosis, fractures and GI ulcers
What is the main possible MOA of colchicine in acute attack of GOUT?
irreversible binding to tubulin protein within the PMN....what does this cause?
the lysosomes cannot get to the crystals bc the tubulin is what guides them
What is the dose for colchicine for an acute attack of gout? the max dose?
0.6mg PO q1-2 hrs
6 mg
How long does it take to see colchicine working in Gout? Faster or slower than NSAIDs?
12-24 hrs (24 hrs = 90% pain free)
slower
What is the major SE of colchicine?
Hyperperistalsis
(also abdominal pain, N&V)
What is the prophylactic dose of colchicine with Gout?
0.6mg QOD or once/twice daily
Where is the site of action of Probenecid? How does it work?
renal tubules (most be secreted in)
blocking the reabsorption of UA, increasing the amount of urate excreted from the body
Does Probenecid have bad AE's? What stones could be formed?
No
uric acid stones; so decrease amount of acidic drinks/foods
What interactions occur with Probenecid: + Penicillin; + APAP; + Indocin; + MTX
increase penicillin levels (benefit?!?)
increase t1/2 of APAP and indocin
increase blood levels of MTX (toxic!!!)

*these occur bc probenecid competes for secretion into renal tubule
What happens with low levels of ASA taken with Probenecid?
Low ASA levels block secretion so Probenecid won't be able to get it and do it's job; inc levels of UA
Besides block xanthine oxidase, how else are these drugs working?
By inhibiting the AMP/GMP feedback mech; these drugs with inc AMP and GMP and if they didn't block the FB mechanism then PRPP would increase to get rid of the levels of AMP/GMP (bad thing with gout)
Allopurinol is good for those patients that are overproduces with ___. And the drug of choice for those with gout and ___ ___ disease.
tophi; chronic kidney
What is allopurinol an analog of? What is it a competitive antagonist of?
hypoxanthine
xanthine oxidase
Allopurinol + xanthine oxidase = ?
Alloxathnie (Oxipurinol)
Competitive or non?
Non-competitive with XO (unlike parent Allopurinol)
What syndrome can be fatal as a result of taking allopurinol?
Allopurinol hypersensitivity syndrome (rash)
Why not give Probenecid with Allopurinol?
Bc allopurinol is excreted along with UA; so it wouldn't be able to have an effect due to probenecid
Is Uloric similar to Allopurinol structurally? Benefit?
NO; it's a non-purine
No interaction with Probenecid and those with decreased renal funt can take as well
Patients with CKD can take Uloric. WHy?
BC metabolized by liver (not kidneys like allopurinol)
Which is less toxic Uloric or Zyloprim
Uloric
How does steroids affect Ca2+ balance?
Negatively; dec GI absorption and renal reabsorption
What do steroids do to osteoBLASTs? To collagen?
decrease its activity
increases breakdown
What does steroids to do RANKL? To OPG?
increase
decrease
What do PG's do to renal blood flow and GFR?
decreases them
What causes Arachondic acid formation?
a stimulus
What Pg does COX go to first?
PgG2
What three things does steroids block?
PLA2, PLC, and COX
What 2 key features that AAcid have that COX-I's mimic?
acid center; double bonds (e- rich area)
COX adds ___ at Carbon #___. This causes a ____ group to form.
O2 at C11
cyclic
Which amino acid forms an ion bond with _COOH of AAcid?
Arg120
What does amino acid Tyr385 contribute to AAcid binding?
being an aromatic amino acid it offers e- density (pi-pi stacking)
Which two C's are oxidized in AAcid rxn?
C9 and C11
How does ASA uniquely modify COX?
by acetylating the Ser530 amino acid --> irreversible bond
ASA acts on Arg120 thru it's _____. What does this cause?
byproduct breakdown
blockage of COX competitively
Do salicylates modify COX like ASA? Why or why not?
No
Bc salicylates are the by-products of ASA, so only works on Arg120 and not Ser530
What is one way to know your ASA is no longer good? What caused this?
a vinegar smell
by moisture cleaving off the acetyl group now leaving only salicylic acid (can't modify COX)
At what form is ASA in to become trapped in the mucous buffer lining of the stomach?
ionized (ASA = weak acid)
If you sub out the hydroxyl group on ASA with an amide (--NH2) what will happen?
increase toxicity bc -NH2 would increase the compounds liphilicity (get into stomach cells easier and thus cause greater damage)
Why is Dolobid reversible?
bc's it only blocks COX, does not modify it
How many rings does Dolobid have? Why is this impt?
2
bc it's more like AAcid with increased e- density
What do added fluro groups do?
increase lipophlicity
yields greater analgesic properties in Sulindac than Indocin
What is Salsalate?
2 salicylic acids bound together
Where is it cleaved?
in the intestines
Why is Salsalate better for ASA intolerable people?
bc it's insoluble in stomach; gets cleaved in the intestines
Which carbon is affected when going from PgG2 to PgH2?
C15 gets oxidized
What amino acid blocks the pocket in COX-1? Why does it block it?
Ile523
bc of the ethyl group is too bulky
What amino acid is at the pocket in COX-2? Why does it allow binding in the pocket?
Val353
bc only a methyl group
What amino acid is inside the pocket of COX?
Arg513
In general how many C's is the acid group away from the ring system in NSAIDs (arylalkanoic acids) SAR?
1 carbon away; if increase the length what happens?
decease in activity of the NSAIDs
Adding a methyl group separating the acid center from the ring system in NSAIDs does what? What is the name classifies those that have that?
increases activity
profens
What is Indocin an analog of?
serotonin
In Indocin, is substitution prefered? If so where and what?
yes
5-position of the indole ring; --OCH3 or F
Is the N necessary for activity for Indocin?
no
The parent of Sulindac is a weak or strong COX-I?
weak
When is the metabolite of Sulindac activated? Why is this beneficial?
once gets thru stomach to liver
Bc less local COX-1 inhib in the stomach
What in Sulindac structure have poor water solubility?
the p-suloxide group (vs the p-Cl group that Indocin has)
Replacing the 5-methyl group (on Indocin) with 5-flouro group (on Sulidac) yields what?
greater analgesic properties
What isomer form is a more potent anti-inflam drug for Sulindac?
Z-isomer (Z same side --> F and sulfide)
Parent drug Sulindac has a t1/2 of ___. And the metabolite has a t1/2 of ___.
8 hours
16 hours
What planar effect is preferred for COX. Which isomer has that in Sulindac?
antiplanar
the Z isomer does
Why is DMSO so good at suspending drugs?
bc very lipohilic
What drug is DMSO reduced like? What's a result of this?
Sulindac
it inhibits/interferes with the metabolism of Sulindac
Tolmentin has strictly _____ properties.
anti-inflammatory
Ketorolac primarily has ____ properties
analgesic
Ketorolac's structure is the fused structure of what drug? What does this fusion do?
Tolmentin
prevents rotation of the compound; so ring is sticking out
What big side effect is increased with Ketorolac?
GI bleeding and post operative bleeding
The pleuotrophic effects of Diclofenac makes it a more potent ____ agent.
anti-inflammatory
What two compounds does Diclofenac inhibit (pleuotrophic effects)?
lipoxygenase synthesis and AAcid release
What is significant about misoprostol in Arthrotec?
it's a synthetic PgE1 --> reduces GI ulcers and erosion
What does the --OOCH3 addition (from --COOH) do to Misoprostol?
Increases the potency and duration of action bc it gets cleaved to the acid
What does the movement of the hydroxyl group from C15 to C16 (farther from the ring) do to Misoprostol?
Allows oral dosage (only 1 in US) and increases the duration of action
How does Etodolac increase some selectivity from COX2?
By decreasing COX 1 selectivity by increasing the number of C's btwn the ring and the acid
Is Etodolac less GI toxic? Which form only has AI activity?
Yes
S+
Where is Nabumetone absorbed? What is special about this drug?
Duodenum
non-acidic prodrug
What is Nabumetone bioactivated into?
6MNA
T/F The higher the irritancy # = the better
True; the lower = more GI problems (Nabumetone is 21.25 and Diclofenac is 0.72)
What chemistry happens to get to 6MNA from Nabumetone?
hepatic oxidation reaction removes 2 C's and adds active carboxy group
Which form of Ibuprofen becomes active in vivo?
R- (it turns into S+ so both become active)
Is extensive ionization good for Ibuprofen?
NO - increases excretion
Is Fenoprofen as good an AI as other drugs? What form is active in mixture?
No
S+
How is Ketoprofen unique in activity?
It stabilizes lysosomal membranes during inflammation; less GI toxicity
Ansaid has enhanced acidity because of these 2 added structure.
F and Ring (added to Ibuprofen back bone)
Anaprox is what from of Naproxen? When is it activated?
R-
In vivo
Naprosyn is what from of Naproxen? When is it activitated?
S+
In vitro
Is Naproxen better at COX-I than Indocin?
NO!!! 300x less COX inhib
6MNA is structurally similar to drug ____ without the ___ group.
Naproxen
methyl (--CH3) --> adds potency to Naproxen
Pirioxicam inhibits COX ___ as Indocin with a ___ half life.
equally
longer
Meloxicam and Piroxicam are interestingly not ___.
acids
3-carboxymide
In Oxicam's SAR what stucture is required for AI properties?
3-carboxymide
For Oxicams, what causes acidity?
resonance and de-localization
What makes Mobic preferential COX2-I?
the methyl-thiazolyl group (ring)
With Mobic what does increased acidity do?
Increase AI properties
What structurally group gives COX2-I selectivity?
p-sulfonamide
Is Celecoxib an acid?
no, non-acid
Celecoxib is metabolized primarily by ___ and inhibits ___ (CYPs)
CYP 2C9
CYP2D6 (inhibits)
What happens if patient is on Celebrex and Fluconazole?
Build up of Celebrex (cannot metabolize)
At high doses what channel did Vioxx bind to in the heart?
K+ channel (HERGG)
COX2 has been shown to be upregulated in what two incidences?
Alzheimer plaque and polyps in the colon
Is APAP more or less acidic?
Less ; basic drug with pKa of 9.5
What does acute alcoholic intake do to APAP metabolism in the liver?
dec the CYP450 enzyme so decreases active metabolite
What does chronic alcoholic intake do to APAP metabolism in the liver?
Upregulates CYP450 oxidases so more good and BAD metabolite being made --> inc risk of toxicity
Decrease in pH (like inflamed tissue) causes a(n) ___ in urate solubility and thus a(n) ___ in crystal formations
decrease
increase
What is Allopurinol a isomer of?
Hypoxanthine
Is Allopurinol competitive or non to Xanthine Oxidase? Is it reversible or not?
Competitive
Reversible
Why is Hypoxanthine and Xanthine ok to have in excess due to Allopurinol?
bc more water soluble that UA, easier to excrete
What contributes to Allopurinol's effect?
It's long active metabolite, Oxypurinol (non-competitive of XO)
What labs should be done with Gout? (5)
CBC, ESR, AST/ALT, Serum urate, and a urinalysis
What 3 medical conditions should be controlled when treating Gout?
HTN, DM, and Hyperlipidemia
Are NSAIDs good for treating geriatric patients with an acute attack of Gout?
no, even in short term use there is increased AE's
Can ppl with recent MI or CABG surgery take NSAIDs?
no
Dose for Indocin when treating Gout?
25-50 mg po qid x 3 days; then taper to 25-50 mg bid x 4-7 days
Dose for Naproxyn when treating Gout?
500 mg po bid x3 days; then 250-500mg qd x4-7 days
Dose for Sulindac when treating Gout?
200 mg po bid x7-10 days
What's the 1st line for Gout (when not CI)? How long should they be used for on average?
NSAIDs
8-10 days
What should be monitored when taking Colchicine long-term?
GI side effects, WBC/RBC count (checked every 6-12), SCr/BUN, Muscle weakness (neuromyopathy)
What are CI for NSAIDs? (4)
severe uncontrolled CHF; severe renal impairment; Active PUD; allergy to ASA (or another NSAID)
How long should Colchicine be used in conjunction with an urate lowering drug
3-6 months
Can Colchicine be used for preventative therapy?
Yes; what's the dose?
0.6 mg QOD to QD
How should Colchicine be taken if pt is also on Verapamil? Why?
two tabs for acute attck (1 then 1 hour later)
bc Verapamil is a moderate inhibitor of CYP3A4 (enzyme Colchicine is metabolized by)
How should Colchicine be taken if pt is also on Clarithromycin? Why?
1 tab followed by a 1/2 tablet 1 hour later
bc Clarithromycin is a strong inhibitor of CYP3A4 (enzyme Colchicine is metabolized by)
What is the current FDA regimen for Colchicine when treating acute attack of Gout?
two 0.6 mg tablets po followed by 1 tab one hour later
Do you get WBC increase with Colchicine?
NO!!! WBC decreases
Name some Colchicine CI's?
Serious renal disease, Serious GI disorder, Serious hepatic disorder, Serious cardiac disorder, and blood disorders
When should Colchicine be D/C when taking for an acute attack?
as soon as pain resolves
What is the Gout regimen for oral prednisone? How should it be tapered?
20-60 mg daily for 3-5 days
taper in 5 mg decrements each day over 7-14 days until discontinuation
What is Intra-articular trimacinolone acetaninde dose in Gout for large joint(s)? Small joint(s)?
large: 10-40 mg
small: 5-20 mg
usual dose for Allopurinol?
300 mg po qd
Name some SE's of Allopurinol.
Skin rash, GI upset, Musculoskeletal complaints, Leukopenia, liver toxicity, and severe hypersensitivity rxn
When should Allopurinol be initiated?
AT LEAST 1 month after acute attack; pt must be completely back to normalcy
Allopurinol and Amoxicillin increases what SE?
rash
Hypersensitivity risk increases when take Allopurinol plus ____ and ____.
ACE-I's and Thiazide diuretics
What labs should be monitiored while on Allopurinol? (5) When should they periodically be checked?
BUN, basic metabolic panel, AST/ALT, SCr, and CBC
6th and 12th months
Where is 90% of Uloric metabolized?
liver
What is the initial dose of Uloric? After 2 weeks and UA >6?
40 mg daily
80 mg daily
Does Uloric require use of a NSAID or Colchicine at initiation?
yes; just like Allopurinol
Is dose modification required on Uloric if there is mild/moderate renal insufficiency?
NO (unlike Allopurinol)
Can Uloric cause Cardiovascular SE's?
Yes...what 3 specifically?
MI, CHF, and thromboembolism (these should be monitored while taking med)
Initial dose of Probenecid? What's the max dose?
250 mg BID x 1-2 weeks; increase gradually to 500-2000mg/day
2 g
Probenecid is ineffective in CrCl that is ______.
less than 50 mL/min
T/F. Probenecid is CI if had a history of urolithiasis?
True
To prevent Kidney stones in GOUT what should protein intake be limited to?
<90 g/day
To increase urine pH what two drugs can be used?
Potassium bicarbonate (citrate) and acetylzolamide
Do OA patients typically have a fever?
No!
Acupuncture had a ___% decrease in pain and improvement in knee functions in OA patients.
40
Whats a good APAP starting dose in treating OA?
500 mg QID -- scheduled
Can APAP be taken along with tramadol or opoids in severe pain in OA?
yes, also with capsaicin and glucosamine (COMBO = Better)
What's the dosage of Tylenol XR or Tylenol Athritis?
650 mg XR; 1-2 tabs TID (no more that 5-6 tabs)
What's Salsalate's OA dosage?
500-1000 mg BID-TID
3g
What's Nabumetone's OA dosage? Max dose?
500 mg qd-bid
2g/day
What's Etodolac's OA dosage? Max dose?
300-500 mg bid
max: 1200 mg/day
What's dicolfenac's OA dosage? Max dose?
75 mg bid; XR 100 mg qd
200 mg/day
What's Piroxicam's OA dosage? Max dose?
10-20 mg qd
20mg/day
What's Meloxicam's OA dosage? Max dose?
7.5 mg qd
15mg/day
What's Ibuprofen's OA dosage? Max dose?
1200-3200 mg qd in 3-4 divided doses
3200 mg/day
What's Naproxen Sodium's OA dosage? Max dose?
275-550 mg bid
1375mg/day
What's Oxaprozin's OA dosage? Max dose?
600-1200 mg qd
1800mg/day
What's Celebrex's OA dosage? Max dose?
100mg bid or 200 mg qd
200 mg
How much should Celebrex's dose be reduced in an OA patient with hepatic impairment?
dec by 50%
What initial labs should be down before starting NSAIDs?
SCr, BUN, K+, CBC, AST/ALT, weight (bc of edema) and vital signs (like BP)
Can diabetes and pre-exisiting HTN/CVD increase risk of renal impairment with NSAIDs?
yes
What are some S/S of renal AE?
increased BP, SCr, Serum K+, BUN, Edema and weight gain
What two NSAIDs have a relatively higher risk of renal toxicity?
Indocin and Piroxicam
What oral agents are preferred in OA patients with CV disease or ischemic heart disease?
APAP, ASA, tramadol, opoids, and non-acetylated salicylates
How often should Capsaicin be used? How long before see full effects?
qid (or tid if after several weeks)
1-2 weeks
Where are topical salicylates used for OA?
the knee
What is Flector indicated for?
minor sprains, strains and bruises
Where is significant improvement seen when Volteran Gel is applied?
hands, knees
How often should Voltaren gel be applied daily? How many grams?
qid
upper = 2 grams (max 8g)
lower = 4 grams (max 16 g)
TOTAL MAX: 32 g
What is Pennsaid indicated for?
OA of the knee
How many times a year can injectable glucocorticoid be used? When will you see the peak pain relief and how long does it last?
3-4 times a year
peaks in 7-10 days; last 4-8 weeks
Glucosamine dose for OA? Which form is best?
at least 500 mg tid (with food)
sulfate over HCL salt form
Can people with shellfish allergy take Glucosamine or Chondroitin?
no
Chondroitin dose of OA?
at least 1200 mg daily with food
Tramadol dose for OA? Max dose?
50 mg q4-6 hours
200 mg/day
At what age and CrCl should Tramadol's dose be decreased?
75
<30mL/min
Name some SE's of Tramadol.
Sweating, constipation, nausea, dec seizure threshold (bad with SSRI's)
What 3 metabolisms does Glucocorticoids regulate?
carbohydrate, lipid and protein
T/F. Mineralocorticoids have AI effects
False
In 3-D space Alpha is ____ and Beta is ___.
coming out (towards you)
going into page (away from you)
Name some consequences of GR activation (AI effects)
Regression of:
BK B1 and B2 receptors;
COX-2;
IL-4R, IL-1beta, IL-6, IL-8. IL-11, iNOS;
PLA
Steroid biosynthesis leads to formation of _____, which serves as the precursor of all adrenocorticoids.
pregnenolone
Cortisone is converted to ____ in vivo.
Cortisol (hydrocortisone)
Which one has better oral bioavailability -- Cortisol or Cortisone?
Cortisol (95%)
Cortisone ____ly goes to MR's.
weak-ly
Cortisone has what unique structure that's converted in vivo?
ketone --> goes to alcohol (-OH) at C-11
What disease is Fludrocortisone used for? Why?
Addison's disease
bc in Addison's there's severe adrenocortical insufficiency and Fludrocortisone is very potent for GR and MR!
In steroids, what structure is required for GR activity? For MR?
11beta-OH group or 11-ketone group on ring C
C21-OH group on ring D
In steroids, why does adding C=C bond at C1-C2 greater for GR activity?
bc of changes in the structure's confirmation; chair --> half-chair --> FLAT-BOAT (which fits better at GR than MR pocket)
The 6alpha-methyl group does what for Methylprednisolone?
decreases affinity for MR and increases GR activity slightly
Why does the 16alpha-methyl group in Dexamethasone increase GR activity?
adds lipophilicity
Is Betamethasone more active than Dexamethasone? Is more toxic than other corticosteroids?
yes
no; less toxic SE's