Pharm Flashcards
Describe the anti-inflammatory effects of steroids?
- bind and block promoter sites of proinflammatory genes IL-1 alpha and IL-2 beta, interacts directly w/ specific DNA sequences and other transcription factors
- decreased production of tumor necrosis factor alpha
- multiple cell specific effects
- inhibition of proinflammatory mediators:
phospholipase A2
cyclooxygenase 2
nitric oxide synthetase
prostaglandins
leukotrienes
thromboxanes
Glucocorticoid effect on leukocytes?
- decreased adherence to vascular endothelium: cant exit circulation as readily, entry to sites of infection and tissue injury impaired
Glucocorticoid effect on other cells (neutrophils, eosinophils, monocytes, lymphocytes)?
- increase in neutrophils results in increased WBC: impaired transport, increased production from bone marrow, decreased apoptosis
- decrease eosinophils: increased apoptosis, trapped in tissues
- decrease in monocytes: decreased tissue accumulation, decreased migration from vasculature
- decrease in lymphocytes - inhibition of T lymphocytes
glucocorticoid effects of acquired immunity?
- decreased ag presenting cells: macrophages, dendritic cells - really decrease T cells and also B cells
If on chronic glucocorticoid therapy - what vaccines are CI?
- live virus vaccines:
MMR, varicella, small pox
What are you at increased risk for if on glucocorticoids? How does duration of therapy change this?
- short term high dose therapy: immediate reduction of phagocytic responses
- long term therapy: main infections:
herpes zoster
staph
candida
Major SEs assoc w/ glucocorticoid therapy?
generally time and dose dependent:
- derm and soft tissue: skin thinning and appearance, alopecia, acne, hirsutism, straie, hypertrichosis
- eye: cataract, IOP, glaucoma, exophthalmos
- CV: arrhythmias, HTN, disturbance of lipoproteins, premature atherosclerotic disease
- GI: gastritis, PUD, pancreatitis, steatohepatitis, visceral perforation
- Renal: hypokalemia, fluid volume shifts
- GU and repro: amenorrhea, infertility, intrauterine growth retardation
- bone: osteoporosis, avascular necrosis
- muscle: myopathy
- neuropsych: euphoria, dysphoria/depression, insomnia, mania/psychosis, pseudotumor cerebri
- endocrine: DM, hypothalamic-pituitary adrenal insufficiency
- infectious disease: heightened risk of typical infetions, opp. infections, herpes zoster
Glucocorticoid actions on the bones?
- bone resorption leading to decreased bone integrity
- decreased osteoblastic activity - decreased bone formation
What should you monitor regularly for pts on chronic steroids?
- BP
- serum glucose
- lipid profile
- eye exam
- bone density
Pros of steroids?
- no dose adjustment needed in renal impairment
- generally give good sx relief for pain secondary to inflammation
What should be used for short term sx management in RA?
- NSAIDs or glucocorticoids can be used
- withdrawal once DMARDs have taken effect
Fxn of NSAIDs in RA?
- may alleviate sxs
- don’t prevent irreversible jt damage
Fxn of glucocorticoids in RA?
- good for quick sx relief
- generally avoid long term admin due to toxicities
- don’t have a very profound effect on decreasing jt destruction
Use of DMARDs and success in RA?
- variable response among pts
- d/c rate high due to toxicity or lack of efficacy
- in general are continued indefinitely unless sig toxicity occurs
- categorized as biological and nonbiological
Nonbiological DMARDs?
- methotrexate
- sulfasalazine
- hydroxychoroquine
- leflunomide
- D-Penicillamine
- gold salt
- azithroprine
- cyclosporine
Biological DMARDs?
- etanercept
- adilimumab
- infliximab
- aakinra
- abatacept
What should you do if there is failure to achieve remission in 3 months on DMARD therapy?
- change DMARD
- or go to combo therapy
How long does it take DMARD to be maximally effective?
- 3-6 months - assess efficacy: if undesirable results add on therapy or switch to another agent
Drug choice is dependent on what factors in RA (DMARDs)?
- disease severity
- prognostic factors
- pt preference
DMARD of choice for initial tx of RA?
- methotrexate (rheumatrex)
- benefit seen in 2-6 wks
- generally well tolerated
- starting dose 7.5 mg once weekly
- also MC used drug for RA
MOA of methotrexate? What needs to be supplemented?
- stimulates adenosine release from fibroblasts and endothelial cells
- reduces neutrophil adhesion
- suppression of cell mediated immunity
- antiproliferative effect on synovial fibroblasts and endothelial cells
- inhibition of IL-1, IL-6, and IL-8
- inhibits synovial collegenase gene suppression
- structual analog of folic acid, inhibits binding of dihydrofolic acid to dihydrofolate reductase inhibiting purine synthesis
- all pts need supplemental folic acid of 1 mg daily
- minimal drug interactions, renal excretion, 50% protein bound
CIs and dosing of methotrexate?
- PO, IM, SQ
- CIs:
women who are contemplating pregnancy
preg
liver disease or excessive ETOH intake
GFR less than 30 ml/min - wk dosing: don’t spread the dose out over the week, otherwise liver toxicity
SEs of methotrexate?
- hepatotoxicity
- pulm toxicity
- myelosuppression
- nephrotoxicity
- fatigue
- decreased ability to concentrate
- alopecia
- nausea
- upset stomach
- loose stools
- soreness of mouth
- rash on extremities
- HA
- fever
- at about 2-5 yrs up to 35% of pts have d/c drug due to SEs
Toxicity of methotrexate? What monitoring is done?
- myelosuppression: worse if concomitant use of NSAIDs
- hepatotoxicity including cirrhosis
- pulm toxicity
monitoring: q 1-2 months
- CBC
- LFTs
- albumin
- Cr
- pre tx CXR
Use of sulfasalazine (azulfdine) for RA? MOA?
- 2nd line drug for RA MOA: -inhibition of PMN cell -migration -reduced lymphocyte responses - inhibits angiogenesis - decreases inflammatory cytokines and IgM rheumatoid factor production
Metabolism and excretion of sulfasalazine?
30% absorbed in small bowel then excreted into feces in the bile = about 90% of drug remains in feces by time it reaches large bowel
- need coliform bacteria to break it down into sulfapyridine and 5-aminosalicylic acid
CI to sulfasalazine?
- sulfa allergy
- preg cat D (at full term)
- GI or GU tract obstruction
- porphyria
- platelet ct less than 50k
- LFTs greater than 3x ULN
- hepatitis
- men that want to conceive
SEs of sulfasalazine?
dose dependent
- nausea and diarrhea
- intestinal or urinary obstruction
- oral ulcers
- orange yellow pigmentation of skin
- HA
- depression
- neutropenia
- thrombocytopenia (this and neutropenia occurs in up to 25% of pts)
- agranulocytosis
Monitoring for toxicity of sulfasalaxine?
- toxicity: myelosuppression
- monitoring:
CBC monthly x 3
then CBC q 3 months
Use of leflunomide (Avara) in RA?
- antiinflammatory
- antiproliferative
- decreases progression of jt erosions and jt space narrowing
MOA of leflunomide (Avara)?
- competitive inhibitor dihydrofolate reductase
- this decreases the production of pyrimidines: decreased B and T cell proliferation
- similar to methotrexate
- MTX inhibits purine synthesis
- leflunomide inhibits pyrimidine synthesis
Half life of Leflunomide? What should women that want to conceive do?
- half life of active metabolite: 15-18 days
washout perior for women who want to conceive is 2 yrs.
Activated charcoal and cholestyramine can be used to reduce the half life to 1 day - time to response: 1-3 months
CI to Leflunomide?
- pregnancy
- preexisting liver disease
- alcoholism
SEs of Leflunomide?
- MC: diarrhea, rash, reversible alopecia, hepatoxicity
- wt loss
- HTN
- bone marrow suppression
Toxicity and monitoring of Leflunomide?
- toxicity: hepatotoxicity bone marrow suppression - monitoring: monthly x 6 mo, then q 2 months CBC liver enzymes Creatinine
Leflunomide (avara) interactions?
- weak inhibitor of CYP2C9
- may increase warfarin levels
- Rifampin may increase levels of leflunomide
- bile acid sequesterants decrease effectiveness of leflunomide
- really only use this if pt isn’t tolerating methotrexate
What is hydroxychloroquine? When is it used?
- antimalarial
- doesn’t limit progression of RA - used as a single agent only with mild RA and no evidence of jt destruction on X-ray, and no inflammatory markers or autoimmune markers on labs - otherwise usually is add on to methotrexate
- time to response:
2-6 months
MOA of hydroxychloroquine? Toxicity and monitoring?
MOA:
interferes w/ normal ag processing, inhibits lysosomal enzymes and IL-1 release, inhibition of PMNs and lymphocyte responses
- toxicty:
macular damage
- monitoring:
fundoscopic and visual field exams q 6-12 months
SEs and drug interaction of hydroxychloroquine?
- SEs: nausea diarrhea abdominal discomfort photosensitivity skin pigmentation changes rash macular damage - drug interactions: decreased metabolism of BBs (except for atenolol and nadolol), may increase cyclosporine and digoxin levels
What do you use in tx of severe RA?
- use of combo DMARD therapy
- switch to another TNF inhibitor w/ different MOA
- may need ongoing glucocorticoid therapy
- may need ongoing NSAIDs
- no role for narcotic analgesics unless end stage disease
What TNF inhibitors are used in tx of RA?
- Etanercept (enbrel)
SQ injection 1-2 times weekly, self admin - Infliximab (remicade): IV infusion q 6 wks
- Adalimumab (Humira): SQ injection q 2 wks
MOA of TNF blockers?
- bind to TNF-alpha making it inactive:
interferes w/ inflammatory activity - decreased production of IL-6 and CRP, ultimately decreasing jt damage - bind to surface TNF alpha, cell lysis occurs
- time to effect: 2-3 doses
SEs of TNF inhibitors?
- injection site infections
- infusion rxn infliximab (remicade)
- serious infections leading to sepsis
- don’t admin live vaccines while on meds
- response to other vaccines may be diminishes
- stop med until infections clear
CIs of TNF inhibitors?
- latent TB infection: BBW: need TB test b/f starting meds
- high risk for opportunistic infections
When can remicade not be used (Interaction)?
- not to be used in conjunction w/ abatacept (orencia) or anakinra (Kineret) due to increased risk of infection
Why is infliximab used in conjunction w/ methotrexate?
- b/c decreases development of infliximab abs
Cost of TNF inhibitors?
- all spendy
- etanercept - usual dose is 25 mg sq wkly or 50mg sq once wkly - $758/wk or $39, 416/yr
Toxicity and monitoring of TNF inhibitors?
- toxicity: injection site rxn increased risk of local or systemic infection - monitoring: PPD prior to therapy periodic CBC
What is Anakinra (Kineret)? MOA?
- immune modulator - recombinant IL-1 receptor antagonist
- daily SQ injection
- MOA: blocks IL-1 receptor to decrease degree of jt destruction and inflammation
- dose response: w/in 12 wks
Cautions w/ Anakinra use?
- decrease dose in w/ GFR less than 30ml/min
- no known pharmacokinetic drug interactions
- don’t give in combo w/ TNF inhibitors due to increased risk of infection
CIs of Anakinra use?
- sensitivity to E coli derived proteins
- preexisting infection or high risk for infection
- not to be used in combo w/ TNF inhibitors
SEs of Anakinra?
- skin irritation at injection site (50% of pts): erythema, inflammation, pain
- infection
- possibility of angioedema and anaphylaxis
- decrease in WBCs:
monitoring - CBC monthly x3 then q 4 months x 1 yr
What are the nonpreferred DMARDs?
- D-penicillamine (depen, cuprimine)
- azithroprine (Imuran)
- cyclosporine A (sandimmune, Neoral)
- gold compounds
What is D-penicillamine (Depen, Cuprimine)? Role in RA?
- chelating agent used for tx of: wilson’s disease, arsenic poisoning, copper, lead and mercury poisoning
- unknown mechanism in RA other than depresses T cell activity
- preg D
What is Azithroprine (Imuran)? Preg? adjust dose for what? Downside?
- prodrug for mercaptopurine
- inhibitrs enzymatic actiivity reqd for DNA sythesis: decreased production of T and B cells
- adjust dose for decreased renal clearance
- preg D
- major toxicity is bone marrow suppression
- carcinogenic:
lymphoma in post transplant pts, hepatosplenic T cell lymphoma in IBD pts
What is the MOA of cyclosporine A (Sandimmune, Neoral)? Major toxicity? BBW?
- blocks activation of T cells and IL-2
- follow blood levels
- many drug interaction that increase its concentration
- sandimmune and neoral are not bioequivalent
- major toxicity is renal failure
- BBW: only physicians experienced in immunosuppressive therapy should rx this - SO STAY AWAY from this!
Use of Gold compounds in tx of RA? MOA?
- parenteral gold (injection) has similar efficacy but greater toxicity compared w/ other traditional (DMARDs) used in RA
- oral gold has less efficacy than most other agents
- starting dose for oral therapy is $1345/month
- MOA: unknown, decreases prostaglandin production
- mostly used as an add on
What meds should a lupus pt avoid that may provoke exacerbations?
- sulfa containing abx: sulfadiazine, trimethoprim/sulfamethoxazole
- minocycline
- oral contraceptives
What meds are notorious for causing drug induced lupus?
- procainamide
- hydralazine
- griseofulvin
- these meds don’t seem to cause exacerbations of idiopathic lupus but may cause drug induced lupus
Meds in lupus targeted for specific organ/system involvement?
- antimalarials work for both cutaneous and MSK involvement: hydroxycholorquine, may prevent renal and CNS damage, may decrease disease flares
- cutaneous: topical therapies whenever possible
- MSK: NSAIDs
What is used in lupus pt if there is sig organ involvement?
glucocorticoids
- cardiopulmonary
- hepatic
- renal
- hemolytic anemia
- immune thrombocytopenia
- other immune modulators used for severe disease and when steroid resistant: methotrexate, cyclophosphamide, azathiprine, mycophenolate, rituximab
What should be the tx for lupus pt if antiphospholipid ab positive?
- lifelong anticoag: warfarin to achieve INR of 2-3
Tx of acute attacks of gout?
1 - NSAIDs
naproxen, indomethacin
2 - colchine
3 - steroids
How can gout be prevented?
- avoidance of meds that increase uric acid
- decrease serum uric acid:
xanthine oxidase inhibitors: allopurinol (zyloprim), febuxostat
uricosuric drugs: probenecid
What are the general principles of gout tx?
- start meds as soon as pt perceives an attack coming on
- ok to stop tx 2-3 days after sx resolution unless steroids then need a slower taper to prevent rebound attack
- don’t initiate urate-lowering therapies in acute gout
Tx in acute gout?
- NSAIDs: if no CI exist (ulcers, renal failure, GI bleeding, allergy)
- colchicine: use if CI to NSAIDs
- corticosteroids: use if CI to NSAIDs and colchicine or if other therapies fail to resolve sxs
MOA of NSAIDs in gout? CIs?
- in general inhibit cyclooxygenase and ultimately production of mediators of inflammation: prostaglandins, prostacyclin, thromboxane
- CIs:
CrCl less than 60ml/min, active duodenal or gastric ulcers, heart failure, uncontrolled HTN, allergy, chronic anticoag
NSAIDs lead to an increased risk of what? For pts on ASA what should they do?
- lead to increased risk of stroke, MI, CHF, afib, CV death
- naproxen at high doses doesn’t seem to increase CV risks but at lower doses is similar to other NSAIDs
- risks seem to increase for long term use (over 1 month)
- for pts on aspirin: take 1 ASA 2 hrs prior to NSAID therapy
Duration of NSAIDs in acute gout tx? What NSAIDs are used?
- key to sx relief is beginning tx at onset of sxs
- 5-7 days of therapy is usual
- can reduce dose if needed after good sx response
- continue for about 2 days after complete resolution of sxs
- Indomethacin: 50 mg TID
- Naproxen: 500 mg BID
- Celecoxib (celebrex) - cox2 inhibitor - less GI bleeding: 800 mg initial dose then decrease to 400 mg BID, avoid if hx of sulfa allergy
When is colchicine (colcrys) used in gout tx?
- for acute attacks
- use if NSAID intolerance or CI
- most likely to be effective if tx started w/in 24 hrs of sx onset
- not beneficial for attacks ongoing for more than 72 hrs
- if loading dose w/in last 2 wks - don’t repeat it
- loading dose is 1.2 mg
- followed by a dose of 0.6 mg 1 hr later then 12 hrs later move to dosing for prophylaxis 0.6 mg QD or BID
- if already on chronic colchine and have acute attack - give a loading dose and then continue on to BID dosing
MOA of colchicine? Metabolism, preg?
- MOA: prevents activation degranulation and migration of neutrophils assoc w/ mediating some gout sxs
- onset of action to pain relief: 18-24 hrs
- metabolism: hepatic via CYP3A4
- half life: 27-31 hrs
- time to peak serum concentration: 30 min to 3 hrs
- preg cat: C
SEs of colchicine?
- diarrhea up to 77%
- nausea
- vomiting
- reversible peripheral neuropathy
- bone marrow suppression
- myopathy: at risk if renal dysfxn, elderly or concomitant use of:
cyclosporine, diltiazem, verapamil, fibrates, statins
When should you make dose adjustments of colchicine?
- older than 70
- CrCl less than 30 ml minute
- avoid in dialysis pts
in these drugs:
- strong CYP3A4 inhibitors: clarithromycin, itraconazole, ketoconazoel, nefazodone, HIV protease inhibitors
- moderate CYP3A4 inhibitors: diltiazem, erythromycin, fluconazole, grape fruit juice, verapamil
- P-glycoprotein inhibitors: cyclosporine, ranolazine, amiodarone
CIs to colchicine?
- renal impairment
- hepatic impairment
If no relief of sxs of gout while on colchicine what should you od?
- add on glucocortiocoid if no relief after 24 hrs
- or may be used cautiously in conjunction w/ an NSAID (if not CI)
Types of glucocortiocoids used in gout?
- intraarticular
- oral: for those who can’t take NSAIDs, colchicine and not candidates for jt injection
- prednisone 30-50 mg daily until resolution then taper off over a wk
- IV or IM: if not a candidate for any other route or med
What is used as management b/t gout attacks?
- avoidance of meds that increase uric acid or inhibit renal excretion of uric acid:
thiazide and loop diuretics
niacin
aspirin - meds to reduce serum uric acid are indicated if:
2 or more episodes/yr
tophi
chronic kidney disease, stage 2 or greater
How long should you wait after an acute attack of gout b/f initiating prevention therapy? What can this stimulate?
- wait 2 wks
- initiation of antihyperuricemic therapy can stimulate a gout attack
- lowering the uric acid levels too quickly can stimulate a gout attack
- prophylactic colchicine therapy is used when initiating urate lowering therapy to reduce attacks:
colchicine 0.6 mg qday to BID
When is allopurinol used? what is goal for serum urate level?
- agent of choice for urate lowering
- xanthine oxidase inhibitor
- goal for serum urate level is less than 6 - check 2-4 wks after dose adjustment, recheck in 3 months to confirm, recheck q 6 months to yearly
MOA of allopurinol?
- inhibits xanthine oxidase needed for eventual conversion of hypoxanthine to uric acid
- onset of action: 1-2 wks
- half life: active metabolite: 18-30 hrs
- adjust dose for renal impairment:
100mg daily for CrCl over 60ml/min
lower dose for less than 60ml/min - normal adult dosing:
100 mg/day and increase weekly to 200-600mg/day depending on disease severity and urate levels
SEs of Allopurinol?
- skin rash: D/C drug
- gout attack
- diarrhea
- nausea
- elevated liver enzymes
- hypersenitivity rxns (SJS):
ACEI, amoxicillin/ampicillin, diuretics - bone marrow suppression:
use w/ caution w/ other drugs that cause myelosuppression - hepatotoxicity
When is probenecid used? MOA? CI?
- 2nd line agent if unable to take allopurinol
- uricosuric agent
- blocks tubular reabsorption of filtered urate and increases uric acid excretion by the kidney
- not effective if CrCl less than 50ml/min
- CI: hx of nephrolithiasis (uric acid or Ca stones)
Drug interactions w/ probenecid? Prevention of uric acid stones?
- lots of drug interactions: causes an increase in concentration of other drugs - PCN
- to prevent development of uric acid stones - pt education to increase fluid intake, may need an agent to alkalinize the urine - potassium citrate to maintain urine pH over 6
What meds decrease uric acid levels?
- losartan
- fenofibrate
- vitamin C 500mg daily
- cherries
NSAIDs and steroids cause what? and what can this cause? What should you monitor?
- they cause fluid retention
- cause HTN
- may cause sig CHF exacerbations
- many hosp admissions for CHF have been caused by admin of these meds
- need to monitor closely for edema in pts at high risk for fluid retention and may need to adjust usual diuretic doses during tx
