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Pharmacology I > Module 2 > Flashcards

Module 2 Flashcards

NSAIDS/APAP/CORTICOSTEROIDS/DMARDS

1
Q

What chemicals are released by damaged cells in inflammation?

A

histamine, kinins, and prostaglandins

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2
Q

First step of inflammation

A

activation of innate and adaptive immune cells and production of cytokines

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3
Q

Second step of inflammation

A

vasodilation and increased permeability of blood vessels

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4
Q

Third step of inflammation

A

phagocyte migration to site of damage and phagocytosis (neutrophils, macrophages, mast cells)

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5
Q

Fourth step of inflammation

A

elimination of microbes and/or damaged cells and eventual tissue repair

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6
Q

Function of cyclooxygenase (COX)

A

converts arachidonic acid into prostaglandins (PGI2) and
related compounds (prostacyclin, thromboxane A2 (TXA2)

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7
Q

Aspirin (Salicylate)

A

irreversible inhibitor of COX-1 and COX-2 (acetylates a serine residue in the active site for both COX-1 and 2)

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8
Q

Non-aspirin NSAIDs mechanism of action

A

reversible (competitive) inhibitors of COX-1 and COX-2

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9
Q

first-generation NSAID mechanism of action

A

nonselective inhibition of both COX-1 and COX-2 (includes aspirin, ibuprofen, naproxen, ketorolac, diclofenac, indomethacin)

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10
Q

second-generation NSAID (celecoxib) mechanism of action

A

selective inhibition of COX-2, metabolized in liver by CYP2C9, half life = 11 hours

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11
Q

acetaminophen (APAP) mechanism of action

A

Reversibly inhibits COX-1 and COX-2 (prostaglandin synthesis) in CNS, has minimal effect on cyclooxygenase in peripheral tissue and therefore has minimal anti-inflammatory effect. Does not affect platelets.

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12
Q

Aspirin metabolism kinetics

A

follows first-order kinetics (where a constant fraction of drug is eliminated per unit of time, half life = 3.5 hrs) at low doses but changes to zero-order kinetics (where a constant amount of drug is eliminated per unit of time, half life = 12 hrs) at high anti-inflammatory doses (more than 4 g/d). Aspirin is rapidly metabolized in the liver and cleared by the kidney.

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12
Q

Advantages of aspirin

A

reduces platelet aggregation at low doses, antipyretic and analgesic at moderate doses, anti-inflammatory at high doses

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13
Q

Disadvantages of aspirin

A

May pose higher risk for GI events due to higher relative selectivity for COX-1 compared to those with lower selectivity for COX-1 (such as celecoxib). If aspirin is used in patients at high risk for GI events, PPIs should be used concomitantly to prevent NSAID-induced ulcers. Poses risk for Reye syndrome in children with viral infection.

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14
Q

Advantages of nonselective NSAIDs

A

Have antipyretic, analgesic, and anti-inflammatory activity through inhibition of both cyclooxygenase enzymes which catalyze the first step in prostaglandin synthesis.

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15
Q

Disadvantages of nonselective NSAIDs

A

Can cause negative gastrointestinal effects ranging from dyspepsia to bleeding. Because nonselective NSAIDs inhibit COX-1, they reduce beneficial levels of prostaglandins PGE2 and PGF and result in increased gastric acid secretion, diminished mucus production, and increased risk for GI bleeding and ulceration. If used in patients at high risk for GI events, PPIs should be used concomitantly to prevent ulcers.

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16
Q

Advantages of celecoxib (COX-2 inh.)

A

Mediates inflammation and pain through inhibition of COX-2, sparing COX-1, which helps maintain gastric mucosa (is associated with less GI bleeding and dyspepsia than other NSAIDs). It has no effect on platelet aggregation. Good treatment for acute pain, RA, and OA.

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17
Q

Disadvantages of celecoxib (COX-2 inh.)

A

increased risk of thrombosis due to selective inhibition of COX-2, renal ischemia, avoid in Sulfa allergy

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18
Q

What are the antiinflammatory effects of glucocorticoids?

A

Glucocorticoids lower circulating lymphocytes and inhibit the ability of leukocytes and macrophages to respond to mitogens and antigens. They also decrease the production and release of proinflammatory cytokines and block the release of arachidonic acid resulting in anti-inflammatory actions. Glucocorticoids also stabilize mast cell and basophil membranes, thereby decreasing histamine release.

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19
Q

Indications for steroid use

A

Can be used to treat severe allergic reactions, asthma, RA, other inflammatory or autoimmune disorders, and some cancers.

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20
Q

Adverse effects of steroid use

A

Osteoporosis is the most common adverse effect of long-term therapy but steroid use can also cause adrenal suppression, increased blood glucose, insomnia, mood swings, psychiatric disturbances, and fluid retention in patients with renal impairment. Sudden discontinuation of steroids can cause acute adrenal insufficiency that can be fatal.

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21
Q

clinical use of aspirin

A

Aspirin reduces fever, inflammation at very high doses, and pain at lower doses. It can also be used to reduce vasoconstriction and platelet aggregation (to reduce the risk of recurrent cardiovascular events) at low doses (commonly 81 mg) through irreversible inhibition of COX-1.

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22
Q

clinical use of nonaspirin nonselective NSAIDs

A

nonselective NSAIDs reduce inflammation, pain, and fever and are used mainly for the management of mild to moderate pain arising from MSK disorders such as OA, gout, and RA. Ibuprofen and naproxen in this class may be used to treat fever

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23
Q

clinical use of nonaspirin selective NSAIDs (celecoxib)

A

celecoxib reduces inflammation and pain and can be used to treat OA, RA, and acute pain

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24
Q

clinical use of acetaminophen

A

reduces pain and fever but is not considered an NSAID. It is used in patients with gastric complaints/risks with NSAIDs and those who do not require the antiinflammatory action of NSAIDs. Best choice for children with viral infections due to the risk of Reye syndrome with aspirin.

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25
Q

Factors that affect the renal elimination of aspirin

A

increasing the pH of urine from 6-8 can increase the rate of aspirin excretion by fourfold whereas renal and cardiovascular disease can decrease the rate of renal elimination due to decreased blood volume/flow

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26
Q

contraindications of aspirin

A

should be avoided in gout if possible or in patients taking probenecid. Avoid in children with viral illnesses due to risk of Reye syndrome. Avoid taking with warfarin, phenytoin, and valproic acid (or reduce dosage) due to potential accumulation of these drugs to toxic levels.

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27
Q

contraindications of NSAIDs

A

CABG patients for peri-operative pain due to increased risk of serious and potentially fatal cardiovascular thrombotic event, patients with cardiovascular risk factors (hypertension, history of MI, angina, edema, etc.), during pregnancy

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28
Q

contraindications for acetaminophen

A

patients with severe hepatic impairment, viral hepatitis, or a history of alcoholism are at higher risk for acetaminophen-induced hepatotoxicity

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29
Q

contraindications for celecoxib

A

patients who are at high risk for gastric ulcers and those who require aspirin for cardiovascular prevention, inhibitors of CYP2C9 such as fluconazole can increase serum levels of celecoxib

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30
Q

short-acting corticosteroids

A

cortisone, hydrocortisone (half-life = 8-12 hours)

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31
Q

intermediate-acting corticosteroids

A

prednisone, prednisolone, methylprednisolone, triamcinolone (half-life = 18-36 hours)

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32
Q

long-acting corticosteroids

A

betamethasone, dexamethasone (half-life = 36-55 hours)

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33
Q

gout

A

the build-up of uric acid crystals in kidneys and joints which causes inflammation

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34
Q

causes of hyperuricemia (gout)

A

purine-rich diet, alcohol, and kidney disease

35
Q

hyperuricemia

A

blood uric acid above 7 mg/dL in men and 6 mg/dL in women which can be caused by excessive production of uric acid or impaired renal excretion of uric acid

36
Q

Xanthine Oxidase Inhibitors

A

Purine analogs that inhibit the last two steps in uric acid biosynthesis catalyzed by xanthine oxidase (competitively bind to xanthine oxidase) thereby reducing hyperuricemia (Allopurinol, febuxostat).

37
Q

Uricosuric acids

A

Act on renal tubules to inhibit the reabsorption of uric acid increasing the excretion of uric acid and reducing hyperuricemia (Probenecid).

38
Q

Indomethacin

A

commonly used NSAID to treat acute gout and inflammation and decreases granulocytes in the area

39
Q

Colchicine

A

Anntiinflammatory agent that inhibits leukocyte infiltration by disrupting microtubules. It has two applications in gout - short-term use to treat acute gouty attacks and long-term use to prevent attacks from recurring.

40
Q

Prednisone

A

NSAIDs are usually preferred but prednisone can be given orally or intramuscularly and is highly effective in relieving an acute gouty attack.

41
Q

Allopurinol (Zyloprim)

A

Drug of choice for chronic tophaceous gout. By reducing blood uric acid levels, allopurinol prevents the formation of new tophi and causes regression of tophi that have already formed, thereby allowing joint function to improve. Reversal of hyperuricemia also decreases the risk for nephropathy from the deposition of urate crystals in the kidney.

42
Q

Febuxostat (Uloric)

A

Febuxostat is an alternative to allopurinol. Like allopurinol, febuxostat lowers urate levels by inhibiting XO. As with allopurinol, symptoms of gout may flare during initial therapy. Accordingly, patients should receive prophylactic NSAIDs or colchicine for up to 6 months after starting treatment.

43
Q

Probenecid (Benuryl)

A

Treats gout by increasing the excretion of uric acid. By lowering plasma urate levels, probenecid also prevents formation of new tophi and facilitates regression of existing tophi. In addition to its use in gout,
probenecid may be employed to prolong the effects of penicillin and cephalosporin by delaying their excretion by the kidneys.

44
Q

Adverse effects of Colchicine

A

causes nausea, vomiting, abdominal pain, and diarrhea and chronic admin may lead to myopathy, neutropenia, aplastic anemia, and alopecia

45
Q

Adverse effects of Allopurinol

A

usually well tolerated but can cause skin rashes and risk is increased in those with reduced renal function

46
Q

Adverse effects of Febuxostat

A

similar to allopurinol but there may be a greater risk in patients with a history of heart disease or stroke as it may be associated with increased risk of these events

47
Q

Adverse effects of Probenecid

A

nausea, vomiting, dermatologic reactions, and rarely, anemia or anaphylactic reactions

48
Q

Colchicine drug interactions

A

statins due to increased risk of rhabdomyolysis, PGP and CYP3A4 inhibitors due to the build-up of colchicine to toxic levels

49
Q

Allopurinol drug interactions

A

warfarin due to the inhibition of hepatic drug-metabolizing enzymes by allopurinol which delays warfarin’s inactivation (dose should be reduced) and other drugs that are substrates for XO (especially theophylline, mercaptopurine, and azathioprine)

50
Q

Febuxostat drug interactions

A

drugs that are substrates for XO (especially theophylline, mercaptopurine, and azathioprine)

51
Q

Probenecid drug interactions

A

salicylates (aspirin) which interfere with the uricosuric action of probenecid, indomethacin and sulfonamides due to probenecid’s inhibition of their renal excretion

52
Q

Colchicine contraindications

A

older and debilitated patients as well as patients with cardiac, renal, hepatic, and GI disease (avoid if CrCl <50 mL/min).
Pregnancy unless perceived benefits outweigh potential risks

53
Q

Allopurinol contraindications

A

patients with renal impairment in which the dose would need to be reduced due to the risk of drug accumulation

54
Q

Aspirin in treatment of gout

A

contraindicated because it competes with uric acid for the organic acids secretion mechanism in the proximal tubule of the kidney

55
Q

Probenecid contraindications

A

patients with CrCL < 50 mL/min

56
Q

Treatment of acute gout

A

indomethacin and nonaspirin NSAIDs are used to treat inflammation and pain in acute gout and colchicine can be used for both acute and chronic gout to decrease immune cell chemotaxis

57
Q

Treatment of chronic gout

A

allopurinol and febuxostat are used to treat chronic gout by reducing uric acid formation and probenecid can be used to treat chronic gout by increasing excretion of uric acid through the kidneys

58
Q

Non-biologic/conventional DMARDs

A

methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine

59
Q

Biologic DMARDS

A

Adalimumab (Humira), Infliximab (Remicade), Etanercept (Enbrel), Anakinra, and Rituximab

60
Q

Methotrexate (MTX, Rheumatrex, Trexall, Rasuvo)

A

Interferes with folate metabolism by acting as a competitive inhibitor for the enzyme dihydrofolate reductase resulting in immunosuppression secondary to reducing the activity of B and T lymphocytes. It is the DMARD of first choice owing to its efficacy, relative safety, and low cost. It can be used in conjunction with other DMARDs to slow disease progression. Therapeutic effects may develop in 3-6 weeks.

61
Q

Leflunomide (Arava)

A

Causes cell arrest of autoimmune lymphocytes by reversibly inhibiting pyrimidine synthesis (dihydrooroate dehydrogenase DHODH) thereby interfering with DNA synthesis that is required for proliferation. Compared with methotrexate, leflunomide is about equally effective but is potentially more hazardous and more expensive. Accordingly, the drug is often reserved for second-line use.

62
Q

Hydroxychloroquine (HCQ, Plaquenil)

A

An antimalarial drug that involves inhibition of phospholipases and antagonism of prostaglandins, decreased platelet aggregation, inhibition of endosomal activation, decreased activation through toll-like receptors, and suppressed antioxidant activity. Typically used in combination with methotrexate to treat early and mild RA. Full therapeutic effects take 3-6 months to develop

63
Q

Sulfasalazine (Azulfidine)

A

Metabolized by gut bacteria into 5-ASA (amino-salicylic acid) and sulfapyridine.
5-ASA reduces inflammation by suppressing prostaglandin synthesis; sulfapyridine causes adverse effects. Has been used for decades to treat IBD. Benefits for RA may result from antiinflammatory and immunomodulatory actions. In patients with RA, sulfasalazine can slow the progression of joint deterioration sometimes with just 1 month of treatment.

64
Q

Etanercept

A

Genetically engineered fusion protein that binds to and inhibits TNF-alpha (human recombinant receptor). Combination of etanercept and methotrexate is more effective than either therapy alone.

65
Q

Infliximab

A

Chimeric IgG monoclonal antibody that binds to TNF-alpha. Combination therapy with methotrexate is recommended.
Not indicated for monotherapy – anti-infliximab antibodies may develop.

66
Q

Adalimumab

A

Human recombinant antibody that binds to TNF-alpha. May be used as monotherapy or in combination therapy.

67
Q

Rituximab

A

Genetically engineered chimeric murine/human monoclonal antibody directed against CD20 antigen on the cell surface of B cells. Treatment with rituximab results in B cell apoptosis (through complement activation and antibody-dependent cell-mediated cytotoxicity). Indicated in patients who have had an inadequate response to anti-TNF therapies.
Used in combination with methotrexate.

68
Q

Anakinra

A

IL-1 receptor antagonist – blocks the IL-1R and prevents endogenous IL-1 binding
May be used alone or in combination with other DMARDs (but not TNF inhibitors).

69
Q

Adverse effects of methotrexate

A

Generally well tolerated at low doses for treatment of RA. Most common side effects include mucosal ulceration and nausea, myelosuppression - cytopenia, hepatotoxicity, rarely cirrhosis of the liver, acute pneumonia-like syndrome – hypersensitivity pneumonitis, CNS symptoms - headache, fatigue, malaise, or impaired ability to concentrate. (Must be supplemented with folic acid which could reduce GI and hepatic side effects).

70
Q

Adverse effects of hydroxychloroquine

A

Well tolerated but possible side effects include abdominal pain, nausea/vomiting (most common), headache, skin rashes, pruritus, ocular toxicity - visual changes, retinopathy. Eye examination is recommended before starting therapy, then within a year from treatment initiation. Dosage should be reduced in patients with renal insufficiency. (Potential interactions: Digoxin, Telbivudine, Penicillamine)

71
Q

Adverse effects of leflunomide

A

headache, nausea, diarrhea.
Monitoring parameters include signs of infection, CBC and LFTs.

72
Q

Adverse effects of sulfasalazine

A

Nausea, vomiting, diarrhea, and abdominal pain all predominate. GI reactions are commonly the reason for stopping this agent. Dermatologic reactions are also common. It’s important to follow liver function and bone marrow while on this agent, given risks for hepatitis and myelosuppresion. Periodic CBC/LFTs necessary.

73
Q

Adverse effects effect of all biologic DMARDs

A

Increased risk for infections such as tuberculosis, fungal opportunistic infections, and sepsis.

74
Q

Adverse effects of rituximab

A

Infusion reactions (urticaria, hypotension, angioedema) are the most common complaints and typically occur during the first infusion. To reduce infusion reactions, methylprednisolone, acetaminophen, and an antihistamine are administered before each infusion.

75
Q

Contraindications for methotrexate

A

pregnancy, periodic liver function tests, complete blood counts, and monitoring for signs of infection are recommended.

76
Q

Contraindications for leflunomide

A

pregnancy, not recommended for patients with liver disease as it can be hepatoxic

77
Q

PGI2

A

produced from PGH2, which is synthesized from prostaglandins, causes vasodilation and inhibits platelet aggregation

78
Q

TXA2 (Thromboxane A2)

A

produced from PGH2, which is synthesized from prostaglandins, promotes vasoconstriction and platelet aggregation

79
Q

COX-1

A

responsible for physiologic production of prostaglandins, “Housekeeping” enzyme that regulates homeostasis

80
Q

COX-2

A

upregulated during inflammation and is induced by oxidative stress, injury, ischemia

81
Q

High potency steroids (long-acting)

A

Betamethasone, dexamethasone (25)

82
Q

Intermediate potency steroids (intermediate-acting)

A

prednisone, prednisolone (4), methylprednisolone, triamcinolone (5)

83
Q

Low potency steroids (short-acting)

A

Hydrocortisone (1), cortisone (0.8)

84
Q

Renal effect of NSAIDs and aspirin inhibition of prostaglandin synthesis

A

PGI2 and PGE2 are vasodilators and so NSAID inhibition of these prostaglandins leads to increased vasoconstriction in the kidney and reduced renal blood flow. Renal and cardiovascular disease also decrease renal blood flow and cirrhosis, nephrosis, heart failure, and diuretics decrease blood volume leading to further vasoconstriction in the kidney (causing severe kidney damage)

85
Q

PGE2

A

produced from PGH2, which is synthesized from prostaglandins, causes vasodilation and increased vascular permeability, edema

Pharmacology I (5 decks)

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