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63 Cards in this Set
- Front
- Back
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Three Phases of Inflammatory Responses
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Acute transient phase – vascular phase
Local vasodilation and increased capillary permeability Delayed, sub acute phase – cellular phase Infiltration of leukocytes and phagocytic cells Chronic proliferative phase – connective tissue or repair phase-want to get here fast Tissue regeneration and fibrosis |
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Mediators of Inflammation
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Serotonin
Prostaglandins---these we attack Bradykinins Leukotrienes-these we attack Interleukins |
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NSAIDs: Non-steroidal Anti-Inflammatory Drugs
anti--- |
(think diuretic scene)
unique features Anti-inflammatory (not tylenol) bigtime ibupro Analgesics Anti-pyretic |
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NSAIDs Mechanism of Action
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Inhibits cyclooxygenase enzyme involved in prostaglandin and thromboxane synthesis
COX-1 expressed in non-inflammatory cells COX-2 expressed in inflammatory cells (would like selective here) only one and not great |
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Two synthesis pathways using arachidonic acid
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Cyclooxygenase (COX) pathway
Lipoxygenase pathway (increase leukotrines) |
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Effects of COX Inhibition
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Inhibition of the mediators of inflammation (prostaglandins and thromboxane)
Inhibition of prostaglandins in the central nervous system stimulated by pyrogens reduces fever (COX-2 effect) Inhibition of prostaglandins in injured tissues, especially inflamed tissue, may result in reduced peripheral pain receptor activation (analgesia------Some NSAIDs analgesia is not fully explained by COX inhibition, suggesting some other mechanism (thus can use at lower dose than expect) *********Reduces cytoprotective prostaglandin production in the gastrointestinal tract (COX-1)*************(ULCER SCENE COX-1) ****Reduces auto regulatory prostaglandins of the kidney (COX-2)****** ********Inhibition of thromboxane A2, a platelet aggregation factor (COX-1) ******** |
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Aspirin
moA dosing scenes |
Aspirin converted to salicylate**********
But aspirin is the only IRREVERsible) not sali Both active Irreversible inhibitor of COX-1 and COX-2 -Three working doses Anti-platelet aggregation – low dose (still last 72 hours) Anti-pyretic and analgesics – moderate dose Anti-inflammatory – high dose |
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Aspirin and Sodium Salicylate
p-kinetics |
Pharmacokinetics
Weak acid absorbed from stomach and small intestine Protein binding is significant****can be issue At 81 mgs (cardio) but at higher can displace sensitive drugs (WARf, HIV drugs,anti convulse) Excreted in urine as salicylate(can be used topically) and metabolites High doses increases half-life from 3 hours to up to 15 hours-cusp of transition first to zero order ? |
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Aspirin and Sodium Salicylate
indications |
Indications
Antipyretic Analgesia Anti-inflammatory (pretty high dose) Rheumatoid arthritis Platelet hyperaggregability Lower risk of colon cancer Menstrual cramps (higher dose and ibupr better |
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Aspirin and Sodium Salicylate
adv RXs |
Adverse effects
-Gastric upset and intolerance (cox-1)—mess bicarb, mucus -Salicylism High dose effect (RA) Vomiting, tinnitus, decreased hearing, vertigo -Elevation of liver enzymes -Decreased renal function*************COX-2 decrease perfusions prostaglandin scene -Bleeding-watch fish oil garlic -Reye’s syndrome----viral kids*****may not be huge relation mitochondria prob liver, brain -Kids also worse for asthma and intoxication(other card) Hypersensitivity/intolerance |
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Aspirin intoxication
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Aspirin intoxication-rare in adults
Mild intoxication is salicylism Moderate to full intoxication -kids Central nervous system dysfunction Convulsions and coma Skin eruptions *********Disruption of acid/base balance*********************esp CHILDREN May be a life-threatening medical emergency |
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Non-selective NSAIDs
moA |
Reversible inhibitors of COX-1 and COX-2
don't use for cardioprotective use aspirin (irreversible) |
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Reversible inhibitors of COX-1 and COX-2
named |
indications similar to aspirin but timing different
Ibuprofen(Standard of NSAIDs)--GOOD Indomethacin (Indocin) and sulindac (Clinoril)-Very effective, very toxic******* Naproxen (Naprosyn) and piroxicam (Feldene)-Half-life of about 12 to 24 hours Ketoprofen (WATCH IT)(Orudis) KEEP hydrated****( Miscellaneous agents Tolmetin (Tolectin) Diclofenac (Voltaren) Etodolac (Lodine)popular in VA sytem |
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Ketoprofen
moA SEs |
Orudis) KEEP hydrated****
Slow release preparation allowing once daily dosing Reversible inhibitors of COX-1 and COX-2 Also inhibits lipoxygenase enzymes that make leukotrienes********** Thus may be good ALT to ASPIRIN (often incr. LK = prob (asthma) |
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COX-2 Inhibitors
indications named |
Similar indications to aspirin
(but when other not acceptable) not major player due to increased CV events (him not much) (others GONE) Minimal effect on platelets Minimal (not =NO) effect on gastrointestinal tract Agents Celecoxib (Celebrex) only one left |
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Acetaminophen
moA indications |
Analgesic, antipyretic
Proposed mechanism of action is central********** inhibition of COX enzyme Limited effect on peripheral COX enzyme explains lack of anti-inflammatory*********** action No effect on platelet aggregation*************** Indications Analgesic and antipyretic like aspirin Preferred in children and aspirin intolerant patients******* (safer in controlled dose) |
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Acetaminophen
pkinetics toxic |
Pharmacokinetics
Orally active Biotransformed by liver-IN TWO PHASES Conjugation primary pathway Cytochrome P450 metabolism forms toxic intermediate normally rapidly detoxified by conjugation with glutathione (PROBLEM WHEN WE DRAIN) TOXIC TO THE LIVER AND THE KIDNEY DELAYED- CAN TAKE DAYS TO TREAT WITH ACETYLCYSTEINE (MUCOMYST)…MUST GIVE EARLY ---NOT AN ANTI-INFLAMMATORY AGENT CAN STAGGER WITH ASPIRIN |
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Steroidal Anti-Inflammatory Drugs
named moA |
---Glucocorticoids
Prednisone (Deltasone) Prednisolone Dexamethasone (Decadron) Triamcinolone (Aristocort) Inhibit all phases of inflammation Inhibit the conversion of membrane phospholipids to arachidonic acid |
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Steroidal Anti-Inflammatory Drugs
indication main side effect |
Moderate to severe inflammation that does not respond to less toxic agents
Glucocorticoids are rarely curative Adverse effects Suppression of Hypothalamic-Pituitary-Adrenal (HPA) Axis Loss of ability to response to stress Acute adrenal insufficiency |
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To minimize HPA suppression
w/glucocort |
Local therapy rather than systemic
Alternative day therapy Withdrawal therapy slowly regardless of duration of therapy |
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Steroidal Anti-inflammatory Drugs
Adverse Effects Early Effects |
Early Effects
Common Weight gain, mood changes, glucose intolerance, transient adrenal suppression Less common but significant Anaphylactoid reactions. Peptic ulcers, acute pancreatis, hypertriglyceridemia |
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Steroidal Anti-inflammatory Drugs
Adverse Effects delayed |
Common
Central obesity, cutaneous fragility, myopathy, osteoporosis, growth failure, prolonged adrenal suppression Less common but significant Aseptic necrosis of bone, cataracts, glaucoma, hypertension, opportunistic infections |
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Gold
named moA |
Agents
Auranofin (Ridaura) Aurothioglucose (Solganal) Mechanism of action Unknown Renal elimination (HYDRATE) |
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Gold
adv Rx indications |
Indications
Patients with active, erosive rheumatoid arthritis that does not respond to other therapies Adverse effects---like heavy metal tox Most common when cumulative dose > 200 – 300 mg Diarrhea, abdominal pain, nausea and anorexia Severe itching followed by dermatitis and stomatitis Blood dyscrasias (potentially fatal) |
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Cytostatic-Cytotoxic Agents
used here-NAMED general moA |
Cyclophosphamide (Cytoxan)
Methotrexate (Rheumatrex) Azathioprine (Imuran) Mechanism of action Mechanisms of action vary but all interfere with DNA function Suppresses inflammatory processes at low doses (STILL CAN INCREASE INFECTION) |
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Cytostatic-Cytotoxic Agents
used here- indications Adv RXs |
Indications
Severe rheumatoid arthritis that has not responded to other therapies Adverse reactions Non-specific suppression of hematological and immunological function Gastrointestinal upset and ulcers |
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Penicillamine
moA indication |
Mechanism of action
Unknown Indications Arthritis not responsive to other treatments (and heavy metal toxicities eg Cu) |
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Penicillamine
Adverse reactions |
Adverse reactions-lots OF RASHES is big problem
Maculopapular pruritic dermatitis Gastrointestinal upset Blood dyscrasias Proteinuria sometimes progressing to nephrotic syndrome |
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Serum urate concentration correlates with
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Age
Serum creatinine level Blood urea nitrogen Male gender *10 Blood pressure Body weight Alcohol intake Urate is end product of purine degradation Purine sources include Diet Conversion from tissue nucleic acids De novo synthesis Normal urate production is 600**** to 800 mg/day |
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Causes of Excess Uric Acid
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Overproduction of uric acid
Increase in phosphoribosyl pyrophosphate (PRPP) synthetase. PRPP is key determinant in purine synthesis Deficiency of hypoxanthine guanine phosphoribosyl transferase (HGPRT)(Lesch–Nyhan syndrome and others)(more common of overprod) Increases metabolism of guanine and hypoxanthine to uric acid **(more common)Underexcretion of uric acid Decline in urinary uric acid excretion Evidence of linkage between sodium reabsorption and uric acid reabsorption in proximal tubule |
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Diagnosis of the cause
of excess uric acid |
Patient is placed on purine free diet for 3 to 5 days
Uric acid in urine for 24 hours measured Normal excrete about 600 mg/day********* Overproducers will excrete more than 600 mg/day Underexcretion will excrete less than 600 mg/day |
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Acute Gouty Arthritis
clin presentation |
Rapid onset of pain, swelling and inflammation
First metatarsophalangeal joint (great toe) Most common Insteps, ankles, heels, knees, wrists, fingers and elbows (order of decreasing occurrence) (further from trunk more infect) |
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Course of events
Acute Gouty Arthritis |
Synovial effusions during day during use
Water reabsorption at night leaves supersaturated monosodium urate in joint Lower temperature of extremity joints may promote crystal formation Attacks most often start at night with patient waking in pain Crystal formation triggers vasodilation, increased vascular permeability and chemotactic activity for polymorphonuclear leukocytes Uric acid crystal phagocytosis by leukocytes triggers cell lysis and inflammatory response Untreated attack may last between 3 and 14 days |
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gout Attack precipitators
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Attack precipitators
Stress, trauma, alcohol ingestion, infection, surgery, rapid lowering of uric acid levels by drugs, certain drugs Drugs that may trigger an attack Diuretics, nicotinic acid, salicylates (incl aspirin)(>2 g/day), ethanol, pyrazinamide, levodopa, ethambutol, cyclosporine, cytotoxic drugs |
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Acute Gouty Arthritis
Sx/labs |
General symptoms
Acute attack of arthritis, nephrolithiasis, gouty nephropathy, deposits of urate (tophi) in cartilage, tendons, and synovial membranes Signs and symptoms Fever, intense pain, erythema, warmth, swelling of involved joints Laboratory tests Elevated serum uric acid, leukocytosis Aspiration of crystal-containing fluid from involved joint(true confirm...neg birefringant... YELLOW) |
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Uric Acid Nephrolithiasis
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Occurs in 10% to 20% of gout patients
Most common when Excessive uric acid in urine Renal calculi risk approaches 50% in patients excreting >1100 mg/day uric acid Urine is acidic******* Urine is concentrated |
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Gouty Nephropathy
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Acute uric acid nephropathy
Blockade of urine flow secondary to uric acid crystal formation in collecting duct and ureters Chronic uric acid nephropathy Long-term deposition of uric acid crystals in renal parenchyma Triggers localized inflammatory response May precipitate hypertension, nephrosclerosis, and even renal failure |
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Treatment of Acute Gouty Arthritis
general acute chronic |
Acute: Termination of inflammatory process
Colchicine Non-steroidal anti-inflammatory drugs Glucocorticoids Long-term: Decreasing uric acid production or increasing excretion Allopurinol (inhibits uric acid synthesis) Probenecid & Sulfinpyrazone (increases excretion) (thus must DX cause) |
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Colchicine
moA indication |
Bind tubulin causing depolymerization (like taxol)
Disrupts mobility of granulocytes to affected area Inhibits synthesis and release of inflammatory leukotrienes Decreases attraction of neutrophils to the affected area Anti-inflammatory activity is specific for gout (LIMITED TO GOUT) Indications Alleviates pain of acute gouty arthritis within 12 hours Slow onset makes colchicine not a treatment of choice*******more for those who can predict, prevent Primary use in prevention of recurrent attacks |
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Colchicine
ADv RX |
Adverse Reactions
Pregnancy Category D Possibly unsafe during breastfeeding Common adverse reactions Abdominal pain Nausea, vomiting Diarrhea Alopecia (splotchy) Serious adverse reactions Severe diarrhea (watch dehydrate) bone marrow toxicity Muscle wasting Neuropathy Hypersensitivity Multiple organ failure Risk of bone marrow toxicity********often limits therapy with colchicine to seven days or less *****look kidney liver blood**** taxolish |
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Indomethacin
moA indications |
Mechanism of action (DOC-for speed but very toxic)
Reversible inhibitor of cyclooxygenase Inhibits prostaglandin synthesis mediating inflammation, fever and pain. Indications Acute gouty arthritis (drug of choice) Ankylosing spondylitis Osteoarthritis of the hip (POWERFUL ANTIINFLAM) (CLOSE PDA) |
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Indomethacin
COMMON adv. RX |
Adverse reactions
****Pregnancy category B****MISLEADING but use is not recommended in third trimester*** (INCREASED BLEEDING RENAL TOXICITY)***** Possibly unsafe for use during breastfeeding Common reactions Dyspepsia****** Nausea, vomiting Inhibition of platelet aggregation (REVERSIBLE SO SHORT TERM Headache Dizziness (serious/BBW in other card) |
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Indomethacin
SERIOUS adv. RX |
Serious adverse reactions
*****Gastric ulceration and bleeding (Black box warning) ********Cardiovascular or cerebrovascular event (Black box warning) Myocardial infarction Stroke Hypertension Nephrotoxicity***WORST of the NSAIDS Hepatotoxicity Hypersensitivity |
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Uric Acid Nephrolithiasis
Tx |
******Hydration sufficient to maintain urine volume of 2-3 liters per day
***Alkalinization of urine by sodium(prob) bicarbonate or acetazolamide***** Avoidance of purine-containing foods(meat) Moderation of protein intake Allopurinol may pick up on routine x-ray |
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Allopurinol
Mechanism of action indications |
Mechanism of action (FOR INC SYNTH PROB)
Inhibits xanthine oxidase required for uric acid biosynthesis Precursors xanthine and hypoxanthine are more water soluble than uric acid Indications Drug of choice in treatment of chronic tophaceous gout Hyperuricemia of gout Hyperuricemia secondary to other conditions (bio-t-formed to active metabolite once daily dose |
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Allopurinol
ADV Rx |
Adverse effects
Pregnancy category C unSafe during breastfeeding Common reactions Hypersensitivity reactions (rashes)-THIS COULD BE FIRST SIGN OF SERIOUS HYPERSENSTIVITY RXs-stop drug Injection site reactions Nausea, vomiting Gout flare-up (XANTHINE crystals though more soluble still precipitate-short term) Concurrent treatment with colchicine and indomethacin recommended Serious adverse effects Hypersensitivity reactions (RASH***********) Bone marrow dysfunction Hepatotoxicity Renal failure |
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Allopurinol
Drug Interactions |
Mercaptopurine or azathioprine(THESE ACCUMULATE)
Allopurinol inhibits inactivation of these cytotoxic agents Requires dosage reduction to ¼ normal dose********************************************************************* |
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Probenecid
Sulfinpyrazone moA |
Uricosuric agents
Mechanism of Action Inhibits urate-anion exchanger in proximal tubule, inhibiting urate reabsorption******* At low doses they block proximal tubular secretion of uric acid*******makes worse must be secreted to be activated compete with uric acid =increase This effect may make acute gouty arthritis worse by increasing serum uric acid levels start with high dose ta avoid |
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Probenecid & Sulfinpyrazone
Adverse reactions |
Adverse reactions-well tollerated
Common reactions Nausea Dyspepsia Rashes Anemia Headache Dizziness Precipitation of acute gouty arthritis and stone formation******** Serious reactions Bone marrow depression Hypersensitivity |
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Probenecid & Sulfinpyrazone
DIs |
Interferes with renal secretion
NSAIDs Penicillin (indicated to increase DoA) Sulfonamides (UTI is primary indication so decrease conc at sight of action) |
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Asymptomatic Hyperuricemia
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usually not treated
Generally does not require treatment even in patients with history of acute gouty arthritis or nephrolithiasis There is some interest in treating asymptomatic hyperuricemia in patients with risk of coronary artery disease as hyperuricemia is often associated with increased risk of renal impairment in patients with hypertension and coronary artery disease |
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Spasticity and Spasm
sk muscle |
Spasm (physical therapy)
Increased tension Unable to relax muscle Spasticity (need to decide central vs. periph) Exaggerated stretch reflex Movement produces contraction (HURTS) Velocity dependent |
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Spasm Treatments
general |
Pharmacotherapy is adjunct to rest***** and physical therapy
Pharmacotherapy often includes non-steroidal anti-inflammatory or acetaminophen |
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spasm Tx.
drugs |
Diazepam (Valium)
Inhibitor of spinal alpha motor neurons Sedation******here at these dose relax is key Cyclobenzaprine (Flexeril) Reduced activity in spinal and brain stem polysynaptic pathways |
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Diazepam
adverse reactions |
(here at low dose as sedative-not muscle)
Adverse effects Sedation (indication) Ataxia Powerful interaction with ethanol*****resp depression---gaba-nergic scene |
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Cyclobenzaprine
adv RXs |
(flexeril)
Adverse effects Anticholinergic (dry)**** Sedation Dizziness |
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Spasticity Treatments
drugs |
Baclofen (Lioresal)
Dantrolene sodium (Dantrium) |
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Baclofen
moA |
Mechanism of action is unclear
Enhancement of GABA-mediated inhibition of motor neurons (GABA-B receptor in spinal cord) Inhibition of polysynaptic pathways (especially motor-centrally)DOC for spacticity in like MS (??works centrally--thus not good for central spasticity??) |
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Baclofen
indication adverse Rxs |
Indications
Drug of choice for spasticity from multiple sclerosis Spinal spasticity Not of value in central spasticity Adverse effects Mild sedation Nausea Mental cloudiness (major complaint), euphoria (abuse potential) and depression |
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Dantrolene sodium
moA |
Mechanism of action
Blocks Ca+2 release from sacroplasmic reticulum and uncouples muscle excitation and contraction ****works on muscle******* |
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Indications
Dantrolene sodium |
Spasticity due to stroke, spinal cord injury, multiple sclerosis or cerebral palsy
Prophylaxis or treatment of malignant hyperthermia---(antipsych...etc.)--rescue treatment******* |
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Dantrolene sodium
ADV RXs |
Muscle weakness, dose-dependent
Drowsiness, dizziness, fatigue *******Liver dysfunction 0.5% symptomatic hepatitis 0.2% fatal***** hepatitis Regular liver enzyme monitoring recommended (continuously) |
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Dantrolene sodium
CIs |
(muscle and LIVER)
Respiratory muscle weakness Cardiac disease Liver disease Pregnancy Increased risk of hepatic disease (MOM) Pregnancy Category C |
