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Six classes of NSAIDs
- Propionic Acid Derivatives
- Acetic Acid Derivatives
- Indole Derivatives
The only drug in the Analgesic-Antipyretic class
Three classes of Glucocorticoids
- Short- to Medium-acting
Two drugs in the Salicylates class
Four drugs in the Propionic Acid derivatives class
Three drugs in the Acetic Acid derivatives class
Onen drug in the Indole derivatives class
Two drugs in the Oxicams class
One drug in the Coxibs class
Five short- to medium-acting Glucocorticoids
One intermediate-acting Glucocorticoid
Two long-acting Glucocorticoids
What is the primary indication/therapeutic strategy of anti-inflammatory drugs?
- Relief of symptoms
- Slowing or arresting the tissue-damaging process
What pharmacokinetic properties are shared by most NSAIDs?
- Most are well absorbed
- Most are highly metabolized (by CYP3A and CYP2C enzymes)
- Primarily eliminated through renal excretion with some biliary excretion/reabsorbtion (enterohepatic circulation)
- Usually highly bound to protein, esp. albumin
What is the general mechanism of action of all NSAIDs?
Inhibition of COX enzymes (both 1 and 2)
How do NSAIDs carry out their function on their target enzymes?
- Reversible, competitive inhibition
- Exception: Aspirin is a irreversible suicide inhibitor of COX enzymes
What is the effect of NSAIDs on the COX/LOX pathways?
- Since they block COX but not LOX, they prevent prostaglandin synthesis but not leukotriene synthesis; arachadonic acid derivatives get shunted to LOX pathway.
- Exception: Sulfasalazine blocks both
What are the three primary pharmacological actions of NSAIDs?
- Analgesic (lowering pain independent of the cause without altering state of consciousness)
- Antipyresis (lowering body temperature)
Anti-inflammatory action of NSAIDs:
- Inhibition of the early phases of the inflammatory rxn via:
- - Inhibition of PG and thromboxane synth
- - stabilization of lysosomal membranes
- - inhibition of plasmin
- - inhibition of the activation and function of PMNs, macrophages, and mast cells
- - No significant effect on specific immune response
Analgesic action of NSAIDs:
- Peripheral pain receptors are normally sensitized by PGs and PG-mediated inflammation; inhibition of PG synth prevents this.
- This effect does not undergo tolerance.
- Some central depressive action at hypothalamus, but minor.
Antipyretic action of NSAIDs:
- Blockage of PG-mediated action on thermoregulatory center of hypothalamus (through inhibition of PG synth).
- Reduce elevated body temperature to normal without affecting normal body temperature.
- Do not reduce hyperthermia due to causes like ox phos uncoupling or hypothalamic damage (heat stroke).
How should NSAIDs be dosed and administered?
On a patient-to-patient basis; remember that they only relieve symptoms and do not modify disease.
Route of Administration, Absorption, Distribution, Biotransformation, and Excretion of Salicylates
- RoA: oral, rectal, parenteral
- Abs: rapidly via oral, with peak [plasma] in 1-2hr
- Dist: entire body
- Trans: aspirin rapidly metabolized to salicylic acid; 85% salicylic acid transformed in liver
- Excr: by kidneys; 15% in acidic urine, 85% in alkaline
Pharmacologic effects of salicylates in the CNS (normal vs high doses)
- Low/Moderate: central antipyresis and depression of hypothalamic pain modulation circuits
- High: stimulation of chemoreceptor trigger zone, afferent stimulation of CNVIII, and diffuse stimulation of cortical and subcortical structures (very high)
Pharmacologic effects of salicylates in the respiratory system (moderate vs toxic doses)
- Moderate/High: stimulation of respiration via the medulla's respiratory center
- Toxic: direct depression of the same center
Pharmacologic effects of salicylates in the cardiovascular system (high doses)
- Direct dilating effect on peripheral blood vessels
- Increase circulating plasma volume (up to 20%)
Pharmacologic effects of salicylates in the kidneys (normal, high, and chronic doses)
- Low/Moderate: inhibition of tubular uric acid secretion and small decrease in GFR
- High: inhibition of tubular uric acid reabsorption; decrease in GFR (can lead to acute renal failure)
- Chronic (2-3yrs): renal lesions
Pharmacologic effects of salicylates in the hematopoietic system (normal vs high doses)
- Low/Moderate: decreased platelet aggregation for 7-8 days
- High: sideropenia and hypoprothrombinemia
Pharmacologic effects of salicylates in the GI system (stomach and liver)
- Stomach: erosive gastritis due to local and systemic effects (irritation, longer emptying time, increased gastric secretion, decreased bicarb/mucus secretion)
- Liver: direct stimulation of bile secretion, severe hepatic injury (Reye's Syndrome)
Pharmacologic effects of salicylates in acid/base imbalances (high vs toxic doses)
- High: respiratory alkalosis compensated by renal bicarb excretion
- Toxic: uncompensated respiratory and metabolic acidosis
Pharmacologic effects of salicylates in metabolism (high doses)
- Uncoupling of ox phos in skeletal muscle (causing hyperthermia)
- Hypoglycemia from increased insulin
- Hyperglycemia and glycosuria from epinephrine release and increased glycogenolysis
- Hyperkalemia from increased K+ reabsorption in kidneys
Sulfasalazine, a salicylate, is used exclusively for what two GI diseases?
- Ulcerative colitis
- Crohn's Disease
What are the most common adverse effects to salicylate treatment?
10-30% experience dyspepsia, heartburn, nauseau, diarrhea, fecal blood loss, and impairment of folate absorption
What are some specific adverse effects of sulfasalazine?
Arthralgia, myalgia, bone marrow suppression, malaise
At what level does mild intoxication of salicylates occur, and what happens?
- Occurs at 400-800ug/mL
- Get headache, dizziness, tinnitus, difficulty in hearing, dimming vision, mental confusion, lassitude, sweating, hyperventilation, nausea/vomiting, diarrhea
At what level does serious salicylate intoxication occur, and what happens?
- Deafness, vertigo, diplopia, respiratory depression, tremors, delirium, hallucinations, generalized convulsions, coma, abdominal cramps, gastric bleeding, acidosis, hyperthermia, dehydration
Salicylate toxicity in pregnancy:
- Does not occur for sulfasalazine and related drugs
- Increased abortion, perinatal mortality, prolonged gestation and labor, pre and postpartum hemorrhage, hemostatic abnormalities in newborn
Who is at risk for aspirin (and other NSAID) hypersensitivity?
- Middle-aged patients with asthma, nasal polyps, or chronic urticaria (in up to 20-25% of these patients).
- This hypersensitivity is an absolute contraindication to any NSAID therapy, as the rxn can be lethal
What is Reye's Syndrome, and how does it present?
A toxicity disease that occurs mainly in children and young adults after salicylate therapy. Etiology is unknown, and predisposing factors include chronic salicylate therapy, and some viruses and toxins. Develops in two phases, initially presenting as a respiratory infection that ~4 days later develops into nausea and vomiting with sudden changes in mental status and liver damage. Can be mild or progress to toxic encephalopathy (rapidly fatal), and serious mental disturbances may remain after recovery.
General features of non-salicylate NSAIDs:
- Much in common with salicylates
- Anti-inflammatory, analgesic, antipyretic, and anticoagulate
- GI and CNS effects less pronounced than salicylates
- Minimal effects on acid/base balance
What class does flurbiprofen belong to, and what are some specific characteristics of this drug?
- Propionic-acid derivative NSAID
- Clinical: inhibition of intraoperative miosis via drops, perioperative analgesia in minor ear, neck, and nose surgery, and sore throat (oral admin)
- Specific tox: all rare; cogwheel rigidity, ataxia, tremor, myoclonus
What class does ibuprofen belong to, and what are some specific characteristics of this drug?
- Propionic-acid derivative
- Anti-inflammatory only at high doses (>2400mg/day), otherwise analgesic
- Clinical: Closes patent ductus arteriosus in infants (oral and IV), primary knee osteoarthritis, postsurgical dental pain, and safe for kids with viruses
- Tox: aseptic meningitis, fluid retention, aplastic anemia
What class does naproxen belong to, and what are some specific characteristics of this drug?
- Propionic-acid derivative; only NSAID that is a single enantiomer
- Clinical: safe for kids with viruses
- Tox: allergic pneumonitis, leukocytoclastic vasculitis, and pseudoporphyria
What class does oxaprozin belong to, and what are some specific characteristics of this drug?
- Propionic-acid derivative
- No enterohepatic circulation
- More useful in gout than other NSAIDs
What class does diclofenac belong to, and what are some specific characteristics of this drug?
- Acetic acid derivative
- MoA: Inhibits both COX and LOX and decreases oxygen radical production
- Clinical: postop eye inflammation, solar keratoses, preemptive analgesia (rectal), and postop nausea (rectal)
- Tox: many mitigated by combo drugs; diarrhea, impairment of renal blood flow and GFR, increase serum aminotransferases
What class does ketorolac belong to, and what are some specific characteristics of this drug?
- Acetic acid derivative
- Only 40% metabolized before excretion
- Clinical: primarily for analgesic, not anti-inflammation, esp. in reducing/replacing opiod use; ocular inflammation
- Tox: common renal tox with chronic use (~60% excreted intact by kidneys)
What class does sulindac belong to, and what are some specific characteristics of this drug?
- Acetic acid derivative
- Kinetics: prodrug that is reversibly metabolized to sulfide metabolite (excreted in bile and reabsorbed)
- Clinical: familial intestinal polyposis; may inhibit colon, breast, and prostate cancer development
- Tox: Steven-Johnson syndrome, cholestatic liver damage
What class does indomethacin belong to, and what are some specific characteristics of this drug?
- Its own class! An indole derivative
- MoA: potent nonselective COX inhibitor; inhibits phospholipase A and C; reduces neutrophil migration and decreases B- and T-cell proliferation
- Clinical: gout, ankylosing spondylitis, closing patent ductus arteriosus, conjunctivitis, gingivitis, and analgesia for postlaminectomy syndrome
- Tox: 1/3 discontinue at high doses; 15-25% headache, dizziness, confusion, depression; rare pancreatitis, hallucinogenic psychosis, thrombocytopenia, aplastic anemia, renal papillary necrosis
- Contraindication: concomitant admin of probenecid (prolongs half-life by competing for renal excretion); late-term pregnancy (ductus arteriosus)
What class does meloxicam belong to, and what are some specific characteristics of this drug?
- Oxicam class
- MoA: highly selective for COX-2; inhibits TXA2 synth
- Clinical: osteoarthritis; does not affect platelet aggregation
What class does piroxicam belong to, and what are some specific characteristics of this drug?
- Oxicam class
- MoA: COX inhibitor; high doses inhibit PMN migration, oxygen radical formation, and lymphocyte function
- Tox: increased incidence of peptic ulcer and bleeding (9.5x)
What class does celecoxib belong to, and what are some specific characteristics of this drug?
- Coxib class, includes anything with -coxib (celebrex)
- MoA: Highly selective COX-2 inhibitor; no effect on platelet aggregation
- Tox: FDA issued black box warning regarding cardiovascular risk
- Contraindications: warfarin; pregnancy (inhibition of labor)
Pharmacokinetics of acetaminophen (RoA, time to peak, half life, metabolism)
- RoA: oral (60-90% bioavailable related to gastric emptying), rectal
- Peak [plasma]: in 30-60min
- T1/2: about 2-3 hours, increased with high dose or liver damage
- Extensive metabolism (95%); some converted to NAPQI (toxic)
Pharmacodynamics of acetaminophen (MoA, actions/effects)
- MoA: potent COX inhibitor in CNS (analgesic); weak COX enzyme inhibitor in inflamed tissue (periphery)
- Analgesic and antipyretic effects similar to NSAIDs
- Peripheral effects from PG synth inhibition absent, and very few adverse effects at normal doses
Clinical pharmacology of acetaminophen (effects and toxicity)
- Uses: Preferred antipyretic in children (viral infection), for analgesia for non-inflammatory pain or NSAID contraindication, or for hemophiliacs, peptic ulcer, or bronchospasms from aspirin
- Toxicity: high doses (adults 10g, kids 250mg/kg) cause glutathione depletion; NAPQI buildup damages liver (centrilobular necrosis)
How do you treat acetaminophen overdose?
- Activated charcoal w/in 4hr of ingestion (decreases absorption)
- N-AcetylCysteine (NAC) within 16hr to prevent liver damage (replenishes glutathione and conjugates NAPQI)
- Liver disease
- Any alcohol consumption
- Glutathione deficiency
How do glucocorticoids modulate inflammation on a cellular level?
- Bind to GCR to form homodimer complex in cytoplasm
- Complex translocates to nucleus, targets genes with glucocorticoid response element (GRE)
- Can also interact with other transcription factors (API, NF-κB) regulating growth factors, pro-inflammation
- Regulates gene transcription of these targets
- 10-20% of all genes expressed in a cell are regulated by glucocorticoids directly or indirectly
What are four primary uses of glucocorticoids?
- Tx of nonadrenal disorders through immune and inflammation suppresion and alteration of leukocyte function
- Tx of disturbed adrenal function (Addison's, post-surgery Cushing's, other insufficiency)
- Stimulation of fetal lung maturation
- Diagnostic for Cushing's disease vs syndrome
How does dexamethasone administration differentiate Cushing's disease and syndrome?
- Cushing's Disease: pituitary adenoma; low dose does not decrease plasma [cortisol] but high doses do
- Cushing's Syndrome: adrenal tumor; no decrease in plasma [cortisol] at either low or high dose
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