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71 Cards in this Set
- Front
- Back
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Non-narcotic analgesics provide analgesia for:
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low to moderate intensity pain
headache, myalgia, arthralgias & other pains arising from integument structures *anti-pyresis is also a prominent action of this group of agents |
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In contrast to acetaminophen, the salicylates and propionic acid derivatives exhibits significant _______________ effects.
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anti-inflammatory
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Where is acetlylsalicylic acid (ASA) absorbed?
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partly from stomach
mostly from the upper small intestine |
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What determines the rate & extent of absorption of ASA?
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disintegration & dissolution rates of tablets
pH at the mucosal surface; acidic conditions favor salicylate absorption (large nonionized fraction) gastric emptying time |
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ASA is rapidly hydrolyzed by tissue and blood esterases to:
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Acetate and Salicylate
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Appreciable salicylate concentrations are found in the plasma in less than ____ min with peak blood levels occurring within ______.
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30
1-2 hrs |
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________ of the salicylate is bound to plasma proteins with the "free" fraction of drug available for either hepatic metabolism or renal elimination
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80-90%
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The metabolism of salicylate in the Liver consists of:
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conjugated w/ glycine to form salicyluric acid
conjugated w/ glucuronic acid to form ester or ether glucuronides metabolized (1%) gentisic acid |
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What is the plasma half-life for salicylate at low and high/toxic doses?
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Low: 2-3 hrs
High: 15--30 *dose-dependent elimination is a result of the limited ability of the Liver to form salicyluric acid & the salicylate fraction to be conjugated w/ glucuronic acid |
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Renal excretion of free salicylate is highly variable and is ______ dependent
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pH
As low as 5% free salicylate is excreted in acidic urine & up to 85% free salicylate in alkaline urine |
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What are some derivatives of propionic acid?
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Ibuprofen
Naproxen Ketoprofen |
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What is the time to peak concentration & half-life of the propionic acid derivatives?
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Ibuprofen & Ketoprofen-- 1-2 hrs / 2 hrs
Naproxen-- 2-4 hrs / 14 hrs |
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Proprionic acid derivatives are extensively (99%) bound to plasma proteins, usually ___________.
Concentration in the ___________ may be higher than in plasma. |
Albumin
synovial fluid |
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More than _____% of an ingested dose of the propionic acid derivatives is excreted in the urine as water soluble metabolites or their conjugates.
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95
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In general, what are the pharmacologic actions of salicylate / propionic acid derivatives?
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Analgesic and anti-inflammatory effects
Reduction of elevated body temperature via inhibition of prostaglandin synthesis in the hypothalamus Decreased tubular reabsorption of urate, reducing serum urate (high dosages of Aspirin only) Decreased platelet aggregation which reduces the incidence of stroke and MI (Aspirin only) |
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Intermediates in PG biosynthesis or PGs themselves ______________ to mediators such as kinins, histamine, 5-HT, which are released due to to tissue damage
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sensitize pain receptors
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Salicylates and priprionic acid derivatives decreases prostaglandin synthesis via inhibition of?
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COX I and COX II at both central and peripheral sites
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________ is constitutive and expressed in most tissues, including those involved w/ renal mechanisms and gastric cytoprotection.
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COX I
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How do prostaglandins protect the gastric mucosa?
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reducing gastric acid production and release
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How do prostaglandins influence salt and water excretion?
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alterations in renal blood flow
direct effects on renal tubules |
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COX II is (constitutive/inducible)
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Inducible
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COX II is activated by?
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Cellular mediators released due to tissue damage
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Salicylate and Propionic acid derivatives inhibit:
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constitutive COX I and inducible COX II
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Inflammation-induced prostaglandin synthesis is reduced by _________ inhibition.
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COX II
*beneficial PG in the gastric mucosa and kidney are reduced due to COX I inhibition |
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___________ is approximately 20 X more potent than Aspirin or Ibuprofen
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Naproxen
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In addition to prostaglandin synthesis inhibition, the salicylates and proprionic acid derivatives have what other anti-inflammatory effects?
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Inhibition of migration of PMNs and Macrophages into sites of inflammation
Stabilization of lysosomal membranes (decreased release of mediators from granulocytes, basophils, mast cells) Inhibition of antigen-antibody aggregation |
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Bacterial pyrogens stimulate the production of _____ which stimulates prostaglandin synthase in or near the ________________.
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IL-1
Hypothalamus |
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The increase in ______ elevates body temperature by interfering with hypothalamic temperature control mechanisms which regulate heat production vs. loss
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PGE2
*aspirin and the propionic acid derivatives block prostaglandin synthesis (inhibit both isoforms); facilitates heat loss and reduce elevated body temperature |
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ASA in the portal system acetylates _______ in platelets irreversibly inhibiting the enzyme thereby blocking the synthesis of ______.
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COX-1
TXA-2 *proprionic acid derivatives do not irreversibly inhibit the enzyme |
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Why are platelets particularly sensitive to ASA's effects?
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They do not synthesize new enzyme
Effects of a single dose can last 8-10 days which is the life of platelets |
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What is the pre-dominant side effect of the administration of salicylates?
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Gastric irritation (up to 40% of patients)
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Aspirin can prolong the bleeding time. How many weeks prior to surgery should Aspirin be stopped?
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2 weeks
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What adverse effects on the Kidney may occur in a patient with renal disease or dehydration who takes Aspirin?
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reversible decrease in renal blood flow and GFR
edema interstitial nephritis |
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____________ is a deadly disease of children and teenagers occurring in the aftermath of a viral infection
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Reye's Syndrome
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Children with chicken pox or flu-like symptoms who take Aspirin may be ____ times more likely to acquire Reye's Syndrome
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25
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What is the pathogenesis of Reye's Syndrome in genetically predisposed individuals who have a viral illness and/or take Aspirin?
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damage to mitochondrial membranes leading to hepatic injury and encephalopathy
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What are some hypersensitivity reactions associated with Aspirin?
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Asthma
Skin rashes Angioedema Potentially anaphylactoid rxns |
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Hypersensitive patients with asthma and nasal polyps may experience:
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bronchospasm and hypotension
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What are the adverse effects of Proprionic acid derivatives?
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Gastric irritation--lesser degree than Aspirin
Reduction in RBF, GFR, interstitial nephritis, nephrotic syndrome in pts. w/ pre-existing renal dis. or dehydration No affect on bleeding time No Reye's Syndrome complications Hypersensitivity rxs similar to Aspirin Birth defects--1st trimester administration; heart defects & other congenital anomalies |
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What are the symptoms of mild Aspirin toxicity (salicylism)?
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headache, dizziness, mental confusion, tinnitus, n/v
*symptoms are dose dependent and resolve with reducing the dosage |
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What are the symptoms of severe Aspirin toxicity?
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Hyperventilation --> resp. alkalosis
*salicylate uncouples oxidative metabolism in skeletal muscle to increase CO2 production *also directly stimulates the medullary respiratory center compensation is increased sodium & potassium bicarb excretion leading to severe disturbances in acid-base balance |
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What will occur if severe Aspirin toxicity goes uncorrected?
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convulsions, coma, period of unconsciousness followed by respiratory failure
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What is the treatment for mild and severe Aspirin poisoning?
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Mild: symptomatic treatment
Severe: administration of IV fluids, correction of acid-base and electrolyte imbalance |
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How can the excretion of free salicylate be increased?
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Alkalinization of the urine
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Ethanol combined with chronic administration of agents which inhibit cyclooxygenase (NSAIDS) enhance the possibility of:
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GI bleeding
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How does Aspirin & Propionic acid derivatives interact with anticoagulants?
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Displace oral anticoagulants from plasma protein binding sites increasing the anticoagulant action
*Increase in free drug seen in agents that are highly bound to plasma proteins |
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Salicylates in small doses (enhance/inhibit) the tubular secretion of uric acid? This (enhances/inhibits) the uricosuric effect of probenecid.
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Inhibits
Inhibits |
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___________ can interfere with the anti-platelet effect of low dose Aspirin, that may render Aspirin less effective when used for cardioprotection and stroke prevention.
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Ibuprofen
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Acetaminophen plasma concentration peaks in _______ with a half-life in plasma of _______.
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30-60 minutes
2-3 hours |
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Acetaminophen is relatively uniformly distributed throughout most of the body with _______% of the drug binding to plasma proteins.
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20-50
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How is Acetaminophen metabolized in the Liver?
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Hepatic conjugation:
with glucouronic acid--60% with sulfuric acid--40% |
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4-5% of Acetaminophen is metabolized via cytochrome P450 mixed function-oxidase system to __________ followed by glutathione conjugation
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NABQ
(N-acetyl-benzoquinoneimine) |
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Acetaminophen has ___________ & ___________ actions comparable to therapeutic doses of aspirin & proprionic acid derivatives.
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Analgesic
Antipyretic |
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Why does Acetaminophen lack anti-inflammatory properties?
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High concentrations of peroxides found at inflammatory sites which inactivate the Acetaminophen molecule
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Recent studies suggest the presence of a _________ isoenzyme which acetaminophen selectively inhibits may explain the actions of this agent.
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COX III
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What are some adverse effects of Acetaminophen?
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Skin rash--localized areas of erythema & urticaria
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What is the most serious toxic effect of acute overdose of Acetaminophen?
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dose-dependent, potentially fatal hepatic necrosis
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Studies have demonstrated that as little as _____ gm of Acetaminophen per day can produce severe liver injury.
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4
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What is the mechanism of Acetaminophen overdose causing hepatic necrosis?
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Toxic doses exceed Liver's capacity to glucuronidate thus more is available for microsomal N-hydroxylation
N-hydroxylate of Acetaminophen is then metabolized to NABQ NABQ usually binds to SH groups of glutathione to form an inactive product excess NABQ depletes glutathione and NABQ ends up binding SH in hepatic proteins producing cellular damage and hepatic necrosis |
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What are the clinical signs of Liver damage due to ingestion of toxic doses of Acetaminophen? When will these become apparent?
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Nausea, vomiting, abdominal pain
2-4 days |
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Induction of hepatic microsomal enzymes by chronic consumption of alcohol increases does what to Acetaminophen metabolism?
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Increases capacity of metabolism into NABQ
*threshold for acetaminophen induced Liver damage can be lowered w/ alcohol abuse |
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What are the treatments for the toxic overdosage with Acetaminophen?
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Induction of vomiting or gastric lavage should be performed in all cases--follow w/ oral administration of activated charcoal (absorbs acetaminophen)
Hemodialysis--w/ in first 12 hours Administration of Sulfahydryl compounds, such as N-acetyl cysteine, increases the hepatic content of Glutathione |
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_______________ can result from long-term abuse of analgesic formulations containing acetaminophen and aspirin combinations.
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Renal Tubular Necrosis
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Nephropathy results from ______________, a metabolite of Acetaminophen, which concentrates in the hypertonic renal papillae.
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p-aminophenol
*p aminophenol depletes reduced glutathione in critical proteins and results in papillary necrosis |
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Displacement of secondary drugs from plasma protein binding sites is (pronounced/minimal) with Acetaminophen.
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Minimal
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Ketorlac is absorbed orally or IM w/ peak blood concentrations occurring within ________. The half-life is ______.
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30-60 minutes
4-6 hours |
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_______ of Ketorlac in the blood is bound to plasma proteins
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98-99%
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How is Ketorlac metabolized?
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40% --conjugated w/ glucuronic acid
60% --excreted unchanged |
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What are the pharmacological actions of Ketorlac?
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Inhibition of COX I and COX II mediated prostaglandin synthesis provides analgesic, antipyretic and anti-inflammatory actions
*potent analgesic actions outweigh use as an antipyretic or anti-inflammatory agent *NOT associated w/ tolerance or dependence |
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What are the indications for use of Ketorlac?
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Short term management of SEVERE pain (5 days max)
Administered oral, IM, or intraocular |
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What are the adverse effects of Ketorlac?
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GI discomfort, dizziness, headache
Inhibits platelet aggregation--bleeding time may be prolonged; post-op blood loss has been reported Bronchospasm--in pts. w/ asthma, nasal polyposis, aspirin sensitivity Increased incidence of gastric ulcers and renal impairment---when admin. for > 5 days Avoid in patients w/ renal dysfunction |
