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36 Cards in this Set

  • Front
  • Back
Overview of non-narcotic analgesics?
Provide analgesia for low to moderate intentsity pain such as
-- headache
-- myalgia
-- arthralgia
-- other pains arising from integument structures

ANTIPYRESIS is also a prominent action of this group of agents
What are the non-narcotic analgesics?

-- Aspirin
-- Ibuprofen
-- Ketorolac
Which NSAIDS also exhibit significant anti-inflammatory effects?
-- aspirin

Propionic acid derivatives
-- ibuprofen
-- ketorolac
ASA absorption?
Absorbed rapidly, partly from the stomach, but mostly from the upper small intestine

Rate and extent of absorption is determined by a number of factors
1. integration and dissolution rates of tablets
2. pH at the mucosal surface; acid conditions favor salicylate absorption
3. gastric emptying time
ASA once absorbed?
Rapidly hydrolyzed by tissue and blood esterases to acetate and salicylate

Acetylsalicylic acid  acetate + salicylic acid

Appreciable salicylate concentrations are found in plasma in less than 30 min w/ peak blood levels occurring w/in 1-2 hours

Free salicylate is distributed throughout most body tissues
-- 80-90% is bound to plasma proteins
-- “free” fraction of drug is available for either hepatic metabolism or renal elimination
What happens to ASA in the liver?
1. conjugated w/ glycine to form salicyluric acid
2. conjugated w/ glucuronic acid to form ester or ether glucuronides
3. metabolized (1%) to gentisic acid

Plasma half-life for salicylate is 2-3hrs in low doses and 15-30hrs at high or toxic doses

Dose-dependent elimination is a result of the limited ability of the liver to form salicyluric acid and the salicylate fraction to be conjugated w/ glucuronic acid
Where else can free salicylate be excreted?
In the urine
-- renal excretion is highly variable and is pH-dependent
-- as low as 5% free salicylate is excreted in acid urine and up to 85% free salicylate in alkaline urine
What are the propionic acid derivatives?

Pharmacodynamics of propionic acid derivatives?
1. are rapidly absorbed after oral administration

2. time to peak concentrations/half lives following oral administration
1-2hrs/2hrs – ibuprofen
1-2hrs/2hrs – ketoprofen

3. are extensively bound (99%) to plasma proteins, usually albumin

4. concentrations in synovial fluid may be higher than in plasma

5. extensively metabolized in liver

6. more than 95% of an ingested dose is excreted in the urine as water soluble metabolites or their conjugates
What are the pharmacologic actions of the NSAIDS?
1. Analgesic and anti-inflammatory actions

2. Reduction of elevated body temp via inhibition of PG synth in the hypothalamus

3. Decrease tubular reabsorption of urate thereby reducing serum urate levels (high dosages of ASA only)

4. Decreased platelet aggregation which reduces the incidence of stroke and recurrence of MI (ASA only)
What do prostaglandins/prostaglandin intermediates do in relation to pain?
They sensitize pain receptors to mediators such as
-- kinins
-- histamine
-- 5-HT
which are released due to tissue damage
What effect do salicylates and prostaglandin derivatives have on PGs?
They DECREASE synthesis of PGs via inhibition of enzyme prostaglandin synthase at both CENTRAL and PERIPHERAL sites
Describe COX-1 and its effect.
-- expressed in most tissues, including those involved w/ renal mechanisms and gastric cytoprotection
-- synthesizes PGs

1. PGs protect the gastric mucosa by reducing gastric acid production and release (serve as a “brake” on acid production)

2. PGs influence salt and water excretion by alterations in renal blood flow and by direct effects on the renal tubules
Describe COX-2 and its effect.
-- activated by cellular mediators released due to tissud damage
-- partly responsible for the inflammatory response
-- synthesizes PGs
How are COX-1 and COX-2 affected by salicylates and propionic acid derivatives?
1. inflammation-induced and PG synth is reduced by COX-1 and COX-2 inhibition

2. beneficial PG synth in gastric mucosa and kidney are reduced

3. considerable variation in potency in the ability to inhibit cyclooxygenase
Anti-inflammatory actions of NSAIDs?
1. inhibition of migration of polymorphonuclear leukocyte and macrophages into inflammation sites

2. stabilization of lysosomal mbrns
-- decreased release of mediators from granulocytes, basophils, and mast cells

3. inhibition of Ag-Ab aggregation
How can NSAIDS reduce elevated body temperature?
Reduce via inhibition of PG synthesis in the hypothalamus
-- bacterial pyrogens stimulate the production of IL-1 and other cytokines
-- IL-1 stimulates PG synth through activation of PG synthase in or near hypothalamus
-- increase in PG (PGE2) elevates body temp by interfering w/ hypothalamic temp control mechs which regulate heat production vs. loss
-- by blocking PG synthesis (probably both COX isoforms), aspirin and the propionic acid derivatives facilitate heat loss and reduce elevated body temp
How does ASA decrease platelet aggregation to reduce stroke and MI incidence?
-- ASA prior to deacetylation by esterases in the portal circulation, acetylates cyclooxygenase in platelets (presystemic inhibition)

-- acetylation IRREVERSIBLY inhibits cyclooxygenase (primarily COX-1) in platelets thereby blocking synth of thromboxane A2

-- platelets are particularly sensitive to ASA’s effects since they do not synth new enzyme

-- effects of a single dose can last 8-10 days (which is the life of platelets)

**propionic acid derivatives do not irreversibly inhibit the enzyme; it has not been established if these agents produce similar benefits
What are the adverse effects of ASA?
1. predominant side effect is gastric irritation (up to 40% of patients)

2. prolonged bleeding time, an extension of the decrease in platelet aggregation, can also occur w/ both acute and chronic admin
-- stop 2wks prior to surgery

3. pts w/ renal disease or dehydration appear to be sensitive to the salicylates such that a reversible decrease in GFR, interstitial nephritis and edema may occur
-- ↓ in PG allow vasoconstriction of renal vessels

4. children w/ chicken-pox or flu-like symptoms who take aspirin may be 25 times more likely to acquire Reye’s Syndrome
-- deadly disease of children and teenagers occurring in aftermath of viral infection
-- aspirin and viral illnesses appear to damage mitoch mbrns in genetically predisposed individuals leading to hepatic injury and encephalopathy

5. HSN rxns
-- asthma (8-20% of adult asthmatics), skin rashes, angioedema, and potentially anaphylactoid rxns
-- HSN pts w/ asthma and nasal polyps (toxicity triad) may experience bronchospasm and hypotension
What are the adverse effects of propionic acid derivatives?
1. gastric irritation to a lesser degree than salicylates (10-15%)

2. reduction in renal blood flow and edema; reversible decrease in GFR; interstitial nephritis, and nephrotic syndrome may also occur in pts w/ pre-existing renal disease or dehydration, especially w use of long-acting agents

3. bleeding time and Reye’s Syndrome do not appear to be evident w/ these agents

4. HSN rxns similar to ASA has been reported

5. birth defects (also w/ selective COX-2 inhibitors)
-- first trimester administration
-- signif higher risk of heart defects and other congenital anomalies
Mild ASA toxicity?
Headache, dizziness, mental confusion, tinnitus (hallmark!), nausea and vomiting

Symptoms are DOSE-dependent and resolve w/ reducing the dosage
Severe ASA toxicity?
1. marked hyperventilation due to increased CO2 production
-- salicylate uncouples oxidative metabolism in skeletal muscle to increase CO2 production
-- salicylate directly stimulates the medullary respiratory center

2. resultant respiratory alkalosis is compensated for by increased sodium and potassium bicarb excretion leading to severe disturbances in acid-base balance

3. if uncorrected, convulsions, coma and, after a period of unconsciousness, death results from respiratory failure

4. symptomatic treatment is sufficient in mild cases of poisoning, but admin of IV fluids, freq measurement and correction of acid-base and electrolyte balance is req’d in more severe cases

5. alkalinization of the urine will increase the excretion of free salicylates
NSAIDS and drug interactions?
1. ethanol combined w/ chronic admin of NSAIDS enhance possibility of GI bleeding

2. oral anticoags are displaced from plasma protein binding sites by ASA, increasing anticoag action

3. salicylate-induced displacement leads to an increase in free drug w/ tolbutamide, chlorpropamide, phenytoin and potentially other agents highly bound to plasma proteins

4. salicylates in small doses inhibit the tubular secretion of uric acid blocking the uricosuric effect of probenecid

5. other than displacement of secondary drugs from plasma protein binding sites, relatively few drug interactions are evident w/ the propionic acid derivatives

6. ibuprofen can interfere w/ the anti-platelet effect of low dose ASA (81mg/day) that may render ASA less effective when used for cardioprotection and stroke prevention
Pharmacokinetics of acetaminophen?
1. rapid and almost complete absorption from the GI tract

2. conc in plasma reaches peak in 30-60min w/ half-life in plasma of 2-3hrs

3. relatively uniformly distributed throughout most body fluids
-- binding of the drug to plasma proteins is 20-50%

4. practically no acetaminophen is excreted unchanged
-- bulk is excreted after hepatic conjugation w/ glucuronic acid (about 60%) or sulfuric acid (40%)

5. 4-5% metabolized via cytochrome P450 mixed fxn-oxidase system to N-acetyl-benzoguinoneimine (NABQ) followed by glutathione conjugation
Pharm actions of acetaminophen?
1. Has ANALGESIC and ANTIPYRETIC actions comparable to therapeutic doses of ASA and the propionic acid derivatives

2. The mech whereby it produces these actions is unclear since it demonstrates weak inhibition of COX-1 and COX-2

3. LACKS anti-inflamm properties possibly due to high conc of peroxides found at inflamm sites which inactivated the acetaminophen molecule

4. Studies suggest presence of a COX-3 isoenzyme which acetaminophen selectively inhibits that may explain the actions of this agent

5. PMN activation or platelet fxn are NOT altered
Adverse effects of acetaminophen?
Usually well tolerated
-- skin rxns (localized areas of erythema and urticaria) and other allergic rxns occur occasionally
Acetaminophen toxicity?
1. potentially fatal hepatic necrosis (primary cause of acute liver failure)

2. renal tubular necrosis
Acetaminophen and hepatic toxicity?
Toxic doses exceed the capacity for glucuronidation w/ more acetaminophen available for N-hydroxylation

1. acetaminophen is metab via microsomal enzyme systems to N-hydroxylate acetaminophen to NABQ

2. NABQ usually binds to sulfhydryl groups in glutathione to form an inactive product
-- excess NABQ exceeds hepatic glutathione stores
-- non-reacted NABQ reacts w/ sulfhydryl groups in hepatic proteins producing cellular damage and hepatic necrosis
Clinical signs of liver damage?
May become apparent w/in 2-4days of ingestion of toxic doses and include nausea, vomiting, and abdominal pain
Alcohol and acetaminophen-induced liver damage?
Induction of hepatic microsomal enzymes by chronic consumption of alcohol increases capacity to N-hydroxylate acetaminophen to NABQ
-- threshold for acetaminophen-induced liver damage can potentially be lowered
-- hepatic glutathione depletion (as might be the case in alcoholics) can further increase the severity of liver injury
-- studies have demonstrated that as little as 4gm of acetaminophen per day (8 extra-strength tablets) can produce severe liver injury
Treatment of toxic overdose of acetaminophen?
Vigorous supportive therapy
1. limit continued absorption of drug must be initiated promptly

2. induce vomiting or gastric lavage should be performed in all cases, and should be followed by oral admin or activated charcoal

3. hemodialysis, if can be initiated w/in first 12hrs, has been advocated for all patients

4. admin of sulfhydryl cmpds such as N-acetyl cysteine, increases the hepatic content of glutathione
Renal tubular necrosis and acetaminophen?
Can result from long-term abuse of analgesic formulations containing acetaminophen and ASA combinations

1. nephropathy results from p-aminophenol, a metabolite of acetaminophen, which concentrates in the hypertonic renal papillae

2. papillary necrosis occurs due to p-aminophenol-induced depletion of reduced glutathione in critical proteins

3. renal effects of aspirin may increase potential nephrotoxicity
Drug interactions w/ acetaminophen?
1. may induce synthesis of hepatic microsomal enzymes, but the effect is not seen w/ usual therapeutic doses

2. displacement of secondary drugs from plasma proteins binding sites is minimal w/ acetaminophen
Pharmacokinetics of ketorolac?
1. rapidly absorbed orally or IM w/ peak blood concentrations w/in 30-60min
-- half-life 4-6hrs
-- IV formulation is also available

2. bound to plasma proteins (98-99%)

3. metabolized in the liver and conjugated w/ glucuronic acid; approx 60% unchanged
Pharm actions of ketorolac?
1. inhibition of COX-1 and COX-2 mediated OG synth provides
-- analgesic
-- antipyretic
-- antiinflamm actions

2. potent analgesic actions OUTWEIGH use as antipyretic or anti-inflamm agent
-- usually admin for multimodal ACUTE pain

3. Not assoc w/ tolerance or dependence

Only designed for use up to 5 days
Adverse effects of ketorolac?
1. S/Es include
-- GI discomfort
-- dizziness
-- headache

2. Inhibits platelet aggregation
-- bleeding time can be prolonged
-- postop blood loss has been reported

3. bronchospasm may occur w/ admin of ketorolac to asthmatic pts, pts w/ nasal polyposis, or those w/ ASA sensitivity

4. increased incidence of gastric ulcers and renal impairment have been reported w/ admin of ketorolac longer than 5 days