Back
Salicylates
Generic drug name:
Aspirin,Choline Salicylate,Magnesium Salicylate(anhydrous),Salicylic
Acid,Salsalate,Sodium Salicylate.
Chemistry:
Salicylates are nonsteroidal anti-inflammatory agents(NSAIAs)that are synthetic
derivatives of salicylic acid.the drugs hydrolyze or dissociate to salicylate(ionized
salicylic acid)in vivo.
Pharmacology:
Salicylates mainly exhibit analgesic,anti-inflammatory,and antipyretic activity.These
effects appear to result principally from the salicylate moity.
The ability of aspirin to acetylate proteins results in some effects, such as inhibition of
platelet aggregation and prolongs bleeding timewhich other currently available
salicylates do not exhibit.
Salicylates alter the hepatic synthesis of blood coagulation foctors VII,IX,andX.It is
also have dose-related effects on urinary excretion of uric acid.
Route of administration:
Salicylates is available in parenteral,rectal,and oral dosage forms,but the oral dosage
forms are used primarily in anti-inflammatory therapy.there are a number of ester and
salt forms,as well as liquid,tablet,and capsule dosage formsof salicylates.
Elimination:
Salicylate is metabolized principally in the liver by microsomal enzyme system.it is
predominantly conjugated with glycine to form salicyluric acid or conjugated with
glucuronic acid to form salicyl phenolic glucuronide.
Salicyluric acid and salicyl phenolic glucuronide are formed by capacity –limited
(saturable) processes which can be characterized by Michaelis-Menten kinetics.other
salicylate metabolites appear to be formed by first – order processes.
Protein binding:
Salicylates exhibit some capacity-limited plasma protein binding,mainly albumin.the
fraction bound to serum proteins depends on both serum Salicylate and serum
albumin concentrations, even with comparable serum albumin concentrations at a
specific serum salicylates concentration,there are interindividual differences in the
amount of drug bound. In healthy individuals,Salicylate is approximately 9095%bound to serum proteins at serum salicylate concentrations up to
100mug/ml,approximately 70-85%bound to serum proteins at serum salicylate
concentrations of 100-400mug/ml,and possibly as little as 25-60%bound to serum
proteins at higher serum salicylate concentrations.
Therapeutic effects:
The usual total serum salicylate concentration associated with analgesia and
antipyresis is 30 –100mug/ml. The usual total serum salicylate concentration require
for anti – inflammatory effect is 150 –300mug/ml, however ,in the treatment of
rhematic fever,many clinicians believe a total serum salicylate concentration of 250 –
350mug/ml is associated with optimum therapeutic effects.
Side effects and toxic plasma concentrations:
* Salicylates (especially aspirin) can cause gastric mucosal damage which may result
in ulceration or bleeding
* It is also can cause nausea and vomiting as a result of local gastric irritation or by
CNC stimulation.
* Gastric accumulation of enteric – coated aspirin tablets , sometimes resulting in
gastric ulceration or salicylate intoxication ,has been reported in some patients with
gastric outlet obstruction.
* Tinnitus,which generally occurs at concentrations more than 200mg/L.
* Hearing loss which is completely reversible.
* Alterations in renal function.
* Decreased platelet activity.
* In the case of acute or chronic overdoses (e.g.: greater than 6g of aspirin daily )
salicylates produce respiratory stimulation by peripheral and central mechanisms,with
resultant changes in acid –base balanced and electrolytes.
* In overdosage , the drugs may cause a marked reduction in creatinine clearance or
acute tubular necrosis with renal failure.
Pregnancy and lactation:
_ Salicylates should be used during pregnancy only when the potetial benefits justify
the possible risks to the fetus.the drug generally should be avoided during the last 3
months . In one study ,maternal ingestion of aspirin during the week before delivery
was associated with an increased incidence of intracranial hemorrhage in premature
neonates.In addition , it has been suggested that premature closure of the ductus
arteriosus secondary to maternal salicylate ingestion may be one cause of persistent
pulmonary hypertention in some infants.
_ Salicylates are distributed into milk in low concentrations , the drugs should be
administered with caution to nursing women.
Drug interactions:
_ Because salicylate is highly protein bound ,it could be displaced from binding sites
by , or could displace from binding sites, other protein – bound drugs such as oral
anticoagulants ,sulfonylureas ,hydantoins ,penicillins , and sulfonamides ;salicylates
could also theoretically displace bilirubin in neonates ,resulting in
hyperbilirubinemia.patients receiving salicylates with any of these drugs should be
observed effects.
_ Salicylates may enhance the hypoprothrombinemic effect of warfarin and other oral
anticoagulants and increase the risk of bleeding complications with these agents;
several mechanisms may be involved
_ Adminstration of salicylates and methotrexate may result in increased serum
concentrations of methotrxate and thereby increase the risk of methotrexate toxicity.
_ Alcohol increases the incidence and severity of salicylate – induced GI bleeding and
increases the risk of gastric mucosal erosions and ulceration.
Bioavailability ( F ) :
In general ,salicylates are rapidly and well absorbed from the GI tract following oral
administration.
In general ,solid oral dosage forms of salicylates appear to be 80-100%absorbed. Oral
aqueous solutions appear to be completely absorbed.
The rate of absorption of an orally administered salicylate depends on many foctors
,including dosage form and its formulation characteristics ,gastric and intestinal PH
,gastric emptying time ,and the presence of food in the GI tract.
Food delays absorption and decreases the rate ,but not the extent of absorption.
The salt form , however ,should be considered when calculating the maintenance dose
because the fraction of salicylic acid in a dose con range from 57% to almost 90%.
Table 1: Dosage forms of salicylates
Compound
Acetylsalicylic acid
(Aspirin)
Sodium salicylate
Choline salicylate
Dosage Forms
Capsules and plain,
chewable, and entericcoated tablets
Tablets
Liquid (870 mg/5 mL)
Equivalents
77% SA
a
86% SA
57% SA
a
SA = Salicylic acid
Volume of distribution (VD):
_ Salicylates are rapidly distributed throughout extra cellular fluid and into most body
tissues and fluids , with high concentrations in the liver and kidney. It is can be
detected in synovial ,peritoneal ,and cerebrospinal fluids.
_ The apparent volume of distribution of salicylate is generally 0.15 – 0.2 L/Kg at
usual therapeutic concentrations but may be higher in neonates.the volume of
distribution appears to increase with increasing dose or serum concentration of
salicylate.
_ Al low salicylate plasma concentrations , the volume of distribution is less than
0.2L/kg , and at concentrations exceeding 200mg/L ,the volume of distribution is
larger. This change in the volume of distribution with increasing plasma
concentrations is due to saturable plasma protein binding , which becomes significant
as serum salicylate concentrations approach and then exceed 100mg/L.
for practical therapeutic purposes ,a volume of distribution of 0.2L/kg is probably a
satisfactory assumption when serum salicylate concentrations are within the
therapeutic range of 100 to 300mg/L.furthermore , the necessity for determining a
more accurate volume of distribution is not usually important clinically because
loading doses of salicylates are unnecessary.
Clearance (cl):
* Within the therapeutic range , salicylates have a plasma clearance of 0.012L /kg /hr ,
and it is declines as plasma concentration.
* The primary route of salicylate elimination occurs through five pathways:a linear
renal pathway , 2 linear metabolic pathways , and 2 capacity – limited metabolic
pathways.
_ Saturable plasma protein binding results in an unbound or free fraction of salicylic
acid of 0.1 at concentrations of 100mg /L and 0.2 at concentrations of 300mg /L.
_ The clearance for salicylates remains relatively stable (linear ) over the therapeutic
range of 100 to 300mg / L because the tow capacity – limited processes offset one
another .
_ Capacity – limited metabolism results in a decreased salicylate clearance , while
capacity – limited plasma protein binding increases salicylate clearance at higher
concentrations .
_ Large anti – inflammatory doses of salicylate are seldom used in patient with
diminished renal function because G.I bleeding and coagulopathies are potentiated.
_ Anti – acids produce minor increase in urinary PH and significantly increase in
urinary clearance of salicylate , so caution should be taken against altering anti –
acid regimen since toxicity or decrease in anti – inflammatory response may result .
Capacity – Limited Metabolism
CPss
CPss Ave
Capacity – Limited Plasma Binding
Rate of Administration
* * As we see in the figure CPss ave verses rate of administration :
_ As the rate of drug administration increases , the plasma concentration
increases((capacity - limited plasma binding ))
_ An increase in the average steady – state plasma concentration ( CPss ave )result in
a decrease in the calculated clearance value ((capacity – limited metabolism )).
Half - life (t 1/2):
The apparent half- life for salicylates is quite variable.serum salicylate half-life is
approximately 2-3 hours ,however , with higher doses 100to300 mg/L ,elimination of
salicylate is capacity limited and the apparent serum salicylate half – life may increase
to 15 – 30 hours the following pharmacokinetic parameters for adults , expressed in
concentrations of salicylate and amounts of salicylate metabolized.
The clinical application of salicylate half –life is limited ,however , because of its
capacity – limited metabolism. One would expect that a steady state would be
achieved within three to four days when anti – inflammatory doses are used ( eg:when
the plasma half – life is approximately 24hours ).Data suggest , however ,that
following a change in the maintenance dose of salicylate , approximately seven days
are required for a new steady state to be achieved. This time requirement , which is
longer than the usual three to five half – life rule , is probably due (at least in part ) to
the capacity – limited metabolism of salicylates.
Time to sample :
_ Plasma samples of salicylates are obtained within one week to evaluate the
relationship between the salicylate concentration and the patients clinical response on
the other hand , salicylate concentration measured more than one week reflect steady
state and can be used as a guide to dose adjustment .
_ little fluctuation in plasma concentration is expected within the dosing interval (T<
t1/2 or T= t 1/2) , the rapid absorption of salicylates as well as the capacity – limited
plasma protein binding tend to complicate the relationship between dose and
measured salicylate concentrations.
Clinical cases:
Question # 1:G.L. is a 40 year-old , 65kg male taking one 325mg aspirin tablet
,(T=6 hrs )for minor joint pain . Calculate the expected steady- state plasma
concentration for salicylate in G.L.
Using the average clearance value of 0.012L /kg /hr, a salt factor (s) of 0.77 and a
bioavailability (F) of 1.0for acetylsalicylic acid (ASA) .
Cl = 0.012 * body weight = 0.012 * 65 kg = 0.78 L /hr
CPss ave = S * F * Dose
Cl * T
= (0.77) (1) (325 )
= 53 mg /L
(0.78) (6)
the perdicted salicylate level of 53 mg /L is lower than the usual range of therapeutic
concentrations . At concentrations below 100mg / L , the salicylate clearance is
generally much greater than the average literature value (0.012 L / kg /hr). For this
reason , the measured serum concentration of salicylate is likely to be considerably
less than the predicted value of 53mg /L .there also is a nonlinear decrease in
salicylate clearance as concentrations approach 100mg / L ; pharmacokinetic
extrapolations based upon concentrations below the therapeutic range should be
avoided.
Question # 2: L.P. a 52year – old , 50 kg female is taking three 325 mg aspirin
tablets ( T = 6 hrs) for her arthritis . What would be the expected steady – state trough
salicylate concentration for L.P ?
Using an average volume of distribution of 0.2 L /kg and an average Cl value of 0.012
L /kg /hr , L.P. should have a volume of distribution , clearance , and elimination rate
constant of approximately
10L, 0.6 L /hr and 0.0 6hr-1, respectively according to the calculations below .
Salicylate Vd = ( 0.2 L /kg ) (50kg)
= 10 L
Salicylate Cl = (0.012L /kg /hr) (50g) = 0.6 L /hr
Kd = Cl / Vd = (0.6 L/hr ) / (10L) = 0.06 hr-1
Using these values, an assumed (s) of 0.77 ,and an F of 1.0 an anticipated trough
concentration can be calculated by use of equation.
CPss min =
S * F * Dose
(e-Kdt)
Vd (1- e-Kdt)
(0.77)(1)(975mg)
=
-1
10L(1 – e-(0.06 hr )(6 hr) )
-1
(e-(0.06 hr )(6) hr) (
= [ 75 mg/L ] [0.7]
0.3
= 175 mg/L
An alternative method for calculating the trough concentration would be to first
estimate the average steady – state level by using equation.
Another way:
CPss ave = S * F * Dose
Cl * T
= (0.77)(1)(975mg/6hr) = 208 mg/L
0.6L/hr
This average plasma salicylate concentration could then be used to estimate the trough
concentration by the following equation:
CPss min = [CPss ave] – [ (0.5) S * F * Dose]
Vd
This equation assumes that the average concentration lies approximately halfway
between the peak and the trough and will be reasonably accurate as long as the dosing
interval is one half – life or less . For example, in this case the expected trough
concentration using above equation is about 170 mg /L as compared to the value of
175 mg /L calculated from before equation.
CPss min = [208 mg/L] – [ (0.5) (0.77)(1)(975 mg)]
10L
= 208 mg – 37.5 mg
= 170.5 mg/L
Question #3: L.P. has experienced some gastrointestinal side effects . What would
be the antacid to her salicylate regimen ?
Antacids markedly decrease serum salicylate level when taken in the therapeutic
amounts . since this decrease can range from 30%to 70% , L .P. s serum salicylate
concentration should decrease to about one – half of the expected value when antacids
are added to her therapy . the decrease in salicylate level is only an approximation ,
however , and should antacids be utilized , additional salicylate monitoring would be
appropriate. In addition , L.P. should be cautioned against altering her antacid
regimen since toxicity or a decreased anti – inflammatory response may result . the
mechanism for the decrease in salicylatye level is an increase in renal clearance due to
the increase in urinary PH associated with antiacid therapy.
Question #4: It was decided that instead of adding an antacid to L.P.s therapy , she
would be changed from acetyl salicylic acid to Choline salicylate. Calculate a dose of
choline salicylate that would be equivalent to 975mg ASA every six hours.
Amount of drug absorbed or
Amount reaching systemic circulation = (S) (F) (Dose)
= (0.77) (1) (975mg) = 750 mg
This amount of salicylic acid can then be converted to the equivalent amount of
choline salicylate using information in table before (table of dosage forms of
salicylates )
Dose of new Dosage form = Amount of drug absorbed from current dosage form
(s) (F) of new dosage form
=
750 mg
= 1316mg
(0.57) (1)
Table 2 : Key Parameters
Therapeutic Range
100-300 mg/L or 10-30 mg/dL
F
100%
S
See Table 1
Vdª
0.2 L/kg/hr
Clb
0.012 L/kg/hr
t1/2c
Free Fraction (α)
10-24 hr
0.1-0.2 (See text)
ª The capacity-limited plasma protein binding results in a volume of distribution
which increases with dose .On average, the Vd is ≈0.2 L/kg at salicylate
concentrations of 200 mg/L .
b
The clearance of salicylates declines as the plasma concentrations increase from <5
to ≈100 mg/L ,but remains relatively stable between 100 and 300mg/L .
c
The half – life of salicylates reflects a complex relationship between the apparent
volume of distribution and clearance . In the therapeutic range ,most patients have a
half –life of approximately 10 to 15 hours.
Back