FARMACOCINETICA CLINICA

1 Fármaco Pres. F.F. Bioavailability Ka

(F)
Oral Tab 60-80%

Cap 90-100%
IV Iny 100%

2 DIGOXINA

Oral 70%-100% 8.06-8.33

Very slow, but
IM
complete 92 %
IV 100%

3 FENITOINA

is absorbed rapidly
from the GI tract with
4 WARFARINA
little interindividual
variation
4 WARFARINA
little interindividual
variation

Oral 17-90%
IM 76-100%

70%

5 METOTREXATO

Oral 10-89 %

IV poor

Optal. none

6 CICLOSPORINA
 Oral

IV

7
TEOFILINA

Oral 50%

IV

5.6

8 AMIODARONA
8 AMIODARONA

9 QUINIDINA Oral 70% to 80%

70%

IM

IV
0.4 to 0.8 L/kg or 33 L/m
Referencias Bibliograficas

1 Micromedex (Drug Dex) 2006

2 Martindale 2006
3 USP Ed. 21
4 Farmacocinética Clínica Básica 2da Ed.1988
 Vd Cl t 1/2
(0.692)(Vd) / Cl
4-7 L/kg 57 ml/min 1.3-2.2 days

6-8 L/kg

1.5-2 days

0.5-1.0 L/kg 22 hours

Distributed into cerebrospinal fluid,

(like metabolite)
saliva, semen, gastrointestinal fluids, bile,
Ethotoin (3-9hours),
and breast milk 120; also crosses the
mephenytoin (7 hours),
placenta, with fetal serum concentrations
and phenytoin (7 hours)
equal to those of the mother

0.11-0.2 L/kg 31-51 hours

20-60 hours
S-warfarine 18-43 hours
S-warfarine 21-43 hours
R-warfarine 20-89 hours
R-warfarine 37-89 hours
 0.4-0.9 L/kg 90-200 ng/mL 8-15 h

0.4 to 0.8 L/kg Low doses: 3 to 10 hours

High doses: 8 to 15 hours

3.5 to 13 L/kg 19 hours.

Children — Approximately
7 hours (range, 7 to 19
hours)

Adults — Approximately
19 hours (range, 10 to 27
hours)
 450 mL/kg 0.0056 to 0.0084 54 to 76 hours, premature
L/hr/kg neonates

ADULTS: 0.3 to 0.7 L/kg ADULTS: 0.65 ADULTS: 8.2 (6.1 - 12.8)
(0.27 - 1.03) hours
(mL/kg/min)

1.3 to 65.8 L/kg 26 to 107 days

Initial: Amiodarone — 2.5

to 10 days
Terminal: Amiodarone —
26 to 107 days (mean 53
days; 40 to 55 days in
most patients).
 2 to 3.5 L/kg in healthy young adults, but
this may be reduced to as little as 0.5 L/kg 3 to 5 mL/min/kg ADULTS: 6-8 hours
in patients with congestive heart failure,
or increased to 3 to 5 L/kg in patients with CHILDREN:3-4 hours
cirrhosis of the liver

4 to 17 hours; average,
approximately 6 hours

3 L/kg, but may be reduced in patients

with congestive heart failure and
increased in patients with cirrhosis
a Básica 2da Ed.1988
 ESCUELA DE SANIDAD DEL EJERCITO DEL PERU

UNMSM : Especialidad de FARMACIA CLINICA

Ke Via Elim
( 0.693/T 1/2)
A. RENAL EXCRETION: 57-80%

B. BILE, 6-8%
C. FECES, 3-5%

Primarily hepatic (biliary/fecal), but

also renal. Elimination is
independent of renal function.
Primarily renal (50 to 70% of an
intravenous dose may be recovered
unchanged in the urine
Digoxin may accumulate
in patients with renal function
impairment

7 mg/kg/day A. RENAL EXCRETION: 92%

4 mg / ml B. FECES very little

(like metabolite) Ethotoin,

mephenytoin, and phenytoin

BREASTFEEDING
( in an inactive form)

A. BREAST MILK
B. BILE (like metabolite)

Renal, up to 92%
A. RENAL EXCRETION: 48-100%
B. Bile 0-10%
C. Feces small degree

Renal (unchanged), 80 to 90% in the

first 24 hours
Biliary, 10% or less

A. RENAL EXCRETION: 6%

B. Only 0.1% of a cyclosporine

dose is eliminated in the urine as
unchanged drug
C. Bile

Biliary/fecal; renal, 6% (0.1%

unchanged)
A. RENAL EXCRETION: 10% to
13%, adults

Renal; approximately 10% excreted

unchanged in the urine in adults

A. RENAL EXCRETION: less than

1%
B. BILE, primary route of
elimination

Biliary

In breast milk — About 25% of

maternal dose is distributed into
breast milk. In
dialysis — Not removable by
hemodialysis
RENAL EXCRETION: 17-50%

FECES, Approximately 1-3%

Renal — Approximately 20% of

quinidine is excreted unchanged in
the urine when urine pH is below 7

Urinary excretion may decrease to

as little as 5% in more alkaline urine

Renal elimination involves both

glomerular filtration and active
tubular secretion, moderated by
pH-dependent tubular reabsorption

Metabolite active
3-hydroxyquinidine, 9-12 hours
 EJERCITO DEL PERU
LA DE SANIDAD DEL EJERCITO DEL PERU

MSM : Especialidad de FARMACIA CLINICA

Q.F. MAGNELIA CARRILLO ESPINOZA

Interaccion
(Severity : Major)
ALPRAZOLAM: Increase digoxin concentrations (5-100%)
AMIODARONA: increases the serum digoxin concentration by

BECLAMIDE: reversible leukopenia

LIDOCAINE: Produce additive cardiac depression
JOHN'S WORT: Reduced phenytoin effectiveness

Trimethoprim: (serum phenytoin concentrations may be increased because

of inhibition of its metabolism by these agents, resulting in increased
effects and/or toxicity of phenytoin; dosage adjustments may be necessary)
(trimethoprim may increase the half-life of phenytoin by up to 50%, and
decrease its clearance by 30% through inhibition of metabolism of
phenytoin

APREPITANT : decrease in international normalized ratio or prothrombin time

ASPIRIN: an increased risk of bleeding
CAPECITABINE: increased risk of bleeding
COTRIMOXAZOLE:an increased risk of bleeding
CRANBERRY:an increased risk of bleeding
GARLIC : increased risk of bleeding
GINKGO : increased risk of bleeding
IMATINIB increased risk of bleeding
LEFLUNOMIDE increased risk of bleeding
LYCIUM increased risk of bleeding
NANDROLONE: potentiation of anticoagulation
ST JOHN'S WORT : reduced anticoagulant effectiveness
SULFAMETHOXAZOLE: increased risk of bleeding
TAMOXIFEN: increased risk of bleeding
TAN-SHEN : increased risk of bleeding
ALCLOFENAC:Increase methotrexate levels and cause toxicity
AMOXICILLIN/CLAVULANIC ACID : Methotrexate toxicity
APAZONE:Use of NSAIDs increase it's levels and cause toxicity
ASPARAGINASE : Decreased antineoplastic activity
ASPIRIN : Methotrexate toxicity
BENTIROMIDE : Methotrexate toxicity
BISMUTH SUBSALICYLATE :Methotrexate toxicity
BISMUTH SUBSALICYLATE :Methotrexate toxicity
COMFREY : Elevated liver transaminases,possible hepatic damage
COTRIMOXAZOLE : Increased risk of methotrexate toxicity
DOXYCYCLINE : Increased risk of methotrexate toxicity
ERYTHROMYCIN/SULFISOXAZOLE :Increased risk of methotrexate toxicity
GERMANDER : elevated liver transaminases possible hepatic damage
JIN BU HUAN : elevated liver transaminases possible hepatic damage
KAVA: Increased risk of liver damage
LIVE VACCINES : Increased risk of infection by the live vaccine
MEZLOCILLIN: Methotrexate toxicity
OMEPRAZOLE :Increased risk of methotrexate toxicity
PENICILLIN : Methotrexate toxicity
PHENYTOIN: decreased phenytoin effectiveness and an increased risk of
methotrexate toxicity
PIPERACILLIN: Methotrexate toxicity
PROBENECID: Methotrexate toxicity
VALERIAN: Increased risk of hepatotoxicity
ALFALFA: reduced immunosuppressive drug effectiveness and acute transplant
rejection
ATORVASTATIN: an increased risk of myopathy or rhabdomyolysis BLACK
COHOSH reduced immunosuppressive drug effectiveness and acute transplant
rejection
BOSENTAN decreased plasma concentrations of cyclosporine and increased
plasma concentrations of bosentan
CASPOFUNGIN increased plasma levels of caspofungin
CERIVASTATIN an increased risk of myopathy or rhabdomyolysis
COLCHICINE an increased risk of cyclosporine toxicity (renal dysfunction,
cholestasis, paresthesias); gastrointestinal dysfunction, hepatonephropathy, and
neuromyopathy
ETOPOSIDE: Increases in etoposide systemic exposure and leukopenia
FELODIPINE increased risk of felodipine toxicity
ITRACONAZOLE an increased risk of cyclosporine toxicity (renal dysfunction,
cholestasis, paresthesias)
LOVASTATIN an increased risk of myopathy or rhabdomyolysis
RED YEAST RICE an increased risk of elevated creatine phosphokinase (CPK)
values
RIFABUTIN reduced cyclosporine effectiveness
RIFAMPIN reduced cyclosporine serum levels and potentially an increased risk
of organ rejection
ROSUVASTATIN :an increase in plasma rosuvastatin concentrations
SIMVASTATIN : an increased risk of myopathy or rhabdomyolysis
ST JOHN'S WORT: decreased cyclosporine levels, acute transplant rejection
TACROLIMUS : an increased risk of nephrotoxicity
Vaccines, live virus of the vaccine virus, and/or may decrease the patient's
antibody response to the vaccine
VORICONAZOLE : increased cyclosporine plasma trough levels through
cytochrome P450 3A4 inhibition

BUPROPION : increased plasma concentrations of theophylline

CIMETIDINE: theophylline toxicity (nausea, vomiting, palpitations, seizures)
CIPROFLOXACIN and PEFLOXACINO: elevated plasma theophylline
concentrations, prolongation of theophylline elimination half-life, and theophylline
toxicity (nausea, vomiting, palpitations, seizures)
ENOXACIN : theophylline toxicity (nausea, vomiting, palpitations, seizures)

ERYTHROMYCIN : theophylline toxicity or decreased erythromycin effectiveness

ERYTHROMYCIN/SULFISOXAZOLE : theophylline toxicity or decreased
erythromycin effectiveness
ETHINYL ESTRADIOL:(with OTHER CONTRACEPTIVES) theophylline toxicity
(nausea, vomiting, palpitations, seizures)
ETINTIDINE: theophylline toxicity (nausea, vomiting, palpitations, seizures)

ETONOGESTREL: theophylline toxicity (nausea, vomiting, palpitations, seizures)

FLUVOXAMINE : theophylline toxicity (nausea, vomiting, palpitations, seizures)

HALOTHANE :cardiac toxicity (ventricular arrhythmias, cardiac arrest)
IMIPENEM: theophylline toxicity (nausea, vomiting, palpitations, seizures)

LEVOFLOXACIN : theophylline toxicity (nausea, vomiting, palpitations, seizures)

PEGINTERFERON ALFA-2A: theophylline toxicity (nausea, vomiting,
palpitations, seizures)
ROFECOXIB:increased plasma theophylline concentrations and possible
theophylline toxicity (nausea, vomiting, palpitations, seizures)
THIABENDAZOLE: theophylline toxicity (nausea, vomiting, palpitations,
seizures)
TROLEANDOMYCIN:theophylline toxicity (nausea, vomiting, palpitations,
seizures)
ZILEUTON :an increased possibility of theophylline toxicity (nausea, vomiting,
palpitations, seizures)
ADENOSINE:an increased risk of cardiotoxicity (QT prolongation, torsades de
pointes, cardiac arrest)
AMPRENAVIR :an increased risk of amiodarone toxicity (hypotension,
bradycardia, sinus arrest)
ANTIPSYCHOTICS :an increased risk of cardiotoxicity (QT prolongation,
torsades de pointes, cardiac arrest)
ARSENIC TRIOXIDE :cardiotoxicity (QT prolongation, torsades de pointes,
cardiac arrest)
AZITHROMYCIN :increased plasma concentrations of amiodarone and an
increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
BETA-ADRENERGIC BLOCKERS :hypotension, bradycardia, or cardiac arrest
CALCIUM CHANNEL BLOCKERS :bradycardia, atrioventricular block and/or
sinus arrest
CIMETIDINE : theophylline toxicity (nausea, vomiting, palpitations, seizures)
CIPROFLOXACIN LEVOFLOXACIN : elevated plasma theophylline
concentrations, prolongation of theophylline elimination half-life, and theophylline
toxicity (nausea, vomiting, palpitations, seizures)
ENOXACIN: theophylline toxicity (nausea, vomiting, palpitations, seizures)
ERYTHROMYCIN ; ERYTHROMYCIN/SULFISOXAZOLE :theophylline toxicity or
decreased erythromycin effectiveness
ETHINYL ESTRADIOLand OTHER CONTRACEPTIVES :theophylline toxicity
(nausea, vomiting, palpitations, seizures)
IDROCILAMIDE: an increased risk of theophylline toxicity (nausea, vomiting,
palpitations, seizures)
IMIPENEM: theophylline toxicity (nausea, vomiting, palpitations, seizures)
MEXILETINE :theophylline toxicity (nausea, vomiting, palpitations, seizures)
NORELGESTROMIN :theophylline toxicity (nausea, vomiting, palpitations,
seizures)
PEGINTERFERON ALFA-2A : theophylline toxicity (nausea, vomiting,
palpitations, seizures)
THIABENDAZOLE : theophylline toxicity (nausea, vomiting, palpitations,
seizures)
ZILEUTON : an increased possibility of theophylline toxicity (nausea, vomiting,
palpitations, seizures)
ACETAZOLAMIDE: quinidine toxicity (ventricular arrhythmias, hypotension,
aggravated CHF)
ADENOSINE: an increased risk of cardiotoxicity (QT prolongation, torsades de
pointes, cardiac arrest)
AMIODARONE : increased quinidine concentrations and increased risk of
toxicities (diplopia, giddiness, hypotension; cardiotoxicity including QT
prolongation and torsades de pointes)

AMITRIPTYLINE : amitriptyline toxicity (dry mouth, urinary retention, sedation)

and an increased risk of cardiotoxicity (QT prolongation, torsades de pointes,
cardiac arrest)
AMOXAPINE : amoxapine toxicity (dry mouth, sedation) and an increased risk of
cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
AMPRENAVIR:an increased risk of quinidine toxicity (ventricular arrhythmias,
hypotension, exacerbation of heart failure)
ANTIPSYCHOTICS: an increased risk of cardiotoxicity (QT prolongation,
torsades de pointes, cardiac arrest)
ARBUTAMINE : an increased risk of cardiac arrhythmias
ARIPIPRAZOLE :increased aripiprazole plasma levels
ARSENIC TRIOXIDE:an increased risk of cardiotoxicity (QT prolongation,
torsades de pointes, cardiac arrest)
ATAZANAVIR:increased plasma concentrations of Class Ia antiarrhythmics
BEPRIDIL :an increased risk of cardiotoxicity (QT prolongation, torsades de
pointes, cardiac arrest)
CHLORAL HYDRATE: an increased risk of cardiotoxicity (QT prolongation,
torsades de pointes, cardiac arrest)
CISAPRIDE:cardiotoxicity(QT prolongation, torsades de pointes, cardiac arrest)
CLARITHROMYCIN, CLINDAMYCIN, ERYTHROMYCIN,
ERYTHROMYCIN/SULFISOXAZOLE :cardiotoxicity (QT prolongation, torsades
de pointes, cardiac arrest)
CLASS I, IA, III, ANTIARRHYTHMIC AGENTS : an increased risk of
cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
COTRIMOXAZOLE:an increased risk of cardiotoxicity (QT prolongation, torsades
de pointes, cardiac arrest)
DIGITOXIN : digitoxin toxicity (vomiting, cardiac arrhythmias)
DIGOXIN: digoxin toxicity (nausea, vomiting, cardiac arrhythmias)
DOLASETRON : cardiotoxicity (QT prolongation, torsades de pointes, cardiac
arrest)
DROPERIDOL : an increased risk of cardiotoxicity (QT prolongation, torsades de
pointes, cardiac arrest)
FLUCONAZOLE:an increased risk of cardiotoxicity (QT prolongation, torsades de
pointes, cardiac arrest)
GATIFLOXACIN, GEMIFLOXACIN, GREPAFLOXACIN, LEVOFLOXACIN,
MOXIFLOXACIN, SPARFLOXACIN an increased risk of cardiotoxicity (QT
prolongation, torsades de pointes, cardiac arrest)
ISOFLURANE : an increased risk of cardiotoxicity (QT prolongation, torsades de
pointes, cardiac arrest)
ITRACONAZOLE : an increased risk of quinidine toxicity (ventricular arrhythmias,
hypotension, exacerbation of heart failure)
MEFLOQUINE: an increased risk of cardiotoxicity (QT prolongation, torsades de
pointes, cardiac arrest) and convulsions
OCTREOTIDE :an increased risk of cardiotoxicity (QT prolongation, torsades de
pointes, cardiac arrest)
PROCAINAMIDE : hypotension and an increased risk of cardiotoxicity (QT
prolongation, torsades de pointes, cardiac arrest)
RITONAVIR, SAQUINAVIR : an increased risk of quinidine toxicity (ventricular
arrhythmias, hypotension, exacerbation of heart failure)
SUCCINYLCHOLINE : succinylcholine toxicity (respiratory depression, apnea)
TELITHROMYCIN : an increased risk of cardiotoxicity (QT prolongation, torsades
de pointes, cardiac arrest)
TERFENADINE : an increased risk of cardiotoxicity (QT prolongation, torsades
de pointes, cardiac arrest)
TUBOCURARINE : tubocurarine toxicity (respiratory depression, apnea)
VASOPRESSIN: an increased risk of cardiotoxicity (QT prolongation, torsades de
pointes, cardiac arrest)
ZOLMITRIPTAN: an increased risk of cardiotoxicity (QT prolongation, torsades
de pointes, cardiac arrest)
 Treatment of OVERDOSES Observation
(Metabolites)
A. Digoxigenin bisdigitoxoside,
(active) (Iisalo, 1977).
B. Digoxigenin
monodigitoxoside, (active)
Previous adjunctive treatments in the
management of non - life-threatening digitalis
intoxication, such as repetitive doses of
activated charcoal, cholestyramine, and/or
colestipol (presumably to interrupt the
enterohepatic recycling of digoxin to enhance
elimination), have not been shown to be
clinically effective

Since there is no specific antidote for overdose

with hydantoin anticonvulsants, treatment is
symptomatic and supportive. To decrease
absorption — Induction of emesis or gastric
lavage. Multiple oral doses of activated
charcoal. and cathartic may shorten the
duration of symptoms.

If excessive increases in prothrombin time (PT)

and/or INR without bleeding or prospective
surgery, occur, the INR should be reduced to a
safe level (e.g., less than 5). If serious bleeding
is present, the INR should be reduced to 1 as S-warfarin exhibits about 2 to 5
soon as possible. Reversal of anticoagulation times the anticoagulant activity
is not maximal for 24 to 48 hours after of R-enantiomer
withholding the anticoagulant. For serious but also has
overdose or life-threatening bleeding, when more rapid clearance
immediate restoration of clotting factors is
necessary, transfusion of fresh plasma or
prothrombin (factor IX) complex concentrate
along with vitamin K 1 may be necessary
 is not maximal for 24 to 48 hours after of R-enantiomer
withholding the anticoagulant. For serious but also has
overdose or life-threatening bleeding, when more rapid clearance
immediate restoration of clotting factors is
necessary, transfusion of fresh plasma or
prothrombin (factor IX) complex concentrate
along with vitamin K 1 may be necessary

Leucovorin is used to minimize the toxicity and

counteract the effect of methotrexate overdose.
Leucovorin therapy should begin as soon as
possible in order to maximize its effectiveness. Metabolites can be
Monitoring of the serum methotrexate converted back to
concentration is essential in determining the methotrexate by hydrolase
optimal dose and duration of treatment of enzymes
leucovorin.

M1 (monohydroxylated
metabolite), active

In general, treatment is symptomatic and

supportive. To decrease absorption — Forced
emesis may be useful for up to 2 hours after
oral ingestion of toxic doses of cyclosporine. To
enhance elimination — Cyclosporine is not
removable by hemodialysis or charcoal
hemoperfusion. Specific treatment — Transient
hepatotoxicity and nephrotoxicity usually
respond to withdrawal of cyclosporine. Patients
in whom intentional overdose is confirmed or
suspected should be referred for psychiatric
consultation
 In neonate: caffeine (30 to 80%), active

There is no antidote for theophylline overdose.

Treatment is symptomatic and supportive.
To decrease absorption
—
Regardless of the route or mode of exposure
resulting in toxicity, oral activated charcoal
(OAC) should be administered. OAC binds
medication remaining in the gastrointestinal
tract and decreases serum concentrations by
interrupting enteroenteric recirculation of
theophylline. Use of an aqueous activated
charcoal preparation is recommended. If the
total dose of OAC is not tolerated, more
frequent administration of smaller doses, slow
instillation through a nasogastric tube, or
concurrent use of an antiemetic may be tried.
The initial dose of charcoal may be followed by
a single dose of sorbitol if the charcoal is not
pre-mixed with sorbitol. Caution is
recommended when giving more than a single
dose of sorbitol since frequent administration
may result in dehydration and electrolyte
imbalance secondary to diarrhea. Sorbitol is
reported to be more effective than magnesium-
containing cathartics and is not associated with
hypermagnesemia;however, the role of
cathartics is questionable.
Ipecac syrup should generally be avoided in the
management of theophylline overdoses

N-desethylamiodarone (DEA),
(active)

Decrease absorption — Recent oral ingestion

may benefit from emesis and/or lavage

Specific treatment

Primarily supportive and symptomatic.

Monitoring of cardiac rhythm and blood

pressure is important

For bradycardia, a beta-adrenergic agonist or

pacemaker may be indicated
Hypotension may respond to positive inotropic
and/or vasopressor agents

A. 3-hydroxyquinidine, (active)
3-hydroxyquinidine (3HQ) has
at least half the antiarrhythmic
activity of the parent
compound, so it may be
responsible for a substantial
fraction of the antiarrhythmic
Treatment should be symptomatic and efficacy. Serum levels of 3HQ
supportive and may include the following: can approach those of
To decrease absorption — Although the use of quinidine in patients receiving
gastric lavage decreased the elimination half-life conventional doses of
of quinidine in one case report, the clinical Quinaglute(R). The volume of
benefit of gastric lavage has not been distribution of 3HQ appears to
confirmed, and it should be used only if be larger than that of quinidine
ingestion has occurred within 1 hour. Similarly, (Prod Info Quinaglute(R),
the use of activated charcoal should be
considered only if ingestion has occurred within
1 hour. To enhance elimination — Medications
that delay the elimination of quinidine, such as
urinary alkalizers (i.e., carbonic-anhydrase
inhibitors, sodium bicarbonate, thiazide
diuretics), should be withdrawn, if possible, to
avoid prolonging the half-life of quinidine.
However, attempting to facilitate quinidine
elimination by acidifying the urine is not
recommended and is considered hazardous.
 avoid prolonging the half-life of quinidine.
However, attempting to facilitate quinidine
elimination by acidifying the urine is not
recommended and is considered hazardous.
Molecula

WARFARINE
METHOTREXATE

CYCLOSPORINE
30 to 80%), active

TEOPHYLLINE