FARMACOCINETICA CLINICA

1 Fármaco Pres. F.F. Bioavailability Ka( F )

2 DIGOXINA

Oral Tab 60-80%

Cap 90-100%

IV Iny 100%

3 FENITOINA

Oral 70%-100% 8.06-8.33

IM

IV 100%

4 WARFARINA

Very slow, but complete 92 %

is absorbed rapidly from the GI tract with little interindividual

variation

4 WARFARINA

5 METOTREXATO

Oral 17-90%IM 76-100%

70%

6 CICLOSPORINA

Oral 10-89 %

IV poor

Optal. none

is absorbed rapidly from the GI tract with little interindividual

variation

6 CICLOSPORINA

7TEOFILINA

Oral

IV

8 AMIODARONA

Oral 50%

IV

5.6

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) 20062 Martindale 20063 USP Ed. 214 Farmacocinética Clínica Básica 2da Ed.1988

Vd Cl(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

0.11-0.2 L/kg 31-51 hours20-60 hours

S-warfarine 18-43 hoursS-warfarine 21-43 hoursR-warfarine 20-89 hoursR-warfarine 37-89 hours

t 1/2

Distributed into cerebrospinal fluid, saliva, semen, gastrointestinal fluids, bile, and

breast milk 120; also crosses the placenta, with fetal serum concentrations

equal to those of the mother

(like metabolite) Ethotoin (3-9hours), mephenytoin (7 hours),

and phenytoin (7 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

ADULTS: 0.3 to 0.7 L/kg

1.3 to 65.8 L/kg 26 to 107 days

0.0056 to 0.0084 L/hr/kg

54 to 76 hours, premature neonates

ADULTS: 0.65 (0.27 - 1.03) (mL/kg/min)

ADULTS: 8.2 (6.1 - 12.8) hours

Initial: Amiodarone — 2.5 to 10 days

Terminal: Amiodarone — 26 to 107 days (mean 53

days; 40 to 55 days in most patients).

3 to 5 mL/min/kg ADULTS: 6-8 hours

CHILDREN:3-4 hours

2 to 3.5 L/kg in healthy young adults, but this may be reduced to as little as 0.5 L/kg in patients with congestive heart failure,

or increased to 3 to 5 L/kg in patients with 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

Farmacocinética Clínica 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%

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

4 mg / ml B. FECES very little

BREASTFEEDING( in an inactive form)

A. BREAST MILK

Renal, up to 92%

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

(like metabolite) Ethotoin, mephenytoin, and phenytoin

B. BILE (like metabolite)

A. RENAL EXCRETION: 48-100% B. Bile 0-10% C. Feces small degree

Biliary, 10% or less

A. RENAL EXCRETION: 6%

C. Bile

Renal (unchanged), 80 to 90% in the first 24 hours

B. Only 0.1% of a cyclosporine dose is eliminated in the urine as unchanged drug

Biliary/fecal; renal, 6% (0.1% unchanged)

Biliary

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

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%

Metabolite active

3-hydroxyquinidine, 9-12 hours

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

EJERCITO DEL PERU

ESCUELA DE SANIDAD DEL EJERCITO DEL PERU

UNMSM : 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 toxicityAMOXICILLIN/CLAVULANIC ACID : Methotrexate toxicityAPAZONE:Use of NSAIDs increase it's levels and cause toxicityASPARAGINASE : 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 toxicityERYTHROMYCIN/SULFISOXAZOLE :Increased risk of methotrexate toxicity GERMANDER : elevated liver transaminases possible hepatic damage JIN BU HUAN : elevated liver transaminases possible hepatic damageKAVA: Increased risk of liver damageLIVE 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 toxicityPIPERACILLIN: 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)

ARBUTAMINE : an increased risk of cardiac arrhythmias ARIPIPRAZOLE :increased aripiprazole plasma levels

ATAZANAVIR:increased plasma concentrations of Class Ia antiarrhythmics

CISAPRIDE:cardiotoxicity(QT prolongation, torsades de pointes, cardiac arrest)

DIGITOXIN : digitoxin toxicity (vomiting, cardiac arrhythmias) DIGOXIN: digoxin toxicity (nausea, vomiting, cardiac arrhythmias)

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)

ARSENIC TRIOXIDE:an increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)

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)

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)

DOLASETRON : cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)

SUCCINYLCHOLINE : succinylcholine toxicity (respiratory depression, apnea)

TUBOCURARINE : tubocurarine toxicity (respiratory depression, apnea)

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)

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)

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 soon as possible. Reversal of anticoagulation is not maximal for 24 to 48 hours after withholding the anticoagulant. For serious overdose or life-

threatening bleeding, when 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

S-warfarin exhibits about 2 to 5 times the anticoagulant activity of R-enantiomer but also has

more rapid clearance

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 soon as possible. Reversal of anticoagulation is not maximal for 24 to 48 hours after withholding the anticoagulant. For serious overdose or life-

threatening bleeding, when 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

S-warfarin exhibits about 2 to 5 times the anticoagulant activity of R-enantiomer but also has

more rapid clearance

Metabolites can be converted back to

methotrexate by hydrolase enzymes

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.

Monitoring of the serum methotrexate concentration is essential in determining the

optimal dose and duration of treatment of 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

Specific treatment

Primarily supportive and symptomatic.

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

Monitoring of cardiac rhythm and blood pressure is important

A. 3-hydroxyquinidine, (active)

For bradycardia, a beta-adrenergic agonist or pacemaker may be indicated

Hypotension may respond to positive inotropic and/or vasopressor agents

Treatment should be symptomatic and supportive and may include the following:

To decrease absorption — Although the use of gastric lavage decreased the elimination half-life

of quinidine in one case report, the clinical benefit of gastric lavage has not been

confirmed, and it should be used only if ingestion has occurred within 1 hour. Similarly,

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.

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 efficacy. Serum levels of 3HQ can approach those of quinidine in patients receiving conventional doses of Quinaglute(R). The volume of distribution of 3HQ appears to be larger than that of quinidine (Prod Info Quinaglute(R),

Treatment should be symptomatic and supportive and may include the following:

To decrease absorption — Although the use of gastric lavage decreased the elimination half-life

of quinidine in one case report, the clinical benefit of gastric lavage has not been

confirmed, and it should be used only if ingestion has occurred within 1 hour. Similarly,

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.

Molecula

WARFARINE

METHOTREXATE

CYCLOSPORINE

In neonate: caffeine (30 to 80%), active

TEOPHYLLINE