Farmacocinetica Medicamentos Mas Usados

FARMACOCINETICA CLINICA 1

Fármaco

Pres. F.F.

Bioavailability

Ka

(F)

2

Oral

Tab

60-80%

IV

Cap Iny

90-100% 100%

DIGOXINA

Oral IM IV 3

4

70%-100% Very slow, but complete 92 % 100%

FENITOINA

WARFARINA

is absorbed rapidly from the GI tract with little interindividual variation

8.06-8.33

4

WARFARINA

little interindividual variation

Oral IM

17-90% 76-100%

70%

5

6

METOTREXATO

CICLOSPORINA

Oral

10-89 %

IV

poor

Optal.

none

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 2 3 4

Micromedex (Drug Dex) 2006 Martindale 2006 USP Ed. 21 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

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

0.11-0.2 L/kg

22 hours

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

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

0.4 to 0.8 L/kg

90-200 ng/mL

8-15 h

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 L/hr/kg

54 to 76 hours, premature neonates

ADULTS: 0.3 to 0.7 L/kg

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

ADULTS: 8.2 (6.1 - 12.8) hours

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 in patients with congestive heart failure, or increased to 3 to 5 L/kg in patients with cirrhosis of the liver

ADULTS: 6-8 hours CHILDREN:3-4 hours

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 4 mg / ml

A. RENAL EXCRETION: 92% 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 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

of R-enantiomer but also has more rapid clearance

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 magnesiumcontaining 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