BUSPIRONE

 

• b. DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed. Norepinephrine should be added if more than 20 micrograms/kilogram/minute of dopamine is needed.
• c. CAUTION: If VENTRICULAR DYSRHYTHMIAS occur, decrease rate of administration. Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred.
• 3. NOREPINEPHRINE
• a. PREPARATION: Add one milligram norepinephrine to 250 milliliters of dextrose 5% in water to produce 4 micrograms/milliliter.
• b. DOSE
• (1) ADULT: 2 to 3 milliliters (8 to 12 micrograms)/minute
• (2) ADULT AND CHILD: 0.1 to 0.2 microgram/kilogram/minute. Titrate to maintain adequate blood pressure.
• (3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised.
• C. SEIZURES
• 1. At the time of this review, seizures have been reported in one patient following a buspirone overdose (Catalano et al, 1998). The seizures were a late finding, which occurred approximately 36 hours after exposure. The authors suggested that the delay in onset of symptoms may have been due to the protective effect of lorazepam (given during transport to the ED).
• 2. SUMMARY
• a. Attempt initial control with a benzodiazepine (diazepam or lorazepam). If seizures persist or recur administer phenobarbital. Benzodiazepines and barbiturates are generally preferred over phenytoin for the control of overdose or withdrawal related seizures.
• b. Monitor for respiratory depression, hypotension, dysrhythmias, and the need for endotracheal intubation.
• c. Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or treat with intravenous dextrose ADULT: 50 milliliters IV, CHILD: 2 milliliters/kilogram 25% dextrose).
• 3. DIAZEPAM
• a. MAXIMUM RATE: Administer diazepam intravenously over 2 to 3 minutes (maximum rate = 5 milligrams/minute).
• b. ADULT DIAZEPAM DOSE: 5 to 10 milligrams initially, repeat every 5 to 10 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 30 milligrams.
• c. PEDIATRIC DIAZEPAM DOSE: 0.2 to 0.5 milligram per kilogram repeat every 5 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 10 milligrams in children over 5 years or 5 milligrams in children under 5 years of age.
• d. RECTAL USE: If an intravenous line cannot be established, diazepam may be given per rectum (generally use twice the usual initial dose because of decreased absorption), or lorazepam may be given intramuscularly.
• e. MIDAZOLAM: has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. PEDIATRIC MIDAZOLAM DOSE: INTRAMUSCULAR: 0.2 milligram/kilogram (maximum 7 milligrams) (Chamberlain et al, 1997); INTRANASAL: 0.2 milligram/kilogram (Lahat et al, 2000). Buccal midazolam, 10 milligrams, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
• 4. LORAZEPAM
• a. MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 milligrams/minute (Prod Info Ativan(R), 1999).
• b. ADULT LORAZEPAM DOSE: 2 to 8 milligrams intravenously. Initial doses may be repeated in 10 to 15 minutes if seizures persist (Prod Info, Ativan(R), 1999; AMA, 1991).
• c. PEDIATRIC LORAZEPAM DOSE: 0.05 to 0.1 milligram/kilogram intravenously, (maximum 4 milligrams/dose) repeated twice at intervals of 10 to 15 minutes (Benitz & Tatro, 1995).
• 5. PHENOBARBITAL
• a. ADULT PHENOBARBITAL LOADING DOSE: 600 to 1200 milligrams of phenobarbital intravenously initially (10 to 20 milligrams per kilogram) diluted in 60 milliliters of 0.9 percent saline given at 25 to 50 milligrams per minute.
• b. ADULT PHENOBARBITAL MAINTENANCE DOSE: Additional doses of 120 to 240 milligrams may be given every 20 minutes.
• c. MAXIMUM SAFE ADULT PHENOBARBITAL DOSE: No maximum safe dose has been established. Patients in status epilepticus have received as much as 100 milligrams/minute until seizure control was achieved.
• d. PEDIATRIC PHENOBARBITAL LOADING DOSE: 15 to 20 milligrams per kilogram of phenobarbital intravenously at a rate of 25 to 50 milligrams per minute.
• e. PEDIATRIC PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 5 to 10 milligrams per kilogram may be given every 20 minutes.
• f. MAXIMUM SAFE PEDIATRIC PHENOBARBITAL DOSE: No maximum safe dose has been established. Children in status epilepticus have received doses of 30 to 120 milligrams/kilogram within 24 hours. Vasopressors and mechanical ventilation were needed in some patients receiving these doses.
• g. MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation.
• h. NEONATAL PHENOBARBITAL LOADING DOSE: 20 to 30 milligrams/kilogram intravenously at a rate of no more than 1 milligram/kilogram per minute in patients with no preexisting phenobarbital serum levels.
• i. NEONATAL PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 2.5 milligrams/kilogram every 12 hours may be given; adjust dosage to maintain serum levels of 20 to 40 micrograms/milliliter.
• j. MAXIMUM SAFE NEONATAL PHENOBARBITAL DOSE: Doses of up to 20 milligrams/kilogram/minute up to a total of 30 milligrams/kilogram have been tolerated in neonates.
• k. CAUTIONS: Adequacy of ventilation must be continuously monitored in children and adults. Intubation may be necessary with increased doses.
• l. SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (20 to 40 micrograms per milliliter).
• 6. PHENYTOIN/FOSPHENYTOIN
• a. Benzodiazepines and/or barbiturates are generally preferred to phenytoin or fosphenytoin in the treatment of drug or withdrawal induced seizures.
• b. PHENYTOIN
• (1) PHENYTOIN INTRAVENOUS PUSH VERSUS INTRAVENOUS INFUSION: Manufacturer does not recommend intravenous infusions due to lack of solubility and resultant precipitation, however infusions are commonly used.
• (a) Administer phenytoin undiluted, by very slow intravenous push or dilute 50 milligrams per milliliter solution in 50 to 100 milliliters of 0.9 percent saline.
• (2) PHENYTOIN ADMINISTRATION RATE: Rate of administration by either method should not exceed 0.5 milligram per kilogram per minute or 50 milligrams per minute.
• (3) ADULT PHENYTOIN LOADING DOSE: 15 to 18 milligrams per kilogram of phenytoin initially. Rate of administration by very slow intravenous push or diluted to 50 milligrams per milliliter should not exceed 0.5 milligram per kilogram per minute or 50 milligrams per minute.
• (4) ADULT PHENYTOIN MAINTENANCE DOSE: Manufacturers recommend a maintenance dose of 100 milligrams orally or intravenously every 6 to 8 hours. The goal is to maintain a serum concentration between 10 to 20 micrograms/milliliter.
• (5) PEDIATRIC PHENYTOIN LOADING DOSE: 15 to 20 milligrams per kilogram or 250 milligrams/square meter of phenytoin. Rate of intravenous administration should not exceed 0.5 to 1.5 milligrams per kilogram per minute.
• (6) PEDIATRIC PHENYTOIN MAINTENANCE DOSE: Repeat doses of 1.5 milligrams per kilogram may be given every 30 minutes to a maximum daily dose of 20 milligrams per kilogram.
• (7) CAUTIONS: Administer phenytoin while monitoring ECG. Stop or slow infusion if arrhythmias or hypotension occur. Be careful not to extravasate. Follow each injection with injection of sterile saline through the same needle.
• (8) SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (10 to 20 micrograms per milliliter).
• c. FOSPHENYTOIN
• (1) ADULT DOSAGE AND ADMINISTRATION: The dose, concentration in dosing solutions, and infusion rate of fosphenytoin are expressed as phenytoin sodium equivalents.
• (2) ADULT LOADING DOSE FOSPHENYTOIN: 15 to 20 milligrams/kilogram of phenytoin sodium equivalents at a rate of 100 to 150 milligrams phenytoin equivalent/minute.
• (3) Fosphenytoin should not be infused at rates greater than 150 milligrams phenytoin equivalent/minute because of the risk of hypotension.
• (4) CAUTIONS: Perform continuous monitoring of respiratory function, cardiac rhythm, and blood pressure throughout infusion and for at least 30 minutes thereafter.
• (5) ADULT MAINTENANCE DOSING: 4 to 6 milligrams phenytoin equivalents/kilogram/day. Rate of administration should not exceed 150 milligrams phenytoin equivalent/minute.
• (6) SERUM LEVEL MONITORING: Monitor serum phenytoin levels over the next 12 to 24 hours; therapeutic levels 10 to 20 microgram/milliliter. Do not obtain serum phenytoin concentrations until at least 2 hours after infusion is complete to allow for conversion of fosphenytoin to phenytoin.
• D. DYSTONIC REACTIONS
• 1. In one acute case involving a 5 milligram dose, diphenhydramine (25 milligrams intramuscularly) and benztropine (1 milligram intramuscularly) had little effect on the myoclonus. The dystonias and myoclonic jerks resolved following administration of 1 milligram of clonazepam (Ritchie et al, 1988).
• E. SEROTONIN SYNDROME
• 1. HYPERTHERMIA
• a. Control agitation and muscle activity. Undress patient and enhance evaporative heat loss by keeping skin damp and using cooling fans.
• b. MUSCLE ACTIVITY - Benzodiazepines may be useful. Diazepam: Adult: 5 to 10 milligrams IV every 5 to 10 minutes as needed, monitor for respiratory depression and need for intubation. Child: 0.25 milligram/kilogram IV every 5 to 10 minutes; monitor for respiratory depression and need for intubation.
• c. Non-depolarizing paralytics may be used in severe cases.
• 2. HYPERTENSION
• a. Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic intervention may not be necessary. For hypertensive emergencies (emergent need to lower mean BP 30 percent within 30 minutes and achieve diastolic BP of 100 mmHg or less within one hour), nitroprusside is preferred.
• b. NITROPRUSSIDE
• (1) NITROPRUSSIDE/INDICATIONS
• (a) Nitroprusside is preferred for hypertensive emergencies (emergent need to lower mean BP 30 percent within 30 minutes and achieve a diastolic BP of 100 mmHg or less within one hour).
• (2) NITROPRUSSIDE/DOSE
• (a) 0.1 to 5 microgram/kilogram/minute intravenous infusion; up to 10 micrograms/kilogram/minute may be required (AHA, 1992).
• (3) NITROPRUSSIDE/SOLUTION PREPARATION
• (a) Dilute a 50-milligram vial in 500 milliliters of dextrose 5 percent in water (100 micrograms/milliliter). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution.
• (4) NITROPRUSSIDE/MAJOR ADVERSE REACTIONS
• (a) Severe hypotension; cyanide toxicity; methemoglobinemia; lactic acidosis; chest pain or arrhthymias (high doses).
• (5) NITROPRUSSIDE/MONITORING PARAMETERS
• (a) Monitor blood pressure every 30 to 60 seconds at onset of drip; once stabilized, monitor every 30 minutes.
• c. NITROGLYCERIN
• (1) In theory, nitroglycerin may help alleviate the serotonin syndrome through nitric oxide mediated downregulation of serotonin.
• (2) ADULT - Begin continuous infusion at 5 micrograms/minute and titrate to desired effect.
• (3) CHILD - Begin infusion at 0.25 to 0.5 micrograms/kilogram/minute and titrate to desired effect.
• 3. HYPOTENSION
• a. Administer 10 to 20 milliliters/kilogram 0.9% saline bolus and place patient in Trendelenburg position. Further fluid therapy should be guided by central venous pressure or right heart catheterization to avoid volume overload.
• b. Control hyperthermia.
• c. Pressor agents with dopaminergic effects may theoretically worsen serotonin syndrome and should be used with caution.
• d. DOPAMINE
• (1) PREPARATION: Add 200 or 400 milligrams to 250 milliliters of normal saline or dextrose 5% in water to produce 800 or 1600 micrograms per milliliter or add 400 milligrams to 500 milliliters of normal saline or dextrose 5% in water to produce 800 micrograms per milliliter.
• (2) DOSE: Begin at 2 to 5 micrograms per kilogram per minute progressing in 5 to 10 micrograms per kilogram per minute increments as needed.
• (3) CAUTION: If VENTRICULAR ARRHYTHMIAS occur, decrease rate of administration.
• e. NOREPINEPHRINE
• (1) PREPARATION: Add 4 milliliters of 0.1 percent solution to 1000 milliliters of dextrose 5% in water to produce 4 micrograms/milliliter.
• (2) INITIAL DOSE
• (a) ADULTS: 2 to 3 milliliters (8 to 12 micrograms)/minute
• (b) ADULT AND CHILD: 0.1 to 0.2 microgram/kilogram/minute. Titrate to maintain adequate blood pressure.
• (3) MAINTENANCE DOSE
• (a) 0.5 to 1 milliliter (2 to 4 micrograms)/minute
• 4. SEIZURES
• a. DIAZEPAM
• (1) MAXIMUM RATE: Administer diazepam intravenously over 2 to 3 minutes (maximum rate = 5 milligrams/minute).
• (2) ADULT DIAZEPAM DOSE: 5 to 10 milligrams initially, repeat every 5 to 10 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 30 milligrams.
• (3) PEDIATRIC DIAZEPAM DOSE: 0.2 to 0.5 milligram per kilogram, repeat every 5 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 10 milligrams in children over 5 years or 5 milligrams in children under 5 years of age.
• (4) RECTAL USE: If an intravenous line cannot be established, diazepam may be given per rectum (not FDA approved), or lorazepam may be given intramuscularly.
• b. LORAZEPAM
• (1) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 milligrams/minute (Prod Info Ativan(R), 1991).
• (2) ADULT LORAZEPAM DOSE: 4 to 8 milligrams intravenously. Initial doses may be repeated in 10 to 15 minutes if seizures persist (AMA, 1991).
• (3) PEDIATRIC LORAZEPAM DOSE: 0.05 to 0.1 milligram/kilogram intravenously, repeated twice at intervals of 15 to 20 minutes (Benitz & Tatro, 1988; Giang & McBride, 1988).
• c. RECURRING SEIZURES: If seizures cannot be controlled with diazepam or recur, give phenobarbital.
• d. PHENOBARBITAL
• (1) SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (15 to 25 micrograms per milliliter).
• (2) ADULT PHENOBARBITAL LOADING DOSE: 600 to 1200 milligrams of phenobarbital intravenously initially (10 to 20 milligrams per kilogram) diluted in 60 milliliters of 0.9 percent saline given at 25 to 50 milligrams per minute.
• (3) ADULT PHENOBARBITAL MAINTENANCE DOSE: Additional doses of 120 to 240 milligrams may be given every 20 minutes.
• (4) MAXIMUM SAFE ADULT PHENOBARBITAL DOSE: No maximum safe dose has been established. Patients in status epilepticus have received as much as 100 milligrams/minute until seizure control was achieved or a total dose of 10 milligrams/kilogram.
• (5) PEDIATRIC PHENOBARBITAL LOADING DOSE: 15 to 20 milligrams per kilogram of phenobarbital intravenously at a rate of 25 to 50 milligrams per minute.
• (6) PEDIATRIC PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 5 to 10 milligrams per kilogram may be given every 20 minutes.
• (7) MAXIMUM SAFE PEDIATRIC PHENOBARBITAL DOSE: No maximum safe dose has been established. Children in status epilepticus have received doses of 30 to 120 milligrams/kilogram within 24 hours. Vasopressors and mechanical ventilation were needed in some patients receiving these doses.
• (8) INDICATIONS FOR INTUBATION: Intubation should be considered after total doses of greater than 20 milligrams/kilogram.
• (9) NEONATAL PHENOBARBITAL LOADING DOSE: 20 to 30 milligrams/kilogram intravenously at a rate of no more than 1 milligram/kilogram per minute in patients with no preexisting phenobarbital serum levels.
• (10) NEONATAL PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 2.5 milligrams/kilogram every 12 hours may be given; adjust dosage to maintain serum levels of 20 to 40 micrograms/milliliter.
• (11) MAXIMUM SAFE NEONATAL PHENOBARBITAL DOSE: Doses of up to 20 milligrams/kilogram/minute up to a total of 30 milligrams/kilogram have been tolerated in neonates.
• (12) CAUTIONS: Adequacy of ventilation must be continuously monitored in children and adults. Intubation may be necessary with increased doses.
• 5. CYPROHEPTADINE
• a. Cyproheptadine is a non-specific 5-HT antagonist that has been shown to block development of serotonin syndrome in animals (Sternbach, 1991). Cyproheptadine has been used in the treatment of serotonin syndrome (Mills, 1997; Goldberg & Huk, 1992). There are no controlled human trials substantiating its efficacy.
• b. ADULT - 4 to 8 milligrams orally repeated every 1 to 4 hours until therapeutic response is observed or maximum of 32 milligrams administered (Mills, 1997).
• c. CHILD - 0.25 milligram/kilogram/day divided every 6 hours, maximum dose 12 milligrams/day (Mills, 1997).
• 6. NITROGLYCERIN
• a. In theory nitroglycerin may help alleviate the serotonin syndrome through nitric oxide mediated downregulation of serotonin. It has been used in human cases with apparent benefit (Brown et al, 1996). There are no human trials substantiating its efficacy
• b. ADULT - Begin continuous infusion at 5 micrograms/minute and titrate to desired effect.
• c. CHILD - Begin infusion at 0.25 to 0.5 microgram/kilogram/minute and titrate to desired effect.
• 7. PROPRANOLOL
• a. Propranolol is a 5-HT1A receptor antagonist (Sternbach, 1991). Propranolol has been used in human cases of serotonin syndrome with apparent benefit (Guze & Baxter, 1986; Dursun et al, 1997). There are no controlled human trials substantiating its efficacy.
• b. PROPRANOLOL/ADULT DOSE
• (1) 1 milligram/dose intravenously, administered no faster than 1 milligram/minute repeated every 2 to 5 minutes until desired response is seen or a maximum of 5 milligrams has been given.
• c. PROPRANOLOL/PEDIATRIC DOSE
• (1) 0.01 to 0.1 milligram/kilogram/dose over 10 minutes. Maximum 1 milligram/dose (Benitz & Tatro, 1988).
• 8. CHLORPROMAZINE -
• a. Chlorpromazine is a 5-HT2 receptor antagonist that has been used to treat cases of serotonin syndrome (Graham, 1997; Gillman, 1996). Controlled human trial documenting its efficacy are lacking.
• b. ADULT - 25 to 100 milligrams intramuscularly repeated in one hour if necessary.
• c. CHILD - 0.5 to 1 milligram/kilogram repeated as needed every 6 to 12 hours not to exceed 2 milligrams/kilogram/day.
• 9. OTHER
• a. Other agents which have been used to treat serotonin syndrome include methysergide and mirtazapine (Mills, 1997; Hoes, 1996).
• 10. NOT RECOMMENDED
• a. BROMOCRIPTINE - Is used in the treatment of neuroleptic malignant syndrome but is NOT RECOMMENDED in the treatment of serotonin syndrome as it has serotonergic effects (Gillman, 1997). In one case the use of bromocriptine was associated with a fatal outcome (Kline et al, 1989).
• 6.11 ENHANCED ELIMINATION
• A. HEMODIALYSIS
• 1. Dialyzability of buspirone has not been evaluated (BuSpar(R) Prod Info, 1995).
• 7.0 RANGE OF TOXICITY
• 7.1 SUMMARY
• A. THERAPEUTIC DOSE is approximately 20 to 30 milligrams/day in divided doses.
• B. TOXIC serum and blood concentrations have not been established.
• C. Humans have tolerated 375 milligrams/day for 30 days but developed nausea, vomiting, tingling sensations, drowsiness, insomnia, and blurred vision.
• 7.2 THERAPEUTIC DOSE
• 7.2.1 ADULT
• A. GENERAL
• 1. THERAPEUTIC - 20 to 30 milligrams/day in divided doses (Mayol et al, 1985; Uhlenhuth, 1982; BuSpar(R) Prod Info, 1995; USPDI, 1999)
• 2. MAXIMUM - The maximum daily dose should not exceed 60 milligrams/day (USPDI, 1999).
• 7.2.2 PEDIATRIC
• A. GENERAL
• 1. NOT RECOMMENDED. The effectiveness and safety of buspirone have not been determined in individuals less than 18 years of age (BuSpar(R) Prod Info, 1995, USPDI, 1999).
• 7.4 MAXIMUM TOLERATED EXPOSURE
• A. GENERAL/SUMMARY
• 1. Humans have tolerated 375 milligrams/day for 30 days, developing side effects of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress (BuSpar(R) Prod Info, 1995).
• B. CASE REPORTS
• 1. A 25-year-old male ingested a dose of 250 milligrams of buspirone combined with 25 milligrams of diazepam with no adverse effects occurring (Tiller et al, 1989).
• 7.5 SERUM/PLASMA/BLOOD CONCENTRATIONS
• 7.5.1 THERAPEUTIC CONCENTRATIONS
• A. GENERAL
• 1. A single 20 mg dose of buspirone in 12 healthy subjects, resulted in an average maximum plasma concentration of 1.15 mcg/L (range, 0.49 to 3.07) at 0.5 to 1.0 hours with an additional second peak observed in 7 of the volunteers averaging 0.47 mcg/L (range, 0.21 to 1.03) between 2 and 4 hours after administration (reviewed in Baselt, 2000).
• a. Plasma concentrations of a metabolite, 1-PP, was approximately twice that of buspirone after a single oral dose.
• 7.7 LD50/LC50
• A. References: Riblet et al, 1982; Prod Info, 1988

§               LD50 - (ORAL) MOUSE: 621.5 mg/kg

§               LD50 - (ORAL) MOUSE: 655 mg/kg

§               LD50 - (ORAL) RAT: 265 mg/kg

§               LD50 - (ORAL) RAT: 196 mg/kg

§               LD50 - (ORAL) DOG: 586 mg/kg

§               LD50 - (ORAL) MONKEY: 356 mg/kg

• 8.0 KINETICS
• 8.1 ABSORPTION
• A. ORAL
• 1. Despite complete absorption after oral dosing, extensive first-pass metabolism limits the bioavailability of buspirone to approximately 4 percent (USPDI, 1999). The presence of food in the stomach decreases the rate of absorption and increases the amount of unchanged (unmetabolized) drug in the system (Mayol et al, 1983; USPDI, 1999).
• 2. Single-dose bioavailability of the tablet is approximately 90% of an equivalent dose of a solution of the drug, but large variability exists (Prod Info BuSpar(R), 1995).
• 8.2 DISTRIBUTION
• 8.2.1 DISTRIBUTION SITES
• A. PROTEIN BINDING
• 1. Approximately 95% is protein bound; 70% is bound to albumin and 30% is bound to alpha(1)-acid glycoprotein (BuSpar(R) Prod Info, 1995; USPDI, 1999).
• 2. Other tightly, highly protein bound drugs were not displaced by buspirone in in-vitro tests (BuSpar(R) Prod Info, 1995). Less tightly bound drugs may be displaced (e.g., digoxin in vitro) (USPDI, 1999).
• B. TISSUE/FLUID SITES
• 1. PYRIMIDINYL PIPERAZINE - (1-PP) (metabolite) appears rapidly after buspirone orally and accumulates in the brain where it attains levels 4 to 5 times that of buspirone (Caccia et al, 1983).
• 2. BUSPIRONE AND 1-PP - have been found in plasma and equally distributed through brain (Gammans et al, 1982).
• C. PEAK PLASMA LEVEL
• 1. Peak plasma levels of 1 to 6 ng/ml were found 40 to 90 minutes after a single oral dose of 20 mg, and less than 60 minutes following an oral dose of 10 mg (Buspar (R) Prod Info, 1995; USPDI, 1999).
• 8.2.2 DISTRIBUTION KINETICS
• A. VOLUME OF DISTRIBUTION
• 1. 433 L (Mayol et al, 1985)
• 8.3 METABOLISM
• 8.3.1 METABOLISM SITES AND KINETICS
• A. GENERAL
• 1. Metabolism time in humans is 1.7 to 2.2 hours (BuSpar(R) Prod Info, 1995).
• 2. The parent compound is metabolized quickly (t1/2 of 30 minutes) in rats and faster after oral administration (Caccia et al, 1983).
• 3. Buspirone undergoes extensive first-pass metabolism (Mayol et al, 1985).
• 8.3.2 METABOLITES
• A. GENERAL
• 1. Hydroxylation and oxidative dealkylation (which produces pyrimidinyl piperazine) are the primary routes of metabolism in man (Gammans et al, 1982).
• 2. 5-hydroxy derivatives and 1-(2-pyrimidinyl)-piperazine (1-PP) have been found in humans. 1-PP is present in up to a 20 fold greater amount than the parent compound. However, this is probably not important in humans (BuSpar Prod Info, 1995).
• a. The hydroxylated derivatives are inactive, 1-PP is active (Caccia et al, 1983) with 25% the activity of the parent compound (BuSpar Prod Info, 1995). The hydroxy derivatives may be excreted as glucuronides.
• 8.4 EXCRETION
• 8.4.1 KIDNEY
• A. Systemic clearance of 2.21 L/minute
• B. 66.8 +/- 11.3% of an oral dose of buspirone was found as metabolites in the urine (Mayol et al, 1985). Of this, approximately 1% was unchanged drug, and 10% hydrolyzable conjugates (Gammans et al, 1982).
• 8.4.2 FECES