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Pharmacology: Pharmacodynamics: Piracetam is a "nootrope" that is to say it is a psychotropic agent which acts directly on the brain to improve efficacy of the telencephalon in both normal subjects and those suffering from some functional deficit. This area of the brain is involved in cognition and also has a role to play in learning and memory, in alertness and in consciousness. Piracetam does not produce either sedation or stimulation.
Piracetam can act on the Central Nervous System in a variety of ways. It will modify neurotransmission within the brain, and can help to improve the metabolic environment essential for good neuronal function. It is also a haemorrheological agent and can improve microcirculation without producing vasodilation.
When given as acute or long-term treatment for patients suffering from a functional CNS deficit, it will heighten alertness and increase cognitive function. These changes are seen as a significant increase in the alpha and beta activity, with a reduction in delta activity, on an EEG trace.
Piracetam will protect and restore cognitive functional capacity after cerebral trauma such as hypoxia or intoxication, and after electroshock therapy.
Piracetam may be given alone, or together with other drugs when treating cortical myoclonia. NOOTROPIL will reduce the duration of vestibular nystagmus.
Piracetam will improve regional oxygen and glucose uptake in the brain in patients suffering from dementia subsequent to multiple infarcts, or in those with cerebral ischaemia.
Piracetam will inhibit the increased aggregation of activated platelets and, in conditions where there is abnormal rigidity of the red blood cell, it can restore deformability and the ability to pass through the microvasculature.
Clinical Studies: see Pharmacodynamics as previously mentioned.
Pharmacokinetics: The pharmacokinetic profile of piracetam is linear and time-independent with low intersubject variability over a large range of doses. This is consistent with the high permeability, high solubility, and minimal metabolism of piracetam. Plasma half-life of piracetam is 5 hours. It is similar in adult volunteers and in patients. It is increased in the elderly (primarily due to impaired renal clearance) and in subjects with renal impairment. Steady state plasma concentrations are achieved within 3 days of dosing.
Absorption: Piracetam is rapidly and extensively absorbed following oral administration. In fasted subjects, the peak plasma concentrations are achieved 1 hour after dosing. The absolute bioavailability of piracetam oral formulations is close to 100%. Food does not affect the extent of absorption of piracetam but it decreases Cmax by 17% and increases Tmax from 1 to 1.5 hours. Peak concentrations are typically 84 μg/ml and 115 μg/ml following a single oral dose of 3.2 g and repeat dose of 3.2 g twice daily, respectively.
Distribution: Piracetam is not bound to plasma proteins and its volume of distribution is approximately 0.6 l/kg. Piracetam crosses the blood brain barrier as it has been measured in cerebrospinal fluid following intravenous administration. In cerebrospinal fluid, the Tmax was achieved about 5 hours post-dose and the half-life was about 8.5 hours. In animals, piracetam highest concentrations in the brain were in the cerebral cortex (frontal, parietal and occipital lobes), in the cerebellar cortex and in the basal ganglia. Piracetam diffuses to all tissues except adipose tissues, crosses placental barrier, and penetrates the membranes of isolated red blood cells.
Metabolism: Piracetam is not known to be metabolized in the human body. This lack of metabolism is supported by the lengthy plasma half-life in anuric patients and the high recovery of parent compound in urine.
Elimination: The plasma half-life of piracetam in adults is about 5 hours following either intravenous or oral administration. The apparent total body clearance is 80-90 ml/min. The major route of excretion is via urine, accounting for 80 to 100% of the dose. Piracetam is excreted by glomerular filtration.
Linearity: The pharmacokinetics of piracetam are linear over the dose range of 0.8 to 12 g.
Pharmacokinetic variables like half-life and clearance are not changed with respect to the dose and the duration of treatment.
Special patient populations: Children: No formal pharmacokinetic study has been conducted in children.
Elderly: In the elderly, the half-life of piracetam is increased and the increase is related to the decrease in renal function in this population (see Dosage & Administration).
Renal impairment: Piracetam clearance is correlated to creatinine clearance. It is therefore recommended to adjust the daily dose of piracetam based on creatinine clearance in patients with renal impairment (see Dosage & Administration). In anuric End Stage Renal Disease subjects, the half-life of piracetam is increased up to 59 hours. The fractional removal of piracetam was 50 to 60% during a typical 4-hour dialysis session.
Hepatic impairment: The influence of hepatic impairment on the pharmacokinetics of piracetam has not been evaluated. Because 80 to 100% of the dose is excreted in the urine as unchanged drug, hepatic impairment solely would not be expected to have a significant effect on piracetam elimination.
Other patient characteristics: Gender: In a bioequivalence study comparing formulations at a dose of 2.4 g, Cmax and AUC were approximately 30% higher in women (N=6) compared to men (N=6). However, clearances adjusted for body weight were comparable.
Race: Formal pharmacokinetic studies of the effects of race have not been conducted. Cross study comparisons involving Caucasians and Asians, however, show that pharmacokinetics of piracetam were comparable between the two races. Because piracetam is primarily renally excreted and there are no important racial differences in creatinine clearance, pharmacokinetic differences due to race are not expected.
Toxicology: Non-Clinical Information: The preclinical data indicate that piracetam has a low toxicity potential. Single dose studies showed no irreversible toxicity after oral doses of 10 g/kg in mice, rats and dogs. No target organ for toxicity was observed in repeated dose, chronic toxicity studies in mice (up to 4.8 g/kg/day) and in rats (up to 2.4 g/kg/day). Mild gastrointestinal effects (emesis, change in stool consistency, increased water consumption) were observed in dogs when piracetam was administered orally for one year at a dose increasing from 1 to 10 g/kg/day. Similarly, i.v. administration of up to 1 g/kg/day for 4-5 weeks in rats and dogs did not produce toxicity. In vitro and in vivo studies have shown no potential for genotoxicity and carcinogenicity.
