Basic Nootropics Overview

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Introduction

At the moment nootropics represent a fast-paced drug class highly sought in various areas of medicine. First of all, nootropics affect metabolic and neurotransmitter processes in brain. Mainly, metabolic effect is associated with GABA. GABA is endogenous inhibitory neurotransmitter involved in brain metabolic processes. Drug effect on brain neurotransmitter systems results in excitation transfer activation in  axoneurons. Thus, it improves brain cognitive functions, learning processes, memory and metabolic processes. Recently, nootropics tend to be created not only on the basis of original chemical substance, but resulted from combination of nootropic drug substance and preparations intensifying its pharmacological properties (i.e., antioxidant, anti-ischemic, mnemotropic ones etc.). Development of drugs with combined nootropic, antioxidant and anti-ischemic properties is a promising area in creation of nootropics.

Nootropics

Nootropics are substances which provide specific influence on higher brain integrative functions, improve memory, help learning process, induce intellectual activity, enhance brain resistance to damaging factors and improve cortical–subcortical interactions. Nootropics are able to ameliorate cognitive functions in healthy people, as well as, especially, in patients with cognitive disorders associated with various diseases.

Unlike mobilising psychostimulants, nootropics do not induce psychomotor agitation, deterioration of systemic functional capabilities, habituation and addiction.

The term ”nootropics” derived from Greek (”noos” – ”thinking” and ”tropos” – ”tendency”). It was introduced in 1972, i.e. in 2 years after piracetam (Nootropil) developed by UCB (Belgium) has appeared in the global market. Now this drug is still a permanent representative of this drug group.

According to a contemporary view, nootropics include:

  • piracetam, homologues and analogues (such as aniracetam, oxiracetam, pramiracetam, nefiracetam etc.).
  • dimethylaminoethanol derivatives: deanol aceglumate, meclofenoxate, centrophenoxine.
  • neural amino acid preparations: gamma-aminobutyric acid (GABA), GABA derivatives (phenibut, nicotinoyl-gamma-aminobutyric acid (picamilon), hopantenic acid (pantogam), glycine, glutamic acid.
  • pyridoxine derivatives: pyritinol (pyriditol, enerbol, encephabol).
  • centrally-acting cholinomimetic: choline alfoscerate.
  • Ginkgo biloba preparations: Bilobil, Memoplant, Revital Ginkgo, Tanakan etc.
  • compounds related to various chemical classes and groups with alternate chemical structure, piracetam-like mechanism of action and ability to facilitate learning process and improve memory.

It should be emphasised that standard classification of nootropics does not exist yet. There are number of underlying reasons but two of them are primary ones:

  1. Mechanism of action related to piracetam, its homologues/analogues and other nootropics is still understudied down to recent times.
  2. Intellectual functioning and learning abilities (i.e., mnestic functions concerning perception and memorizing of new information) can be improved by means of:
  • direct activation of neuronal energy-producing processes;
  • enhancement of cerebral blood flow and microcirculation;
  • metabolic changes in several neurotransmitters and their ability to interact with membrane receptors;
  • neurotrophic and neuromodulatory effects.

Hence, parallel to nootropics providing predominant effect on mnestic functions, several literature sources include broad-spectrum drugs mentioned below in this pharmacological group:

  • drugs to increase cerebral blood flow, microcirculation and metabolism: vinpocetine, vincamine, vinkonat, nicergoline, cinnarizine, flunarizine, nimodipine, pentoxifylline-based xanthic compounds, carnitine, phosphatidylserine, sodium oxybate, vitamins and their derivatives (pyridoxine, pantothenic acid, folic acid, vitamin E).
  • cellular metabolic intermediates: orotic and amber acids.
  • energy-giving substrates: riboxin, ATP, RNA, glucose-1- and glucose-6-phosphate.
  • combined drugs: instenon.

Despite different effects, all the drugs listed above provide beneficial effect on memory (i.e., nootropic action) without frank effects of conventional psychotropic and cardiotropic drugs. Apart from some cholinergic agents, nootropics have several specific properties such as low toxicity and absence of significant side effects (even in subtoxic doses).

Therapeutic action of nootropics is based on several mechanisms:
  • improvement of neuronal energy condition (i.e. ATP synthesis enhancement, antihypoxic and antioxidant effects).
  • activation of plastic processes in CNS due to RNA/protein synthesis enhancement.
  • intensification of CNS synaptic transmission.
  • amelioration of glucose disposal.
  • membrane stabilizing action.

In line with direct effect on damaged mnestic functions, number of nootropics are used to improve overall life activity level decreased due to various diseases and extreme factors such as ischemia, traumatic brain injuries, intoxication, fatigue, pain syndromes, stress, perinatal conditions.

Basic properties of nootropics:
  • to promote neuronal metabolism due to optimization of neuronal bioenergetic processes.
  • to improve neuronal activity both in normal and extreme conditions.
By virtue of these properties, nootropics are often called ”neurometabolic cerebral protectants”. The reason is that these agents are generally characterised by promotion of metabolic processes in nerve tissue (especially, in case of various disorders) improving abnormal metabolism.

Nootropics may enhance GABA effects, dopamine synthesis and cerebral noradrenaline level. Piracetam and meclofenoxat provide increase in synaptic acetylcholine level and cholinergic receptor density. Several drugs can increase cerebral serotonin level. Intensity of nootropic impact on CNS can be ranged as follows:

Phenibut – aminalon – pantogam – picamilon – piracetam – pyritinol – meclofenoxate

Depressing action is the most significant property of phenibut; psychostimulant properties are the most distinctive for meclofenoxate.

First of all, healthy people use nootropics to prevent stress-producing conditions and support  working capacity in an emergency. These agents are also used in pediatric and geriatric patients. Nootropics are indicated for treatment of cerebral insufficiency and asthenia, combined therapy of minor depression associated with retardation, therapy of early Alzheimer’s disease and alcoholic encephalopathy, rehabilitation after cerebral inflammatory infections and traumatic brain injuries.

Chemical structure of piracetam (nootropil) is similar to GABA. That’s why, sometimes it is considered as a derivative of this amino acid. However, it is not transformed into GABA within body, and cerebral GABA level does not increase after piracetam administration. Nevertheless, piracetam can enhance GABAergic inhibitory processes due to relatively high dosage and repeated administration.

Piracetam has two basic types of action (i.e., ”neuroprotective” and ”vascular” effects). Also, piracetam promotes glucose oxidative decomposition (hexose monophosphate shunt) resulting in increased ATP metabolism and cAMP level. Activity of this shunt is associated with formation of substances neutralising free radicals and inhibiting membrane lipid peroxidation. The drug induces adenylate kinase activity providing metabolism without lactate formation. Drug administration results in increased glucose metabolism, local cerebral blood flow, extraction factor and local oxygen metabolism in affected site and surrounding functionally inactive area in patients with acute ischemic stroke. Piracetam interacts with neurotransmitter system providing modulatory effect on cholinergic and aminacidergic (aspartate, glutamate) neurotransmittion. This is of particular importance because disorders of synaptic transmission involving acetylcholine and glutamate cause ”age-related” impairments of memory and other cognitive functions. The drug is also promotes interhemispheric information exchange resulting in recovery of verbal functions after prior stroke. Piracetam influences on vestibular system due to impact on mechanisms of signal transmission from sources of visual and proprioceptive sensibility, as well as effect on vestibular nucleus in brain stem. Also, piracetam has a beneficial anticonvulsant effect. Neuroprotective action of piracetam is used to treat chronic alcoholic and drug intoxications. Vascular action is associated with decreased platelet aggregation, increased erythrocyte deformability, reduced erythrocyte adhesion to endothelial surface and lowered viscosity of plasma and whole blood. Due to decreased vascular spasm without vasodilatory effect and hypotension, piracetam provides beneficial effect on cerebral blood flow which is not associated with changes in general hemodynamics.

Primary therapeutic indications of piracetam are listed below:

  1. Cerebrovascular diseases:
  • intensive therapy of isсhemic stroke.
  • post-stroke rehabilitation.
  • chronic cerebrovascular insufficiency decompensation.
  • acute traumatic brain injuries.
  • coma.
  1. Impairment of memory and other higher mental functions:
  • ”physiological” ageing.
  • Dementia.
  • mental retardation, barriers to learning.
  1. Verbal disorders:
  • aphasia.
  • pediatric dyslexia (critical learning disability related to graphic language).
  1. Dizziness
  2. Encephalopathy:
  • alcoholism
  • drug intoxication
  • neuroinfectional sequelae
  • post-hypoxic state
  1. Combined therapy:
  • psychosis, asthenic depression, apathy associated with schizophrenia/treatment-resistant depression
  • management of side effects and complications related to psychotropic therapy

Piracetam is characterized by the fact that pharmacological action appears only after long-term repeated administration of quite high doses.

Table 1. Piracetam (nootropil): primary advantages, disadvantages and drug interaction

Advantages Disadvantages Drug interaction
Improved blood circulation in ishemic areas and brain metabolism. Increased tissue resistance to hypoxia and toxicity. Enhanced potential neurophysiological abilities. Activated mental activity (i.e., thinking, learning and memory). Recovered and stabilised brain functioning. Ameliorated mood, attention and memory in healthy people and patients. Certain anticonvulsant properties. Hyperexcitability, anxiety, irritability, insomnia. Weakness, sleepiness. Dizziness, tremor. Nausea, vomiting, diarrhea and abdominal pains. Angina. Contraindications: terminal renal impairment, pregnancy, lactation, children under 1 year old, hypersensitivity. Enhanced action of antianginal drugs, decreases need for nitroglycerin and increases antidepressant efficiency. Co-administration of piracetam

(1.6 g) and alcoholic drinks does not influence on serum piracetam/alcohol level. Piracetam co-administered with thyroxin and triiodothyronine causes anxiety, irritability and sleep disturbances.

Piracetam remains effective medication with ever-growing use for more than 40 years. New available dosage forms are adapted to patient’s state. However, there no commercially available second-generation piracetam derivatives (such as oxiracetam (Italy), aniracetam (Switzerland, Japan) and pramiracetam (USA)) in Russia. As compared with piracetam, these drugs with broader spectrum are better tolerated by patients. In particular, due to significant antihypoxic properties, they can be used to treat various brain diseases and traumas. In early 90s nefiracetam presenting high affinity to GABA receptor, attracted great interest It increases glutamate decarboxylase activity, enhances GABA circulation in cortex of cerebral hemispheres and provides significant antiamnestic action.

In terms of chemical structure, aminalon is gamma-aminobutyric acid (GABA) which is the most important CNS inhibitory neurotransmitter involved in brain energy provision. As compared with piracetam, this drug has less clinical efficiency along with absence of clear stimulating effects. GABA increases efficiency of GABAergic inhibitory processes. Indications: chronic cerebral circulatory insufficiency associated with impairments of memory, attention and speech, as well as dizziness or headache; cerebrovascular diseases; status post stroke and traumatic brain injuries; alcoholic encephalopathy; pediatric mental retardation.

Nicotinoyl-gamma-aminobutyric acid (picamilon) combines properties of GABA and nicotinic acid providing vasoactive properties, and impacts on tissue respiration. The drug may provide both neurometabolic and vascular actions (i.e., decrease in vascular resistance, increase in linear and space velocity of brain blood flow, as well as improvement of microcirculation). Picamilon has moderate anxiolytic activity providing recovery of mental and physical working capacity in the setting of overfatigue. Indications: several stages of ischemic stroke, vegetative-vascular dystonia, depression, combined therapy of asthenia associated with neuropsychic conditions or increased psycho-emotional loads, traumatic brain injuries, neuroinfections and chronic alcoholism.

Phenibut is a derivative of GABA and phenylethylamine providing nootropic and tranquilizing activities. The drug decreases asthenic manifestations, vaso-vegetative symptoms (headache, carebaria), irritability, emotional instability and increases mental capacity. Indications: asthenic syndrome, anxiety neuroticism, sleep disturbances, dizziness, motion sickness prevention, pediatric stuttering and tics; combined therapy of alcohol withdrawal syndrome.

Hopantenic acid (pantogam) is the mildest metabolic cerebral protectant with the least stimulating effect on CNS. Probably, metabolic activity of the drug is associated with substitution of p-alanine fragment in a molecule of hopantenic acid for GABA. The drug improves cerebral energy metabolism, influences on oxidative processes of tricarboxilic acid cycle playing a significant part in provision of multiple types of cellular metabolism (including energy one). Indications: intellectual and mnestic functioning disorders associated with prior neuroinfections and traumatic brain injuries; pediatric mental retardation; combined therapy of several types of epilepsy.

Table 2. Neural amino acid preparations: primary advantages, disadvantages and drug interaction

Drug Advantages Disadvantages Drug interaction
Gamma-aminobutyric acid

(aminalon)

Influence on specific GABA receptors. Recovered cerebral metabolic processes, increased resistance to hypoxia, promotion of brain glucose disposal and removal of toxic byproducts. Blood flow acceleration. Improved memory and thinking; moderate psychostimulant/anticonvulsant/hypotensive effect; slight decrease in heart rate. Decreased glycemic level in patients with diabetes. Potential nausea, vomiting, insomnia, arterial blood pressure instability, dyspepsia, increased body temperature, fever sensation, dyspnoe. Contraindication: hypersensitivity. Enhanced effect of benzodiasines, various hypnotics and anticonvulsants.
Hopantenic acid

(pantogam)

Increased cerebral resistance to hypoxia and toxicity, ameliorated cerebral glucose/oxygen disposal. Promotion of neuronal anabolic processes. Anticonvulsant properties. Potential allergic reactions: rhinitis, conjunctivitis and skin rashes. Prolonged barbiturate action.
Nicotinoyl-gamma-aminobutyric acid (picamilon) Nootropic, antioxidative, antihypoxic, tranquilising and psychostimulant effects. Promotion of nerve tissue metabolism and enhancement of brain energy processes. Improved thinking, attention, memory, speech and learning capacity. Ameliorated cerebral blood flow and microcirculation; decrease in cerebral vascular resistance and platelet aggregation. Potential nausea, headache, dizziness, irritability, excitation, anxiety and allergic reactions. Contraindications: hypersensitivity, renal diseases. Decrease in inhibitory CNS

effect of drugs containing ethanol.

Phenibut Nootropic, antioxidative, tranquilizing and anticonvulsant effects. Decreased tension and anxiety, sleep improvement. Reduction of asthenic manifestations, headache, carebaria and irritability. Amelioration of mental activity, attention and memory. Potential sleepiness associated with the first administrations; allergic reactions. Contraindications: hypersensitivity, hepatic impairment. Careful use in patients with GIT diseases (due to irritative action of phenibut) and patients whose work requires special attention. Enhanced effect of antiparkinsonian agents, neuroleptics, hypnotics, anesthetics and narcotic analgesics.


Pyritinol
(pyriditol, enerbol, encephabol) consists of 2 pyridoxine molecules joined by disulphide ”bridge”. Pyridoxal phosphate is the main co-enzyme of pyridoxine involved in GABA metabolism along with other various functions. Glutamic acid decarboxylase (i.e., pyridoxal-dependent enzyme) is a single enzyme of GABA synthesis. Probably, that’s why, this drug can stimulate GABA formation. Pyritinol provides more cost-effective energy substrate disposal followed by energy output required for synthesis of macromolecular compounds (ATP, RNA). The drug enhances glucose transport through blood brain barrier, increases glucose disposal given decreased tissue oxygen consumption, accelerates glucose oxidation, decreases excessive formation of lactic and acetic acids in brain tissues, increases brain tissue resistance to hypoxia, stabilizes cellular membranes and improves their functional status. Indications: broad spectrum of psychoorganic syndromes of different origin associated with impairments of memory, thinking and ability to concentrate, easy fatigability, deficiency of impulses and motivations; oligophrenia, encephalopathy, rheumatoid arthritis; combined therapy of post-traumatic encephalopathy/cerebrovascular diseases/neuroinfections/intoxication. Besides, pyritinol is one of few nootropics having significant number of serious side effects and contraindications .

Table 3. Pyritinol: primary advantages, disadvantages and drug interaction

Drug Advantages Disadvantages Drug interaction
Pyritinol (pyriditol, enerbol, encephabol) Improved metabolic processes in brain tissue; increase in resistance to hypoxia, glucose fixing and metabolism, as well as nucleic acid metabolism. Activated cholinergic processes. Stabilized cellular membranes; inhibition of lysosomal enzyme activity and free radical formation. Improvement of blood rheological properties, blood flow and increase in oxygen delivery and disposal in ischemic brain areas. Increase in mental capacity, memory and learning ability. Potential sleep disturbances, hyperexcitability, headache, dizziness, fatigability, anorexia, dyspeptic disorders, cholestasis, allergic reactions; rare events – arthralgia, lichen planus,  pemphigoid skin reactions, alopecia, stomatitis, eosinophilia, thrombocytopenia, leukopenia,  agranulocytosis, increase in blood antinuclear antibody level; very rare events – onychoptosis, dyspnoe, muscle weakness, paresthesia, polymyositis, cholestasis, hepatitis, hematuria, autoimmune hypoglycemic syndrome. Contraindications: hypersensitivity, frank psychomotor agitation, epilepsy, hepatic/renal impairment, significant changes in peripheral blood presentation, diffuse conditions of connective tissues, myasthenia and pemphigus. Do not use during pregnancy and lactation. Increased probability of side effects induced by penicillamine, gold preparations and sulfasalazine.

Memory processes are closely related to cholinergic mediation system. Deficiency of cholinergic transmission holds one of top positions in dementia neuropathology (including Alzheimer’s disease). Due to enhanced acetylcholine synthesis, impact on receptors and acetylcholinesterase inhibition, cholinomimetics provide three-level effect. That’s why, these agents are used to treat diseases mentioned above.

Conclusion

Recently, nootropics tend to be created not only on the basis of original chemical substance, but resulted from combination of nootropic drug substance and preparations intensifying its pharmacological properties (i.e., antioxidant, anti-ischemic, mnemotropic ones etc.). Development of drugs with combined nootropic, antioxidant and anti-ischemic properties is a promising area in creation of nootropics. Combined nootropics have already become available in Russia and Ukraine. It should be noted that life expectancy is constantly increasing. Moreover, people over 65 years of age are the fastest growing part of overall population. Thus, incidence of age-related diseases (such as dementia etc.) is expected to increase significantly, and nootropics would be more and more popular. Nomenclature of national nootropics is significantly less than one related to this pharmaceutical group in foreign drug market. So, it is often insufficient to satisfy needs of medical practice. Moreover, some of mentioned drugs are old-fashioned (i.e., pyritinol) or can be replaced by more effective analogues.

Product photos

Pantogam activ Encephabol

AminalonPicamilon

Nootropil (Piracetam) Phenibut

Where to buy?

http://rupharma.com/cognitive-enhancement/
http://mospharma.com/cognitive-enhancement/

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