Product Code Database
Synthetic drugs refer to substances that are artificially modified from naturally occurring drugs and are capable of exhibiting both therapeutic and psychoactive effects.
In the medical setting, synthetic drugs possess psychotropic effects which can cure insomnia. Since there are limited clinical trials and human studies, the pharmacology and drug effects of most of the synthetic drugs are not well-known. Misuse of synthetic drugs can be fatal so take advice from the professionals before use.
Substances that possess the latter effect are known as Designer drug (NPS). Their purpose is to mimic the actions of illicit substances by altering the structure of the original drug. By doing so, the "synthesized drug" can appear in the market without being easily detected. However, the uncertainty in the toxic effects of these substances puts the public's health at risk. At present, these drugs are monitored by the Early Warning System (EWS).The major categories of NPS include synthetic stimulants, synthetic cannabinoids and synthetic depressants. Common examples from these categories are phenethylamines, cannabinoids and benzodiazepines. To exert the psychoactive effect, specific receptors such as cannabinoid, dopamine and serotonin receptors are either stimulated or inhibited
Synthetic can cause cardiovascular problems such as tachyarrhythmia, , psychological disorders and potential effects. Addiction and withdrawal symptoms which are linked to chronic use of synthetic cannabinoid include cognitive disturbances (e.g. difficulties in thinking), 'profuse sweating', central nervous system and gastrointestinal disturbances (e.g. nausea and vomiting).
The adverse effect of Phenethylamines depends on the type of the drug. 'D series' cause more long-lasting effects than other phenylethylamines such as tachycardia. At high doses, '2C series' produce hallucinogenic and entactogenic effects.
Alprazolam can cause central nervous system disturbances and thoughts of suicide.
Pregnant women are also not recommended to take phenethylamines as the effects on fetus are not known. In addition, use of phenethylamine might cause people with bipolar disorder to convert from depression to mania and worsened schizophrenia symptoms. As the drug also affects the central nervous system, administration of such drug before surgery is not recommended.
Benzodiazepines can cross the placenta and can be excreted in breast milk therefore Alprazolam is contraindicated in pregnancy and lactation. Alprazolam is a CYP3As substrate so we should avoid CYP3As inhibitors such as cimetidine which is a CYP3A4 inhibitor.
Phenethylamines, which can act as either stimulants or hallucinogens, are indirectly acting sympathomimetic amines. Stimulants can modulate the levels and action of monoamine such as dopamine, serotonin and noradrenaline for vasoconstriction and elevation in blood pressure. For example, 10-100 μM amphetamine can reach the vasoconstriction effect. Hallucinogen (Psychedelic drug) can mediate specific serotonin-receptor activities and produce hallucinations. They may have residue stimulant activity as well. In some animal studies, Phenethylamines have negative Inotrope in isolated cardiac tissues of rats due to stimulation of TAAR1, which is in contrast with human pharmacology.
Alprazolam binds to GABA type-A benzodiazepine receptor sites which are the members of the pentameric ligand-gated ion channel (PLGIC) superfamily. It mediates phasic inhibition and extrasynaptically to mediate tonic inhibition. Once attached, conformational changes occur which stabilize the receptors and inhibitory signals are produced
Phenethylamines are first-order kinetics with half life of 5 to 10 minutes which are absorbed by ingestion. The drugs have low concentration in the brain due to low biological half-life. It is difficult to measure the plasma concentration due to low stability of Phenethylamine. There are two possible metabolism pathways. The first possible pathway is metabolism by MAO-B (an intracellular enzyme mainly in the brain and tightly bound to the outer membrane of mitochondria which deaminates free primary and secondary amines) to form phenylacetic acid due to MAO-B selectivity on non-polar aromatic amines. Then, the metabolites undergo N-methylation by non-specific N-methyltransferase(NMT) or by phenylethanolamine-N-methyltransferase (PNMT) (found in the adrenal medulla) to form secondary amines and sympathetic neurotransmitter noradrenaline. The second possible pathway is deamination of the drug by the semi-carbazide-sensitive amine oxidases (SSAO) (found in the vascular tissue and have similar metabolism to MAO). An alpha-methyl side chain renders the drug immune to deamination in the gut. The drugs are mainly excreted in feces and urine.
Alprazolam has high oral bioavailability (84-91%) in which its maximum plasma concentration (Cmax) is reached after 1 to 2 hours. When taken with food, Cmax is increased by 25%. The half-life profile of this drug for different populations is illustrated in the following table:
| +Half-life profile !Population !Half-life (hrs) | |
| Healthy individuals | 11.2 |
| Obese | 10.7-15.8 |
| Alcoholic liver disease | 19.7 |
In terms of race, the half-life is 25% higher in Asian patients compared to Caucasians. For the extended-release formulation, it has a half-life of 10.7-15.8 hours in healthy adult patients. Alprazolam has a volume of distribution following oral administration of 0.8-1.3L/kg. Its protein binding in plasma is 80% (mainly albumin bound) and capable of crossing the blood-brain barrier. It is metabolized to less effective metabolites by various CYP450 enzymes including CYP3A4, CYP3A5, CYP3A7, and CYP2C9. The majority of alprazolam metabolism is mediated by hydroxylation via CYP3As. 4-hydroxyalprazolam has 20% the binding affinity of the parent drug, alpha-hydroxyalprazolam has 66% the affinity, and the benzophenone metabolite has <1% the affinity. The drugs are mainly excreted in urine as unchanged Alprazolam. <10% of the dose is eliminated as alpha-hydroxy-alprazolam and 4-hydroxy-alprazolam.
A typical agonist consists of the following components: head, linker core and tail. Altering the structure from each component will affect the drug's affinity to the cannabinoid receptors. For instance, when a fluoride or nitrile group is attached to the carbon chains, the affinity for CB1 will increase. The Aromaticity from the aminoalkylindole class also play the role of enhancing the affinity by forming a hydrophobic cavity to stabilize the CB1 receptors. As legislation becomes tightened under the monitoring of Early Warning System (EWS), attempts are made to alter the structure which produce new analogues such as the Cyclopropylindoles (UR-144) and APINACA (APINACA).
| + !Steps !Procedure | |
| 1 | Formal notification |
| 2 | Monitoring and response |
| 3 | Initial report writing |
When the EWS detects a new drug, the substance will be reported to EMCDDA along with any analytical data such as structures, analysts or components found pertaining to that particular drug. Then, an interconnected system is established to closely monitor the development of the substance. If harm is induced, an initial report is drafted to document the adverse effects of the drug.
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