Designer drugs

A brief overview of designer drugs, their categories, their structures ; their toxicities and the management of their toxicities. A brief note on the concerns regarding designer drugs

1. Designer Drugs Presented by- Deepak Pandey

2. Outline Introduction Brief overview of different categories of Designer drugs with a typical example of each group Concerns Conclusion References

3. Introduction Designer drugs- Novel substances Derived from illegal alterations of well known drugs of abuse Preserving or enhancing pharmacologic effects Remaining outside of legal control Include substances that originate from industrial or academic research & never receive medical approval Duplicate technical sophistication of research community for manufacturing and marketing Till 1960s, major drugs of abuse were heroin, cocaine, LSD and amphetamine By 1970s- Different structural activity relationship studies developed and published   PIHKAL  and  TIHKAL  (standing for  Phenethylamines  and  Tryptamines  I Have Known And Loved ) by Alexander Shulgin described different psychoactive agents and their synthesis

4. Introduction Information exchange of drug discovery process- Scientific journals, books, patents and different internet forums (OPIOPHILE) By 1970s and 1980s, clandestine laboratories developed designer drugs with similar pharmacologic effects but different structures to evade provisions of national control policies. Designer drug enforcement act of 1986 (US) defined designer drug as— “A substance other than a controlled substance in schedule I and II that has a chemical structure substantially similar to that of a controlled substance or that was specifically designed to produce an effect substantially similar to that of a controlled substance.”

5. Introduction They are divided into different categories based on the dominant neurobehavioral effects- Stimulants- Increased level of alertness, feeling of physical and mental well being, exhilaration, elevated motor activity, postponement of fatigue Sedatives- facilitate sleep, coping with stress by reducing anxiety, Dissociatives - sensory dissociation, amnesia Synthetic Cannabinoids- Sense of relaxation and euphoria Psychedelics- Altered state of consciousness, hallucinations Miscellaneous

6. Stimulants Amphetamines and Phenethylamine derived designer drugs Cathinone and Pyrovalerone derivatives Benzofuran and Indole derivatives

7. Amphetamine derived designer drugs Studies on molecular structure and neurobehavioral effects of PEA (Phenethylamine- a naturally occurring alkaloid), Amphetamine to establish structure activity relationship with psychological effects. Discovery of novel drugs for potential therapeutic uses Exploitation of knowledge- several amphetamine designer drugs without approved medical uses available- MDMA, Methamphetamine

8. Amphetamine derived designer drugs MDMA- Most popular amphetamine designer drug. First synthesized in 1912 as a precursor in a new chemical pathway 1980s- MDMA started to be used in psychotherapy Recreational drug under the street name ‘‘ecstasy, Mechanism of action- Inhibit reuptake of norepinephrine, serotonin and dopamine or mediating efflux into synaptic cleft

9. Amphetamine derived designer drugs Adverse effects--- Anxiety Insomnia Headaches Mydriasis Dry mouth Hypertension, tachycardia, chest pain, palpitations- Due to sympathetic overactivation Anorexia, nausea, vomiting, and abdominal pain Hyperthermia- Significant contributor to potential adverse effects including DIC, renal failure, and rhabdomyolysis

10. Cathinone and pyrovalerone derivatives β - ketoamphetamine - cathinone of Phenethylamine class, an alkaloid that is found in the leaves of the Catha edulis plant – Amphetamine like euphoric effects Synthetic cathinones had been developed as antidepressant or anorectic agents- concerns about abuse Pyrovalerone derivatives- Subgroup of synthetic cathinones based on the structure of pyrovalerone- developed in the 1960s as a treatment option for lethargy, fatigue, and obesity. Pyrovalerone analogs- “Bath salts”, “bath crystals”, “plant food”, “screen cleaner”, “insect repellant”, and “herbal incense”

11. Cathinone and pyrovalerone derivatives Abuse of synthetic cathinones - Euphoria, heightened alertness, increased energy, talkativeness, openness Similar structure- mimics Amphetamines in MOA and Adverse effects Other adverse effects- Tachyphylaxis, dependence and withdrawal Routine investigations- negative results Management of toxicity- No specific antidote available Conservative methods- Supportive care, intravenous fluid replacement, and benzodiazepines to control agitation, anxiety, hyperthermia, and seizures Aggressive cooling methods for hyperthermia HTN- Vasodilators (Sodium Nitroprusside and Nitroglycerin); (Beta blockers to be avoided)

12. Benzofuran and indole derivative Analogues of MDMA and its metabolite 3,4 methylenedioxyamphetamine (MDA)- 5-aminopropylbenzofuran (5-APB) Mechanism of action- Norepinephrine reuptake inhibition, selectivity in inhibiting 5-HT vs. dopamine reuptake, Adverse effects Agitation, insomnia, headache, drowsiness, dry mouth, dry eyes, bruxism, hyperthermia, tachycardia, palpitations, nausea, diarrhoea

13. Sedatives Synthetic Opioids Designer Benzodiazepines Gamma Hydroxybutyrate (GHB) analogues

14. Synthetic Opioids Morphine- Prototypic opioid analgesic. Thousands of analogs- Synthesized and evaluated with the goal of developing a more potent analgesic devoid of morphine’s side effects Structure–activity relationship (SAR) studies in 1970s had identified very potent analgesics in the piperidine-based class. Due to the ease of synthesis and availability of starting materials, the piperidine class (fentanyl group) of opioids- Dominant “designer drug” developed- Methylfentanyl (“China white”)

15. Synthetic Opioids They induce euphoria, anxiolysis, feelings of relaxation, and drowsiness Mechanism of action- Agonism at μ -opioid receptors Potency- Several thousands folds higher than morphine Adverse effects- Dizziness, a lower level of consciousness, miosis, central nervous system depression, respiratory depression, pulmonary edema , hypoxia, bradycardia, pruritus, nausea, vomiting, constipation, and also such symptoms as agitation, hypertension, and tachycardia and withdrawal symptoms Antidote- Naloxone- competitive antagonist at μ -opioid receptors

16. Designer benzodiazepines Designer BZD developed to abuse- facilitate sleep, cope with stress, ease effects of stimulants, Limited potential as euphoriants when administered alone- enhance the euphoric effects of opioid use

17. Designer benzodiazepines Mechanism of action- Agonists at GABA A receptors Adverse effects of designer BZDs- Fatigue Impairment of thinking, confusion, dizziness, drowsiness, lethargy, amnesia, blurred vision, slurred speech, auditory and visual hallucinations Palpitations, Muscle weakness, At high doses- Delirium, seizures and coma The concurrent use of Designer BZD with opioids or alcohol- Potentially fatal respiratory depression Atypical adverse effects- agitation, tachycardia, hyperthermia Chronic use- Dependence and Tolerance

18. Gamma Hydroxybutyrate (GHB) analogues It is a short-chain fatty acid analogue of the inhibitory neurotransmitter GABA. Ability to induce feelings of euphoria and relaxation, reduced social anxiety An endogenous compound Its sodium salt- approved as a prescription drug for narcolepsy GHB and its analogues- Designer drugs- widespread illicit production in clandestine laboratories eg. - 4-methyl-substituted GHB derivative gamma- hydroxyvaleric acid (GHV) and 4-amino-3-phenyl-butyric acid

19. Gamma Hydroxybutyrate (GHB) analogues Mechanism of action of GABA analog- Agonist at GABA B receptor and GABA A receptor Adverse effects of GABA analogs – Lower level of consciousness, Hypothermia, Respiratory depression, aspiration, bradycardia, gastrointestinal upset, agitation, seizures, and myoclonus short duration and are usually managed with supportive care Rapid development of tolerance Withdrawal- Agitation, anxiety, confusion, disorientation, paranoia, aggression, insomnia, auditory and visual hallucinations, tremors, sweating, hypertension, and tachycardia. T/t- Benzodiazepines

20. Dissociative designer drugs Ketamine- 1962- short acting anaesthetic Phencyclidine(PCP)- similar effects- not in clinical use d/t unfavourable side effects Designer drugs derived from ketamine and PCP for dissociative effects, sensory and tactile distortions, euphoria and depersonalization eg - Methoxetamine

21. Dissociative designer drugs Mechanism of action- Non-competitive antagonists at ionotropic glutamatergic NMDA receptors- mediates the dissociative effects; Inhibition of reuptake of norepinephrine and dopamine Adverse effects- Agitation, confusion, disorientation, dissociation, hallucinations, amnesia, nystagmus, slurred speech, diaphoresis, hypertension, tachycardia, renal insufficiency, nausea, ataxia and muscle rigidity Chronic use- Neurological impairment- cerebellar toxicity

22. Synthetic Cannabinoids Endogenous cannabinoids- including cognition, behavior, memory, motor control, pain sensation, appetite, gastrointestinal motility, and immunoregulation. CB1 receptors- Basal ganglia, cerebellum, hippocampus, and cortex- psychoactive effects of cannabinoids. CB2 receptors- immunomodulatory effects of cannabinoids. Exogenous cannabinoids- Cannabis sativa and Cannabis Indica Synthetic cannabinoids- 1960s- maximize the analgesic and anti-inflammatory properties of D9-tetrahydrocannabinol (D9-THC) while eliminating the psychotropic effects. Designer drugs- desired effects of relaxation, euphoria, and disinhibition

23. Synthetic Cannabinoids Mechanism of action- agonists at CB1 and CB2 receptors Adverse effects- Anxiety, paranoia, agitation, delusions, tachycardia, diaphoresis, nausea, vomiting, and xerostomia. Psychosis, acute kidney injury, seizures, hypertension, hypotension, palpitations, hyperthermia, rhabdomyolysis Management of toxicity- No specific antidote available Acute management of synthetic cannabinoid toxicity should include supportive care and parenteral benzodiazepines for seizures, agitation, or anxiety.

24. Psychedelics Tryptamines Lysergamides

25. Tryptamines The core structure of tryptamine designer drugs- similar to 5-HT. DMT(Di Methyl Tryptamine)- Ingredient in the psychoactive brew ayahuasca; psilocybin that is in Psilocybe mushrooms- used in sociocultural and ritual contexts for psychoactive effects. Mechanism of action- Agonist at 5-HT1A and 5-HT2A receptors with similar affinity; 5-HT2A receptor agonism- psychedelic effect 5- HT

26. Tryptamines Adverse effects- Altered perception of reality Acute psychosis, restlessness, disorientation, clouding of consciousness, confusion, hallucinations, amnesia, catalepsy, mydriasis, tachypnea , hypertension, and tachycardia Severe cases- Rhabdomyolysis and renal failure

27. Lysergamides Designer drugs derived from LSD 1-acetyl-LSD (ALD-52), 1-propionyl-LSD (1PLSD), and 1-butyryl-LSD (1B-LSD)- metabolized to LSD Mechanism of action of lysergamides - Agonist at 5 HT-2A receptor Adverse effects of Lysergamides - Hypertension, tachycardia Poor concentration, imbalance, feelings of exhaustion, dizziness, headache, dry mouth, lack of appetite, and nausea

28. Miscellaneous designer drugs Performance-enhancing designer drugs- Designer doping agents- anabolic steroids, peptide hormones, growth factor mimetics, and hormone and metabolic modulators- performance and image enhancement Evade the different doping tests Adverse effects- secondary hypogonadism, gynecomastia, infertility, hypertension, ischemic stroke, cardiotoxicity, hepatotoxicity, and renal failure

29. Concerns- Quality assurance of designer drugs are not guaranteed- not subject to regulations. lack of information about purity, mislabeling Potentially severe drug-drug interactions used in combination with other substance hindering precise evaluations of the degree of involvement of individual substances to clinical toxicity in patients. Remain undetected by routine drug screenings- abuse Easy accessibility and rapid emergence of new designer drugs- availability through Internet, at raves and night clubs, The controlled substance acts and other regulations- intended for drugs for human consumption. Designer drugs- marketed with label as “Not for Human consumption”

30. Conclusion- Number of available designer drugs- Constantly growing, trends and patterns of use change over time Newly emerging drugs- remain undetected by routine drug screening, and information about associated adverse effects is scarce. The Internet plays a crucial role in the distribution of designer drugs and in the acquisition of information about them Healthcare workers need to have a thorough knowledge of the available designer drugs, common signs and symptoms of toxicity associated with these agents, and potential effective treatment modalities to appropriately manage these patients. + ve note- few drugs marked earlier as Designer drugs- developed as prescription drugs-MDMA- under Phase 3 trial as prescription drug for the treatment of post-traumatic stress disorder.

31. References- Luethi D, Liechti ME. Designer drugs: mechanism of action and adverse effects. Archives of toxicology. 2020 Apr;94(4):1085-133. Musselman ME, Hampton JP. “Not for human consumption”: a review of emerging designer drugs. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy. 2014 Jul;34(7):745-57. Weaver MF, Hopper JA, Gunderson EW. Designer drugs 2015: assessment and management. Addiction science & clinical practice. 2015 Dec;10(1):1-9. Carroll FI, Lewin AH, Mascarella SW, Seltzman HH, Reddy PA. Designer drugs: a medicinal chemistry perspective. Annals of the New York Academy of Sciences. 2012 Feb;1248(1):18-38. Chen X, Choo H, Huang XP, Yang X, Stone O, Roth BL, Jin J. The first structure–activity relationship studies for designer receptors exclusively activated by designer drugs. ACS chemical neuroscience. 2015 Mar 18;6(3):476-84.

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