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
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
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 GABAA 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 GABAB receptor and
GABAA 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.
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.
