DEXTROMETHORPHAN AND BENZYDAMINE’S USE AND MISUSE
Drugs

Author: luca davicco
Date: 30/07/2014

Description

A cura di Alessandra PUGLIESE e Luca DAVICCO

INTRODUCTION

Drug abuse is not just about street drugs. Besides marijuana, legal medicines are the most commonly abused drugs in the U.S and Europe.

Dextromethorphan and Benzydamine are easily-found ingredients of over-the-counter (OTC) and prescription drugs, used as antitussive (DM) and anti-inflammatory (BZ) agents; they can produce neurobehavioral effects if the dose is increased above the therapeutic threshold.
The widespread and easy access makes these drugs particularly appreciated for their abuse-recreational use.

Our purpose is to study the mechanisms and the clinical effects of commonly OCT-drugs abuse, like BRONCHENOLO TOSSE (Dextromethorphan) and TANTUM ROSA (Benzydamine).

DEXTROMETHORPHAN AND ABUSE

Dextromethorphan (DM) is a common ingredient of more than 100 cough and cold remedies available since 1954 as an antitussive agent; DM has a strong safety and efficacy profiles without sedative or addictive properties at the recommended doses.(1)

It has now been recognized that DM could also be used as an analgesic in the treatment of pain associated with cancer if administered at higher doses than typically prescribed for the treatment of cough with a mechanism that appears to be related to a N-methyl-D aspartate (NMDA) receptor blocking effect (low-affinity, non-competitive NMDA receptor antagonist).(2)

The abuse of this substance, easily found in cough medicines among children and adolescents has been well documented for decades.(3)

MOLECULE

DM is the D-isomer of the codeine analogue, levorphanol. As morphinans family, it’s a polycyclic compound with a four-ring skeleton with three condensed sixmember rings forming a partially hydrogenated phenanthrene moiety, one of which is aromatic while the two others are alicyclic.

IUPAC NAME: (+)-3-methoxy-17-methyl-(9α,13α,14α)-morphinan

Even if similar, in contrast to its L-isomer and others MOP opioids-agonists:
- it has no effect on the opioid receptors;(4)
- its effect is not suppressed by naloxone-antagonism;(4), (5), (6)
- does not possess analgesic or addictive properties at recommended doses; (7)
- does not have major opioid-like respiratory or hemodynamic side effects, neither histamine released-complications or classical addictive properties;(8)

POSOLOGY

The currently recommended adult doses for the therapeutic action are 10-30 mg orally, three to six times daily; a bigger dose (100-600mg) is required to obtain neurobehavioral effects.

PHARMACOKINETIC

DM is a prodrug: dextrorphan is the active metabolite that produces neurobehavioral effects in reason of a greater affinity to NMDA receptors, while DM does not reach the same efficacy.
The hepatic conversion to dextrorphan is an important determinant of the abuse potential.(9)

MECHANISM OF ACTION

Antitussive action is not well understood; however DM is a low-affinity, non-competitive NMDA receptor antagonist and the capacity of binding and antagonize the NMDA receptor is probably due to a structural architecture common to the family of dissociative agents, as Ketamine and Phencyclidine.(10)

According to other studies (in animals), DM shows also:
- an agonist action to the opioid sigma 1 and sigma 2 receptors;
- an antagonist action to alpha3/beta4 nicotinic receptor;
- targets the serotonin reuptake pump;(11)

The relationship of these receptor binding sites and the pharmacological mechanism of the antitussive effects of dextromethorphan is not well known; however, coupling these observations with the inability of naloxone to antagonize the antitussive effects of DM, studies suggest that cough suppression can be achieved by different mechanisms.(12)

USE AND EFFECTS

Dextromethorphan has equal antitussive effects as codeine, so it is wildly appreciated as antitussive agent. It is clear that it increases the cough threshold, but the pharmacological mechanism and the specific central sites upon which it exerts its effect are still uncertain. It is postulated that the action could be direct on the cough center in the medulla brain, with a multi-mechanism probably distinct from those of opioids.

Dextromethorphan is also used recreationally as a dissociative hallucinogen thanks to his antagonist action on NMDA receptor. Laboratory studies suggest that dissociative drugs, including PCP, ketamine, and DM, cause their effects by disrupting the actions of glutamate receptors who plays a major role in cognition (including learning and memory), emotion, and the perception of pain.(13), (14)
There is evidence that the effects of ketamine and PCP to cause alteration in sensory perception and dissociative anaesthesia are largely attributed to non-competitive antagonism of NMDA receptor.(15)

With key roles in essential brain functions ranging from the basics of excitatory neurotransmission to the complexities of learning and memory, the N-methyl-D-aspartate (NMDA) receptor can be considered one of the fundamental neurotransmitter receptors in the brain; it has a critical role in excitatory synaptic transmission, plasticity and excitotoxicity in the CNS.(16)

The NMDA receptor belongs to the family of ionotropic receptors for the excitatory amino acid glutamate and is characterized by high affinity for glutamate, a high unitary conductance, high calcium permeability, and a voltage-dependent block by magnesium ions;16 the involvement of NMDARs in mentioned processes reflects their unique features, in particular voltage-sensitive block, a high permeability to Ca2+ and unusually slow ‘activation/ deactivation’ kinetics.(17)

Otherwise, activation of NMDA receptors by the glutamate requires glycine as an essential coagonist; two of each are required for the maximal activation, by binding different subunits of the receptor; this characteristic has been exploits in the research of competitive agonists and antagonists.(16)

The NMDA receptor subunit has similar structural characteristics as other members of the ionotropic glutamate receptor family, with an extracellular N-terminus, intracellular C-terminus and a re-entrant transmembrane domain.

Over the past decade, a variety of NMDAR subunits have been identified: the ubiquitously expressed NR1 subunit; a family of four distinct NR2 subunits (A, B, C and D); and two NR3 subunits; there is general agreement that glutamate molecules bind with high affinity to the NR2 subunits of the NMDAR while glycine molecules bind to the NR1 subunits.(17)

The most obvious subunit dependent properties of NMDARs are their single-channel conductances and their block by extracellular Mg2+. Thus, diheteromeric NMDARs containing NR2A or NR2B subunits generate ‘high-conductance’ channel openings with a high sensitivity to block by Mg2. (17)

Returning to primary function, during excitatory neurotransmission, presynaptic release of glutamate activates glutamate receptors in the postsynaptic membrane, resulting in the generation of an excitatory postsynaptic potential (EPSP).(17)
The NMDA receptor functions as a modulator of synaptic response and a co-incidence detector. At resting membrane potentials, NMDA receptors are inactive. This is due to a voltage dependent block of the channel pore by magnesium ions, preventing ion flows through it. Sustained activation of AMPA receptors by, for instance, a train of impulses arriving at a pre synaptic terminal, depolarises the post-synaptic cell, releasing the channel inhibition and thus allowing NMDA receptor activation.(18)

These receptors are permeable to sodium, calcium and potassium ions, following the direction of their natural gradient: l’activation leads to the opening of ion channel, resulting in the influx of Na+ and Ca++ ions and efflux of K+ ions.(16)
NMDA receptors can contribute significantly to the amplitude of unitary evoked postsynaptic potentials plasticity and the entry of calcium into the postsynapse permits coupling of electrical synaptic activity to biochemical signaling via activation of Ca++-dependent enzymes and downstream signaling pathways.(16)

The following pathways are implicated with NMDA Calcium-influx (18)
- activation of CaMKII and phosphorylation of the GluA2 AMPA receptor subunit resulting in LTP (HFS)
- activation of PICK1 to drive the PKC-dependent synaptic insertion of AMPA receptors during LTP
- activation of hippocalcin, a Ca2+-binding protein that recruits AP2 to the GluA2 AMPA receptor subunit prior to internalisation during LTD (LFS)
- activation of PI3K/Akt/GSK3 to modulate LTP

DM has been shown to reduce and regulate the influx of intracellular calcium through the NMDA receptor-gated channels. (19)
The blockage of NMDA receptors by DM and metabolites result in production of specific neurobehavioral findings such as dissociative, “out-of-body” experiences, like ketamine mechanism of dissociative anesthesia (9). A further aspect that can be considerate, DM bind D2 receptors leading to psychoses, visual hallucinations and manic symptoms (such as restlessness, insomnia, irritability, and racing thoughts).(20)

ABUSE

The 2013 annual US Drug Use and Health report, revealed that in 2006 around 3.1 million people in the United States aged 12–25 used OTC cough and cold medicine to “get high’’(21); in addition, dextromethorphan misuse and abuse among children and adolescents has been well documented for decades with evidence of plateau occurred since 2006.(3)
The 29th Annual Report of the AAPCC National Poison Data System published in December 2012, documents 74,995 exposures to cold and cough preparations. This accounts for 2.73% of all exposures called into United States poison centers and ranks “cold and cough preparations” number eleven on the list of top 25 substance categories most frequently involved in human exposures. Over 9,400 (12.5%) of the exposures to cough and cold preparations were the result of intentional abuse or misuse.(3)

The dose of ingested dextromethorphan determines the neurobehavioral effects which begin within 30–60 minutes from ingestion and persist for approximately 6 hours.
The first plateau (100 and 200 mg) is a mild stimulant effect similar to that of methylenedioxymethamphetamine.
The second plateau (200 and 400 mg) is described as similar to a combination of concurrent ethanol and marijuana intoxication, although some users describe hallucinations as occurring at this stage.
The third level (300 and 600 mg) is a dissociative, “out-of body” state, like that produced by a low recreational dose of ketamine, and the fourth plateau (600–1,500 mg) is a fully dissociative condition similar to that produced by ketamine intoxication. (22), (23)

The clinical presentation of dextromethorphan intoxication therefore depends on the ingested dose: minimally intoxicated persons may develop tachycardia, hypertension, vomiting, mydriasis, diaphoresis, nystagmus, euphoria, loss of motor coordination, and giggling or laughing; in addition to the above findings, persons with moderate intoxication may demonstrate hallucinations and a distinctive, plodding ataxic gait that has been compared with “zombie-like” walking (34). Severely intoxicated individuals in a dissociated state may be agitated or somnolent (24), (25), (26), (27).
Extremely agitated patients may develop hyperthermia and metabolic acidosis.

Although dextromethorphan is not thought to have addictive properties, susceptible individuals may develop craving and habitual use of the drug. An abstinence syndrome may be associated with cessation of dextromethorphan abuse that is characterized by dysphoria and intense cravings. Toxic psychosis and cognitive deterioration may arise from chronic use of the drug (9).

Drug interactions exist between dextromethorphan and other substances, the best characterized of which is serotonin syndrome. This condition typically occurs from the interaction between dextromethorphan and selective serotonin reuptake inhibitors or monoamine oxidase inhibitors, but concurrent administration of antibiotics (eg, linezolide), opiate analgesics (eg, meperidine and tramadol), or drugs of abuse (eg, Syrian rue) could precipitate the condition (28).

Expectorants, like Guaifenesin, a ubiquitous expectorant found in OTC cough medicines, has minimally toxic effects limited to mild gastrointestinal irritation. It can be considered a safer alternative for use in patients with addiction to or dependence on other antitussives with high abuse potential.

BENZYDAMINE AND ABUSE

Benzydamine has analgesic and anti-inflammatory activities, particularly when applied topically (29). Its preparations are used throughout the world for the symptomatic treatment of oropharyngeal and gynaecological conditions.
In Italy, for example, benzydamine is marketed as mouthwash or tablets for oral use (ex. TANTUM VERDE o OROSAN, GOLA ACTION), or as vaginal wash (ex. TANTUM ROSA, now renamed as GINETANTUM).

We focused on this last product of benzydamine, because it figure also among the substances of abuse with hallucinogenic effects and sensory alteration.