ABUSED DRUGS MECHANISMS AND WITHDRAWAL SYMPTOMS

Before describing the various drugs of abuse and the possible mechanisms of action, it is important to define terms. The management of drug abuse and addiction must be individualized according to the drugs involved and the associated psychosocial problems of the individual patient. An understanding of the pharmacology of the drug or combination of drugs ingested by the patient is essential to rational and effective treatment.
 

Addiction: A primary chronic neurobiological disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following 5Cs: chronicity, impaired control over drug use, compulsive use, continued use despite harm, and craving.

Physical dependence: A state of adaptation that is manifested by a drug class–specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.

Drug dependence and the older term drug addiction describe the human condition in which drug taking becomes compulsive, taking precedence over other needs, often with serious adverse consequences. This generally implies a state of physical, as well as psychological, dependence. Drug dependence (physical dependence) can be viewed as a reversible pharmacological phenomenon, readily induced in animals, whereas addiction(psychological dependence)is a chronic, relapsing human condition, as distinct from an acute illness that can be cured by abstinence. Drug abuse and substance abuse are more general terms, meaning any recurrent use of substances that are illegal or that cause harm to the individual, including drugs in sports. Tolerance-the decrease in pharmacological effect on repeated administration of the drug-often accompanies the state of dependence, and it is possible that related mechanisms account for both phenomena. Withdrawal syndrome or abstinence syndrome describes the adverse effects, both physical and psychological and lasting for a few days or weeks, of stopping taking a drug. Several psychotropic drugs, including antidepressant and antipsychotic agents, produce withdrawal symptoms but are not addictive, so it is important to distinguish this type of commonly observed 'rebound' phenomenon from true dependence.

Neurobiological basis of drug addiction

Reward pathways:

Virtually all dependence-producing drugs so far tested, including opioids, nicotine, amphetamines, ethanol and cocaine; activate the reward pathway-the mesolimbic dopaminergic pathway, which runs, via the medial forebrain bundle, from the ventral tegmental area of the midbrain to the nucleus accumbens and limbic region. Even though their primary sites of action are generally elsewhere in the brain, all these drugs increase the release of dopamine in the nucleus accumbens, as shown by microdialysis and other techniques.

Synaptic Plasticity & Addiction:

Long-term potentiation (LTP) is a form of experience-dependent synaptic plasticity that is induced by activating glutamate receptors of the N- methyl-D-aspartate (NMDA) type. Since NMDA receptors are blocked by magnesium at negative potentials, their activation requires the concomitant release of glutamate (presynaptic activity) onto a receiving neuron that is depolarized (post-synaptic activity). Correlated pre- and postsynaptic activity durably enhances synaptic efficacy and triggers the formation of new connections. Because associativity is a critical component, LTP has become a leading candidate mechanism underlying learning and memory. LTP can be elicited at glutamatergic synapses of the mesolimbic reward system and is modulated by dopamine. Drugs of abuse could therefore interfere with LTP at sites of convergence of dopamine and glutamate projections (e.g. ventral tegmental area [VTA], nucleus accumbens, or prefrontal cortex). Interestingly, exposure to an addictive drug triggers LTP at excitatory afferents and reduces GABA_A receptor-mediated inhibition of the VTA, thus increasing the excitability of dopamine neurons

Role of DOPAMINE in addiction:

To understand the long-term changes induced by drugs of abuse, their initial molecular and cellular targets must be identified. A combination of approaches in animals and humans, including functional imaging, has revealed the mesolimbic dopamine system as the prime target of addictive drugs. This system originates in the ventral tegmental area (VTA), a tiny structure at the tip of the brain stem, which projects to the nucleus accumbens, the amygdala, the hippocampus, and the prefrontal cortex. Most projection neurons of the VTA are dopamine-producing neurons. When the dopamine neurons of the VTA begin to fire in bursts, large quantities of dopamine are released in the nucleus accumbens and the prefrontal cortex. Direct application of drugs into the VTA also acts as a strong reinforcer, and systemic administration of drugs of abuse causes release of dopamine. As a general rule, all addictive drugs activate the mesolimbic dopamine system. Since each addictive drug has a specific molecular target that engages distinct cellular mechanisms to activate the mesolimbic system, three classes can be distinguished. A first group binds to G_io protein-coupled receptors, a second group interacts with ionotropic receptors or ion channels, and a third group targets the dopamine transporter.

In the VTA, the action of these drugs is preferentially on the g-aminobutyric acid (GABA) neurons that act as local inhibitory interneurons. Addictive drugs that bind to ionotropic receptors and ion channels can have combined effects on dopamine neurons and GABA neurons, eventually leading to enhanced release of dopamine. Finally, addictive drugs that interfere with monoamine transporters block reuptake or stimulate nonvesicular release of dopamine, causing an accumulation of extracellular dopamine in target structures. Since neurons of the VTA also express somatodendritic transporters, which normally clear dopamine released by the dendrites. This is consistent with the observations that antidepressants that block serotonin and norepinephrine uptake, but not dopamine uptake, do not cause addiction even after prolonged use.

Drug dependence:

With chronic exposure to addictive drugs, the brain shows signs of adaptation. For example if morphine is used for pain at regular intervals, the dose has to be progressively increased to maintain the analgesic effect.

Many variables or factors operate simultaneously to influence that a given person would become drug addict. These variables are classified in to three categories:

Ø  Drug dependent

Ø  User dependent

Ø  Environment dependent

Drug dependent	User dependent	Environment dependent
·         Availability ·         Cost ·         Purity/potency ·         Mode of administration	·         Heredity ·         Innate tolerance ·         Psychiatric symptoms ·         Prior experience propensity toward drug	·         Social settings ·         Community attitude ·         Peer influences ·         Employment and educational opportunities

Pharmacological basis of Drug Abuse

Since all addictive drugs increase dopamine concentrations in target structures of the mesolimbic projections, we classify them on the basis of their molecular targets and the underlying mechanisms.
I-Drugs that activate G₁₀ –coupled receptors:
The first group contains the Opioids, cannabinoids, g-hydroxybutyric acid (GHB), and the hallucinogens, which all exert their action through G_io protein-coupled receptors.

II-Inotropic receptors activators:
Second group includes nicotine, alcohol, the benzodiazepines, dissociative anesthetics, and some inhalants, which interact with ionotropic receptors or ion channels.

III-Drugs act through biogenic amine transporters:
The last group comprises cocaine, amphetamines, and ecstasy, which all bind to monoamine transporters. The non-addictive drugs are classified using the same criteria.

I-Drugs That Activate G_io-Coupled Receptors:

a-Opioids:
Although Opioids may have been the first drugs to be abused (preceding stimulants), they are still among the most commonly used for nonmedical purposes.

Mechanism of addiction:
Opioids comprise a large family of endogenous and exogenous agonists at three G protein-coupled receptors: the μ-, Ҡ-, and δ-Opioids receptors. Although all three receptors couple to inhibitory G proteins (i.e. they all inhibit adenylyl cyclase), they have distinct, sometimes even opposing effects, mainly because of the cell type-specific expression throughout the brain. In the VTA, for example, μ-Opioid receptors are selectively expressed on GABA neurons (which they inhibit), whereas Ҡ-Opioids receptors are expressed on and inhibit dopamine neurons. This may explain why μ-Opioids agonists cause euphoria, whereas Ҡ-agonists induce dysphoria.

Opioid drugs:
The most commonly abused μ-Opioids include morphine, heroin (diacetylmorphine, which is rapidly metabolized to morphine), codeine, and oxycodone.  Meperidine abuse is common among health professionals. All of these drugs induce strong tolerance and dependence.

Withdrawal syndrome:
 May be very severe (except for codeine) and includes intense dysphoria, nausea or vomiting, muscle aches, lacrimation, rhinorrhea, mydriasis, piloerection, sweating, diarrhea, yawning, and fever. Beyond the withdrawal syndrome, which usually last no longer than a few days, individuals who have received Opioids as analgesics, only rarely develop addiction. In contrast, when taken for recreational purposes, Opioids are highly addictive.

Treatment:
The Opioids antagonist naloxone reverses the effects of a dose of morphine or heroin within minutes. This may be life-saving in the case of a massive overdose. Naloxone administration also provokes an acute withdrawal (precipitated abstinence) syndrome in a dependent person who has recently taken an Opioids. In the treatment of Opioids addiction, a long-acting Opioids (eg, methadone, buprenorphine) is often substituted for the shorter-acting, more rewarding, Opioids (e.g., heroin). Using a partial agonist (buprenorphine) and the much longer half-life (methadone and buprenorphine) may also have some beneficial effects (e.g. weaker drug sensitization, which typically requires intermittent exposures), but it is important to realize that abrupt termination of methadone administration invariably precipitates a withdrawal syndrome; that is, the subject on substitution therapy remains dependent.

b-Cannabinoids:

Endogenous cannabinoids that act as neurotransmitters include 2-arachidonyl glycerol (2-AG) and anandamide, both of which bind to CB1 receptors. Exogenous cannabinoids, e.g. in marijuana, include several pharmacologically active substances including 9-tetrahydrocannabinol (THC), a powerful psychoactive substance.

Mechanism of addiction:
These very lipid-soluble compounds are released at the postsynaptic somatodendritic membrane, and diffuse through the extracellular space to bind at presynaptic CB1 receptors, where they inhibit the release of either glutamate or GABA. Because of such backward signaling, endocannabinoids are called retrograde messengers. In the hippocampus, release of endocannabinoids from pyramidal neurons selectively affects inhibitory transmission and may contribute to the induction of synaptic plasticity during learning and memory formation. Like Opioids, THC causes disinhibition of dopamine neurons, mainly by presynaptic inhibition of GABA neurons in the VTA.

Pharmacological effects:
The most prominent effects are euphoria and relaxation. Users also report feelings of well-being, grandiosity, and altered perception of passage of time. Dose-dependent perceptual changes (e.g., visual distortions), drowsiness, diminished coordination, and memory impairment may occur. Cannabinoids can also create a dysphoric state and, in rare cases following the use of very high doses, may result in visual hallucinations, depersonalization, and frank psychotic episodes. Additional effects of THC, e.g. increased appetite, attenuation of nausea, decreased intraocular pressure, and relief of chronic pain, have led to the use of cannabinoids in medical therapeutics.

Withdrawal syndrome: that includes restlessness, irritability, mild agitation, insomnia, nausea, and cramping, Sleep EEG disturbance.

C-Gamma-Hydroxybutyric Acid:

Gamma-hydroxybutyric acid (GHB) is produced during the metabolism of GABA, but the function of this endogenous agent is unknown at present. The pharmacology of GHB is complex because there are two distinct binding sites. The low-affinity binding site has been identified as the GABA_B receptor.

GHB causes euphoria, enhanced sensory perceptions, a feeling of social closeness, and amnesia. These properties have made it a popular "club drug" that goes by colorful street names such as "liquid ecstasy," "grievous bodily harm," or "date rape drug." As the latter name suggests, GHB has been used in date rapes because it is odorless and can be readily dissolved in beverages.

Although GABA_B receptors are expressed on all neurons of the VTA, GABA neurons are much more sensitive to GHB than dopamine neurons. Because GHB is a weak agonist, only GABA neurons are inhibited at the concentrations typically obtained with recreational use. At higher doses, however, GHB also hyperpolarizes dopamine neurons, eventually completely inhibiting dopamine release. Such an inhibition of the VTA may in turn preclude its activation by other addictive drugs and may explain why GHB might have some usefulness as an "anticraving" compound.

II-Drugs that Mediate Their Effects via Ionotropic Receptors:

a-Nicotine:
In terms of numbers affected, addiction to nicotine exceeds all other forms of addiction, touching more than 50% of all adults in some countries. Nicotine exposure occurs primarily through smoking of tobacco, which causes associated diseases that are responsible for many preventable deaths. The chronic use of chewing tobacco and snuff tobacco is also addictive.

Mechanism of addiction:
Nicotine is a selective agonist of the nicotinic acetylcholine receptor (nAChR) that is normally activated by acetylcholine. The rewarding effect of nicotine requires involvement of the VTA in which nAChRs are expressed on dopamine neurons. When nicotine excites projection neurons, dopamine is released in the nucleus accumbens and the prefrontal cortex, thus fulfilling the dopamine requirement of addictive drugs.

Withdrawal  symptoms:
Nicotine withdrawal is mild compared with Opioids withdrawal and involves irritability and sleep problems. However, nicotine is among the most addictive drugs and relapse after attempted cessation is very common.

Treatment:
Treatments for nicotine addiction include nicotine itself in forms that are slowly absorbed and several other drugs. Nicotine that is chewed, inhaled, or transdermally delivered can be substituted for the nicotine in cigarettes, thus slowing the pharmacokinetics and eliminating the many complications associated with the toxic substances found in tobacco smoke. The antidepressant bupropion is approved for nicotine cessation therapy. It is most effective when combined with behavioral therapies.

b-Benzodiazepines:

Benzodiazepines are commonly prescribed as anxiolytics and sleep medications. They represent a moderate risk for abuse, which has to be weighed against their beneficial effects. Benzodiazepines are abused by some persons for their euphoriant effects, but most often abuse occurs concomitant with other drugs, e.g. to attenuate anxiety during withdrawal from Opioids.

Barbiturates, which preceded benzodiazepines as the most commonly abused sedative hypnotics (after ethanol), are now rarely prescribed to outpatients.

Withdrawal Symptoms:
Include irritability, insomnia, phono- and photophobia, depression, muscle cramps, and even seizures. Typically, these symptoms taper off within 1–2 weeks.Benzodiazepines are positive modulators of the GABA_A receptor, increasing both single-channel conductance and open-channel probability. GABA receptors on dopamine neurons of the VTA lack α₁, a subunit that is typically present in GABA neurons. In addition, GABA_A receptors are expressed in much higher density on interneurons, so that a disinhibition of the mesolimbic dopamine system may explain the rewarding effects of benzodiazepines.

c-Alcohol:

Alcohol’s mechanism of action is complex, and no single receptor mediates all of its effects. On the contrary, alcohol alters the function of several receptors and cellular functions, including GABA_A receptors, adenosine reuptake (through the equilibrative nucleoside transporter, ENT1), glycine receptor, NMDA receptor, and 5-HT₃ receptor. They are all, with the exception of ENT1, either ionotropic receptors or ion channels. It is not clear which of these targets is responsible for the increase of dopamine release from the mesolimbic reward system.

Withdrawal syndrome:
That may include tremor (mainly of the hands), nausea and vomiting, excessive sweating, agitation, and anxiety. In some individuals, this is followed by visual, tactile, and auditory hallucinations 12–24 hours after cessation. Generalized seizures may manifest after 24–48 hours. Finally, 48–72 hours after cessation, an alcohol withdrawal delirium (delirium tremens) may become apparent in which the person hallucinates, is disoriented, and shows evidence of autonomic instability. Delirium tremens is associated with 5–15% mortality.

Treatment:
Treatment of ethanol withdrawal is supportive and relies on benzodiazepines. As in the treatment of all chronic drug abuse problems, heavy reliance is placed on psychosocial approaches to alcohol addiction. The pharmacologic treatment of alcohol addiction is limited, although several compounds, with different goals, have been used.

d-Inhalants:

Inhalant abuse is defined as recreational exposure to chemical vapors, such as nitrates, ketones, and aliphatic and aromatic hydrocarbons. These substances are present in a variety of household and industrial products that are inhaled by "sniffing," "huffing," or "bagging." Sniffing refers to inhalation from an open container, huffing to the soaking of a cloth in the volatile substance before inhalation, and bagging to breathing in and out of a paper or plastic bag filled with fumes. It is common for novices to start with sniffing and progress to huffing and bagging as addiction develops. Inhalant abuse is particularly prevalent in children and young adults.

Mechanism of addiction:
The exact mechanism of action of most volatile substances remains unknown. Altered function of ionotropic receptors and ion channels throughout the central nervous system has been demonstrated for a few. Nitrous oxide, for example, binds to NMDA receptors and fuel additives enhance GABA_A receptor function. Most inhalants produce euphoria; increased excitability of the VTA has been documented for toluene and may underlie its addiction risk. Other substances, such as amyl nitrite ("poppers"), primarily produce smooth muscle relaxation and enhance erection, but are not addictive. With chronic exposure to the aromatic hydrocarbons (e.g. benzene, toluene), toxic effects can be observed in many organs, including white matter lesions in the central nervous system. Management of overdose remains supportive.

III-Drugs That Bind to Transporters of Biogenic Amines:

a-Cocaine

Cocaine is an alkaloid found in the leaves of Erythroxylon coca, a shrub indigenous to the Andes. For more than 100 years, it has been extracted and used in clinical medicine, mainly as a local anesthetic and to dilate pupils in ophthalmology. Sigmund Freud famously proposed its use to treat depression and alcohol dependence, but addiction quickly brought an end to this idea.

 Mechanism of addiction:
In the peripheral nervous system, cocaine inhibits voltage-gated sodium channels, thus blocking initiation and conduction of action potentials. This effect, however, seems responsible for neither the acute rewarding nor the addictive effects. In the central nervous system, cocaine blocks the uptake of dopamine, noradrenalin, and serotonin through their respective transporters. The block of the dopamine transporter (DAT), by increasing dopamine concentrations in the nucleus accumbens, has been implicated in the rewarding effects of cocaine. The activation of the sympathetic nervous system results mainly from blockage of the norepinephrine transporter (NET) and leads to an acute increase in arterial pressure, tachycardia, and often, ventricular arrhythmias. Users typically lose their appetite, are hyperactive, and sleep little. Cocaine exposure increases the risk for intracranial hemorrhage, ischemic stroke, myocardial infarction, and seizures. Cocaine overdose may lead to hyperthermia, coma, and death. Susceptible individuals may become dependent and addicted after only a few exposures to cocaine. Although a withdrawal syndrome is reported, it is not as strong as that observed with Opioids.

b-Amphetamines

Amphetamines are a group of synthetic, indirect-acting sympathomimetic drugs that cause the release of endogenous biogenic amines, such as dopamine and noradrenaline.

Mechanism of action:
Amphetamine, methamphetamine, and their many derivatives exert their effects by reversing the action of biogenic amine transporters at the plasma membrane. Amphetamines are substrates of these transporters and are taken up into the cell. Once in the cell, amphetamines interfere with the vesicular monoamine transporter (VMAT) depleting synaptic vesicles of their neurotransmitter content. As a consequence, levels of dopamine (or other transmitter amine) in the cytoplasm increase and quickly become sufficient to cause release into the synapse by reversal of the plasma membrane DAT. Normal vesicular release of dopamine consequently decreases (because synaptic vesicles contain less transmitter), whereas nonvesicular release increases. Similar mechanisms apply for other biogenic amines (serotonin and norepinephrine).

  In general, amphetamines lead to elevated catecholamine levels that increase arousal and reduce sleep, whereas the effects on the dopamine system mediate euphoria but may also cause abnormal movements and precipitate psychotic episodes. Effects on serotonin transmission may play a role in the hallucinogenic and anorexigenic functions as well as in the hyperthermia often caused by amphetamines. Unlike many other abused drugs, amphetamines are neurotoxic. The exact mechanism is not known, but neurotoxicity depends on the NMDA receptor and affects mainly serotonin and dopamine neurons. Hypertensive crisis and vasoconstriction may lead to stroke.  

 Withdrawal symptoms:
Withdrawal consists of dysphoria, drowsiness (in some cases, insomnia), and general irritability.

c-Ecstasy (MDMA)

Ecstasy is the name of a class of drugs that includes a large variety of derivatives of the amphetamine-related compound methylene-dioxymethamphetamine (MDMA). MDMA was originally used in some forms of psychotherapy but no medically useful effects were documented.

Mechanism of action:
Similar to the amphetamines, MDMA causes release of biogenic amines by reversing the action of their respective transporters. It has a preferential affinity for the serotonin transporter (SERT) and therefore most strongly increases the extracellular concentration of serotonin. This release is so profound that there is a marked intracellular depletion for 24 hours after a single dose. With repetitive administration, serotonin depletion may become permanent, which has triggered a debate on its neurotoxicity. Although direct proof from animal models for neurotoxicity remains weak, several studies report long-term cognitive impairment in heavy users of MDMA.

In contrast, there is a wide consensus that MDMA has several acute toxic effects, in particular hyperthermia, which along with dehydration (e.g., caused by an all-night dance party) may be fatal. Other complications include serotonin syndrome (mental status change, autonomic hyperactivity, and neuromuscular abnormalities) and seizures.
Withdrawal symptoms:
Withdrawal is marked by a mood "offset" characterized by depression lasting up to several weeks. There have also been reports of increased aggression during periods of abstinence in chronic MDMA users.

Non-addictive Drugs of Abuse

Some drugs of abuse do not lead to addiction. This is the case for substances that alter perception without causing sensations of reward and euphoria, such as the hallucinogens and the dissociative anesthetics. Unlike addictive drugs, which primarily target the mesolimbic dopamine system, these agents primarily target cortical and thalamic circuits. Lysergic acid diethylamide (LSD), for example, activates the serotonin5-HT_2A receptor in the prefrontal cortex, enhancing glutamatergic transmission onto pyramidal neurons. These excitatory afferents mainly come from the thalamus and carry sensory information of different modalities, which may constitute a link to enhanced perception. Phencyclidine (PCP) and Ketamine produce a feeling of separation of mind and body (which is why they are called dissociative anesthetics) and, at higher doses, stupor and coma. The principal mechanism of action is a use-dependent inhibition of glutamate receptors of the N -methyl-D-aspartate (NMDA) type.

Concurrent effects on both thalamocortical and mesolimbic systems also exist for other addictive drugs. Psychosis-like symptoms can be observed with cannabinoids, amphetamines, and cocaine, which may reflect their effects on thalamocortical structures. For example, cannabinoids, in addition to their documented effects on the mesolimbic dopamine system, also enhance excitation in cortical circuits through presynaptic inhibition of GABA release.Hallucinogens and NMDA antagonists, even if they do not produce dependence or addiction, can still have long-term effects. Flashbacks of altered perception can occur years after LSD use. Moreover, chronic use of PCP may lead to an irreversible schizophrenia-like psychosis.

References

Ø  Bertram G. katzung, Susan B. Masters, Anthony J. Trevor, Basic and clinical pharmacology, 11^th edition.

Ø  Principles of Pharmacology, The Pathophysiologic Basis of Drug Therapy 2^nd Edition. David E. Golan MD, PhD, Armen H. Tashjian Jr. MD.

Ø  Applied therapeutics,The clinical use of drugs(9^th edition).koda kimble.

Ø  Goodman & Gilman’s The Pharmacological Basis of THERAPEUTICS eleventh edition.

Ø  Pharmacotherapy Handbook Seventh Edition.Barbara G. Wells, PharmD, FASHP, FCCP, BCPP.

Ø  Pharmacology 4^th Edition Lippincott Illustrated Reviews.