Drug Of Abuse - Updated PDF

Drug of Abuse Week 12 Dr. Fatemah Alherz  Some Important Pharmacological Terms Tolerance Decreased effect of a drug that develops with continued use Acquired tolerance results when repeated administration of a drug shifts the dose–response curve of the drug to the right, so that a la...

Drug of Abuse Week 12 Dr. Fatemah Alherz  Some Important Pharmacological Terms Tolerance Decreased effect of a drug that develops with continued use Acquired tolerance results when repeated administration of a drug shifts the dose–response curve of the drug to the right, so that a larger dose of the drug is required to produce the same effect. Innate tolerance refers to preexisting interindividual variations in sensitivity to the drug (i.e., variations that are present before the first administration of the drug).  Acquired tolerance includes pharmacokinetic, pharmacodynamic, and learned components. Pharmacokinetic tolerance: Develops when the capacity to metabolize or excrete the drug increases as a result of drug Acquired exposure. Tolerance Increased metabolism is typically attributable to induction of metabolic enzymes such as the cytochrome P450s In such cases, pharmacokinetic tolerance results in a lower concentration of drug at its site of action for any given dose. Acquired tolerance Pharmacodynamic tolerance: is caused by neuronal adaptations resulting in reduced response to the same concentration of drug at its site of action in the nervous system. Short-term exposure to a drug can induce neuroadaptive changes in neurotransmitter release and clearance from the synapse, a decrease in the number of neurotransmitter receptors, altered conductance of ion channels, or modified signal transduction. Longer term administration of the drug can cause neuroadaptive changes in the expression of genes relevant to the pharmacologic action of the drug; these changes are closely linked with adaptations in the brain that are thought to be involved in learning and memory formation. Alcohol Alcohol modulates the major inhibitory and excitatory neurotransmitter systems of the brain via effects on GABAA and NMDA receptors (GABAA-R and NMDA-R), respectively. Alcohol increases chloride conductance through GABAA receptors, resulting in cellular hyperpolarization. Alcohol also decreases calcium conductance through NMDA receptors, further decreasing cellular excitation. These dual actions on GABAA and NMDA receptors contribute to alcohol’s anxiolytic, sedative, and CNS-depressant effects.  Molecular adaptations to chronic alcohol exposure (1) internalization and decreased surface expression of “normal” α1 subunit-containing GABAA receptors, (2) Increased surface expression of “low alcohol sensitivity” α4 subunit-containing GABAA receptors, (3) Increased phosphorylation of NMDA receptors containing “high conductance” NR2B subunits. Thus, neuroadaptation results in tolerance to the acute depressant effects of alcohol and occurs concomitantly with dependence. During withdrawal (i.e., in the dependent state but in the absence of alcohol), these adaptations result in generalized hyperexcitability of neurons. CNS excitation is expressed as anxiety, insomnia, delirium, and potentially seizures.  Cocaine Acute cocaine exposure inhibits dopamine reuptake transporters (DAT), resulting in increased synaptic dopamine levels and increased postsynaptic dopamine receptor activation at synapses in the nucleus accumbens; in turn, these effects cause feelings of euphoria and increased energy. Increased extrasynaptic dopamine also results in D2 autoreceptor activation, which decreases dopamine synthesis. During withdrawal (i.e., in the dependent state but in the absence of psychostimulant), the decreased synaptic levels of dopamine that result from reduced dopamine synthesis and increased clearance through DAT cause decreased activation of postsynaptic dopamine receptors and feelings of dysphoria, fatigue, and anhedonia. Dependence Physical dependence: Characterized by withdrawal symptoms upon discontinuation of the drug New terminology used: dependence. Psychological dependence: Craving for the drug even after acute withdrawal symptoms have subsided Individual is prone to relapse New terminology used: addiction. Addiction: Also referred to as substance dependence Has drug-seeking behavior as its fundamental element "Rewiring of the brain": Persistent adaptations to drug use modify existing synapses and create new ones. Explains the craving & relapses long after drug use has been discontinued. Dependency The medial forebrain bundle and ventral tegmental area (VTA) in the midbrain have been termed pleasure centers or the foci of reward in the brain. A subset of dopaminergic neurons projects directly from the VTA to the nucleus accumbens (NAc) via the medial forebrain bundle. It is believed that these neurons are crucial for the brain reward pathway, which reinforces motivated behavior and facilitates learning and memory via links to the hippocampus, amygdala, and prefrontal cortex. Severing this pathway, or blocking dopamine receptors in the NAc with a dopamine receptor antagonist, decreases electrical self-stimulation of the VTA. https://www.yalemedicine.org/news/how-an-addicted-brain-works  Variables Affecting the Development of Substance Use Disorders The development of substance use disorder is dependent on: The nature of the drug Genetic Acquired Psychological Social traits of the drug user Environmental factors. The ability of a drug to activate reward mechanisms is strongly correlated with its ability to cause addiction.  Variables Affecting the Development of Substance Use Disorders cont. Pharmacokinetic properties of the drug can significantly influence its effects on the brain: o The more rapid the rise in drug concentrations at the target neurons, the greater the activation of reward pathways. (highly lipophilic and can easily permeate the blood–brain barrier). o Direct injection or rapid absorption of drug through a large surface area (e.g., through the lungs via smoking) is more highly reinforcing than slower absorption through the intestinal or nasal mucosa. o Rapidly eliminated drugs are more addictive than slowly eliminated drugs, since slow clearance of a drug maintains the drug concentration at the site of action for a longer duration, diminishing the severity of acute withdrawal.  Drug misuse: refers to the use of a substance for a purpose that is not consistent with legal or medical guidelines, most often with prescription medications. Drug abuse E.g.: Taking OTC medication for unapproved and medical use, duration, or dose for faster or misuse….!! better effect (not for euphoric feeling) Drug abuse: uses a drug to elicit certain feelings.  Drugs of Abuse Drug is abused - means used in ways NOT medically approved. Addictive Drugs activate the mesolimbic dopamine pathway. Some are prescribed for accepted medical purposes, e.g.: Opioids, Benzodiazepines, Stimulants & Barbiturates. Some are not prescribed but available from illicit sources, e.g.: Cocaine, Heroin, Cannabinoids, Phencyclidine (PCP) & LSD MIND ALTERING DRUGS: can contain CNS depressant, CNS stimulant, and/or hallucinogenic properties. E.g.: -THC (Tetrahydrocannabinol) (Marihuana, hash, hash oil...), so-called weed, dope, joints. - Inhalants (ether, glue...) Agents that can cause CNS CNS dependence depressant stimulant maybe  A “psychostimulant” can be defined as a psychotropic substance with the capacity to stimulate the central nervous system. It causes excitation and elevated mood, as well as increased alertness and arousal. Its global effect is to speed up signals in the brain. What are 1- Psychomotor stimulants: psychostimulants? Cause excitement and euphoria Decrease feeling of fatigue Increase motor activity 2- Hallucinogens/psychedelics Produce profound changes in the thought and mood  Caffeine: antagonist of adenosine in the CNS Nicotine: activates nicotinic receptor 1-Psychomotor stimulants Cocaine: binds and blocks monoamines reuptake (especially dopamine) Amphetamines: increases the amounts of monoamine neurotransmitters through inhibition of VMAT2+ reverses the reuptake transporters (Promote neurotransmitters release) 2-Hallucinogens/psychedelics Lysergic acid diethylamide (LSD) Phencyclidine (PCP) Tetrahydrocannabinol (THC) Nicotine Represents a major source of preventable medical morbidity and mortality. Activation of central nicotinic receptors also produces anxiolytic effects, increases arousal, and suppresses appetite While activation of peripheral nicotinic receptors increases blood pressure and stimulates smooth muscle contraction. Activation of presynaptic nicotinic receptors on dopaminergic axon terminals facilitates the release of dopamine. These strong and direct effects on the mesolimbic reward pathway (addiction) Has high addiction potential>>Due to strong and direct effects on the mesolimbic reward pathway, combined with the inhalational route of administration and short half-life of nicotine. Nicotine Nicotine (cont..) Withdrawal symptoms: Anxiety, irritability, & sleep disturbance Autonomic stimulation Intense craving (→ drug-seeking behavior) Treatment of nicotine withdrawal (aid in smoking cessation): Administration of nicotine via a sustained-release transdermal patch or via chewing gum (The dose is tapered slowly to allow the patient to avoid many of the unpleasant effects of nicotine withdrawal). Nicotine partial agonist- Varenicline Antidepressant – bupropion (inhibits dopamine reuptake within the synaptic cleft.)  Nicotine activates nicotinic acetylcholine receptors (nAChR), causing neuronal excitation. Nicotine withdrawal causes a rapid decrease in nAChR activity and a withdrawal syndrome associated with intense craving. Treatment with the partial nAChR agonist varenicline results in partial activation of nAChR and alleviation of withdrawal symptoms, but this activation is insufficient to cause dependence or a “high.” Importantly, binding of the high-affinity varenicline molecule to nAChRs prevents the lower - affinity nicotine molecule from binding to and activating the receptor. Thus, varenicline can prevent the subjective “high” associated with nicotine use. Amphetamine & Cocaine Have CNS stimulant effect Amphetamine clinical Use: nasal decongestants, antidepressants, diet pills, and for the treatment of attention-deficit hyperactivity disorder (ADHD). Cocaine clinical use: Local anesthetic effect due to blockade of voltage gated Na+ channels (used locally during eye, nose, ear, and throat surgery) Amphetamine & Cocaine Cocaine and many amphetamine-related drugs have substantial abuse liability; hence, other medications with lower risk profiles have taken their place for many of their uses. They are highly reinforcing because of the profound sense of well-being, energy, and optimism associated with stimulant intoxication. However, this state can rapidly progress to psychomotor agitation, severe paranoia, and even psychosis due to augmented dopamine neurotransmission. Mechanism of action By blocking or reversing the direction of the neurotransmitter transporters that mediate reuptake of the monoamines dopamine, norepinephrine, and serotonin into presynaptic terminals Cocaine and amphetamine potentiate dopaminergic, adrenergic, and serotonergic neurotransmission. Cocaine is most potent at blocking the dopamine transporter (DAT), although higher concentrations block the serotonin and norepinephrine transporters as well (SERT and NET, respectively).  Methylxanthines: Caffeine, theophylline, theobromine Found in coffee, tea, cola drinks, chocolate, & many OTC medications. CNS stimulant effect Alerting effect Improved performance Insomnia.  Methylxanthines(cont..) Mechanism of Action: Adenosine is a natural promoter of sleep & drowsiness The Methylxanthines block adenosine receptors, which leads to DA & NE release →stimulation Withdrawal mechanism: Up-regulation of the adenosine system after chronic caffeine administration appears to be a neurochemical mechanism underlying caffeine withdrawal syndrome. This mechanism results in increased functional sensitivity to adenosine during caffeine abstinence, and it likely plays an important role in the behavioral and physiological effects of caffeine withdrawal. Withdrawal symptoms: Headache, lethargy, irritability Can resolve without treatment Benzodiazepines and Barbiturates Benzodiazepines and barbiturates are two of the major classes of sedative and hypnotic agents. Benzodiazepines are widely prescribed for management of patients with anxiety and insomnia. For both of these drug classes, euphoric feelings are often reported in the early stage of intoxication and typically are the expressed reason for drug self-administration. Anxiolytic and tension-reducing properties may also contribute to the reinforcing actions and abuse potential of these drugs. Benzodiazepines and Barbiturates Benzodiazepines and barbiturates increase the efficiency of GABAergic pathways, and chronic use can induce down-regulation of these pathways by neuroadaptation. Benzodiazepines and barbiturates would have little or no potentiating effect on the binding of GABA to the receptor. Down-regulation of inhibitory GABAergic pathways would be expected to leave the brain “under-inhibited,” increasing the possibility of seizures and delirium upon abrupt withdrawal of the benzodiazepine or barbiturate Also, benzodiazepines increase the firing of dopamine neurons of the ventral tegmental area by positively modulating GABAA receptors in nearby interneurons, triggering drug-evoked synaptic plasticity in excitatory afferents onto dopamine neurons and underlying drug reinforcement.  Alcohol Early effect: oDepression of inhibitory control >>euphoria & CNS stimulation oImpairment of memory, insight, & discrimination Higher blood levels: oAffects motor coordination, emotional control, & judgement oOverdose: respiratory depression (esp. combination with other psychoactive drugs). Withdrawal: can be life-threatening Alcohol Ethanol affects GABAA receptors, NMDA glutamate receptors, and cannabinoid receptors.” the specific sites of action are unknown” GABAA channels :mediate the anxiolytic and sedative effects of alcohol, effects of alcohol on motor coordination, tolerance, dependence, and self-administration. NMDA receptors in the development of tolerance and dependence to alcohol, and NMDA receptors also have a role in the alcohol withdrawal syndrome. The rewarding effects of alcohol may also be mediated in part by indirect activation of cannabinoid receptors. Endogenous cannabinoids are “retrograde” neuromodulators that act as a feedback mechanism to enhance dopaminergic activity in the mesolimbic reward pathway Alcohol Endocannabinoids can modulate VTA dopaminergic neuronal activity by inhibiting GABAergic (inhibitory) inputs to the VTA. OPIATES Opiates are drugs that are derived from the Poppy Plant and are Central Nervous System (CNS) depressants. The most common opiates are: Opium Heroin Morphine Codeine Opioids Addicts describe an intense euphoric feeling (“rush”) that lasts for less than a minute upon the intravenous injection of heroin, and that seems to be the reason for abuse. There appear to be two pathways by which opioids interact with the brain reward system. One site of action lies in the ventral tegmental area, where GABAergic interneurons tonically inhibit the dopaminergic neurons responsible for activating the brain reward pathway in the nucleus accumbens. Administration of exogenous opioids decreases GABA release and disinhibition of the dopaminergic reward neurons. The increased release of dopamine in the nucleus accumbens signals a strong reward. Treatment of addiction Pharmacologic treatment The first step in the treatment of substance use disorder is detoxification. The goals of detoxification are to allow the body to adapt to the absence of drug or alcohol, and to prepare the patient for long-term rehabilitation. E.g. use of sustained release transdermal patch of nicotine or chewing gum (in smoking cessation) Another example is the administration and tapering of the long-acting opioid methadone for the treatment of opioid withdrawal. Treatment of addiction cont. Pharmacologic treatment Chronic treatment: to diminish craving & prevent relapse The first of these strategies is the chronic administration of an agent that causes aversive effects when the drug of abuse is used. For example, disulfiram inhibits aldehyde dehydrogenase, a critical enzyme in the alcohol metabolism pathway. As a result, causes acetaldehyde accumulation causing a number of aversive symptoms, including facial flushing, headache, nausea, vomiting, weakness, orthostatic hypotension, and respiratory difficulty. Thus, discourage further drinking of alcohol Treatment of addiction cont. Pharmacologic treatment A second strategy used to treat addiction is to block the effects of the drug of abuse. Naltrexone is an opioid antagonist that competitively blocks the binding of opioids to the opioid receptor. Thus, a patient who injects an opioid, such as heroin, while taking naltrexone will not experience the “high” that normally accompanies drug use. Treatment of addiction Psychosocial treatment Counseling techniques: cognitive behavioral therapy Self-help programs: e.g. Alcoholics Anonymous Integration of the two, i.e Pharmacologic and Psychosocial approaches has better outcome. Question???