TOXOLOGY OF DRUGS OF ABUSE

1. TOXOLOGY OF DRUGS OF ABUSE • The terminology used in discussing drug dependence, abuse, and addiction has long been confusing. • Confusion stems from the fact that repeated use of certain prescribed medications can produce neuroplastic changes resulting in two distinctly abnormal states. • The first is dependence, sometimes called "physical" dependence, produced when there is progressive pharmacological adaptation to the drug resulting in tolerance.

2. TOXOLOGY OF DRUGS OF ABUSE • In the tolerant state, repeating the same dose of drug produces a smaller effect. • If the drug is abruptly stopped: • a withdrawal syndrome ensues in which the adaptive responses are now unopposed by the drug. • Thus, withdrawal symptoms are opposite to the original drug effects.

3. TOXOLOGY OF DRUGS OF ABUSE • The appearance of withdrawal symptoms is the cardinal sign of "physical" dependence. • As thus defined, dependence can occur with the use of: • - opioids • - β blockers • - antidepressants • - benzodiazepines • - stimulants • even when these agents are used as prescribed for therapeutic purposes.

4. TOXOLOGY OF DRUGS OF ABUSE • The state of "physical" dependence is a normal response • easily treatable by tapering the drug dose • and is not in itself a sign of addiction. • The second abnormal state that can be produced by repeated drug use occurs in only a minority of those who initiate drug use. • It leads progressively to compulsive, out-of-control drug use.

5. TOXOLOGY OF DRUGS OF ABUSE • Unfortunately, in 1987 the American Psychiatric Association (APA) chose to use the word "dependence“ • when defining the state of uncontrolled drug use more commonly known as addiction • The word "addiction" was at that time considered pejorative and thus to be avoided.

6. TOXOLOGY OF DRUGS OF ABUSE • The result, over the last two decades, is that confusion has developed between dependence as a normal response and dependence as addiction. • The newest version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) due to be released in 2012 will correct this confusion.

7. TOXOLOGY OF DRUGS OF ABUSE • This distinction between dependence and addiction is important • because patients with pain sometimes are deprived of adequate opioid medication • simply because they have shown evidence of tolerance • or they exhibit withdrawal symptoms if the analgesic medication is stopped or reduced abruptly.

8. TOXOLOGY OF DRUGS OF ABUSE • Modern neuroscience has greatly increased our understanding of the phenomenology of addiction. • Using animal models as well as human brain imaging studies and clinical observations, addiction can be defined fundamentally as a form of maladaptive memory. • It begins with the administration of substances (e.g., cocaine) or behaviors (e.g., the thrill of gambling) that directly and intensely activate brain reward circuits. • Activation of these circuits motivates normal behavior and most humans simply enjoy the experience without being compelled to repeat it.

9. TOXOLOGY OF DRUGS OF ABUSE

10. ADDICTION • 1- Addiction involves progressive loss of frontal cortical • 2- behavioral control and increasing limbic temporal lobe • 3- negative feelings • The loss of behavioral control that underlies addiction has at least two components

11. ADDICTION • decreased frontal cortical regulation of attention and cognitive flexibility and increased limbic fear-negative feelings (Fig. 1). • The frontal lobes of brain are involved in decision • making and other executive functions such as motivation

12. TOXOLOGY OF DRUGS OF ABUSE • CNS depressants, including: • - alcohol • - other sedatives hyponotics such as Barbiturates • - nicotine and tobacco • - opioids; cannabinoids • - psychedelic drugs; • - inhalants (volatile solvents, nitrous oxide, and ethyl ether)

13. TOXOLOGY OF DRUGS OF ABUSE • CNS Depressants • Ethanol • - Experimentation with is almost universal, and a high proportion of users find the experience pleasant. • - Ethanol is classified as a depressant because it indeed produces sedation and sleep. • - However, the initial effects of alcohol, particularly at lower doses, often are perceived as stimulation owing to a suppression of inhibitory systems in the brain.

14. TOXOLOGY OF DRUGS OF ABUSE • CNS Depressants • Those who perceive only sedation from alcohol generally choose not to drink when evaluated in a test procedure. • Alcohol impairs recent memory • in high doses, produces the phenomenon of "blackouts": • the drinker has no memory of his or her behavior while intoxicated.

15. TOXOLOGY OF DRUGS OF ABUSE • CNS Depressants • The effects of alcohol on memory are unclear • but evidence suggests that reports from patients about their reasons for drinking and their behavior during a binge are not reliable. • Alcohol-dependent persons often say that they drink to relieve anxiety or depression. • When allowed to drink under observation, however, alcoholics typically become more dysphoric as drinking continues • thus not supporting the idea that alcoholics drink to relieve tension.

16. TOXOLOGY OF DRUGS OF ABUSE • CNS Depressants • Tolerance, Physical Dependence, and Withdrawal • Mild intoxication by alcohol is familiar to almost everyone, but the symptoms vary among individuals. • Some simply experience motor incoordination and sleepiness. • Others initially become stimulated and garrulous. • As the blood level increases, the sedating effects increase, with eventual coma and death occurring at high alcohol levels.

17. TOXOLOGY OF DRUGS OF ABUSE • CNS Depressants • Tolerance, Physical Dependence, and Withdrawal • The initial sensitivity (innate tolerance) to alcohol varies greatly among individuals and is related to family history of alcoholism • Experience with alcohol can produce greater tolerance (acquired tolerance) such that extremely high blood levels (300-400 mg/dL) can be found in alcoholics who do not appear grossly sedated. • In these cases, the lethal dose does not increase proportionately to the sedating dose • thus the margin of safety (therapeutic index) is decreased.

18. TOXOLOGY OF DRUGS OF ABUSE • CNS Depressants • Tolerance, Physical Dependence, and Withdrawal • Heavy consumers of alcohol not only acquire tolerance but also inevitably develop a state of physical dependence. • This often leads to drinking in the morning to restore blood alcohol levels diminished during the night. • Eventually, they may awaken during the night and take a drink to avoid the restlessness produced by falling alcohol levels.

19. TOXOLOGY OF DRUGS OF ABUSE • CNS Depressants • Tolerance, Physical Dependence, and Withdrawal • The alcohol-withdrawal syndrome generally depends on the size of the average daily dose • and usually is "treated" by resumption of alcohol ingestion. • Withdrawal symptoms are experienced frequently but usually are not severe or life-threatening until they occur in conjunction with other problems • such as infection, trauma, malnutrition, or electrolyte imbalance. • In the setting of such complications, the syndrome of delirium tremens becomes likely.

20. Signs and Symptoms of CNS Depressant Intoxication and Withdrawal • Intoxication (similar to alcohol) • Disinhibition (e.g., inappropriate sexual or aggressive behavior, impaired judgment, mood lability) • Somnolence, stupor, or coma • Impaired attention or memory • Slurred speech • Incoordination • Unsteady gait • Nystagmus

21. Signs and Symptoms of CNS Depressant Intoxication and Withdrawal • Alcohol or any CNS DEPRESSANTS Withdrawal Syndrome • Alcohol craving • Tremor, irritability • Nausea • Sleep disturbance • Tachycardia • Hypertension • Perceptual distortion

22. Continue …….Alcohol or any CNS DEPRESSANTS Withdrawal Syndrome • Seizures (6-48 hours after last drink) • Visual (and occasionally auditory or tactile) hallucinations (12-48 hours after last drink) • Delirium tremens (48-96 hours after last drink; rare in uncomplicated withdrawal) • Severe agitation • Confusion • Fever, profuse sweating • Diarrhea • Dilated pupils

23. Continue …….Alcohol or any CNS DEPRESSANTS Withdrawal Syndrome • Delirium tremens Abbreviation: DT • - The most severe expression of alcohol withdrawal syndrome marked by: • - visual, auditory, or tactile hallucinations • - extreme disorientation • - restlessness, and hyperactivity of the autonomic nervous system (evidenced by such findings as pupillary dilation • - fever, tachycardia, hypertension, and profuse sweating). • - About 15% of affected patients may die, usually as a result of comorbid illnesses. In most affected patients, recovery occurs within 3 to 5 days. SYN:alcoholicdelirium

25. Alcohol addiction produces cross-tolerance to other sedatives such as benzodiazepines. • This tolerance is operative in abstinent alcoholics, • but while the alcoholic is drinking, the sedating effects of alcohol add to those of other sedatives, making the combination more dangerous. • This is particularly true for benzodiazepines, which are relatively safe in overdose when given alone but potentially are lethal in combination with alcohol.

26. The chronic use of alcohol and other sedatives is associated with the development of depression • The risk of suicide among alcoholics is one of the highest of any diagnostic category. • Cognitive deficits have been reported in alcoholics tested while sober. • These deficits usually improve after weeks to months of abstinence. • More severe recent memory impairment is associated with specific brain damage caused by nutritional deficiencies common in alcoholics due to thiamine deficiency).

27. Alcohol is toxic to many organ systems. • As a result, the medical complications of alcohol abuse and dependence include liver disease • cardiovascular disease, • endocrine and GI effects, and malnutrition • Alcohol crosses the placental barrier, producing the fetal alcohol syndrome, a major cause of mental retardation to the fetus

28. Pharmacological Interventions • Detoxification • A patient who presents in a medical setting with an alcohol-withdrawal syndrome should be considered to have a potentially lethal condition. • Although most mild cases of alcohol withdrawal never come to medical attention • severe cases require general evaluation; attention to hydration and electrolytes; vitamins, • especially high-dose tthiamine; and a sedating medication that has cross-tolerance with alcohol.

29. Pharmacological Interventions • Detoxification • To block or diminish the symptoms of alcohol toxicity, a short-acting benzodiazepine such as oxazepam can be used at a dose of 15-30 mg every 6-8 hours according to the stage and severity of withdrawal • A patient who presents in a medical setting with an alcohol-withdrawal syndrome should be considered to have a potentially lethal condition. • some authorities recommend a long-acting benzodiazepine unless there is demonstrated liver impairment. • Anticonvulsants such as carbamazepine have been shown to be effective in alcohol withdrawal

30. Pharmacological Interventions • Pharmacotherapy • Detoxification is only the first step of treatment. • Complete abstinence is the objective of long-term treatment, and this is accomplished mainly by behavioral approaches. • Medications that aid in the prevention of relapse are under development. • Disulfiram (ANTABUSE; has been useful in some programs that focus behavioral efforts on ingestion of the medication

31. Pharmacological Interventions • Pharmacotherapy • Disulfiram blocks aldehyde dehydrogenase, the second step in ethanol metabolism, resulting in the accumulation of acetaldehyde • which produces an unpleasant flushing reaction when alcohol is ingested. • Knowledge of this unpleasant reaction helps the patient to resist taking a drink. • Although quite effective pharmacologically, disulfiram has not been found to be effective in controlled clinical trials because so many patients failed to ingest the medication.

32. Pharmacological Interventions • Naltrexone (REVIA) an opioid receptor antagonist that blocks the reinforcing properties of alcohol, is FDA- approved as an adjunct in the treatment of alcoholism. • Chronic administration of naltrexone resulted in a decreased rate of relapse to alcohol drinking in the majority of published double-blind clinical trials . • It works best in combination with behavioral treatment programs that encourage adherence to medication and abstinence from alcohol. • A depot preparation with a duration of 30 days (VIVITROL) was approved by the FDA in 2006; it greatly improves medication adherence, the major problem with the use of medications in alcoholism.

33. Pharmacological Interventions • A significant development in identifying a potential endophenotype of alcoholism has grown out of the clinical experience with naltrexone. • Animal studies have demonstrated that alcohol causes the release of endogenous opioids in brain reward systems • disinhibition or activation of dopamine neurons, a condition common to all drugs of abuse. • Blocking opioid receptors prevents this dopaminergic effect and results in less stimulation or reward from alcohol.

34. Pharmacological Interventions • A functional allele of the gene for the μ opioid receptor that naltrexone blocks has been associated with alcohol stimulation and with good response to naltrexone treatment among alcoholics. • Acamprosate (campral), another FDA-approved medication for alcoholism , is a competitive inhibitor of the N-methyl-D-aspartate (NMDA)–type glutamate receptor. • The drug appears to normalize the dysregulated neurotransmission associated with chronic ethanole intake and thereby to attenuate one of the mechanisms that lead to relapse

35. Pharmacological Interventions • Barbiturates and Older Sedatives • The use of barbiturates and older non-benzodiazepine sedating medications such as: • - chloral-hydrate • - meprobamatee • - glutethimide • has declined greatly in recent years owing to the increased safety and to the efficacy of the benzodiazepines and the newer agents ZOLPIDEM , ESZOPICLONE , AND ZALEPLON • Abuse problems with barbiturates resemble those seen with benzodiazepines in many ways

36. Pharmacological Interventions . Treatment of abuse and addiction should be handled similarly to interventions for the abuse of alcohol and benzodiazepines. • Because drugs in this category frequently are prescribed as hypnotics for patients complaining of insomnia, physicians should be aware of the problems that can develop when the hypnotic agent is withdrawn. • Insomnia rarely should be treated with medication as a primary disorder except when produced by short-term stressful situations.

37. Pharmacological Interventions . . Insomnia often is a symptom of an underlying chronic problem, such as: • depression or respiratory dysfunction, or may be due simply to a change in sleep requirements with age. • Prescription of sedative medications, however, can change the physiology of sleep with subsequent tolerance to these medication effects. • When the sedative is stopped, there is a rebound effect with worsened insomnia. This medication-induced insomnia requires detoxification by gradual dose .

38. Pharmacological Treatment of Withdrawal Syndromes from Substances of Abuse

39. Opiates andOpioids

40. Opioid receptor subtypes, their functions 1- μ (mu) • Supraspinal and spinal analgesia; • sedation; inhibition of respiration • slowed gastrointestinal transit • modulation of hormone and neurotransmitter release 2- δ (delta) • Supraspinal and spinal analgesia; • modulation of hormone • and neurotransmitter release

41. Opioid receptor subtypes, their functions 3- κ (kappa) • Supraspinal and spinal analgesia • Psychotomimetic effects • slowed gastrointestinal transit

42. Opioids • Opioid drugs are used primarily for the treatment of pain • Some of the CNS mechanisms that reduce the perception of pain also produce a state of well-being or euphoria. • Thus, opioid drugs also are taken outside medical channels for the purpose of obtaining the effects on mood. • This potential for abuse has generated much research on separating the mechanism of analgesia from that of euphoria • in the hope of eventually developing a potent analgesic that does not activate the brain reward systems.

43. Opioids • options for the treatment of pain, but none of these currently is available for clinical use. • Progress in pain control stems from a greater understanding of the mechanism of tolerance to μ opiate receptor–mediated analgesia, which involves NMDA receptors • Experimentally, by combining morphine with dextromethorphan • , an NMDA- receptor antagonist, tolerance is impaired and analgesia is enhanced without an increase in the dose of opioid.

44. Opioids • Tolerance, Dependence, and Withdrawal • Injection of a heroin solution produces a variety of sensations described as warmth, taste, or high and intense pleasure ("rush") often compared with sexual orgasm. • There are some differences among the opioids in their acute effects, with morphine producing more of a histamine-releasing effect • and meperidine producing more excitation or confusion.

45. Opioids • Tolerance, Dependence, and Withdrawal • Heroin has high lipid solubility, crosses the blood-brain barrier quickly • and is deacetylated to the active metabolites 6-monoacetyl morphine and morphine. • After the intense euphoria, which lasts from 45 seconds to several minutes, • there is a period of sedation and tranquility ("on the nod") lasting up to an hour.

46. Opioids • Tolerance, Dependence, and Withdrawal • The effects of heroin wear off in 3-5 hours, depending on the dose. • Experienced users may inject two to four times per day. • Thus, the heroin addict is constantly oscillating between being "high" and feeling the sickness of early withdrawal • This produces many problems in the homeostatic systems regulated at least in part by endogenous opioids.

47. For example, the hypothalamic-pituitary-gonadal axis and the hypothalamic-pituitary-adrenal axis are abnormal in heroin addicts. • Women on heroin have irregular menses, • and men have a variety of sexual performance problems. • Mood also is affected. Heroin addicts are relatively docile and compliant after taking heroin, • but during withdrawal, they become irritable and aggressive.

48. Based on patient reports, tolerance develops early to the euphoria-producing effects of opioids. • There also is tolerance to the respiratory depressant, analgesic, sedative, and emetic properties. • Heroin users tend to increase their daily dose, depending on their financial resources and the availability of the drug. • If a supply is available, the dose can be increased progressively 100 times.

49. OPIOIDS • Heroin users commonly acquire: • bacterial infections producing skin abscesses; • endocarditis; • pulmonary infections, especially tuberculosis; and viral infections producing hepatitis C and acquired immune deficiency syndrome (AIDS).

50. OPIOIDS The opioid-withdrawal syndrome is very unpleasant but not life-threatening. It begins within 6-12 hours after the last dose of a short-acting opioid and as long as 72-84 hours after a very long-acting opioid medication. Heroin addicts go through early stages of this syndrome frequently when heroin is scarce or expensive