Stimulants

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  • ASAM Principles of Addiction Medicine Section 2, Chapter 5 Section 5, Chapter 5 Section 6, Chapter 6
  • Average dose ~2 mg per cup of coca tea. 1860- Albert Niemann isolated cocaine as active ingredient in coca leaves. Vin Mariani – 6-8 mg cocaine per ounce 1882- Fluid extract of coca (0.5 mg/ml) first appeared in US pharmacopeia. 1884- Geman ophthalmologist, Koller, discovered cocaine’s efficacy as a local anesthetic during surgery. 1884- Uber Coca- Sigmund Freud published first treatise on its psychological effects with N=1 (himself), suggested is as a treatment for morphine addiction. 1886- Coca Cola – 4.5 mg cocaine per 6 ounces? Versus 60 mg. 1886- First report of cocaine-related stroke and heart attack 1887- Amphetamine first synthesized in Germany by Lazar Edaleanu 1903 – Coca Cola removed cocaine from the formula (a)   1887- amphetamine by Edeleau (b)   1919- methamphetamine synthesized by Akira Ogata (c)    1930s- Benzedrine inhaler (d)   1933- CNS properties recognized- weight loss, narcolepsy, depression, and childhood hyperactivity (e)   1937- switch to prescription status (f)     WWII- both Allied and Axis powers used amphetamines for troops and workers, but stockpiles widely abused in Japan and Sweden leading to tight restrictions. (g)   1959- FDA banned Benzadrine inhalers 1970 – Controlled substances act placed cocaine, amphetamine and methamphetamine as Schedule II because of high abuse potential and accepted medical use only with severe restrictions. Number of prescription stimulants in US has declined from 65 in 1970 (marketed by 40 companies) to 8 marketed by 6 companies in 1995. Crack 300 mg cocaine per “rock”
  • Varies over time and geography Use peaked in 1980s at about 3% in previous 12 months, then declined by about 50% to steady levels of about 1.5% use in previous 12 months. In 1994, 2.7% lifetime prevalence of dependence In 2002, most frequently cited illicit drug in ED visits in 17/21 Major cities surveyed- Atlanta, Baltimore, Boston, Chicago, Denver, Detroit, Honolulu, Los Angeles, Miami, Minneapolis/St. Paul, Newark, New Orleans, New York, Philadelphia, Phoenix, St. Louis, San Diego, San Francisco, Seattle, Texas, and Washington, DC. ED rates were highest in Chicago, Philadelphia, Atlanta, Baltimore, and Miami in the first half of 2002. Rates for cocaine were much higher than those for methamphetamine in west coast areas. Worldwide, cocaine is most prevalent in the Western Hemisphere, some use in Western Europe, little or no use in Africa and Asia. Amphetamine misuse is most prevalent in Oceania, East and Southeast Asia and Western Europe, some use in North and Central America with little or no use elsewhere. Oral cocaine use is legal in Andean countries with lifetime use up to 90% in Bolivia and 30% in Peru. Refined cocaine suitable for insufflation, injection or smoking is illegal and use is similar to that in US. Risk factors for cocaine use: most likely cocaine user is an unemployed male high school dropout living on the West Coast who smokes cigarettes and drinks heavily. Cigarette smokers and heavy alcohol drinkers are 10 times more likely to use cocaine than nonsmokers or moderate alcohol drinkers. Current cocaine users are twice as likely to suffer anxiety or depression than non-users. (Kandel, Huang, 2001) Among past year users of cocaine, 27.8 percent (1.6 million) were classified with dependence on or abuse of cocaine. NHSDUH 2004
  • The number of past month methamphetamine users who met criteria for illicit drug dependence or abuse in the past 12 months increased from 164,000 (27.5 percent of past month methamphetamine users) in 2002 to 346,000 (59.3 percent) in 2004 The NSDUH Report
  • From “Epidemiologic Trends in Drug Abuse: Abuse of Stimulants and Other Drugs- January 2005. Two types of methamphetamine labs: Superlabs- 10 to 20+ pounds of methamphetamine per cooking cycle, relatively pure. Located primarily in Mexico, California, but increasingly in other states. Seizure of superlab in suburban Atlanta in 2005 (Copeland, 2005). Mom and Pop shops: Widespread throughout the country, produce about 1 pound per cycle, relatively impure.
  • NSDUH
  • NSDUH (2005). Only statistically different figures are in past month Meth use and illicit drug dep or abuse between 2002 and 2005- significant increase.
  • NSDUH (2005) Cocaine tied as second most common drug among those reporting drug dependence symptoms.
  • Synthetic stimulants are closely related to monoamine neurotransmitters derived from tyrosine.
  • (a) Serotonergic hallucinogens fall into two structural categories: (1)    Indolealkylamines- (DMT, LSD, harmaline) (2)    Phenylalkylamines- basic structure for monoamine neurotransmitters and for designer drugs. (i)       Phenylethylamines (mescaline, peyote)- Dopamine, norepinephrine (2 hydroxy groups on phenyl group) (ii)     Phenylisopropylamines (DMA, MDA, MDMA) (b) “designer drugs” - controlled substance analogues (1)    Clandestine chemists create chemicals that are structurally related to controlled substances thus avoiding laws controlling addicting substances. (2)    The effects of these substitutions are not always predictable. (3)    Amphetamine (phenylisopropylamine) is a central stimulant with few hallucinogenic properties. (4)    In general, the more methyl-groups that are substituted, the more hallucinogenic properties and the less stimulant properties the new compound possesses. (5)    Amphetamine, methamphetamine, cathinone, and methcathinone share primarily central stimulant properties. (6)    the addition of two oxygen atoms connected by a carbon atom to the benzene ring in MDA confers more hallucinogenic properties- though it retains many stimulant properties. The addition of a methylgroup to the amine group, would be expected to increase stimulant properties similar to the enhancement of stimulant properties of amphetamine to methamphetamine; however, this addition conferred a new property- empathogenicity The phenylpropanolamine stimulants have stereoisomeric forms. In general, the d-isomer has 3 – 5 times as much CNS activity as the l-isomer. D-methamphetamine is a potent CNS stimulant. L-methamphetamine is sold OTC as a decongestant (Vicks inhaler).
  • Caffeine is most common world-wide. Cocaine is most common illicit stimulant in U.S. Ephedra – Protected from FDA regulation by the 1994 Dietary Supplement Health and Education Act (Sen. Orin Hatch) until banned by the FDA in April 2004; N. America and East Asia. Ephedrine and pseudoephedrine are naturally occurring alkaloids with a phenethylamine chemical structure found in several Ephedraceae species. Ephedra is a preparation of the dried young branches of Ephedra species, typically containing at least 1% ephedrine. This may be converted into tea, a capsule, tincture or liquid extract. Ephedra products are widely used in East Asia and N. America. They appear in the pharmacopoeias of China, Japan, and Germany. Steve Bechler, Baltimore Orioles pitching prospect, died of sudden cardiac death in spring training in 2003. A bottle of nutritional supplement containing ephedra was found in his locker. Sean Riggins, a 16 year old from Illinois, also died of sudden cardiac death from taking Ephedra while training. Ephedra has no proven performance enhancing properties, but increases risk of sudden death. Khat- common in East Africa and southern Arabian peninsula. Fresh leaves of the Catha edulis plant contain at least 2 stimulants- cathinone (schedule I) and cathine (schedule IV). Both inhibit presynaptic dopamine and serotonin transporters with a potency similar to amphetamines. Khat leaves have been chewed or less commonly brewed into a tea for centuries (predating caffeine). Moderate use reduces fatigue and appetite. Khat looses much of its potency within 2 days of harvest as cathinone is converted to cathine. Extent of abuse or dependence is unclear. The Combat Methamphetamine Epidemic Act of 2005 has been incorporated into the Patriot Act signed by President Bush on March 9, 2006. The act bans over-the-counter sales of cold medicines that contain the ingredient pseudoephedrine, which is commonly used to make methamphetamine. The sale of cold medicine containing pseudoephedrine is limited to behind the counter. The amount of pseudoephedrine that an individual can purchase each month is limited and individuals are required to present photo identification to purchase products containing pseudoephedrine. In addition, stores are required to keep personal information about purchasers for at least two years. This law went into effect Sept 30, 2006. Clinical uses:
  • IN addition to FDA indications, amphetamine, methylphenidate, and pemoline have been used as short-acting antidepressants (two to three day) especially for those who are medically ill, elderly, HIV positive or those who cannot tolerate side effects of antidepressant medications. Amphetamines, mazindol, and methylphenidate have been used to potentiate opioid analgesia and to counteract opioid induced sedation and respiratory depression. Cocaine has been used for this purpose as part of Brompton’s cocktail (Opioid, alcohol, cocaine). Ephedrine and phenylephrine are used parenterally to counteract hypotension associated with spinal anesthesia. Recent longitudinal prospective studies have shown decreased risk of SUDs in children with ADHD treated with stimulants.
  • Chemical properties predict route of administration Powder cocaine sold on the street is usually about 60% pure cocaine. It is “cut” to enhance dealer profits either with inactive ingredients such as mannitol, dextrose that resemble cocaine HCL or with other stimulants that mimic the local anesthetic properties of cocaine such as lidocaine, procaine or benzocaine or provide some psychoactive effect such as PCP, ephedrine, amphetamine, caffeine). Street cocaine may also contain contaminants such as benzene, acetone, or sodium bicarbonate from preparation process.
  • Synthetic stimulants are closely related to monoamine neurotransmitters
  • Smoked stimulants (cocaine and methamphetamine) are rapidly absorbed through the lungs and reach the brain in 6 to 8 seconds. Peak brain concentrations occur within several minutes of intake. Intravenous use reaches the brain in 15 to 40 seconds and peak brain uptake in 4 to 7 minutes. For cocaine, clearance to half-peak brain levels requires 17 to 30 minutes. The rapid offset is often experienced as a “crash” by users of smoked or IV stimulants. Intranasal and oral stimulants have a slower absorption and onset of effect (30 to 45 minutes) Coca leaf chewing produces less than half the peak cocaine plasma concentrations of an equivalent dose of intranasal cocaine. However, even a single 2 mg oral dose of coca tea may produce detectable levels of benzoylecgonine in urine.
  • Slide 8: How Does Ecstasy Work: Serotonin Pathways in the Brain The nerve pathway that is affected by Ecstasy is called the serotonin pathway. Serotonin is a neurotransmitter that is synthesized, stored, and released by specific neurons in this pathway. It is involved in the regulation of several processes within the brain, including, mood, emotions, aggression, sleep, appetite, anxiety, memory and perceptions. Tell the students that you will show them how a chemical like serotonin can regulate these processes. First, describe how serotonin pathways innervate (connect to) different brain regions. Point to the cell bodies of the serotonin pathway that are located in the brainstem area “the Raphe nucleus” in pink). Show students how these neurons send long axons to higher centers in the brain including the neocortex (yellow) and the limbic system (e.g., the amygdala--red and hippocampus--blue). Point to a 2nd pathway for serotonin neurons that descends down the spinal cord; these neurons control muscle activity - tell the students that you will talk about this in more detail in a few minutes. Indicate that the function of serotonin depends on the region of the brain into which it is released (it also depends on the type of serotonin receptor present in that region--see discussion in Slide 9). For example, the serotonin neurons in the neocortex in the front of the brain (frontal cortex) regulate cognition, memory, and perceptions. The serotonin neurons in the hippocampus regulate memory and mood. The serotonin neurons in other limbic areas such as the amygdala also regulate mood.
  • Leonard Howell
  • Tolerance the need for increased amounts of the substance in order to achieve the desired effect; or markedly diminished effect with use of the same amount of substance. Withdrawal: symptoms; or the use of the substance to avoid or relieve withdrawal.
  • Due to direct effect of drug, hyperthermia, excessive muscle activity and trauma
  • Currently, the most effective treatments for meth addiction are behavioral therapies. One particular type, known as the Matrix Model for meth addiction, has demonstrated efficacy in helping people sustain abstinence. Initially developed in the 1980s for treating cocaine addiction, the Matrix Model is a 16-week program of group and individual therapy, and includes elements addressing relapse prevention, behavioral changes, family communication, healthy environments, and other topics relevant to maintaining abstinence. When applied to meth abusers, the Matrix Model has resulted in a sizable percentage of meth-free urine samples at program completion and 6-month follow-up. Promising Medications . NIDA-supported studies are developing medications for all aspects of meth abuse. For many people, depression is a complicating factor in recovery. In fact, imaging studies show that during withdrawal, the brains of meth addicts resemble those of depressed patients. Antidepressants may help during these beginning stages of treatment. Bupropion, marketed as Welbutrin¨, offers promise as an anti-addiction medication for several illicit drugs. Recent study findings reveal that bupropion reduced acute meth-induced subjective effects as well as cue-induced cravings. A recently completed Phase II clinical trial with bupropion has shown it to be significantly effective in reducing meth abuse in low/moderate users. A follow-up trial is planned. Another clinical trial has focused on topiramate, an anti-epileptic medication already on the market as TOPAMAX®. A NIDA-supported Phase I safety interaction study between topiramate and meth has been completed, with no safety concerns. A Phase II outpatient study with topiramate in meth-addicted individuals is underway, in collaboration with OrthoMcNeil Pharmaceuticals. Also, a preliminary study with gamma-vinyl GABA (GVG), a different anti-epileptic medication (approved in Europe but not in the U.S.), marketed as Vigabatrin¨ or Sabril¨, has shown that half of the treated patients remained drug-free for approximately 6 weeks, despite living in their normal home environments with ready access to drugs. To continue to identify novel anti-addiction medications for meth and other drugs of abuse, in 2006, NIDA requested applications for pilot clinical studies of new compounds whose utility has been documented in preclinical models--so as to establish an adequate foundation for more extensive clinical research. A new generation of monoclonal antibody-based medications, designed to provide a rapid reversal of meth effects in an emergency room setting and reduce or prevent long-term medical problems, has shown positive results in animal studies. Advances in the development of technology for large-
  • Dackis et al: Neuropsychopharmacology, Jan 2005. 62 treatment seeking cocaine dependent patients.
  • Stimulants

    1. 1. Cocaine, Stimulants, and MDMA
    2. 2. ASAM’s 2008 Review Course in Addiction Medicine ACCME required disclosure of relevant commercial relationships : Dr. Drexler has nothing to disclose.
    3. 3. Objectives <ul><li>The participant will be able to understand: </li></ul><ul><li>How chemical structure of stimulants influences pharmacology </li></ul><ul><li>Basic neurobiology of stimulant dependence </li></ul><ul><li>How to recognize and manage acute stimulant intoxication and withdrawal </li></ul>
    4. 4. Overview <ul><li>Background </li></ul><ul><li>Stimulant- structure and pharmacology </li></ul><ul><li>Neurobiology of stimulant addiction </li></ul><ul><li>Management of acute intoxication and withdrawal </li></ul><ul><li>Relapse Prevention </li></ul>
    5. 5. Background <ul><li>Stimulants have been used by humans for thousands of years to increase energy. </li></ul><ul><li>Plant-derived stimulants have been refined and new drugs developed to increase potency and duration. </li></ul><ul><li>As potency increases negative effects become apparent. </li></ul>
    6. 6. History of Stimulant Use <ul><li>3000 B.C. – Ma-Huang </li></ul><ul><li>0 A.D. – Coca leaf chewing and coca tea </li></ul><ul><li>1860 – Cocaine isolated </li></ul><ul><li>1887 – Amphetamine synthesized </li></ul><ul><li>1914 – Harrison Narcotic Act </li></ul><ul><ul><ul><li>MDMA </li></ul></ul></ul><ul><li>1919 – Methamphetamine </li></ul><ul><li>1930s – Benzedrine inhaler </li></ul><ul><li>1959 – Benzedrine banned </li></ul><ul><li>1980s – Crack </li></ul>
    7. 7. Epidemiology <ul><li>Cocaine </li></ul><ul><ul><li>2 nd most widely used illicit drug in U.S. </li></ul></ul><ul><ul><li>Most frequent illicit drug in ED visits </li></ul></ul><ul><ul><li>In 2004 (NHSDA and DAWN) </li></ul></ul><ul><ul><ul><li>11.2% lifetime use; 1.5% past year; 0.8% past month </li></ul></ul></ul><ul><ul><ul><li>2.7% lifetime prevalence of dependence </li></ul></ul></ul><ul><ul><ul><li>19% of drug-related ER visits </li></ul></ul></ul><ul><ul><ul><li>39% of drug-related deaths </li></ul></ul></ul>
    8. 8. Cocaine Abuse/Addiction Liability
    9. 9. Epidemiology <ul><li>Synthetic Stimulants </li></ul><ul><ul><li>Non-prescription use peaked at 1.3% in 1985 </li></ul></ul><ul><ul><li>In 2004 (NHSDA) </li></ul></ul><ul><ul><ul><li>6.6% lifetime non-prescription use </li></ul></ul></ul><ul><ul><ul><li>1.7% lifetime prevalence of dependence </li></ul></ul></ul><ul><ul><ul><li>Methamphetamine </li></ul></ul></ul><ul><ul><ul><ul><li>Most commonly used synthetic stimulant </li></ul></ul></ul></ul><ul><ul><ul><ul><li>In 2004, 59% of users had a use disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Up from 27.5 % in 2002. </li></ul></ul></ul></ul></ul>
    10. 10. Methamphetamine Lab Seizures
    11. 11. Trends in Illicit Drug Use
    12. 12. Trends in Methamphetamine Use
    13. 13. Trends in Drug Use Disorders
    14. 14. Club Drugs Epidemiology DAWN, July 2001
    15. 15. Overview <ul><li>Background </li></ul><ul><li>Stimulant- structure and pharmacology </li></ul><ul><li>Neurobiology of stimulant addiction </li></ul><ul><li>Management of acute intoxication and withdrawal </li></ul>
    16. 16. Structure and Pharmacology <ul><li>All stimulant drugs share a common basic phenylalkylamine structure. </li></ul><ul><ul><li>Additions to the phenyl group tend to increase hallucinogenic properties. </li></ul></ul><ul><ul><li>Additions of a methyl group to the nitrogen atom tend to increase the stimulant properties. </li></ul></ul>N OH OH
    17. 18. Stimulant Drugs <ul><li>Plant-derived </li></ul><ul><ul><li>Caffeine </li></ul></ul><ul><ul><li>Cocaine </li></ul></ul><ul><ul><li>Ephedra </li></ul></ul><ul><ul><li>Khat </li></ul></ul><ul><li>Synthetic </li></ul><ul><ul><li>Amphetamine </li></ul></ul><ul><ul><li>Methamphetamine </li></ul></ul><ul><ul><li>Methylphenidate </li></ul></ul><ul><ul><li>Mazindol </li></ul></ul><ul><ul><li>Phenylpropanolamine </li></ul></ul><ul><ul><li>Ephedrine </li></ul></ul><ul><ul><li>Pseudoephedrine </li></ul></ul><ul><ul><li>Phenylephrine </li></ul></ul><ul><ul><li>MDA / MDMA* </li></ul></ul>
    18. 19. Clinical Uses of Stimulants ADHD Narcolepsy II Rits, Vit R Ritalin Methylphenidate ADHD Wt control II Ice, crystal Meth, Speed Adipex Desoxyn Methamphetamine Wt control IV Sanorex Mazindol Local anesthetic II Coke, Crack Flake, Snow Cocaine ADHD, Wt control Narcolepsy II Amp, Dex Bennies Adderal Dexedrine Amphetamine Indications CSA Street name Trade name Drug
    19. 20. Cocaine Chemical Properties <ul><li>Cocaine HCl </li></ul><ul><ul><li>High melting point (195 °C) </li></ul></ul><ul><ul><li>Pyrolysis destroys most of the drug </li></ul></ul><ul><ul><li>Soluble in water (EtOH:H 2 O = 1:8) </li></ul></ul><ul><ul><li>Easily dissolved for injection or absorption across mucous membranes </li></ul></ul><ul><li>Crack or Freebase </li></ul><ul><ul><li>Low melting point (98 °C) </li></ul></ul><ul><ul><li>Easy to smoke </li></ul></ul><ul><ul><li>Insoluble in water (EtOH:H 2 O = 100:1) </li></ul></ul><ul><ul><li>Difficult to dissolve for injection </li></ul></ul>
    20. 21. Stimulant Chemical Properties <ul><li>Most variations on phenylethylamine </li></ul><ul><li>Phenylisopropylamine stimulants have stereoisomers </li></ul><ul><ul><li>D-isomers - 3 – 5 times more CNS activity </li></ul></ul><ul><ul><ul><li>D-methamphetamine – potent stimulant </li></ul></ul></ul><ul><ul><ul><li>L-methamphetamine- OTC decongestant </li></ul></ul></ul>N OH OH
    21. 22. MDMA Properties <ul><li>3,4- Methylenedioxymethamphetamine </li></ul><ul><li>Stimulant, hallucinogenic, empathogenic </li></ul><ul><li>Taken orally as a pill </li></ul><ul><ul><li>50 mg to 250 mg </li></ul></ul><ul><ul><li>“ Stacking” with other drugs (LSD, DM, ephedra) </li></ul></ul><ul><li>Non-linear kinetics </li></ul><ul><ul><li>Saturation of high-affinity enzymes </li></ul></ul><ul><ul><li>Large increase in response to small dose increase </li></ul></ul>
    22. 23. Clinical Uses of Stimulants <ul><li>Prescription cocaine </li></ul><ul><ul><li>Local anesthetic </li></ul></ul><ul><li>Prescription stimulants </li></ul><ul><ul><li>ADHD </li></ul></ul><ul><ul><li>Narcolepsy </li></ul></ul><ul><ul><li>Weight loss </li></ul></ul><ul><ul><li>Bronchdilation </li></ul></ul><ul><ul><li>Depression, pain* </li></ul></ul><ul><li>Parenteral phenylephrine </li></ul><ul><ul><li>Spinal anesthesia </li></ul></ul><ul><ul><li>Antihypotensive </li></ul></ul><ul><ul><li>Terminate SVT </li></ul></ul><ul><li>OTC stimulants </li></ul><ul><ul><li>Decongestion </li></ul></ul><ul><ul><li>Bronchodilation </li></ul></ul><ul><li>None for MDMA </li></ul>
    23. 24. Methamphetamine <ul><li>Brand name: Desoxyn </li></ul><ul><li>ADHD: 20 – 25 mg / day </li></ul><ul><li>Obesity: 15 mg / day </li></ul><ul><li>Binge: 125 mg – 1000 mg/dose </li></ul><ul><li>Toxic doses*: </li></ul><ul><ul><li>4- 6 mg/kg q2h (>3 gm/day) </li></ul></ul><ul><ul><li>37% loss of dopamine </li></ul></ul>*Segal et al: 2003; Neuropsychopharmacology
    24. 25. Pharmacokinetics <ul><li>Smoking and IV </li></ul><ul><ul><li>Reaches brain in 6 – 8 seconds </li></ul></ul><ul><ul><li>Onset of action and peak occur in minutes </li></ul></ul><ul><ul><li>Rapid decline in effect </li></ul></ul><ul><ul><li>Rapid onset of withdrawal symptoms and craving </li></ul></ul><ul><li>Intranasal and oral </li></ul><ul><ul><li>Slower absorption and peak effect (30 – 45 minutes) </li></ul></ul><ul><ul><li>Longer peak effect and gradual decline </li></ul></ul><ul><ul><li>Peak intensity less than smoking or IV </li></ul></ul><ul><ul><li>Alkalinization enhances absorption </li></ul></ul>
    25. 26. Pharmacokinetics Smoked Oral
    26. 27. Metabolism and Elimination <ul><li>Cocaine </li></ul><ul><ul><li>Hydrolysis of ester bonds </li></ul></ul><ul><ul><ul><li>Ecgonine methylester </li></ul></ul></ul><ul><ul><ul><li>Benzoylecgonine </li></ul></ul></ul><ul><ul><li>Cytochrome P450 </li></ul></ul><ul><ul><li>Eliminated in urine </li></ul></ul><ul><ul><ul><li>Benzoylecgonine detectable for ~3 days </li></ul></ul></ul><ul><ul><ul><li>Acidifying  s excretion </li></ul></ul></ul><ul><li>Amphetamines </li></ul><ul><ul><li>To metabolites </li></ul></ul><ul><ul><ul><li>Deamination- inactive </li></ul></ul></ul><ul><ul><ul><li>Oxidation- active </li></ul></ul></ul><ul><ul><ul><li>Parahydroxylation- active </li></ul></ul></ul><ul><ul><li>Eliminated in urine- </li></ul></ul><ul><ul><ul><li>Increased by lower pH </li></ul></ul></ul>
    27. 28. Drug Interactions <ul><li>Other stimulants-  sympathetic activity </li></ul><ul><ul><ul><li>Cardiac arrhythmia </li></ul></ul></ul><ul><ul><ul><li>Hypertension </li></ul></ul></ul><ul><ul><ul><li>Seizure </li></ul></ul></ul><ul><ul><ul><li>Death </li></ul></ul></ul><ul><li>MAOIs- inhibit metabolism of stimulants </li></ul><ul><li>Tricyclics- may block presynaptic uptake </li></ul><ul><li>Cocaine + EtOH = cocaethylene </li></ul><ul><ul><li> cardiac toxicity due to longer half-life </li></ul></ul>
    28. 29. Stimulant Effects <ul><li>Range of effects vary depending on </li></ul><ul><ul><li>Structure </li></ul></ul><ul><ul><li>Dose </li></ul></ul><ul><ul><li>Route of administration </li></ul></ul><ul><ul><li>Duration and intensity of use </li></ul></ul><ul><li>Typical initial doses for desired effects: </li></ul><ul><ul><li>5 to 20 mg of oral amphetamine, methylphenidate </li></ul></ul><ul><ul><li>100 to 200 mg of oral cocaine </li></ul></ul><ul><ul><li>15 to 20 mg of smoked cocaine </li></ul></ul><ul><ul><li>50 to 250 mg of MDMA </li></ul></ul>
    29. 30. Acute Stimulant Effects <ul><li>CNS </li></ul><ul><ul><li>Euphoria (low dose) </li></ul></ul><ul><ul><ul><li> energy, alertness </li></ul></ul></ul><ul><ul><ul><li> sociability </li></ul></ul></ul><ul><ul><ul><li> appetite </li></ul></ul></ul><ul><ul><li>Dysphoria (high dose) </li></ul></ul><ul><ul><ul><li>Anxiety, panic attacks </li></ul></ul></ul><ul><ul><ul><li>Irritability, agitation </li></ul></ul></ul><ul><ul><ul><li>Suspciousness </li></ul></ul></ul><ul><ul><ul><li>Psychosis </li></ul></ul></ul><ul><ul><ul><li>Movement disorders </li></ul></ul></ul><ul><ul><ul><li>Seizures </li></ul></ul></ul><ul><li>Cardiovascular </li></ul><ul><ul><li> HR, BP, vascular resistance, temperature </li></ul></ul><ul><ul><li>Acute myocardial infarction (AMI), ischemia, arrhythmia </li></ul></ul><ul><ul><li>Stroke </li></ul></ul><ul><li>Pulmonary </li></ul><ul><ul><li>Shortness of breath </li></ul></ul><ul><ul><li>Bronchospasm </li></ul></ul><ul><ul><li>Pulmonary edema </li></ul></ul>
    30. 32. Acute Stimulant Effects (cont) <ul><li>Musculoskeletal </li></ul><ul><ul><li>Rhabdomyolysis </li></ul></ul><ul><li>Renal </li></ul><ul><ul><li>Acute renal failure secondary to myoglobinuria </li></ul></ul><ul><li>Endocrine </li></ul><ul><ul><li>Ketoacidosis in diabetics </li></ul></ul><ul><ul><li>Activation of HPA </li></ul></ul><ul><li>Sexual function </li></ul><ul><ul><li>Increased arousal </li></ul></ul><ul><ul><li>Prolonged erections </li></ul></ul><ul><li>Head and neck </li></ul><ul><ul><li>Chronic rhinitis, nasal septal perforation </li></ul></ul><ul><ul><li>Xerostomia </li></ul></ul><ul><ul><li>Bruxism </li></ul></ul><ul><li>Fetal effects </li></ul><ul><ul><li>Most Category C </li></ul></ul>
    31. 33. Mechanisms of Action <ul><li>All stimulants enhance monoamine activity </li></ul><ul><ul><li>Inhibition of presynaptic monoamine transporters </li></ul></ul><ul><ul><ul><li>Dopamine – reward, psychosis </li></ul></ul></ul><ul><ul><ul><li>Norephinephrine – physiological arousal </li></ul></ul></ul><ul><ul><ul><li>Sertonin – mood elevation, psychosis </li></ul></ul></ul><ul><ul><li>OTC stimulants bind to and activate norepinephrine receptors </li></ul></ul>
    32. 34. Mesocorticolimbic Pathway Ventral tegmental area Nucleus accumbens Anterior cingulate Prefrontal cortex
    33. 40. Dopamine (DA) <ul><li>Stimulants acutely enhance dopamine activity </li></ul><ul><ul><li>Cocaine, methylphenidate- transporter blockers </li></ul></ul><ul><ul><li>Amphetamines- false substrates </li></ul></ul><ul><li>Stimulants chronically deplete dopamine </li></ul><ul><li>DA activity key in mediating addictive potential </li></ul><ul><ul><li>Fluctuations in mesolimbic DA parallel cocaine self-administration </li></ul></ul><ul><ul><li>Stimulant potency correlates with potency for binding at DA transporter </li></ul></ul>
    34. 41. Cocaine Microdialysis in Awake Squirrel Monkeys
    35. 42. Norepinephrine (NE) <ul><li>Stimulants acutely block NE transporter </li></ul><ul><ul><li> plasma NE and epinephine </li></ul></ul><ul><ul><li>NE release correlates with subjective and physiological stimulant effects </li></ul></ul><ul><li>Ephedrine related compounds stimulate alpha-adrenergic NE receptors </li></ul>
    36. 43. Serotonin (5-HT) <ul><li>All stimulants acutely enhance 5-HT activity by blocking serotonin transporter </li></ul><ul><ul><li>MDMA  s 5-HT by blocking transporters </li></ul></ul><ul><ul><li>Cocaine acutely  s firing in mesolimbic serotonergic neurons, but  s firing in dorsal raphe nucleus </li></ul></ul><ul><li>Serotonin appears to play a permissive, but not obligatory role in reward </li></ul>
    37. 44. Other Neurotransmitters <ul><li>Endogenous opioid activity </li></ul><ul><ul><li>No direct stimulant effect </li></ul></ul><ul><ul><li>Cocaine indirectly  s </li></ul></ul><ul><li>Mesolimbic glutamate </li></ul><ul><ul><li>Cocaine  s </li></ul></ul><ul><ul><li>Amphetamine  s </li></ul></ul><ul><li>Acetylcholine </li></ul><ul><ul><li>Cocaine  s </li></ul></ul><ul><li>Sodium channel blockade (cocaine only) </li></ul>
    38. 45. Overview <ul><li>Background </li></ul><ul><li>Stimulant- structure and pharmacology </li></ul><ul><li>Neurobiology of stimulant addiction </li></ul><ul><li>Management of acute intoxication and withdrawal </li></ul>
    39. 46. DSM-IV Substance Dependence <ul><li>>/= 3 of the following over a 12-month period: </li></ul><ul><ul><li>Tolerance </li></ul></ul><ul><ul><li>Characteristic withdrawal </li></ul></ul><ul><ul><li>Larger amounts than intended </li></ul></ul><ul><ul><li>Persistent efforts to cut down or control use </li></ul></ul><ul><ul><li>A great deal of time spent getting the substance, taking it, or recovering </li></ul></ul><ul><ul><li>Important activities given up or reduced </li></ul></ul><ul><ul><li>Continued use despite psychological or physical problem caused by or exacerbated by use </li></ul></ul>
    40. 47. Neurobiology of Dependence <ul><li>Sensitization of incentive salience </li></ul><ul><ul><li>Drug </li></ul></ul><ul><ul><li>Conditioned cues </li></ul></ul><ul><li>Impairment of inhibition of urges to use </li></ul><ul><li>Chronic effects of drug </li></ul><ul><ul><li>Signal transduction </li></ul></ul><ul><ul><li>Gene transcription </li></ul></ul>
    41. 48. Mesocorticolimbic Pathway Ventral tegmental area Nucleus accumbens Anterior cingulate Prefrontal cortex
    42. 49. Amygdala – Limbic Connections Nucleus accumbens Amygdala
    43. 50. Prefrontal - Limbic Inhibition Nucleus accumbens Orbitofrontal cortex
    44. 51. Left Right -34 mm -19 mm -9 mm +34 mm +19 mm +9 mm insula anterior cingulate amygdala subcallosal cortex nucleus accumbens area drug use - neutral Cocaine craving-related neural activations: Men
    45. 52. Overview <ul><li>Background </li></ul><ul><li>Stimulant- structure and pharmacology </li></ul><ul><li>Neurobiology of stimulant addiction </li></ul><ul><li>Management of acute intoxication and withdrawal </li></ul>
    46. 53. Initial Evaluation of Stimulant Intoxication <ul><li>Drug history </li></ul><ul><li>Physical examination </li></ul><ul><li>Laboratory examination </li></ul><ul><li>Manage basic life support functions </li></ul><ul><ul><li>T> 102 °F – Cooling blanket </li></ul></ul><ul><ul><li>T> 106 °F – Cool saline hydration, ice water lavage </li></ul></ul><ul><li>Remove drug from GI tract </li></ul><ul><ul><li>Activated charcoal or gastric lavage </li></ul></ul><ul><ul><li>If within one hour of ingestion </li></ul></ul>
    47. 54. Management of Severe Agitation <ul><ul><li>Benzodiazepines- first line </li></ul></ul><ul><ul><ul><li>Protect against CNS and cardiovascular toxicity </li></ul></ul></ul><ul><ul><ul><li>Lorazepam 2 – 4 mg PO or IV q 15 min until sedate </li></ul></ul></ul><ul><ul><ul><li>Repeat every 1 – 3 hours </li></ul></ul></ul><ul><ul><li>Antipsychotics- second line </li></ul></ul><ul><ul><ul><li>May prevent heat dissipation, lower seizure threshold, prolong QTc, increase dyskinesias </li></ul></ul></ul><ul><ul><ul><li>Haloperidol 2 to 10 mg PO, IM or IV q 6 – 24 hours </li></ul></ul></ul><ul><ul><li>Avoid physical restraints </li></ul></ul>
    48. 55. Cardiovascular Effects of Stimulants <ul><li>Myocardial ischemia is common. </li></ul><ul><ul><li>Vasoconstriction </li></ul></ul><ul><ul><li>Increased myocardial workload </li></ul></ul><ul><ul><li>Increased platelet aggregation </li></ul></ul><ul><ul><ul><li>Differential - AMI, aortic dissection, pneumothorax, endocarditis, or pneumonia </li></ul></ul></ul><ul><li>Arrhythmias </li></ul><ul><ul><li>Due to ischemia, catecholamines, or sodium channel blockade </li></ul></ul>
    49. 56. Management of Chest Pain <ul><li>Observe for 12 – 24 hours </li></ul><ul><li>ECG- </li></ul><ul><ul><li>Low sensitivity (36%) </li></ul></ul><ul><ul><li>Low predictive value (18%) </li></ul></ul><ul><li>Cardiac enzymes: </li></ul><ul><ul><li>Serial CPK- MB or troponin </li></ul></ul><ul><li>~ 15% of patients with stimulant-induced chest pain will have AMI. </li></ul>
    50. 57. Management of Arrhythmias <ul><li>Treat underlying conditions </li></ul><ul><ul><li>AMI </li></ul></ul><ul><ul><li>Electrolyte and acid-base abnormalities </li></ul></ul><ul><ul><li>Hypoxia </li></ul></ul><ul><li>Many will resolve without treatment </li></ul><ul><li>Avoid Class I antiarrhythic drugs </li></ul><ul><li>Follow ACLS guidelines </li></ul>
    51. 58. Management of Seizures <ul><li>Benzodiazepines </li></ul><ul><ul><li>Lorazepam 2 to 10 mg IV over 2 minutes </li></ul></ul><ul><ul><li>Diazepam 5 to 10 mg IV over 2 minutes </li></ul></ul><ul><ul><li>Repeat as needed </li></ul></ul><ul><ul><li>Monitor respirations, intubation available </li></ul></ul>
    52. 59. Management of Rhabdomyolysis <ul><li>Diagnosis requires high suspicion </li></ul><ul><ul><li>Muscle swelling and myalgia often absent </li></ul></ul><ul><ul><li>Plasma CK > 5 times normal </li></ul></ul><ul><ul><li>Urinalysis positive for heme without RBCs </li></ul></ul><ul><li>IV hydration – urine output 2 ml/kg/hour </li></ul><ul><li>Urine pH > 5.6 – sodium bicarbonate </li></ul>
    53. 60. Management of Hypertension <ul><li>Benzodiazepines first line </li></ul><ul><ul><li>Lower myocardial oxygen demand </li></ul></ul><ul><ul><li>Lower seizure risk* </li></ul></ul><ul><li>If severe hypertension persists </li></ul><ul><ul><li>Alpha-adrenergic blocker </li></ul></ul><ul><ul><ul><li>Phentolamine 2 to 20 mg IV over 10 min </li></ul></ul></ul><ul><ul><li>No beta-adrenergic blockers </li></ul></ul><ul><ul><ul><li>Unopposed alpha stimulation  s vasoconstriction </li></ul></ul></ul>
    54. 61. DSM-IV Cocaine Withdrawal <ul><ul><li>A. Cessation of (or reduction in) cocaine use that has been heavy and prolonged. </li></ul></ul><ul><ul><li>B. Dysphoric mood and two (or more) : </li></ul></ul><ul><ul><ul><li>Fatigue </li></ul></ul></ul><ul><ul><ul><li>Vivid, unpleasant dreams </li></ul></ul></ul><ul><ul><ul><li>Insomnia or hypersomnia </li></ul></ul></ul><ul><ul><ul><li>Increased appetite </li></ul></ul></ul><ul><ul><ul><li>Psychomotor retardation or agitation </li></ul></ul></ul>
    55. 62. Management of Withdrawal <ul><li>Most symptoms resolve within 2 weeks without treatment </li></ul><ul><li>Hospitalization for suicidality or psychosis </li></ul><ul><li>Pharmacologic treatment not necessary </li></ul>
    56. 63. Relapse Prevention <ul><li>Psychosocial treatment </li></ul><ul><ul><li>Cognitive behavioral therapy (CBT) </li></ul></ul><ul><ul><li>Contingency management (MIEDAR) </li></ul></ul><ul><ul><li>12-step facilitation- ? </li></ul></ul><ul><ul><li>Motivation Enhancement Therapy- ? </li></ul></ul><ul><ul><li>MATRIX model </li></ul></ul><ul><li>Treat comorbidities </li></ul><ul><li>Pharmacotherapy </li></ul><ul><ul><li>No FDA approved medications </li></ul></ul><ul><ul><li>Antidepressants </li></ul></ul><ul><ul><li>Dopaminergic agents </li></ul></ul><ul><ul><li>Disulfiram </li></ul></ul><ul><ul><li>Anticonvulsants (GVG, topiramate) </li></ul></ul>
    57. 65. Disulfiram Patients Have Less Cocaine Use Carroll et al, 2004
    58. 66. Modafinil Decreases Cocaine Use Dackis 2005
    59. 67. Summary <ul><li>Stimulants are common causes of drug-related morbidity and mortality. </li></ul><ul><li>Chemical structure of stimulants relates to the pharmacologic properties. </li></ul><ul><li>Neurobiology of stimulant addiction is related to blockade of monoamine transporters. </li></ul><ul><li>Management of acute intoxication and withdrawal is symptom driven. </li></ul><ul><li>Relapse prevention is based on comprehensive biopsychosocial treatment. </li></ul>

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