Central Nervous System Stimulants Flashcards

Overview and Classification of Stimulants

• Stimulants are chemical agents that elevate physiological and mental activity, counteracting fatigue and maintaining wakefulness.

• Restricted Stimulants:

  • Subject to legal restrictions, controlled substance scheduling, and high abuse potential.

  • Primary Examples: Cocaine, Amphetamines, and Methamphetamine.

• Readily Available Stimulants:

  • Unrestricted or widely accessible legal substances.

  • Primary Examples: Caffeine and Nicotine.

History, Botanical Origins, and Early Regulation of Cocaine

• Botanical Origin:

  • Cocaine is derived from the coca bush (Erythroxylum coca), an evergreen shrub native to the Andean regions of South America (primarily modern-day Peru, Bolivia, and Colombia).

  • Coca leaves have been cultivated and utilized for over $800\,\text{years}$.

• Indigenous and Cultural Usage:

  • The coca leaf held religious, ceremonial, and economic value in Inca culture, where it was utilized as a medium of exchange/currency.

  • Indigenous Andean populations continue the traditional practice of chewing coca leaves mixed with lime to alleviate physical fatigue, hunger, and high-altitude hypoxia.

• European Popularization:

  • Cocaine was not widely known or consumed in Europe until the mid-to-late $19\text{th}\,\text{century}$.

  • Angelo Mariani developed "coca wine" by infusing coca leaf extract into wine. He subsequently introduced coca extract into various commercial products, including teas, lozenges, and elixirs.

• Chemical Isolation and Extraction:

  • Pure cocaine alkaloid was first isolated prior to 1860$.\n - Extraction Ratio: Crude chemical processing of 500\,\text{kg}$of raw coca leaves yields approximately$1\,\text{kg} of pure cocaine.\n- **Early Medical and Psychiatric Applications**:\n - The commercial availability of pure cocaine, combined with the invention of the hypodermic syringe, enabled precise pharmacological administration.\n - Local Anesthesia: Dr. W. S. Halsted, known as the "father of modern surgery," pioneered the medical use of cocaine as a local nerve-block anesthetic.\n - Psychiatric Experimentation: Sigmund Freud extensively researched cocaine, publishing endorsements for its therapeutic use in treating clinical depression and morphine addiction. Freud later abandoned drug therapies and publicly opposed pharmacological interventions after managing a colleague's severe, drug-induced paranoid psychosis.\n- **Patent Medicines and Patent Elixirs**:\n - Prior to statutory drug regulation, cocaine was freely incorporated into unregulated patent medicines, tonics, and over-the-counter remedies.\n  \n  \n  \n - Example: *Cocaine Toothache Drops*, produced by the Lloyd Manufacturing Company in Albany, N.Y. (registered March 1885$and sold for$15\,\text{cents} by druggists), was marketed as an instantaneous cure for dental pain.\n- **Early Legal Controls and Racialized Public Policy**:\n - In the late 19\text{th}\,\text{century}$and early$20\text{th}\,\text{century}, popular press outlets and medical journals published sensationalized, unsubstantiated claims linking cocaine use by Black men to violent crime.\n - Driven by racialized public fear, 46\,\text{states}$passed legislation regulating cocaine sale and distribution between$1887$and$1914$, creating the framework for national prohibition under the Harrison Act of$1914.\n\n# Chemical Forms, Administration Routes, and Pharmacokinetics of Cocaine\n\n- **Forms of Cocaine**:\n - **Coca Paste**: A crude, unrefined extract generated during the initial chemical processing of coca leaves. It is insoluble in water and is traditionally mixed with tobacco and smoked in South America.\n - **Cocaine Hydrochloride**: A stable, water-soluble salt produced by neutralizing cocaine base with hydrochloric acid. It cannot be smoked because high heat decomposes the molecule; it is administered via intranasal snorting or intravenous injection.\n - **Freebase**: Produced by extracting cocaine base from hydrochloride salt using volatile organic solvents such as ether. The resulting pure base can be heated to inhale cocaine vapors directly into the lungs.\n - **Crack Cocaine**: A smokable form of cocaine base produced by mixing cocaine hydrochloride with water and household baking soda (sodium bicarbonate), then heating and drying the mixture into solid chunks or "rocks."\n - *Chemical Identity*: Powder cocaine (hydrochloride salt) and crack cocaine (freebase) contain the identical active psychoactive alkaloid (cocaine base).\n- **Physical and Operational Differences Between Powder and Crack**:\n - **Powder Cocaine**: White crystalline substance; snorted, rubbed onto mucosal membranes (gums), or dissolved in aqueous solution for IV injection.\n - **Crack Cocaine**: Hardened off-white or brown rock; smoked in glass pipes.\n- **Routes of Administration and Pharmacokinetic Profiles**:\n - The route of administration determines the rate of absorption, onset, peak intensity, and duration of action:\n - *Oral Chewing/Sucking*: Slow mucosal absorption, gradual onset, prolonged mild effects.\n - *Intranasal Snorting*: Mucosal absorption through nasal capillaries, rapid onset (3\text{--}5\,\text{minutes}), intermediate intensity and duration.\n - *Intravenous Injection*: Direct systemic delivery, extremely rapid brain bioavailability, maximum peak intensity, short duration.\n - *Inhalation/Smoking*: Inhaled vapors cross alveolar membranes directly into pulmonary circulation, reaching the brain within seconds. Yields the fastest onset, highest peak intensity, and shortest duration of action.\n - *Binge Dynamics*: The rapid fall in brain concentration following smoking or IV injection prompts rapid repeated dosing (bingeing), significantly elevating addiction potential.\n- **Metabolism and Elimination Kinetics**:\n - Cocaine is rapidly metabolized by plasma and liver enzymes (cholinesterases).\n - Plasma Half-Life: Approximately 1\,\text{hour}$. Half of the active drug is cleared every$60\,\text{minutes}$($1/2$remaining after$1\,\text{hour}$,$1/4$after$2\,\text{hours}$,$1/8$after$3\,\text{hours}).\n - Duration of Action: Subjective psychoactive effects persist for roughly 2\,\text{hours}.\n - Metabolites: Major inactive metabolites (e.g., benzoylecgonine) have an extended half-life of roughly 8\,\text{hours}$and are detected by standard urine drug screens for up to$3\,\text{days}$($72\,\text{hours}) post-administration.\n\n# Contemporary Legal Controls, Federal Sentencing Disparities, and Demographics\n\n- **Evolution of Public Perception and Availability**:\n - Late 1960\text{s}$to early$1980\text{s}: Cocaine was expensive, imported in powdered form, and viewed as a drug for high-status, affluent individuals.\n - Mid-to-Late 1980\text{s}$: Crack cocaine entered urban markets in inexpensive, single-use doses ($5\,\text{dollars} per dose), dramatically broadening access across lower-income communities.\n- **Anti-Drug Abuse Legislation**:\n - **Anti-Drug Abuse Act of 1986**: Imposed strict mandatory minimum federal prison sentences that established a 100:1$quantity disparity between powder cocaine and crack cocaine. Distribution of$5\,\text{g}$of crack carried the same mandatory$5\text{-year}$penalty as distribution of$500\,\text{g} of powder cocaine.\n - **1988 Statutory Amendment**: Expanded mandatory 5\text{-year}$prison terms to apply to simple possession of$5\,\text{g} of crack cocaine, even for first-time offenders with no prior criminal record.\n- **U.S. Sentencing Commission Policy Analysis**:\n - Commission evaluations determined that federal sentencing disparities:\n - Impacted Black defendants disproportionately compared to White defendants.\n - Exaggerated the physiological and social harms of crack relative to powder cocaine.\n - Target low-level street distributors rather than high-level drug trafficking organizations.\n - Created arbitrary mandatory penalties that lacked statutory proportionality.\n- **Demographics of Federal Crack Cocaine Convictions (1992\text{--}2018)**:\n\n| Year | Black Offenders (N, %) | Hispanic Offenders (N, %) | White Offenders (N, %) | Other Offenders (N, %) |\n|---|---|---|---|---|\n| 1992 | 2,096 (91.4%) | 121 (5.3%) | 74 (3.2%) | 3 (0.1%) |\n| 2000 | 4,069 (84.7%) | 434 (9.0%) | 269 (5.6%) | 33 (0.7%) |\n| 2006 | 4,411 (81.8%) | 452 (8.4%) | 474 (8.8%) | 56 (1.0%) |\n| 2010 | 3,723 (78.7%) | 615 (13.0%) | 345 (7.3%) | 47 (1.1%) |\n| 2014 | 1,973 (83.4%) | 203 (8.6%) | 154 (6.5%) | 36 (1.5%) |\n| 2018 | 1,144 (80.0%) | 186 (13.0%) | 90 (6.3%) | 10 (0.7%) |\n\n- **Epidemiological Trends and Supply**:\n - National Survey on Drug Use and Health: 7\text{--}9\% of young adults report past-month cocaine use.\n - Monitoring the Future Study: High school senior annual prevalence dropped from a peak of 12\%$in the early$1980\text{s}$to under$3\% in recent years.\n - Supply Source: Overwhelming majority of illicit U.S. cocaine originates in Peru, Bolivia, and Colombia.\n\n# Medical Applications, Overdose Management, and Toxicity of Stimulants\n\n- **Biochemical Mechanism of Action**:\n - Primary Mechanism: Cocaine binds to presynaptic reuptake transporters, blocking the reuptake of dopamine, norepinephrine, and serotonin into presynaptic terminals. This increases synaptic neurotransmitter concentrations.\n - Secondary Interactions: Behavioral effects involve complex modulation across monoamines, acetylcholine, GABA, and glutamate systems.\n- **Approved Medical Applications**:\n - Medical local anesthetic since 1884 (initially eye surgery and dentistry).\n - Modern Synthetic Alternatives: Synthetic local anesthetics (e.g., lidocaine, procaine) lacking CNS activity have largely replaced cocaine.\n - Modern Indications: Cocaine remains FDA-approved as a topical local anesthetic and vasoconstrictor for specialized surgical procedures involving nasal, laryngeal, and esophageal mucous membranes.\n- **Overdose Dynamics and Reversal Protocols**:\n - **Naloxone (Narcan)**: Reverses opioid-induced respiratory depression for 30\text{--}90\,\text{minutes}. It has **no pharmacological efficacy** against cocaine, amphetamines, or other non-opioid stimulants.\n - Stimulant Overdose Protocol: Requires emergency medical support (cardiovascular stabilization, airway management, hyperthermia mitigation).\n- **Acute Toxicity Concerns**:\n - Low/Occasional Doses: Low health risk in healthy individuals.\n - High Doses: Profound central nervous system overstimulation, precipitating hyperpyrexia, tonic-clonic seizures, malignant hypertension, cardiac arrest, or fatal respiratory failure.\n - Adulterants: Illicit street cocaine is commonly cut with bulking agents or adulterants (e.g., levamisole, synthetic opioids like fentanyl) to maximize dealer profit margins or increase potency, often exceeding the intrinsic toxicity of cocaine itself.\n- **Chronic Toxicity and Psychiatric Effects**:\n - Continuous, repeated high-dose administration precipitates irritability, restlessness, severe paranoia, and paranoid psychosis.\n - Clinical Features: Agitation, auditory/visual hallucinations, persecutory delusions, violent behavior, and homicidal/suicidal ideation.\n - Clinical Recovery: Paranoid psychosis generally resolves spontaneously once the drug and its active metabolites are fully eliminated from the central nervous system.\n\n# Reproductive and Pregnancy Effects of Stimulants\n\n- **Placental Transfer Mechanism**:\n - Stimulants, alcohol, tobacco, and illicit drugs readily cross the placental barrier, achieving fetal exposure levels comparable to maternal circulation.\n- **Critical Analysis of the "Crack Baby" Phenomenon**:\n - Media reports in the 1980\text{s} exaggerated the long-term cognitive, behavioral, and developmental deficits of prenatal crack cocaine exposure.\n - Empirical Evidence: Controlled longitudinal clinical research demonstrates no consistent independent associations between prenatal cocaine exposure and long-term academic, behavioral, or cognitive measures when controlling for socioeconomic status, maternal health, and environmental factors.\n- **Physiological Pregnancy Complications**:\n - Cocaine-induced vasoconstriction of uterine and placental arteries increases the incidence of spontaneous abortion (miscarriage).\n - Comparative Stillbirth Risks (NICHD Studies):\n - Tobacco Use: 1.8$\times$ to $2.8$\times elevated risk of stillbirth (dose-dependent).\n - Marijuana Use: 2.3$\times$ elevated risk of stillbirth.

  • Combined Stimulants, Marijuana, or Prescription Pain Relievers: $2.2$\times elevated risk of stillbirth.\n - Passive Environmental Tobacco Smoke Exposure: 2.1$\times$ elevated risk of stillbirth.

History, Chemistry, and Pharmacology of Amphetamines and Methamphetamine

• Botanical Antecedents and History:

  • Chinese herbal medicine utilized a tea prepared from Ma Huang (genus Ephedra) for thousands of years to treat respiratory ailments.      

    

  • Active Ingredient: Ephedrine, a sympathomimetic drug that stimulates the sympathetic branch of the autonomic nervous system to produce bronchodilation.

• Amphetamine Synthesis and Historical Usage:

  • Amphetamine is a synthetic chemical structurally similar to ephedrine, patented in 1932$.\n - Initial Medical Indications: Asthma, narcolepsy, pediatric hyperactivity/ADHD, appetite suppression, and short-term alertness.\n - Military Use: Administered to military personnel during WWII to combat fatigue and increase operational endurance.\n - Post-War Escalation: Mid-1960\text{s}$"speed scene" involved IV administration of amphetamines alone or combined with heroin ("speedballs"). Misuse led to strict legal scheduling under federal dangerous drug laws in$1965$.

  • Shift to Methamphetamine: Regulatory restrictions on prescription amphetamines stimulated clandestine underground synthesis of methamphetamine ("crank").

• Chemical Structure and Pharmacological Mechanisms:

  • Basic Amphetamine Structure: Closely resembles catecholamine neurotransmitters (dopamine and norepinephrine).

  • Methamphetamine Structure: Addition of a methyl group increases lipophilicity, facilitating rapid clearance across the blood-brain barrier. Yields increased central nervous system activity and reduced peripheral sympathomimetic side effects compared to amphetamine.

  • Mechanism of Action: Amphetamines increase synaptic levels of monoamines (dopamine, norepinephrine, serotonin) by promoting their direct presynaptic release and inhibiting reuptake.

• Pharmacokinetics of Amphetamines:

  • Onset Times:

  • Oral Ingestion: Peak effects occur $1$\text{--}$1.5\,\text{hours}$ post-ingestion.

  • Intranasal Insufflation: Peak effects occur $5$\text{--}$20\,\text{minutes}$ post-insufflation.

  • Intravenous Injection or Inhalation/Smoking: Peak effects occur $5$\text{--}$10\,\text{minutes}$ post-administration.

  • Plasma Half-Life: $5$\text{--}$12\,\text{hours}$. Complete urinary elimination requires $2$\text{--}3\,\text{days}$.\n - Tachyphylaxis: Rapid acute tolerance can develop rapidly when high doses are administered repeatedly over short intervals.\n- **Clandestine Synthesis and Methamphetamine Prevalence**:\n - Clandestine Production: Synthetic processes utilize toxic, volatile precursor chemicals (e.g., drain cleaner, battery acid, paint thinner, lighter fluid), though residual solvents are removed during final purification.\n - Prevalence: In 2018$, approximately$1\,\text{million} individuals reported current methamphetamine use in the United States.\n - Addiction Incidence: Less than 15\% of individuals who try methamphetamine transition to formal addiction; the vast majority consume the drug without long-term functional impairment.\n\n# Therapeutic Uses, Performance Effects, and Adverse Reactions of Amphetamines\n\n- **Clinical Indications**:\n - **Depression**: Primary pharmaceutical therapy during the 1950\text{s}$and early$1960\text{s}. Currently used as an adjunctive antidepressant agent due to its rapid onset of subjective relief.\n - **Weight Control**: FDA-approved for short-term appetite suppression in obesity treatment, though long-term efficacy remains unproven.\n - **Narcolepsy**: Prescribed to control daytime somnolence and sudden muscular weakness (cataplexy).\n - **Attention-Deficit/Hyperactivity Disorder (ADHD)**:\n - Characterized by executive dysfunction, short attention span, impulsivity, and hyperactivity.\n - Therapeutic Mechanism: Stimulant medications reverse underlying catecholamine deficits within prefrontal cortical circuits, reducing activity levels and enhancing task concentration.\n - Pediatric Adverse Effects: Height and weight growth suppression, appetite suppression, insomnia, and abdominal pain.\n - Epidemiological Impact: Evidence shows that appropriate stimulant therapy for ADHD serves as a protective factor against future substance use disorders.\n- **Cognitive Enhancers ("Smart Pills") and Athletics**:\n - Low Doses: Reverses baseline fatigue and sleep-deprivation decrements on simple cognitive performance tasks.\n - High Doses: Disrupts performance on complex, multi-step cognitive tasks.\n  \n  \n  \n - *Performance Data Summary (Figure 6.3)*:\n - *Simple Task (Reaction Time)*: In simple reaction time tasks, methamphetamine doses of 12\,\text{mg}$,$25\,\text{mg}$, and$50\,\text{mg}$per$70\,\text{kg}$body weight progressively reduce reaction times from a baseline of$\sim 1420\,\text{msec}$down to$\sim 960\,\text{msec} at the highest dose.\n - *Complex Task (False Alarms)*: In complex discrimination tasks, methamphetamine fails to improve accuracy. Moderate-to-high doses (25\,\text{mg}$and$50\,\text{mg}$per$70\,\text{kg}$) significantly disrupt performance, elevating false alarm rates from a baseline of$\sim 0.21$up to$\sim 0.36.\n - Athletics: Moderate doses produce minor improvements in athletic performance under specific conditions.\n- **Amphetamine Toxicity and Psychosis**:\n - Acute Toxicity: High doses produce agitation, severe behavioral toxicity, and paranoia, compounded by sleep deprivation and malnutrition.\n - Chronic Toxicity & Psychosis: Sustained, chronic high-dose amphetamine administration causes paranoid psychosis characterized by persecutory delusions, auditory/visual hallucinations, and paranoia indistinguishable from acute paranoid schizophrenia.\n - Etiology & Recovery: Driven by excessive dopaminergic stimulation in the mesolimbic system. Full recovery following complete abstinence can require extended periods, sometimes taking up to 7\,\text{years} of abstinence.\n\n# Synthetic Cathinones and Illicit Manufacturing Practices\n\n- **Synthetic Cathinones ("Bath Salts")**:\n - Synthetic cathinones are chemical derivatives structurally analogous to natural cathinone (found in the *Catha edulis* plant) and amphetamine.\n - Over the past 15\,\text{years}$$, synthetic cathinones surged in popularity due to their mood-elevating and stimulant effects similar to cocaine and amphetamines.

• Adulteration Dynamics in Illicit Markets:

  • Clandestine manufacturers cut psychoactive drugs with cheap inactive powders (e.g., baking soda, lactose, starch) to expand product volume and maximize profit per batch.

  • Unannounced additives (e.g., synthetic opioids like fentanyl) are introduced into street stimulants to increase potency, dramatically elevating accidental overdose risks for consumers.