Pharmacology of stimulant substances
Stimulants People use these substances to stay awake, lose weight, or boost mood or athletic performance. Stimulants can be addictive and may induce an aftermath crash into fatigue, headaches, irritability, and depression. Background Stimulants (analeptics) produce a variety of different kinds of effects by enhancing the activity of the central and peripheral nervous systems. Common effects, which vary depending on the substance in question, may include enhanced alertness, awareness, wakefulness, heart rate and blood pressure for food and sleep. Many stimulants are also capable of improving mood and relieving anxiety, and some can even induce feelings of euphoria. Background Stimulants exert their effects through a number of different pharmacological mechanisms, the most prominent of which include facilitation of norepinephrine (noradrenaline) and/or dopamine activity (e.g., via monoamine transporter inhibition or reversal), and nicotinic acetylcholine receptor agonism. Therapeutic indications Stimulants are used both individually and clinically for therapeutic purposes in the treatment of a number of indications, including the following: To counteract lethargy and fatigue throughout the day while at work or while doing other activities. To reduce sleepiness and to keep the person awake when necessary, as well as to treat narcolepsy. To decrease appetite and promote weight loss, as well as to treat obesity. To improve concentration and focus while at work or school, especially for those with attentional disorders such as ADHD. Caffeine Caffeine is a mild stimulant compound that is found naturally in coffee, tea, and to a lesser degree, in cocoa or chocolate. It is included in many soft drinks, as well as a larger amount in energy drinks. Caffeine is the world's most widely used psychoactive drug and by far the most common stimulant. Caffeine is also included in some medications, usually for the purpose of enhancing the effect of the primary ingredient, or reducing one of its side effects (especially drowsiness). Nicotine Nicotine is the active chemical constituent in tobacco, which is available in many forms, including cigarettes, cigars, chewing tobacco, and smoking cessation aids such as nicotine patches and nicotine gum. Nicotine is used widely throughout the world for its stimulating effects. Amphetamines Amphetamines are a group of phenylethylamine stimulants such as amphetamine and methamphetamine. Amphetamine increases the levels of norepinephrine and dopamine in the brain via reuptake inhibition; however, the more important mechanism by which amphetamines cause stimulation is through the direct release of these catecholamines from storage vesicles in cells. Amphetamines are known to cause elevated mood and euphoria as well as rebound depression and anxiety. Amphetamines Amphetamine Dextroamphetamine Methamphetamine Methylphenidate Phenylpropanolamine Phentermine 4- Hydroxyamphetamine Phenmetrazine Mechanism of action of amphetamines At high doses amphetamine increases the concentration of dopamine in the synaptic cleft in 4 ways: 1- Induction the release of dopamine 2- Interaction with dopamine containing synaptic vesicles 3- Prevent degradation of dopamine by binding to MAO 4- Binding to dopamine reuptake transporter Mechanism of action Mechanism of action 3,4- Methylenedioxymethamphetamine (MDMA) Street names ECSTASY WHIZZ BOMB LOVE DRUG MDM LOVE HEART ESSENCE X TABLET CALIFORNIA E BUFFALO BEAN DOUBLE DIAMOND XTC M&M ADAM ROLL WHIZZ DOVE Pharmaceutical dosage forms Tablet ( Contain 80- 120 mg of MDMA) Capsule Powder Suppository MDMA Pharmacokinetic Absorption: Readily absorbed Onset - 30 to 60 minutes Peak effect - approximately 90 minutes with a peak plasma concentration of 2 to 3 hours following ingestion Duration - up to 8 hour or more Tolerance - tolerance to the desired effects can occur with frequent and repeated use of MDMA MDMA Pharmacokinetic DISTRIBUTION: A) VOLUME OF DISTRIBUTION Although it has not been fully established, it is thought to be large (>5L/kg) B) PEAK PLASMA LEVEL MDMA - Following a single oral dose of 50 mg was 0.106 mg/L MDMA Pharmacokinetic Metabolism MDMA is metabolized in the liver by Cytochrome P- 450. MDMA is metabolized by N- demethylation to form MDA. MDMA Pharmacokinetic • Excretion Urinary excretion of unchanged drug and its metabolites is complete usually with in 24 hours. As much as 75% of a dose of MDMA is excreted unchanged and 7% is excreted as MDA. Pharmacodynamic Its ability to stimulated both the sympathetic and central nervous system results from its structural similarity to the endogenous catecholamines (Epinephrine & Norepinephrine) and Dopamine. MDMA produce toxicity to serotonergic neurons in the brain. Single doses of MDMA have also been shown to produce long- lasting serotonin depletion ( 30% of neurons for up to 2 weeks). Axonal and cell body damage of serotonin nerve fiber in the cerebral cortex Clinical effects Desired effects: Self Confidence Feeling Happiness feeling Euphoria Libido Increasing Empathy Clinical effects (acute) Undesired Effects: Acute Effects : Mild intoxication Agitation, Hypertension, Tachycardia, Mydriasis, Trismus, Diaphoresis, Fatigue, Difficulty Concentrating, Headache, Insomnia, Nasea, Xerostomia Moderate intoxication: Anxiety, Confusion, Delirium, Panic attacks, Hallucinations, Antisocial Behaviors Clinical effects (acute) Severe intoxication: Hyperthermia Seizure Rhabdomyolysis Dysrhythmias Acute Renal Failure(ARF) Clinical effects (chronic) Paranoia Flash Back Memory impairment Data processing impairment Personality disorders Suicide Attempt Judgment impairment Depression Introduction Methamphetamine or methamfetamine, methylamphetamine, N-methylamphetamine, or desoxyephedrine, known as “crystal, meth or ice", is a psychostimulant of the phenethylamine and amphetamine class of psychoactive drugs. Chemical structure Methamphetamine is chiral, with two isomers, levorotatory and dextrorotatory. The levorotatory form, called levomethamphetamine, is an OTC drug used in inhalers for nasal decongestion. Levomethamphetamine does not possess any significant CNS activity or addictive properties. Street names Meth S Crystal Speed Crystal meth Snap Glass Tina Shabu Crank Shaboo Shabs Ice Shard Go fast Batu Street names Tik (South Africa) Piko (Czech Republic) Bato (Philippines) ( شيشهIran) Vint (Russia) Ya ice (Thailand) Yaa Baa (Thailand) P (New Zealand) Shabu (Japan, Hong Kong, Indonesia, Malaysia) Bay (Vietnam) Methamphetamine (Strawberry) Methamphetamine (Ice) Methamphetamine (Crystal) Methamphetamine forms Routes of administration Studies have shown that the subjective pleasure of drug use (the reinforcing component of addiction) is proportional to the rate at which the blood level of the drug increases. IV injection is the fastest route of drug administration, causing blood concentrations to rise the most quickly, followed by Suppository (anal or vaginal insertion), Insufflation (snorting), and Ingestion (swallowing). Smoking route of administration Use Meth on foil paper Pharmacokinetics Following oral administration, methamphetamine is readily absorbed with peak methamphetamine concentrations occurring in 3 to 6 hours. The amphetamine metabolite peaks at 10 to 24 hours. Methamphetamine is also well absorbed following inhalation and following intranasal administration. It is distributed to most parts of the body. Methamphetamine has a high lipophilicity and is distributed across the BBB and crosses the placenta. Pharmacokinetics Methamphetamine is metabolized in the liver with the main metabolites being amphetamine (active) and 4hydroxymethamphetamine. Other minor metabolites include: 4-hydroxyamphetamine Norephedrine 4-hydroxynorephedrine Pharmacokinetics It is excreted by the kidneys, with the rate of excretion into the urine heavily influenced by urinary pH. Between 30-54% of an oral dose is excreted in urine as unchanged methamphetamine and 10-23% as unchanged amphetamine. The half-life of methamphetamine is variable with a mean value of between 9 and 12 hours. Pharmacology Methamphetamine is a potent CNS stimulant that affects neurochemical mechanisms responsible for regulating heart rate, body temperature, blood pressure, appetite, attention, mood and emotional responses associated with alertness or alarming conditions. The acute physical effects of the drug closely resemble the physiological and psychological effects of an epinephrine-provoked fight-or-flight response, including increased heart rate and blood pressure, vasoconstriction, bronchodilation, and hyperglycemia. Methamphetamine is a potent neurotoxin, shown to cause dopaminergic degeneration. It has been proposed that dopamine plays a role in methamphetamine-induced neurotoxicity, because experiments that reduce dopamine production or block the release of dopamine decrease the toxic effects of methamphetamine administration. When dopamine breaks down, it produces ROS such as hydrogen peroxide. Physical Effects (Acute) Physical effects can include: Anorexia, hyperactivity, dilated pupils, flushing, restlessness, dry mouth, headache, tachycardia, bradycardia, tachypnea, hypertension, hypotension, hyperthermia, diaphoresis, diarrhea, constipation, blurred vision, dizziness, twitching, insomnia, numbness, palpitations, arrhythmias, tremors, dry and/or itchy skin, acne, convulsions, heart attack, stroke, and death. Long-term effects Depression, suicide Ideations, serious heart disease, Psychosis, Anxiety, Violent behaviors. Methamphetamine also has a very high addiction risk. Methamphetamine is neurotoxic and is associated with an increased risk of Parkinson's disease. Methamphetamine abuse can cause neurotoxicity which is believed to be responsible for causing persisting cognitive deficits, such as memory, impaired attention and executive function. Over 20 % of people addicted to methamphetamine develop a long-lasting psychosis resembling schizophrenia after stopping methamphetamine which persists for longer than 6 months and is often treatment resistant. Meth Mouth Meth mouth Methamphetamine users and addicts may lose their teeth abnormally quickly, a condition informally known as meth mouth. It is probably caused by a combination of drug- induced psychological and physiological changes resulting in xerostomia , extended periods of poor oral hygiene, frequent consumption of highcalorie, carbonated beverages and bruxism . Some reports have also speculated that the caustic nature of the drug is a contributing factor. Crank Bugs All Meth users suffer from what they call "Crank Bugs". Meth is manufactured with chemicals that are toxic to the human body, and once the drug is taken the chemicals remain. The body's natural reaction is to try and eliminate the toxins. Users itch and scratch which causes the open sores. Crank Bugs Methadone قرص و شربت متادون Methadone dosage forms Each tablet contains 5 mg or 10 mg methadone hydrochloride. Pharmacology: The Mode of Action Methadone acts by binding to the µ-opioid receptor for the effects of analgesia and respiratory depression. Methadone also binds to the glutamatergic NMDA (N-methyl-D- aspartate) receptor . Glutamate is the primary excitatory neurotransmitter in the CNS. Acting as an NMDA antagonist may be one mechanism by which methadone decreases craving for opioids and tolerance. Pharmacology: Metabolism Methadone has a slow metabolism and very high fat solubility, making it longer lasting than morphine-based drugs. Methadone has a typical elimination half-life of 15 to 60 hours. However, metabolism rates vary greatly between individuals. Methadone metabolism is largely a function of liver enzyme activity involving cytochrome P450 isoform. Pharmacology: Metabolism Methadone is stored extensively in the liver and secondarily in other body tissues. The major urinary excretion products are methadone itself, and metabolites EDDP and EMDP. Metabolism rates vary greatly between individuals. A single day’s maintenance dose in a tolerant dult can cause life-threatening respiratory depression in an adult who is not tolerant, and as little as 10 mg can be fatal in a child. Methadone abuse Most methadone bought from the black market is thought to be bought by already opioid-dependent persons attempting to circumvent the substance abuse treatment system and detoxify themselves with the methadone or simply by people wishing to use the drug recreationally, just as other opiates are used. Methadone abuse Although, in general, methadone is not a drug of choice for opioid addicts due to its long-acting nature and relatively little euphoria associated with its use, especially when compared to other drugs of abuse such as heroin and Oxycodone, it is used by addicts to relieve withdrawal symptoms when their opiate of choice cannot be obtained. Tramadol ترامادول Tramadol is used similarly to treat moderate to severe pain. Tramadol pharmaceutical dosage forms capsules (regular and extended release) tablets (regular, extended release, chewable, low-residue and/or uncoated tablets that can be taken by the sublingual and buccal routes) suppositories effervescent tablets and powders ampules of sterile solution for SC, IM, and IV injection preservative-free solutions for injection by the various spinal routes (epidural, intrathecal, caudal, and others) powders for compounding liquids both with and without alcohol for oral and sub-lingual administration, available in regular and bottles, dropper bottles, bottles with a pump similar to those used with liquid soap and phials with droppers built into the cap tablets and capsules containing (acetaminophen), aspirin and other agents. Tramadol mechanism ULTRAM® (tramadol hcl) contains tramadol, a centrally acting synthetic opioid analgesic. At least two complementary mechanisms appear applicable: ⚝ Binding of parent and M1 metabolite to μopioid receptors ⚝ Weak inhibition of reuptake of norepinephrine and serotonin. Tramadol pharmacokinetic Tramadol absorption The mean absolute bioavailability of a 100 mg oral dose is approximately 75%. Food effect: Oral administration of ULTRAM® (tramadol hcl) with food does not significantly affect its rate or extent of absorption, therefore, ULTRAM® (tramadol hcl) can be administered without regard to food. Tramadol metabolism Tramadol is extensively metabolized after oral administration by a number of pathways, including CYP enzymes, as well as by conjugation of parent and metabolites. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The major metabolic pathways appear to be N- and Odemethylation and glucuronidation or sulfation in the liver. Tramadol elimination Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. Tramadol abuse Tramadol is a widely prescribed drug. Abuse of tramadol as well as tramadol-related deaths have been increasingly reported in Iran. Tramadol-related deaths in 2008 were 32.5 times more than in 2005 in Iran. Tramadol-related fatalities are growing in Iran especially in substance abusers. Tramadol abuse Tramadol related deaths قواننی مربوط به داروهای حتت کنرتل آئني انمه توليد فرآورده هاي دارويي حتت كنرتل (خمدر و روانگردان) داروی تحت کنترل به فراورده دارويی اطالق می شود که از سوی وزارت بهداشت ،درمان و آموزش پزشکی در زمره داروهايی طبقه بندی شده است که توليد ،توزيع ،عرضه و تجارت (خريد ،فروش ،واردات و صادرات) آن ها فقط در چارچوب مقررات معين و تحت نظارت ويژه امکان پذير است. اين تعريف کليه داروهايی را که با نام شيميايی يا نام غير اختصاصی بين المللی در فهرست جاری هيئت بين المللی نظارت بر مواد مخدر مربوط به داروهای مخدر (کنوانسيون 1961و اصالحی )1972و داروهای روانگردان در بر می گيرد. توضيح فهرست مواد و داروهاي حتتكنرتل اين فهرستها شامل فهرستهايسهگانهموادتحتمراقبتهيأتبينالملليكنترلموادمخدر )(INCBاست كه طبق معاهدات بينالمللي مورد پذيرش جمهوري اسالمي ايران (كنوانسيونهاي 1971 ،1961و 1988سازمان ملل متحد) تحت مراقبت بيـنالمللي ميباشند. انجام كليه امور مربوط به واردات و صادرات اين اقالم از جمله مراحل ثبت سفارش ،ورود و ترخيص از گمركات كشور مستلزم كسب موافقت قبلي از وزارت بهداشت ،درمان و آموزش پزشكي (ادارهكل نظارت بر امور دارو و مواد مخدر) است. اينمواددرسهگروهمجزاطبقهبنديميشوندكهعبارتنــداز: -1 موادمخدر(موضوع كنوانسيون )1961در فهرستزرد)(Yellow List -2 موادروانگردان(موضوع كنوانسيون )1971درفهرستسبز)(Green List -3 موادشيمياييوپيشسازهايمخدروروانگردان(موضوع كنوانسيون )1988درفهرستقرمز )(Red List صدور اقالم تحتكنترل به ديگر كشورها منوط به اخذ مجوز صادرات از وزارت بهداشت ،درمان و آموزش پزشكي( ادارهكل نظارت بر امور دارو و مواد مخدر) است كه بر اساس كنوانسيونهاي ،1961 1971و 1988سازمان ملل متحد فقط با ارائه مجوز از مرجع ملي نظارتي مربوط به كنوانسيونهاي فوقالذكر در كشور مقصد صادر ميشود. صدور اقالم تحتكنترل بدون اخذ مجوزهاي الزم موجب توقيف محموله در كشور مقصد خواهد شد. اقالم تحتكنترل كه بدون كسب مجوز قبلي وارد كشور شوند ،توقيف خواهند شد. هر گونه جابجايي و تجارت (واردات و صادرات) موادي مانند هروئين ،ترياك ،كوكائين ،حشيش و موارد مشابه كه مورد مصرف مجاز پزشكي ندارند ممنوع است. ورود ترامادول به فهرست داروهای حتت کنرتل شواهد موجود حاكي از افزايش وقوع عوارض و گسترش سوءمصرف داروي ترامادول در سطح جامعه بهويژه بين برخي نوجوانان و جوانان ميباشد به طوري كه اثر بر گيرندههاي اپيوئيدي و قابليت سوءمصرف ،بخشي از بازار قابلمالحظه آن را به مصارف غيردرماني اختصاص داده است. در سوءمصرف اين دارو ،پيامدهاي نامطلوبي چون دپرسيون تنفسي و ايجاد وابستگي فيزيكي قابل انتظار و حتي در مصارف درماني نيز وقوع عوارض جدي نظير تشنج محتمل است. ورود ترامادول به فهرست داروهای حتت کنرتل داروي ترامادول طبق رأي جلسه مورخه 1386/2/26كميسيون حمرتم تشخيص صالحيت ساخت و ورود در زمره داروهاي حتتكنرتل حمسوب و مقررات مربوط به فرآوردههاي دارويي خمدر و روانگردان در مورد توليد ،واردات، صادرات ،توزيع و عرضه كليه اشكال دارويي آن اعمال ميشود. مقررات مربوط به توزيع ترامادول توزيـع كليه اشكال دارويي ترامادول از اين تاريخ فقط از طريق عاملينمجـازتوزيعداروهاي مخدرمجــاز خواهد بود. توزيع و مصرف شكل دارويي آمپول ترامادول طبق بخشنامه ادارهكل نظارت بر امور دارو و مواد مخدر همچنان محدود به بيمارستانها و مراكز درماني مجهز به بخش اورژانس است. اين دارو تنها با نسخه معتبر پزشك (هرنسخهفقطيكبار) قابل عرضه است ،در صورت ادامه نياز بيمار، دريافت دوباره آن مستلزم تجويز مجدد پزشك و صدور نسخه جديد خواهد بود. Social problems correlated to drug abuse 1. Accidental Poisonings 2. Drug Abuse Cases 3. Drug Facilitated Crime Suicidal Poisonings Homicidal Poisonings Incapacitate victims of kidnapping, robbery, or sexual assaults Common Street Names of Cocaine Toot Snow Blow Flake White lady Snowbirds Paradise Cocaine potentiates the synaptic actions of dopamine, norepinephrine, and serotonin by blocking their reuptake. Cocaine Pharmacokinetics Absorption snorted thru mucous membranes (cocaine HCL) injected (cocaine HCL) smoked (crack cocaine) can be taken orally (coca leaf chewing, cocaine HCL) Oral Intranasal Intravenous (Cocaine HCL) (Cocaine HCL) Inhalation (crack) (Cocaine HCL) Onset 10min-30min 2min -3min 30-45sec 8-10sec High 15-30min 30-45min* 10-20min 5-10min Average dose 100-200mg 5 X 30mg 25-50mg 250-1000 Pharmacokinetics Absorbed from all application sites. Penetrates brain rapidly (brain concentrations exceed blood plasma), then it is rapidly redistributed to other tissues. Rapidly and almost completely metabolized by enzymes located both in plasma and in the liver. Urine is the commonest rout of excretion. Psychological Effects Low Doses Immediate euphoria* Giddiness Enhanced selfconsciousness Forceful boastfulness High Doses Psychological effects intensified, but followed by: Depression Dysphoria Anxiety Somnolence Drug craving Side Effects and Toxicity Hypertensive crises Heart attacks/ failure Hemorrhage Edema Infection Anxiety, hyper vigilance, paranoia, persecutory fears, toxic paranoid psychosis. Sleep deprivation Sudden death Khat Khat is a natural stimulant from Catha Edulis, a small tree or large shrub. Fresh leaves and shoot tips of this plant have been chewed or brewed as a tea to produce stimulating properties Khat alkaloids Khat contains cathinone and cathine, which resemble amphetamine. Khat consumption induces mild euphoria and excitement, reduces appetite, increases heart rate and blood pressure. Cathinone Main psychoactive alkaloid in khat Produces amphetamine-like action - a naturally occurring amphetamine Cathinone effects are not distinguishable from amphetamines. Functions by releasing catecholamines (dopamine) from presynaptic storage sites in CNS. Khat Pharmacology Main Constituents: Cathinone and Cathine. Varies from 77.7 to 342.8 mg/100g Mechanism of Action Central Increases the levels of Dopaminergic and Noradrenergic transmission in the brain Serotonin levels are increased in response to Cathinone administration Peripheral Indirect sympathomimetic actions Methods of Khat Administration Methods of administration - Fresh leaves and tops are chewed less frequently dried and consumed as tea. Mephedrone Street names Mephedrone is the most popular derivative of the cathinone . ‘Legal high’,‘plant food’, ‘meow meow’, ‘miaow’, ‘drone’, ‘meph’, ‘bubbles’, ‘spice E’, ‘charge’, ‘M-Cat’, ‘rush’, ‘Ronzio’, ‘Fiskrens’ and ‘MMC hammer Definition Mephedrone is a psychoactive research chemical that elicits stimulant and effects similar to amphetamines, cocaine, metamphetamine, and MDMA. Amphetamines and cathinones pharmacology Both amphetamines and cathinones bind to noradrenalin, dopamine and serotonin transporters, each of them differing from each other by its relative binding potency. Mephedrone vs. amphetamines Cathinones’ (mephedrone) potencies are mostly lower than those of amphetamines as beta-keto amphetamines show a reduced ability to cross the blood–brain barrier due to the presence of the beta group. Mephedrone commercial appearance Mephedrone occurs as a white, or slightly yellowish, powder or fine crystals. Less frequently, it is marketed as capsules or tablets of various colours, shape and thickness, with or without a logo. Although mainly sold in powder and crystal forms, mephedrone may be commercially available in tablets and included within vegetable-based capsules. Mephedrone Mephedrone Routes of administration The most common routes for recreational use include insufflation (snorting) and oral ingestion. Because of its solubility in water, mephedrone is reportedly used by rectal administration (dissolved in an enema or within gelatine capsules) as well or injected intravenously. Insufflation is likely to be the most common route. Peak time to get high When snorted, mephedrone elicits its effects within a few minutes, with the peak being reached in <30 min followed by a rapid comedown. Pan Parag Pan parag is a combination of Betel Nuts, Cardamom, Lime, Catechu and Natural perfumes. Betel chewing has been claimed to produce a sense of well-being, euphoria, heightened alertness, sweating, salivation, a hot sensation in the body and increased capacity to work. Betel chewing also leads to habituation, addiction and withdrawal. Pan Parag chewing gum Betel nut The Areca nut is the seed of the Areca palm (Areca catechu), which grows in much of the tropical Pacific, Asia, and parts of east Africa. It is commonly referred to as "betel nut" as it is often chewed wrapped in betel leaves. Areca Nut An areca nut bunch hanging from the palm. Areca nuts wrapped in Betel leaves, appearing as they are commonly prepared and sold in Taiwan Areca nut vendor with red mouth from areca consumption preparing betel leaves and lime
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