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Drugs of Abuse II Dr. Simran Kaur [email protected] Commonly abused substances include: i. Opiates and narcotics - - powerful painkillers with sedative and euphoric qualities Include: Heroin, Opium, Codeine, Pethidine (meperidine), hydromorphone, oxycontin ii. Central Nervous system (CNS) stimulants Include cocaine, amphetamines, dextroamphetamine, methamphetamine and methylphenidate (Ritalin) - Most commonly used stimulants are caffeine and nicotine. - These drugs have a stimulating effect and produce tolerance - iii. CNS depressants - Include barbiturates (amobarbital, secobarbital, pentobarbital), benzodiazepines (diazepam, lorazepam, alprazolam), chloral hydrate and paraldehyde. - Most commonly used is Alcohol - Produce a soothing sedative effect and anxiety-reducing effect and can lead to dependence iv. Hallucinogens - - Include LSD (Lysergic acid diethylamide, derived from ergot, a grain fungus), mescaline (from cacti), psilocybin (‘magic mushrooms') and phencyclidine (PCP or Angel Dust) Have hallucinogenic properties and produce psychological dependence v. Tetrahydrocannabinol (THC) - Active ingredient in cannabis, marijuana and hashish. - Used for their relaxing properties but THCderived drugs can also lead to paranoia and anxiety. TREATMENT OF DRUG DEPENDENCE Pharmacological Approaches 1. Substitution/Replacement treatment - to alleviate withdrawal symptoms/ long-term maintenance and detoxification or withdrawal -- Involves administration under medical supervision of a prescribed medicine with similar action to the drug of dependence 2. Blocking response Use of antagonists 3. Aversive therapy Induce unpleasant response to drug of abuse concerned 4. Modification of craving Use of drugs to relieve withdrawal symptoms Non-pharmacological approach 1. Cognitive- Behavioural Therapy (CBT) short-term focused approach to helping drugdependent individuals become abstinent from drugs CBT CBT attempts to help patients recognize, avoid and cope RECOGNIZE the situations in which they are most likely to use drugs AVOID these situations in which they are most appropriate and COPE more effectively with a range of problems and problematic behaviours associated with substance abuse 2. Cognitive Therapy a system of psychotherapy that attempts to reduce excessive emotional reactions and selfdefeating behaviour by modifying the faulty or erroneous thinking and maladaptive beliefs that underlie these reactions. 3. Community Reinforcement Approach a broad-spectrum behavioural treatment approach for substance abuse problems, that utilizes social, recreational, familial and vocational reinforcers to aid clients in the recovery process. 4. Motivational Enhancement Therapy based on principles of motivational psychology and employs motivational strategies to mobilize the client’s own change resources. I. NARCOTIC ANALGESICS Drugs that reduce pain without producing unconsciousness (cf Anaesthetics) OPIATES (also opioids) : A class of very potent painkillers SOURCE From Opium – an extract from the poppy plant Papaver somniferum The major active ingredients include: Morphine Codeine Thebaine Narcocotine TYPES OF NARCOTIC ANALGESICS 1. Natural narcotics Morphine Codeine Thebaine 2. Semi-synthetic narcotics Heroin Hydromorphone Oxycodone Etorphine 3. Synthetic narcotics Buprenorphine Fentanyl Methadone Pethidine (Meperidine) Pentazocine (Talwin) Propoxyphene (Dextropropoxyphene) Structures 4. Endogenous opioids Peptides which are produced in the brain and have opiate-like pharmacological effects Derived from precursor peptides by protease cleavage b-endorphin (Pro-opiomelanocortin, POMC) met-enkephalin and leu-enkephalin (Proenkephalin) dynorphin (Prodynorphin) ADVERSE EFFECTS OF OPIATES Dose-related and depend on rate of absorption a. Low or moderate doses of opiates: Effects on CNS have an analgesic effect depress respiration cause constriction of pupils impair ability to concentrate suppress cough reflex reduce appetite Effects on GI tract reduce gut motility (leads to constipation – has been used to relieve diarrhoea and dysentery) b. Higher doses or when drug is administered via intravenous/inhalation: lead to state of euphoria induce nausea and vomiting (due to effect on chemical trigger zone – the area postrema) c. At the highest dose/ overdose: lead to unconsciousness fall in body temperature and blood pressure respiratory pressure ultimately death Opioid receptor binding studies Binding of radioactive 3H naloxone to rat brain show the classic saturation binding curve. As the concentration of the opiate ligand increases, binding to receptors increases linearly until receptors are fully occupied. Opiate Bioassay Han Kosterlitz et al. (1970, 1975) Opioid Receptor subtype Endogenous ligand Functions m (mu) Endomorphins endorphins Analgesia (+++) Reinforcement (nucleus accumbens) Cardiovascular and respiratory depression Cough suppressant Emesis Sensorimotor integration d (delta) Enkephalin endorphins Analgesia (+) Reinforcement Cognitive function Modulating olfaction Motor integration k (kappa) Dynorphins Analgesia (++) Dysphoria Feeding Gut motility Neuroendocrine function Temperature control Water balance OPIOID AGONISTS AND ANTAGONISTS 1. Pure agonists high affinity for m receptors and lower affinity for d and k receptors include most morphine-like drugs: Morphine, codeine, dextropropoxyphene, methadone, pethidine, etorphine, fentanyl 2. Partial agonists (mixed agonists and antagonists) Nalorphine (low dose antagonist at m receptors and partial agonist on d receptor and k receptors. Pentazocine antagonist at m receptors and partial agonist on d receptor and k receptors. 3. Antagonists Block m, d and k receptors Naloxone (short acting 2-4 hours) and Naltrexone (longer duration of acting t1/2 = 10 hours) Mechanism of action of Opioids Reduction of membrane excitability (hyperpolarization due to increased K+ conductance) Inhibition of neurotransmitter release (inhibition of Ca2+ entry) Suppressing firing rate of inhibitory interneurons (increasing activity in some neuronal pathways) All the opioid receptors are G-protein coupled receptors 1. They are coupled to the inhibitory G protein Gi : Inhibition of adenylate cyclase reduce cAMP decreased function of cAMP-dependent protein kinases (partially responsible for ion channel changes) 2. Direct coupling to ion channels reducing synaptic transmission: a. Postsynaptic inhibition Opioid binding to receptors activate G protein Open K+ channel Increase K+ conductance Hyperpolarization (inhibitory post-synaptic potential IPSP) decreases rate of firing. b. Axoaxonic inhibition Opioid receptors on presynaptic terminal activate G protein Closes Ca2+ channel Decreases conductance of Ca2+ Decreases release of neurotransmitters (e.g. noradrenaline, dopamine or glutamate and substance P released on afferent sensory neurons that transmit pain signals) c. Presynaptic autoreceptors Via G protein activation of K+ channel opening and Ca2+ channel closing: Somatodendritic autoreceptors hyperpolarize cells and reduce cell firing Presynaptic autoreceptors reduce the release of neurotransmitters Rewarding effects of Opiates (Opioid reinforcement) Linked to the mesolimbic dopaminergic pathway GABAergic cells inhibit this pathway by limiting dopamine release b-endorphin and opiate drugs decrease the release of GABA by -opening K+ channels -reducing influx of Ca2+ on GABA terminals The inhibition of GABA cells lead to: increased firing greater dopamine release into the nucleus accumbens By means of similar mechanisms, k receptor agonists (dynorphin) inhibit dopamine neurons and reduce dopamine release b-endorphin stimulates the pathway In contrast, k receptor agonists reduce dopaminergic neuronal activity and suppress the pathway Opioid Tolerance and Dependence Himmelsbach Hypothesis (1943) the nervous system adapts to the presence of opiates so tolerance develops in the event of sudden withdrawal of drug, the adaptive mechanism continues to function, causing a rebound in physiological effects (withdrawal syndrome). Acute Effects of Opiates and Rebound Withdrawal Symptoms Acute action Withdrawal Sign Analgesia Pain and irritability Constipation Diarrhoea Decreased blood pressure Increased blood pressure Drying of secretions Lacrimation (tearing), rhinorrhoea (runny nose) Euphoria Dysphoria and depression Flushed and warm skin Chilliness and ‘gooseflesh’ Hypothermia Hyperthermia Respiratory depression Panting and yawning Relaxation and sleep Restlessness and insomnia Tranquilization Fearfulness and hostility Pharmacological treatment of opiate addiction/dependence 1. Detoxification Elimination of abused opiate from body by substitution therapy a. Methadone with gradual dose reduction over a 5-7 day period b. Symptomatic relief i. Clonidine, an a2 adrenoceptor agonist to reduce noradrenaline activity relieve withdrawal symptoms: chills, lacrimation, rhinorrhoea, yawning, sweating ii. Promethazine or hydroxyzine for nausea and vomiting iii. Loperamide for diarrhoea iv. Methocabamol for muscle cramps and joint pain 2. Maintenance Therapy Methadone, LAAM (L-alpha-acetyl-methadol), Buprenorphine or narcotic antagonist, Naltrexone have been used. Methadone maintenance programmes are the most popular (Methadone Clinic) - Supervised daily administration of the oral form II. CNS Stimulants (Pysvhomotor stimulants) Substances which produce a sense of euphoria or a feeling of being more awake Used as therapeutic drugs or recreational drugs to increase alertness Used to suppress appetite Also used and sometimes abused to boost endurance and productivity A. COCAINE Source Cocaine is an alkaloid found in the leaves of the coca shrub (Erythroxylon), which grows in the Andes (particularly Bolivia, Colombia and Peru in South America). Coca leaves contain 0.6-1.8 % cocaine. Coca paste contains ~80 % cocaine MECHANISMS OF ACTION Cocaine binds to the neurotransmitter reuptake transporters on presynaptic membranes of dopaminergic neurons and blocks reuptake of Dopamine (DA) Noradrenaline (Norepinephrine, NE) Serotonin (5HT) A build up of neurotransmitter levels in the synaptic cleft occurs. Subsequently leading to increased activation of the dopaminergic reward pathway and a sense of euphoria and arousal. As the cocaine level decreases, so does the dopamine level in the pathway resulting in depression and a craving for the drug Pharmacological effects Increased stimulation of the sympathetic nervous system: By blocking the reuptake of NE Tachycardia Hypertension Mydriasis (pupil dilation) Tremors Binding affinity of cocaine: 5HT transporter > DA transporter > NE transporter Blockade of DA reuptake accounts for cocaine’s ability to: STIMULATE REINFORCE CAUSE ADDICTION Local anaesthetic action At relatively high concentrations (~200 mg, 2-3 mg/kg), cocaine prevents action potential generation by: Inhibiting voltage-gated Na+ channels in nerve cell axons via: The membrane (hydrophobic pathway) The open channel gate (hydrophilic pathway) The blockade prevents voltage-dependent Na+ conductance, which results in local nerve block Time course of Plasma Cocaine Concentration As a function of different routes of administration Physiological effects of cocaine Exhilaration and Euphoria Heightened energy Sleep disturbances Talkativeness (pressure of speech) Hyperactive ideation Anger, verbal aggression Irritability, hostility Extreme energy or exhaustion Insomnia Rambling, incoherent speech Mild to moderate anorexia High self-confidence Severe anorexia Delusions of grandiosity Disjointed flight of ideas Possible extreme violence ADVERSE EFFECTS (repeated or high doses) Stroke or seizure Cardiovascular problems (cardiac arrythmias, cardiac myopathy, myocardial infarction) Organ damage (pulmonary oedema, hepatotoxicity, kidneys) Perforation of nasal septum Abnormality in development of offspring (attention deficits, behavioural, cognitive) Panic attacks/temporary paranoid psychosis B. AMPHETAMINES Amphetamine derivatives are synthetic stimulants Dextroamphetamine Methamphetamine Methylphenidate Mechanisms of Action Binds to presynaptic dopaminergic neurons and induces release of dopamine from nerve terminals Interacts with dopaminecontaining synaptic vesicles and provokes release into cytoplasm of the terminal Binds to DAT (dopamine reuptake transporters) causing them to act IN REVERSE. (i.e. Dopamine reuptake reduced and free Dopamine also transported out of the nerve terminal) At higher concentrations: Inhibits MAO-A Induces release of NE into synaptic cleft and inhibits NE reuptake transporters. Pharmacological Effects High dose or Chronic Use Central effects: Heightened alertness Increased confidence Feeling of exhilaration Reduced fatigue Euphoria and excitement Insomnia Psychotic reactions: Visual and/or auditory hallucinations Behavioural disorganization Stereotyped behaviour Exarcebating schizophrenia Risk of dependence Enhanced peipheral sympathomimetic action: Hypertension Inhibition of GI motility Neurotoxicity: Reduced numbers of DAT Damage to DA axons and terminals (animal studies) Muscle Damage Renal Failure Clinical Use Treatment of ADHD in children (a behavioural disorder characterized by inattention, hyperactivity and impulsivity) [methylphenidate] Narcolepsy (a sleep disorder with episodes of uncontrollable sleepiness during waking hours) Appetite suppressant, for obesity (Amphetamine derivatives, e.g. fenfluramine/dexfenfluramine abandoned due tendency to cause pulmonary hypertension) CNS Stimulant Withdrawal Syndromes Depression, Hypersomnia, Fatigue, Headache, Irritability, Poor Concentration and Restlessness are characteristic. Drug craving is prolonged and intense In severe cases, suicide attempts, paranoia and acute psychosis may occur. Pharmacological Treatment Determined by specific withdrawal symptoms: i. Paranoid psychosis: Haloperidol and thioridazine ii. Depression: Tricyclic antidepressants, desipramine or SSRIs. iii. Panic Attacks: Antidepressant or Benzodiazepine iv. Generalized withdrawal symptoms: adrenergic agonists and calcium channel blockers C. METHYLXANTHINES Source: Various beverages: Coffee Tea Cocoa Main components: Caffeine Theophylline Mechanism of Action 1. By antagonizing Adenosine activity at A1 and A2A adenosine receptors 2. Inhibition of cAMP-phosphodiesterase (intracellular metabolism of cAMP) - increasing intracellular cAMP In CNS, Adenosine: Exerts a pre- or postsynaptic depressant action Reduces motor activity Depresses respiration Induces sleep Reduces anxiety Pharmacological Effects CNS stimulation Diuresis Stimulation of cardiac muscle Relaxation of bronchial smooth muscle Unwanted Effects: Very few but An overdose of caffeine (a very rare event) can result in: Restlessness Nervousness Excitement Insomnia Flushed face Diuresis Muscle twitching Tachycardia Psychomotor agitation Gastrointestinal complaints III. CANNABIS (Marijuana) Source: From flowering hemp of the weed-like plant Cannabis sativa Contains over 60 unique chemicals known as cannabinoids Is available in different forms: Marijuana (intoxicating plant) – crude mixture of dried and crumbled leaves, small stems and flowering tops of plants Hashish/ hash oil – a resin preparation obtained by solvent extraction, containing a very high content of cannabinoids Major important active ingredient is D9-tetrahydrocannabinol (THC) formed from its precursor of Cannabidiol. The inactive metabolite Cannabinol is formed spontaneously from THC Cannabinoid Receptors 1. 2. 3. 4. Are G-protein coupled receptors that: Inhibit adenylate cyclase activity (Gi) Inhibit calcium channels Activate Potassium channels Inhibit release of neurotransmitters [ACh, DA, NE, 5-HT, Glutamate and d-aminobutyric acid (GABA)] RECEPTOR TYPES a. Brain cannabinoid Receptors (CB1 subtype) Located mainly in Hippocampus (memory impairments) Cerebellum Substantia nigra (motor disturbances) Cortex Mesolimbic dopamine pathway (Reward) Also found on terminals (presynaptic) (Inhibit neurotransmitter release) b. Peripheral cannabinoid receptors (CB2 subtype) Located mainly in the Immune (lymphoid) system (Inhibitory) ~ 45 % homology with the CB1 subtype But show different pharmacological specificity from CB1 receptors Function NOT well established ENDOCANNABINOIDS Endogenous cannabinoid Agonist synthesized by the brain ANANDAMIDE (amide derivative of arachidonic acid producing short-lasting cannabinoid-like effects) Antagonist Rimonabant (Acomplia) used for obesity Pharmacological Effects of THC a. CENTRAL EFFECTS A mixture of psychomimetic and depressant effects Feeling of relaxation and well-being Exhilaration and disinhibition Enhanced visual and auditory perception Visual Illusions Slowing of passage of time OTHERS: Impairment of Motor-coordination Short term memory Catalepsy (retention of fixed unnatural postures) Analgesia Antiemetic action Stimulation of appetite b. PERIPHERAL EFFECTS Bronchodilation Vasodilation (characteristic of cannabis smokers: bloodshot eyes) Tachycardia Reduction of intraocular pressure TOLERANCE AND DEPENDENCE Only occur to minor degree in heavy users No evidence of psychological dependence Withdrawal Symptoms: Relatively mild No compulsive urge to take drug Similar to that of ethanol/opiate withdrawal PHARMACOLOGICAL TREATMENT OF DEPENDENCE Protocols in trials included: Antidepressants: Bupropion (Wellbutrin/Zyban) and Nefazodone (Serzone, withdrawn due to hepatotoxicity) Mood stabilizers: Divalproex (Depakote, originally indicated for epilepsy and bipolar disorder) Oral THC: during initial withdrawal period Pharmacological Usage Use of cannabis is still illegal in most countries Anecdotal usage Symptomatic treatment for patients suffering from: A. AIDS Chronic Neuropathic Pain Anorexia-cachexia (wasting syndrome) B. Multiple Sclerosis Pain Muscle Spasms C. Chemotherapy-induced nausea and emesis Nabilone (Cesamet), a derivative of cannabinoids D. Glaucoma REFERENCES CANNABIS: Piomelli, D. et al. (2000) The endocannabinoid system as a target for therapeutic drugs. Trends in Pharmacological Sciences. 21: 218-224 DA: Spanagal and Weis (1999) The dopamine hypothesis of reward: past and current research. Trends in Neurosci. 22: 521-527 OPIATES: Musto (1991) Opium, cocaine and marijuana in American history. Scientific Am. 265: 40-47 Kieffer (1999) Opioids: first lessons from knockout mice. Trends in Pharmacol Sci. 20:19-26 Snyder and Pasternak (2003) Historical review: opioid receptors. Trans Pharmacol Sci. 2: 198-204 ANALGESICS AND PAIN Yaksh (1999) Trends in Pharmacol Sci 20: 329-337 COCAINE Johanson and Fischman (1998) Pharmacol Rev. 41: 3-47 CAFFEINE Fredholm (1999) Pharmacol Rev. 51: 83-133