Substance, Addiction, and Withdrawal Lecture PDF

Substances & neurotransmission Substances that enter the body may interfere with the body's normal chemical processes. There are four basic mechanisms by which a drug may change functional activity: I. increasing the release of a neurotransmitter II. directly activating or blocking the...

Substances & neurotransmission Substances that enter the body may interfere with the body's normal chemical processes. There are four basic mechanisms by which a drug may change functional activity: I. increasing the release of a neurotransmitter II. directly activating or blocking the neurotransmitter receptors III. inhibiting the reuptake (transport) of the transmitter into the neuron (this keeps it in the synapse where it is free to interact with receptors again) IV. inhibiting enzymes in, or near, the neuron that would break down the neurotransmitter. Neurotransmitters - substance addiction Brick, et al. (2012) Brain areas affected by substance use https://www.drugabuse.gov/publications/teaching-packets/understanding- drug-abuse-addiction/section-i/3-brain-regions-their-functions The physiological reward pathway The neural circuits of the ventral tegmental area (VTA), the nucleus accumbens, and the prefrontal cortex are critical in learning both natural and drug reward behaviour. Dopamine is the neurotransmitter most associated with reward and its release produces a pleasurable sensation and motivates us to repeat behaviours https://www.drugabuse.gov/publications/teaching- packets/understanding-drug-abuse-addiction/section- i/4-reward-pathway DSM 5 - Substance Use Disorders According to the DSM-5, a “substance use disorder describes a problematic pattern of using alcohol or another substance that results in impairment in daily life or noticeable distress.” Two groups of substance-related disorders: substance-use disorders (addiction) substance-induced disorders Image: https://druginfo.sl.nsw.gov.au/drugs/a-to-z-of-drugs DSM 5 - Substance Use Disorders DSM-5 states that in order for a person to be diagnosed with a disorder due to a substance, they must display 2 of the following 11 symptoms within 12 months Consuming more alcohol or other substance than originally planned Worrying about stopping or consistently failed efforts to control one’s use Spending a large amount of time using drugs/alcohol Use of the substance results in failure to fulfil major role obligations” Craving the substance Continuing the use of a substance despite health problems caused or worsened by it. Repeated use of the substance in a dangerous situation ( Giving up or reducing activities in a person’s life because of the drug/alcohol use Building up a tolerance to alcohol or drug. Experiencing withdrawal symptoms after stopping use. DSM 5 - Substance-induced disorders Intoxication Immediate effects of substance use Withdrawal Immediate effects of discontinuing a substance, called substance Substance addiction Addiction can be defined as a persistent, compulsive dependence on a behaviour or substance (http://medical-dictionary.thefreedictionary.com/addiction). Two concepts –’‘ pleasure’ and ‘craving’ Pleasure seeking - refers to the pleasurable, rewarding aspect of addiction the opiate (endorphin). GABA or glutamatergic systems may be more involved in a pleasure-seeking aspect of addiction. Drug craving – refers to the craving aspect of addiction and is generally associated with withdrawal. Dopamine may be more involved in the drug-seeking (craving) component of addiction through the reward pathway.  Substances and the brain 1. Drug stimulates an increase in dopamine signalling from the ventral tegmental area (VTA) to the nucleus accumbens. 2. The nucleus accumbens “perceives” this dopamine signal and measures the “goodness” of the agent or the natural reward based on the size of the dopamine release. 3. Glutamate projections from the nucleus accumbens instruct the prefrontal cortex to remember the environment and behaviours which lead up to the occurrence of the “goodness”. 4. In addiction, excess signalling of glutamate neurons in the prefrontal cortex stimulates the nucleus accumbens, triggering drug-seeking behaviours at the expense of naturally rewarding or good behaviours. Image: https://raisinghealthychildreninanalcoholichome.wordpress.com/2015/02/26/new-research-adds-to-our-understanding-that-alcoholism-is-a-brain-disease-not-a- moral-problem/ Substance addiction Herman, M. A., & Roberto, M. (2015). Tolerance Physiological tolerance refers to adjustments made by the body to compensate for the continued presence of a substance Homeostatic processes that work through feedback loops Homeostatic control centres are ‘reset’ in the presence of the substance (for example if a substance blocks receptors then the body may compensate by increasing the number of receptors or the amount of neurotransmitters) thus more substance is required to have the same effect Substance withdrawal When neurotransmitter amount is decreased or ceased, the lower number of neurotransmitters not receiving the required amount of the drug and withdrawal syndrome occurs. Generally withdrawal symptoms occur more in substances that are excreted from the body quickly e.g. nicotine. Treatment for withdrawal generally centres around providing a reducing regime of the substance or a similar substance to control the onset of withdrawal symptoms. Treatment for withdrawal http://www.drugrehab.org/images/drugs-in-three-stages.png Sedative/Hypnotics Curtin University is a trademark of Curtin University of Technology CRICOS Provider Code 00301J Sedative/hypnotics Two major categories of sedative hypnotics. Similar in chemical structure or effect. Barbiturates - Pentobarbital (Nembutal) Benzodiazepines - Diazepam, Alprazolam, Oxazepam, Nitrazepam, Temazepam A Few Sedative/Hypnotics do not fit either category Choral Hydrate Sedative/hypnotics Effects are mediated by their ability to modify the effects of the inhibitory transmitter gamma-aminobutyric acid (GABA). GABA has two receptor sites GABAA and GABAB GABAA receptor site is directly linked to gated chloride channel. When GABA is released at the synapse it interacts with the GABAA receptor and directly opens the chloride channel to stabilise the cell membrane and make it more difficult to fire. In this way GABA acts as an inhibitory transmitter. Barbiturates and Benzodiazepines each have their own receptor sites that enhance the action of GABA Sedative/hypnotics GABAB receptor is also has an inhibitory effect Stimulation of the GABAB receptor releases a second messenger that opens the potassium channel GABAB1 receptors are operating all the time to maintain inhibitory tone in the brain, where GABAB2 receptors operate intermittently and are not affected by barbiturates and benzodiazepines. Sedative/hypnotics Desired effects when used Decrease anxiety Induce sleep Offset effects of other drug classes Intoxication Sedation Occasional elation secondary to depression of inhibitions and judgment Pupils are generally midpoint and slowly reactive Hiccups can be seen in long term benzodiazepine use Sedative/hypnotics Benzodiazepine Overdose Sedation with decrease in level of consciousness Decrease in respiratory rate Hypotension Decrease in temperature Gastric paralysis Respiratory compromise Pulmonary oedema Sedative/hypnotics Benzodiazepine & Barbiturate withdrawal is more likely to be severe if: Therapeutic dose is used every day for 4 - 6 months Increased therapeutic dose used repeatedly Rapidly eliminated drug is used Highly potent drug (Ativan, Xanax) Abrupt discontinuation of drug Schedule of use not fixed History of dependency History of concurrent alcohol use History of panic attacks Benzodiazepine withdrawal Can last 3 - 5 weeks Very much like acute alcohol withdrawal Time course and severity depend on Dose of benzodiazepine Duration of use (does not worsen after one year of use) Duration of the specific drug’s actions Age (prolonged in the elderly) One treatment protocol for outpatient withdrawal The sedative-hypnotic can be decreased by 10% of the starting dose per week. For the final 20%, decrease by 1/2 of the initial doses per week Inderal for increased blood pressure and tremors OPIAITES Curtin University is a trademark of Curtin University of Technology CRICOS Provider Code 00301J Opiates Definitions Opium - Fluid obtained from the poppy plant Opiate - a substance derived from opium (e.g. morphine and codeine) Opioid - a substance with morphine-like actions, but not derived directly from the poppy plant (e.g.. Heroin) There are at least 20 alkaloids (organic pharmacological agents) in the fluid of poppy pods Opioids Opioid drugs can be either illicit (predominantly heroin) or prescription (including codeine). They include: opiates—drugs naturally derived from the opium poppy, such as codeine Semi-synthetic opiates, such as hydromorphone and oxycodone Synthetic opioids, such as fentanyl and methadone. Opioids are medically prescribed for two main reasons: pain management and the treatment of heroin and other opioid dependence Australian Statistics indicate recent increases in the use of opioids, and opioid-related poisonings, overdoses and deaths and this is reflected in international trends. Opioids Opioids exert their effects through specific receptors in the brain and spinal cord The primary groups of opioid receptors are designated by the Greek letters mu (μ), kappa (κ), and delta (δ) Most opioids are mu receptor agonists or partial agonist-antagonists at mu and kappa receptors. mu (μ) agonists Analgesic and intoxicating effects Codeine, heroin, hydrocodone, morphine, oxycodone kappa (κ) agonists Produce analgesia, sedation, and dysphoria (without the potentially dangerous respiratory depression that mu agonists produce) Opiate receptors and activation effect Mu1 (μ1) analgesia, euphoria Mu2 (μ2) constipation, respiratory depression Kappa spinal analgesia, dysphoria Delta analgesia thru the endorphin, encephalin and dynorphin system Effect of Common Opiates at MU Receptor Heroin, morphine, methadone Agonist Buprenorphine Partial Agonist Naltrexone, Nalmefene Antagonists Opiates Desired effects of use “The Rush” Sedation Euphoria Analgesia After IV Injection Warm skin rush Pruritis (severe itchiness), especially with morphine use which releases histamines Pleasure, relaxation and satisfaction in 45 seconds Opiate intoxication Most common Miosis (small pupils) Nodding Hypotension Depressed respiration Bradycardia (slow heart rhythm) Euphoria Floating feeling Opiate overdose Classic triad is seen in overdose I. Miosis (small pupils) II. Coma III. Respiratory depression Pulmonary edema Seizures Boyer, E. W. (2012). http://2.bp.blogspot.com/- 9Y5fHVNLmI0/UAdVX1DgciI/AAAAAAAAC6Y/Qhapfw5ag vg/s1600/Opioid-Overdose-large.jpg Opiate withdrawal In general, opiate withdrawal signs and symptoms are the same for all opiates; what differs is the time of onset and the length and intensity of withdrawal. The withdrawal is divided into early, middle and late phases to show the progression of symptoms when the patient is not treated. Opiate withdrawal Early Phase - Lacrimation (eyes water), yawning, rhino rhea (runny nose), sweating, sense of anxiety and doom, though not life- threatening Middle Phase - Restless sleep, dilated pupils, (mydriasis), anorexia, gooseflesh, irritability, tremor Late Phase - Increase in all previous signs and symptoms, increase in heart rate, increase in blood pressure, nausea and vomiting, diarrhea, abdominal cramps, labile mood, depression, muscle spasm, weakness, bone pain Intoxication or withdrawal? The pupil size can give very good clinical information. Withdrawal Intoxication Medications for opiate addiction Methadone Naltrexone Buprenorphine Stimulants Curtin University is a trademark of Curtin University of Technology CRICOS Provider Code 00301J Stimulants Caffeine Nicotine Amphetamine types - MDMA (Ecstasy), Speed and Base, Ice and Methamphetamine. Cocaine - Cocaine Hydrochloride is a white crystalline powder. Stimulants All have a common effect on synapses that use a monoamine as a transmitter Primarily effect synapses that use serotonin and the catecholamines (Adrenaline, Noradrenaline and Dopamine) Cause transmitter to leak spontaneously out of the synaptic cleft and into the synapse Increase neurotransmitter release in response to the arrival of the action potential at the synapse Block the reuptake of neurotransmitters into presynaptic cells and prolong the duration and intensity of their effect Stimulants In the CNS all monoamine systems are known to be effected by stimulants but the behavioural effects result from their effect on Dopamine (DA) DA stimulates the nigrostriatal system between the substantia nigra and striatum which is important for motor activity Stimulants increase DA in nucleus accumbens, part of the mesolimbic pathway involved in reward and motivation Increased DA exerts control over the pituitary gland – inhibits the secretion of prolactin (reduced milk production and sexual dysfunction in males) Cocaine blocks sodium ion channels in cell membranes having anaesthetic action Stimulants Desired effects Increased alertness Feeling of well being Euphoria Increased energy Decrease in appetite/weight loss Heightened sexuality Stimulants Intoxication Increase in heart rate (30-50%) Pupils dilated Increase in blood pressure (15-20%) Nausea/vomiting Confusion Tremors Weight loss Chest pain/arrhythmia Electrocardiogram abnormalities (QRS and QT intervals are prolonged) Stimulants Intoxication Headache (most common neurologic complaint) Seizures (can occur after only one use of cocaine, usually need more than one-time use for amphetamines to cause seizures) Priapism (painful penile erection) Renal failure secondary to rhabdomyolysis and myoglobinuria (muscle cells in the urine) Overdose All of the signs and symptoms of intoxication are only worse Myocardial infarction (heart attack) Stroke Severe prognosis if hyperthermia (abnormally high body temperature) present Stimulants Next day hangover after use Insomnia Drowsiness Fatigue Sore jaw muscles Headaches Loss of balance Stimulants Withdrawal Dysphoria Fatigue Unpleasant dreams Insomnia Hypersomnia (extreme sleepiness) Increased appetite Psychomotor retardation Agitation Stimulants Treatment for withdrawal and dependency No medication regimen has been proven totally effective for stimulant dependence treatment In amphetamine overdose  Acidify urine  Never use chlorpromazine (worsens hyperpyrexia and increases the possibility of seizures) To lower blood pressure can use benzodiazepines, phentolamine, and sodium nitroprusside. Inderal and calcium channel blockers may cause an increase in cardiovascular toxicity Hallucinogens Curtin University is a trademark of Curtin University of Technology CRICOS Provider Code 00301J Hallucinogens LSD Mescaline found in peyote cactus Lophophoria williamsii Anhalonia lewinii Psilocybin found in mushrooms  Hallucinogens Classified according to their resemblance to neurotransmitters Serotonin like – LSD, Psilocybin, Harmine Noradrenaline like – Mescaline, Estascy Acetylcholine like – Anticholinergics, Image: https://pixshark.com/hallucinogens-effects.htm Hallucinogens Desired Effects Modification of perception Hallucinations Distortions (trails) Insight Synesthesia (cross over or mixing of the senses “smell a sound”) Onset in 60 minutes with the peak in 2 - 4 hours Hallucinogens Intoxication Rapid tolerance ( 3 - 4 days for LSD ) Depersonalization Confusion Acute anxiety and panic Depression Flashbacks Temporary psychosis Loss of coordination Increase in pulse rate and temperature Dilated pupils Nausea and vomiting 30 - 120 minutes after mescaline use Increase in cortisol and prolactin hormone levels Hallucinogens Intoxication (continued) Flashbacks Marijuana, LSD, psilocybin, mescaline, PCP and MDMA use 15 - 77% of users report brief flashbacks Taper off over time Benzodiazepines can be used (better than antipsychotics) to treat problematic flashbacks Psychosis Psychiatric diagnosis most commonly seen with LSD use is paranoid schizophrenia like syndrome ( the patient usually reports auditory and not visual hallucinations as seen in schizophrenia) Post LSD psychosis - similar presentation to schizoaffective disorders Cannabinoids Curtin University is a trademark of Curtin University of Technology CRICOS Provider Code 00301J Cannabis How is it used? Leaves and flowering tips are dried Smoked Consumed as tea Mixed into food Resin from flowering heads Smoked Mixed with tobacco Alcohol extract (cannabis oil) is mixed with tobacco and smoked Cannabis Tetrahydrocannabinol (THC) 80 probable biologically inactive metabolites of THC 11-hydroxy-THC is the primary active metabolite THC is eliminated in the faeces and 33% in the urine Peripheral and central effect Low dose- a mixture of depression and stimulation High dose- CNS depression Cannabinoids There are two main receptors for cannabinoids in humans CB1(in the brain) If stimulated produces euphoria, impaired short-term memory and impaired sense of time CB2 (in the spleen, peripheral sites) If stimulated produces immunosuppressant activity (not psychoactive) Cannabinoids Cannabinoid receptors function as neuromodulators altering the function of other neurotransmitters Increase the synthesis of noradrenalin, dopamine, serotonin and GABA Potentiate the action of noradrenalin, dopamine, acetylcholine, GABA and opiate peptides Alter the functioning of noradrenalin, dopamine and acetylcholine Cannabinoids Receptors have also been found in the Cerebellum – body movement and coordination Cortex – higher cognitive functions Nucleus accumbens – reward Basal ganglia – movement control Hypothalamus – body temperature, salt and water balance, reproductive functions, hunger Amygdala – emotional responses, fear Image: https://www.crchealth.com/addiction/marijuana/ Cannabinoids Desired effects of the user Sense of well being Relaxation Euphoria Modified level of consciousness Altered perceptions Intensified sensory experiences Altered time sense Sexual disinhibition Cannabinoids Intoxication Decrease vigilance Decrease motor coordination Decrease strength Increase pulse rate (not blood pressure or temperature) Galactorrhea (breast milk production) in 20% of female users Decrease testosterone (decrease in sperm count and motility) Decrease in helper T cells and interference with macrophage antigen processing (killer cells are unable to process foreign bodies – impaired immune system) Cannabinoids Intoxication (continued)  Inability to learn  Acute panic  Delirium  Depersonalization  Paranoia  Hallucinations  Flashbacks Toxicity and adverse effects Cardiovascular System Increase heart rate Cannabis alone 29-36 beat/min increase Cannabis & cocaine 49 beat/min increase Decrease blood pressure Increase myocardial infarction risk Pulmonary Tracheitis (inflammation of the trachea) 3 cannabis cigarettes = 20 tobacco cigarettes with significantly more carcinogens Toxicity and adverse effects Mental health issues have been seen to co-occur in users. Transient panic and anxiety, Depersonalization, Bizarre behavior, Delusions, Hallucinations, Acute mania, Acute paranoia, Depression, Psychosis, Aggression Immune System CB2 receptors on immune system cells = immune modulation, Decrease macrophage function, Decrease killer cell function, Increase in HIV - 1 host infections Reproductive / Endocrine System Alters pituitary hormones, decreases prolactin, decreases growth hormone, decreases luteinizing hormone, galactorrhea (decrease testosterone in males, decrease sperm production, decrease sperm motility Withdrawal Difficult to demonstrate 10-hour onset and 5-day duration Anxiety, mental clouding, insomnia, anorexia, irritability, tremor, depression, headache, craving, tremor of the tongue and extremities, insomnia, sweats, lateral gaze nystagmus (rhythmic oscillation of the eyeball on lateral gaze), exaggerated deep tendon reflexes Very similar to nicotine withdrawal Withdrawal may be due to the release of corticotropin-releasing factor (CRF) in the amygdala Similar release in opiate, alcohol and cocaine withdrawal 71% of marijuana users relapse to marijuana use within 6 months after achieving initial 2 weeks of abstinence Dissociative Anesthetics Curtin University is a trademark of Curtin University of Technology CRICOS Provider Code 00301J Dissociative Anesthetics Phencyclidine (PCP) Arylcyclohexylamine group of dissociative anesthetics Antagonist of the NMDA receptor in the brain Anticholinergic properties (impact on the part of the nervous system that controls the heart rate, blood pressure and other responses to stress) Stimulant properties Dissociative anesthetics - PCP Desired effects Visual illusions Hallucinations Distortion of body image Feelings of strength Special insight Dissociative anesthetics - PCP Intoxication Low dose – Dreamy, mood elevation, panic, impaired judgment Moderate dose - Inebriated like state, dissociated, ataxia, confused, decrease in pain, amnesia High dose -All of the previous, hallucinations, catatonia, blank stare drooling, delirium, psychotic behavior, hypertensive crisis Dissociative anesthetics - PCP Intoxication Anxiety Feelings of doom Outbursts of hostility Violence (#1 cause of death in users) Incoordination Nystagmus Paranoia Vomiting Fever Dissociative anesthetics - PCP Withdrawal (*Similar to cocaine withdrawal) Depression Craving Increased appetite Increased sleep Dissociative anesthetics - PCP Treatment Disruption of sensory input by PCP causes unpredictable, exaggerated, distorted and violent reactions to environmental stimuli. The cornerstone of treatment is therefore minimization of sensory input for the PCP intoxicated patient. Acidify the urine to increase excretion Naloxone (Narcan) can treat the decrease in respiratory rate Valium can treat the muscle rigidity Inhalants/Solvents Curtin University is a trademark of Curtin University of Technology CRICOS Provider Code 00301J Inhalants/solvents The mechanism of action is not exactly known. Three effects appear to account for the physiological effects; I. Enhancement of the inhibitory transmitter GABA II. Enhancement of the effects of glycine III. Attenuation of NMDA receptor for the excitatory transmitter glutamate Inhalants/solvents Desired effects of use Euphoria Excitement Altered perceptions “A cheap high” Inhalants/solvents Indications of use Chemical odor Paint stains Hidden containers (whiteout, glue) Drunk Dizzy Gait impairment Slurred speech Red running nose and eyes Inhalants/solvents Intoxication Nervous system - ototoxicity (impaired hearing), peripheral neuropathy, multiple sclerosis-like syndrome, slowly reversible trigeminal neuropathy, vertical nystagmus, slurred speech, ataxia, impaired judgment, lack of coordination Renal - distal type tubular acidosis (difficulty with handling acids), Decrease in potassium, decrease in calcium, hyperchloremic acidosis, Acute tubular necrosis (death of kidney tissue), chronic renal failure Hepatic - Cancer Pulmonary - pulmonary hypertension, bronchospasm Cardiac - “sudden sniffing death”, cardiac arrhythmias, dilated cardiomyopathy Other - pigmented hands and face, weight loss, muscle weakness, impulsive behaviour Inhalants/solvents Withdrawal  Neurological effects allowed to wear off Treatment Prevention Symptomatic