Substance Use Disorder😍 Flashcards

Question

Opioid intolerance

Answer 1

• Decrease in functional opioid receptors 1. Desensitisation and internalisation G proteins become uncouples due to phosphorylation by G-protein receptor Kinases and arrestin binding. Receptor pulled inside cell and degraded. Involves GPCR phosphorylation, B-arrestin binding, receptor recycling. 2. Desensitisation with lack of internalisation Leads to sustained and abnormal signalling and adaptations in downstream cell and circuits Receptor stays on membrane but becomes less responsive. Greater tolerance occurs to: Analgesia Euphoria Emesis Respiratory depression

Answer 2

Driven by increased noradrenaline release from locus coeruleus?? • One of the most powerful factors driving opioid dependence and addiction • Tolerance occurs rapidly to opioids (within days) • Abstinence triggers: Increased irritability: Diarrhoea; Loss of weight • COWS (Clinical Opioid Withdrawal Scale) used to measure withdrawal. Assessed using COWS scale (Clinical Opioid Withdrawal Scale). 11 commonly seen signs and symptoms included Begins: 6–12 hours after last dose. Peaks: 1–3 days. Duration: 5–10 days (longer in severe dependence). Symptoms: Diarrhoea, vomiting, muscle aches, irritability, insomnia, cravings, severe weight loss. Can occur after short-term use due to rapid tolerance and dependence

Answer 3

Common situations that trigger the urge to smoke include: •Drinking coffee or taking breaks at work •Talking on the phone •Drinking alcohol •Driving your car •Spending time with friends

Answer 4

Nicotine acetylcholine receptors (nAChRs) : ligand gated ion channels Widely distributed in CNS 9 subunits identified Alpha 7 (cognition & focus) and alpha4Beta2 subtypes (in reward pathway) predominate in the CNS ———————————————————————— Acts on nicotinic acetylcholine receptors (nAChRs) in CNS: Key subtypes: α4β2: Involved in addiction → located on dopamine neurons in VTA. α7: Linked to cognitive enhancement. Stimulates dopamine release into nucleus accumbens: Directly via receptors on dopamine neurons. Indirectly via glutamate and GABA modulation. Rapid onset via inhalation → fast spike in dopamine, reinforcing use.

Answer 5

• Nicotine is an agonist at nAChRs in VTA • On DA, Opioid and Glu neurones Directly excites DA neurones • nAChR on DA cell body • Increased release of Glu onto DA cell body • Indirectly inhibits GABA neuronos. which disinhibits DA neurone ———————————————————————— Nicotine – Sites of Action in the Reward Pathway Acts mainly within the VTA and also influences the nucleus accumbens. Nicotinic acetylcholine receptors (nAChRs) are found: Presynaptically on glutamate inputs from other brain areas. Directly on dopamine neuron cell bodies → excitatory → stimulates dopamine release. Also acts on opioid input to GABAergic neurons → inhibits GABA → disinhibits dopamine neurons. Overall effect: Increased dopamine release into the nucleus accumbens → reinforces addiction.

Answer 6

Rapid desensitization of α4β2 receptors: Short-lived dopamine effect → frequent use throughout the day. Differential desensitization: α4β2 desensitize quickly; α7 much slower. Differential desensitisation occurs • Differential desensitisation of nAChRs is important for nicotine's action in the VTA • ß2 subunit containing receptors on DA and GABA neurones terminals desensitise rapidly • a7 on glutamate terminals do not sensitise as easily which causes excitation of DA neurones Leads to: Frequent dosing. Strong physical and psychological dependence. ————- Nicotine – Fast Onset and Receptor Desensitization Inhaled nicotine enters the bloodstream rapidly and activates α4β2 nicotinic receptors in the VTA. Causes a quick spike in dopamine release → leads to short-term euphoria. 🔁 Rapid Desensitization α4β2 receptors quickly become desensitized → enter a period of inactivity. Further nicotine intake during this period produces little to no dopamine effect. Leads to frequent use to chase the short-lived dopamine surge. 🔄 Tolerance and Dependence Tolerance builds quickly but is intermittent due to receptor recovery. Dependence forms rapidly, driven by: Short duration of effect. Both physical and psychological components.

Answer 7

• Physical and psychological dependence occurs Common symptoms of withdrawal are • Cravings • Restlessness and trouble concentrating / sleeping • Irritability • Anxiety • Increases in appetite and weight Main withdrawal symptom: intense cravings. Driven by strong environmental cues (e.g. coffee, social settings, routine activities). Cravings persist during abstinence due to these conditioned associations.

Answer 8

Nicotine Replacement Therapy (NRT): Controlled nicotine doses → taper withdrawal. Bupropion: Blocks nicotine receptors, dopamine/NA reuptake inhibitor. > Inhibits dopamine and noradrenaline reuptake > Antagonises nicotine at nAChRs Although less dopamine released, it prolongs its action therefore smaller more prolonging effects to help withdrawal Decreases cravings, depressed mood, and weight gain. Initiated before stopping smoking (nicotine begins to have less pleasurable effects and patient more prepared to stop) & prescribed for up to 10 weeks Varenicline (Champix): Selective Partial α4β2 agonist of alpha4beya2 nicotinic acetylcholine receptors (less effect than nicotine, prevents nicotine from binding to receptor if smoking while on treatment) • Increases the dopaminergic tone in relevant brain areas which decreases the craving for nicotine and alleviates the symptoms of withdrawal • Reduces nicotine-induced dopamine release and, consequently, its rewarding/reinforcing effects Provides mild stimulation of dopamine. Blocks full nicotine effects if smoked during treatment. Restores dopaminergic tone, aids abstinence.

Answer 9

Most pharmacological treatments mimic the original substance in a controlled way. Gradual tapering helps avoid severe withdrawal. Reduces risk of relapse. All substances of misuse ↑ dopamine in nucleus accumbens, but: Mechanisms vary (e.g. opioids via disinhibition, nicotine via direct excitation). Addiction risk is closely tied to speed and magnitude of dopamine release. Substances like psychedelics and MDMA have less dopaminergic involvement, → lower addiction potential.

Answer 10

Short-term & Long-term Effects: Short-term effects: Acute poisoning from binge drinking. Long-term: Chronic liver disease, cancers (including liver and others), heart disease, mental health conditions. Men: ~2× higher mortality than women. Highest mortality: Deprived areas (2x more as likely than least deprived). Hospital Admissions: Significant burden on NHS and families. Treatments: First-line: Cognitive Behavioural Therapy (CBT) Pharmacological (not responded to CBT/want pharmacological: Disulfiram, Acamprosate calcium Disulfiram: 4 suffers Discovery in rubber industry: Antioxidant prevents oxidation of liver =build of acetaldehyde = unpleasant hangover = don’t want to drink Disulfiram = Irreversible inhibitor of aldehyde dehydrogenase → buildup of acetaldehyde → intense hangover symptoms (headache, nausea, tachycardia). Discourages alcohol consumption through aversive reaction. Covalent binding to enzyme’s cysteine residue deactivates it. Acetaldehyde: Toxic (carcinogen). Hangover, fast heartbeat, headache, upset stomach. Daily dose of Disulfiram = 200-500mg. Discourages drinking as leads to build of acetaldehyde. Connection to metabolism of ethanol: ethanol that is oxidized by alcohol dehydrogenase in the first step to give acetaldehyde.And that's the thing that gives you the hangover. next step is another oxidation step to give acetate. And acetate then goes into the TCA, the Tricitric acid cycle. Coenzyme NAD analyses this second oxidation. Disulfiram stops this second step & inhibits this step. IRREVERSIBLE COVALENT INHIBITOR OF ALDEHYDE DEHYDROGENASE (ALDH) Cysteine residue on ALDH undergoes dislufide exchange is the Disulfiram. PREVENT METABOLISM OF ACETALDEHYDE (inactive ALDH (aldehyde dehydrogenase is created, can no longer metabolise the acetyldehyde ) Acamprosate Calcium: (calcium salt) Ethanol acts on cans by binding to GABAA receptor, increasing effects of GABA (positive allosteric modulator) When ethanol no longer consumed, GABAA receptor no longer sensitive to GABA. Acamprosate enhances GABA signalling at the GABAA receptor: positive allosteric modulator) GABA analogue, positive allosteric modulator of GABA-A receptor. Mimics ethanol’s calming effect without intoxication. Calcium salt aids blood-brain barrier (BBB) penetration.

Answer 11

NRT: long acting transdermal patches, short actin lozenges, gum, sublingual tablets, inhaler, nasal sprays, vapes Bupropion Hydrochloride: Hydrochloride salt • NDR (noradrenaline-reuptake inhibitor • Start 1-2 weeks before the target stop date • Discontinue if abstinence not achieved at 7 weeks • 150 mg daily for 6 days, then 150 mg twice daily • Reduces the severity and craving for nicotine withdrawal symptoms • Partially ionized at pH 7.4 → log D (2.88)< log P (3.47). Amine group can be protonated. PKa around 8. Secondary amine. LMW (239.7). 1 Hydrogen bond doner. • Therefore, passes BBB via passive diffusion. • NOTE: Derivative of the illegal stimulant Cathinone Varenicline tartrate: • Selective nicotine receptor partial agonist (similar effect to nicotine) • Start 1-2 weeks before target stop day • 500 micrograms once daily for 3 days, 500 micrograms twice daily for 3 days, 1 mg twice daily for 11 weeks Chat: Partial agonist at nicotinic ACh receptors → mimics nicotine effect. Helps reduce cravings and withdrawal symptoms. Dosing titrated to 1 mg twice daily over 10 weeks. Administered as tartrate salt. Complex ring structure includes chair and planar elements.

Answer 12

Requires medical, social and psychological treatment Heroin: Metabolised to morphine; more lipophilic due to 2 ester groups → better BBB penetration. Leads to addiction and crime when used illicitly. Diamorphine (clinical heroin): used for pain/end-of-life care. Crosses BBB THROGH PASSIVE : 1.58 LOG P, 1.24 log D (PH7.4,partly ionised), LMW: 368 , PKa 9.1 (tertiary amine). 0 Hydrogen bind doners. BUT morphine, what diamorphine is metabolised into(2 esters hydrolysed by esterases), has poor bioavailability to brain. Diamorphine has better brain penetration. Mu?-opiod substitution therapy: (replaces heroin) Methadone: Substitution therapy to replace heroin • Long-acting -opioid agonist (long half-life) (same MOA as heroin • Single daily oral dose: start at 10-30 mg, increase until no withdrawal symptoms: usual dose 60-120 mg/day • Swaps the addiction from heroin to less dangerous methadone • Morphine to methadone: LOSS of 4 rings • Administered as the hydrochloride salt • Given as racemic mixture in UK • R-enantiomer: TWICE as active as morphine • S-enantiomer: INACTIVE • Obeys Lipinski's & BBB rules -orally active logP: 4.2 logD: 2.8 (pH 7.4) pKa: 9.1 MW: 309.5 Da HBD: 0 PSA: 20 A^2 Full opioid agonist. Good BBB penetration, long half-life. Used under supervision (e.g., “methadone milkshake” misuse risk). Reduces street crime and associated harm. Buprenorphine: Partial opioid agonist. Less sedating than methadone, safer for working/driving individuals. Sublingual tablet Usual dose 12-24mg Structurally similar to morphine. No methyl groups All rings intact M-Opiod receptor: Partial agonist • &-Opiod receptor: Antagonist • k-Opiod receptor Antagonist Obeys Lipinski's rules MW 468 Da 5 H bond acceptors 2 H bond donors LogP 5 • 7 chiral carbons Formulated as Hydrochloride salt

Answer 13

• 1960: Chlordiazepoxide (Librium) 1963: Diazepam (Valium) • 1964: Oxazepam 1981: Alprazolam • Short-term: treatment of insomnia or anxiety • AVOID long term use: tolerance, physical dependence, benzodiazepine withdrawal symptoms. Used for short-term anxiety/insomnia. High addiction risk if misused or taken long-term. Mechanism: Allosteric modulator of GABA-A receptor (not at GABA binding site). Dangerous in combination with alcohol or opioids (e.g., methadone).Overdose: deep unconsciousness Street misuse: Increasing concern; black-market availability. Overdose risk: Alone: moderate. Combined with opioids: high fatality risk. • Benzodiazepines bind to an allosteric binding site of the y-aminobutyric acid (GABA,) receptor. • Careful prescribing & monitoring: -NOT with opioids (including methadone) as risk of respiratory depression & death. -Treatment of addiction: gradual lowering of the dose and support from healthcare professionals

Answer 14

Fentanyl: 100× more potent than morphine (not as lipophilic as heroin) , 50× more than heroin. Structurally unrelated to morphine but same pharmacological effect. Extremely dangerous even in small doses. Starting to cause more ‘street-drug’ related deaths Nitazenes: New class of synthetic opioids, up to 300× morphine potency. Often sold as disguised products (e.g., "bath salts"). Major contributor to opioid death crisis (esp. in US). Hard to regulate due to packaging and internet distribution. Found in: street heroin, cocaine, black market vapes, fake online prescriptions. 45 x more potent than fentanyl.

Answer 15

ALCOHOL ADDICTION • Appreciate that alcohol is attributed to many deaths & hospital appts. • Understand how ethanol is metabolised. • Know about the discovery of Disulfiram. • Be able to explain the MOA of Disulfiram and Acamprosate NICOTINE DEPENDANCE & SMOKING CESSATION • Know the types of nicotine replacement therapy. • Understand the properties of drugs wrt their ability to cross the BBB. SUBSTANCE DEPENDANCE • OPIOID addiction: treatment with methadone & buprenorphine. • Understand the dangers of benzodiazapines, fentanyl and nitazenes.

Answer 16

Alcohol: Treatment/Intervention: CBT, Disulfiram, Acamprosate BBB Penetration: Acamprosate via calcium salt Abuse Risk: High Notes: Acetaldehyde buildup deters use Mechanism of Action: Disulfiram: Irreversible inhibitor of aldehyde dehydrogenase → acetaldehyde buildup → aversive reaction Acamprosate: GABA analogue; positive allosteric modulator of GABA-A receptor Counseling Points: Patient must be motivated to quit before pharmacological treatment Warn about severe reaction if alcohol is consumed while on disulfiram Nicotine: Treatment/Intervention: Bupropion, Varenicline BBB Penetration: Both cross BBB Abuse Risk: High Notes: Gradual cessation aid Mechanism of Action: Bupropion: Norepinephrine-dopamine reuptake inhibitor (NDRI) Varenicline: Partial agonist at α4β2 nicotinic receptors Counseling Points: Start 1–2 weeks before quit date Discontinue if no cessation by 7 weeks (bupropion) Warn about potential mood changes or insomnia Heroin Treatment/Intervention: Methadone, Buprenorphine BBB Penetration: Diamorphine > Morphine Abuse Risk: Very High Notes: Linked to crime & relapse Mechanism of Action: Diamorphine (heroin): Metabolized to morphine; μ-opioid receptor agonist Methadone: Full μ-opioid agonist with long half-life Buprenorphine: Partial μ-opioid agonist Counseling Points: Supervised consumption often required (e.g., methadone) Safer than street heroin due to known dose and quality Methadone may cause sedation; buprenorphine is less sedating Benzodiazepines Treatment/Intervention: Short-term prescription BBB Penetration: Yes Abuse Risk: High Notes: Risk increases with alcohol/opioids Mechanism of Action: Allosteric modulators at GABA-A receptor (enhance inhibitory neurotransmission) Counseling Points: Use for short-term only (e.g., 2–4 weeks max) Avoid combining with alcohol or opioids due to overdose risk Taper gradually to avoid withdrawal Fentanyl/Nitazenes Treatment/Intervention: N/A (avoidance + control) BBB Penetration: Yes Abuse Risk: Extremely High Notes: 100–300× potency vs morphine Mechanism of Action: Potent μ-opioid receptor agonists Counseling Points: Extremely potent — fatal even in microgram doses Illicit forms often mislabelled or mixed with other drugs Naloxone may be less effective or require repeated doses

Answer 17

Euphoric effect: produces euphoric effects therough the dopamine neurones of the mesolimbic system NMDA: Alcohol inhibits NMDA receptors & results in upregulation of GABA receptors GABA: Chronic consumption of alcohol leads to GABA receptor desensitisation & tolerance, potentating the loss of drinking control. Absorption: Mostly absorbed in the digestive tract’s mucosal lining, specifically at the proximal small intestine, where B vitamins are absorbed. Consequences: Vitamin B9 , Vitamin B1 deficiency This can lead to hyporeflexia, oral ulcers, stomatitis, glossitis

Answer 18

Happens when someone who regularly drinks heavily suddenly stops or significantly reduces their alcohol intake. Alcohol affects the neurotransmitters in the brain (i.e. GABA and glutamate) and reduce its natural calming mechanisms. Brain becomes overactive when alcohol is removed, leading to withdrawal symptoms. Time Frames & Symptoms 6-12hrs after last drink: Mild symptoms • Anxiety, nervousness or irritability • Insomnia • Headache • Excessive sweating • Tremors (Hand shaking) 12-48hrs after last drink: Moderate symptoms • Increase heart rate and blood pressure • Confusion or trouble thinking • Mood swings • Hallucinations (Seeing and hearing things that are not there) 24-72hrs after last drink: Severe symptoms • Delrium Tremens (A dangerous condition with severe confusion, agitation, fever, hallucinations and even death if untreated) • Seizures • Dehydration and electrolyte imbalances

Answer 19

First day give 30mg Chlordiazepoxide, monitor hourly for withdrawal symptoms, give 30mg PRN. CIWA score is between 10-21 so is classed as moderate Second day CIWA score is below 16 so no further treatment is required, gradually taper down dosage QDS over 5-7 days. Check news score · respiration rate · oxygen saturation · systolic blood pressure · pulse rate · level of consciousness or new confusion* Pharmacological Treatment Chlordiazepoxide Administration - Initial Dose: If CIWA-m score is between 10-21, administer 30 mg chlordiazepoxide. - Monitoring: Conduct hourly CIWA-m assessments. - Subsequent Doses: If the score remains between 16-21 after 24 hours, administer 20 mg of chlordiazepoxide every two hours as needed. Monitoring - Vital Signs: Regular monitoring of respiratory rate, temperature, heart rate, and blood pressure. - CIWA-m Assessments: Perform hourly assessments initially, adjusting frequency based on symptom severity and response to treatment. Other Care - Hydration and Nutrition: Ensure adequate fluid intake and nutrition to prevent dehydration and electrolyte Chlordiazepoxide is a long-acting benzodiazepine that increases GABA activity.

Answer 20

Acamprosate is used for alcohol dependence and paroxetine is used for social anxiety. However, paroxetine can increase the risk of depression and emotional blunting in some individuals recovering from alcohol dependence. A different SSRI like sertraline is generally better tolerated in alcohol use disorder and has a lower risk of emotional numbing. Paroxetine has a higher risk due to its strong serontonin reuptake inhibition and additional anticholinergic effects. Explain to patient —> i see that your doctor has prescribed two medications to support your recovery - one to help with alcohol cravings, and one for your anxiety. However, this particular anxiety medication may not be the best choice for you as it can sometimes make people in recovery feel emotionally numb/low. There is another medication called sertraline that works in a similar way but is generally better tolerated for people who have had an alcohol dependence. Would you be open to discussing this with me or your doctor so we can find the best option for you? Benzos arent used for long term treatment due to addiction risk - only short term for withdrawal symptoms. acamprosate is started because it reduces the cravings for alcohol long term. Also less frequent dosing increases adherence

Answer 21

Acamprosate Functional Groups: sulfonic acid Secondary amide LogP: 1.8 – 2.8 pKa: 1.1 Acid =, 0.88 Base ≈ –1.5 Mechanism of Action: structural analog of GABA Thought to directly bind and inhibit GABA B receptors and indirectly affect GABA A receptors Use: in combination with psychological intervention for relapse prevention in patients with moderate and severe alcohol dependence, to start after successful assisted withdrawal Disulfiram Functional Groups: Disulphide LogP: 3.88 pKa: (not provided) Mechanism of Action: blocks the oxidation of alcohol through its irreversible inactivation of aldehyde dehydrogenase Use: alternative for patients in whom acamprosate calcium and oral naltrexone hydrochloride are not suitable Naltrexone Functional Groups: Cyclopropylmethyl Methylene LogP: 1.92 pKa: Acid = 10.2 Base = 9.35 Mechanism of Action: blocks opioid receptors in the body thought to act as a competitive inhibitor at mu, kappa, and delta types of opioid receptors in the CNS blocking the effects of endogenous opioids Use: in combination with psychological intervention for relapse prevention in patients with moderate and severe alcohol dependence, to start after successful assisted withdrawal Nalmefene Functional Groups: cyclopropylmethyl Ketone LogP: 1.27 pKa: Acid = 10.35 Base = 9.57 Mechanism of Action: Same as above Use: reduction of alcohol consumption in patients with alcohol dependence who have a high drinking risk level, without physical withdrawal symptoms, and who do not require immediate detoxification Benzodiazepines (e.g. diazepam) Functional Groups: Diazepine ring Benzene ring LogP: 3.08 pKa: Acid = 8.2 Base = 2.92 Mechanism of Action: Positive allosteric binding to GABA A receptors enhances the inhibitory effects of gamma-aminobutyric acid (GABA) Use: Long acting benzodiazepines can be used for assisted alcohol withdrawal in patients with moderate to severe alcohol dependence

Substance Use Disorder😍 Flashcards

(45 cards)