A. Addiction Management

Drugs of Abuse Management

• Objectives: Identify clinical presentation of intoxication and withdrawal syndromes for commonly abused substances in the US. Understand the pathophysiology of these substances. Provide accurate treatment based on the identified substance of abuse.

Dependence vs. Addiction

• Tolerance: Adaptive changes in response to repeated drug exposure, requiring higher doses to maintain the same effect.
• Addiction: Compulsive, relapsing drug use despite negative consequences, often triggered by cravings.
• Dependence: Withdrawal symptoms appear when the abused drug is no longer available; a combination of such signs is called withdrawal syndrome.

Dependence vs. Addiction (Continued)

• Physical Dependence is a sign of dependence.
• Psychological Dependence is a sign of addiction.
• Compulsive drug seeking and relapse are hallmarks of addiction.

Drug Mechanisms

• Common Mechanisms: Dopamine (DA) pathways, extracellular signal-regulated kinase (ERK) pathways, decreased calmodulin-related genes, and increased transcription of lipid/cholesterol and Golgi/endoplasmic reticulum (ER) function genes, along with glutamate and GABA receptor activity. These responses are seen across many abused drugs.

Tolerance & Withdrawal

• Tolerance: Downregulation/up-regulation of brain adaptation. Repeated exposure to addictive drugs leads to brain adaptation.
• Withdrawal: Adaptive changes become apparent once drug exposure ends.

Drugs That Activate G Protein-Coupled Receptors

• Opioids Act on μ-OR (Gio) with disinhibition response.
• Cannabinoids Act on CB₁R (Gio) with disinhibition response.
• GHB Act on GABA_BR (Gio) with weak agonist and disinhibition response.
• Other drugs listed in the table.

Drugs That Bind to Ionotropic Receptors and Ion Channels

• Nicotine Act on nAChR (α4β2) with excitation response.
• Alcohol Act on GABAAR, 5-HT₃R, nAChR, NMDAR, Kir3 channels with excitation and disinhibition.
• Other drugs listed in the table.

Cocaine

• Source: Alkaloid ester from Erythroxylum coca leaves.
• Clinical Use: Local anesthetic and vasoconstrictor.
• Mechanism of Action:
  • Reversibly binds and inactivates sodium channels.
  • Binds differentially to dopamine, serotonin, and norepinephrine transport proteins, preventing their reuptake.
• Targets: Sodium-dependent dopamine transporter, noradrenaline transporter, serotonin transporter, sodium channel protein type 5, 10, and 11, and muscarinic acetylcholine receptors M1 & M2.
• Effects: Euphoria, hyperactivity, appetite suppression, local anesthesia, and possible sudden death due to cardiac arrest.

Cocaine Continued

• Toxicity: Intense agitation, convulsions, hypertension, rhythm disturbance, coronary insufficiency, hyperthermia, rhabdomyolysis, and renal impairment.
• Acute Intoxication Management: Benzodiazepines (diazepam), phentolamine. Hyperthermia management: cold water immersion. Consider nitroglycerin for refractory hypertension. Use B-blockers with caution.

Amphetamine Type

• Structure: Similar to catecholamines (aromatic ring and nitrogen).
• History: Used for wakefulness during World War II, then became restricted.
• Common Types: Amphetamine (AMPH), methamphetamine (METH), methylphenidate (MPH), and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy)
• Mechanism of Action: Taken into presynaptic nerve terminals (with sodium ions and chloride). Actively transported by monoamine reuptake transporters. Displaces other monoamines leading to storage within vesicles and retro-transport.
• Targets: Synaptic vesicular amine transporter antagonist, Vesicular monoamine transporter 2 (VMAT2) antagonist, Sodium-dependent dopamine transporter modulator, and Sodium-dependent noradrenaline/serotonin transporter modulators and MAO antagonist, Alpha and Beta adrenergic receptor agonist.
• Effects: Elevated catecholamine levels, arousal, reduced sleep, euphoria, abnormal movements, psychotic episodes, effects on serotonin transmission (hallucinogenic), and effects on anorexia and hyperthermia.
• Toxicity: Acute amphetamine overdose causes hyperthermia, respiratory depression, seizures, metabolic acidosis, renal failure, hepatic injury, coma, neurologic effects (agitation, hallucinations), cardiovascular effects (arrhythmias, myocardial infarctions), GI tract effects (pain, vomiting), and adrenal medulla/neurotransmission effects.

Amphetamine Type Continued

• Factors Leading to Toxicity: Mitochondrial dysfunction, oxidative stress, excitotoxicity, and hyperthermia.
• Elimination: Urine (40%–90% within 72 hours), and pH dependent.

Lysergic Acid Diethylamide (LSD)

• Mechanism of Action: Activates serotonin 5-HT2A receptors, enhances glutamatergic transmission. Repeated doses result in rapid downregulation.
• Target: 5-hydroxytryptamine receptor 1A, 2B, 6 agonist.
• Effects: Mood alteration, anxiety, tachycardia, increased blood pressure and body temperature, dizziness, decreased appetite, sweating, loss of judgment.

Marijuana

• Components: Cannabis sativa and Cannabis indica; over 400 chemical compounds, including 61 cannabinoids (THC and CBD).
• Mechanism of Action: THC acts as a weak partial agonist at cannabinoid-1 (CB1R) and cannabinoid-2 (CB2R) receptors. CBD acts as a negative allosteric modulator of CB1 receptors.
• Effects: Increased appetite, reduced pain, and changes in emotional & cognitive processes.

Marijuana Continued

• Targets: Cannabinoid receptor 1 & 2 modulator, glycine receptor subunit alpha-1, -3, alpha-1/beta, N-arachidonyl glycine receptor agonist.

Nicotine

• Source: Principal neuroactive alkaloid in tobacco.
• Mechanism of Action: Binds stereo-selectively to nicotinic cholinergic receptors, stimulating autonomic ganglia and the adrenal medulla, and having effects on the locus ceruleus and limbic system. Results in reward and increased stimulation.
• Effects: Stimulation effects, potentially leading to addiction and withdrawal symptoms.
• Targets: Neuronal acetylcholine receptor subunit alpha-3, -4, -5, -6, -7, -9, -10; beta-2, -3, -4 agonist. Cytochrome P450 19A1 antagonist, Choline O-acetyltransferase antagonist.

Nicotine Continued

• Toxicity: Addiction, adverse health effects.
• Mechanisms of Nicotine-Induced Plasticity: Upregulation and downregulation of nAChRs, interactions in catecholaminergic, GABAergic and glutamatergic neurotransmission, and structural changes in specific neural structures.

Ethanol

• Characteristics: Clear, colorless liquid readily absorbed from the GI tract, distributed throughout the body and having antibacterial activity (used as topical disinfectant; widely used as solvent and preservative in pharmacy, and as base of alcoholic beverages.)
• Mechanism of Action: Affects membranes, ion channels, and various receptor sites (GABA, Glycine, NMDA, Ach, serotonin.) Alters osmolyte balance.
• Effects: Reduced inhibition, increased excitation, mesolimbic depression, reduced DA release, dysphoria, anxiety, seizures, confusion, and increased sensitivity to stress.
• Absorption: Rapidly absorbed, reaching peak blood levels within 30 minutes.
• Metabolism: Primarily metabolized by alcohol dehydrogenase (ADH) in the stomach and liver, followed by other enzymes.
• Elimination: 40% eliminated in urine (pH dependent) 72h after oral administration.
• Targets: GABA receptor-operated channels, Glycine receptor-operated channels, NMDA receptor-operated channels, Nicotinic ACh receptor-operated channels, Serotonin receptor-operated channels, G-protein couples inwardly rectifying K channels and voltage-gated calcium channels/Large-conductance Ca2+/voltage-activated K channels. (Slo1 containing subunits).
• Treatment Medications: Disulfiram (inhibits ALDH), Naltrexone (µ-opioid receptor antagonist), Acamprosate (unknown mechanism, inhibits glutamate state, reduces sensations for alcohol).