Pharma Lecture 12

Pharmacological Treatments of Addiction

• Lecture 12, Psychopharmacology (CPY 490)
• Objectives: Describe drug use disorders, commonly abused drugs, their mechanism of action and effects, and describe treatments of drug-related disorders (intoxication, withdrawal, and dependence)

Substance-Related Disorders

• DSM-5 classifies substance-related disorders into:
  • Substance use disorders (e.g., addiction)
  • Substance-induced disorders (e.g., intoxication, withdrawal, substance-induced mental disorders)

Substance-Related Disorders (continued)

• Addiction: Characterized by chronicity, impaired control of drug use, compulsive use, continued use despite harm, and craving.
• Intoxication: A substance-specific syndrome caused by recent substance ingestion and presence in the body.
• Physical dependence: A state of adaptation manifested by a drug class-specific withdrawal syndrome, produced by abrupt cessation.
• Tolerance: A reduction in drug's effects over time due to adaptation from drug exposure

Commonly Abused Substances

• Central nervous system depressants: Alcohol, Benzodiazepines, Opiates (Heroin, Hydrocodone)
• Central nervous system stimulants: Cocaine, Amphetamines (Methamphetamine)
• Hallucinogens: Marijuana/Hashish, Cannabinoids
• Other substances: Nicotine

Neurological Model of Drug Addiction

• Activation of reward mesolimbic dopaminergic pathway (acute mechanism).
• Most significant pathway: Ventral tegmental area (VTA) to nucleus accumbens (NAC) via dopamine.
• Other pathways: Include emotional and memory processing in the frontal cortex.
• Addictive drugs increase dopamine release in the brain's reward regions promoting repeated intake, leading to addiction.
• Adaptation occurs following prolonged exposure.

Mechanisms of Drug Abuse

• Direct effects: Drugs increase dopamine transmission by inhibiting reuptake or causing direct dopamine release.
• Indirect effects: Drugs inhibit GABA, which indirectly increases dopamine release.
• Other neurotransmitters : Serotonin has hallucinogenic effects.

Mechanisms of Drug Abuse (Opiates)

• Opiates bind to opiate receptors on presynaptic neurons, inhibiting GABA (inhibitory of dopamine), leading to massive dopamine efflux into the synaptic cleft.

Mechanisms of Drug Abuse (Benzodiazepines and Barbiturates)

• Benzodiazepines and barbiturates activate GABA-A receptors, reducing GABA release. This disinhibits dopamine, increasing dopamine levels.

Alcohol

• Also known as ethanol, the most commonly abused substance.
• Mechanism of action: Enhances the effects of the inhibitory neurotransmitter GABA, acting as a CNS depressant.
• High doses can cause coma and respiratory depression.
• Withdrawal symptoms exist.
• Chronic alcohol abuse linked to severe health effects: cardiomyopathy, fatty liver, alcoholic hepatitis, cirrhosis, myopathy, pancreatitis, testicular atrophy (males), fetal alcohol syndrome, and spontaneous abortion (females).

Cocaine

• CNS stimulant with low oral bioavailability.
• Often snorted, solubilized, or injected (crack cocaine can be smoked).
• Effects include euphoria, agitation, tachycardia, hypertension, respiratory failure, hyperthermia, chest pain, convulsion.

Amphetamines

• CNS stimulants with clinical effects and toxicity management similar to cocaine.

Treatments of Drug-Related Disorders

• Treat intoxication (e.g., overdose): Use antagonists (antidotes) to reverse substance effects; only if necessary, symptomatic.
• Treat withdrawal symptoms: Use agonists for longer duration, and milder withdrawal; gradual discontinuation.
• Treat dependence: Aim to prevent relapse through anti-craving medications.

Treatments of Intoxication

• Avoid drug therapy if possible.
• Drug therapy might be needed if patients are agitated, combative, or psychotic, usually through IV/IM medications for short-term use (few doses)
• Immediate toxicology screening (blood or urine).

Treatments of Intoxication (Benzodiazepines and Opiates Overdose)

• Benzodiazepine overdose :Flumazenil, Caution: not for all cases, risks of seizures, precipitates withdrawal.
• Opiate intoxication: Naloxone, Use to revive patients with respiratory depression, precipitates withdrawal.

Treatments of Intoxication (Cocaine and Hallucinogens)

• Cocaine intoxication: Pharmacologic treatment only if patient is agitated or psychotic, use lorazepam, antipsychotics, treat seizures supportively.
• Hallucinogen intoxication: reassurance, antianxiety and/or antipsychotic medications.

Treatment of Withdrawal from Drugs of Abuse

• Alcohol: Maintain fluids and electrolyte balance, vitamin deficiencies; benzodiazepines (lorazepam preferred) during detoxification.
• Alcohol withdrawal seizures: Supportive care unless they progress to status epilepticus.
• Benzodiazepine withdrawal: Use the same drugs and dosages as used for alcohol withdrawal (lorazepam).
• Opiates: Methadone, synthetic opiate, taper dosing. Clinicians use schedules of 30–180 days.

Treatments of Substance Use Disorders

• Primarily behavioral-based.
• Lifelong process aiming to prevent relapses, commonly done using anti-craving treatment methods.

Treatment of Alcohol Dependence

• Medications: Disulfiram (Antabuse), Naltrexone, Acamprosate, antidepressants, mood stabilizers.
• Disulfiram: Deterrent, averse reaction upon alcohol consumption.
• Naltrexone/Others: Anti-craving medication, usually for long-term maintenance.

Disulfiram

• Inhibits aldehyde dehydrogenase, prolonging alcohol metabolism.
• Requires close monitoring of liver function especially in patients with hepatic disorders.

Naltrexone

• Opioid antagonist, reducing craving and drinking days.
• Contraindicated for currently opioid-dependent patients as it can induce withdrawal.
• Monthly intramuscular (depot) formulation for long-term use. Liver failure and hepatitis patients need close observation.

Treatment of Nicotine

• First line treatments- Bupropion sustained release, Nicotine Replacement Therapy (nicotine gum, inhaler, lozenge, nasal spray, patch), Varenicline.
• Second line treatments- Nortriptyline if first line treatments fail.

Bupropion

• Antidepressant. Contraindicated in patients with seizure disorder, anorexia nervosa, or recent use of monoamine oxidase inhibitors (within 14 days).
• Caution concerning concurrent use with other medications that lower seizure threshold.

Varenicline

• Partial nicotinic acetylcholine receptor agonist.
• Prescribed for 12 weeks; a second 12-week treatment may be needed for failure.
• Can result in higher cessation rates than bupropion.
• Behavioural adverse effects and cardiovascular events are potential side effects.