Drugs of abuse Flashcards
Ethanol influences several cellular functions:
- GABAA receptors
- Kir3/GIRK channels
- Adenosine reuptake
- Glycine receptors
- NMDA receptors
- 5-HT3 receptors.
Delirium tremens
Occurs 48-72 hours post alcohol withdrawal.
Delirium tremens is associated with 5-15% mortality
Three drugs are FDA-approved for treatment of alcoholism:
- Disulfiram: Aldehyde dehydrogenase inhibitor. Used to create aversion to drinking.
- Naltrexone: Orally available opioid antagonist. Reduces craving for alcohol.
- Acamprosate: NMDA receptor antagonist. Prevents relapse.
TREATMENT OF ALCOHOL WITHDRAWAL
- Long half-life benzodiazepines are the preferred agents: Diazepam and chlordiazepoxide.
- Because of their long half-life, withdrawal is smoother, and rebound withdrawal symptoms are less likely to occur.
- Lorazepam and oxazepam are intermediate-acting drugs.
- Not as dependent on hepatic metabolism as other benzodiazepines,
- They may be preferable in the elderly and those with liver failure.
TREATMENT OF ALCOHOL ADDICTION:
Topiramate
- Facilitates GABA function, antagonizes glutamate receptors.
- May reduce cravings.
- Not FDA-approved
BENZODIAZEPINES: WITHDRAWAL SYNDROME
- Signs and symptoms include: tremors, anxiety, perceptual disturbances, dysphoria, psychosis, and seizures.
- The syndrome can be life-threatening.
MANAGEMENT OF BENZODIAZEPINE WITHDRAWAL
- If the patient is on a short-acting drug, they are switched to a long-acting drug.
- Diazepam is the most used agent.
- Then the dose is gradually reduced
PSYCHOSTIMULANTS
Methylxanthines
- Caffeine, theophylline & theobromine.
Cocaine
Amphetamines
Methylxanthines
- Caffeine, theophylline & theobromine.
MOA
- Methylxanthines block presynaptic adenosine receptors.
- Activation of adenosine receptors inhibits norepinephrine release.
- Therefore blockade of adenosine receptors increases norepinephrine release
METHYLXANTHINES: ACTIONS on CNS
- 100–200 mg caffeine (1 - 2 cups of coffee) cause decrease in fatigue and increased mental alertness.
- 1.5 g caffeine (12 to 15 cups of coffee) produces anxiety and tremors.
- The spinal cord is stimulated only by very high doses (2–5 g) of caffeine.
COCAINE: MECHANISM OF ACTION
- Cocaine inhibits dopamine, norepinephrine and serotonin reuptake.
- The prolongation of dopaminergic effects in the brain’s limbic system produces the intense euphoria that cocaine initially causes.
COCAINE: ACTIONS CNS
CNS
• Stimulation of cortex and brainstem.
• Increases mental awareness and produces a feeling of well-being and euphoria.
• Paranoia may occur after repeated doses.
• At high doses: tremors and convulsions, followed by respiratory and vasomotor depression.
COCAINE: ACTIONS SNS
SYMPATHETIC NERVOUS SYSTEM
• Peripherally, cocaine potentiates the action of norepinephrine resulting in adrenergic stimulation.
• Adrenergic stimulation produces the characteristic physical findings of tachycardia, hypertension, mydriasis, and diaphoresis.
COCAINE: WITHDRAWAL SYNDROME
tx for addiction?
- Dysphoria, depression, sleepiness, fatigue, cocaine craving and bradycardia.
- Cocaine withdrawal is generally mild.
- Treatment of withdrawal symptoms is usually not required.
- No effective tx for cocaine addiction!
AMPHETAMINES: MECHANISM OF ACTION
- Amphetamines increase release of catecholamines.
- They are also weak inhibitors of MAO.
- They are also possible direct catecholaminergic agonists in the brain.
AMPHETAMINES: USES
- Attention deficit syndrome: Amphetamine and methylphenidate.
- Narcolepsy: Amphetamine and methylphenidate
NICOTINE: MECHANISM OF ACTION
- Full agonist of the nicotine receptor.
- The rewarding effect of nicotine requires involvement of the ventral tegmental area , where nicotinic receptors are expressed on dopamine neurons.
- When nicotine excites these neurons, dopamine is released.
NICOTINE: ACTIONS CNS
- Cigarette smoking or administration of low doses of nicotine produces some degree of euphoria and relaxation.
- Improves attention, learning, problem solving, and reaction time.
- High doses of nicotine result in central respiratory paralysis and severe hypotension caused by medullary paralysis.
- Nicotine is an appetite suppressant.
TREATMENT FOR NICOTINE ADDICTION
NICOTINE REPLACEMENT THERAPY
• Nicotine can be administered by transdermal patch, gum, nasal spray, vapor inhaler or by lozenge for buccal absorption.
SUSTAINED-RELEASE BUPROPION
• Mechanism unclear.
VARENICLINE
• Partial agonist at nicotinic receptors in the CNS.
OPIOIDS
most commonly abused?
Among health professionals?
The most commonly abused opioids are heroin, morphine, codeine and oxycodone, and –among health professionals- meperidine and fentanyl.
OPIOIDS: TOLERANCE, DEPENDENCE & WITHDRAWAL
- All opioids induce strong tolerance and dependence.
- Addiction to heroin or other short-acting opioids produces behavioural disruptions and usually is incompatible with a productive life.
- The withdrawal syndrome is unpleasant but not life-threatening.
- It includes dysphoria, lacrimation, rhinorrhea and yawning.
OPIOIDS: TREATMENT OF OPIOID WITHDRAWAL
DETOXIFICATION USING OPIOID AGONISTS
• The illicit agent is replace by a long-acting opioid.
• The dose is slowly reduced.
• Drugs used: Methadone or buprenorphine.
OPIOIDS: TREATMENT OF OPIOID WITHDRAWAL:
DETOXIFICATION USING ADRENERGIC AGONISTS
Drugs used: Clonidine and lofexidine. They are α2 agonists.
• Chronic opioid intake leads to tolerance to the effects of opioids on the ANS, mediated by adrenergic pathways.
• Withdrawal leads to a rebound firing of the neurons.
• A noradrenergic storm results and is responsible for many of the withdrawal symptoms.
- NALTREXONE for those who choose to remain opioid free
MARIJUANA: MECHANISM OF ACTION
- Two cannabinoid receptor subtypes:CB1 & CB2.
- Both are G protein-linked receptors.
- Both couple to Gi.
- CB1 receptors are found primarily in the brain and mediate the psychological effects of THC.
- CB2 receptors are present mainly on immune cells.
MARIJUANA: ACTIONS
- THC can produce euphoria, followed by drowsiness and relaxation.
- Affects short-term memory and mental activity.
- Impairs highly skilled motor activity.
- Other effects: appetite stimulation, xerostomia, visual hallucinations, delusions, enhancement of sensory activity.
- At high doses: toxic psychosis
MARIJUANA: USES
- Therapeutic THC is called dronabinol.
- Dronabinol is FDA-approved for:
- Anorexia associated with weight loss in patients with AIDS.
- Nausea and vomiting associated with cancer chemotherapy (second line).
PSYCHEDELIC AGENTS
LSD MESCALINE PSILOCIBIN PHENCICLIDINE MDMA
LSD: MECHANISM OF ACTION
The hallucinogenic actions of LSD appear to be mediated by agonist effects at 5-HT2 receptors in the CNS.
LSD: CLINICAL PRESENTATION
present with a combination of somatic and psychomimetic symptoms.
• Somatic symptoms are usually due to sympathomimetic effects.
• Somatic symptoms include: mydriasis, hypertension, tachycardia, increased body temperature, flushing, sweating, tremors and piloerection.
PHENCYCLIDINE (PCP) MOA
- Dissociative anesthetic.
- Blocks reuptake of norepinephrine and dopamine.
- Causes cholinergic and anticholinergic effects.
- Has actions at nicotinic and opioid receptors.
The dissociative properties of PCP are believed to be due to its actions as a non-competitive antagonist at NMDA recept
PHENCYCLIDINE: CLINICAL PRESENTATION
- Clinical manifestations include violent or bizarre behavior, psychosis, nystagmus, tachycardia, hypertension, diaphoresis, miosis, anesthesia, and analgesia.
- An important diagnostic clue is nystagmus.
