Neuropharmacology

Drugs of Abuse & CNS Agents

Mechanisms, toxicity, withdrawal syndromes, and clinical pharmacology of major central nervous system drugs.

🧠 Overview · Drugs of Abuse

  • Substances that produce psychoactive effects and carry a risk of dependence, tolerance, and withdrawal
  • Act primarily on central neurotransmitter systems:
    • Dopamine (DA) β€” reward, motivation, psychosis
    • Norepinephrine (NE) β€” arousal, sympathetic tone
    • Serotonin (5HT) β€” mood, perception, appetite
    • GABA β€” inhibitory tone, sedation, anxiolysis
    • Endogenous opioid system β€” analgesia, euphoria
  • Key clinical concerns:
    • Acute toxicity β€” overdose, seizures, hyperthermia, cardiorespiratory depression
    • Withdrawal syndromes β€” vary by drug class; may be life-threatening (e.g., alcohol, barbiturates)
    • Long-term sequelae β€” organ damage, neuropsychiatric disorders, infectious complications
  • Withdrawal severity and danger correlate with the drug's receptor adaptation and dependence liability
  • Management often requires supportive care, symptom-triggered therapy, and long-term psychosocial support

⚑ CNS Stimulants

  • Primary agents: cocaine, amphetamines (including methamphetamine)
  • Shared neurotransmitter targets: NE, DA, 5HT

❄️ Cocaine

  • Mechanism: blocks reuptake of DA, NE, and 5HT at presynaptic transporters
  • Also exerts local anesthetic effect via Na⁺ channel blockade
  • Effects:
    • NE-mediated: tachycardia, hypertension, mydriasis, hyperthermia
    • DA-mediated: euphoria, paranoia, stereotyped behaviors, psychosis
    • 5HT-mediated: aggression, dyskinesias, appetite suppression
  • Toxicity:
    • Cardiac: arrhythmias, ischemia, MI, stroke
    • Neuropsychiatric: cocaine delirium, major psychosis, seizures
    • Serotonin syndrome possible
    • Hyperpyrexia, multiorgan failure
  • Withdrawal:
    • Intense craving, anhedonia, profound depression, anxiety
    • Managed with antidepressants and supportive care

πŸ’Š Amphetamines

  • Mechanism:
    • Block reuptake of NE and DA
    • Promote release of amines from the mobile cytoplasmic pool
    • Weak MAO inhibitors
  • Effects: sympathomimetic (similar to cocaine), psychostimulation, euphoria, decreased appetite
  • Toxicity:
    • Cardiovascular: arrhythmias, hypertensive crises, stroke
    • Psychiatric: psychosis, paranoia, agitation
    • Hyperthermia, rhabdomyolysis
  • Withdrawal:
    • Similar to cocaine: depression, fatigue, craving, anhedonia
    • May be prolonged; managed with antidepressants
FeatureCocaineAmphetamines
Primary MOAReuptake blockade (DA, NE, 5HT)Reuptake blockade + release + weak MAOI
Local anestheticYes (Na⁺ channel)No
Psychosis riskHigh (DA-mediated)High (DA-mediated)
Withdrawal dangerModerate (not life-threatening)Moderate (not life-threatening)

πŸ’€ CNS Depressants

  • Primary classes: benzodiazepines, barbiturates, ethanol
  • Key neurotransmitter: GABA β€” the major inhibitory neurotransmitter in the CNS

πŸ’Š Benzodiazepines

  • Mechanism:
    • Positive allosteric modulation of GABAA receptors
    • Bind to BZ1 and BZ2 sites to enhance GABA affinity
    • Increase frequency of Cl⁻ channel opening
  • Effects: light to moderate CNS depression, anxiolysis, sedation, anterograde amnesia, muscle relaxation
  • Toxicity:
    • Overdose: sedation, respiratory depression (less severe than barbiturates)
    • Antidote: flumazenil (competitive antagonist)
  • Withdrawal: rebound insomnia, rebound anxiety, tremors; can be protracted

πŸ’Š Barbiturates & Ethanol

  • Barbiturate mechanism:
    • Prolong GABA-mediated Cl⁻ channel opening
    • At high doses, act as GABA mimetics
  • Ethanol mechanism:
    • Enhances GABAA receptor function
    • Also inhibits NMDA receptors (glutamate)
  • Effects: any plane of CNS depression β€” from sedation to coma
  • Toxicity:
    • Severe respiratory depression, apnea, coma, death
    • Barbiturate overdose: no specific antidote (supportive care)
  • Withdrawal (barbiturates):
    • Agitation, anxiety, hyperreflexia, tremors
    • Life-threatening seizures
  • Withdrawal (ethanol):
    • Autonomic hyperactivity, tremor, seizures
    • Delirium tremens (DTs): hallucinations, delusions, severe agitation
    • Medical emergency; manage with benzodiazepines
  • Barbiturate and ethanol withdrawal can be fatal β€” seizures and delirium tremens require aggressive inpatient management
  • Benzodiazepine withdrawal is less dangerous but still clinically significant

πŸ’Š Opioids

  • Prototypical agents: morphine, heroin, methadone, fentanyl
  • Neurotransmitters involved: NE, DA, 5HT, GABA, and others
  • Mechanism of action:
    • Activate ΞΌ (mu), ΞΊ (kappa), and Ξ΄ (delta) opioid receptors
    • ΞΌ-receptor agonists have the highest abuse and dependence liability
    • ΞΌ-receptor activation β†’ increased dopaminergic transmission in the mesolimbic reward pathway
  • Clinical effects:
    • Euphoria, analgesia, sedation
    • Cough suppression, constipation
    • Miosis (pinpoint pupils) β€” except meperidine, which causes mydriasis
  • Toxicity:
    • Severe respiratory depression β€” the most dangerous acute effect
    • Nausea, vomiting, pruritus, urinary retention
    • Antidote: naloxone (competitive ΞΌ-receptor antagonist)
  • Withdrawal:
    • Early: lacrimation, yawning, diaphoresis, rhinorrhea, restlessness
    • Progressive: muscle cramps, bone pain, diarrhea, vomiting, piloerection
    • Not life-threatening in healthy individuals (unlike alcohol or barbiturates)
AgentReceptor ActivityKey Features
MorphineFull ΞΌ agonistGold standard; extensive metabolism
HeroinFull ΞΌ agonist (pro-drug)Rapid CNS penetration; high abuse potential
MethadoneFull ΞΌ agonistLong half-life; used for maintenance therapy
FentanylFull ΞΌ agonistVery potent; high lipophilicity; rapid onset
BuprenorphinePartial ΞΌ agonistCeiling effect; lower respiratory depression risk
NaloxoneCompetitive antagonistReverses respiratory depression; short half-life
  • Miosis is a hallmark of opioid intoxication β€” meperidine is the exception (anticholinergic-like mydriasis)
  • Naloxone reversal of respiratory depression may precipitate acute withdrawal in dependent patients

πŸŒ€ Hallucinogens

  • Primary classes: marijuana (cannabinoids) and classic hallucinogens (LSD, psilocybin, mescaline)

🌿 Marijuana (Cannabis)

  • Active component: Δ⁹-tetrahydrocannabinol (THC)
  • Mechanism:
    • Interacts with CB1 (CNS) and CB2 (peripheral) cannabinoid receptors
    • Modulates neurotransmitter release (inhibitory presynaptic effects)
  • Effects:
    • Sedation, euphoria, relaxation
    • Tachycardia, conjunctival injection (red eyes)
    • Altered perception, delusions, hallucinations at high doses
  • Toxicity:
    • Acute: anxiety, panic, paranoia, impaired coordination
    • Chronic: cognitive impairment, respiratory issues (smoking), possible flashbacks
  • Withdrawal: irritability, anxiety, insomnia, decreased appetite β€” generally mild

πŸŒ€ Classic Hallucinogens

  • Examples: LSD, psilocybin, mescaline
  • Mechanism:
    • Primarily act on 5HT (serotonin) receptors β€” especially 5HT2A
    • Alter cortical processing and sensory gating
  • Effects:
    • Perceptual distortions, synesthesia, hallucinations
    • Sympathomimetic effects (tachycardia, hypertension, mydriasis)
    • Dysesthesias (altered tactile sensation)
  • Toxicity:
    • Acute: "bad trips" β€” panic, confusion, hyperthermia
    • Flashbacks (hallucinogen persisting perception disorder)
    • Poorly characterized long-term toxicity
  • Withdrawal: not well-characterized; no classic dependence syndrome
  • Classic hallucinogens have minimal physiological toxicity but significant psychological distress potential
  • Marijuana use is associated with impaired cognition and motivation, especially in adolescents

⚠️ Miscellaneous Abused Drugs

  • PCP (Phencyclidine):
    • NMDA-receptor antagonist (glutamate receptor)
    • Effects: analgesia, paranoia, dissociation
    • Distinctive signs: horizontal and vertical nystagmus
    • Toxicity: rhabdomyolysis, seizures, hyperthermia, coma, death
    • Overdose is common; management is supportive
  • Ketamine:
    • Similar to PCP but milder in effect
    • Glutamate-receptor antagonist (NMDA)
    • Produces dissociation, hallucinations, analgesia
    • Increasing use in treatment-resistant depression (sub-anesthetic doses)
  • Anticholinergics (e.g., scopolamine, atropine-like agents):
    • Block muscarinic acetylcholine receptors
    • Effects: delirium, confusion, dry mouth, tachycardia, urinary retention
    • Classic toxidrome: "red as a beet, dry as a bone, blind as a bat, mad as a hatter"
  • MDMA ("Ecstasy") & related compounds (MDA, MDEA):
    • Amphetamine-like structure with strong 5HT pharmacology
    • Effects: empathogenic, stimulant, hallucinogenic
    • Toxicity: hyperthermia, hyponatremia, serotonin syndrome
    • Long-term: neurotoxicity (serotonergic neuron damage)
  • Inhalants (solvents, nitrites, aerosols):
    • Multiple organ damage β€” CNS, liver, kidneys, bone marrow
    • Acute: "sudden sniffing death" β€” cardiac arrhythmia or asphyxia
    • Chronic: peripheral neuropathy, encephalopathy, cognitive decline
  • PCP intoxication should be suspected in patients with nystagmus, agitation, and rhabdomyolysis
  • MDMA toxicity often presents with hyperthermia and hyponatremia β€” aggressive cooling and fluid management are critical

πŸ“‹ CNS Drug Classifications

Sedative-Hypnotics

  • Barbiturates: phenobarbital
  • Benzodiazepines: alprazolam, diazepam, lorazepam, oxazepam
  • Others: buspirone, zolpidem, zaleplon
  • Antagonist: flumazenil (BZ receptor antagonist)

Anticonvulsants

  • Carbamazepine, ethosuximide, valproic acid, phenytoin
  • Diazepam, lorazepam (acute seizure control)
  • Gabapentin, lamotrigine, felbamate, topiramate
  • Tiagabine, vigabatrin

Anesthetics (IV)

  • Fentanyl, ketamine, midazolam
  • Propofol, thiopental

Anesthetics (Inhaled)

  • Desflurane, sevoflurane, nitrous oxide

Local Anesthetics

  • Lidocaine, bupivacaine, mepivacaine, procaine
  • Cocaine (also a local anesthetic via Na⁺ channel blockade)

Skeletal Muscle Relaxants

  • Depolarizing: succinylcholine
  • Nondepolarizing: rocuronium, atracurium

Opioid Analgesics

  • Full agonists: morphine, meperidine, methadone, fentanyl, heroin
  • Partial agonists: buprenorphine, codeine
  • Mixed agonist-antagonists: nalbuphine
  • Antagonists: naloxone, naltrexone, methylnaltrexone

Antipsychotics

  • Typicals: chlorpromazine, fluphenazine, thioridazine, haloperidol
  • Atypicals: clozapine, risperidone, olanzapine, aripiprazole, quetiapine, ziprasidone

Antiparkinsonian Drugs

  • DA agonists: levodopa, bromocriptine, pramipexole
  • MAO-B inhibitor: selegiline
  • AAAD inhibitor: carbidopa
  • Muscarinic blockers: benztropine, trihexyphenidyl
  • COMT inhibitor: tolcapone
  • DA releaser + M blocker: amantadine

Antidepressants

  • MAOIs: phenelzine, tranylcypromine
  • TCAs: amitriptyline, imipramine, clomipramine
  • SSRIs: fluoxetine, paroxetine, sertraline
  • Others: bupropion, mirtazapine, trazodone, venlafaxine

Bipolar Disorder

  • Lithium (mood stabilizer)

ADHD

  • Methylphenidate (stimulant)
  • Atomoxetine (non-stimulant, NE reuptake inhibitor)
  • Understanding drug class mechanisms is essential for predicting adverse effects, drug interactions, and withdrawal syndromes
  • Many CNS drugs have overlapping mechanisms β€” receptor binding profiles determine clinical use and side-effect patterns