Drugs Acting on the CNS - MBBS Overview

1. Sedative-Hypnotic Drugs

• Mechanism: Enhance GABA-A receptor activity by increasing Cl- channel opening frequency
• Uses: Anxiety, insomnia, epilepsy, alcohol withdrawal, pre-anesthesia
• Key advantage: Safer than barbiturates - dose-response curve plateaus before lethal doses
• Antidote: Flumazenil (benzodiazepine antagonist)
• Note: Lorazepam and oxazepam are preferred in elderly due to less age-related pharmacokinetic change

• Mechanism: Enhance GABA-A at a different site - increase Cl- channel opening duration
• Linear dose-response: sedation → hypnosis → anesthesia → respiratory depression → death
• Uses: Epilepsy (phenobarbitone), induction of anesthesia (thiopental)
• High overdose risk; largely replaced by benzodiazepines

• Zolpidem, zaleplon, eszopiclone
• Act on BZD site of GABA-A receptor; more sleep-selective
• Less residual sedation ("hangover")

• Anxiolytic without sedation or addiction
• Mechanism: Partial agonist at 5-HT1A receptors
• Onset delayed (1-2 weeks); not for acute anxiety

2. General Anesthetics

• Examples: Halothane, isoflurane, sevoflurane, desflurane, nitrous oxide
• Mechanism: Not fully understood - likely enhance inhibitory (GABA-A) and inhibit excitatory (NMDA) receptors; may act on lipid membranes
• Potency measured by MAC (Minimum Alveolar Concentration) - the lower the MAC, the more potent
• Nitrous oxide: weak anesthetic but excellent analgesic; used in combination

• Propofol: GABA-A agonist; rapid induction/recovery; antiemetic; used for TIVA
• Ketamine: NMDA antagonist; produces "dissociative anesthesia"; preserves airway reflexes; bronchodilator; can cause emergence delirium
• Thiopental: Ultra-short acting barbiturate; still used for induction
• Etomidate: Minimal cardiovascular depression; preferred in haemodynamically unstable patients
• Dexmedetomidine: α2 agonist; sedation with preserved airway

3. Opioid Analgesics

• Morphine: Prototype; used for severe acute and cancer pain; causes constipation, nausea, respiratory depression, miosis
• Fentanyl: 100x more potent than morphine; used in anesthesia and patches
• Codeine: Prodrug converted to morphine by CYP2D6; also antitussive
• Oxycodone, hydromorphone, meperidine (pethidine)

• Buprenorphine: Partial μ agonist, κ antagonist; used in opioid dependence and pain
• Pentazocine: Mixed agonist-antagonist; can precipitate withdrawal

• Naloxone: Pure antagonist; used for opioid overdose reversal (IV); short acting
• Naltrexone: Oral; used for opioid and alcohol dependence

4. Antiepileptic Drugs (AEDs)

• Ethosuximide: drug of choice for absence (petit mal) seizures
• Valproate: broad spectrum but teratogenic (neural tube defects)
• Phenytoin: zero-order kinetics; narrow therapeutic index; gingival hyperplasia, hirsutism
• Carbamazepine: drug of choice for trigeminal neuralgia; induces CYP450
• Lamotrigine: used in bipolar disorder too

5. Antipsychotic Drugs

• Mechanism: D2 receptor blockade
• Examples: Chlorpromazine (low potency), haloperidol (high potency), fluphenazine, trifluoperazine
• Uses: Schizophrenia, mania, psychotic agitation
• ADRs: Extrapyramidal symptoms (EPS) - akathisia, dystonia, parkinsonism, tardive dyskinesia; anticholinergic effects (dry mouth, urinary retention), orthostatic hypotension (α1 block), neuroleptic malignant syndrome (NMS)

• Mechanism: D2 + 5-HT2A blockade (lower EPS risk)
• Clozapine: Most effective for treatment-resistant schizophrenia; risk of agranulocytosis (requires CBC monitoring)
• Olanzapine, quetiapine, risperidone, aripiprazole, ziprasidone
• ADRs: Metabolic syndrome (weight gain, dyslipidemia, diabetes - especially olanzapine/quetiapine)
• Aripiprazole: Partial D2 agonist; weight neutral

6. Antidepressants

• Fluoxetine, sertraline, paroxetine, citalopram, escitalopram
• Mechanism: Block serotonin transporter (SERT); increase synaptic 5-HT
• First-line for MDD, anxiety, OCD, PTSD, PMDD
• ADRs: Sexual dysfunction, GI upset, insomnia, serotonin syndrome (with MAOIs), SIADH
• Fluoxetine: Longest half-life (active metabolite norfluoxetine); fewer discontinuation symptoms

• Venlafaxine, duloxetine, desvenlafaxine
• Used for depression, anxiety, and neuropathic pain (duloxetine)

• Imipramine, amitriptyline, clomipramine, nortriptyline
• Mechanism: Block 5-HT and NE reuptake + anticholinergic + antihistamine effects
• Highly effective but narrow therapeutic index; lethal in overdose (cardiac arrhythmias)
• Amitriptyline: used in neuropathic pain and migraine prophylaxis
• Clomipramine: drug of choice for OCD (most serotonergic TCA)

• Phenelzine, tranylcypromine (irreversible); moclobemide (reversible - RIMA)
• Mechanism: Inhibit MAO-A/B → increase monoamines
• Serious interactions: Tyramine (cheese reaction → hypertensive crisis), meperidine, serotonergic drugs
• Reserved for treatment-resistant depression

• Mirtazapine: α2 antagonist + 5-HT2/3 blocker; weight gain; good for elderly with poor appetite
• Bupropion: NE/DA reuptake inhibitor; used for depression and smoking cessation; no sexual dysfunction; lowers seizure threshold
• Trazodone: 5-HT2A antagonist + SERT block; sedating; used for insomnia

7. Drugs for Parkinson's Disease

• Levodopa + Carbidopa: Gold standard. Levodopa crosses BBB; carbidopa inhibits peripheral decarboxylation, reducing side effects and increasing CNS availability. Causes "on-off" fluctuations with long-term use.
• Dopamine agonists: Bromocriptine, pramipexole, ropinirole - act directly on D2 receptors; used as adjuncts or early monotherapy
• MAO-B inhibitors: Selegiline, rasagiline - inhibit dopamine breakdown in brain
• COMT inhibitors: Entacapone, tolcapone - prolong levodopa effect by blocking peripheral/central COMT

• Benztropine, trihexyphenidyl
• Reduce excessive cholinergic activity; particularly useful for tremor and young patients

8. Drugs for Alzheimer's Disease

• Donepezil, rivastigmine, galantamine
• Increase ACh in synaptic cleft; slow symptomatic progression

• Memantine - blocks excitotoxic glutamate effects

9. CNS Stimulants

• Amphetamines (amphetamine, methamphetamine): Release DA and NE; used for ADHD, narcolepsy
• Methylphenidate (Ritalin): Blocks DA/NE reuptake; first-line for ADHD
• Modafinil: Promotes wakefulness; mechanism unclear; used for narcolepsy and shift-work disorder
• Caffeine: Adenosine receptor antagonist; weakest stimulant; found in OTC headache medications
• Cocaine: Local anesthetic + monoamine reuptake blocker; high abuse potential

10. Drugs for Bipolar Disorder

• Lithium: Mechanism not fully understood - may inhibit inositol phosphatase and GSK-3β; narrow therapeutic index (0.6-1.2 mEq/L); monitor thyroid and renal function; teratogenic (Ebstein's anomaly)
• Valproate: Broad-spectrum mood stabilizer; first-line for rapid cycling and mixed states
• Carbamazepine: Especially useful in bipolar with neurological comorbidity
• Atypical antipsychotics: Quetiapine, olanzapine - also approved for bipolar

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