CNS basics

 

CENTRAL NERVOUS SYSTEM (CNS) – BASIC CONCEPTS (Detailed Notes)

(Rang & Dale + K.D. Tripathi integrated)

1. Organization of the Nervous System

The nervous system is divided into:

A. Central Nervous System (CNS)

• Brain + Spinal cord
• Functions: Integration, processing, higher functions (memory, emotion, cognition).

B. Peripheral Nervous System (PNS)

• Somatic NS: voluntary control of skeletal muscles
• Autonomic NS (ANS): involuntary, controls smooth muscles, glands, heart
• Sympathetic
• Parasympathetic
• Enteric NS

2. Neuron – Structure & Function

Basic functional unit.

Parts

• Dendrites → receive signals
• Cell body (Soma) → processes signals
• Axon → transmits signals
• Axon terminals → neurotransmitter release

Key Properties of Neurons

1. Excitability – respond to stimuli
2. Conductivity – transmit impulses
3. Secretion – release neurotransmitters

3. Synapse

A junction between two neurons.

Types:

• Chemical synapse (most common)
• Electrical synapse (gap junction)

Steps of synaptic transmission (chemical):

1. Action potential arrives
2. Voltage-gated Ca²⁺ channels open
3. NT vesicles fuse
4. NT released into synaptic cleft
5. NT binds to post-synaptic receptors
6. Response generated
7. NT termination by:
• reuptake
• enzymatic degradation
• diffusion

4. Neurotransmitters

(KDT classification)

Excitatory

• Glutamate
• Aspartate
• ACh (nicotinic sites)

Inhibitory

• GABA
• Glycine
• Serotonin (mostly inhibitory)

Modulatory

• Dopamine
• Noradrenaline
• Acetylcholine (muscarinic)
• Neuropeptides (substance P, endorphins)

5. Receptors in the CNS

Ionotropic (Fast)

Ligand-gated ion channels
Examples:

• NMDA, AMPA (Glutamate)
• GABA-A
• Nicotinic ACh
• Glycine

Characteristics:

• Rapid action
• Short duration
• Actions in milliseconds

Metabotropic (Slow)

G-protein coupled receptors
Examples:

• GABA-B
• Dopamine (D1, D2)
• Serotonin (5-HT1, 5-HT2)
• Muscarinic ACh
• Adrenergic receptors

Characteristics:

• Slow onset
• Longer duration
• Effects via second messengers

6. Blood–Brain Barrier (BBB)

(Rang & Dale + KDT)

Structure

• Tight junctions in brain capillaries
• Astrocyte foot processes
• Basement membrane

Functions

• Protect CNS from toxins
• Maintain stable environment
• Control drugs entering CNS

Drugs NOT crossing BBB

LMWH mnemonic:

• Large molecules
• Most proteins
• Water-soluble drugs
• Highly ionized drugs
• Heparin

Drugs that easily cross BBB

• Lipid soluble
• Unionized
• Small molecules
  Examples: benzodiazepines, barbiturates, opioids.

7. CNS Excitation & Inhibition Balance

A critical concept for drug actions.

Excitatory pathway

• Glutamate → NMDA/AMPA activation → Ca²⁺ influx
• Excess leads to excitotoxicity (stroke, trauma)

Inhibitory pathway

• GABA → GABA-A → Cl⁻ influx → Hyperpolarization
• Deficit leads to seizures

Clinical relevance

• Benzodiazepines ↑ GABA action → sedative / antiepileptic
• Ketamine blocks NMDA → dissociative anesthesia
• Antipsychotics block dopamine D2 receptors

8. Mechanism of Action of CNS Drugs

Three basic ways (KDT):

1. Modifying synthesis/storage/release of NT

• Amphetamine ↑ release
• Reserpine ↓ storage
• Botulinum toxin ↓ ACh release

2. Receptor agonists/antagonists

• Benzodiazepines → GABA-A agonists
• Antipsychotics → D2 blockers
• Ketamine → NMDA antagonist

3. Inhibiting NT termination

• SSRIs inhibit serotonin reuptake
• MAO inhibitors prevent breakdown
• Physostigmine → AChE inhibitor

9. CNS Depressants

1. Sedatives–Hypnotics (benzodiazepines, barbiturates)
2. Opioids
3. Alcohol
4. General anesthetics
   Mechanism: enhance GABA inhibition / reduce glutamate.

10. CNS Stimulants

1. Methylxanthines (caffeine)
2. Amphetamines
3. Cocaine
4. Nicotine
   Mechanism: increase catecholamines (DA, NA), block reuptake.

11. Plasticity & Adaptation (Rang & Dale)

• Neurons adapt to prolonged drug exposure
• Explains tolerance & dependence

Examples:

• ↓ GABA receptors → benzodiazepine tolerance
• ↑ NMDA → alcohol withdrawal seizures

12. Important Pathways (high-yield)

Dopaminergic pathways

1. Nigrostriatal → Parkinsonism
2. Mesolimbic → schizophrenia (positive symptoms)
3. Mesocortical → negative symptoms
4. Tuberoinfundibular → prolactin release

Serotonergic pathways

Mood, sleep, pain

Noradrenergic pathways

Attention, arousal

13. MNEMONICS (Exam-friendly)

BBB – Drugs that Cross Easily

"LIPID"

• Lipid soluble
• Ionization low
• Partition coefficient high
• Increases CNS entry
• Drugs like Diazepam

Neurotransmitters – Excitatory vs Inhibitory

"GAS IN"

·        Glutamate – Excitatory

·        ACh (nicotinic) – Excitatory

·        Substance P – Excitatory

·        Inhibitory → GABA

·        N → Noradrenaline (modulatory but mostly inhibitory in cortex)

Ionotropic vs Metabotropic

"FAST ION, SLOW META"

• IONotropic → FAST
• METAbotropic → SLOW

CNS Actions of Dopamine (DOPAMINE mnemonic)

• Drive (motivation)
• Opiate modulation
• Prolactin ↓
• Attention
• Motor control
• Inhibition
• Nausea
• Endocrine regulation

14. High-Yield Notes for DI / RRB / PharmD

• CNS drugs mainly act on ion channels or GPCRs.
• Lipid-solubility = most important factor for CNS penetration.
• Glutamate toxicity → stroke, trauma, ALS.
• GABA deficiency → seizures, anxiety.
• Dopamine blockade → EPS (drug-induced Parkinsonism).
• Receptor adaptation → tolerance and withdrawal.

CENTRAL NERVOUS SYSTEM (CNS) PHARMACOLOGY + CHEMISTRY (FULL NOTES)

1. GENERAL PRINCIPLES OF CNS DRUGS

1.1 BBB Entry Requirements (VERY IMPORTANT)

Lipophilic
Unionized
Small size
High lipid/water partition coefficient

Poor penetration: ionized, polar, protein-bound drugs.

1.2 Mechanisms by Which CNS Drugs Work

1. Modulate neurotransmitter synthesis, release, uptake, metabolism
2. Bind to receptors (agonist/antagonist)
3. Modulate ion channels
4. Alter signal transduction (GPCRs)

2. SEDATIVES & HYPNOTICS

Pharmacology

2.1 Benzodiazepines

Examples: Diazepam, Lorazepam, Alprazolam

Mechanism:
↑ Frequency of Cl⁻ channel opening via GABA-A.

Effects: anxiolytic, hypnotic, anticonvulsant, muscle relaxant.

Adverse effects: tolerance, dependence, anterograde amnesia.

2.2 Barbiturates

Phenobarbital, Thiopental

Mechanism:
↑ Duration of Cl⁻ channel opening (GABA-A).

More toxic + narrow therapeutic index.

2.3 Z-drugs (Non-BZDs)

Zolpidem, Zaleplon, Zopiclone
Selective α1 GABA-A agonists → sleep onset.

Medicinal Chemistry (SAR) – Sedatives/Hypnotics

2.4 Benzodiazepines SAR

Core: 1,4-benzodiazepine-2-one

Key points:

• 7-nitro / halogen → ↑ potency (e.g., clonazepam)
• 1-alkyl → ↑ lipid solubility
• 2-keto group essential
• Triazolo or imidazo ring → fast onset (e.g., alprazolam)

2.5 Barbiturates SAR

Core: Barbituric acid (pyrimidine-2,4,6-trione)

SAR:

• 5,5-disubstitution → hypnotic activity
• ↑ Carbon chain = ↑ lipophilicity = rapid onset
• Branched chain = ↑ hypnotic action
• Sulfur replacing O = thiobarbiturates (ultra-short acting)

2.6 Z-drugs SAR

Imidazopyridines
Pyrrolopyrimidines
Act on BZ1 (α1) site selectively.

3. ANTIPSYCHOTICS (NEUROLEPTICS)

Pharmacology

3.1 Typical Antipsychotics

Chlorpromazine, Haloperidol

Mechanism: D2 blockade
Effects: ↓ positive symptoms
ADR: EPS, tardive dyskinesia, hyperprolactinemia

3.2 Atypical Antipsychotics

Clozapine, Risperidone, Olanzapine, Quetiapine

Mechanism:
5-HT2A > D2 blockade (two-hit hypothesis)

Less EPS, helps ↓ negative symptoms.

Medicinal Chemistry (SAR) – Antipsychotics

3.3 Phenothiazines SAR

General structure: tricyclic ring + side chain at N-10

• Electron-withdrawing group at position 2 → ↑ potency
• Cl, CF3 (trifluoro)
• Side chain determines class:
• Aliphatic (chlorpromazine) – low potency
• Piperazine (prochlorperazine) – high potency
• Piperidine (thioridazine) – sedative, anticholinergic

3.4 Butyrophenones SAR

Haloperidol

• p-fluoro on benzene ↑ potency
• Tertiary amine side chain required
• Modifying ketone → diphenylbutylpiperidines (pimozide)

3.5 Atypical SAR (General)

• Dibenzodiazepines (clozapine) → multiple receptor blockade
• Benzisoxazoles (risperidone) → strong 5-HT2A affinity

4. ANTIDEPRESSANTS

Pharmacology

4.1 TCAs

Amitriptyline, Imipramine
Block reuptake of NE + 5-HT
ADR: anticholinergic, cardiotoxicity.

4.2 SSRIs

Fluoxetine, Sertraline
Selective 5-HT reuptake blockers.

4.3 SNRIs

Venlafaxine, Duloxetine
Block both serotonin and noradrenaline uptake.

4.4 MAO inhibitors

Phenelzine, Tranylcypromine
↑ all monoamines
Interaction with cheese → HT crisis.

Medicinal Chemistry (SAR)

4.5 TCAs SAR

Three rings + side chain

• Tertiary amines → more 5-HT block
• Secondary amines → more NE block

4.6 SSRIs SAR

Phenoxy-phenylpropylamine structure

• Substitution on phenyl ring determines potency
• S-enantiomer stronger (Escitalopram)

4.7 MAO inhibitors SAR

Hydrazines or cyclopropylamines
Bind irreversibly to MAO-A and MAO-B.

5. ANTIEPILEPTICS

Pharmacology

Mechanisms:

1. ↑ GABA (Valproate, Benzodiazepines)
2. ↓ Na⁺ channel firing (Phenytoin, Carbamazepine)
3. ↓ Ca²⁺ T-current (Ethosuximide)
4. Inhibit glutamate (Topiramate)

Medicinal Chemistry (SAR) – Antiepileptics

5.1 Hydantoins SAR (Phenytoin)

• Core structure: imidazolidine-2,4-dione
• 5,5-diphenyl substitution essential
• Sodium salt → more soluble (fosphenytoin = prodrug)

5.2 Barbiturates SAR

Already covered.

5.3 Succinimides SAR (Ethosuximide)

• α-methyl-α-ethyl succinimide
• Ethyl substitution → anti-absence activity

5.4 Newer Drugs

• Lamotrigine: triazine derivative
• Topiramate: sulfamate-substituted monosaccharide
• Levetiracetam: S-enantiomer of pyrrolidone derivative

6. OPIOID ANALGESICS

Pharmacology

6.1 Pure agonists

Morphine, Fentanyl

6.2 Partial agonists

Buprenorphine

6.3 Mixed agonist-antagonist

Pentazocine

6.4 Antagonists

Naloxone, Naltrexone

Mechanism:
Bind to μ, κ, δ receptors.

Effects: analgesia, euphoria, respiratory depression, miosis.

Medicinal Chemistry (SAR) – Opioids

6.5 Morphine SAR

• Phenanthrene nucleus essential
• 3-OH and 6-OH important for activity
• 3-O-methyl → codeine (prodrug)
• 6-keto or 14-OH substitutions ↑ potency
• N-methyl → required (N-cyclopropyl = antagonism)

6.6 Fentanyl SAR

Anilidopiperidine

• Phenyl + piperidine essential
• Modifications = ↑ potency (Sufentanil > Fentanyl)

7. LOCAL ANESTHETICS

Pharmacology

Mechanism:
Block voltage-gated Na⁺ channels.

Types:

• Esters: Procaine, Benzocaine
• Amides: Lidocaine, Bupivacaine

Medicinal Chemistry (SAR) – Local Anesthetics

7.1 General SAR

Three segments:

1. Lipophilic aromatic ring
2. Intermediate chain (ester/amide)
3. Tertiary amine

More lipophilic = ↑ potency
More protein binding = ↑ duration

7.2 Ester vs Amide

Esters: metabolized by pseudocholinesterase
Amides: liver metabolism

8. GENERAL ANESTHETICS

Pharmacology

8.1 Inhalational

Nitrous oxide
Halothane
Isoflurane
Sevoflurane

Mechanism:
Enhance GABA-A, inhibit NMDA.

8.2 IV anesthetics

Propofol, Ketamine, Thiopental, Etomidate

Medicinal Chemistry

8.3 Ether derivatives → Isoflurane, Sevoflurane

Halogenation → stable + potent.

8.4 Propofol

Phenolic structure → high lipid solubility.

8.5 Ketamine

Arylcyclohexylamine → NMDA blocker.

9. DRUGS FOR PARKINSONISM

Pharmacology

9.1 Dopamine precursors

Levodopa + Carbidopa

9.2 Dopamine agonists

Bromocriptine, Pramipexole, Ropinirole

9.3 MAO-B inhibitors

Selegiline, Rasagiline

9.4 COMT inhibitors

Entacapone, Tolcapone

9.5 Anticholinergics

Trihexyphenidyl, Benztropine

Medicinal Chemistry (SAR) – Anti-Parkinson Drugs

9.6 Levodopa

Structural analog of dopamine

• Carboxylate needed for transport across BBB
• Decarboxylation gives active dopamine

9.7 Dopamine agonists SAR

Ergot derivatives (bromocriptine)
Non-ergot (pramipexole) = better selectivity.

10. DRUGS FOR ALZHEIMER’S DISEASE

Pharmacology

• AChE inhibitors: Donepezil, Rivastigmine, Galantamine
• NMDA antagonist: Memantine

Medicinal Chemistry

10.1 AChE inhibitors

• Donepezil: piperidine derivative
• Rivastigmine: carbamate
• Galantamine: alkaloid

10.2 Memantine

Adamantane derivative → blocks NMDA.

11. CNS IMPORTANT Mnemonics

Phenothiazines Positions

“2-EW = potency”
(Electron withdrawing at 2 increases potency)

BZDs

“FREQ with BENZO”
(BZDs ↑ frequency of Cl⁻ opening)

Barbiturates

“Duration = BARB”
(Barbs ↑ duration of Cl⁻ opening)

MAO inhibitors

“MAO = ALL monoamines ↑”