HA Pharmacology & Pharmacy – Unit 4

Drugs Acting on Central Nervous System – CTEVT Second Year Notes

According to CTEVT Syllabus (2024) | Health Science (PCL)

Introduction to CNS Drugs

Drugs acting on the Central Nervous System (CNS) are among the most clinically important medications, used to manage conditions ranging from anxiety and epilepsy to surgical anesthesia and psychiatric disorders. This unit covers the pharmacology of drugs that alter brain function, including their mechanisms, therapeutic uses, and adverse effects.

Clinical Importance: CNS drugs require careful dosing and monitoring due to their effects on consciousness, mood, and neurological function. Understanding these medications is crucial for safe administration in surgical, psychiatric, and neurological settings.

1. General Anesthesia

Definition & Goals

General anesthesia is a reversible, drug-induced state characterized by:

Unconsciousness
Loss of awareness

Analgesia
Absence of pain perception

Amnesia
No memory of procedure

Muscle Relaxation
For surgical access

Reflex Suppression
Autonomic stability

Stages of General Anesthesia (Guedel’s Classification)

Stage	Name	Characteristics	Clinical Significance	Duration
Stage I	Analgesia	Conscious, pain perception reduced, hearing exaggerated, amnesia begins	Minor procedures (dental, wound suturing)	From induction to loss of consciousness
Stage II	Excitement/Delirium	Unconscious but reflexive, irregular breathing, vomiting, pupil dilation, increased muscle tone	Dangerous stage – avoid stimulation, risk of aspiration	Brief, should be minimized
Stage III	Surgical Anesthesia	Regular breathing, pupil constriction, progressive muscle relaxation, absent reflexes	Ideal for surgery, divided into 4 planes of increasing depth	Maintained throughout surgery
Stage IV	Medullary Paralysis	Respiratory arrest,瞳孔 dilation, cardiovascular collapse	Overdose – requires immediate resuscitation	Fatal if prolonged

General Anesthetic Drugs

Nitrous Oxide (N₂O)

Class: Inhalational anesthetic

Mechanism: NMDA receptor antagonism, weak anesthetic but potent analgesic

Indications: Dental procedures, labor analgesia, minor surgery (adjunct)

Key Points: Low potency (MAC 104%), rapid onset/offset, minimal metabolism, “laughing gas”

Adverse Effects: Diffusion hypoxia (post-op), nausea, megaloblastic anemia with chronic use

Dose: 30-70% with oxygen (never 100%)

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Halothane

Class: Inhalational anesthetic (halogenated hydrocarbon)

Mechanism: Enhances GABAₐ and glycine receptors, inhibits NMDA

Indications: Induction (especially pediatric) and maintenance of anesthesia

Key Points: Pleasant odor, bronchodilator, potent (MAC 0.75%), sensitizes myocardium to catecholamines

Adverse Effects: “Halothane hepatitis” (immune-mediated), malignant hyperthermia, arrhythmias

Dose: Induction 2-4%, Maintenance 0.5-1.5%

Ketamine

Class: IV anesthetic (arylcyclohexylamine)

Mechanism: Noncompetitive NMDA receptor antagonist → dissociative anesthesia

Indications: Emergency/trauma surgery, pediatric procedures, burns dressing, refractory depression

Key Points: Produces catalepsy with eyes open, profound analgesia, bronchodilator, increases BP/HR

Adverse Effects: Emergence reactions (hallucinations), increased intracranial/intraocular pressure

Dose: IV: 1-2 mg/kg, IM: 4-6 mg/kg (premedicate with benzodiazepine)

📌 Clinical Tips: General Anesthesia

Balanced anesthesia: Combination of drugs to achieve all components (e.g., opioid + muscle relaxant + inhalational agent)
Minimum Alveolar Concentration (MAC): Measure of potency – lower MAC = more potent
Malignant hyperthermia: Life-threatening reaction to volatile anesthetics – treat with dantrolene
Pre-anesthetic medication: Benzodiazepines (anxiety), anticholinergics (reduce secretions), antiemetics

2. Sedatives-Hypnotics

Benzodiazepines

Mechanism: Potentiate GABAₐ receptor → ↑ chloride influx → neuronal hyperpolarization

Drug	Half-life	Key Uses	Adult Oral Dose	Special Notes
Diazepam	20-50 hours	Anxiety, muscle spasm, alcohol withdrawal, status epilepticus (IV)	2-10 mg 1-4× daily	Active metabolites, IV formulation irritant
Alprazolam	6-12 hours	Panic disorder, generalized anxiety	0.25-0.5 mg 2-3× daily	High abuse potential, difficult withdrawal
Lorazepam	10-20 hours	Anxiety, pre-anesthetic, status epilepticus	1-4 mg/day in divided doses	No active metabolites, preferred in liver disease
Clonazepam	18-50 hours	Epilepsy (absence, myoclonic), panic disorder	0.5-2 mg/day (max 20 mg)	Long-acting, tolerance develops to anticonvulsant effect

Common Side Effects: Drowsiness, ataxia, confusion, anterograde amnesia

Serious Risks: Respiratory depression (esp. with opioids), dependence, withdrawal seizures

Contraindications: Sleep apnea, acute narrow-angle glaucoma, pregnancy (teratogenic)

Antidote: Flumazenil (competitive antagonist)

Barbiturates (Phenobarbitone)

Mechanism: Prolong GABAₐ receptor opening → stronger effect than benzodiazepines

Uses: Epilepsy (generalized tonic-clonic, partial), neonatal seizures, status epilepticus

Dose: 60-120 mg/day oral (therapeutic level: 15-40 μg/mL)

Adverse Effects: Sedation, respiratory depression, enzyme induction (reduces efficacy of other drugs), dependence

Clinical Note: Largely replaced by benzodiazepines due to safety profile; still used in refractory epilepsy

3. Antiepileptic Drugs (AEDs)

Drug	Mechanism	Primary Seizure Types	Key Side Effects	Special Considerations	Dose Range
Carbamazepine	Blocks voltage-gated Na⁺ channels, ↓ high-frequency firing	• Partial (focal) seizures • Generalized tonic-clonic • Trigeminal neuralgia	• Dizziness, diplopia • Hyponatremia (SIADH) • Rash (SJS risk) • Bone marrow suppression	• Autoinduction (dose ↑ over weeks) • Teratogenic (neural tube defects) • Check Na⁺, CBC, LFT	200-600 mg BD Therapeutic: 4-12 μg/mL
Phenytoin	Use-dependent Na⁺ channel blockade, inhibits glutamate release	• Generalized tonic-clonic • Partial seizures • Status epilepticus (IV)	• Gingival hyperplasia • Hirsutism, coarsening • Ataxia, nystagmus • Megaloblastic anemia	• Non-linear kinetics (small dose ↑ → large level ↑) • IV: cardiac monitoring (risk of arrhythmia) • Fetal hydantoin syndrome	100-300 mg/day Therapeutic: 10-20 μg/mL
Valproic Acid (Sodium Valproate)	• ↑ GABA synthesis/inhibition of breakdown • Blocks Na⁺ channels • T-type Ca²⁺ channel blockade	• Broad spectrum • Absence seizures • Myoclonic, tonic-clonic • Bipolar disorder, migraine prophylaxis	• Weight gain, tremor • Hair loss (transient) • Hepatotoxicity (children <2 yr) • Pancreatitis, thrombocytopenia	• High teratogenic risk (neural tube defects) • Check LFT, platelets • Enteric-coated to reduce GI upset	500-2000 mg/day Therapeutic: 50-100 μg/mL

📌 Clinical Guidelines for AEDs

Initiation: Start low, go slow. Monotherapy preferred. Wait 4-5 half-lives between dose adjustments.

Monitoring: Drug levels (if available), CBC, LFT, electrolytes. Watch for signs of toxicity.

Withdrawal: Taper slowly over weeks to months to avoid withdrawal seizures.

Pregnancy: Valproate highest risk, lamotrigine/levetiracetam preferred. Folic acid supplementation.

4. Antipsychotics & Antidepressants

Antipsychotics

Typical (First-Generation)

Mechanism: D₂ receptor antagonism in mesolimbic pathway

Examples: Haloperidol, Chlorpromazine, Fluphenazine

Extrapyramidal Symptoms (EPS): Acute dystonia, akathisia, parkinsonism, tardive dyskinesia

Atypical (Second-Generation)

Mechanism: 5-HT₂ₐ > D₂ antagonism, some with partial D₂ agonism (aripiprazole)

Examples: Olanzapine, Risperidone, Quetiapine, Clozapine

Metabolic Effects: Weight gain, diabetes, dyslipidemia (olanzapine worst)

Key Drugs

Olanzapine: 5-20 mg/day, for schizophrenia, bipolar. High metabolic risk.

Haloperidol: 1-10 mg/day, acute psychosis, IV for delirium. High EPS risk.

Chlorpromazine: 100-400 mg/day, schizophrenia, antiemetic. Sedating.

Antidepressants

Class	Mechanism	Examples & Doses	Key Side Effects	Clinical Notes
SSRIs (Selective Serotonin Reuptake Inhibitors)	Block SERT → ↑ synaptic serotonin	• Fluoxetine (20-40 mg/day) • Escitalopram (10-20 mg/day) • Paroxetine (20-40 mg/day) • Sertraline (50-150 mg/day)	• Nausea, headache • Sexual dysfunction • Serotonin syndrome (risk with MAOIs) • Withdrawal on discontinuation	First-line for depression, anxiety. Delayed onset (2-4 weeks). Fluoxetine long half-life (7-15 days).
TCAs (Tricyclic Antidepressants)	Block NET & SERT → ↑ NE & 5-HT, also anticholinergic, antihistaminic, α-blocking	• Amitriptyline (25-150 mg/day) • Imipramine • Clomipramine	• Anticholinergic (dry mouth, constipation, urinary retention) • Sedation, weight gain • Cardiac arrhythmias (overdose fatal) • Orthostatic hypotension	Used in neuropathic pain, migraine prophylaxis. Lethal in overdose. Therapeutic window.
Other	Various mechanisms	• Venlafaxine (SNRI) • Bupropion (NE/DA reuptake) • Mirtazapine (α₂ antagonist)	Class-dependent: hypertension (venlafaxine), seizures (bupropion), weight gain (mirtazapine)	Second-line or when specific side effect profile needed (e.g., bupropion for sexual dysfunction).

Mood Stabilizer: Lithium

Indications: Bipolar disorder (acute mania & maintenance), augmentation in depression

Mechanism: Inhibits inositol monophosphatase, modulates glutamate/GABA

Dose: 600-1200 mg/day, target level 0.6-1.2 mEq/L (acute: 0.8-1.2, maintenance: 0.6-0.8)

Side Effects: Fine tremor, polyuria/polydipsia (nephrogenic DI), weight gain, hypothyroidism

Monitoring: Serum levels (12h post-dose), renal function, TSH, electrolytes. Narrow therapeutic index.

5. Migraine Management & Other CNS Drugs

Migraine-Specific Drugs

Triptans (Sumatriptan)

Mechanism: 5-HT_1B/1D agonist → cranial vasoconstriction, inhibits neurogenic inflammation

Use: Acute migraine attack (not for prophylaxis)

Dose: 50-100 mg oral, 6 mg SC, 20 mg nasal spray

Cautions: Contraindicated in CAD, stroke, uncontrolled HTN, hemiplegic migraine

Ergot Alkaloids (Ergometrine)

Mechanism: Nonselective 5-HT agonist, also α-adrenergic/dopaminergic effects

Uses: Migraine (less preferred), postpartum hemorrhage (uterine contraction)

Dose: 0.5-1 mg IM/IV for PPH; migraine: ergotamine 1-2 mg oral

Risks: Ergotism (gangrene), nausea, contraindicated in pregnancy (except PPH), peripheral vascular disease

Drug Class	Drug	Primary Use	Key Mechanism	Dose	Important Notes
Parkinson’s	Levodopa + Carbidopa	Parkinson’s disease	Dopamine precursor + peripheral DDC inhibitor	Levodopa: 250-1000 mg/day Carbidopa: 25-100 mg/day	“On-off” phenomena, dyskinesias, never give with MAOIs
Opioid Analgesics	Morphine	Severe pain (cancer, MI, trauma)	μ-opioid receptor agonist	5-10 mg IM/SC q4h 2.5-5 mg IV	Respiratory depression, constipation, miosis, addiction potential
Opioid Analgesics	Pethidine (Meperidine)	Moderate-severe pain, labor	μ-opioid agonist, anticholinergic	50-100 mg IM q3-4h	Active metabolite normeperidine → seizures with renal impairment
Opioid Antagonist	Naloxone	Opioid overdose reversal	Competitive opioid receptor antagonist	0.4-2 mg IV/IM/SC, repeat q2-3min	Short half-life (1-2h) → monitor for renarcotization, can precipitate withdrawal
Stimulant	Amphetamine	ADHD, narcolepsy	↑ NE/DA release, reuptake inhibition	5-30 mg/day in divided doses	High abuse potential, insomnia, anorexia, cardiovascular effects

One Page Summary: CNS Drugs

GENERAL ANESTHESIA
• Stages: I (Analgesia), II (Excitement), III (Surgical), IV (Medullary paralysis)
• Nitrous oxide: Dental, labor pain, diffusion hypoxia
• Halothane: Hepatotoxicity, arrhythmias
• Ketamine: Dissociative anesthesia, hallucinations, ↑ BPSEDATIVES-HYPNOTICS
• Benzodiazepines: GABA potentiation, anxiolytic, hypnotic, muscle relaxant
• Diazepam: Long-acting, active metabolites
• Lorazepam: No active metabolites, status epilepticus
• Phenobarbitone: Enzyme inducer, respiratory depression risk

ANTIEPILEPTICS
• Carbamazepine: Na⁺ channel blocker, hyponatremia, SJS risk
• Phenytoin: Gingival hyperplasia, non-linear kinetics
• Valproate: Broad spectrum, hepatotoxicity, teratogenic

ANTIPSYCHOTICS
• Typical: D₂ antagonists → EPS (haloperidol)
• Atypical: 5-HT₂ₐ > D₂ → metabolic effects (olanzapine)
• Olanzapine: 5-20 mg/day, weight gain
• Haloperidol: 1-10 mg/day, high EPS

ANTIDEPRESSANTS
• SSRIs: First-line (fluoxetine, escitalopram), sexual dysfunction
• TCAs: Amitriptyline, anticholinergic side effects, lethal in overdose
• Lithium: Bipolar, narrow therapeutic index (0.6-1.2 mEq/L), monitor levelsMIGRAINE
• Triptans (sumatriptan): 5-HT_1B/1D agonists, acute attack
• Ergots: Vasoconstrictors, ergotism risk

OTHER CNS DRUGS
• Levodopa/carbidopa: Parkinson’s, on-off phenomena
• Morphine: μ-opioid agonist, respiratory depression
• Pethidine: Metabolite causes seizures
• Naloxone: Opioid overdose antidote, short half-life
• Amphetamine: ADHD, stimulant, abuse potential

MNEMONICS
• Benzodiazepine reversal: Flumazenil
• Phenytoin side effects: Hirsutism, Hyperplasia, Hematologic, Ataxia
• SSRIs side effects: Sexual dysfunction, Sleep disturbance, Serotonin syndrome

Key Clinical Points:
Monitor drug levels for phenytoin, lithium, valproate. Know reversal agents: flumazenil (BZDs), naloxone (opioids).

Clinical Application Scenarios

Scenario 1: Status Epilepticus

Presentation: 25-year-old with continuous tonic-clonic seizures for 10 minutes.

Immediate Management: ABCs, IV access, glucose check.

Drug Sequence: Lorazepam 4 mg IV → If persists: Phenytoin/fosphenytoin loading → Refractory: midazolam infusion, propofol.

Monitoring: Airway, respiratory status, ECG with phenytoin.

Scenario 2: Opioid Overdose

Presentation: Unconscious, pinpoint pupils, respiratory rate 6/min, SpO₂ 85%.

Diagnosis: Opioid toxicity (heroin/morphine overdose).

Treatment: Naloxone 0.4-2 mg IV/IM, repeat q2-3min until breathing adequate.

Key: Monitor for renarcotization (naloxone half-life shorter than opioids).

Scenario 3: Acute Migraine

Presentation: 30-year-old with unilateral throbbing headache, nausea, photophobia.

First-line: NSAIDs (ibuprofen) + antiemetic (metoclopramide).

If severe: Triptan (sumatriptan 50-100 mg oral).

Contraindications: Avoid triptans if history of stroke, CAD, hemiplegic migraine.

Key Clinical Takeaways

General anesthesia stages: Aim for Stage III, avoid Stage II (excitement) and IV (overdose).
Benzodiazepines enhance GABA; flumazenil reverses overdose. Avoid abrupt discontinuation.
Antiepileptic drug choice depends on seizure type: carbamazepine for partial, valproate for generalized.
Antipsychotics: Typical cause EPS, atypical cause metabolic syndrome. Clozapine for treatment-resistant but requires CBC monitoring.
SSRIs are first-line antidepressants but have delayed onset (2-4 weeks) and sexual side effects.
Opioid overdose: triad of coma, pinpoint pupils, respiratory depression; treat with naloxone.

Quick Self-Check

Question 1: Which stage of general anesthesia is characterized by irregular breathing and increased reflexes?

Question 2: Match the drug to its reversal agent:

1. Benzodiazepines

2. Opioids

3. Heparin

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