Comprehensive Pharmacology Notes on Sedative-Hypnotics, Antiepileptics, Antiparkinsonians, Psychotropics, and Opioids

Sedative-Hypnotics

• Sedative Definition: A drug that subdues excitement and calms the subject without inducing sleep, though drowsiness may be produced. Sedation refers to decreased responsiveness to stimulation; it is associated with some decrease in alertness, ideation, and motor activity.
• Hypnotic Definition: A drug that induces and/or maintains sleep, similar to normal arousable sleep. This is not to be confused with "hypnosis," which refers to a trance-like state where the subject becomes passive and highly suggestible.
• Increasing Grades of CNS Depression: Sedation $\rightarrow$ Hypnosis $\rightarrow$ General Anaesthesia. Hypnotics given in high doses can produce general anaesthesia. However, benzodiazepines (BZDs) are not considered nonselective or global CNS depressants like barbiturates.
• Time-Action and Dose-Action Relationships:
  • Hypnotics: Preferred drugs are those with quicker onset, shorter duration, and steeper dose-response curves.
  • Sedatives: Prefer drugs with a slower action and flatter dose-response curves.
  • Overlap: A hypnotic at a lower dose may act as a sedative.
• Historical Context:
  • Oldest Hypnotics: Alcohol and opium.
  • Bromides (1857): Became obsolete long ago.
  • Chloral Hydrate (1869) and Paraldehyde (1882): Also obsolete.
  • Barbiturates: Fischer and von Mering introduced barbitone ($1903$) and phenobarbitone ($1912$). Barbiturates reigned until the $1960s$, after which benzodiazepines replaced them.
  • Other Redundant Drugs: Glutethimide, methyprylon, and methaqualone.
  • Novel Hypnotics: Ramelteon (melatonin receptor agonist) and suvorexant (orexin receptor antagonist).

Sleep Architecture and Cyclic Processes

• Stage 0 (Awake): From lying down to falling asleep and occasional nocturnal awakenings. Constitutes $1-2\%$ of sleep time. EEG shows $\alpha$ activity when eyes are closed and $\beta$ activity when open. Irregular or slowly rolling eye movements.
• Stage 1 (Dozing): $\alpha$ activity interspersed with $\theta$ waves. Neck muscles relax. Occupies $3-6\%$ of sleep time.
• Stage 2 (Unequivocal Sleep): $\theta$ waves with interspersed spindles. K complexes can be evoked. Subjects are easily arousable. Comprises $40-50\%$ of sleep time.
• Stage 3 (Deep Sleep Transition): EEG shows $\theta, \delta$, and spindle activity. K complexes are evoked only with strong stimuli. Comprises $5-8\%$ of sleep time.
• Stage 4 (Cerebral Sleep): $\delta$ activity predominates. Eyes are practically fixed. Night terrors occur here. Comprises $10-20\%$ of sleep time. Stages 3 and 4 reflect "slow wave sleep" (SWS).
• REM Sleep (Paradoxical Sleep): EEG shows waves of all frequencies. Marked, irregular, and darting eye movements. Dreams and nightmares occur. Heart rate and BP fluctuate; respiration is irregular. Comprises $20-30\%$ of sleep time.
• EEG Wave Frequencies:
  • $\alpha$: High amplitude, $8-14\,c.p.s.$ (cycles per second).
  • $\beta$: Low amplitude, $15-35\,c.p.s.$.
  • $\theta$: Low amplitude, $4-7\,c.p.s.$.
  • $\delta$: High amplitude, $0.5-3\,c.p.s.$.
  • K Complex: Deep negative wave followed by a positive wave and spindles.

Barbiturates

• Chemical Nature: Substituted derivatives of barbituric acid (malonyl urea). Barbituric acid itself is not a hypnotic; substitution on $C5$ with alkyl or aryl groups is required. Replacement of $O$ with $S$ at $C2$ yields thiobarbiturates (e.g., thiopentone), which are more lipid-soluble.
• Pharmacological Actions (CNS): Dose-dependent depression (Sedation $\rightarrow$ Sleep $\rightarrow$ Anaesthesia $\rightarrow$ Coma).
  • Effect on Sleep: Shortens time to sleep, increases total duration. Reduces REM and Stages 3 and 4. Discontinuation leads to "REM rebound" (nightmares).
  • Hangover: Morning dizziness, irritability, and lethargy following a night dose.
  • Anticonvulsant Property: Phenobarbitone has a high anticonvulsant-to-sedative ratio.
• Mechanism of Action: Acts at the $GABA:BZD$ receptor-$Cl^-$ channel complex. Potentiates GABAergic inhibition by increasing the lifetime of $Cl^-$ channel opening. At high concentrations, barbiturates directly increase $Cl^-$ conductance (GABA-mimetic) and inhibit $Ca^{2+}$-dependent neurotransmitter release.
• Pharmacokinetics:
  • Redistribution: Highly lipid-soluble compounds like thiopentone enter the CNS rapidly but redistribute quickly to muscle and fat, terminating the initial anaesthesia ($6-10\,min$).
  • Metabolism: Intermediate lipid-solubility barbiturates are oxidized in the liver; $t_{1/2}$ is $12-36\,hours$.
  • Excretion: Low lipid-solubility drugs like phenobarbitone are excreted unchanged in urine ($t_{1/2}$ is $80-120\,hours$). Alkalinization of urine increases phenobarbitone excretion.
  • Enzyme Induction: Barbiturates induce several hepatic microsomal enzymes (CYP3A4/5, CYP2D6).
• Acute Poisoning: Manifests as shallow respiration, fall in BP, cardiovascular collapse, and renal shutdown. Treatment: Gastric lavage (activated charcoal), supportive ventilation, alkaline diuresis (for long-acting types), and haemodialysis.

Benzodiazepines (BZDs)

• Advantages over Barbiturates:
  • BZDs have a "lower ceiling" CNS depression and a high therapeutic index.
  • Minimal effect on respiration or cardiovascular function at hypnotic doses.
  • Less distortion of sleep architecture; less REM rebound.
  • No microsomal enzyme induction.
  • Low abuse liability and mild withdrawal syndrome.
  • Specific antagonist available: Flumazenil.
• Mechanism of Action: Selective BZD receptors are located at the interface of $\alpha$ and $\gamma$ subunits of the $GABAA$ receptor complex. BZDs increase the frequency of $Cl^-$ channel opening induced by GABA. They do not increase $Cl^-$ conductance on their own (no GABA-mimetic action).
• Receptor Subtypes:
  • $\alpha_1$ Subunit: Involved in sedative, hypnotic, and amnesic actions.
  • $\alpha_2$ Subunit: Mediate anxiolytic and muscle relaxant actions.
• Hypnotic BZDs:
  • Flurazepam: Long-acting ($t_{1/2}\approx 50-100\,hours$); suitable for frequent nocturnal awakenings.
  • Nitrazepam: Intermediate duration; equipotent to diazepam.
  • Lorazepam: Absorbed slowly; no active metabolites; minimal residual drowsiness.
  • Alprazolam: Potent, used for anxiety and night-time hypnotic; significant withdrawal on discontinuation.
  • Triazolam: Very potent, ultra-short duration; risk of rebound insomnia and "day-time anxiety."
  • Midazolam: Extremely rapid absorption; used as i.v. anaesthetic.
• Adverse Effects: Dizziness, ataxia, amnesia, and paradoxical irritability. Chronic use leads to tolerance to sedative effects. Birth defects risk is disputed, but labor administration can cause floppiness in neonates.

Non-Benzodiazepine Hypnotics and Other Classes

• Zopiclone: Acts on BZD receptor subtypes. Does not diminish REM; prolongs Stages 3 and 4 ($t_{1/2}\approx 5-6\,hours$).
• Zolpidem: Selective for $\alpha_1$ subunit BZD receptors. Pronounced hypnotic effect with minimal antianxiety or anticonvulsant activity ($t_{1/2}\approx 2\,hours$).
• Zaleplon: Shortest acting ($t_{1/2}\approx 1\,hour$); effective for sleep-onset insomnia; can be taken late at night without morning sedation.
• Eszopiclone: (S) enantiomer of zopiclone; suitable for chronic insomnia.
• Melatonin and Agonists:
  • Melatonin: Hormone from the pineal gland. Acts on $MT_1$ and $MT_2$ receptors to entrain circadian rhythms. Used for jet lag.
  • Ramelteon: Selective $MT_1/MT_2$ agonist for sleep-onset insomnia ($t_{1/2}\approx 1-3\,hours$). No GABAergic action.
• Orexin Antagonists: Suvorexant blocks $OX_1R$ and $OX_2R$. Promotes sleep by blocking wakefulness-promoting neuropeptides. Metabolized by CYP3A4 ($t_{1/2}\approx 12\,hours$).

Antiepileptic Drugs

• Classification of Seizures:
  • Generalized Tonic-Clonic (GTCS): Aura $\rightarrow$ Cry $\rightarrow$ Tonic spasm $\rightarrow$ Clonic jerking.
  • Absence Seizures: Brief loss of consciousness ($3\,Hz$ spike and wave pattern).
  • Partial Seizures: Localized origin (Simple vs. Complex/Psychomotor).
  • Status Epilepticus: Seizure activity $> 30\,min$ or multiple seizures without consciousness recovery.
• Phenytoin (Diphenylhydantoin):
  • Mechanism: Prolongs inactivated state of voltage-sensitive neuronal $Na^+$ channels. Inhibits high-frequency discharges.
  • Kinetics: Capacity-limited; shifts from first-order to zero-order over therapeutic range ($10-20\,\mu g/ml$).
  • Adverse Effects: Gum hypertrophy ($20\%$ incidence), hirsutism, coarsening of facial features, megaloblastic anaemia, and Foetal Hydantoin Syndrome.
• Carbamazepine: First-line for partial seizures and GTCS. Drug of choice for Trigeminal Neuralgia. Autoinduction occurs (half-life decreases from $20-40\,hrs$ to $10-20\,hrs$ with chronic use).
• Ethosuximide: Primary drug for absence seizures. Blocks T-type $Ca^{2+}$ currents in thalamocortical pacemakers.
• Valproic Acid (Sodium Valproate): Broad-spectrum (GTCS, Absence, Myoclonic). MoA: Prolongs $Na^+$ channel inactivation, attenuates T-current, inhibits GABA-transaminase. Potential for hepatotoxicity in children and spina bifida in offspring.
• Newer Agents:
  • Lamotrigine: Blocks $Na^+$ channels and prevents glutamate release. Broad-spectrum.
  • Gabapentin and Pregabalin: Modulate $\alpha_2\delta-1$ subunits of voltage-sensitive $Ca^{2+}$ channels to reduce glutamate release. Used for neuropathic pain.
  • Levetiracetam: Binds to synaptic vesicular protein SV2A.
  • Vigabatrin: Irreversible inhibitor of GABA-transaminase. Risk of visual field contraction.

Antiparkinsonian Drugs

• Pathophysiology: Imbalance between dopaminergic (inhibitory) and cholinergic (excitatory) systems in the striatum due to degeneration of nigrostriatal (SN-PC) neurons.
• Levodopa: Precursor of dopamine (DA). Administered because DA does not cross the Blood-Brain Barrier.
  • Peripheral Metabolism: $95\%$ is decarboxylated peripherally. Combining with Carbidopa (DDC inhibitor) increases CNS entry and reduces nausea.
  • Late Complications: Dyskinesias and "on-off" fluctuations develop after $2-5\,years$ of therapy.
• Dopamine Agonists:
  • Bromocriptine: Ergot derivative. D2 agonist.
  • Ropinirole and Pramipexole: Non-ergoline D2/D3 agonists. Lower incidence of dyskinesias.
• MAO-B Inhibitors: Selegiline and Rasagiline. Block DA degradation in the brain. Rasagiline is more potent and lacks amphetamine metabolites.
• COMT Inhibitors: Entacapone and Tolcapone. Block peripheral degradation of levodopa to $3-O-methyldopa$. Tolcapone has risk of fatal hepatitis.
• Anticholinergics: Trihexyphenidyl (Benzhexol). Beneficial for tremors by reducing cholinergic overactivity.

Antipsychotic and Antimanic Drugs

• Neuroleptics (Typical Antipsychotics): e.g., Chlorpromazine (CPZ), Haloperidol.
  • Mechanism: Potent D2 receptor blockade in the limbic system.
  • EPS Side Effects: Parkinsonism, Acute dystonia (muscle spasms), Akathisia (restlessness), Tardive Dyskinesia (late involuntary movements), and Neuroleptic Malignant Syndrome (rigidity, hyperthermia).
• Atypical Antipsychotics: e.g., Clozapine, Risperidone, Olanzapine.
  • Mechanism: Potent $5-HT_2$ antagonism with weak D2 blockade. Improved efficacy for "negative" symptoms of schizophrenia.
  • Side Effects: Clozapine (Agranulocytosis), Olanzapine (Weight gain and diabetes).
• Lithium (Antimanic): Standard mood stabilizer.
  • Mechanism: Inhibits inositol monophosphatase, depleting the supply of free inositol for secondary messengers ($IP_3/DAG$).
  • Therapeutic Monitoring: Narrow index ($0.5-0.8\,mEq/L$ for maintenance; toxicity at $> 1.5\,mEq/L$). Side effects: Polyuria, fine tremors, hypothyroidism (goiter).

Antidepressants and Antianxiety Drugs

• Tricyclic Antidepressants (TCAs): e.g., Imipramine, Amitriptyline. Block reuptake of NA and $5-HT$. Side effects: Anticholinergic (dry mouth, blurred vision) and cardiotoxicity (arrhythmias in overdose).
• Selective Serotonin Reuptake Inhibitors (SSRIs): e.g., Fluoxetine, Sertraline. Preferred first-line due to safety. Side effects: Nausea, sexual dysfunction.
• Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs): e.g., Venlafaxine, Duloxetine. Used for depression and neuropathic pain.
• Reversible Inhibitors of MAO-A (RIMAs): Moclobemide. No "cheese reaction" (hypertensive crisis) with tyramine intake.
• Buspirone: Antianxiety drug. Partial agonist at $5-HT_{1A}$. No sedation, tolerance, or dependence.

Opioid Analgesics and Antagonists

• Morphine: Principal opium alkaloid. Strong agonist at $\mu$ receptors.
  • CNS Effects: Analgesia (spinal and supraspinal), euphoria, respiratory depression ($CO_2$ insensitivity), miosis (pinpoint pupil), cough suppression.
  • Peripheral Effects: Constipation, biliary spasm, histamine release (bronchoconstriction).
  • Poisoning: Pinpoint pupils, shallow breathing, and coma. Antidote: Naloxone ($0.4-0.8\,mg\,i.v.$).
• Opioid Receptor Types:
  • $\mu$ (Mu): Supraspinal analgesia, euphoria, physical dependence.
  • $\kappa$ (Kappa): Spinal analgesia, dysphoria, miosis.
  • $\delta$ (Delta): Affective behavior, spinal analgesia.
• Endogenous Peptides: Endorphins ($\mu$-preferring), Enkephalins ($\delta$-preferring), Dynorphins ($\kappa$-preferring).
• Pure Antagonists:
  • Naloxone: Ultra-short acting, used for poisoning.
  • Naltrexone: Long-acting ($1-2\,days$), orally active; used for post-addict blockade therapy and alcohol craving.

Case Study & Discussion Sections

• Sedatives (Problem 29.1): A $70$-year-old may require a short-acting hypnotic like triazolam or a non-BZD like zaleplon for unpredictable sleep-onset difficulties without morning sedation.
• Epilepsy (Problem 30.1): In a lady with fits following head injury (post-traumatic epilepsy), initial therapy usually starts with a single drug like carbamazepine or valproate after diagnostic evaluation.
• Parkinson's (Problem 31.1): A $70$-year-old experiencing "end-of-dose" wearing off and peak-dose dyskinesia may benefit from reducing the levodopa-carbidopa dose while adding a COMT inhibitor (entacapone) or a DA agonist (ropinirole).
• Antipsychotics (Problem 32.1): In severe restlessness (Akathisia), the dose of haloperidol should be reduced or changed to an atypical agent like quetiapine. BZDs or propranolol can help.
• Antidepressants (Problem 33.1): Sertraline ($50\,mg$) side effects like nausea and gastric distress are common initially; improvement in major depression typically takes $2-3\,weeks$.
• Opioids (Problem 34.1): For severe trauma with neurogenic shock risk, Morphine ($10-15\,mg\,i.m.$ or small doses $i.v.$) is used to prevent shock and allay excruciating pain.