Central Nervous System - Analgesics

Central Nervous System - Analgesics

• Analgesics are medications used to relieve pain.
• Opioid analgesics are further categorized into strong and weak opioids.
  • Strong opioids include morphine, fentanyl, and methadone.
  • Weak opioids include codeine.
• Opioid mechanism:
  • Stimulate postsynaptic opioid receptors, leading to mainly inhibitory actions on the CNS by opening potassium channels.
  • Stimulate presynaptic receptors to prevent neurotransmitter release (e.g., Substance P) by blocking calcium channels.
• Therapeutic uses of opioid analgesics:
  • Analgesic for severe pain (e.g., post-operative, fracture, acute MI, cancer pain); meperidine (pethidine) preferred for biliary colic due to atropine-like action.
  • Acute pulmonary edema treatment (sedative, vasodilator, decrease pulmonary pressure).
  • Anaesthesia (fentanyl is more potent).
  • Cough suppressant (codeine, dextromethorphan).
  • Anti-diarrheal (loperamide & diphenoxylate).
• Adverse effects of opioid analgesics:
  • Respiratory depression (most critical; treated with naloxone).
  • Bronchospasm, biliary spasm, urine retention, delayed labor, vomiting, constipation, ileus, truncal rigidity, hypotension, and bradycardia.
  • Addiction and withdrawal syndrome (major concern with chronic use).
• Contraindications and precautions:
  • Hypovolemia (to prevent hypotension).
  • Head injury (risk of increased intracranial pressure).
  • Acute abdominal pain (potentially masking diagnosis).
  • Respiratory/liver disease (e.g., asthma, COPD).
  • Late-stage labor (to prevent neonatal asphyxia).
• Morphine substitute (Meperidine Hydrochloride/Pethidine):
  • No antitussive action.
  • Has atropine-like action.
  • Shorted duration of action than opium.
  • Uses: biliary colic, obstetric anesthesia, post-operative pain, minor surgeries.
• Tramadol:
  • Inhibits norepinephrine and serotonin reuptake.
  • Atropine-like effects.
  • Uses: moderate pain (oral, parenteral, rectal).
• Opioid antagonists:
  • Naloxone (IV, short-acting): used to treat respiratory depression from opioid overdose (toxicity) and neonatal asphyxia.
  • Naltrexone (oral, long-acting): used to prevent opioid addiction.
• Acute opioid toxicity:
  • Respiratory depression, deep sleep, stupor, coma, pinpoint pupil, reduced respiratory rate, cyanosis, hypotension, decreased urine output, decreased temperature, clammy skin, and death (from respiratory failure).
• Treatment of acute opioid overdose:
  • Induce vomiting or gastric lavage.
  • Artificial respiration.
  • Administer naloxone (2-4 hours).
• Chronic opioid toxicity:
  • Constricted pupils, constipation, skin infections, needle-scar abscesses, itching.
  • Withdrawal symptoms (intense craving, insomnia, yawning, sneezing, vomiting, diarrhea, tremors, sweating, mental depression, muscle aches, pain, chills, and anxiety).
• Non-Opioid Analgesics:

Non-Steroidal Anti-inflammatory Drugs (NSAIDs)

• Types:
  • Acetylsalicylic acid (aspirin, salicylates).
  • Enolic acid (novalgina, phenylbutazone).
  • Oxicams (piroxicam).
  • Propionic acid (ibuprofen, naproxen).
  • Acetic acid (indomethacin, diclofenac).
  • Coxibs (celecoxib).
• Mechanism of action of salicylates (e.g., aspirin):
  • Antithrombotic (antiplatelet): low doses (75-150 mg/day) irreversibly inhibit cyclooxygenase enzyme (COX-1), thereby preventing thromboxane A2 production & platelet aggregation(affect for 4 days).
  • Analgesic and antipyretic: higher doses (300 mg tds) inhibit COX-2 and prostaglandin formation.
  • Anti-inflammatory: even higher doses (500 mg qid or more) have anti-inflammatory effects.
• Indications of salicylates:
  • Antithrombotic: angina, myocardial infarction, transient ischemic attacks, cerebral infarction.
  • Analgesic: mild and moderate pain (headache, dental, muscle, gynecological).
  • Antipyretic: fever.
  • Anti-inflammatory: rheumatic fever and arthritis.
  • Recent treatment - for pregnancy-induced hypertension.
• Adverse effects of salicylates:
  • GIT upset (heartburn, peptic ulcers, hematemesis).
  • Increased bleeding tendency (especially with warfarin).
  • Hepatic enzyme increases (SGOT and SGPT).
  • Hypersensitivity reactions (skin rash, bronchospasm).
  • Renal effects (salt and water retention, hypertension, edema).
  • Acute interstitial nephritis, acute renal failure.
  • Reye's syndrome (fatal liver failure and encephalopathy in children with flu).
  • Hyperuricemia (with moderate doses).
  • Acute salicylate toxicity (salicylism).

Paracetamol (Acetaminophen)

• Mechanism: analgesic & antipyretic effects by inhibiting CNS prostaglandin synthesis (hypothalamus).
• No antithrombotic or anti-inflammatory actions.
• Safe drug, no GIT problems.
• Uses: substitute for aspirin (when contraindicated), analgesic for headache, dysmenorrhea, arthralgia, myalgia, teething, post-tonsillectomy, and antipyretic for bacterial/viral infections.
• Overdose symptoms:
  • Hepatic toxicity (general malaise, delirium, seizures, coma, death, nausea, vomiting, fever, vascular collapse).
  • Nephrotoxicity (when used with aspirin long term).
• Treatment of paracetamol overdose:
  • Induce vomiting or gastric lavage; activated charcoal.
  • Oral N-acetylcysteine (mucomyst) inactivates acetaminophen metabolites.

Sedative Hypnotics, Anxiolytics - Benzodiazepines

• Mechanism: Enhance GABA-induced opening of chloride channels by binding to the GABA A receptor's gamma subunit; leads to hyperpolarization and neuronal inhibition.
• Classification:
  • Short-acting: triazolam.
  • Intermediate-acting: alprazolam.
  • Long-acting: diazepam.
• Uses: Anxiety disorders, sedation in agitation (e.g., alcohol withdrawal), hypnotics for insomnia and parasomnia (e.g., sleepwalking), anesthesia for minor procedures and pre-anesthetic medication, muscle relaxant (for spastic states), and seizures (IV diazepam for status epilepticus).
• Adverse effects:
  • Anterograde amnesia (inability to remember recent events).
  • Learning difficulties (in children).
  • Motor coordination problems.
  • Hangover effect (residual sleep and next-day impairment).
  • Decreased lag period.
  • Increased NREM sleep.
  • Decreased REM sleep.
  • Benzodiazepine dependence (tolerance, withdrawal syndrome –rebound insomnia, increased nightmares).
  • Acute toxicity (CVS & respiratory depression). Treatment: flumazenil (competitive benzodiazepine antagonist).