2. Anesthetic and Anti pyretic drug
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Anesthetic and Antipyretic Drugs
PART 1: ANESTHETIC DRUGS
Anesthetics are drugs that cause loss of sensation. They are broadly divided into:
- General anesthetics (IV and inhalational)
- Local anesthetics
A. General Anesthetics
General anesthesia involves a reversible state of unconsciousness, analgesia, amnesia, and muscle relaxation. It is achieved through IV agents, inhalational agents, or a combination.
1. Intravenous (IV) Anesthetics
| Drug | Class | Mechanism | Key Features |
|---|---|---|---|
| Propofol | Alkylphenol | Enhances GABA-A (↑ Cl⁻ currents) | Most commonly used IV anesthetic; rapid onset/offset; antiemetic effect; causes ↓BP via ↓SVR |
| Thiopental | Barbiturate | GABA-A receptor agonist | Rapid onset; accumulates with prolonged use; cerebral protection; contraindicated in porphyria |
| Ketamine | Phencyclidine derivative | NMDA receptor antagonist | Dissociative anesthesia; preserves airway reflexes; sympathomimetic (↑HR, ↑BP); analgesic; risk of psychotomimetic effects; also used as antidepressant |
| Etomidate | Imidazole derivative | GABA-A receptor agonist | Minimal cardiovascular/respiratory effects; preferred in hemodynamically unstable patients; inhibits adrenocortical synthesis (single induction dose can suppress cortisol) |
| Midazolam | Benzodiazepine | GABA-A receptor agonist | Anxiolysis and amnesia; flumazenil reversal agent; prolonged effect in hepatic/renal failure |
| Dexmedetomidine | Alpha-2 agonist | Agonist at α₂-adrenergic receptors (locus coeruleus) | Sedation, sympatholysis, analgesia; minimal respiratory depression; used for ICU sedation and procedural sedation |
- Miller's Anesthesia, 10e, p. 2453-2455
Key point on Propofol: Its context-sensitive half-time is ~10 min for infusions <3 hours, rising to <40 min for infusions up to 8 hours. It produces a dose-dependent decrease in arterial blood pressure mainly via reduced systemic vascular resistance, and has a unique antiemetic property even at sub-sedating concentrations.
Ketamine is uniquely stimulating - it preserves cardiovascular reflexes (unlike other agents), making it useful in trauma/hypovolemic patients. However, it can cause emergence delirium - managed with benzodiazepine premedication.
Etomidate - note that even a single induction dose inhibits adrenocortical steroidogenesis (blocks 11β-hydroxylase), which can be significant in critically ill patients.
2. Inhalational Anesthetics
Used for maintenance (and sometimes induction) of general anesthesia. Key agents:
| Drug | Key Properties |
|---|---|
| Sevoflurane | Rapid onset/offset; preferred for inhalation induction (children); low airway irritation |
| Desflurane | Fastest emergence; airway irritant (not used for induction) |
| Isoflurane | Lowest critical rCBF threshold (best cerebral protection) |
| Nitrous oxide (N₂O) | Analgesic/anesthetic adjunct; associated with increased PONV; 50% N₂O in O₂ was previously favored |
Minimum Alveolar Concentration (MAC) - the concentration of inhaled anesthetic at which 50% of patients do not move in response to a surgical stimulus. Lower MAC = more potent.
Malignant Hyperthermia (MH): A life-threatening complication triggered by volatile anesthetics (e.g., halothane, sevoflurane) and succinylcholine. Propofol, etomidate, barbiturates, opioids, midazolam, and nondepolarizing muscle relaxants are all safe in MH-susceptible patients. Treatment: dantrolene.
- Miller's Anesthesia, 10e, p. 8048-8050; Morgan and Mikhail's Clinical Anesthesiology, 7e, p. 2454
B. Local Anesthetics
Local anesthetics block nerve conduction by dose-dependent blockade of voltage-gated sodium channels, preventing action potential propagation.
Classes
| Class | Examples | Key Feature |
|---|---|---|
| Amino Esters | Cocaine, procaine, chloroprocaine, tetracaine | Metabolized by plasma pseudocholinesterase |
| Amino Amides | Lidocaine, bupivacaine, ropivacaine, levobupivacaine, mepivacaine | Metabolized by liver |
Memory trick: Amides have 2 "i"s in their name (lidocaine → locaine); Esters have only 1 "i".
Physicochemical Properties
- pKa: Lower pKa → faster onset (more drug in uncharged form, which penetrates nerve membrane). All local anesthetics are ineffective in acidic (inflamed) tissue because they stay ionized and cannot penetrate the nerve.
- Protein binding: Higher protein binding → longer duration of action
- Hydrophobicity (lipid solubility): Greater hydrophobicity → greater potency
Toxicity
Early signs of local anesthetic systemic toxicity (LAST): numbness/tingling of tongue or lips, metallic taste, lightheadedness, tinnitus, visual disturbances → progressing to slurred speech, seizures → cardiovascular collapse.
Bupivacaine cardiotoxicity is especially difficult to treat (cardiac sodium channel block). Treatment of LAST: lipid emulsion therapy (Intralipid 20%).
Liposomal bupivacaine - encapsulated in multivesicular liposomes; can provide up to 72 hours of analgesia after local infiltration. However, evidence does not consistently show superior pain control compared with standard local anesthetics.
- Sabiston Textbook of Surgery, p. 1552-1560
PART 2: ANTIPYRETIC DRUGS
Antipyretics reduce fever by inhibiting prostaglandin synthesis (primarily PGE₂) in the hypothalamic thermoregulatory center.
Mechanism of Fever
Infection/inflammation → WBC activation → release of pyrogens (cytokines: IL-1, TNF-α) → stimulate COX-2 → ↑PGE₂ → raises the set-point of the anterior hypothalamus → fever.
Antipyretics block this pathway by inhibiting COX → ↓PGE₂ → thermostat resets to normal → heat dissipation via peripheral vasodilation and sweating.
Important: Antipyretics only lower elevated (febrile) temperature - they have no effect on normal body temperature.
The Cyclooxygenase (COX) Pathway
- COX-1: Constitutive enzyme - governs gastric cytoprotection, platelet aggregation, vascular homeostasis, renal function
- COX-2: Induced by inflammatory mediators (TNF-α, IL-1); also constitutively expressed in brain, kidney, bone. Inhibition of COX-2 → anti-inflammatory/analgesic effects
Major Antipyretic Drug Classes
1. NSAIDs (Non-Selective COX Inhibitors)
NSAIDs are chemically dissimilar agents classified by chemical structure:
| Chemical Class | Examples |
|---|---|
| Salicylic acid | Aspirin, diflunisal, salsalate |
| Propionic acid | Ibuprofen, naproxen, ketoprofen |
| Acetic acid | Indomethacin, diclofenac, ketorolac, etodolac |
| Enolic acid | Piroxicam, meloxicam |
| Fenamates | Mefenamic acid, meclofenamate |
Three major therapeutic actions: Anti-inflammatory, analgesic, antipyretic.
Aspirin is unique - it is an irreversible inhibitor of cyclooxygenase (acetylates the enzyme). All other NSAIDs are reversible inhibitors.
Antipyretic doses:
- Aspirin: 2 × 325 mg tablets → analgesia; 12-20 tablets/day → anti-inflammatory (dose-dependent)
- Ibuprofen, naproxen: commonly used for fever
Adverse effects of NSAIDs:
- GI: ulceration, bleeding (COX-1 inhibition reduces gastric mucosal protection)
- Renal: reduced renal blood flow (especially in volume-depleted states)
- Platelet dysfunction: aspirin irreversibly inhibits platelet COX-1 → ↓TXA₂ → ↓aggregation
- Cardiovascular: selective COX-2 inhibitors and some NSAIDs increase thrombotic risk
- Reye syndrome: Aspirin use in children (<19 years) with viral infections (varicella, influenza) → associated with Reye syndrome → use avoided in children
- Pregnancy: NSAIDs contraindicated in 3rd trimester (premature closure of ductus arteriosus)
2. Selective COX-2 Inhibitor: Celecoxib
- Mechanism: Selectively and reversibly inhibits COX-2 (unlike aspirin's irreversible inhibition)
- Uses: RA, osteoarthritis, acute pain
- Advantage: Less GI bleeding and dyspepsia than non-selective NSAIDs
- Disadvantage: ↑cardiovascular thrombotic risk; benefit over GI safety lost when combined with aspirin
- Metabolism: CYP2C9 in liver; half-life ~11 hours
- Avoid in severe hepatic or renal disease
3. Acetaminophen (Paracetamol)
- Mechanism: Inhibits prostaglandin synthesis in the CNS → antipyretic + analgesic effects. Has minimal effect on peripheral COX (inactivated peripherally) → weak anti-inflammatory action. Does not affect platelet function. Not an NSAID.
- Uses: Fever and mild-to-moderate pain; preferred in:
- Children with viral infections (safe alternative to aspirin - no Reye risk)
- Pregnant women needing analgesia/antipyresis
- Patients with GI intolerance to NSAIDs
Metabolism and Toxicity:
At normal doses: Acetaminophen → conjugated to glucuronide/sulfate (inactive) → excreted in urine. A small portion is oxidized via CYP450 to NAPQI (toxic intermediate), which is rapidly neutralized by glutathione → mercapturic acid (nontoxic).
At toxic doses (overdose): Glutathione depleted → NAPQI accumulates → binds sulfhydryl groups of hepatic proteins → hepatic necrosis (potentially fatal).
High-risk groups for hepatotoxicity: Hepatic disease, chronic alcoholism, malnutrition, viral hepatitis.
Antidote: N-acetylcysteine (NAC) - replenishes glutathione stores.
- Lippincott Illustrated Reviews: Pharmacology, p. 1331-1366
Summary Comparison Table
| Feature | NSAIDs | Celecoxib | Acetaminophen |
|---|---|---|---|
| COX selectivity | Non-selective (COX-1 + COX-2) | COX-2 selective | Minimal peripheral COX inhibition |
| Anti-inflammatory | Yes | Yes | Minimal |
| Analgesic | Yes | Yes | Yes |
| Antipyretic | Yes | Yes | Yes |
| Platelet effect | ↓Aggregation (aspirin irreversibly) | Minimal | None |
| GI risk | High | Low | None at therapeutic doses |
| Hepatotoxicity | Low | Low | High (overdose) |
| Safe in children with viral illness | No (Reye risk for aspirin) | No | Yes |
| Safe in pregnancy | Avoid 3rd trimester | Avoid | Preferred |
| Antidote in overdose | - | - | N-acetylcysteine |
Sources:
- Lippincott Illustrated Reviews: Pharmacology (NSAIDs and Acetaminophen chapter)
- Miller's Anesthesia, 10e (IV anesthetics and general anesthesia)
- Sabiston Textbook of Surgery (local anesthetic drugs)
- Morgan and Mikhail's Clinical Anesthesiology, 7e (MH, IV agents)
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