Loco- Pharmacology

• Aspirin (acetylsalicylic acid) irreversibly acetylates a serine residue at the active site of COX.

• This permanent inactivation lasts for the lifetime of the enzyme.

• Platelets, which lack nuclei, cannot synthesize new COX → aspirin’s antiplatelet effect lasts 7–10 days (life span of platelets).

• This unique mechanism explains why aspirin is used in low doses for cardioprotection (anti-thrombotic effect via inhibition of thromboxane A2).

❌Why Other Options Are Incorrect

• Acetaminophen – not a classic NSAID, weak COX inhibitor in peripheral tissues (acts mainly in CNS, antipyretic/analgesic but not anti-inflammatory). Also reversible.

• Diclofenac – reversible NSAID.

• Mefenamic acid – reversible NSAID.

• Naproxen – reversible NSAID.

• NAC is the specific antidote for acetaminophen poisoning.

• It acts by:

  1. Replenishing glutathione stores → allowing detoxification of NAPQI.

  2. Acting as a direct sulfhydryl donor to neutralize NAPQI.

  3. Improving microcirculatory blood flow in the liver, aiding recovery.

• The earlier NAC is given (within 8–10 hours), the more effective it is.

❌Why the Other Options are Incorrect

• Activated charcoal – useful if given within 1 hour of ingestion to prevent absorption, but not an antidote.

• Protamine sulfate – antidote for heparin toxicity, not acetaminophen.

• Sodium bicarbonate – used for tricyclic antidepressant overdose (to counter arrhythmias), and in metabolic acidosis, not here.

• Sulphapyridine – not an antidote, rather an antimicrobial sometimes used in inflammatory bowel disease.

Aspirin is contraindicated in children with viral illnesses (e.g., chickenpox, influenza) because it is associated with Reye’s syndrome, a rare but potentially fatal condition.

• Reye’s syndrome = acute encephalopathy + liver failure (microvesicular fatty change in hepatocytes).

• The exact mechanism is unclear, but aspirin is thought to impair mitochondrial function in the liver during viral infections.

• Clinical features: vomiting, confusion, seizures, coma, elevated liver enzymes, hyperammonemia.

❌ Why the other options are incorrect:

• Fanconi syndrome → Proximal tubule dysfunction, not aspirin-related.

• Gastric bleeding → Possible with aspirin but not specific to children with viral illness.

• Nephrotoxicity → Seen with NSAIDs in general, not the major contraindication here.

• Thrombocytopenia → Aspirin impairs platelet aggregation, but not the reason for contraindication in viral illness.

• Cyclooxygenase (COX) enzymes:

  • COX-1 → constitutive enzyme, maintains gastric mucosa, renal blood flow, platelet aggregation.

  • COX-2 → inducible enzyme, mediates inflammation, pain, and fever.

• Aspirin (acetylsalicylic acid):

  • Irreversibly inhibits both COX-1 and COX-2.

  • At low doses → mainly COX-1 inhibition (antiplatelet effect).

  • At higher doses → inhibits both, giving analgesic, anti-inflammatory, and antipyretic effects.

Why not the others?

• Paracetamol / Acetaminophen → weak inhibitor of COX in the periphery, acts mainly in the CNS; not a strong COX-1/2 inhibitor. ❌

• Dipyrone (metamizole) → a prodrug with weak COX inhibition, more of an analgesic & antipyretic, not a classical NSAID. ❌

• Antipyrine → older analgesic/antipyretic, weak COX inhibitor, not used commonly now. ❌

• Dantrolene is a direct-acting skeletal muscle relaxant.

• It works by inhibiting calcium release from the sarcoplasmic reticulum in skeletal muscle.

• This reduces excitation-contraction coupling, leading to muscle relaxation.

• It is commonly used for:

  • Malignant hyperthermia

  • Spasticity in neurological disorders

❌ Why Other Options Are Incorrect:

• Diazepam → Acts centrally by enhancing GABAergic inhibition; not direct on muscle.

• Chlorzoxazone → Central muscle relaxant; acts on the CNS, not skeletal muscle directly.

• Tizanidine → Central alpha-2 adrenergic agonist; reduces spasticity via CNS.

• Succinylcholine → Depolarizing neuromuscular blocker; acts at the neuromuscular junction, not directly on the muscle fiber contractile machinery.

• Aspirin is a non-selective NSAID that irreversibly inhibits both COX-1 and COX-2 enzymes.

• COX-1 inhibition → reduces protective prostaglandins in the stomach and platelets → can cause gastric irritation and antiplatelet effects.

• COX-2 inhibition → reduces inflammatory prostaglandins, leading to analgesic, antipyretic, and anti-inflammatory effects.

• Because it inhibits both COX-1 and COX-2, aspirin affects pain, inflammation, fever, and platelet aggregation.

❌ Why Other Options Are Incorrect:

• Acetaminophen → Mainly inhibits COX centrally; very weak anti-inflammatory effect; not a true COX-1/2 inhibitor.

• Allopurinol → Xanthine oxidase inhibitor; used in gout, not a COX inhibitor.

• Celecoxib → Selective COX-2 inhibitor; spares COX-1, reducing GI side effects.

• Misoprostol → Prostaglandin analog; protects gastric mucosa, does not inhibit COX enzymes.

• Aspirin irreversibly acetylates and inhibits cyclooxygenase (COX-1 enzyme) in platelets.

• COX-1 is required for the formation of thromboxane A₂ (TXA₂), a potent promoter of platelet aggregation and vasoconstriction.

• Because platelets lack nuclei, they cannot synthesize new COX-1 enzyme → the effect lasts for the lifespan of the platelet (~7–10 days).

• This is why aspirin is used as an antiplatelet drug in prevention of myocardial infarction, stroke, and thrombosis.

❌ Why Other Options Are Incorrect:

• Activating antithrombin III and inhibiting thrombin → This is the mechanism of heparin, not aspirin.

• Blocking platelet receptor for ADP → This is how clopidogrel, prasugrel, ticlopidine work.

• Inhibiting hepatic vitamin K dependent clotting factor synthesis → This is the mechanism of warfarin.

• Stimulate fibrinogenic synthesis → Not correct; fibrinogen is part of the coagulation cascade, and aspirin does not stimulate it.

• Acetaminophen (paracetamol) is primarily metabolized in the liver.

• In overdose, the normal conjugation pathways (glucuronidation, sulfation) are overwhelmed.

• Normally detoxified by glutathione, but in overdose glutathione stores are depleted.

• Result: acute liver failure, the leading cause of death.

❌ Why Other Options Are Incorrect:

• Status epilepticus → Acetaminophen does not cause seizures; overdose causes hepatic toxicity, not neurotoxicity.

• A-V conduction disturbance → Seen with some cardiac drugs, not acetaminophen.

• Acute nephropathy → Kidney damage can occur secondarily, but it is not the primary cause of death.

• Status asthmaticus → No relation to acetaminophen toxicity.

• Aspirin irreversibly inhibits COX-1 and COX-2, reducing prostaglandin synthesis.

• Prostaglandins normally maintain gastric mucosal protection by stimulating mucus and bicarbonate secretion and maintaining blood flow.

• Chronic aspirin use → decreased protection → gastric mucosal damage → gastric ulcers and bleeding.

• This is one of the most important adverse effects limiting its long-term use.

❌ Why Other Options Are Incorrect:

• Headache → Not a chronic adverse effect; aspirin actually relieves headaches.

• Vertigo → More commonly seen with high-dose salicylate toxicity (salicylism), not routine chronic use.

• Gout → Low-dose aspirin can reduce uric acid excretion (→ hyperuricemia), but the hallmark chronic complication is GI ulceration, not gout.

• Heart failure → NSAIDs may worsen heart failure in predisposed patients, but this is less specific compared to the classic gastric ulcer risk of aspirin.

• Acetaminophen (Paracetamol) is primarily an analgesic and antipyretic.

• It has very weak anti-inflammatory properties, which is why it’s not considered useful in inflammatory conditions like rheumatoid arthritis.

• Unlike NSAIDs, it does not inhibit peripheral cyclooxygenase strongly, and most of its effects are central (acting in the CNS).

❌ Why Other Options Are Incorrect:

• Celecoxib → A selective COX-2 inhibitor; has strong anti-inflammatory properties, not weak.

• Indomethacin → A potent NSAID with strong anti-inflammatory action, especially in acute gout.

• Colchicine → Used in acute gout attacks; acts by inhibiting microtubule formation, not primarily as an analgesic or antipyretic.

• Probenecid → A uricosuric drug used in chronic gout to increase uric acid excretion; not an analgesic or antipyretic.

• Aspirin (acetylsalicylic acid) is unique among NSAIDs because it irreversibly acetylates and inactivates cyclooxygenase (COX-1 and COX-2).

• This irreversible effect lasts for the lifespan of the platelet (~7–10 days), since platelets cannot synthesize new proteins.

• Other NSAIDs (like ibuprofen, naproxen, indomethacin) reversibly inhibit COX, so their effects wear off once the drug is cleared.

• Clinically, this is why low-dose aspirin is used for antiplatelet therapy (to reduce risk of myocardial infarction and stroke).

❌ Why the Other Options Are Incorrect:

• Decreases fever → True, but not unique; all NSAIDs have antipyretic action.

• Prevents episodes of gouty arthritis with long-term use → Aspirin is not used for chronic gout prophylaxis (low doses actually worsen uric acid retention).

• It selectively inhibits cyclooxygenase enzyme → Aspirin is nonselective; it affects both COX-1 and COX-2.

• Increases the risk of colon cancer → Opposite effect; long-term low-dose aspirin use actually reduces colorectal cancer risk.

Step 1: Symptomatic treatment focus

• The goal in symptomatic therapy is to improve neuromuscular transmission.

• This is achieved with acetylcholinesterase inhibitors, which prevent breakdown of acetylcholine at the NMJ → more ACh available to bind to the few remaining receptors.

• The drug of choice: Pyridostigmine.

Step 2: Evaluate each option

• Albuterol ❌
  A β₂-agonist used for asthma/COPD. Not used in MG.

• Atropine ❌
  A muscarinic antagonist — in fact, it would worsen MG symptoms by blocking acetylcholine action.

• Diazepam ❌
  A benzodiazepine used for anxiety, seizures, and muscle relaxation. Not part of MG therapy.

• Prednisone ❌
  This is used as an immunosuppressant for long-term disease control, but it’s not the first-line symptomatic treatment.

• Pyridostigmine ✅
  An acetylcholinesterase inhibitor that provides symptomatic relief by prolonging acetylcholine activity at the neuromuscular junction.

Methylxanthines (like theophylline, aminophylline) act mainly by inhibiting the enzyme phosphodiesterase (PDE). Normally, PDE breaks down cyclic AMP (cAMP). By inhibiting PDE, methylxanthines increase intracellular cAMP, which leads to:

• Bronchodilation (relaxation of smooth muscle)

• Anti-inflammatory effects (reduced mediator release)
  Additionally, methylxanthines block adenosine receptors, contributing to bronchodilation and CNS stimulation.

❌ Why the other options are incorrect:

• Beta-adrenergic receptor stimulation: This is the mechanism of β₂ agonists (e.g., salbutamol), not methylxanthines.

• Alpha-adrenergic receptor stimulation: This causes vasoconstriction (seen in drugs like phenylephrine), unrelated to methylxanthines.

• Regulation of intracellular fluoride levels: Not a physiological mechanism in pharmacology.

• Regulation of intracellular sodium levels: This is related to sodium channels or sodium-potassium pump activity, not the action of methylxanthines.

Curare works by inhibiting motor nerve end-plates. Specifically, it acts as a competitive antagonist of nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction. By binding to these receptors without activating them, curare prevents acetylcholine from binding and triggering muscle contraction, resulting in flaccid paralysis.

• Stimulates cells in the anterior horn of the spinal cord → Incorrect. Curare does not act on the spinal cord or motor neurons directly; its action is peripheral at the neuromuscular junction.

• Prevents saltatory conduction of nerve impulses → Incorrect. That mechanism is typical of demyelinating diseases (e.g., multiple sclerosis) or sodium channel blockers, not curare.

• Excites neuromuscular junctions → Incorrect. Curare blocks excitation instead of promoting it.

• Slows conduction of nerve impulses → Incorrect. Nerve conduction velocity is unaffected; the block occurs at the synapse (NMJ), not along the nerve axon.

• Inhibits motor nerve end-plates → Correct. Curare blocks nicotinic receptors at the motor end-plate, preventing depolarization and contraction.

Glucocorticoids are powerful anti-inflammatory and immunosuppressive agents, but their chronic use comes with significant adverse effects.

• Exaggeration of inflammatory reaction → Incorrect. Glucocorticoids suppress inflammation, they don’t exaggerate it.

• Osteoporosis → Correct. Glucocorticoids decrease osteoblast activity, increase osteoclast activity, and reduce calcium absorption in the gut, leading to bone loss and osteoporosis.

• Alopecia → Not a typical side effect of glucocorticoids. In fact, they can sometimes cause hirsutism (excess hair growth).

• Ototoxicity → Not associated with glucocorticoids. This effect is more common with aminoglycosides and cisplatin.

• None of these → Incorrect, because osteoporosis is indeed a classical side effect.

Leflunomide is a disease-modifying antirheumatic drug (DMARD) that inhibits dihydroorotate dehydrogenase, leading to decreased pyrimidine synthesis and suppression of T-cell proliferation. Its adverse effects are well-documented.

• Cytotoxicity → Correct, because leflunomide suppresses immune cell proliferation, giving it a cytostatic effect.

• Alopecia → Also correct; hair loss is a common adverse effect due to inhibition of rapidly dividing cells.

• Ototoxicity → Not typically associated with leflunomide; this is more a feature of aminoglycosides and cisplatin.

• Nephrotoxicity → Not a classical side effect of leflunomide; drugs like cyclosporine or aminoglycosides are more nephrotoxic.

• All of these → Incorrect, because not all the listed options are seen with leflunomide. The correct side effect from the list is alopecia.

Methotrexate is an antimetabolite and folate antagonist used in cancer chemotherapy and autoimmune diseases. Its most important and common side effect is myelosuppression due to inhibition of DNA synthesis in rapidly dividing cells, particularly bone marrow.

• Myelosuppression → Correct. This occurs because methotrexate inhibits dihydrofolate reductase, impairing thymidylate and purine synthesis, leading to suppression of bone marrow cell proliferation.

• Ototoxicity → Typically seen with drugs like aminoglycosides and cisplatin, not methotrexate.

• Pulmonary fibrosis → More commonly associated with bleomycin, busulfan, and amiodarone. Methotrexate can rarely cause interstitial pneumonitis, but pulmonary fibrosis is not its classical hallmark side effect.

• Anaphylactic reaction → Not a typical adverse effect of methotrexate; hypersensitivity reactions are rare.

• None of these → Incorrect because one of the listed options (myelosuppression) is correct.

Botulinum toxin (produced by Clostridium botulinum) is one of the most potent toxins known. It prevents exocytosis of acetylcholine vesicles from presynaptic nerve terminals by cleaving SNARE proteins (such as synaptobrevin, SNAP-25, syntaxin), which are essential for vesicle fusion.

• Without acetylcholine release, the postsynaptic muscle fiber cannot depolarize, leading to flaccid paralysis.

• Clinically, it causes botulism (descending paralysis, cranial nerve palsies, respiratory failure) and is also used in controlled doses for therapeutic and cosmetic purposes (e.g., Botox).

Why the other options are wrong

• Blocks the uptake of acetylcholine → No such mechanism; acetylcholine is not “taken up” but released.

• Decreases the formation of acetylcholine → That would involve inhibition of choline acetyltransferase, which botulinum toxin does not do.

• Increases the release of acetylcholine → Opposite effect; this is the action of black widow spider toxin (α-latrotoxin).

• Breaks down the acetylcholine → That is the action of acetylcholinesterase enzyme, not botulinum toxin.

Rickets is caused by vitamin D deficiency in children, leading to defective bone mineralization, especially at growth plates. It results in bone pain, deformities, and delayed growth.

First-line treatment:

• Cholecalciferol (Vitamin D₃) is the most appropriate choice for:

  • Nutritional rickets

  • Added to diet (e.g., milk) or given orally

  • It is converted in the liver to 25-hydroxyvitamin D, then in the kidney to active calcitriol (1,25-dihydroxyvitamin D)

This approach mimics the natural pathway and corrects the deficiency safely.

❌ Why the Other Options Are Incorrect

• Gallium nitride:
  ❌ This is not a drug — it’s a semiconductor material used in electronics.

• Teriparatide:
  ❌ A recombinant PTH analog used in osteoporosis, not suitable or approved for children or rickets.

• Plicamycin (Mithramycin):
  ❌ An antineoplastic antibiotic used in Paget’s disease and testicular cancer; not used for rickets.

• Calcitriol:
  ❌ Active form of vitamin D — reserved for patients with renal failure or genetic rickets (e.g., vitamin D–resistant rickets).

  • In nutritional rickets, it’s better to give cholecalciferol and let the body activate it naturally.

Reye’s syndrome is a rapidly progressive encephalopathy with hepatic dysfunction, typically occurring in children recovering from viral infections such as influenza or varicella (chickenpox). The syndrome presents with vomiting, confusion, seizures, lethargy, and can quickly progress to coma and death.

🔄 Mechanism of Risk with Aspirin:

Although the exact mechanism is not completely understood, salicylates (like aspirin) are thought to impair mitochondrial function, especially in the liver. This leads to:

• Mitochondrial dysfunction
• Fatty liver with microvesicular steatosis
• Increased intracranial pressure due to cerebral edema

For this reason, aspirin is contraindicated in children under 16 years unless specifically indicated (e.g., Kawasaki disease).

❌ Why the Other Options Are Incorrect:

• Chediak-Higashi Syndrome:
  A rare autosomal recessive disorder involving a defect in lysosomal trafficking, leading to immunodeficiency and partial albinism. Aspirin is not contraindicated here.
• Thorn’s Syndrome:
  This term is outdated and not commonly used in clinical settings. It may refer to adrenal insufficiency, but it’s unrelated to aspirin or viral illnesses.
• Banti’s Syndrome:
  A condition involving congestive splenomegaly due to portal hypertension without cirrhosis. Again, no link with aspirin use in viral infections.
• Barlow Syndrome:
  An old term for mitral valve prolapse. This cardiac condition has no association with Reye’s syndrome or contraindication of aspirin.

Methylxanthines, such as theophylline, caffeine, and aminophylline, are bronchodilators and CNS stimulants whose primary mechanism of action involves inhibition of the enzyme phosphodiesterase (PDE).

🔬 How It Works:

• Phosphodiesterase (PDE) is an enzyme that breaks down cyclic AMP (cAMP).
• By inhibiting PDE, methylxanthines increase cAMP levels inside cells.
• Increased cAMP in airway smooth muscle leads to:
  • Bronchodilation
  • Reduced inflammatory mediator release
• This is why drugs like theophylline are used in the treatment of asthma and COPD.

Additionally, methylxanthines antagonize adenosine receptors, which contributes to CNS stimulation (e.g., increased alertness with caffeine).

❌ Breakdown of Incorrect Options:

• Alpha-adrenergic receptor stimulation
  → This leads to vasoconstriction and increased blood pressure; not the action of methylxanthines.
• Regulation of intracellular sodium levels
  → This describes the mechanism of drugs like cardiac glycosides (e.g., digoxin), not methylxanthines.
• Beta-adrenergic receptor stimulation
  → Beta agonists (like salbutamol) do cause bronchodilation but through direct receptor stimulation, whereas methylxanthines act by increasing cAMP via PDE inhibition.
• Regulation of intracellular fluoride levels
  → Not relevant in pharmacology or methylxanthine action

Acetaminophen (also known as paracetamol) is a widely used analgesic (pain-reliever) and antipyretic (fever-reducer), but it lacks significant anti-inflammatory activity compared to NSAIDs like aspirin or ibuprofen.

Its exact mechanism of action is not fully understood, but a key proposed mechanism involves inhibition of cyclooxygenase-3 (COX-3) — a variant of COX-1 predominantly expressed in the central nervous system (CNS).

Here’s the breakdown:

• COX enzymes (Cyclooxygenases) are responsible for the production of prostaglandins, which are mediators of pain, inflammation, and fever.
• COX-1 is constitutive (always present) and involved in physiological functions like protecting gastric mucosa, platelet aggregation, and renal blood flow.
• COX-2 is inducible during inflammation and is a target for many anti-inflammatory drugs.
• COX-3 is a splice variant of COX-1, primarily located in the brain and possibly involved in fever and pain regulation.

Acetaminophen is thought to act centrally by inhibiting COX-3, reducing the synthesis of prostaglandins in the brain, thus lowering fever and relieving pain without much peripheral anti-inflammatory action.

Acetaminophen (also known as paracetamol) is a widely used analgesic (pain-reliever) and antipyretic (fever-reducer), but it lacks significant anti-inflammatory activity compared to NSAIDs like aspirin or ibuprofen.

Its exact mechanism of action is not fully understood, but a key proposed mechanism involves inhibition of cyclooxygenase-3 (COX-3) — a variant of COX-1 predominantly expressed in the central nervous system (CNS).

Here’s the breakdown:

• COX enzymes (Cyclooxygenases) are responsible for the production of prostaglandins, which are mediators of pain, inflammation, and fever.
• COX-1 is constitutive (always present) and involved in physiological functions like protecting gastric mucosa, platelet aggregation, and renal blood flow.
• COX-2 is inducible during inflammation and is a target for many anti-inflammatory drugs.
• COX-3 is a splice variant of COX-1, primarily located in the brain and possibly involved in fever and pain regulation.

Acetaminophen is thought to act centrally by inhibiting COX-3, reducing the synthesis of prostaglandins in the brain, thus lowering fever and relieving pain without much peripheral anti-inflammatory action.

Rickets is a disease of impaired bone mineralization in children, most often due to vitamin D deficiency. It leads to soft, weak bones, bowed legs, and growth disturbances.

While calcium supplementation is essential, vitamin D is also crucial because it:

• Enhances calcium and phosphate absorption from the gut
• Helps with bone mineralization
• Prevents hypocalcemia by working on the parathyroid hormone axis

Among the forms of vitamin D, cholecalciferol (vitamin D₃) is the standard supplement given in most cases of nutritional rickets.

✅ Why Cholecalciferol Is Correct:

• It is the natural form of vitamin D produced in the skin upon UVB exposure.
• It is often given orally to children with rickets to restore vitamin D levels.
• In the liver, cholecalciferol is converted to calcidiol (25-hydroxyvitamin D), and in the kidneys, to calcitriol (1,25-dihydroxyvitamin D) — the active form.
• Most rickets cases respond well to cholecalciferol and calcium, unless there’s a problem in the kidney or liver metabolism.

❌ Why the Other Options Are Incorrect:

• Dehydrocholesterol
  • A precursor of vitamin D in the skin.
  • Not used therapeutically — it’s converted by sunlight, not given as a drug.
• Calcitriol
  • The active form of vitamin D.
  • Given only in renal rickets or when vitamin D activation is impaired, because it bypasses kidney conversion.
  • Not first-line in nutritional rickets due to risk of hypercalcemia if overdosed.
• Cyanocobalamin
  • A form of vitamin B12.
  • Used in megaloblastic anemia, not in bone disease.
• Levothyroxine
  • A thyroid hormone replacement.
  • Used in hypothyroidism, has no role in rickets.

✅ Reye’s Syndrome – Correct.
Aspirin is strictly contraindicated in children with viral infections like influenza or varicella (chickenpox) due to the risk of Reye’s syndrome — a rare but potentially fatal condition characterized by acute encephalopathy and fatty liver degeneration. The exact mechanism isn’t fully understood, but it’s believed that aspirin may trigger mitochondrial dysfunction in susceptible children during viral illness.

Now let’s explore why the other options are incorrect:

❌ Rickets – This is a vitamin D deficiency disorder affecting bone mineralization in growing children. It is not related to aspirin use.

❌ Osteoporosis – This is a progressive loss of bone density, primarily seen in older adults, and is not related to aspirin or viral infections in children.

❌ Paget’s Disease – This involves abnormal bone remodeling, mostly in older adults. It has no association with aspirin or childhood viral infections.

❌ Osteopetrosis – A rare genetic condition where bones become overly dense and brittle due to defective osteoclasts. It is unrelated to aspirin or viral illness.

Aspirin belongs to the class of nonsteroidal anti-inflammatory drugs (NSAIDs). It is widely used for its analgesic, antipyretic, anti-inflammatory, and antiplatelet effects. These effects stem from its action on a specific enzyme system.

✅ Inhibition of cyclooxygenase (COX) – Correct.
Aspirin irreversibly inhibits both COX-1 and COX-2 enzymes, which are critical in converting arachidonic acid into prostaglandins and thromboxanes. Prostaglandins mediate pain, inflammation, and fever, while thromboxanes are involved in platelet aggregation. By inhibiting COX, aspirin reduces inflammation (like knee joint swelling), pain, and fever.

Now the incorrect choices:

❌ Inhibition of platelet formation – Aspirin doesn’t inhibit the formation of platelets. It inhibits their aggregation by preventing thromboxane A2 production, but platelet production in the bone marrow remains unaffected.

❌ Inhibition of lipoxygenase – Lipoxygenase is involved in the leukotriene pathway, not the prostaglandin pathway. Aspirin has no direct action on lipoxygenase.

❌ Inhibition of leukocytes – Aspirin doesn’t inhibit the number or function of leukocytes directly; its anti-inflammatory effect comes from reduced prostaglandin-mediated recruitment and activation.

❌ Inhibition of erythrocyte formation – There is no effect of aspirin on red blood cell formation.

🔹 Acetaminophen (Paracetamol) – MOA

• Acetaminophen is an analgesic and antipyretic, but not an anti-inflammatory drug.

• Unlike NSAIDs, it has very weak peripheral COX-1 and COX-2 inhibition.

• Its primary action is thought to be inhibition of COX-3, an isoenzyme expressed mainly in the CNS.

🔹 Why COX-3 Inhibition Matters

• By inhibiting COX-3 in the brain:

  • ↓ Prostaglandin synthesis in CNS → ↓ fever (antipyretic effect).

  • ↓ Prostaglandin-mediated pain transmission → analgesic effect.

• Because it does not significantly inhibit COX-1/2 in peripheral tissues, it has:

  • Minimal anti-inflammatory action.

  • No significant effect on platelet aggregation or gastric mucosa.

❌ Why the Other Options Are Wrong

• Inhibits COX-1 and COX-3 → Wrong, main central effect is on COX-3 only; peripheral COX-1 inhibition is negligible.

• Inhibits COX-1, COX-2, and COX-3 → Wrong, peripheral COX-1 and COX-2 inhibition is too weak to be clinically relevant.

• Inhibits COX-1 → Wrong, not the main mechanism.

• Inhibits COX-2 → Wrong, selective COX-2 inhibitors (like celecoxib) do that, not acetaminophen.

⚠️ Acetaminophen (Paracetamol) Overdose:

🔬 Mechanism of Toxicity:

• Normally, acetaminophen is metabolized in the liver by glucuronidation and sulfation.
• A small fraction is converted by CYP450 enzymes (especially CYP2E1) to a toxic intermediate:
  NAPQI (N-acetyl-p-benzoquinone imine)
• NAPQI is detoxified by glutathione, forming harmless conjugates
• In overdose, glutathione stores are depleted → NAPQI accumulates → hepatocellular necrosis

💊 Antidote: N-acetyl cysteine (NAC)

• NAC replenishes hepatic glutathione
• It can also directly bind NAPQI and neutralize it
• Most effective when given within 8–10 hours of ingestion, but still beneficial later

❌ Why the Other Options Are Incorrect:

• Naltrexone
  • Opioid receptor antagonist
  • Used for opioid or alcohol dependence, not acetaminophen toxicity
• Nalbuphine
  • Mixed opioid agonist-antagonist
  • Used for pain, not as an antidote
• Calcium gluconate
  • Used for hyperkalemia, calcium channel blocker overdose, and hydrofluoric acid burns
  • Irrelevant for acetaminophen toxicity
• N-methyl arginine
  • Experimental nitric oxide synthase inhibitor
  • Not used clinically as an antidote

This question evaluates your understanding of the mechanism of action of bisphosphonates, a class of drugs crucial in the management of bone resorption disorders such as osteoporosis, Paget’s disease, and bone metastases.

🔬 Mechanism of Action of Bisphosphonates:

• Bisphosphonates are structural analogs of pyrophosphate, a natural regulator of bone mineralization.
• They have a high affinity for hydroxyapatite in bone, allowing them to accumulate at sites of active bone resorption.

🦴 What do they do?

• When osteoclasts begin to resorb bone, they ingest bisphosphonates, which then:
  • Induce apoptosis (programmed cell death) in osteoclasts.
  • Inhibit farnesyl pyrophosphate synthase in the mevalonate pathway (in nitrogen-containing bisphosphonates), which is essential for osteoclast function.
• The end result is inhibition of osteoclastic activity, leading to reduced bone resorption.

❌ Why the Other Options Are Incorrect

It helps in bone resorption

• Incorrect: Bisphosphonates are anti-resorptive agents. They prevent, not promote, bone resorption.

It causes the loss of bone density

• Incorrect: Bisphosphonates help preserve or increase bone density by reducing bone breakdown.

It inhibits osteoblastic activity

• Incorrect: Osteoblasts are bone-forming cells. Bisphosphonates have no direct inhibitory effect on them.

It helps in bone formation

• Not directly true: Bisphosphonates do not stimulate bone formation. Instead, they reduce bone loss, which may indirectly improve bone density over time.

Aspirin (acetylsalicylic acid) is a non-steroidal anti-inflammatory drug (NSAID) that works by irreversibly inhibiting the cyclooxygenase enzymes — COX-1 and COX-2.

These enzymes are responsible for converting arachidonic acid into prostaglandins, which are mediators of inflammation, pain, and fever. By inhibiting COX enzymes:

• Pain and swelling are reduced (due to decreased prostaglandin production).

• Platelet aggregation is also reduced because COX-1 inhibition in platelets prevents formation of thromboxane A₂, a potent aggregator.

✅ Inhibition of cyclooxygenase — Correct. This is the primary mechanism of aspirin, making it effective as an analgesic, antipyretic, anti-inflammatory, and antiplatelet drug.

❌ Inhibition of erythrocyte formation — Incorrect. Aspirin does not affect red blood cell production.

❌ Inhibition of platelet formation — Incorrect. Aspirin inhibits platelet function, not formation.

❌ Inhibition of lipoxygenase — Incorrect. This would describe drugs like zileuton, not aspirin.

❌ Inhibition of leukocytes — Incorrect. While aspirin may indirectly reduce leukocyte activity by reducing prostaglandins, it does not directly inhibit leukocytes.

Among all calcium salts, calcium carbonate is the most commonly used preparation for dietary supplementation and treatment of calcium deficiency. It is widely available, inexpensive, and contains a high percentage of elemental calcium.

🔹 Why Calcium Carbonate Is Preferred:

• Contains 40% elemental calcium — the highest among common calcium salts.

• Commonly available in tablets and chewables.

• Best absorbed when taken with food, as it requires gastric acid for proper absorption.

• Used in:

  • Osteoporosis

  • Hypocalcemia

  • As an antacid

❌ Why the Other Options Are Less Common:

• Calcium glubionate
  → Used in pediatric syrup formulations; less elemental calcium.

• Calcium gluconate
  → Preferred IV form for acute hypocalcemia, but not for routine oral supplementation.

• Calcium citrate
  → Better absorbed in patients with low stomach acid, but more expensive and less elemental calcium per tablet (21%).

• Calcium lactate
  → Low elemental calcium content (13%), not commonly used due to inefficiency.

In acetaminophen (paracetamol) overdose, excess amounts of the drug saturate normal conjugation pathways, leading to accumulation of the toxic metabolite NAPQI (N-acetyl-p-benzoquinone imine). If not adequately detoxified by glutathione, NAPQI binds to hepatocellular proteins, causing centrilobular hepatic necrosis and ultimately liver failure — the most serious complication of overdose.

✅ Liver failure — Correct. This is the hallmark and most feared consequence of acetaminophen overdose.

❌ Status asthmaticus — Severe asthma attack; not related to acetaminophen toxicity.

❌ Status epilepticus — Continuous seizures; not a feature of acetaminophen toxicity.

❌ Acute nephropathy — Although rare renal injury may occur secondarily, primary concern is liver failure.

❌ AV conduction disturbance — Cardiac conduction is not typically affected in acetaminophen overdose.

Dopamine acts as a vasoconstrictor at higher doses by stimulating alpha-1 adrenergic receptors on vascular smooth muscle, leading to vasoconstriction. At lower doses, it can act on dopamine receptors and beta-1 receptors, but with increasing dose, alpha-1 effects dominate, causing vasoconstriction.

✅ Dopamine — Correct. It can act as a vasoconstrictor via alpha-1 receptor activation.

❌ Aspartate — An amino acid involved in protein metabolism and neurotransmission; does not act as a vasoconstrictor.

❌ None of these — Incorrect, since dopamine is a vasoconstrictor.

❌ Histamine — Typically acts as a vasodilator by stimulating H1 receptors on endothelial cells.

❌ Glutamate — An excitatory neurotransmitter; not involved in vascular tone regulation.

Leflunomide is an immunosuppressive drug commonly used in rheumatoid arthritis. It is a prodrug that is converted to its active metabolite (A77 1726), which inhibits dihydroorotate dehydrogenase, affecting pyrimidine synthesis.

Leflunomide is known for having a long half-life (can be several weeks), partly because of enterohepatic recirculation. It is also known to cause side effects such as hepatotoxicity and alopecia.

✅ Short lifetime — Correct. This statement is inappropriate because leflunomide has a long half-life, not a short one.

❌ Prodrug — This is true; leflunomide is a prodrug.

❌ None of these — Incorrect; one inappropriate statement is present.

❌ Hepatotoxic — True; leflunomide is hepatotoxic.

❌ Alopecia — True; alopecia is a known side effect of leflunomide.

• 5-lipoxygenase is involved in the leukotriene pathway, not the prostaglandin pathway.

• NSAIDs do not act on 5-lipoxygenase.

• Drugs that do inhibit this enzyme are drugs like zileuton, used in asthma therapy.

✔️ Why the Other Options Are Correct (True Statements):

Aspirin acetylates cyclooxygenase irreversibly

• True.

• This is unique to aspirin among NSAIDs.

• It irreversibly inhibits COX by acetylating a serine residue on the enzyme — particularly important in its antiplatelet action.

They inhibit cyclooxygenase-1 (COX-1) enzyme activity

• True.

• Most NSAIDs (like ibuprofen, naproxen) inhibit both COX-1 and COX-2.

• COX-1 inhibition is responsible for GI side effects (like ulcers).

They inhibit cyclooxygenase-2 (COX-2) enzyme activity

• True.

• This is the main anti-inflammatory effect of NSAIDs.

• Some drugs, like celecoxib, selectively inhibit COX-2 to reduce inflammation with fewer GI side effects.

They inhibit prostaglandin synthesis

• True.

• Since prostaglandins are products of COX enzymes, their synthesis is reduced by NSAIDs.

• This explains their antipyretic, analgesic, and anti-inflammatory actions.

📌 What are Conventional DMARDs (csDMARDs)?

These are non-biologic, synthetic drugs that slow disease progression in autoimmune conditions like rheumatoid arthritis.
They work by modulating the immune system — not just relieving symptoms.

✅ Conventional DMARDs include:

All of these are true csDMARDs ✅

❌ So why is Acetaminophen the odd one out?

• Also called paracetamol

• A non-opioid analgesic and antipyretic

• Has no anti-inflammatory or immunosuppressive effect

• Provides symptomatic pain relief only, but does not prevent joint damage or disease progression

• ❌ Not a DMARD — does not modify the disease

🔬 Summary Table:

Let’s analyze leflunomide like you’re reviewing for a pharmacology viva or OSCE.

🔬 What is Leflunomide?

• A prodrug that gets converted in the body to teriflunomide (A77 1726) — the active metabolite

• Used in rheumatoid arthritis and psoriatic arthritis

• Inhibits dihydroorotate dehydrogenase (DHODH) → ↓ pyrimidine synthesis → inhibits T-cell proliferation

✅ Let’s break down the options:

. Prodrug → ✅ Appropriate

• Leflunomide itself is inactive

• Converted in the liver to teriflunomide, the active form
  ✔️ Correct description

. Hepatotoxic → ✅ Appropriate

• Known to cause elevated liver enzymes, hepatotoxicity is a well-documented side effect

• Regular LFT monitoring is required
  ✔️ True

. Alopecia → ✅ Appropriate

• Hair thinning/loss is a documented side effect, though usually reversible
  ✔️ True

. Short lifetime → ❌ Inappropriate

• This is the incorrect statement, making it the correct answer for the question.

• Leflunomide (actually, its active form teriflunomide) has a very long half-life — up to 2–3 weeks

• Due to enterohepatic recirculation, the drug persists in the system for weeks to months

• This is why cholestyramine is sometimes given to accelerate drug elimination (e.g., before pregnancy)

🟥 Long half-life is a hallmark of leflunomide — so calling it “short lifetime” is inappropriate

. None of these

• ❌ Incorrect, because option C is clearly false → so “None of these” is wrong

To answer this, you need to classify opioids based on their origin — a high-yield concept in pharmacology.

🔹 Opioid Classification by Source:

🔍 So, what is Codeine?

• A natural narcotic (also called a natural opioid)

• Extracted directly from opium poppy

• Undergoes hepatic demethylation to convert to morphine (its active form)

• Commonly used for:

  • Mild to moderate pain

  • Cough suppression (antitussive)

🟩 Codeine = natural origin + narcotic analgesic → correct answer ✅

❌ Why the Other Options Are Incorrect:

. Methadone

• A synthetic opioid

• Used in opioid withdrawal management and chronic pain

• ❌ Not natural

. Pethidine = . Meperidine

• Same drug, different names (Pethidine = British; Meperidine = US)

• A fully synthetic opioid

• Used for moderate to severe pain, especially in labor

• ❌ Synthetic, not natural

. Tramadol

• Also synthetic

• Dual mechanism:

  • Weak μ-opioid agonist

  • Inhibits serotonin and norepinephrine reuptake

• ❌ Not natural

Let’s break this down from first principles.

🔬 Cyclooxygenase (COX) Enzymes — Quick Recap:

• COX-1: Constitutively active — maintains gastric mucosa, renal blood flow, platelet aggregation

• COX-2: Inducible — upregulated in inflammation, fever, and pain

🔹 Aspirin: The Classic Non-Selective COX Inhibitor

• Aspirin irreversibly inhibits both COX-1 and COX-2 via acetylation.

• That means:

  • ↓ Prostaglandins (→ less pain, fever, inflammation)

  • ↓ Thromboxane A2 (→ inhibits platelet aggregation)

• Used as an NSAID, analgesic, antipyretic, and antiplatelet

This broad inhibition defines aspirin’s efficacy but also its toxicity profile (e.g., GI ulcers, bleeding, Reye’s syndrome in children).

❌ Why the Other Options Are Incorrect:

. Paracetamol / Acetaminophen

(Same drug, different names — paracetamol is UK/Europe; acetaminophen is US/Canada)

• Primarily acts in the CNS, not a true COX-1/COX-2 inhibitor in peripheral tissues.

• It weakly inhibits COX enzymes in the brain but not in inflammatory sites (because it’s inactivated by peroxides in inflamed tissue).

• ❌ NOT classified as an NSAID and lacks anti-inflammatory action.

. Antipyrine

• An older antipyretic/analgesic with poor selectivity, and limited use today.

• Has weak, non-specific COX inhibition but isn’t considered a reliable COX-1/COX-2 inhibitor like aspirin.

• ❌ Obsolete and less relevant clinically

. Dipyrone (Metamizole)

• Used in some countries for pain and fever, especially post-op.

• Likely works via central COX inhibition and other mechanisms (e.g., cannabinoid and opioid-like pathways).

• It has very weak peripheral anti-inflammatory action, and its exact mechanism is still debated.

• ❌ Not a definitive COX-1/COX-2 inhibitor like aspirin