Pharmacology

Analgesics

  1. Opioids

    • Mimic endogenous opioids by acting at opioid receptors in the CNS.
    • Act on mu receptors.
    • Work via G proteins to open potassium and calcium channels.
    • Diamorphine: More lipid-soluble than morphine, therefore faster acting.

  2. NSAIDs

    • Inhibit prostaglandin production by acting on Cyclo-oxygenase enzyme (COX).
    • COX 1 exists in normal tissues.
    • COX 2 is present only at sites of inflammation.
    • Unselective COX inhibition: Results in inhibition of prostaglandin production where needed, such as in gastric mucosa.

  3. Paracetamol

    • Weakly inhibits COX and prostaglandin formation.
    • Also has a central action.

  4. Local Anaesthetics

    • Work by blocking sodium channels in neurons, preventing the formation of an action potential.
    • Very pH-dependent:
      • Increased action in alkaline environment.
      • Decreased action in acidic environment.
    • Block conduction in small myelinated fibers first, then unmyelinated, and large myelinated axons.
    • A and C fibers are blocked first.

  5. Glucocorticoids

    • Anti-inflammatory and immunosuppressive effects.
    • Act on all parts of the inflammatory cascade.
    • Modify gene transcription, altering protein synthesis (e.g., inhibit transcription of the gene that codes for COX 2 synthesis).
    • Directly suppress macrophage function.
    • Impair lymphocyte transport.

    Side Effects:

    • I WAS HOPPING MAD:
      • Infection, Wasting and proximal myopathy, Adrenal insufficiency, Sugar disturbance, Hypotension, Osteoporosis, Peptic ulceration, Pancreatitis, Necrosis, Glaucoma, Madness (psychiatric disturbances).

Anticoagulants

Clotting Cascade

  1. Intrinsic Pathway
    • Activated by exposure of collagen from damaged blood vessels to Factor 12.
    • Measured using APTT (Activated Partial Thromboplastin Time).
  2. Extrinsic Pathway
    • Activated by the release of thromboplastin by cell damage.
    • Measured by Prothrombin Time (PT).
  3. Common Pathway
    • Both pathways coalesce at the common pathway where Factor 10 is involved.
    • Factor 10 becomes Factor 10a, converting Prothrombin (Factor 2) to Thrombin.
    • Thrombin converts Fibrinogen (Factor 1) to Fibrin, forming a lattice to entrap platelets and produce a clot.

Drugs Affecting Clotting

  1. Warfarin

    • Similar in structure to vitamin K, which it antagonizes.
    • Inhibits vitamin K-dependent clotting factors by preventing carboxylation of glutamine residues.
    • Prevents factors from binding calcium, rendering them useless in the clotting cascade.
    • Factors affected: 2, 7, 9, 10, and Proteins C and S.
    • Long half-life (40 hours).
    • Takes 24-48 hours to work, as new clotting factors must replace old ones.
    • Metabolized in the liver, so liver disease is a contraindication.
    • Reversed by giving vitamin K, which forms more normal clotting factors.

  2. Heparin

    • Naturally occurring glycosaminoglycan.
    • Short acting, with a half-life of 4-6 hours.
    • Requires close monitoring with APTT.
    • Forms a complex with Antithrombin 3, which inactivates thrombin, preventing fibrinogen conversion to fibrin.
    • Also affects Factor 10a.
    • Reversed with Protamine.

  3. LMWH (Low Molecular Weight Heparin)

    • Forms a complex with Antithrombin 3, selectively inhibiting Factor 10a only.
    • Longer half-life; requires only once-daily dosing.

    Side Effects:

    • Bleeding (more common with pure heparin).
    • Heparin-induced thrombocytopenia.
    • Osteoporosis with long-term use.

  4. Fondaparinaux

    • Synthetic pentasaccharide.
    • Selectively inhibits Factor 10a.
    • Shown to work better than LMWH in some trials.

  5. Rivaroxiban

    • Direct action on Factor 10a.
    • No effect on platelets or thrombin directly.
    • Good oral bioavailability but expensive.

  6. Dabigatran

    • Direct thrombin inhibitor.
    • No reversibility in the event of major bleeding.
    • Good oral bioavailability.

  7. Aspirin

    • Binds with COX 1, inhibiting prostaglandin production.
    • Prevents platelet aggregation by inhibiting thromboxane A2 (a prothrombotic agent secreted by platelets).
    • Acts as an anticoagulant.

Drugs Acting on Bone Metabolism

  1. Bone Remodeling Process
    • Cytokines (IL6) recruit osteoclasts.
    • Osteoclasts secrete hydrogen ions and proteolytic enzymes that dig pits in trabecular bone.
    • Bone factors such as Insulin Growth Factor 1 (IGF-1) recruit osteoblasts to these pits.
    • Osteoblasts, primed by PTH and 1,25 Vit D, secrete osteoid into the pits along with IGF-1 and release IL-6.
    • Osteoid is mineralized by calcium hydroxyapatite.
    • IL6 released by osteoblasts recruits osteoclasts, restarting the cycle.

Drugs Affecting Bone Metabolism

  1. Bisphosphonates
    • Comprised of a PCP backbone, resistant to phosphatases.
    • No enzyme can metabolize bisphosphonates, so they remain in the bone until completely resorbed.
    • Types:
      • Nitrogen-containing: Act by inhibiting the mevalonate pathway (e.g., Etidronate, Clodronate).
      • Non-nitrogen-containing: Create a toxic ATP analogue (e.g., Zoledronate, Alendronate, Pamidronate).
    • Modes of Action:
      • Inhibit osteoclasts directly, preventing ruffled border formation and causing apoptosis.
      • Stabilize hydroxyapatite crystals.
    • Useful for bone pain due to increased turnover (e.g., Paget’s disease or osteogenesis imperfecta).
  2. Strontium
    • Similar in composition to calcium but not subject to bone metabolism.
    • Has both anabolic (increases bone formation) and catabolic (decreases bone resorption) effects.

Anti-Rheumatoid Drugs

  1. Non-Disease Modifying
    • Steroids.
    • Cyclophosphamide.
  2. Disease Modifying (DMARDs)
    • Methotrexate, Azathioprine (Purine metabolism inhibitors).
    • TNF Inhibitors:
      • Etanercept, Infliximab (All drugs ending in ‘mab’ are TNF inhibitors).
    • Penicillamine: Reduces T lymphocytes.
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