Pharmacology - Musculoskeletal, Skin, Connective Tissue

Reversibly inhibits cyclooxygenase, mostly in CNS.- inactivated peripherally Clinical use:- antipyretic- analgesic- not anti-inflammatory- used instead of aspirin to avoid Reye syndrome in children with viral infection Adverse effects:- Overdose produces hepatic necrosis- Acetaminophen metabolite (NAPQI) depletes glutathione and forms toxic tissue biproducts in liver- N-acetylcysteine ist antidote – regenerates glutathione

NSAID that irreversibly inhibits COX-1 and COX-2 by covalent acetylation → ↓ synthesis of TXA2 and prostaglandins.COX-1 is expressed in most tissues and regulates normal cellular processes (eg, gastric protection, platelet function). By inhibiting COX-1 in platelets, aspiring prevents the synthesis of TXA2 → ↓ thrombus formation. - ↑ bleeding time- No effect on PT, PTT- Effect lasts until new platelets are produced. Clinical use:- Low dose (< 300 mg/day): ↓ platelet aggregation- Intermediate dose (300-2400 mg/day): antipyretic and analgesic- High dose (2400-4000 mg/day): anti-inflammatory Adverse effects:- Gastric ulceration- Tinnitus, ↓ hearing - often first signs of toxicity- Allergic reactions (especially in patients with asthma or nasal polyps)- Chronic use can lead to acute renal failure, interstitial nephritis, GI bleeding- Risk of Reye syndrom (encephalopathy) in children treated with aspirin for viral infection.- Toxic dose cause early respiratory alkalosis, but transitions to mixed metabolic acidosis-respiratory alkalosis.

Reversibly and selectively inhibits COX-2, which is found in inflammatory cells and vascular endothelium and mediates inflammation and pain.- spares COX-1, which helps maintain gastric mucosa→ less corrosive effects on GI lining→ spares platelet function (TXA2 production is dependent on COX-1) → no antithrombotic effect Clinical use: Rheumatoid arthritis, osteoarthritis Adverse effects:- ↑ risk of thrombosis- Sulfa allergy

- Ibuprofen, naproxen, indomethacin, ketorolac, diclofenac, meloxicam, piroxicam - Reversibly inhibit COX-1 and COX-2. Block prostaglandin synthesis Clinical use:- antipyretic- analgesic- anti-inflammatory- Indomethacin is used to close PDA- Naproxen and indomethacin have uricosuric activity (in low doses) Adverse effects:- Interstitial nephritis- Gastric ulcer (prostaglandins protect gastric mucosa)- Renal ischemia (prostaglandins vasodilate afferent arteriole)

Reversibly inhibits dihydroorotate dehydrogenase, preventing pyrimidine synthesis.- Suppresses T-cell proliferation Clinical use:- Rheumatoid arthritis- Psoriatic arthritis Adverse effects:- Diarrhea- Hypertension- Hepatotoxicity- Cytopenias- Teratogenicity

Alendronate, ibandronate, risedronate, zoledronate Pyrophosphate analogs. Bind hydroxyapatite in bone, inhibiting osteoclast activity.Osteoclasts that reabsorb the bone take up the bisphosphanate and are unable to adhere to the bony surface to continue absorption. - Also decrease osteoclast proton production, induce osteoclast apoptosis decrease development of osteoclast precursor cells. Clinical use:- Osteoporosis- Hypercalcemia- Paget's disease of the bone- Metastatic bone disease- Osteogenesis imperfecta Adverse effects:- Esophagitis (patients are advised to take with water and remain upright for 30 minutes)- Osteonecrosis of the jaw- Atypical femoral stress fractures

Recombinant PTH analog given subcutaneously daily. - ↑ osteoblastic activity when administered in pulsatile fashion. Clinical use:- Osteoporosis- Causes ↑ bone growth compared to antiresorptive therapies (eg, biphosphonates). Adverse effects:- ↑ risk of osteosarcoma (avoid use in patients with Paget disease of the bone or unexplained elevation of alkaline phosphatase).- Avoid in patients who have had prior cancers or radiation therapy.- Transient hypercalcemia.

Chronic gout drug (preventive). Competitive inhibitor of xanthine oxidase → ↓ conversion of hypoxanthine and xanthine to urate. - Also used in lymphoma and leukemia to prevent tumor lysis-associated urate nephropathy. - ↑ concentrations of azathioprine and 6-MP (both normally metabolized by xanthine oxidase).

Chronic gout drug (preventive). Inhibits xanthine oxidase.

Chronic gout drug (preventive). Recombinant uricase that catalyzes metabolism of uric acid to allantoin (a more water-soluble product).

Chronic gout drug (preventive). Inhibits reabsorption of uric acid in proximal convoluted tubule (also inhibits secretion of penicillin). - Can precipitate uric acid calculi.

Binds and stabilizes tubulin to inhibit microtubule polymerization, impairing neutrophil chemotaxis and degranulation. Acute and prophylactic value for gout. Adverse effects:- GI side effects- Neuromyopathic side effects

Fusion protein (decoy receptor for TNF-α + IgG Fc) produced by recombinant DNA. Clinical use:- Rheumatoid arthritis- Psoriasis- Ankylosing spondylitis Adverse effects: Predisposition to infection, including reactivation of latent TB, since TNF is important in granuloma formation and stabilization. Can also lead to drug-induced lupus.

Anti-TNF-α monoclonal antibody  Clinical use:- Inflammatory bowel disease- Rheumatoid arthritis- Ankylosing spondylitis- Psoriasis Adverse effects: Predisposition to infection, including reactivation of latent TB, since TNF is important in granuloma formation and stabilization. Can also lead to drug-induced lupus.

- Recombinant uricase that catalyzes metabolism of uric acid to allantoin - prevention and treatment of tumor lysis syndrome

- ↓ calcineurin --> ↓ activation of T-cell transcription factors --> ↓ IL-2, IL-3, and interferon-γ Uses:- Cyclosporine is DOC for organ and tissue transplantation- Tacrolimus used alternatively to cyclosporine in renal and liver transplants Side effects:- nephrotoxicity (both)- gingival overgrowth (cyclosporine)

- inhibitor of de novo synthesis of purines - has adjunctive immunosuppressant actions - permits dose reductions of cyclosporin to limit toxicity

- immunosuppressant converted to 6-mercaptopurine Side effects:- bone marrow suppression

- antagonist to ERB-B2 (Her 2) Use:- breast cancer

- Hepatitis B and C - Leukemias - Melanoma

Use: Multiple sclerosis

Chronic granulomatous disease --> ↑ TNF

- suppresses T-cell proliferation Use: kidney transplant

Leukotriens:- LTC4, LTD4, LTE4: ↑ bronchial tone- LTB4: ↑ Neutrophil chemotaxis Prostacyclin:- PGI2: ↓ platelet aggregation, ↓ vascular tone (Epoprostenol) Prosaglandins:- PGE1: ↓ vascular tone (Alprostadil)- PGE2: ↑ uterine tone (Dinoprostone)- PGF2α: ↑ uterine tone (Carboprost) Thromboxane:- TXA2: ↑ platelet aggregation, ↑ vascular tone

Ibuprofen, naproxen, indomethacin, ketorolac, diclofenac, meloxicam, piroxicam Reversibly inhibit cyclooxygenase (both COX-1 and COX-2). Block prostaglandin synthesis. Clinical use: Antipyretic, analgesic, anti-inflammatory- Indomethacin is used to close PDA. Adverse effects:- Interstitial nephritis- Gastric ulcer (prostaglandins protect gastric mucosa)- Renal ischemia (prostaglandins vasodilate afferent arteriole)- Aplastic anemia

Topical vitamin D analog Causes inhibition of keratinocyte proliferationa nd stimulation of keratinocyte differentiation. Can be used in psoriasis.

Main substance: isotretinoin (Vitamin A derivative) given systemically Indication: in moderate to severe acne Mechanism of action: Retinoids normalize keratinization by inhibiting and modulating keratinocytes → ↓ sebum production Contraindications:- Pregnancy, women of childbearing age without contraception: strong teratogenic effects- Liver disease- Simultaneous tetracycline treatment Precautions (in all females of childbearing potential)- 1 month before initiating therapy1. A serum/urine pregnancy test2. Two methods of contraception (oral contraceptive therapy + barrier contraception/IUD)- During therapy: monthly pregnancy test and continuous use of two methods of contraception- After completing therapy:1. Continue two methods of contraception for 1 month2. A pregnancy test at the end of 1 month Side effects:- Dry skin, xerostomia, cheilitis, pruritus- Headaches, arthralgias, alopecia, fatigue Laboratory tests:- Blood disorders (e.g., anemia)- ↑ Triglycerides, ↓ HDL, ↑ glucose- ↑ AST, ↑ ALT

Folic acid antagonist (antimetabolite) → purine nucleotide and thereby ↓ DNA synthesis Clinical use:- Treatment of severe psoriasis and rheumatoid arthritis- In neoplastic diseases like gestational choriocarcinoma, chorioadenoma, and hydatidiform mole Side effects:- Pancytopenia and/or macrocytic anemia- Mucositis (particularly stomatitis, enteritis), susceptibility to infection- Hepatotoxicity, nephrotoxicity- Nausea and vomiting, diarrhea- Pulmonary fibrosis and toxicity- Hair loss

TNF & IL-1 suppressor Side effects:- Retinopathy