PHARM 233 Pharmacology PDF Winter 2024

PHARM 233 Pharmacology Agents for Rheumatoid Arthritis, Gout and Hyperuricemia Ayman El-Kadi, PhD Faculty of Pharmacy and Pharmaceutical Sciences Winter 2024 Learning Objectives Understand the mechanism and mediators of inflammation. Understand different classes of drugs used to treat rheumatoid art...

PHARM 233 Pharmacology Agents for Rheumatoid Arthritis, Gout and Hyperuricemia Ayman El-Kadi, PhD Faculty of Pharmacy and Pharmaceutical Sciences Winter 2024 Learning Objectives Understand the mechanism and mediators of inflammation. Understand different classes of drugs used to treat rheumatoid arthritis and gout. Understand the mechanisms of different antiinflammatory drugs. Understand the clinical uses and pharmacokinetics of different anti-inflammatory drugs. Understand the side effects and toxicities of different anti-inflammatory drugs. Antiinflammatory Drugs Drugs used to treat inflammation and rheumatoid arthritis are divided into five major groups: 1. Non-steroidal anti-inflammatory drugs (NSAIDs) and the coxibs. 2. Disease-modifying antirheumatic drugs (DMARDs), including some immunosuppressants. 3. The glucocorticoids. 4. Anticytokines and other biological agents. 5. Other drugs that do not fit into these groups, including antihistamines. 1. Nonsteroidal Antiinflammatory Drugs (NSAIDs) NSAIDs are antiinflammatory drugs that do not possess a steroidal structure (nonsteroidal). Common Drugs 1. Nonselective Prototype: ibuprofen Others: Propionic acid derivatives: naproxen, fenoprofen, ketoprofen, flurbiprofen Acetic acid derivatives: diclofenac, ketorolac, indomethacin, etodolac, sulindac, piroxicam, meloxicam, nabumetone, tolmetin, mefenamic acid, meclofenamate, flufenamic acid 2. Cyclooxygenase (COX)-2 selective Prototype: celecoxib Others: rofecoxib, valdecoxib 1. Nonsteroidal Antiinflammatory Drugs (NSAIDs) NSAIDs have three major therapeutic actions, mainly through inhibition of the COX-2 isoform. They are as follows: An anti-inflammatory action: the decrease in prostaglandin E2 and prostacyclin reduces vasodilatation and, indirectly, edema. Accumulation of inflammatory cells is not directly reduced. An analgesic effect: decreased prostaglandin generation means less sensitisation of nociceptive nerve endings to inflammatory mediators such as bradykinin and 5hydroxytryptamine. Relief of headache is probably a result of decreased prostaglandin-mediated vasodilatation. An antipyretic effect: interleukin-1 releases prostaglandins in the central nervous system, where they elevate the hypothalamic set point for temperature control, thus causing fever. NSAIDs prevent this. 1. Nonsteroidal Antiinflammatory Drugs (NSAIDs) 1. Nonsteroidal Antiinflammatory Drugs (NSAIDs) Mechanism of Action: Inhibit the activity of cyclooxygenase enzymes (COX-1 and/or COX-2). COX is an enzyme that catalyzes the conversion of arachidonic acid to prostaglandin There are actually two major isoforms of the COX enzyme: COX-1 and COX-2. COX-1 is a constitutive enzyme, while COX-2 is an inducible enzyme. COX-1 play protective role, responsible for production of cytoprotective mucus in the stomach and for platelet aggregation (clotting). The main stimuli for COX-2 induction are inflammatory mediators, and thus COX-2 is typically associated with inflammation. 1. Nonsteroidal Antiinflammatory Drugs (NSAIDs) Ibuprofen: Reversible inhibition of COX-1, weak inhibition of COX-2. Aspirin: Irreversible acetylation of COX; weakly COX-1 selective. Paracetamol: Inhibition of COX-1, COX-2 and also the recently identified COX-3 which occurs predominantly in the CNS. Celecoxib: Selective inhibition of COX-2 – the enzyme that is induced in areas of inflammation. – celecoxib is 10–20 x more active on COX-2 than COX-1 1. Nonsteroidal Antiinflammatory Drugs (NSAIDs) Pharmacokinetics Most NSAIDs are well absorbed, and food has little effect on their bioavailability. Most NSAIDs undergo extensive hepatic metabolism, many through either the CYP3A or CYP2C families. Many nonselective COX inhibitors have short to intermediate half-lives (2 to 12 hours), requiring frequent administration. The newer COX-2 selective inhibitors typically have longer half-lives and are administered once daily. Many NSAIDs are available in topical dosage forms Indomethacin is also available as a rectal suppository. 1. Nonsteroidal Antiinflammatory Drugs (NSAIDs) Indications Pain Inflammation Fever Contraindication Active peptic ulcer Side Effects Nonselective Gastrointestinal effects occur because of the inhibition of COX-1–mediated production of cytoprotective mucus in the stomach. Edema: PG inhibition leads to salt and water retention. 1. Nonsteroidal Antiinflammatory Drugs (NSAIDs) Acute renal failure: Renal PGs often play a protective role in high-risk patients by counteracting the effects of vasoconstrictors such as angiotensin 2 and vasopressin. COX-2 Selective Cardiovascular: by disruption of the balance between the platelet-activating effects of COX-1 and the plateletinhibiting effects of COX-2. All Central nervous system (CNS): Confusion, dizziness, depression, and hallucinations may occur. The mechanism is not confirmed, but COX-2 is the most abundant COX isoform in the CNS, and COX-2 may play a role in neurotransmission 2. Disease-modifying antirheumatoid drug (DMARD) 2. Disease-modifying antirheumatoid drug (DMARD)-Synthetic Methotrexate Has marked anti-inflammatory action in rheumatoid disease and cytotoxic in the larger doses used to treat cancer. MOA Folate antagonist and thus interferes with thymidylate synthesis (which is essential for DNA synthesis). Pharmacokinetics Given orally; has active metabolite. Half-life 6–9h. Indication Rheumatoid arthritis; also used in psoriasis, ankylosing spondylitis, polymyositis and vaculitis. Side effects Gastrointestinal disturbances, dose-related liver toxicity. Bone marrow depression and pneumonitis can occur. 2. Disease-modifying antirheumatoid drug (DMARD)-Synthetic Sulfasalazine MOA In the colon the salicylic acid moiety is released, is absorbed and has anti-inflammatory action. Pharmacokinetics Given orally; only ~15% is absorbed in the GIT. Half-life 6– 16h. Indication Rheumatoid arthritis, juvenile arthritis, inflammatory bowel disease. Side Effects Nausea & vomiting, headaches, rashes. About a third of patients discontinue the drug because of side effect 2. Disease-modifying antirheumatoid drug (DMARD)-Synthetic Leflunomide MOA Gives rise to a metabolite that inhibits dihydrooratate dehydrogenase; this results in inhibition of T-cell proliferation and decreased production of autoantibodies by B cells. Pharmacokinetics Absorbed orally. The metabolite undergoes enterohepatic cycling, half-life thus ~18 days. Indication Rheumatoid arthritis. Side effects ~25% of patients get diarrhoea. Increased BP, weight gain can occur. 2. Disease-modifying antirheumatoid drug (DMARD)-Targeted Synthetic Targeted synthetic DMARD: – RA: tofacitinib, baricitinib They Inhibit Janus Kinase (JAK) – Psoriatic arthritis (PsA): apremilast, tofacitinib Apremilast: The drug acts as a selective inhibitor of the enzyme phosphodiesterase 4 (PDE4) and inhibits spontaneous production of TNF-alpha from human rheumatoid synovial cells. Tofacitinib: JAK inhibitor 2. Disease-modifying antirheumatoid drug (DMARD)-Biologics An anticytokine antirheumatoid drug. Reduces joint inflammation and symptoms of rheumatoid arthritis. Reduces symptoms of Crohn’s disease. Common Drugs: Infliximab Adalimumab is also an anti-TNFalpha antibody (half-life 10– 20 days). Etanercept another anti-TNF-alpha antibody (given subcut. twice a week; half-life ~5 days). MAO It is a monoclonal antibody against TNF- that binds with the TNF-alpha and prevents its interaction with cell surface receptors in inflammatory cells Pharmacokinetics Given by i.v. infusion every 4 weeks. Half-life 9–12 days. 2. Disease-modifying antirheumatoid drug (DMARD)-Biologics Indication Active rheumatoid arthritis – usually combined with methotrexate if other DMARDs haven’t worked. Ankylosing spondylitis and psoriatic arthritis – if other therapy hasn’t worked. Side effects Nausea, vomiting, headache, upper respiratory tract infections with cough. 3. Glucocorticoid and other DMARD Drugs Used in Gout Colchicine is used to treat crystal-associated arthritis, most commonly gout (a disease caused by uric acid crystal deposition in joints). Prototype: Colchicine MOA (Mechanism of Action) Inhibit multiple proinflammatory mechanisms, while enabling increased levels of anti-inflammatory mediators by following mechanisms; inhibits microtubule polymerization by binding to its constitutive protein, tubulin, which is essential to mitosis. inhibits activation and migration of neutrophils to sites of inflammation interferes with the inflammasome complex found in neutrophils and monocytes that mediate interleukin-1β activation, a component of inflammation inhibits superoxide anion production in response to urate crystals interrupts mast cell degranulation Drugs Used in Gout Pharmacokinetics The half-life of the tubulin-colchicine complex is 20 to 30 hours. Although clearance is primarily via the liver, renal clearance accounts for about 20%, and renal insufficiency is a very strong risk factor for toxicity. Indications Gout Acute attacks Long-term prevention of recurrent attacks as an adjuvant to uric acid–lowering therapies Contraindication Renal failure: increased risk of toxicity Drugs Used in Gout Side Effects Colchicine has a narrow therapeutic index. Gastrointestinal: Diarrhea is virtually a guaranteed side effect when colchicine is given in doses suitable for acute attacks of gout. Bone marrow suppression: Antimitotics preferentially target rapidly dividing cells, such as those found in the bone marrow. Myopathy may occur. Neuropathy may occur. Uricosurics Uricosurics lower uric acid levels in blood as a treatment for gout. Prototype and Common Drugs Prototype: Probenecid Others: Sulfinpyrazone MOA (Mechanism of Action) Uric acid levels in the blood are elevated in gout, and one treatment strategy is to lower uric acid levels by enhancing uric acid excretion. Probenecid is completely reabsorbed by the proximal tubule and prevent uric acid reabsorption. Uricosurics Pharmacokinetics One uricosuric drug may either add to or inhibit the action of another. The biphasic effect may be seen within the normal dosage range with some drugs such as salicylates. Twice-a-day and up to four-times-a-day administration has resulted in probenecid being used by fewer patients compared with another class of gout therapies, the xanthine oxidase inhibitors, which decrease uric acid synthesis. Indications Gout Uricosurics Contraindications Renal insufficiency. Urolithiasis (renal stones or calculi). Peptic ulcer. Side Effects Probenecid is well tolerated. Gastrointestinal irritation is usually mild. Allergic reactions usually are mild and occur in 2% to 4% of patients. Uricosurics Xanthine oxidase inhibitors decrease uric acid synthesis and are used in gout. Prototype and Common Drugs Prototype: Allopurinol Others: Febuxostat MOA (Mechanism of Action) Allopurinol is a purine analogue of hypoxanthine and is a substrate for, and inhibitor of, the enzyme xanthine oxidase. Xanthine oxidase converts hypoxanthine to xanthine to uric acid; inhibition therefore reduces the production of uric acid Uricosurics Febuxostat is a new nonpurine inhibitor of xanthine oxidase. A significant difference from allopurinol is that being a nonpurine, it does not inhibit purine or pyrimidine synthesis, while allopurinol does. Pharmacokinetics Allopurinol increases the half-life of probenecid and enhances its uricosuric effect. Mercaptopurine, azathioprine, and theophylline are metabolized by xanthine oxidase, and coadministration with allopurinol will dramatically increase levels of these drugs. Uricosurics Indications Gout Renal stones composed of uric acid Complicated hyperuricemia Contraindication Previous hypersensitivity reactions to allopurinol Uricosurics Side Effects Allopurinol Skin reactions: Both mild and severe reactions can occur. Rarely, toxic epidermal necrolysis or Stevens-Johnson syndrome occurs, which can be fatal. Liver reactions: Severe hepatic reactions including elevations of liver enzymes, fever, eosinophilia, and rash may occur. Renal insufficiency. Febuxostat Febuxostat appears to not produce the hypersensitivity reactions that occur with allopurinol. Increase in the risk of myocardial infarction, stroke, and cardiovascular death with febuxostat. References Rang & Dale's Pharmacology 8th Edition Applied Pharmacology 1st Edition