Chapter 3: States and Regimes Overview
Concepts of anarchy, social contract theory, and naturalization in the context of political philosophy with insights from thinkers like Thomas Hobbes, John Locke, and Jean-Jacques Rousseau. Dive into the fundamental principles of governance, state structures, and regime types presented through a comparative case study of Botswana and Somalia in this informative chapter outline.
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Gout is a metabolic disease characterized by recurrent episodes of acute arthritis due to deposits of uric acid in joints and cartilage. Uric acid renal calculi, tophi, and interstitial nephritis may also occur. Gout is usually associated with hyperuricemia (high serum levels of uric acid that is the major end product of purine metabolism). The aims of treatment are to decrease the symptoms of an acute attack, decrease the risk of recurrent attacks and lower serum urate levels.
Treatment of Acute Gout: The most common mistake in managing gout is starting treatment for both acute arthritis and hyperuricemia simultaneously. 1-NSAIDs: NSAIDs are now the first-line drugs for treatment of acute gout. Mechanism, duration. Indomethacin, naproxen, sulindac, and celecoxib all are effective. Aspirin is not used because it can inhibit urate excretion at low doses. Active peptic ulcer, impaired renal function and a history of allergic reaction to NSAIDsare contraindications.
2-Colchicine: Although colchicine is more specific in gout than the NSAIDs. Colchicine relieves the pain and inflammation of gouty arthritis in 12 24 hours without altering . It produces its anti-inflammatory effects by the inhibition of leukocyte migration, phagocytosis and metabolic activity in inflamed area. 3-Corticosteroids: Sometimes used in the treatment of severe symptomatic gout, by intra-articular, systemic, or SC routes. Best reserved for patients who are unable to take oral NSAIDs.
Treatment of Chronic Attacks: 1-Colchicine: The main indication for colchicine is in the prevention of recurrent gout, but prophylaxis with colchicine alone is undesirable as the plasma urate remains high. It can be used when allopurinol or uricosuric agents are started to suppress the acute attacks that can be precipitated by sudden reduction in serum uric acid level. Indomethacin can also be used.
2-Allopurinol: Allopurinol inhibits xanthine oxidase thus prevents the synthesis of uric acid. It is the preferred and standard therapy for gout in the period between acute episodes. Both allopurinol and its primary metabolite oxypurinol inhibit xanthine oxidase. When starting allopurinol, colchicine or a NSAID should also be used until steady-state serum uric acid is normalized. Thereafter colchicine or the NSAID can be stopped, while allopurinol is continued. Allopurinol for the primary hyperuricemia of gout (gouty nephropathy, renal urate stones, tophaceous hyperuricemia. deposits) and the secondary
3-Uricosuric drugs: (Probenecid and Sulfinpyrazone) These drugs enhance the excretion of uric acid by decreasing reabsorption of uric acid in the proximal tubule. Sulfinpyrazone is a metabolite of an analog of phenylbutazone. With the increase in uric acid excretion 4-Febuxostat: Is a potent and selective inhibitor of xanthine oxidase and has recently been approved by the FDA. Febuxostat is more effective than allopurinol at a standard dose but not . Approved for the treatment of chronic gout.
Drugs contraindicated in gout: 1-All diuretics except spironolactone. 2-Aspirin in low doses. 3-Ethambutol, Pyrazinamide. 4-Nicotinic acid. 5-Alcohol.
Drug Therapy of Rheumatoid Arthritis
Rheumatoid arthritis is an immunologic disease that causes significant systemic effects which shorten life in addition to the joint disease that reduces mobility and quality of life. There is no known cure for rheumatoid arthritis, thus the main aim of using drugs in this disease is to: 1-Reduce joint inflammation and pain. 2-Reduce stiffness and improve mobility, thereby maximizing joint function. 3-Prevent chronic deformity by preventing joint destruction and bone erosions.
First Line or Fast Acting drugs: 1-Non steroidal anti-inflammatory drugs (NSAIDs): NSAIDs are the initial drugs of choice and all of them are equivalent in efficacy. They offer mainly symptomatic relief but they have little effect on the progression of bone and cartilage destruction. For nonselective NSAIDs, GIT side effects To reduce this toxicity either .
2-Corticosteroids: Their effects are prompt and dramatic, and they are capable of slowing the appearance of new bone erosions. There is controversy regarding their serious side effects .. Corticosteroids may be administered for certain serious extra-articular manifestations or during periods of exacerbation. Atypical starting dose is 5 10 mg/day of prednisone. In the setting of an acute exacerbation, (typically 20-40 mg/day of prednisone or equivalent) Patients with major symptomatology confined to one or a few joints may be treated with intra-articular steroid injections 5 20 mg of triamcinolone which should be performed with intervals of at least 3 months.
Second Line or Slow Acting drugs (DMARDS): Interest has therefore centered on finding treatments that might arrest or at least slow the progression of joint destruction and deformity by modifying the disease itself. May take several weeks or months to become evident. The beneficial effects of these drugs are not dependent on any anti-inflammatory or analgesic property.
1-Methotrexate: Methotrexate (an immunosuppressant) is now considered the DMARD of first choice to treat rheumatoid arthritis and is used in 50 70% of patients. It is active in this condition at much lower doses . It is the treatment of choice for patients with severe rheumatoid arthritis that fail to respond to NSAIDs. The most common dosing regimen is (7.5 mg once orally/week). Beneficial effects in 3-6 weeks. GIT side effects are the most common, serious effects although rare include interstitial pneumonitis, hepatotoxicity and bone marrow suppression.
2-Tumour Necrosis Factor (TNF) Inhibitors: Etanercept, Infliximab Cytokines play a central role in the immune response and in rheumatoid arthritis. TNF- appears to be particularly important in the inflammatory process. It activates lymphocytes and leucocytes. TNF inhibitors are frequently added to the treatment of patients who have not responded favorably to methotrexate alone. A regimen of infliximab or etanercept plus methotrexate decreases the rate of formation of new erosions more than methotrexate alone. The use of TNF inhibitors increase the incidence of bacterial infections.
3-Sulfasalazine: It consists connected by a diazo bond. It is metabolized by bacterial azoreductase in the distal ileum and colon and is split into its components. Its mode of action is unclear but may have some anti- inflammatory action and inhibit immune reactivity. Sulfasalazine is effective in active rheumatoid arthritis and prevents progression of joint damage. Side effects are usually not serious and include GIT disturbance, malaise and headache. Rarely, Hemolytic anemia and methemoglobinemia may occur. of sulfapyridine and 5-aminosalicylic acid
4-Leflunomide: Leflunomide is an immunosuppressant drug used for the treatment of active rheumatoid arthritis in adults, either alone or combined with methotrexate. It suppresses the activity of immune cells responsible for inflammation by inhibiting inhibiting the enzyme dihydrooratate dehydrogenase. An initial loading dose of 100 mg daily is given for the first 3 days followed by a maintenance of 20 mg daily. The most frequently reported side effects are diarrhea, nausea, rash, headache, hypertension, alopecia, weight loss and chest pain. Because of its teratogenicity, it is contraindicated during pregnancy. 5-Older agents are now very rarely used. pyrimidine synthesis through
Many surgical procedures require inhibition of voluntary muscle tone and reflex contraction. The adjunctive use of neuromuscular blocking drugs makes it possible to achieve adequate muscle relaxation for all types of surgical procedures without the cardiorespiratory depressant effects produced by deep anesthesia and also facilitates tracheal intubation. All neuromuscular blockers currently available for use are devoid of central effects because they cannot pass the blood-brain barrier.
Neuromuscular transmission: The arrival of an impulse at the motor nerve terminal causes an influx of calcium and release of the neurotransmitter acetylcholine at the nerve endings which produces transient depolarization and this triggers the action potential which is associated with muscle contraction. Acetylcholine diffuses across the synaptic cleft to activate the nicotinic receptors located on the motor end plate leading to muscle contraction. Neuromuscular blockers used clinically affect this process.
Competitive (non depolarizing) Neuromuscular Blockers: Mechanism of action: Competitive, reversed byAnticholinesterases. 1-Tubocurarine: The prototype although it is no longer in widespread clinical use. Causes motor weakness, followed by flaccid paralysis. Smaller muscles are involved first followed by larger muscles and Recovery of muscles usually occurs in reverse order. Tubocurarine can produce hypotension (histamine release, and with larger doses, ganglionic blockade ), bronchospasm.
Synergism and antagonism: Effects of tubocurarine are potentiated by certain drugs as the inhalational anesthetics and aminoglycoside antibiotics. Antagonized by anticholinesterases as neostigmine. Neostigmine aggrevates the hypotension and bronchospasm. In such circumstances sympathomimetics, atropine and antihistaminics may be useful. Onset and duration of action: IV, it acts within 6 minutes and lasts for 80-120 minutes.
2-Other clinically useful competitive blockers: Have nearly similar actions to tubocurarine and include: a-Long Pipecuronium. b-Intermediate Atracurium, Rapacuronium, rocuronium. c-Short acting (10-15 min): as Mivacurium. Their effects on histamine release and ganglion blockade are comparatively less. acting (80-120 min): as Pancuronium and acting (30-60 min): as Vecuronium,
Depolarizing Neuromuscular Blockers Mechanism of action: 1-Phase I block (depolarizing): Succinylcholine reacts with the nicotinic receptor to open the channel and cause persistent depolarization of the motor end plate. Augmented, not reversed, by cholinesterase inhibitors. 2-Phase II block (desensitizing): With prolonged exposure to succinylcholine, the initial end plate depolarization decreases and the membrane cannot easily be depolarized again because it is desensitized Later, blockade are nearly identical to those of a competitive block with possible reversal by acetylcholinesterase inhibitors.
Succinylcholine: Following the administration of succinylcholine, transient muscle fasciculations occur over the chest and abdomen within 30 seconds, these are less common in anesthetized patients. As paralysis develops rapidly (< 90 seconds), the arm, neck, and leg muscles are initially relaxed followed by facial, masticatory, lingual, pharyngeal and laryngeal muscles and last the respiratory muscles and diaphragm.
Onset and duration of action: 1-IV, onset in 1 min, reaches maximal within 2 min and persists for 5-10 min. Transient apnea can occur at the maximal effect. This ultrashort duration of action is due to succinylcholine's rapid hydrolysis by butyrylcholinesterase in the plasma (and liver). 2-The effect of succinylcholine can be prolonged by repeated injections at appropriate intervals, by continuous IV infusion or by prior administration of hexafluorenium IV; a selective inhibitor of butyrylcholinesterase. 3-In some individuals there is a hereditary defect in the amount or kind of butyrylcholinesterase and thus cannot destroy the drug as rapidly as in normal. In such cases, paralysis lasts for hours and the drug produces apnea (succinylcholine apnea). Treatment consists of applying intermittent positive pressure artificial respiration with oxygen until the patient recovers. No antagonists are available for depolarizing blockers.
Toxicity: The malignant hyperthermia syndrome encountered in genetically susceptible patients receiving halogenated inhalational anesthetics and depolarizing muscle relaxants such as succinylcholine. Therapeutic Uses of Neuromuscular Blocking Drugs: 1-As an adjuvant to general anesthesia to obtain skeletal muscle relaxation is the main therapeutic use. Competitive blockers are used for major surgical procedures as their duration of action is longer while depolarizing blockers are used for short procedures to facilitate intubation and endoscopies. 2-In electroconvulsive therapy (ECT) they are used to prevent injury due to violence of the fit.
