NSAIDS
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PGs and Eicosanoid antagonists
Remaining portion of lec
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EFFECTS OF PGs
LT C4 & LTD4 BRONCHOCONSTRICTION
LTB4 CHEMOTACTIC FACTOR
PGE2 & PROSTACYCLIN VASODILATION
PGE1 & DERIVATIVES PROTECTION ON GASTRIC MUCOSA
PGE1 & PGE2 RELAX VASCULAR & OTHER SMOOTH MUSCLE
THROMBOXANE PLATELET AGGREGATION
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DRUGS
PGE2 – dinoprostone, used at term before induction of labour with oxytocin
PGE1 – misoprostol, safest abortifacient and also to maintain patency of the ductus arteriosus in infants & to prevent peptic ulcers
PG12 – epoprostenol, in severe pulmonary hypertension & to prevent platelet aggregation in dialysis machines
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PGE1 – alprostadil, in tx of impotence
PGF2a – latanoprost, used in glaucoma
bimatoprost, travoprost, noprostine
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THERAPEUTIC EFFECTS
Obstetrics
Pediatrics
Pulmonary hypertension & dialysis
Peptic ulcer associated with NSAID use
Urology
Ophthalmology
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EICOSANOID ANTAGONISTSCorticosteroids_inhibit the synthesis of COX-2
NSAIDS _inhibit cyclooxygenase and also thromboxane, prostaglandin, prostacyclin
Leukotriene antagonists_enzyme inhibitor drug, ZILEUTON and receptor blocker, ZAFIRLUKAST & MONTELUKAST_____used for ASTHMA
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ANTI-INFLAMMATORY DRUGS
NSAIDS
RHEUMATOID ARTHRITIS
GOUT
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The inflammatory response is complex, involving immune system and various endogenous agents like PGs, bradykinin, histamine, chemotactic factors, superoxide free radicals formed by the action of lysosomal enzymes
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ANTI-INFLAMMATORY DRUGS
NSAIDS
COX-2 INHIBITORS
ACETAMINOPHEN
DRUGS FOR ARTHRITIS
DRUGS FOR GOUT
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NSAIDSASPIRIN & OTHER SALICYLATE DRUGS
PROPIONIC ACID DERIVATIVES • Ibuprofen• Naproxen• Fenoprofen• Ketoprofen• Flurbiprofen• Oxaprozin
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ACETIC ACID DERIVATIVES
• Indomethacin
• Sulindac
• Etodolac
OXICAM DERIVATIVES
• Piroxicam
• Meloxicam
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FENAMATES• Mefenamic• meclofenamate
OTHER AGENTS• Diclofenac• Ketorolac• Tolmetin & Nabumetone• Diflunisal
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COX-2 SELECTIVE NSAIDS
Celecoxib
Valdecoxib
Rofecoxib
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OTHER ANALGESICS OR NON-NARCOTIC
ANALGESICS
Acetaminophen
Phenacetin
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ASPIRIN
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Pharmacodynamics
Effects on different organ, tissue or cells
Pharmacokinetics
Therapeutic uses
Adverse effects
Toxicity by aspirin and treatment
Prescription to medically compromised patients
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NSAID
↑ Leukocyte-EndothelialInteractions
Capillary Obstruction
IschemicCell Injury
Proteases +Oxygen Radicals
Endo/EpithelialCell Injury
Mucosal Ulceration
Loss o
f PGE 2
and P
GI 2 m
edia
ted in
hibiti
on
of aci
d sec
retio
n and c
ytopro
tect
ive
effe
ct
Loss of PGI2 induced inhibition of LTB4 mediated endothelial adhesion and activation of neutrophils
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MECHANISM OF ACTION OR PHARMACODYNAMICS
ANTI-INFLAMMATORY EFFECT
ANALGESICS EFFECT
ANTIPYRETIC EFFECT
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ANTI-INFLAMMATORY EFFECT
Is due to the inhibition of the enzyme prostaglandin H synthase ( cyclooxygenase or COX), which converts arachidonic acid to prostaglandins and to TXA2 & prostacyclin
Aspirin irreversibly inactivates COX-1 and COX-2 by acetylation of a specific serine residue. Its an important difference b/w other NSAIDS, which reversibly inhibit COX-1 and COX-2
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NSAIDS have no effect on lipoxygenase and thus do not inhibit the production of leukotrienes
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ANALGESIC EFFECT
It is related to the peripheral inhibition of prostaglandin production and it may also be due to the inhibition of pain stimuli at a subcortical site
NSAIDS prevent the potentiating action of PGs on endogenous mediators of peripheral nerve stimulation (eg, bradykinin)
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ANTIPYRETIC EFFECT
Its related to inhibition of the interlukin-1 & interlukin-6-induced production of PGs in the hypothalamus & the resetting of thermoregulatory system, leading to vasodilation and increased heat loss
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PHARMACOKINETIC PROPERTIES
Salicylates are weak organic acids, aspirin has a pKa of 3.5
These agents are rapidly absorbed from the intestine as well as from the stomach, where low pHfavors absorption. The rate of absorption is increased with rapidly dissolving (buffered) or predissolved (effervescent) dosage forms
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Salicylates are hydrolyzed rapidly by plasma and tissue esterases to acetic acid and the active metabolite salicylic acid
Half life 3-6 hrs after acute administration & chronic administration of high doses or toxic overdose increases the t1/2 to 15-30hrs – enzymes for glycine and glucuronide conjugation become saturated
Unmetabolized salicylates are excreted by the kidney
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Actions of aspirin
Anti-inflammatory – inhibits inflammation in arthritis
Analgesic action – repress sensation of pain, combination of opioids and NSAIDS are effective in treating pain caused by a malignancy
Antipyretic action- anterior hypothalamic thermoregulatory centre is elevated
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Effect on Respiration: triphasic 1. Low doses: uncoupling phosphorylation → ↑
CO2 → stimulates respiration. 2. Direct stimulation of respiratory center →
Hyperventilation → resp. alkalosis → renal compensation
3. Depression of respiratory center and cardiovascular center → ↓ BP, respiratory acidosis, no compensation + metabolic acidosis also
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GI system PGI2 inhibits gastric acid secretion & PGE2 and
PGF2a stimulate synthesis of protective mucus in stomach and small intestine
prostanoids are not formed, resulting in increased gastric acid secretion & diminished mucus protection – epigastric distress, ulceration or hemorrhage
1. Dose dependent hepatitis2. Reye’s syndrome
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Effect on platelets
Aspirin can irreversibly inhibit thromboxane production in platelets without affecting TXA2 production in the endothelial cells of the blood vessel
Platelet aggregation is reduced, producing an anticoagulant effect with a prolonged bleeding time
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Actions on the kidney
Decreased synthesis of PGs can result in retention of sodium & water and may cause edema and hyperkalemia
Interstitial nephritis can also occur with all NSAIDS except aspirin
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Metabolic1. Uncoupling of Oxid. Phosphorylation2. Hyperglycemia and depletion of muscle
and hepatic glycogen
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THERAPEUTIC USES
1. Inflammation• NSAIDS are first-line drugs used to arrest
inflammation & the accompanying pain of rheumatic and nonrheumatic diseases, including rheumatoid arthritis, juvenile arthritis, osteoarthritis, psoriatic arthritis, ankylosing spondylitis, Reiter’s syndrome, dysmennorhea
• Bursitis & tendonitis also respond to NSAIDS
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2. Analgesia-alleviate mild-moderate pain but less effective than opioids
• more effective against pain associated with integumental structures than that associated with viscera
3. Antipyresis-reduce elevated body temperature
4. Miscellaneous uses
reduces formation of thrombi
is used prophylactically to reduce recurrent transient ischemia, unstable angina, incidence of thrombosis after coronary artery bypass grafts
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5. Topically to treat corns, calluses & epidermophytosis
methyly salicylate- cutaneous counterirritant in liniments
6. Chronic use of aspirin reduces the incidence of colorectal cancer
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ADVERSE EFFECTSPlatelet Dysfunction Gastritis and peptic ulceration with bleeding (inhibition of PG + other effects)Acute Renal Failure in susceptible Sodium+ water retention and edemaAnalgesic nephropathyProlongation of gestation and inhibition of labor.Hypersenstivity (not immunologic but due to PG inhibition)
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Hypersensivity – urticaria, bronchoconstriction or angioedema, fatal anaphylactic shock (rare)
Reye syndrome (is an often fatal, fulminating hepatitis with cerebral edema), aspirin is given during viral infections and this occurs in children instead of aspirin, given acetaminophen to reduce fever
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Drug interactions• The action of anticoagulants may be
enhanced by their displacement by aspirin from binding sites on serum albumin. Aspirin displaces tolbutamide, phenytoin & others
• Antacids may alter the absorption of aspirin• Aspirin competes for tubular reabsorption
with penicillin G& prolongs its half life• Alcohol may increase GI bleeding when
taken with alcohol
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Headache - timmitus - dizziness – hearing impairment – dim visionConfusion and drowzinessSweating and hyperventilationNausea, vomitingMarked acid-base disturbancesHyperpyrexiaDehydrationCardiovascular and respiratory collapse, coma convulsions and death
Aspirin Toxicity - Salicylism
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Decrease absorption - activated charcoal, emetics, gastric lavage
Enhance excretion - alkalinize urine, forced diuresis, hemodialysis
Supportive measures - fluids, decrease temperature, bicarbonate, electrolytes, glucose, etc…
Aspirin Toxicity - Treatment
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OTHER NSAIDS
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PROPIONIC ACID DERIVATIVES
DRUGS
• Ibuprofen
• Naproxen
• Ketoprofen anti-inflammatory
• Fenoprofen analgesic
• Flurbiprofen antipyretic activity
• oxaprozin
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Used in chronic treatment of rheumatoid arthritis & osteoarthritis
Reversible inhibitors of cyclooxygenases
Well absorbed on oral administration
Bound to serum albumin
Hepatic metabolism & are excreted by the kidney
Adverse effects – GI; dyspepsia to bleeding;
CNS, headache, tinnitus, dizziness
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ACETIC ACID DERIVATIVES
DRUGS
• Indomethacin anti-inflammatory
• Sulindac analgesic
• Etodolac anti-pyretic activity
•Reversibly inhibiting
Cyclooxygenase
•Generally not used to lower
fever
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Indomethacin – use to treat acute gouty arthritis, ankylosing spondylitis , osteoarthritis
Sulindac – used in the treatment of rheumatoid arthritis, ankylosing spondylitis, osteoarthritis , acute gout ( less potent than indomethacin)
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OXICAM DERIVATIVES
DRUGS
• Piroxicam used to treat rheumatoid
• Meloxicam arthritis, ankylosing
spondylitis, osteoarthritis
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FENAMATES
DRUGS
• Mefenamic acid
• Meclofenamate
Side effects: diarrhea
hemolytic anemia
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OTHER AGENTS
DICLOFENAC
• Long term use in the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis
• More potent than indomethacin or naproxen
• Ophthalmic preparation available
• Diclofenac stimulates in synovial fluid
• Route of excretion for drug and its metabolites in urine
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KETOROLAC
• Administered intramuscularly- tx of postoperative pain
• Topically for allergic conjunctivitis
• Hepatic metabolism
• Metabolites eliminated via urine
TOLMETIN & NABUMETONE
• Treating adult or juvenile rheumatoid arthritis or osteoarthritis
DIFLUNISAL
• More potent than aspirin
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COX-2-SELECTIVE NSAIDsCELECOXIB
More selective for inhibition of COX-2, its time-dependent & reversible
Used for the treatment of osteoarthritis & rheumatoid arthritis
Readily absorbed
Extensively metabolized in liver by cyt P450
Excreted in the feces & urine
Half-life, 11 hrs
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Adverse effects:• Abdominal pain• Diarrhea• Dyspepsia• Gastrointestinal ulcers• Chronic renal insufficiency• Severe heart disease shd be • Volume depletion avoided• Hepatic failure• Anaphylactoid reactions• CI, allergic to sulfonamides
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Drug interactions
Inhibitors of CYP2C9, such as fluconazole, fluvastatin, zafirlukast, increse serum levels of celecoxib
It could elevate the level of some B-blockers, antidepressants, antipsychotic drugs
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OTHER ANALGESICS
ACETAMINOPHEN
Do not cause physical dependence or tolerance
It is a substitute for aspirin to treat mild to moderate pain for selected pts who are intolerant to aspirin, with gastric complaints
Acetaminophen does not antagonize the uricosuric agent probenecid, & may be used in pts with gout who are taking that drug
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Rapidly absorbed
First pass metabolism – in luminal cells of intestine & hepatocytes
Is conjugated in liver to form inactive glucuronidated or sulfated metabolites
It is hydroxylated to form N-acetylbenzoiminoquinone – a highly reactive & potentially dangerous metabolites that reacts with sulfhydryl gps
At normal doses – forming nontoxic substance
Excretion in urine
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ADVERSE EFFECTS
Skin rash
Minor allergic reactions
Alterations in leukocyte count
Renal tubular necrosis & hypoglycemic coma – rare
Hepatic necrosis
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DISEASE-MODIFYING ANTIRHEUMATIC AGENTS
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Methotrxate
Leflunomide
Chloroquine & hydroxychloroquine
D-Penicillamine
Gold salts
Anticytokine drugs in rheumatoid arthritis
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Methotrexate
Methotrexate – It is an immunopressant agent. used in rheumatoid or psoriatic arthritis, have not responded to aspirin
Adverse effects: mucosal ulceration & nausea, cytopenias, cirrhosis of liver, acute pneumonia like syndrome
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Chloroquine & Hydroxychloroquine
Used in rheumatic arthritis & malaria
Mechanism uncertain- inhibiting NA synthesis, they stabilize lysosomal membranes & trap free radicals
These drugs- slow progression of erosive bone lesions & may induce remission
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Adverse effects
Low doses- chemosuppression of malaria
Higher doses- GIT upset, pruritus, headaches, visual disturbances
Discoloration of nail beds & mucus memb.
Cautiously in pts with hepatic dysfunction or severe GI problems or in pts with neurologic or blood disorders
Dermatitis
Psoriasis or porphyria
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LEFLUNOMIDE
Immunomodulatory agent –causes cell arrest of autoimmune lymphocytes thru its action on dihydroorotate dehydrogenase (DHODH)
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Dihydroorotate dihydroorotate orotate
dehydrogenase
Orotidine 5’monophosphate UMP
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Well absorbed
Extensively bound to albumin
Half-life, 14-18 hrs
Rapidly metabolized
Excretion in urine and feces
Adverse effects, headache, nausea, diarrhea, weight loss, allergic reactions-flu like syndrome, skin rash, alopecia, hypokalemia
CI: in pregnancy & women of child bearing potential
Caution in pts with liver disease
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D-Penicillamine – aacid of cysteine
Used in rheumatoid arthritis
Slow progress of bone destruction & rheumatoid arthritis
Adverse effects, dermatologic problems to nephritis, aplastic anemia
Chelating agent in tx of poisoning by heavy metals & also in treating cystinuria
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GOLD SALTS, gold sodium thiomalate, aurothioglucose
Taken up by macrophages & suppress phagocytosis and lysosomal enzyme activity- retards progression of bone & articular destruction
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ANTICYTOKINE THERAPIES IN RHEUMATOID ARTHRITIS
Etanercept
Infliximab
Adalimumab
Anakinra
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Etanercept
• Tx in rheumatoid & psoriatic arthritis
• Combination with methotrexate, more effective than alone
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Infliximab
• Monoclonal antibody
• For Crohn’s disease & rheumatoid arthritis
• Used in combination with Methotrxate
• Adverse effects:
-Long term used, antibodies developed
-Infusion reactions, fever chill pruritus urticaria
-Leading to pneumonia & cellulitus
-Leukopenia, neutropenia, thrombocytopenia, pancytopenia
-Lymphoma
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Adalimumab
• Tx of rheumatoid arthritis
• Recombinant monoclonal antibody –TNFa receptor site
• Reaction ,rash, headache, nausea
• Predisposed injection – pneumonia
Anakinra
• Receptor antagonists to IL-1
• Tx of rheumatoid arthritis
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GOUT
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DRUGS USED IN THE TREATMENT OF GOUT
Is a metabolic disorder – high levels of uric acid in the blood
Hyperuricemia results in the deposition of sodium urate crystals in tissues (kidney & joints)
Sodium urate is the end product of purine metabolism
Deposition of urate crystals initiates an inflammatory process involving infiltration of granulocytes that phagocytize urate crystals
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Process generates oxygen metabolites, which damage tissue, release of lysosomal enzymes that evoke an tissues increases
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Preventing deposition of urate crystals
1. Interfering with uric acid synthesis with allopurinol
2. Increasing uric acid excretion with probenecid or sulfinpyrazone
3. Inhibiting leukocyte entry into the affected joint with colchicine
4. Administration of NSAIDs
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DRUGS
• Colchicine
• Allopurinol
• Uricosuric agents – Probenecid &
Sulfinpyrazone
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COLCHICINETreatment of acute gouty attacks
It binds tubulin, causes depolarization. Disrupts cellular functions, mobility of granulocytes, decreasing migration into affected area
Also inhibits synthesis and release of the leukotrienes
Adverse effects: nausea, vomiting, abdominal pain, diarrhea. Chr adm; myopathy, agranulocytosis, aplastic anemia, alopecia
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CI: not be used in pregnancy
Caution in pts with hepatic, renal or CV disease
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ALLOPURINOL
Reduces production of uric acid by competitive inhibits – xanthine oxidase
Treatment of primary hyperuricemia of gout & secondary to other conditions, like malignancies or in renal disease
Alloxathine (oxypurinol) – xanthine oxidase inhibitor
Adverse effects; hypersensitivity reactions, nausea, diarrhea,
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Drug interaction; interferes with metabolism of anti-cancer agent 6-mercaptopurine & azathioprine (immunosuppressant), requiring a reduction in dosage
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Probenecid & Sulfinpyrazone
Are organic weak acids that reduce urate levels by acting at anionic transport site in the renal tubule to prevent reabsorption of uric acid
Used for chronic gout
Undergo rapid oral absorption
Inhibit excretion of other drugs (penicillin, NSAIDs, cephalosporins, methtrexate) that are actively secreted by renal tubules
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Increased urinary concentration of uric acid - urolithiasis. This risk is decreased with ingestion of large volumes of fluid or alkalinization of urine with potassium citrate
Low doses of uricosuric agents & salicyltes inhibit uric acid secretion.
Aspirin is CI in gout
Adverse effects; GI disturbances, dermatiitis, blood dyscrasias (rare)
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Tx – ACUTE GOUT
Excessive alcohol consumption, diet rich in purines, kidney disease
Tx – indomethacin; decrease movement of granulocytes into affected area & NSAIDs ; decrease pain and inflammation
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Tx – CHRONIC GOUT
Genetic defect- increase in rate of purine synthesis, renal deficiency, lesch-nyhan syndrome, increase synthesis of uric acid with cancer chemotherapy
Tx – uricosuric drugs, allopurinol
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ANTITUSSIVES
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COUGH
Cough receptors, specialized stretch receptors in the trachea & bronchial tree, send vagal afferents to cough centre & trigger the cough reflex
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ANTITUSSIVE AGENTS
Codeine, Hydrocodone, Hydromorphone
Dextromethorphan
Benzonatate
Diphenhydramine
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Codeine, Hydrocodone, Hydromorphone
Decrease sensitivity of central cough centre to peripheral stimuli & decrease mucosal secretions
Actions occur at doses lower than those required for analgesia
Produce constipation, nausea , respiratory depression
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DEXTROMETHORPHAN
L-isomer opioid
Active as an antitussive
Devoid of analgesic or addictive liability
Less constipating than codeine
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BENZONATE
Glycerol derivative chemically similar to procaine
Reduces activity of peripheral cough receptors
Also reduce threshold of central cough centre
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DIPHENHYDRAMINE
Antitussive activity is not mediated at H1 receptor
Acts centrally to decrease the sensitivity of cough centre to afferents
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LEVOPROPOXYPHENE
Weak opioid agonist dextropropoxyphene
Sedation as a side effects
50-100mg every 4 hrs
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DEXTROMETHORPHAN
Methylated derivative of levorphanol
Free of addictive properties & produces less constipation than codeine