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Non-Opioid Analgesic Agents

Non-Opioid Analgesic Agents

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Published by: anaeshkl on Apr 07, 2012
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 Non-steroidal anti-inflammatory drugs
 Noradrenalineand serotonin reuptake inhibitors
tramadol, tricyclicantidepressants
gabapentin, pregabalin
n-methyl d-aspartateantagonists
alpha2 receptor agonists
a 20-carbon fatty acid that contains 4 double-bonds,released from membrane phospholipids by phospholipaseA2 (PLA2)
 precursor of eicosanoids
following mobilisation, arachidonicacid is oxygenated by 4 separate routes
cyclooxygenaseor prostaglandin endoperoxidesynthase
P450 epoxygenase
Mediators derived from arachidonicacid
Acute inflammatory mediatorsCOX isoenzymes
PGH synthase-1 (COX-1)
constitutively expressed in almost all tissues,always present
responsible for the production of  prostaglandins that are important for homeostatic functions
maintaining the integrity of gastricmucosa,
mediating normal platelet function,and
regulating renal blood flow, vascular homeostasis and autocrineresponse tocirculating hormones
PGH synthase-2 (COX-2)
rapidly inducible and tightly regulated
upregulated20-fold in macrophage,monocytes, synoviocytes, chondrocytes,fibroblasts, osteoblastsand endothelial cells byvarious inflammatory stimuli
governs increased production of prostanoidsthat mediate inflammation, pain, and fever 
also upregulatedin
colorectal adenomas and carcinomas,
 breast, head and neck cancers
 production decreased by glucocorticoids,cytokines IL-4, IL-13
 both are 60% homologous
small differences lining the COX active sites
COX-2 inhibitor binding site is 25% larger thanCOX-1 and has a secondary internal pocket off the inhibitor binding site not seen in COX-1
differences lead to the distinct inhibition profiles between COX-1 and -2 inhibitors
weak organic acids
follows pharmacokinetics for acidic drugs
albumin binding, low pKa, effect of  pH on transfer across membrane
except nabumetone, a ketoneprodrugthat ismetabolised to an acidic active drug
inhibit prostaglandin biosynthesis
decrease the production of free radicals andsuperoxides
interact with adenylylcyclaseto alter thecellular concentrations of cAMP
 Non-opioidanalgesic agents
 NC Hwang 2009
Ratio of COX-1/COX-2 inhibition (selectivity)
ratios more than 1 indicate more COX-1 selective
the ratio of IC
of COX-2 to COX-1 defines COX-2selectivity
COX-1 ratio <0.01 indicates moreCOX-2 selective (rofecoxib, celecoxib, valdecoxib, parecoxib)
Common features of NSAIDs
Upper gastrointestinal side effects
high risk: azapropazone
intermediate risk: diclofenac, piroxicam, naproxen,ketoprofen
low risk: ibuprofen, meloxicam
minimal risk: specific cox-2 inhibitors (coxibs)
Renal effects
in the kidneys COX-2 is constitutively expressed inendothelial and smooth muscle cells of the renalvasculature and in the podocytesof the glomerulus
 prostacyclinand PGE2 maintain renal blood flow instates of effective volume depletion such as congestiveheart failure, liver cirrhosis, and true volume depletion inchronic diuretic therapy, by antagonising thevasoconstrictiveeffects of angiotensinII andnorepinephrine
 NSAIDsuse may be associated with acute renal failurein patients with hypovolaemia, altered intrarenalplasmaflow, nephroticsyndrome with interstitial nephritis, and papillary necrosis
rare, but agranulocytosisand aplasticanaemiaare mostsevere
 NSAIDscauses a direct hypoprothrombinaemiceffect by depressing vitamin K-synthesis of clotting factors VII,IX, X
 NSAIDsdisplaces warfarinfrom albumin
 platelets contain COX-1 and not COX-2, non COX-2selective agents demonstrate antiplateleteffects
Cartilage effects
 prostaglandins are well-documented modulators of cartilage metabolisms, bone resorption, and ossificaiton
 NSAIDscan exacerbate cartilage erosion and produce bony destruction of the femoral head in OA
COX-2 may have a role in cartilage repair 
Pulmonary effects
4 to 14-fold increase in COX-2 in asthmatic subjects
COX-2 blockade may be therapeutic in asthma, whereasolder NSAIDscan cause bronchoconstrictionandoedema
Cardiovascular effects
causes hypertension
 by inhibiting prostaglandin synthesis, NSAIDsinterferewith
systemic and renal vasodilatation
tubular secretion of fluids and electrolytes
adrenergic neurotransmission
cardiovascular deaths
Adenoma Prevention with Celecoxib(APC)trial suspended
0.9% (placebo), 2.2% (celecoxib400mg), 3.0%(celecoxib800mg)
Prevention of spontaneous AdenomatousPolyps (PreSAP) trial suspended
1.8% (placebo), 1.7% (celecoxib400mg)
cardiovascular events (MI, stroke, DVT, PE)
2 separate valdecoxibtrials, 10 and 14 days, for acute pain after CABG
valdecoxib40mg twice daily (study1), and valdecoxib20mg twice daily(study 2)
risk of cardiovascular events
intravenous form 2%, oral form 1%, placebo 0.5%
Alzheimer’s Disease Anti-inflammatoryPrevention Trial (ADAPT) suspended
naproxen 220mg vscelecoxib40mg
apparent increase in CV events innaproxen arm compared to placebogroup
Central nervous system effects
can aggravate
 psychiatric illness
Other effects
 peripheral oedema
Salicylic acid and its derivatives
aspirin, acetylsalicylic acid, ASA, has pKaof 3.5
rapidly absorbed from the stomach and upper small intestine, yielding peak plasmaconcentration within 1-2 hours
acid medium keeps large fraction of the drug innonionisedform, promoting absorption
 passage through gastric mucosa may damagemucosal barrier 
raising the pH by a buffer to 3.5 or higher, gastric irritation is decreased
 Non-opioidanalgesic agents
 NC Hwang 2009
aspirin is rapidly hydrolysed to acetic acid andsalicylateby esterasesin tissue and blood
salicylateis bound to albumin, as the serumconcentration of salicylateincreases, a greater fraction remains unbound and available to thetissues
majority undergoes conjugation
 pathway is saturable
when aspirin is administered in low dose (600mg), salicylateelimination is in accordance tofirst-order and serum t½is 3-5 hours
with higher dosage, a mix of capacity-limitedand zero-order kinetics prevails
at anti-inflammatory dosage (>4g/day), t½increases to 12 hours or more
excreted unchanged (2-30% of the salicylate)or as water-soluble conjugated form by thekidney
alkalinisation of urine increases the rate of excretion of free salicylate
Mechanism of action
inhibit cyclooxygenaseI and II irreversibly, decreasingthe formation of prostaglandins and thromboxaneA2
scavenge free radicals
reduces synthesis of eicosanoidmediators
interferes with the chemical mediators of the kallikreinsystem
inhibits granulocyte adherence to damagedvasculature
stabilizes lysosomes
inhibits migration of polymophonuclear leukocytes and macrophages into the site of inflammation
Analgesic effect
effective for mild to moderate intensity
 peripherally though its effects on inflammation
 pain stimuli at subcorticalsite
alleviates pain from various causes
 pain of muscular, vascular and dental origin
 postpartum states
arthritis, bursitis
Antipyretic effect
 blocks pyrogen-induced production of prostaglandins
 blocks central nervous system response to interleukin-1
IL-1 released by macrophages duringinflammatory responses, where its principal roleis to activate lymphocytes
reset the temperature control in hypothalamus,facilitating heat dissipation by vasodilatation
Anti-platelet effects
irreversible inhibition of platelet aggregation secondaryto inhibition of thromboxanesynthesis
action lasts for up to 8 days, until new platelets areformed
lifespan of platelets 8.9 (0.6) days
has longer duration of action than other compounds thatinhibit platelet aggregation, such as ticlopidineanddipyridamole
inhibition of platelet aggregation
slow cataract formation
lower incidence of colon cancer 
Adverse effects
gastrointestinal system
gastritis due to
local irritation by the undissolvedtablet
absorption in the stomach of unionizedsalicylate
inhibition of protective prostaglandins
erosive gastritis with bleeding
vomiting due to central stimulation after absorption of large doses of aspirin
central nervous system
reversible by reducing the dose
tinnitus, decreased hearing, vertigo
hyperpnoea through direct effect onthe medulla,
low toxic concentrations, respiratoryalkalosis
higher concentrations, acidosis withaccumulation of salicylic acidderivatives and depression of respiratory centre
hyperuricaemiawith daily dose of 2 g or less
hypouricaemiawith daily dose of 4 g or more
mild, asymptomatic hepatitis
especially in patients with systemic lupuserythematosusand rheumatoid arthritis
reversible decrease of glomerularfiltration rate
toxic amounts depress cardiac function, and dilate peripheral blood vessels
in patients with asthma, and nasal polyps
after viral infection in children, associated with increasein incidence of Reye’s syndrome
Drug interactions
increased absorption with metoclopramide,domperidone
increased excretion in alkaline urine, with antacids, andadsorbents
increased risk of bleeding with anticoagulants,corticosteroids, alcohol
reduced plasma salicylateconcentration withcorticosteroid
enhanced salicylatetoxicity with acetazolamide,ammonium chloride
 Non-opioidanalgesic agents
 NC Hwang 2009

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