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Non steroidal anti-inflammatory drugs
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Dr. Jannatul FerdoushAssistant ProfessorDepartment of Pharmacology
Pain
Unpleasant sensory & emotional experience
associated with actual or potential tissue damage.
Component of pain:
Perception of pain- drugs act on this by
increasing threshold for pain
Emotional response
Component of regulationPeripheral factor: Tissue damage ↓ Release of certain factor bradykinin, PG
Brady kinin- pain producing subs.PG- for inflammation PGE1 & PGI2 is responsible.Bradikinin sensitize PG to produce pain.
For pain relief:Antagonist of BK ( not available)PG synthesis Blocker –NSAID-act by inhibiting Cyclooxygenase or
PG synthase.
Central regulation of painPain R are distributed in pain pathway,
hypothalamus, limbic system, spinal cord.
Brain
Nociceptive pathway(spinal, supraspinal- thalamus, cortex)
Spinal cordglutamate,Subs P, neurokinin, NO
BK, 5HTPG
Afferent nerve
(-) NSAID
Periphery
Opioids stimulates
DescendingInhibitoryPathway(Enchephalin,5HT, NE)
Dorsal horn
Pain pathway
Tissue injury
We can block nociceptive pathway Peripheral R Ascendind pain pathway
Pain transmitted by Pain inhibited by NO Opiates Glutamate Enkaphalin Subs P 5HT,
GABA,NE
Classification of AnalgesicBased on – Peripherally acting -Centrally acting
Peripheally acting : NSAID or non narcotic analgesic (Block
nociceptive impulse) e.g. Paracetamol, Diclofenac, Ibuprofen
Centrally acting: Narcotic analgesic ( act on opioid R act mainly on neuronal
pathway - Spinal, Supraspinal)
Choice of analgesicDepends on: Origin – visceral / somaticSeverity of pain (mild,moderate, severe)
Mild pain: Headache, Myalgia Non narcotic analgesic: 1)Paraceatamol, if not response – 2)antiinflammatory drug- ketoprofen, ibuprofen3)Then diclofenac
If visceral pain : opioid analgesicMild to moderate pain with an antiinflammatory
componant, generally chronic pain E.g. RAUse: NSAID + low efficacy opioid
• Severe Pain:If visceral (acute pain) MI , biliary colic etc.Use: opioid analgesic- morphine ,pathedrinePurely visceral with an antiinflammatory componant:Gout, bone metastesis, post operative pain
Intolarable Pain: High efficacy opioid analgesic + anxiolytic , sometimes
adjuvant drug.
Neuropathic painNeurological damage to the nervous system Drug use which inhibit pain pathway.
e.g. 5HT agonist.
Narcotic:
Depress CNSProduce sedation & drowsinessAct by central mechanismThey also cause euphoria, physical
dependence & tolerance.
Non-narcotic: Act chiefly peripherallyRelief somatic pain (muscle,joint, skin)Do not produce physical dependence &
tolerance
Adjuvant Medication
Usually not used for pain but rather for other management.
They are not themselves analgesic, though they may modify the perception or the concomitants of pain that make it worse (anxiety, fear, depression), e.g. psychotropic drugs, steroid, antidepressant.
They may modify underlying cases, e.g. spasm of smooth or of voluntary muscle eg. Local anasthetics,alpha 2 agonist
Mechanism of pain
Noxious stimuli(temp, mechanical , chemical) ↓Stimulate sensory R (periphery)(1st order neuron) ↓Transmitted to lateral spinothalamic tract or
spinal cord (2nd order neuron)
↓ Thalamus (interation) ↓ Sensory area of cortex( interpretetion)( area no 1,2,3 Post cetral gyrus)
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Chemical classification –
Para-amino phenol derivatives : Paracetamol (acetaminophen)
Salicylic acids :Aspirin, Diflunisal, Benorilate
Acetic acids : Indomethacin, Sulindac, Diclofenac sodium, Etodolac, Ketorolac
Fenamic acid :Mefenamic acid, Meclofenamic acid
Propionic acids :Ibuprofen, Ketoprofen, Fenoprofen,
Naproxen, Flurbiprofen, Oxaprozin
Enolic acids :Piroxicam, Meloxicam, Nabumetone
NSAIDs may be categorized according to their COX specificity as:
COX-2 selective compounds-
CelecoxibEtorocoxib
NON-selective – all other NSAIDs.These drugs inhibit COX-1 as much, or even more than, COX-2.
According to potency of anti-inflammatory effect:
Strong anti-inflammatory drug: IndomethacinPiroxicamAspirinDiclofenacTenoxicum
Moderate anti-inflammatory drug: NaproxenKetoprofen Ibuprofen
Weak anti-inflammatory drug: Paracetamol is not a NSAID.
Most of the NSAIDs have three major types of effect:
Anti-inflammatory effects:
In acute inflammation
PGE2 & PGI2 generated by local tissue & PGD2 released by mast cell
↓These are powerful vasodilator and potentiate other
inflammatory Vessodilatator ( Histamine and bradykinin) ↓ the combined dilator action on precapillary arterioles cause
redness & ↑ blood flow in the areas of inflammation. ↓Blocks PG synthesis and thereby suppress pain, swelling, ↑
blood flow associated with inflammation
NSAIDs have some general properties in common:
All but one of the NSAIDs are weak organic acids as given; the exception, nabumetone, is a ketone pro-drug that is metabolized to the acidic active drug.
Most of the NSAIDs are highly metabolized, some by phase I followed by phase II mechanisms & others by direct glucoronidation (phase II) alone
Metabolism proceeds, in large part, by way of P450 enzymes in the liver
Pharmacokinetics of NSAIDs
Renal excretion is the most important route for final elimination
Nearly all undergo varying degrees of biliary excretion & reabsorption (enterohepatic circulation)
Most of the NSAIDs are highly protein bound (98%), usually to albumin
All NSAIDs can be found in synovial fluid after repeated dosing
Analgesic actionTrauma
↓Pain↓
Tissue damage ↓
Liberation of chemical sustance bradykinin & prosglandin.
↓Bradykinin sensitize pain R to PG.
↓NSAID blocks PG synthesis
↓Relieve of pain
Antipyretic effect
Normal body temperature regulates a center of hypothalamus .
Inflammatory reaction bacterial endotoxin
release of a pyrogen-IL-1 from macrophage stimulate the generation of PGE2 in hypothalamus Disturbance of this hypothalamic ‘thermostate’ leads to the set point of body temperature being raised causes the elevation of the set-point for temperature fever
So, NSAID inhibit PGE2 production & release in the hypothalamus antipyretic effect
Anti-platelet action Low dose Aspirin
Primary dysmennorhea:
Mefenamic acid is used to reduce the production of PGs
by the uterus which cause uterine hypercontractility &
pain.
Patency of the ductus arteriosus:
As PGs maintain the patency, indomethacin given to a
new-born child with a patent ductus arteriosus can
result in closure, avoiding the alternative of surgical
ligation
Unwanted effects of NSAIDs
Unwanted effects of NSAIDs
Renal effect: Prolong high dose of NSAID
↓ ↓PGI2
↓ No renal Vessodilatation
↓ Renal ischemia
↓↓GFR
↓ Na & water retention
↓ HTN, HF aggravates.
NSAID induce gastric ulcer:
Aspirin which is acidic drug remains unionized in gastric acidic environment.
So, drug enters into cell by simple diffusion
In cell pH is high, the drug become ionized & trapped & cannot diffuse back. So an ion trapping occur and this may cause gastric erosion, ulceration.
Drug interactions of NSAIDs
NSAID + Warfarin: the risk of hemorrhage.
NSAID + Antidiabetics: Azapropazone & phenylbutazone inhibit the metabolism of sulfonylurea hypoglycemics, their toxicity
Aspirin + phenytoin, valproic acid: the plasma conc. of phenytoin, valproic acid
Antihypertensives: Their effect is lessened due to sodium retention by inhibition of renal PG formation
Diuretics: NSAIDs causes Na+ retention & reduce diuretic & antihypertensive efficacy
Lithium: NSAIDs delay the excretion of lithium by the kidney & may cause lithium toxicity
ACEI & angiotensin II antagonists: there is a risk of renal impairment & hyperkalemia
Caution & contraindications
In the elderly, allergic disorders, during pregnancy & breast feeding, & coagulative defects.
In patients with renal, hepatic or cardiac disease.
• In patient with bronchial asthma –
• NSAIDs or aspirin block the COX-1enzyme →↓ TXA2 & PGE2→ overproduction of leukotrienes & produces the severe asthma and allergy-like effects.
Over expression of both the LT R & the LTC4 synthase enzyme in respiratory tissue from patients with aspirin-induced asthma, cause ↑ response to LT & ↑ production of LT.
Paracetamol
Acetaminophen inhibits PG synthesis in the CNS.
This explains its antipyretic & analgesic properties.
Acetaminophen has less effect on COX in peripheral tissues,
which accounts for its weak anti-inflammatory
Inactivated in the liver principally by conjugation as glucoronide & sulphate.
Minor metabolites of paracetamol are also formed N-acetyl-p-benzoquinoneimine (NABQI), is highly reactive chemically.
This substance is normally rendered harmless by conjugation with glutathione.
• At normal doses of paracetamol, the NABQI reacts with the sulfhydryl group of glutathione, forming a nontoxic substance.
• But the supply of hepatic glutathione is limited & In overdose,
• NABQI formed is greater than the glutathione available,
then the toxic metabolite accumulates & reacts with nucleophilic constituents in the cell.
• The excess metabolite oxidises thiol (SH-) groups of key enzymes, which causes cell death.
• Cause hepatic & renal tubular necrosis.
Paracetamol poisoningTreatment –
Gastric lavage followed by oral activated charcoal if ingested within 1 hour
liver damage can be prevented by giving agents that increase glutathione formation in the liver (acetylcysteine intravenously, or methionine orally)
If more than 12 hours of ingestion of a large dose, the antidotes, which themselves can cause adverse effects (nausea, allergic reactions), are less likely to be useful
Aspirin (acetylsalicylic acid) is the prototype of traditional NSAIDs
The bark of the willow tree (Salix) contains salicin from which salicylic acid is derived; it was used for fevers in the 18th century as a cheap substitute for imported cinchona (quinine) bark
Rarely used as an anti-inflammatory medication; it has been replaced by ibuprofen & naproxen
Effective, available as OTC & safe .
Aspirin
Aspirin is a weak organic acid
Irreversibly acetylates (& thus inactivates) COX, so preventing the formation of products including thromboxane, prostacyclin & other PGs
The other NSAIDs, including salicylate, are all reversible inhibitors of COX.
Aspirin is rapidly deacetylated (hydrolysed) by esterases in the plasma, producing salicylate
Has anti-inflammatory, anti-pyretic & analgesic effects but additionally exerts important effects on respiration, intermediary metabolism & acid-base balance
Mode of action of aspirin
Actions of aspirin:Aspirin has 3 major therapeutic actions –
They reduce - Inflammation (anti-inflammation) Pain (analgesia)Fever (antipyrexia)
Anti-inflammatory action: Nonselective inhibitor of both COX isomers. irreversibly inhibits COX activity the formation of PGs &, thus, modulates those aspects
of inflammation in which PGs act as mediators.
Antiplatelet action: Low doses (75mg daily) of aspirin can irreversibly inhibit
TXA2 production in platelets without markedly affecting PGI2 production in the endothelial cells of the blood vessel.
As a result of the in TXA2, platelet aggregation (the 1st step in thrombus formation) is reduced, producing an anticoagulant effect with a prolonged bleeding time.
• The acetylation of COX is irreversible. Because platelets lack nuclei, they cannot synthesize new enzyme, & the lack of TXA2 persists for the lifetime of the platelet (3-7 days). This contrasts with the endothelial cells, which have nuclei &, therefore, can produce new COX.
Respiratory action: At therapeutic doses, aspirin alveolar ventilation. Salicylates uncouple oxidative phosphorylation elevated
CO2 respiration. Higher doses work directly on the respiratory center in the
medulla, resulting in hyperventilation & respiratory alkalosis that is usually compensated by the kidney ( bicarbonate excretion).
At toxic levels, central respiratory paralysis occurs, & respiratory acidosis ensures due to continued production of CO2
GIT effects: PGI2 inhibits gastric acid secretion.
PGE2 & PGF2α stimulate synthesis of protective mucus in both the stomach & small intestine.
Aspirin (-) PG synthesis → gastric acid secretion & mucus protection
Actions on the kidney: COX inhibitors prevent the synthesis of PGE2 & PGI2 –
PGs maintain renal blood flow, particularly in the presence of circulating vasoconstrictors.
synthesis of PGs can result in retention of sodium & water & may cause edema & hyperkalemia in some patients.
Aspirin in high dose reduces renal tubular reabsorption of urate
Low dose (< 2g/d) inhibit urate secretion, causing urate retention
Dosage of aspirin:
75-300 mg/d are used routinely to prevent thromboembolic vascular occlusion;
Low doses (75mg or 100mg) are to be prescribed following bypass surgery & post MI
300 mg as immediately after the diagnosis of IHD. Aspirin decrease the mortality after MI;
300-900 mg every 4-6 hourly when necessary for analgesia
Salicylates, especially methyl salicylates, are absorbed through intact skin.
Aspirin has a PKa of 3.5. After oral administration, in the stomach aspirin is un-ionised & thus lipid-soluble & diffusible.
In gastric epithelial cells (PH 7.4) it will ionise, become less
diffusible & so harms, the gastric mucosa.
In the body aspirin is metabolised to salicylic acid (Pka 3.0), which at PH 7.4 is highly ionised & thus remain in the ECF.
salicylic acid in the plasma are filtered by the glomeruli & pass into the tubular fluid, which is generally more acidic than plasma & causes a proportion of salicylic acid to become un-ionised & lipid-soluble so diffuses back into the tubular cells.
P/K of aspirin
At normal low dosages (650 mg/d), aspirin (half-life 15 minutes) is hydrolysed to salicylate & acetic acid by esterases in tissues & blood.
Salicylate is converted by the liver to water-soluble conjugates (glycine conjugation) that are rapidly cleared by the kidney, resulting in elimination with first-order kinetics & a serum half-life of 3.5 hours.
At anti-inflammatory dosages (> 4g/d), the hepatic metabolic pathway becomes saturated, & zero-order kinetics are observed, with the drug having a half-life of 15 hours or more
Salicylate is an organic anion & in addition to undergoing glomerular filtration, is secreted by the proximal renal tubule
Alkalinising the urine with sodium bicarbonate causes more salicylic acid to become ionised & lipid-insoluble so that it remains in the tubular fluid, & is eliminated in the urine
Most absorption of aspirin, however, occurs in the ileum because of the extensive surface area of the microvilli
Rectal absorption of salicylates is slow & unreliable, but it is a useful route for administration to children with vomiting. Salicylates (except diflunisal) cross both BBB & the placenta.
GIT: Epigastric distress, nausea, vomiting
Blood: prolonged bleeding time due to (-) platelet aggregation. Should not be taken for at least one week prior to surgery.
Allergy: severe rhinitis, urticaria, angioedema, asthma or shock. Those who already suffer from urticaria, nasal polyps or asthma are more susceptible
Adverse effects of aspirin
Salicylism: occurs with repeated ingestion of large doses of
salicylate. It is a syndrome consisting of tinnitus (a high-pitched
buzzing noise in the ears), vertigo, hearing, dizziness, headache & confusion.
Sometimes also nausea & vomiting
Reye’s syndrome: Rare disorder in children. It is a combination of liver disorder & encephalopathy
(CNS disturbances) that can follow an acute viral illness & has a 20-40% mortality.
Should not be given to children under 12 years unless specially indicated, e.g. for juvenile arthritis, should be avoided in those up to & including 15 years (paracetamol is preferred)
Respiratory alkalosis develops: Salicylates uncouple oxidative phosphorylation (mainly
in the skeletal muscle) → O2 consumption & production of CO2. This stimulates respiration, which is also stimulated by a direct action on the respiratory center.
The resulting hyperventilation causes a respiratory alkalosis that is normally compensated by renal mechanisms involving HCO3
- excretion
The blood pH thus rises, & renal loss of HCO3- is
accompanied by Na+ & K+ as well as water; dehydration & hypokalemia result
Salicylate poisoning
Metabolic acidosis : Accumulation of lactic & pyruvic acids due to
interference with TCA cycle enzymes stimulation of lipid metabolism causing
production of ketone bodies. Late toxic respiratory depression may also cause
CO2 retentionSalicylate poisoning -More serious in children than in adults. -The acid-base disturbance seen in children is
usually a metabolic acidosis whereas that in adults is a respiratory alkalosis
Treatment:Activated charcoal: adsorbs salicylate & prevents
its absorption from the alimentary tract; gastric lavage or the use of an emetic is no longer recommended
Correction of dehydration: alkalosis or mixed alkalosis/acidosis need no specific treatment.
Metabolic acidosis is treated with sodium bicarbonate, which alkalinises the urine & accelerates the removal of Salicylate in the urine
Hemodialysis: may be necessary, either if renal failure develops or the plasma salicylate concentration exceeds 900 mg/l
COX-2 selective inhibitors, or coxibs, were developed in an attempt to inhibit PG synthesis by the COX-2 isoenzyme induced at sites of inflammation without affecting the action of the constitutively active “house-keeping” COX-1 isoenzyme found in the GIT, kidneys, & platelet
COX-2 selective NSAIDs
COX-2 inhibitors have analgesic, antipyretic, & anti-inflammatory effects similar to those of nonselective NSAIDs but with an approximate halving of GI adverse effects
These selective agents also have no significant effects on platelets
The COX-2 inhibitors (like the traditional NSAIDs) may cause renal insufficiency .
Clinical data have suggested a higher incidence of cardiovascular thrombotic events associated with COX-2 inhibitors such as rofecoxib & valdecoxib, resulting in their withdrawal from the market
Celecoxib is useful for long term use in chronic arthritis. It has minimal side effects
Etorocoxib is indicated for symptomatic relief of osteoarthritis & acute gout
Nimesulide, a relatively selective COX-2 inhibitor is useful in mild to moderate arthritis, somatic pain & fever
Aceclofenac has a chondroprotective property, which may be useful for long term management of osteoarthritis. It is also effective in rheumatoid arthritis & alkylosing spondylitis. It is well tolerated, thus suitable for the elderly
COX I & COX II
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