4. Aspirin
• In the 1800s, researchers across Europe
explored salicylic acid. French pharmacist
Henri Leroux isolated it in 1829.
• Hermann Kolbe discovered synthetic
salicylic acid in 1874, but when
administered often in large doses, patients
experienced nausea and vomiting, and
some even went into a coma. A buffer was
needed to ease the effects of this acid on
the stomach. 4
5. • Alexei Nicholaevich Romanov of Russia
(Hemophilia) – murder of last Tzar.
• Aspirin's uses for heart patients came to light in
1948 when California physician Dr. Lawrence
Craven recommended an aspirin a day to reduce
heart attack risk, based on what he had observed
in patients.
• The Nobel Prize in medicine in 1982 was awarded
to researchers who demonstrated the reason - it
inhibits production of hormones called
prostoglandins. Prostoglandins are responsible for
the formation of clots that leads to heart attacks
and strokes, and aspirin prevents that clotting from
John Vane , Sune
Bergström and Bengt
Samuelsson
5
6. Dose
• The recommended oral dose for adults:
• Prevention of myocardial infarction or heart attack: 75-325 mg/day.
• Stent implantation: 325 mg 2 hr pre-operative, then 160-325 mg/day.
• Pain and fever: 325-650 mg 4-6 hourly. Maximum: 4 g/day.
• Pain and inflammation associated with musculoskeletal and joint
disorders:
Initial dose: 2.4-3.6 g/day.
Maintenance dose: 3.6-5.4 g/day.
• Aspirin Tablets BP 75 mg is not indicated for use in children and young
people less than 16 years of age. 6
7. Indications
• Local analgesic
• Anti pyretic
• Anti inflammatory
• Anti platelet
• Rheumatic fever and arthiritis
External Use
• Colon cancer
• CVS application
• Prophylactically to decrease
incidence of heart attack and MI 7
8. Contraindications
Absolute Contraindications
• Active peptic ulcer
• Aspirin allergy or intolerance
• Bleeding disorders
• H/O recent GI bleeding
• H/O of recent intracranial
bleeding
• Renal failure
• Severe liver disease
Relative Contraindications
• Age < 21 years (Reye
Syndrome)
• Concurrent use of anti
coagulant therapy
• Concurrent use of NSAIDs
• Poorly controlled hypertension
(Risk of intracranial bleeding).
8
9. Pregnancy
• Low doses (up to 100 mg/day) :
• Doses of 100- 500 mg/day :
• Doses of 500 mg/day and above : Inhibition of prostaglandin synthesis
may adversely affect the pregnancy and/or the embryo/fetal
development.
• Data from epidemiological studies suggest an increased risk of
miscarriage and of cardiac malformation and gastroschisis (birth
defect of the abdominal wall) after use of a prostaglandin synthesis
inhibitor in early pregnancy.
9
10. During the third trimester of pregnancy, all prostaglandin synthesis inhibitors
may expose the fetus to:
• cardiopulmonary toxicity (with premature closure of the ductus arteriosus
and pulmonary hypertension);
• renal dysfunction, which may progress to renal failure with oligo-
hydroamniosis;
• the mother and the neonate, at the end of pregnancy, to:
• possible prolongation of bleeding time, an anti-aggregating effect which may
occur even at very low doses.
• inhibition of uterine contractions resulting in delayed or prolonged labor.
Consequently, acetylsalicylic acid at doses of 100 mg/day and higher is
contraindicated during the third trimester of pregnancy.
Potter Syndrome
10
14. Pharmacodynamic properties
Aspirin inhibits platelet aggregation.
• Experimental data suggest that Ibuprofen may inhibit the effect of low dose
aspirin on platelet aggregation when they are dosed concomitantly.
• In one study, when a single dose of Ibuprofen 400mg was taken within 8
hours before or within 30 minutes after immediate release aspirin (81mg) a
decreased effect of aspirin on the formation of thromboxane or platelet
aggregation occurred.
• However, the limitations of these data and the uncertainties regarding
extrapolation of ex vivo, data to the clinical situation imply that no firm
conclusions can be made for regular ibuprofen use, and no clinically
relevant effect is considered to be likely for occassional ibuprofen use.
.
14
15. Pharmacokinetic properties
• Non ionised acetylsalicylic acid is absorbed from the stomach. There
is also absorption of acetylsalicylates from the intestines.
• Aspirin appears rapidly in all body tissues. It does cross the placenta
and appears in breast milk and it is moderately bound to plasma
proteins.
• Excretion is as salicylic acid and as compounds in the urine and
increases as the pH rises.
15
16. Overdose
• considered that the toxic dose is about
200mg/kg in adults and 100mg/kg in
children.
• The lethal dose of acetylsalicylic acid is
25-30 grams. Salicylate poisoning is
usually associated with plasma
concentrations > 300mg/L (2.5 mmol/L).
Plasma concentrations above 500mg/l in
adults and 300mg/l in children generally
cause severe toxicity.
16
18. Tramadol
• Tramadol (brand name: Ultram) is an
oral, opioid pain-relieving drug that is marketed
under a variety of of trade names – with Ultram
and Ultracet being the most widely prescribed
and recognized.
• Tramadol is most often prescribed to treat
moderate levels of pain including dental,
osteoporosis, and neuropathy in both acute and
chronic settings. It is also approved for treating
cancer pain in periods less than 3 months.
18
19. History of Tramadol
• Compared to other drugs and medications, tramadol is
relatively young. The drug was created by a German
drug company that specializes in treating pain in 1962.
The medication was tested for 15 years in Germany
before being approved and brought to the foreign
market in 1977 under the name Tramal. The drug was
a success for the company.
• Tramadol is widely prescribed around the world for pain
relief. However, it was not until 1995 that the drug
became available in the US. Now, the medication is
quite popular in America. 19
20. Tramadol is thought to be safe due to lower risk of tolerance, abuse, and
dependence, but it has lower clinical value than other opiates. The drug has
only about one-tenth of the pain-reducing qualities of morphine.
Tramadol stands apart from other opiates for 2 reasons:
1. Tramadol is a fully synthetic drug, which means that it is man-made and
does not occur in nature. This is in contrast to morphine and codeine – which
are natural opiates derived from the opium poppy.
2. Tramadol has an uncommon, dual-acting benefit. Tramadol works as an
opiate in the expected way to manage the perception of pain, but beyond that,
it allows increased availability of two other neurotransmitter chemicals in the
brain called norepinephrine and serotonin. Norepinephrine is noted for its ability
to improve concentration, and serotonin manages an array of functions
including sleep and mood. 20
21. Drug Abuse
• Even though the drug is thought to be relatively safe due to its low
potential for abuse, addiction to tramadol has been a growing problem in
the US and around the world. When the drug is abused, it has desired
effects similar to other opiates including:
• Feelings of euphoria.
• Feeling numb or detached from one’s body.
• Feeling lethargic and heavy.
• Feeling relaxed and calm.
21
22. Dosage
• Adults and children over 12 years
• Acute pain: Adults and children over age 12 years: 50-
100mg 3-4 times daily.
• Chronic pain: An initial dose of 50mg or 100mg is
followed by doses of 50mg or 100mg, every 4 to 6
hours, according to pain severity.
• A total daily dose of 400mg should not be exceeded.
• Older people
• > 75 years , drug dosage adjustment due to delayed
elimination
22
23. • Patients with renal impairment/renal dialysis
• Patients with hepatic impairment
• Paediatric population : Children under 12 years: Not recommended.
Special Warning : 1 in 8000 (Addiction or Drug dependency)
23
24. CYP2D6 Metabolism
• Tramadol is metabolised by the liver enzyme CYP2D6.
• If a patient has a deficiency or is completely lacking this enzyme an adequate
analgesic effect may not be obtained. Estimates indicate that up to 7% of the
Caucasian population may have this deficiency. However, if the patient is an
ultra-rapid metaboliser there is a risk of developing <side effects> of opioid
toxicity even at commonly prescribed doses.
• General symptoms of opioid toxicity include confusion, somnolence, shallow
breathing, small pupils, nausea, vomiting, constipation and lack of appetite.
• In severe cases this may include symptoms of circulatory and respiratory
depression, which may be life threatening and very rarely fatal.
24
25. Post-operative use in children
• There have been reports in the published literature that tramadol given post-
operatively in children after tonsillectomy and/or adenoidectomy for obstructive
sleep apnea, led to rare, but life-threatening adverse events.
• Extreme caution should be exercised when tramadol is administered to children
for post-operative pain relief and should be accompanied by close monitoring for
symptoms of opioid toxicity including respiratory depression.
Children with compromised respiratory function
• Tramadol is not recommended for use in children in whom respiratory function
might be compromised including neuromuscular disorders, severe cardiac or
respiratory conditions, upper respiratory or lung infections, multiple trauma or
extensive surgical procedures. <These factors may worsen symptoms of opioid
toxicity>. 25
26. Pregnancy
• Category C drug
• Tramadol - administered before
or during birth - does not affect
uterine contractility. In new-born
infants it may induce changes in
the respiratory rate which are
usually not clinically relevant.
• Chronic use during pregnancy
may lead to neonatal withdrawal
symptoms.
26
27. Pharmacokinetic properties
Absorption : More than 90% of tramadol is absorbed after oral administration.
The mean absolute bioavailability is approximately 70 %, irrespective of the
concomitant intake of food. The difference between absorbed and non-
metabolised available tramadol is probably due to the low first-pass effect. The
first-pass effect after oral administration is a maximum of 30 %.
Distribution : Tramadol has a high tissue affinity. It has a plasma protein
binding of about 20 %.
Tramadol passes the blood-brain and placental barriers. Very small amounts
of the substance and its O-desmethyl derivative are found in the breast-milk
(0.1 % and 0.02 % respectively of the applied dose).
27
28. Elimination
Elimination half-life t1/2,ß is approximately 6 h, irrespective of the mode of
administration. In patients above 75 years of age it may be prolonged by a
factor of approximately 1.4.
Biotransformation
The inhibition of one or both types of the isoenzymes CYP3A4 and CYP2D6
involved in the biotransformation of tramadol may affect the plasma
concentration of tramadol or its active metabolite.
Tramadol and its metabolites are almost completely excreted via the kidneys.
Cumulative urinary excretion is 90 % of the total radioactivity of the
administered dose. In cases of impaired hepatic and renal function the half-life
may be slightly prolonged.
28
29. Overdose
• Symptoms of overdosage are typical of other
opioid analgesics and include miosis, vomiting,
cardiovascular collapse, sedation and coma,
seizures and respiratory depression.
• Supportive measures such as maintaining the
patency of the airway and maintaining
cardiovascular function should be instituted;
naloxone should be used to reverse respiratory
depression; fits can be controlled with diazepam.
29
30. • In case of intoxication orally, gastrointestinal decontamination with
activated charcoal or by gastric lavage is only recommended within 2 hours
after tramadol intake.
• Gastrointestinal decontamination at a later time point may be useful in case
of intoxication with exceptionally large quantities.
• Tramadol is minimally eliminated by hemodialysis and hemofiltration.
Therefore treatment of acute intoxication with tramadol by hemodialysis or
hemofiltration is not recommended.
30
31. Ketorolac
• Ketorolac was developed in 1989 by Syntex Corp.
(now part of Roche).
• It was approved for medical use in the United
States in 1989.
• The eye-drop formulation was approved by the
FDA in 1992.
• An intranasal formulation was approved by the
FDA in 2010.
31
32. Therapeutic Indications
• Ketorolac Injection is indicated for the
short-term management of moderate to
severe acute post-operative pain.
• Treatment should only be initiated in
hospitals. The maximum duration of
treatment is 2 days.
32
33. Dose
Adults : The recommended initial dose of Ketorolac Injection is 10mg
followed by 10 to 30mg every four to six hours as required.
In the initial post-operative period, Ketorolac Injection may be given as often
as every two hours if needed.
The lowest effective dose should be given.
A total daily dose of 90mg for non-elderly and 60mg for the elderly, patients
with renal impairment and patients less than 50kg should not be exceeded.
The maximum duration of treatment should not exceed two days.
The dosage in patients under 50kg should be reduced.
33
34. Opioid analgesics (e.g. morphine, pethidine) may be used concomitantly,
and may be required for optimal analgesic effect in the early post-operative
period when pain is most severe.
Ketorolac does not interfere with opioid binding and does not exacerbate
opioid-related respiratory depression or sedation. When used in association
with Ketorolac Injection, the daily dose of opioid is usually less than that
normally required.
However, opioid side-effects should still be considered, especially in day-
case surgery.
34
35. Contraindications
• active peptic ulcer, or any history of gastrointestinal bleeding, ulceration or
perforation
• hypersensitivity to ketorolac trometamol or any of the excipients
• NSAIDS are contraindicated in patients who have previously shown
hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in
response to ibuprofen, aspirin or other non-steroidal anti-inflammatory drugs
(severe anaphylactic-like reactions have been observed in such patients).
• severe heart failure, hepatic failure and renal failure
• patients on anti-coagulants including warfarin and low dose heparin (2500 -
5000 units twelve hourly)
35
36. • Ketorolac inhibits platelet function and is, therefore, contraindicated in
patients with suspected or confirmed cerebrovascular bleeding, patients who
have had operations with a high risk of hemorrhage or incomplete
hemostasis and those at high risk of bleeding such as those with
hemorrhagic diatheses, including coagulation disorders.
• moderate or severe renal impairment (serum creatinine> 160 μmol/l) or in
patients at risk for renal failure due to volume depletion or dehydration
36
37. Drug Abuse and Dependence
• Ketorolac is devoid of addictive potential. No withdrawal symptoms
have been observed following abrupt discontinuation of ketorolac.
37
38. Fertility, pregnancy and lactation
• In view of the known effects of NSAIDs on the fetal cardiovascular
system (risk of closure of the ductus arteriosus) ketorolac is
contraindicated during pregnancy, labur or delivery.
• The safety of ketorolac during human pregnancy has not been
established.
• Ketorolac is contraindicated in labor and delivery because, through
its prostaglandin synthesis inhibitory effect it may adversely affect
fetal circulation and inhibit uterine contractions, thus increasing the
risk of uterine hemorrhage.
38
39. • Ketorolac and its metabolites have been shown to pass into the
foetus and milk of animals.
• Ketorolac has been detected in human milk at low concentrations
therefore ketorolac is contra-indicated in mothers who are breast-
feeding
39
40. Pharmacodynamics
• Ketorolac is a potent analgesic agent of the non-steroidal, anti-
inflammatory class (NSAID).
• It is not an opioid and has no known effects on opioid receptors. Its
mode of action is to inhibit the cyclo-oxygenase enzyme system and
hence prostaglandin synthesis and it demonstrates a minimal anti-
inflammatory effect at its analgesic dose.
40
41. Pharmacokinetics
Intramuscular
Following intramuscular administration, ketorolac was rapidly and
completely absorbed.
A mean peak plasma concentration of 2.2μg/ml occurred an average
of 50 minutes after a single 30mg dose.
Age, kidney and liver function affect terminal plasma half-life and
mean total clearance as outlined in the table below (estimated from a
single 30mg IM dose of ketorolac).
41
42. Intravenous
• Intravenous administration of a single 10mg dose of ketorolac resulted in a mean
peak plasma concentration of 2.4μg/ml at an average of 5.4 minutes after dosing.
The terminal plasma elimination half-life was 5.1 hours, average volume of
distribution 0.15 l/kg, and total plasma clearance 0.35ml/min/kg.
• The pharmacokinetics of ketorolac in man following single or multiple doses are
linear. Steady-state plasma levels are achieved after dosing every six hours for
one day. No changes in clearance occurred with chronic dosing. The primary
route of excretion of ketorolac and its metabolites is renal: 91.4% (mean) of a
given dose being found in the urine and 6.1% (mean) in the faeces.
• More than 99% of the ketorolac in plasma is protein-bound over a wide
concentration range.
42
43. Piroxicam
• It was originally brought to market by Pfizer
under the tradename Feldene in 1980,
became generic in 1992, and is marketed
worldwide under many brand names.
• FELDENE is indicated:
• For relief of the signs and symptoms
of osteoarthritis, rheumatoid arthritis,
ankylosing spondylitis.
43
44. Dose
• The maximum recommended daily dose is 20mg.
• Adults: Initially 20mg given as a single daily dose. The majority of patients
may be maintained on 20mg a day, a relatively small group of patients may
be maintained on 10mg daily.
• Children: Not recommended for children under 12 years of age.
• Elderly: There are no specific modifications required in the elderly, except
where hepatic, renal or cardiac function is impaired, in which case dosage
should be individually assessed.
44
45. Contraindications
• Hypersensitivity to the active substance
• History of previous serious allergic drug reaction of any type, especially
cutaneous reactions such as erythema multiforme, Stevens-Johnson syndrome,
toxic epidermal necrolysis.
• Patients with active peptic ulcer, inflammatory gastrointestinal disorder or
gastrointestinal bleeding.
• Piroxicam should not therefore be administered to patients in whom aspirin and
other NSAIDs induce the symptoms of angioneurotic oedema, asthma, rhinitis,
nasal polyps or urticaria.
45
46. Pharmacodynamic properties
• Piroxicam is a non-steroidal anti-inflammatory agent with analgesic and
antipyretic activity.
• Piroxicam inhibits prostaglandin (thromboxane) synthesis in the platelets,
rendering them less sticky.
• Like other NSAIDs, it acts as an uterotropic agent by inhibiting the synthesis of
prostaglandins in the uterus which are normally increased in amount in the
hours before parturition.
• Piroxicam also helps to promote salt and water retention by interfering with the
prostaglandin-induced inhibition of both chloride re-absorption and the action
of ADH.
46
47. • Prostaglandins, particularly E1 and E2, are synthesized by the gastric
mucosa and seem to promote integrity of that mucosa by stimulating the
secretion of cytoprotective mucus. Piroxicam, by inhibiting the synthesis of
these prostaglandins may lead to gastric erosions and ulceration.
• Absorption: Piroxicam is absorbed from the GI tract. Absorption is not
influenced by either food or antacids.
47
48. • Distribution: Peak plasma concentrations are reached 3-5 hours after
an oral dose. Piroxicam plasma concentrations do not appear to be
significantly influenced by concomitant aspirin, iron or antacids.
• In man it penetrates into the synovial fluid of patients with rheumatoid
arthritis, osteoarthritis and re-active synovitis, where mean
concentrations are approximately 40% of those in the plasma; it is also
demonstrable in synovial tissues.
• Pharmacokinetics do not appear to be age related, and renal function
has only a limited influence on the elimination of piroxicam, but plasma
concentrations are increased in patients with severe liver dysfunction.
48
49. • Biotransformation: It is metabolised in the liver by hydroxylation and
conjugation with glucuronic acid.
• Elimination: Excreted predominantly in the urine and smaller
amounts in the feces. Less than 5% of a dose is excreted
unchanged. Piroxicam is extensively bound to plasma proteins
(about 99%) and has a long plasma half-life of about 50 hours.
49
50. Corticosteroids
• Corticosteroids are a class of are a class of steroid hormones steroid
hormones that are produced in the that are produced in the adrenal cortex
adrenal cortex.
• immune response immune response and regulation of and regulation of
inflammation
• Glucocorticoids
• Mineralocorticoids
50
51. • Glucocorticoids such as such as cortisol control carbohydrate, fat
and protein metabolism and carbohydrate, fat and protein
metabolism and are anti-inflammatory by preventing are anti-
inflammatory by preventing phospholipid release, decreasing
release, decreasing eosinophil l action and a number of other
mechanisms.
• Mineralocorticoids such as such as aldosterone control electrolyte
and water levels, mainly by control electrolyte and water levels,
mainly by promoting sodium retention in the
51
53. Coopman Classification
• Group A : Hydrocortisone class hydrocortisone, prednisolone (short to
medium acting)
• Group B : Acetonide and related substances triamcinolone acetonide,
fluocionide
• Group C : Betamethasone type betamethasone, dexamethasone
• Group D : Esters
• Group D1 : Halogenated (less labile) betamethasone valproate,
halomethasone
• Group D2 : Labile prodrug esters prednicarbate
53
54. Indications
• Steroids are particularly useful as adjuvant therapy for metastatic bone
pain, neuropathic pain, and visceral pain.
• As adjuvant agents, corticosteroids can directly reduce pain, reduce pain
in concert with opioid use, allow for reduction of opioid dose, and have
beneficial symptomatic effects outside of pain relief.
• Glucocorticoids reduce pain by inhibiting prostaglandin synthesis, which
leads to inflammation, and reducing vascular permeability that results in
tissue edema. Glucocorticoids are also lipophilic molecules that can cross
the blood-brain barrier.
54
55. • Research has shown that steroid receptors are found in the central
and peripheral nervous systems and are responsible for growth,
differentiation, development, and plasticity of neurons.
• Corticosteroids have been shown to reduce spontaneous discharge
in an injured nerve, which reduces neuropathic pain.
• Dexamethasone is the most commonly prescribed corticosteroid for
pain, but prednisone or prednisolone can also be used.
55
57. Discontinue use …
• Withdrawal : low doses of corticosteroids can suppress the hypothalamic-
pituitary-adrenal axis in the long term.
• Taper the dose ? (The most appropriate method of tapering has not been
determined in the literature.)
• If a stressful event, such as a serious infection or surgery, occurs within 1 week
after discontinuation of steroid therapy, stress-dose steroid should be provided.
• Addisonian crisis is a life-threatening complication that can cause confusion,
coma, cardiovascular shock, and even death. Notably in palliative patients,
corticosteroid withdrawal is known to exacerbate terminal restlessness.
Melissa Vyvey Steroids as pain relief adjuvants Can Fam Physician. 2010 Dec; 56(12): 1295–
1297.
57
58. Anesthetic Nerve Block
• Nerve blocks are used for pain treatment and management.
• Therapeutic nerve blocks are used to treat painful conditions. Such
nerve blocks contain local anesthetic that can be used to control
acute pain.
• Diagnostic nerve blocks are used to determine sources of pain.
These blocks typically contain an anesthetic with a known duration of
relief.
58
59. • Prognostic nerve blocks predict the outcomes of given treatments.
For example, a nerve block may be performed to determine if more
permanent treatments (such as surgery) would be successful
in treating pain.
• Preemptive nerve blocks are meant to prevent subsequent pain from
a procedure that can cause problems including phantom limb pain.
• Nerve blocks can be used, in some cases, to avoid surgery.
59
61. Neurological Anesthesia
• Neurosurgical anesthesia, or neuroanesthesia, focuses on patients
undergoing brain or spinal cord surgery. This type of surgery is called
neurosurgery.
• There are many similarities between neurosurgical and general
anesthesia.
• Neuroanesthetic management, however, is different because it can
have a major effect on the brain and spinal cord through the control of
blood flow, blood pressure and energy consumption of these organs.
61
Felix G. Freund Neurological Anesthesia JAMA. 1965;193(5)
63. Misuse of Analgesics
• In a research conducted among 295 clients of French pharmacies, it
has been stated that the problem of misusing OTC pain relievers
may concern 6.8–17% of users.
• The risk of abuse was higher in the case of paracetamol users.
• In another study conducted among adults of Wroclaw, Poland, the
“heavy users” more regularly bought medicines with ibuprofen –
57%.
• paracetamol misused by almost 53.8% of the participants, which
shows the highest and the next in line was ibuprofen (30.8%).
63
Dass and Khandelwal Misuse of prescription analgesics and predictors of
analgesic misuse among urban young adults of Sikkim, India Indian J. Pharm.
Biol. Res., 2017; 5(2):18-23
64. Conclusions
• Nature of problem along with consideration of risk factors in an
individual patient directs the initial selection
• Drugs differ quantitatively in producing different side effects
• Analgesics are definitively useful in reducing pain and improving the
quality of life, but they have their own spectrum of adverse effects.
• Large inter individual differences. No single drug is superior to all
others for every patient. Choice of drug is inescapably empirical.
64
65. • Analgesic. 2002. eTG complete [Internet]. Melbourne:
Therapeutic Guidelines Ltd; 2006 Jan. Accessed 2006 April 9.
• Fischer HBJ & Pinnock CA, 2004, ‘Fundamentals of Regional
Anaesthesia’, Cambridge University Press, Worcestershire
• Rice S. A. et.al. 2003, ‘Clinical Pain Management: Practical
Applications and Procedures’, Oxford University Press, London.
• Felix G. Freund Neurological Anesthesia JAMA. 1965;193(5)
• KD Tripathi
65
66. • Bertolini et al Current Topics in Medicinal Chemistry, 2007, Vol. 7, No. 3
• Vane, J.R.; Botting, R. Mechanism of action of nonsteroidal antiinflammatory drugs.
Am. J. Med. 1998, 104, S 2- S 8.
• Vane, J.R.; Botting, R.M. Anti-inflammatory drugs and their mechanism of action.
Inflamm. Res. 1988, 47, S78-S87.
• Martel-Pelletier, Lajeunesse, Reboul, et al Dual inhibitors of 5-LOX and COX and
NSAIDs Ann Rheum Dis 2003;62:501–509
• United Nations Office on Drugs and Crime, Government of India Ministry of Social
Justice and Empowerment. Injecting drug use and HIV in India: an emerging
concern. 2004.
• MedhiGK,MahantaJ,AdhikaryR,AkoijamBS,LiegiseB,SarathyK,etal.Spatial
distribution and characteristics of injecting drug users (IDU) in five north eastern
states of India. BMC Public Health 2011;11:64.
• LaranceB,AmbekarA,AzimT,MurthyP,PandaS,DegenhardtL,etal.Theavailability,
diversionandinjectionofpharmaceuticalopioidsinSouthAsia.DrugAlcoholRev 66
69. Why Cox-2 inhibitors are banned
• COX-2 inhibitors may decrease vascular prostacyclin (PGI 2) production
and may affect the balance between prothrombotic and antithrombotic
eicosanoids and may tip the balance in favour of prothrombotic
eicosanoids (thromboxane A2) and lead to increased cardiovascular
thrombotic events.
• COX-2 inhibitors have also been shown to increase blood pressure (BP).
Rise in BP after NSAID use may be due to alterations in the renin
angiotensin pathway, sodium and water retention by the kidney due to
inhibition of vasodilating PG’s and production of various vasoconstricting
factors, including endothelin-1 and P450-mediated metabolites of
arachidonic acid 69
70. • Locally synthesized PGI2 , PGE2 and PGD2 cause vasodilatation,
decreased vascular resistance and enhanced perfusion with
redistribution of blood flow from the renal cortex to nephrons in the
juxta-medullary region.
• Moreover, PGE2 and PGF2µ cause diuresis by inhibiting the transport
of Na and Cl in the thick ascending limb of loop of Henle and collecting
ducts.
• Nephrotoxicity with NSAIDs includes acute tubular necrosis, acute
tubulointerstitial nephritis, glomerulonephritis, renal papillary necrosis,
salt and water retention, chronic renal failure, hypertension,
hyperkalemia and hypoaldosteronism.
• Macular eruptions, urticaria, pseudo porphyria and erythema
multiforme have also been reported with COX2 inhibitors 70
71. • However, presently the choice of COX-2 selective inhibitors for a
particular patient should be based upon their relative efficacy,
toxicity, concomitant drug use, concurrent disease states, hepatic
and renal function and relative cost.
71
72. Anaphylactic vs Anaphylactoid reaction
• The term “immunologic anaphylaxis” is used to denote IgE-medicated,
possibly IgG- mediated (described in animals), and immune complex
and/or complement-mediated reactions.
• “Nonimmunologic anaphylaxis” is caused by agents or events that induce
sudden, massive mast cell or basophil degranulation in the absence of
immunoglobulins.
• These reactions may be due to activation of complement without immune
complex formation, e.g., medications containing Cremophor EL; direct
mast cell and basophil activation resulting in histamine release, e.g.,
vancomycin; and opiates; or other mechanisms. e.g., activation of the
kallikrein-kinin pathway; and perhaps much more yet to be defined. “ 72
73. 1. Simons FE, Ardusso LR, Bilo MB, Cardona V, Ebisawa M, El-Gamal YM, et al. International consensus
on (ICON) anaphylaxis. World Allergy Organ J. 2014;7(1):9
2. Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. Revised nomenclature for
allergy for global use: Report of the Nomenclature Review Committee of the World Allergy
Organization, October 2003. J Allergy Clin Immunol. 2004;113(5):832-6
• Nonimmunologic anaphylaxis” is felt to involve reactions to
NSAIDS, local anesthetics, monoclonal antibodies, and
chemotherapeutic agents.
• The newer terminology, “nonimmunologic anaphylaxis” would
replace the older terminology which described these reactions as
“anaphylactoid”. One purported reason for the change in
terminology was to reinforce the risk and potential fatality of all
types of anaphylaxis, regardless of the mechanism of action, as
many patients and even professionals associated “anaphylactoid”
with a less serious condition.
73
74. Drugs (NSAIDs) not recommended in
Alcoholics
• Analgesic consumption poses special risks for regular users of alcohol.
Among the numerous adverse health effects are acetaminophen toxicity
and gastrointestinal (GI) bleeding associated with nonsteroidal anti-
inflammatory drug (NSAID) use.
• An alcohol-acetaminophen hypothesis contends that alcohol enhances
acetaminophen toxicity. Because 22% of adults use acetaminophen each
week and 5% to 10% of the population is alcoholic, the healthcare
implications of serious adverse interactions are considerable.
• However, such interactions are rare when NSAID doses remain in the
therapeutic range.
74
75. Dart RC The use and effect of analgesics in patients who regularly drink alcohol. Am J
Manag Care. 2001 Dec;7(19 Suppl):S597-601.
Alcohol and NSAIDs Increase Risk for Upper GI Bleeding Am Fam
Physician. 2000 May 1;61(9):2863-2864.
• Although clinical studies fail to support anecdotal case reports of liver
damage associated with consumption of therapeutic doses of
acetaminophen by alcohol users, such reports are probably inaccurate
because of the uncritical acceptance of patient history by the clinician and
a lack of well-designed prospective trials. Over-the-counter (OTC)
NSAIDs, such as aspirin, naproxen, and ketoprofen, are other analgesic
options, but each carries the risk of GI bleeding.
• Because the risk of GI bleeding or ulceration may be higher in alcoholic
patients, the optimal strategy in prescribing pain relievers to those who
consume alcohol is to use 1 drug at a time and to clearly communicate its
generic name
75
76. Drugs taking both the LT and Cox pathways
Various classes of dual COX/5-LOX inhibitors are described in the
scientific literature:
1) modified NSAIDs (indomethacin derivatives, fenamate derivatives,
tepoxaline, tepoxalin-atreleuton derivatives, celecoxib derivatives)
2) di-tert-butylphenols (tebufelone, DHDMBF, PGV-20229, darbufelone,
S-2474, etc.)
3) thiophene derivatives (RWJ-63556)
4) pyrazoline derivatives (phenidone)
5) pyrrolizine derivatives (licofelone, etc.)
76
77. K+ / Na+ in Diclofenac
• Oral formulations of diclofenac are formulated as either the sodium or
potassium salt. The sodium salt is found in the original prescription-only
formulation of Voltarol (enteric coated) 25mg and 50mg tablets and its
generic equivalents that account for most oral diclofenac preparations
currently used in the UK.
• The potassium salt is contained in POM Voltarol Rapid 25mg and 50mg
products and their generic equivalents; as well as in the over-the-counter
products such as Voltarol Joint Pain, Voltarol Pain-eze, and Actavis’s
Double Action Pain Relief tablets, which are also marketed as Boots
Diclofenac Potassium Tablets.
77
78. • The currently available OTC oral diclofenac preparations, which
contain the potassium salt, have a faster onset of action than the
standard diclofenac enteric-coated tablets containing the sodium
salt.
• The potassium content of OTC diclofenac potassium is low.
• Patients watching their potassium intake may have advanced renal
disease or be taking angiotensin-converting enzyme inhibitors,
angiotensin receptors blockers or potassium sparing diuretics. Such
patients should avoid oral non-steroidal anti-inflammatory drugs.Question from practice: diclofenac salts: potassium or sodium? Thomas A The Pharmaceutical
Journal 1 AUG 2011 78
