Analgesics

Dr. apt. Adriani Susanty, M.Farm

SEKOLAH TINGGI ILMU FARMASI RIAU
FARMAKOLOGI- 2021
 *Session : 1
1. Introduction 8. NSAIDs
2. Definitions 9. Paracetamol
3. Pain 10. Ibuprofen
4. Classifications
11. Diclofenac
5. Opioids :
12. Conclusion
Morphine Reference
6. Nonopioi
7. Cox
ds
2
*Session : 2 1.

2.
Aspirin
Tramadol
3. Ketorolac
4. Piroxicam
5. Corticosteroids
6. Neurological analgesia
7. Anesthetic nerve
blockade
8. Conclusion
9. References

3
 *Introduction
• Nyeri adalah bentuk pengalaman sensorik dan emosional
yang tidak menyenangkan yang berhubungan dengan
kerusakan atau cenderung akan terjadi kerusakan
jaringan.
• Nyeri merupakan kondisi yang umum dan memiliki

pengaruh yang signifikan terhadap kualitas hidup. Nyeri

adalah alasan utama saat ini dalam pelayanan kesehatan
karena nyeri merupakan keluhan yang paling sering
dikeluhkan pasien sehingga datang ke petugas medis.
• Profesional kesehatan harus memahami obat analgesik
5

untuk memastikan pengobatan nyeri yang efisien dan

 *Definisi
Analgesik: Obat yang secara selektif meredakan nyeri
dengan mekanisme kerja pada SSP atau mekanisme kerja
pada syaraf perifer, tanpa mengubah kesadaran secara
signifikan.

5
• Pain : The International Association for the Study of Pain (IASP)
defined pain as “an unpleasant sensory and emotional
experience associated with actual or potential tissue damage or
described in terms of such damage”.
- Harold Merskey (1964)

- IASP 1979

• Algesia : (from Greek work algesis) sensitivity to the pain.

6
Nyeri dapat digolongkan dalam berbagai
cara:

1. Menurut asalnya
2. Jenis
3. Penyebab
4. Derajat nyeri

7
 *Berdasarkan asalnya

1. Nyeri somatik =
nyeri yang berasal dari kulit (nyeri superfisial), nyeri yang
tajam dam umumnya dapat dilokalisasi
2. Nyeri viseral
Nyeri yang berasal dari organ dalam/internal (terdapat di
dada: jantung, pembuluh darah besar, limfe node, sistem
respirasi, abdomen: sistem gastrointestinal, struktur urologi,
sistem reproduksi dan pelvic region (daerah panggul), nyeri yang
tumpul dan sukar dilokalisasi dan bisa menyebar ke tempat lain.
 *Pain
Nyeri nosiseptif
• Acute • Somatic
Neuropatik • Chronic • Visceral
Psikologis
Idiopatik
Campuran

9
 *Persyarafan Nyeri
* Saraf vagus (saraf yang berfungsi untuk pengontrol otot dan
kelenjar di organ dalam)
* Simpatis
* Parasimpatis (jantung, paru, esophagus, lambung, usus halus,
kolon proksimal, liver, kandung empedu, pankreas, ginjal,
ureter, kolon, rectum, kandung kemih, anus dan genetalia)
 *Analgesics
1. Opioids
2. Nonopioids and NSAIDs
3. Corticosteroids
4. Neurological analgesia
5. Anesthetic nerve blockade

11
 *Classifications
• Analgesics can be divided into 2 groups:
A. Opioids / narcotic / morphine like analgesics.
B. Nonopioids / non-narcotic / antipyretic / aspirin like
analgesics or nonsteroidal anti-inflammatory drugs.
(NSAIDs).

12
*OPIOIDS
 *Brief History
• Obtained from poppy { papaver somniferous } capsule called
“ opium ”, known from earliest times.

• Mentioned in Eber’s papyrus[1500BC] and in writings

of theophrastus [300BC] and Galen [ 2nd century AD ]

• Serturner ,a pharmacist isolated the active principle of opium

in 1806 and named it ‘ morphine ’ after a Greek god of dreams
Morpheus . 14
15
 *Klasifikasi Analgeti opioid
berdasarkan sumbernya
•Natural/alami • Synthetic opioids
A. Opium alkaloids A. Pethidine
B. Morphine B. Fentanyl
C. & Codeine. C. Methadone
•Semi synthetic opiates D. Dextropropoxyphene
A. Diacetylmorphine E. Ethoheptazine
B. oxymorphone F. Tramadol
C. Pholcodeine
16
• Chemically • Based on receptor
occupation
A. Phenanthrene group:
Morphine A. Agonists : Morphin
B. Benzolisoquino line group B. Antagonists: Naloxone
: Papaverin
C. Mixed agonist antagonist
: Nalorphin
classification of the classical opioid receptors over time.
Reseptor

Ð (delta)

K (kappa)

Μ (mu)
• In clinical practice the stimulation of the differing opioid receptors produces a
range of effects, which are often dependent upon the location of the receptor,
along with analgesia.
• Agonists binding to MOP receptors may cause analgesia, but also sedation,
respiratory depression, bradycardia, nausea and vomiting and a reduction in
gastric motility.
• Activation of DOP receptors can cause spinal and supraspinal analgesia
and reduce gastric motility, while KOP receptor stimulation may produce
spinal analgesia, diuresis and dysphoria.

• Spinally, NOP has been shown to produce analgesia and hyperalgesia, dependent
upon the administered concentration, and allodynia. 17
 *Morphi
ne
• Morphine, the main component of opium,
is perhaps the oldest drug known to man.
• Pure morphine was isolated in 1803 by
Sertürner (Schmitz 1985), and its structure
was elucidated 120 years later.
• In January 2017, morphine was
approved by FDA for the treatment of
chronic pain.
18
 *Pharmacodynami
•
cs
Morphine is a narcotic pain management agent indicated for the relief
of pain in patients who require opioid analgesics for more than a few
days.
• Morphine interacts predominantly with the opioid mu-receptor.
• These mu-binding sites are discretely distributed in the human
brain, with high densities in the posterior amygdala, hypothalamus,
thalamus, nucleus caudatus, putamen, and certain cortical areas.
• They are also found on the terminal axons of primary afferents
within laminae I and II (substantia gelatinosa) of the spinal cord and
in the nucleus of the trigeminal nerve.
spinal 19
• In clinical settings, morphine exerts its principal pharmacological effect
on the central nervous system and gastrointestinal tract.

• Its primary actions of therapeutic value are analgesia and sedation.

Morphine appears to increase the patient's tolerance for pain and to
decrease discomfort, although the presence of the pain itself may
still be recognized.

• In addition to analgesia, alterations in mood, euphoria and dysphoria,

and drowsiness commonly occur. Opioids also produce respiratory
depression by direct action on brain stem respiratory centers. 20
 *Mechanism of Action
• The precise mechanism of the analgesic action of morphine is
unknown. However, specific CNS opiate receptors have been
identified and likely play a role in the expression of analgesic effects.

• Morphine first acts on the mu-opioid receptors.

• The mechanism of respiratory depression involves a reduction in

the responsiveness of the brain stem respiratory centers to
increases in carbon dioxide tension and to electrical stimulation.
22
• It has been shown that morphine binds to and inhibits GABA
inhibitory interneurons.

• These interneurons normally inhibit the descending

pain inhibition pathway.

• So, without the inhibitory signals, pain modulation can proceed

downstream.
23
• Absorption : bioavailability is 30 %
• Volume of distribution : 1-6 L / kg
• Protein binding : 30 – 40 %

• Metabolism : Primarily hepatic (90%), converted to dihydromorphinone

and normorphine. Also converted to morphine-3-glucuronide (M3G) and
morphine-6-glucuronide. Virtually all morphine is converted to glucuronide
metabolites; only a small fraction (less than 5%) of absorbed morphine is
demethylated.
 Morphine > morphine-6-glucuronide
 Morphine > morphine-3-glucuronide 23


• Route of elimination : A small amount of glucuronide conjugates are
excreted in bile, with minor enterohepatic recycling. Seven to 10%
of administered morphine sulfate is excreted in the feces.

• Half life : 2-4 hrs

• Clearance : 20 – 30 mL/min/kg [Adult]

1852 +/- 116 mL/min [Chinese]
1495 +/- 80 mL/min [Caucasian]

25
• Toxicity : LD50 = 461 mg/kg (rat, oral), 600 mg/kg (mouse,
oral). Human lethal dose by ingestion is 120-250 mg of
morphine sulfate. Symptoms of overdose include cold, clammy
skin, flaccid muscles, fluid in the lungs, lowered blood
pressure, "pinpoint" or dilated pupils, sleepiness leading to
stupor and coma, slowed breathing, and slow pulse rate.

26
 *Side Effect :
• Drug dependence & Addiction

27
 NONOPIOID
ANALGESICS
AND NSAIDS
 *Cox (Cyclooxygenase)
• Cyclooxygenase (COX), officially known as prostaglandin-
endoperoxide synthase (PTGS), is an enzyme (specifically, a family
of isozymes, EC 1.14.99.1) that is responsible for formation of prostanoids,
including thromboxane and prostaglandins such as prostacyclin,
from arachidonic acid.

• The names "prostaglandin synthase (PHS)", "prostaglandin synthetase

(PHS)", and "prostaglandin-endoperoxide synthetase (PES)" are older terms
still sometimes used to refer to COX.
29
 *Cox 1 vs Cox 2
• In the 1990s it was discovered that there are two forms of the
cyclooxygenase enzyme: COX-1 and COX-2.
• The latter is the one responsible for inflammation. COX-1 is known to be
present in most of the tissues in our bodies. In the gastrointestinal tract,
COX-1 maintains the normal lining of the stomach and intestines,
protecting the stomach from the digestive juices.
• The enzyme is also involved in kidney and platelet function.

30
• COX-2, on the other hand, is primarily found at sites of
inflammation.
• Both COX-1 and COX-2 produce the prostaglandins that
contribute to pain, fever, and inflammation, but since COX-1's
primary role is to protect the stomach and intestines and
contribute to blood clotting, using drugs that inhibit it can lead to
unwanted side effects.

31
Classification :Analgesic and Anti inflammatory
NON-SELECTIVE COX INHIBITORS
1. Salicylates – Aspirin, Salicylamide, Benorylate, Diflunisal.
2. Pyrazolone derivatives – Phenyl butazone, Oxyphenyl-butazone.
3.Propionic acid derivatives – Ibuprofen, Naproxen, Ketoprofen,
Fenoprofen, Flurbiprofen, Oxaprozin.
4. Indole derivatives – Indomethacin, Sulindac.
5. Anthranilic acid derivative – Mephanimic acid, Flufenamic acid.
6. Aryl acetic acid derivative – Diclofenac, Tolmetin.
7. Oxicam derivative – Piroxicam, Tenoxicam.
34
8. Pyrrolo pyrrole derivatives – Ketorolac
B. Preferential COX-2 inhibitors
Nimesulide
Meloxicam
Nabumetone C. Selective COX-2
inhibitors
Valdecoxib
Celecoxib
Rofecoxi

35
 D. Analgesics with poor Anti- inflammatory action
1.Paraminophenol derivative - Paracetamol (Acetaminophen)
2. Pyrazolone derivative - Metamizol, Propiphenazone
3. Benzoxazocine derivative - Nefopam

36
 *Chemical Classification
of the NSAIDs

37
 *Mechanism of actions of NSAIDs
 cox 1 and cox 2 pathway
Lipo-oxygenase pathway
Interferencewith G-protein-mediated signal transduction by NSAIDs
may form the basis of an analgesic mechanism unrelated to inhibition
of prostaglandin synthesis.
Central action may be mediated by endogenous opioid peptides
or blockade of the release of serotonin (5-hydroxytryptamine; 5-
HT).
Mechanism involving inhibition of excitatory amino acids of N-methyl-D-
38
aspartate receptor activation has also been proposed
 *Pharmacological actions
 CNS – Depressant and stimulant action
 CVS – Causes vasodilation
 GIT – Constipation
Smoothmuscles – Increased ureter contraction,
Bronchoconstriction
 ANS – Mild hyperglycemia

39
 *Efek samping
A. Saluran pencernaan: Gangguan epigastrik, nausea,
vomiting, erosive gastritis, peptic ulcer,
B. Reaksi alergi: kemerahan pada kulit dan photo sensitivity
C. Hemolisis
D. Nefrotoksisitas

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 *Fungsi NSAIDs
1. Menurunkan suhu tinggi saat demam (antipiretik)
2. Mengurangi peradangan (antiinflamasi)
3. Mengurangi rasa sakit (analgetik)
4. NSAID memiliki sifat anti-pembekuan darah.
Aspirin, membantu mencegah penyumbatan arteri
yang dapat menyebabkan serangan jantung atau
stroke.

42
*Indikasi NSAIDs
• Acute or chronic conditions where pain and inflammation
are present.
- Rossi 2006
• Rheumatoid arthritis (radang sendi)
• Osteoarthritis
• Inflammatory arthropathies (e.g. ankylosing spondylitis, )
• Acute gout
• Dysmenorrhoea
43
• Metastatic bone pain
• Headache and migraine
• Postoperative pain
• Mild-to-moderate pain due to inflammation and tissue injury
• Pyrexia
• Renal colic
• They are also given to just born infants whose ductus
arteriosus is not closed within 24 hours of birth
44
 *Contraindications of
• Ulcer
NSAIDs
• Chronic allergic disorders
• Asthma • Chronic liver disease
• Patient with nasal polyp • Renal failure
• Diabetes • Salicylate allergy
• Gout • Breast feeding mothers
• Influenza (Reye’s syndrome) • Pregnancy
• Hypo coagulation state
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 *Paracetamol (500 mg)
first synthesized in 1878 by Morse and introduced for medical usage in
1883. However, due to misinterpretation of its safety profile, it enjoyed
only limited use until the 1950s, when the chemically similar, and up until
then preferred analgesic, phenacetin was withdrawn because of renal
toxicity.

• Paracetamol is now probably the most commonly used drug worldwide,

available over the counter, used in almost all ages, and forming Step 1 of
the WHO analgesic ladder.
Twycross et al. Therapeutic Reviews: Acetaminophen Journal of Pain and
Symptom Management Vol. 46 No. 5 November 2013 46
• First-line treatment for pain and pyrexia, it plays an important
role in multimodal analgesia, and is considered to possess a
generally excellent safety profile except in significant overdose,
with few drug interactions.

• Other constituents : Maize Starch, Pre gelatinised Maize Starch,

Stearic Acid

47
• To reduce the chance of unintentional overdose, the United
States Food and Drug Administration has recommended
that:
• the amount of acetaminophen in a prescription tablet,
capsule, or other dosage unit is limited to a maximum of 325
mg by the end of 2013
• the maximum single dose is lowered to 650 mg
• a boxed warning is added highlighting the potential for
severe liver injury
• patients should not exceed a total
48
daily dose of 4 g.
 *Mechanism of action
• It is surprising that after more than 100 years, the exact mechanism of
action of paracetamol remains to be determined. There is evidence for a
number of central mechanisms, including effects on prostaglandin
production, and on serotonergic, opioid, nitric oxide (NO), and cannabinoid
pathways, and it is likely that a combination of interrelated pathways are in
fact involved.

Chhaya C Sharma, Vivek Mehta Paracetamol: mechanisms and updates

Continuing Education in Anaesthesia Critical Care & Pain, Volume 14, Issue 4, 1
August49
2014, Pages 153–158, https://doi.org/10.1093/bjaceaccp/mkt049
 *Dose
• The Medicines and Healthcare products Regulatory Agency
(MHRA) licensed dose of paracetamol is the same for all routes of
administration in adults over 50 kg (i.e. 1 g up to four times a day),
with a minimum of 4 h between each administration (6 h for those
with renal impairment, i.e. creatinine clearance ≤30 ml min−1).

• Adults including the elderly and children over 16 years: One to two
tablets every 4-6 hours as required, to a maximum of 8 tablets daily
in divided doses.
50
• Children 10-15 years: One tablet every 4-6 hours as
necessary to a maximum of 4 doses in 24 hours.
• Children under 10 years: Not recommended for children
under 10 years of age. Alternative presentations of
paracetamol are recommended for paediatric usage in order
to obtain suitable doses of less than 500mg.

51
52
 *Peripartum drug handling
• Paracetamol is safe for use in pregnancy and lactation, with only a
negligible amount of the drug reaching breast milk. Interestingly, the
total clearance of paracetamol has been demonstrated to be higher in
women at delivery (including by Caesarean section) compared with
10–15 weeks postpartum, which itself was significantly lower than in
the normal healthy volunteer population data.
• The increased total paracetamol clearance at delivery is attributed to a
disproportionate increase in glucuronidation clearance and a
proportional increase in both its oxidation clearance and of unchanged
paracetamol. 53
 *Pharmacokinetics
Absorption
• Paracetamol is readily absorbed from the gastrointestinal tract.
Distribution
• Peak plasma concentrations occur about 10 to 60 minutes after
oral doses. Paracetamol is distributed into most body tissues. It
crosses the placenta and is present in breast milk. Plasma-protein
binding is negligible at usual therapeutic concentrations but
increases with increasing concentrations.

54
 Biotransformation
• It is metabolised in the liver. A minor hydroxylated metabolite
which is usually produced in very small amounts by mixed-
function oxidases in the liver and which is usually detoxified
by conjugation with liver glutathione may accumulate
following paracetamol overdosage and cause tissue damage.
Elimination
• It is excreted in the urine, mainly as the glucuronide and sulfate
conjugates. The elimination half-life varies from about 1 to 4
hours.
55
 *Drug interactions
•Anticoagulants - the effect of warfarin and other coumarins may
be enhanced by prolonged regular use of paracetamol with
increased risk of bleeding. Occasional doses have no significant
effect.
•Metoclopramide – may increase speed of absorption of
paracetamol.
•Domperidone – may increase speed of absorption of
paracetamol.
•Colestyramine – may reduce absorption if given within one hour
of paracetamol.
56

• Imatinib - restriction or avoidance of concomitant regular

 *Overdose
Liver damage is possible in adults who have taken 10g or more of
Paracetamol. Ingestion of 5g or more of Paracetamol may lead to
liver damage if the patient has risk factors (see below).
Risk Factors: If the patient
a, Is on long term treatment with carbamazepine, phenobarbital,
phenytoin, primidone, rifampicin, St John's Wort or other drugs than
induce liver enzymes.
B, Regularly consumes ethanol in excess of recommended
amounts.
 *Symptoms :
• Symptoms of Paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting,
anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after
ingestion.
• Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe
poisioning, hepatic failure may progress to encephalopathy, haemorrhage,
hypoglycaemia, cerebral oedema, and death.
• Acute renal failure with acute tubular necrosis, strongly suggested by loin pain,
haematuria and proteinuria, may develop even in the

absence of severe liver damage. Cardiac arrhythmias and pancreatitis

have been reported.
58
 *Management
 activated charcoal
 N- acetyl cysteine
If no vomiting : oral methionine

59
 * Novel uses
• When administered before induction of anaesthesia, 1 g i.v. paracetamol was
found to be equally successful to ketamine (0.5 mg kg−1 bolus before
induction, followed by 5 µg kg−1 min−1) in preventing remifentanil-induced
hyperalgesia, with the added advantage of reduced time to extubation and
full anaesthetic recovery.

• During i.v. regional anaesthesia, adding paracetamol to the injected lidocaine

was shown to improve the overall quality of the block. Onset of motor block
was sooner, tourniquet pain was reduced, and recovery of motor and sensory
block was delayed, resulting in lower intraoperative pain scores and total
systemic analgesic requirements. In view of the overall consensus that
paracetamol’s actions are centrally mediated, an analgesic benefit con6f0erred
from its addition to a peripherally sequestered pool of drug is a surprising
* Ibuprofen
 *Composition
Lactose monohydrate
:
•

• Potato Starch
• Hypromellose
• Sodium starch glycolate Type A
• Colloidal Anhydrous Silica
• Magnesium Stearate
• Sucrose
• Talc
• Titanium Dioxide (E171)
• Maize Starch
• Pregelatinised Starch 62
 *Therapeutic indications
Adults, elderly and Children over 12 years :
Rheumatic or muscular pain, backache, neuralgia, migraine,
headache, dental pain, dysmenorrhoea, feverishness,
symptoms of colds and influenza.

Children under 12 years of age: Not recommended

63
• Ibuprofen is rapidly absorbed following administration and is rapidly
distributed throughout the whole body. The excretion is rapid and
complete via the kidneys.

• Maximum plasma concentrations are reached 45 minutes after

ingestion if taken on an empty stomach. When taken with food, peak
levels are observed after 1 to 2 hours. These times may vary with
different dosage forms.

• The half-life of Ibuprofen is approximately 2 hours.

64
• In limited studies Ibuprofen appears in the breast milk in very
low concentrations.

• Ibuprofen is metabolised in the liver to two inactive metabolites

and these, together with unchanged ibuprofen, are excreted
by the kidney either as such or as conjugates. Excretion by
the kidney is both rapid and complete.

• Ibuprofen is extensively bound to plasma proteins.

65
 *Dosage
• For oral administration and short term use only :
• Undesirable effects may be minimized by using the lowest effective
dose for the shortest duration necessary to control symptoms (see
section 4.4).
• Adults, the elderly and children over 12 years :
• The minimum effective dose should be used for the shortest time necessary
to relieve the symptoms. The patient should consult a doctor if symptoms
persist or worsen, or if Ibuprofen tablets are required for more than 10 days.
66

• 200mg – 400mg, to be taken up to three times a day as required.

• Leave at least four hours between doses and do not take more
than 1200mg in any 24-hours period.
• If in adolescents (age range: ≥ 12 years to < 18 years) this
medicinal product is required for more than 3 days, or if
symptoms worsen a doctor should be consulted.
• Children under 12 years of age: Not recommended.

67
 *Contraindications :
• Patients who have previously shown hypersensitivity reactions (e.g.
asthma, rhinitis, angioedema or urticaria) in response to aspirin or
other non-steroidal anti-inflammatory drugs.
• Active or history of recurrent peptic ulcer/haemorrhage (two or more
distinct episodes of proven ulceration or bleeding).
• History of gastrointestinal bleeding or perforation, related to previous
NSAIDs therapy.

68
• Ibuprofen should not be given to patients with conditions
involving an increased tendency to bleeding
• Severe hepatic failure, renal failure or severe heart failure
(NYHA Class IV)
• Last trimester of pregnancy

69
 *Special Precautions
• :
Patients with rare hereditary problems of galactose intolerance, the
Lapp lactase deficiency or glucose-galactose malabsorption should not
take this medicine.
• As with other NSAIDs, ibuprofen may mask the signs of infection.
• The use of Ibuprofen with concomitant NSAIDs, including
cyclooxygenase-2 selective inhibitors, should be avoided due to
the increased risk of ulceration or bleeding

• Gastrointestinal bleeding, ulceration and perforation

70
 * SLE and mixed connective tissue
disease
• an increased risk of aseptic meningitis
Dermatological effects
• Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-
Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely
in association with the use of NSAIDs. Patients appear to be at highest risk of
these reactions early in the course of therapy, the onset of the reaction occurring
within the first month of treatment in the majority of cases. Ibuprofen should be
discontinued at the first appearance of skin rash, mucosal lesions, or any other sign
of hypersensitivity.
Impaired female fertility
• There is limited evidence that drugs which inhibit cyclo-oxygenase/ prostaglandin
synthesis may cause impairment of female fertility by an effect on ovulation. 71This is
reversible upon withdrawal of treatment.
 *Drug Interactions
Ibuprofen should be avoided in combination with:
Acetylsalicylic acid:
• Concomitant administration of ibuprofen and acetylsalicylic acid is not
generally recommended because of the potential of increased adverse
effects.
• Other analgesics and cyclooxygenase-2 selective inhibitors: Avoid
concomitant use of two or more NSAIDs, including Cox-2 inhibitors, as this
may increase the risk of adverse effects.
• Anticoagulants: NSAIDS may enhance the effects of anti-coagulants,72
such as warfarin
• Antihypertensives, beta-blockers and diuretics: NSAIDs may reduce
the effect of anti-hypertensives, such as ACE inhibitors, beta-blockers
and diuretics.
• Diuretics can also increase the risk of nephrotoxicity of NSAIDs.
Corticosteroids: May increase the risk of adverse reactions in the
gastrointestinal tract including gastrointestinal ulceration or
bleeding
• Zidovudine: Increased risk of haematological toxicity when NSAIDs
are given with zidovudine. There is evidence of an increased risk of
haemarthroses and haematoma in HIV (+) haemophiliacs receiving
concurrent treatment with zidovudine and ibuprofen.
73
• Ciclosporin: Increased risk of nephrotoxicity.
 *Diclofenac Potassium (50
mg)
• The drug was launched in the UK in 1979 and a growing body

of clinical trials accumulated so that, by the mid-1980s,

diclofenac was confirmed as at least as effective as other
NSAIDs in the treatment of rheumatoid and osteoarthritis, with
safety comparable to that of ibuprofen and naproxen, and fewer
adverse reactions than other NSAIDs.

74
• In the Early 2000, an extensive analysis of CV events with individual
NSAIDs concluded that diclofenac carries a CV risk comparable to
that of the cyclo-oxygenase 2 (COX2) inhibitor rofecoxib, which led to
its withdrawal in 2004.

• Thus it was recommended that diclofenac should be removed from

the World Health Organization Essential Medicines Lists (EMLs),
and the European Medicines Agency (EMA) is currently reviewing
treatment guidance for the drug.

75
 *Composition
• Also contains Lecithin Soya E322.
• This medicine contains 0.150
mmol (5.85mg) potassium per
50mg tablet.
• Silica colloidal anhydrous
• Sodium starch glycollate
• Povidone
• Starch maize
• Calcium hydrogen phosphate
• Magnesium stearate
• Tablet Coating:
• Polyvinyl alcohol partially
hydrolysed
• Titanium dioxide E171
• Talc
• Lecithin Soya E322
• Iron Oxide red E172
• Iron Oxide yellow E172
• Xanthan gum E415
76
 *Indications :
• Rheumatoid arthritis
• Osteoarthrosis
• Low back pain
• Migraine attacks
• Acute musculo-skeletal disorders and trauma such as periarthritis (especially
frozen shoulder), tendinitis, tenosynovitis, bursitis, sprains, strains and
dislocations; relief of pain in fractures
• Ankylosing spondylitis
• Acute gout
• Control of pain and inflammation in orthopaedic, dental and other minor
surgery
• Pyrophosphate arthropathy and associated disorders 77
 *Dosage
Adults
• The recommended daily dose is 100 – 150 mg in two or three divided
doses. For milder cases, 75 – 100 mg daily in two or three divided doses
is usually sufficient.
• In migraine an initial dose of 50 mg should be taken at the first signs of an
impending attack. In cases where relief 2 hours after the first dose is not
sufficient, a further dose of 50 mg may be taken. If needed, further doses
of 50 mg may be taken at intervals of 4 – 6 hours, not exceeding a total
dose of 200 mg per day.
78
 * Paediatric population

• For children over 14 years of age, the recommended daily

dose is 75-100mg in two or three divided doses. Diclofenac
Potassium 25mg Tablets are not recommended for children
under 14 years of age.

• The use of Diclofenac Potassium 50 mg tablets in

migraine attacks has not been established in children.

79
 * Absorption
• Diclofenac is rapidly and completely absorbed from sugar-
coated tablets. Food intake does not affect absorption.

• Peak plasma concentration after one 50 mg sugar-coated tablet

was
3.9 µmol/l after 20-60 minutes. The plasma concentrations show
a linear relationship to the size of the dose.

• Diclofenac undergoes first-pass metabolism and is extensively

80
metabolised.
 * Distribution

• Diclofenac is highly bound to plasma proteins (99.7%),

chiefly albumin (99.4%)

• Diclofenac was detected in a low concentration (100ng/mL)

in breast milk in one nursing mother. The estimated amount
ingested by an infant consuming breast milk is equivalent to
a
0.03 mg/kg/day dose.
81
 * Elimination
• The total systemic clearance of diclofenac in plasma is 263 ±
56 ml/min (mean ± SD).
• The terminal half-life in plasma is 1 – 2 hours.
• Repeated oral administration of Diclofenac Potassium tablets for 8
days in daily doses of 50 mg t.d.s does not lead to accumulation
of diclofenac in the plasma.
• Approx. 60% of the dose administered is excreted in the urine in the
form of metabolites, and less than 1% as unchanged substance. The
remainder of the dose is eliminated as metabolites through the bile
in the faeces.
82
 *Contraindications :
• Active, gastric or intestinal ulcer, bleeding or perforation.
•Active, or history of recurrent peptic ulcer / haemorrhage (two or more
distinct episodes of proven ulceration or bleeding).
•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.
•Established congestive heart failure (NYHA II-IV), ischemic heart disease,
peripheral arterial disease and/or cerebrovascular disease.
• During the last trimester of pregnancy 83
*Pregnancy and
Lactations

84
 *Undesirable Effects
• very common: (>1/10); common (≥ 1/100, <1/10); uncommon (≥
1/1,000, <1/100); rare (≥1/10,000, <1/1000); very rare
(<1/10,000); Unknown: cannot be estimated from available
data.

85
86
87
 *Overdose
:
• There is no typical clinical picture resulting from diclofenac

over dosage.
• Symptoms include headache, nausea, vomiting, epigastric
pain, gastrointestinal bleeding, rarely diarrhoea, dizziness,
disorientation, excitation, coma, drowsiness, tinnitus, fainting,
occasionally convulsions.
• In rare cases of significant poisoning acute renal failure and
liver damage are possible.
88
 *Vulture crisis : Ecological
•
effect
Around the same time that the CV effects of diclofenac were being
identified, the drug’s likely impact on the Asian vulture population was
widely reported.
• Numbers declined rapidly during the 1990s and early 2000s so that, by
2007, the Indian population of white backed vultures was 0.1 per cent of
previous levels and long-billed and slender billed vulture populations
were down to 3.2 per cent of earlier levels.
• The dramatic mortality was attributed largely to renal failure caused
by exposure to diclofenac in livestock carcasses on which the birds
fed.
• Although not the most endearing species, vultures are important
environmental scavengers and, since veterinary use of diclofenac was
90
 *Conclusion
• The choice of analgesic when treating pain sometimes
represents a challenge for health professionals. Being aware
of the potential risks of the drugs should not be an impediment
for health professionals to initiate an analgesic therapy when
considered needed.

• The patient remains at the center of care, and treatment

decisions must take into account all medical and
environmental factors that might influence the safety and
91
efficacy of drugs.
• Non-opioid and opioid analgesics remain among the most
widely used drugs worldwide and it is thus important for health
professionals to pay more attention to their use.

• It goes without saying that the patients should be closely

evaluated and monitored during treatment, especially when risk
factors are present.

• Careful monitoring still remains the main way of early

detecting safety issues related to analgesics.
92
 *Referenc
• es
Rainsford anti-inflammatory drugs in 21st century
• KD Tripathi
• Pathan, Williams Basic opioid pharmacology: an update British Journal of
Pain 6(1)
• J.C. Phero, D. Becker / Dent Clin N Am 46 (2002) 691–705
• Cashman NSAIDS in Analgesia: Mechanisms of Action Drugs 1996; 52
Suppl. 5

93
 Dr. Sushma R. Galgali
Dr. Aruna D. R.
Dr. Vinayak S. Gowda
Dr. Rajiv N. P.
Dr. Avinash J. L.
Dr.Rekha S. M.
Dr. Sandeep J. N.
Dr.Shashikala T.
Dr. Sowmya M. S.

94
Nitric oxide role in endothelial
dysfunction
• In 1980, Furchgott and Zawadzki showed that the presence of
vascular endothelial cells is essential for acetylcholine to induce
relaxation of isolated rabbit aorta.
• If the vascular endothelium was removed, the blood vessel failed to
relax in response to acetylcholine but still responded to glyceryl trinitrate.
• This endothelium dependent relaxation of vascular smooth muscle to
acetylcholine is mediated by an endogenous mediator initially
named endothelium derived relaxing factor (EDRF), which was
subsequently identified as nitric oxide.
96
• Nitric oxide (NO) is a soluble gas continuously synthesized
from the amino acid L-arginine in endothelial cells by the
constitutive calcium-calmodulin-dependent enzyme nitric oxide
synthase (NOS).

• This substance has a wide range of biological properties that

maintain vascular homeostasis, including modulation of vascular
dilator tone, regulation of local cell growth, and protection of the
vessel from injurious consequences of platelets and cells
circulating in blood, playing in this way a crucial role in the
97
endothelial
normal function.
• A growing list of conditions, including those commonly associated as
risk factors for atherosclerosis such as hypertension,
hypercholesterolemia, smoking, diabetes mellitus and heart failure
are associated with diminished release of nitric oxide into the arterial
wall either because of impaired synthesis or excessive oxidative
degradation.

• The decreased production of NO in these pathological states causes

serious problems in endothelial equilibrium and that is the reason why
numerous therapies have been investigated to assess the possibility
of reversing endothelial dysfunction by enhancing the release of nitric
oxide from the endothelium. 98
 *Flow mediated
cytometry
• Flow cytometry is a popular cell biology technique that
utilizes laser-based technology to count, sort, and profile
cells in a heterogeneous fluid mixture.

• Using a flow cytometer machine, cells or other particles

suspended in a liquid stream are passed through a laser light
beam in single file fashion, and interaction with the light is
measured by an electronic detection apparatus as light scatter
intensity
and fluorescence 99

.
• If a fluorescent label, or fluorochrome, is specifically and
stoichiometrically bound to a cellular component, the
fluorescence intensity will ideally represent the amount of that
particular cell component.

• Flow cytometry is a powerful tool because it allows simultaneous

multiparametric analysis of the physical and chemical characteristics
of up to thousands of particles per second.

• This makes it a rapid and quantitative method for analysis and

purification of cells in suspension. Using flow, we can determine the
phenotype and function and even sort live cells. 100