Classifications pharmacokinetics pharmacodynamics & applied knowledge of analgesics & antipyretics with special emphasis on NSAIDS.

1. ANALGESICS &
ANTIPYRETICS
DR TARAK NATH CHATTOPADHYAY
MBBS, MD GENERAL MEDICINE

2. Let’s start
65 female presented with pain in both knees, more on left
side. Pain worsens while walking or standing. X-ray shows
joint space narrowing, mild effusion & osteophytic projection.
She had a heart attack 1y back & treated with angioplasty.
She is taking aspirin 75mg regularly
What analgesic to be given?
Which analgesic should be avoided?

3. PAIN & FEVER
Pain: Pain is a symptom of inflammation
Fever: When the temperature is above 100.4 F
Analgesic: A drug that selectively relieves pain by acting on
CNS or on peripheral pain mechanisms without significantly
altering consciousness.
Antipyretic: A drug that reduces fever by lowering body
temperature

6. Pain RECEPTOR
Free nerve endings located in various body tissues
responding to thermal, mechanical, chemical stimuli
Injured tissue releases chemicals Prostaglandins &
Leucotrienes that make pain receptor more sensitive

7. PHYSIOLOGY OF PAIN
Source (Injury/ Inflammation/Heat/Cold)
Pain receptors
Discharge impulse
Electrical activity to spinal cord & brain
In brain: electrical activity becomes experience of pain

8. CLASSIFICATIONS
OPIOIDS: Morphine & morphine like substance
Non Opioid: NSAIDS, ACETAMINOPHEN,

10. NSAIDS

11. Mechanism of action
Analgesia: PG induces analgesia by altering transduction property of free nerve
endings. NSAIDs inhibit PG synthesis in Brain & spinal cord(Central
mechanism). Also they block pain sensitisation by Bradykinin, TNF@,
Interleukins (Perpheral mechanism).
Anti inflammatory : Inhibition of COX2>COX1 at site of injury. However
inflammation is the result of concerted participation of vasoactive, chemotactic &
proliferation factors at different stages. Apart from PG there are other mediators
like LT, PAF, Cytokines.
Antiplatelet: By inhibiting proaggregatory TXA2 & antiaggregatory PGI2 through
COX1 inhibition. Low dose Aspirin inhibits platelet aggregation but at high anti
inflammatory dose this advantage get lost. NSAID increases bleeding tendency
by this mechanism

12. Mechanism of action
Parturition: sudden spurt of PG synthesis occurs before
labour begins which trigger & facilitate labour. NSAIDS can
delay labour
Ductus arteriosus closure: In foetal circulation DA is kept
patent by local elaboration of PGE2. It gets closed during birth
spontaneously. When it fails small dose of Indomethacin
given to cause this. Administration of NSAID near term can
cause premature closure of DA & thus should be avoided

13. Mechanism of action
Gastric mucosal damage: COX1 mediated synthesis of PGE2 & PGI2
protects gastric mucosa. Deficiency of PG causes reduction of mucus,
HCO3, increases H+ secretion thus causing gastric erosion. Selective
COX 2 inhibitor & paracetamol is free from this adverse effect. Also PG
analogue can be administered to counteract NSAID induced gastric
toxicity.
Renal effect: Hypovolaemia causes PG synthesis which causes it rare all
adjustments by vasodilation, inhibits tubular Cl- absorption( Na, H2O
accompany). NSAID causes renal blood flow reduction, juxtaglomerular
COX2 inhibition causes Na & H2O retention, papillary necrosis. These
changes are marked in patients with CHF, Cirrhosis of liver, CKD. Diuretic
& antihypertensive action reduced.

14. Classification
Nonselective COX inhibitor: Salicylate ( Aspirin), Propionic acid
derivative( Ibuprofen, Naproxen), Acetic acid derivative ( Indomethacin,
ketorolac), Fenamate( Mephenamic acid), Enolic acid ( Piroxicam),
Pyrazolone (Phenylbutazone)
Preferential COX 2 inhibitor: Diclofenac, Aceclofenac, Nimesulide
Selective COX2 inhibitors: Celecoxib, Etoricoxib, Parecoxib

15. Aspirin
Acetyl salicylic acid
Acetylation of COX
Weak analgesic. .(3-.6 g 6-8 hourly) Ineffective in visceral pain
Potent anti inflammatory at high dose 3-6 gm/day Acute rheumatic fever, RA
Antiplatelet action at low dose 75-150 mg/day. Action lasts for about a week
T1/2 15-20 min. Together with salicylic acid 3-5 hour. T1/2 of anti inflammatory dose 8-
12 hour while during poisoning may be up to 30 hours
Adverse effects: Gastric mucosal damage & PUD, Hypersensitivity! Reye’s syndrome
in children

16. Contraindications
PUD
Children with chicken pox/ influenza
CLD
Frank heart failure with low output status
1 week before surgery
Breast feeding mother
Repeated dose in pregnancy causes LBW baby, delayed/ prolonged labour,
premature closure of DA

17. Other NSAIDS
Ibuprofen: Better tolerated than aspirin . Not to be given in pregnancy. Used as analgesic 400-600 mg 2-3 times
a day
Naproxen: Longer duration of action12-16 hour. Effective in Gout, RA, Migraine,Ankylosing spondylosis. Gastric
bleed more common but lower thrombotic risk.
Mephenamic acid: Effective in Dysmenorrhea. Diarrhoea is major AE.
Ketorolac: Potent analgesic, comparable to opioids. Used in post operative , dental pain. Not to be used for more
than 5 days
Indomethacin: Potent analgesic, anti inflammatory. Malignancy associated fever, Reactive arthrithritis, GI side
effects are more prominent. Leukopenia, hypersensitivity reaction are more common. Causes dizziness,
hallucinations psychosis. Contraindicated in driver, machinery worker, psychiatric/epilepsy patients, women
children
Nimesulide: weaker analgesic. Completely absorbed orally. Effective in sinusitis, sport injuries, . Withdrawn due to
high incidence of fulminant hepatic failure. Used in patients having bronchospasm/ intolerance to other NSAID
Diclofenac: somewhat COX2 selective. Good tissue permeability, stays 3 times longer in synovial fluid. Increased
hepatic dysfunction, high incidence of cardiac events.

18. COX2 inhibitor
Less gastric mucosal damage, lower incidence of PUD
Does not suppress TXA2. No Antiplatelet function
But reduces PGI2. High incidence of cardiac events
Used in Gout, RA, AnkSpon, Dental pain

19. Acetaminophen
Potent antipyretic, negligible anti inflammatory, weak analgesic. Analgesic action is additive with
aspirin
Poorly understood MOA. Weak Inhibitor of Pg synthesis in peripheral tissue but inhibits COX in brain.
Postulated to be inhibitor of COX3
T1/2 2-3 hours
Well tolerated. GI side effects are negligible
Poisoning: occurs specially in children with hepatic dysfunction. Occurs in > 150mg/kg or > 10g/day
in adult. Fatal dose 250mg/kg. N acetyl p benzoquinoneimine ( metabolite of PCM ) gets detoxified in
liver by conjugation with glutathione. With high dose glucoronidation capacity saturated, hepatic
glutathione depleted, metabolite binds to hepatic cells causing necrosis. In chronic alcoholic CYP2E1
is induced causing more production of NABQI. Hepatic toxicity can occur with 5gm/day dosage. Not
recommended in infants < 2kg.
Antidote: N. acetyl cysteine replenishes hepatic glutathione storage. Ineffective if started > 16 hours

20. Local NSAID
Diclofenac 1%
Ibuprofen 10%
Naproxen10%
Nimesulide1%
Ketoprofen 2.5%
Flurbiprofen5%
Piroxicam.5%

21. Choice of drugs
Mild/moderate pain with little inflammation: paracetamol/ low dose
ibuprofen
Postoperative, short lasting: injectable Diclofenac, ketorolac
Renal colic, dental pain, fracture, trauma: injectable PCM/NSAID
Inflammatory pain( RA, AS, GOUT, ARF): naproxen, Indomethacin, high
dose aspirin
Gastric intolerance, Asthma, : COX2 inhibitor (avoid if cardiac
comorbidities)

22. 65 female presented with pain in both knees, more on left side.
Pain worsens while walking or standing. X-ray shows joint
space narrowing, mild effusion & osteophytic projection. She
had a heart attack 1y back & treated with angioplasty. She is
taking aspirin 75mg regularly
What analgesic to be given?
Which analgesic should be avoided?

23. Thank you
For not sleeping!!