Pain Therapeutics- 3 Aspirin Vs Paracetamol

Dr. Syed Shariq

At the end of the lecture you should

be able to understand:

• Aspirin

Uses of Aspirin

ADRs of Aspirin

• Paracetamol

Why it is not a good anti- inflammatory agent?

Why it is an exceptional antipyretic agent?

Treatment of Paracetamol Poisioning?

Treatment of Aspirin Poisoning

Correct Dehydration & Electrolyte Imbalances

↓ A sorptio

↑ Eli i atio

< 1hr 1. Activated Charcoal- 2 g/kg (Minimum- 30 g)

2. Whole Bowl Irrigation (WBI): Polyethylene Glycol- especially

for coated tablets

3. Syrup Ipecac: <30 minutes to induce vomiting

1. Volume Expansion: NS or Ringer lactate10 ml/kg/hr to

maintain an urinary output of 1 ml/kg/hr

2. ↑ pH to 7.5 Alkali e : a) Sodium bicarbonate:

I. Bolus- 1mEq/kg

II. IV infusion: 3 ampoules X 44 mEq/kg in 1 liter of D5

3. Citrate or Malate of Sodium and Potassium

a) 1 citrate metabolized in liver to give 3 bicarbonates

4. Prevent hypokalemia

a) ↓ Alkalizatio

b) Sodium bicarbonate causes intracellular shift of K+

Uses of Aspirin Analgesic

Anti-inflammatory

Antipyretic

Antiplatelet

Peculiar

81-325mg/ day

500-1000 mg/ day

3000-5000 mg/ day

3000-5000 mg/ day

Pain with Inflammation

Headache, Toothache

Muscular Pain (Myalgia)

Musculoskeletal Pain

Dysmenorrhea – PGF2α

Ischemic Pain- MI

Neurological Pain

Rheumatoid Arthritis

Osteoarthritis Gout

NOT Used for

Acute Rheumatic Fever Paracetamol

is preferred

Prevention & T/T of MI, Angina

Prevention & T/T of Stroke, TIA DVT, PE

Closure of Ductus Arteriosus

Delaying onset of Alzheimer's Disease

Prevention of Colon/Rectal Cancer (Polyposis)

Treatment of PIH / Preeclampsia

Decrease the Cataract Progression

ADRs &

Contraindications of Aspirin

ADRs (Mn: Aspirin)

A- Allergic Reactions, Aspirin induced Asthma

S- Salicylism

P- Peptic Ulcer, Premature closure of DA

I- Intestinal Blood Loss

R- Reye’s Sy dro e

I- Idiosyncrasy

N- Nephropathy, Noise (Tinnitus)

Contraindications (Mn: Labor)

Labor : 3rd Trimester

L: Liver Disease

A: Allergy

B: Bleeding

O: ↓ Output of Uri e Nephropathy

R: Reye’s Sy dro e < years ith iral i fe tio

Interactions of Aspirin

Drug Mechanism Effect

1 Anticoagulants Additive Effect ↑ chances of bleeding

2 Lithium Inhibit renal elimination ↑ serum lithium levels

3 Anti-

Hypertensive/

Diuretics

↓ local PGs in renal

system regulating renal

blood flow and GFR

↓ effects of drug

4 Probencid ↓ Urate excretion Antagonizes the uricosuric effect of

probencid

Paracetamol (Acetaminophen)

Properties Aspirin Paracetamol

Binding with COX Irreversible Reversible

Actions

1 Analgesic

2 Antipyretic

3 Anti-inflammatory

4 Antiplatelet

+++ +++

+ +++

+++ +/-

+++ -

ADRs

1 GI Ulceration, Bleeding

2 Acid Base & Electrolyte

imbalance

3 Safety in children

+++ +

+++ -

Reye’s Sy dro e Safe

4 Antidote NO N-Acetyl Cystine

Site of Inflammation

Peroxides

Poor Anti- inflammatory activity of Paracetamol

Core

Tepe

ratu

re ᵒC

37

38

39

40

Time

Noxious Stimuli

Pyrogenic Cytokines

(IL1, IL6, TNF-α, IFN)

& PGE2

Hypothalamus

Preoptic Area

in Anterior

Hypothalamus

Temp.

Set point

Elevated

Sympathetic

Nervous System

Vasomotor Centre

Piloerection

Thermogenesis ↑ Heat Produ tio

Vasoconstriction ↓ Heat loss

Cold & Shivery

Warm & Dry

Noxious Stimuli

Temp.

Set point

Lowered

Warm, Flushed

& Sweaty

Exceptionally good antipyretic activity of Paracetamol

COX-3 Isoenzyme

Paracetamol PK

• Dose: 500-600 mg 8 hourly

• Absorption: Good

• Metabolized : Liver

Paracetamol Metabolism

Acetaminophen Conjugation Conjugation Glucuronide

Moiety

Non- Toxic

Sulfate

Moiety

Non- Toxic CYP 2E1

NAPQI

N-Acetyl p-benzo-Quinone Imine

Toxic

Cysteine & Mercapturic Acid

Conjugates

Non- Toxic

Glutathione

(GSH)

Free

Radicals

SH

(Thiol)

Minor Product

Paracetamol Poisoning

Paracetamol overdose

• >10g - fatal

• Lower- Chronic alcoholics or with liver disease.

Clinical features

• Up to 24 hours: None

Nausea and vomiting

• > 24 hours: Nausea and vomiting,

Right upper quadrant pain,

Jaundice, Encephalopathy

Management: Paracetamol Poisoning

• Initial Management: Emesis,

Gastric lavage

Activated charcoal (Orally)

Supportive measures- IV fluids

• Hepatic failure

• Acute renal failure (acute tubular necrosis)

• Specific antidote: N-Acetylcysteine

150mg/kg IV infusion over 15 min

Than, same dose IV infusion over next 20 hrs.

36-72 hours

after Ingestion

Paracetamol Metabolism

Acetaminophen Conjugation Conjugation Glucuronide

Moiety

Non- Toxic

Sulfate

Moiety

Non- Toxic CYP 2E1

NAPQI

N-Acetyl p-benzo-Quinone Imine

Toxic

Cysteine & Mercapturic Acid

Conjugates

Non- Toxic

Glutathione

(GSH)

Free

Radicals

SH

(Thiol)

Minor Product

Limited Supply

Free

Radicals

N- Acetyl Cysteine SH

(Thiol)

Drugs Route &

Formulation Properties

2 Sulindac

Oral

Dose: 200mg 12

hourly

Congener of I do etha i to ↓ ADRs

Half as potent as indomethacin

ADR: Headache <10%

GIT ~ 20%

1 Indomethacin

Oral, Eye Drops,

Suppositories

Dose: 50mg

8 hourly

20 times more Potent Than Aspirin

Also inhibits phospholipase A & C

Inhibits migration of Neutrophils in

inflamed areas

COX independent Vasoconstriction

action

ADR: 25-50% Patients

More CNS &GIT side effects

Pain killer which causes Pain

Drugs Route &

Formulation Properties

3 Diclofenac

Oral, IM, Rectal,

Topical, Eye

Drops

Loading Dose:

100 mg

Maintenance: 50

mg 8 hourly

Not given IV

Potent anti- inflammatory (more than

indomethacin)

COX-2 Preferential

↓ Free i tra ellular AA in the

leukocytes

Selectively accumulates in synovial

fluid Therapeutic effect longer then

T ½

ADRs: ~ 20%

More hepatotoxic (5-15%)

4 Ibuprofen/

Ketoprofen

Oral, Topical

Dose: 200-400

mg 8 hourly

Moderate Anti- inflammatory

Accumulates in Synovial Fluid

Better Tolerated than aspirin

Can be used children

Interfere with antiplatelet function of

aspirin

ADR: 5-15%

Caution: Pregnant/ Nursing mothers

Drugs Route &

Formulation Properties

5 Naproxane

Oral,

Dose 250- 500mg

12 hourly

Additional usage: Juvinile RA,

Tendonitis, Bursitis, Acute Gout

Inhibit Leukocyte and platelet

functioning

Variable T1/2: Young:14 hr

Old: 28 hr

Decreases incidence of MI by 10%

(Aspirin: 20-25%)

Drugs Route &

Formulation Properties

6 Ketorolac

Oral, IM, IV,

Transdermal,

Drops

Dose: 10mg

Potent analgesic (Acute Severe Pain)

Modest anti inflammatory

Used in Renal Colic, Post Operative and

Cancer Pain

ADR: Black Box Warning

(< 5Days, Not in presence of GI or Renal

Disease, or Bleeding)

7 Mephenamic acid

Oral

Dose: 250-500mg

8 hourly

Central as well as Peripheral analgesia

Useful in Dysmenorrhea

ADR- Diarrhea

8 Nabumetone Oral,

Dose 1000mg OD

Potent anti inflammatory (Arthritis)

Off label use: Soft tissue injuries

ADR: GIT side effects

Drugs Route &

Formulation Properties

9 Piroxicam Oral, Topical

Dose 20mg OD

Potent anti inflammatory

Inhibit Activation of Neutrophils

Inhibit Proteoglycanase/ Collagenase

Long acting (T ½- 50 hrs)

More GIT side effects

10 Nimesulide Oral

Dose: <100mg BD

Preferential COX-2 Inhibitors

Inhibit Neutrophil activation

Decrease cytokine production

Decrease destructive enzyme

production

Activate Glucocorticoid receptor

Less GIT ADRs

ADR: Causes Hepatitis

Banned in Many countries

Case 1

A 20 year old

student

complaints

of

Headache.

She has a

exam on the

next day.

Case 2

A 25 year old

female

complaints

of headache.

She is

pregnant.

Case 3

A 25 year old

female had a

C- section 2

hour back.

Now

complaints

of pain.

Case 6

A 70 year old

patient with

diagnosed

diabetic

neuropathy.

Having altered

sensation &

pain in feet

Case 4

A 2 year old

boy fell down

on his elbow.

Crying

inconsolable

Case 5

A 55 year old

patient

complaints

of severe

pain in Joints

for last 10

days

Questions!!!!