This document provides information on paracetamol (acetaminophen), including its history, physical properties, dosage forms, pharmacokinetics, mechanisms of action, indications, interactions, and toxicity. Paracetamol is a widely used analgesic and antipyretic that was first marketed in the United States in 1955 as Tylenol. It is generally safer for patients than NSAIDs in terms of gastrointestinal and renal toxicity, but overdose can cause hepatotoxicity. Paracetamol is metabolized in the liver and exhibits weak inhibition of COX-1 and COX-2 enzymes.

1. PARACETAMOL
(ACETAMINOPHEN)

2. GENERAL INTRODUCTION
• VERY FAMOUS ANALGESIC & ANTIPYRETIC
• AVAILABLE AS BOTH OTC & POD
• FIRST TIME SALE IN USA AS TYLENOL IN 1955
• MORE THAN 80 BRANDS ALL OVER WORLD
• ABOUT 173 BRANDS IN PAKISTAN & MORE THAN 70
MANUFACTURERS
• 500 mg TAB. IN 1955 IN UK AS PANADOL
• PANADOL ELIXIR IN 1958
• ADDITION INTO BP IN 1963

3. PHYSICAL PROPERTIES
• WHITE , ODOURLESS & CRYSTALLINE POWDER
WITH BITTER TASTE
• SOLUBLE IN 7 PARTS OF ALCOHOL(95%) & 70
PARTS OF WATER
• SOLUBILITY IN SOLUTIONS OF ALKALI HYDROXIDES
• INSOLUBLE IN BENZENE & ETHER
• PH OF SOLUTION IS 6 AND STABLE FOR 20 YEARS
• MIXTURE WITH ASPIRIN STABLE IN DRY
CONDITIONS

4. HISTORY OF PARACETAMOL
• IDENTIFICATION OF ANTIPYRETIC PROPERTIES OF
ANILINE & ACETANILIDE IN 1886 BY CONN & HEPP
• RECOMMENDATION OF NAPTHALENE FOR WORMS
BY PROF. STRASSBURG IN 1880 & MISTAKE OF
PHARMACY
• DERIVATIVES SYNTHESIS OF ACETANILIDE BY
BAYERS
• SYNTHESIS OF PARACETAMOL BY JOSEPH VON
MERING IN 1893
• METABOLISM OF PHENACETIN IN BODY

5. SYNTHESIS OF PARACETMOL
• STEP-I : NITRATION OF PHENOL
HO
NANO3
OH
NO2
OH
NO2
H2SO4

6. STEP-II : REDUCTION OF NITRO TO AMINO GROUP
OH
NO2
NABH4
Pd / 1 mol dm-3
NaOH
OH
NH2
STEP-III : FORMATION OF AN AMIDE
OH
NH2
OH
HN
C
O
CH3
Ethanoic anhydride
Room Temp

7. DOSAGE FORMS
• TABLETS,ELIXIRS,SUPPOSITORIES,SUSPEN
SION, I/M & I/V
• COMBINATIONS WITH OPIODS LIKE
CODEINE,OXYCODONE & HYDROCODONE
• ALSO IN COMBINATION WITH BUTALBITAL,
CAFFEINE & CODIENE
• IMPORTANT COMBINATION WITH OR
WITHOUT ASPIRIN
• PANADOL EXTRA® & NOPAIN®

8. PHARMACOKINETICS
• ORAL ADMINISTRATION & ABSORPTION RELATED
TO GASTRIC EMPTYING RATE
• PEAK BLOOD CONC. IN 30-60 MINUTES
• METABOLISM PRIMARILY IN LIVER(60-90%) &
CONVERTION TO INACTIVE COMPOUND BY
CONJUGATION
• SMALL FRACTION(5-10%)VIA CYTOCHROME
P450(CYP2E1)
• TOXIC EFFECTS DUE TO METAVOLITE “N-ACETYL-P-
BENZOQUINONE IMINE(NAPQI)
• DETOXIFICATION OF NAPQI BY BINDING WITH
SULPHYDRYL GROUPS OF GLUTATHIONE

9. MECHANISM OF ACTION
• WEAK INHIBITOR OF COX-I & COX-II IN
PERIPHERAL TISSUES
• RECENT EVIDENCE ALSO SUGGEST
INHIBITION OF COX-III, ONLY PRESENT IN
BRAIN & SPINAL CORD
• COMPARISON OF MECHANISM WITH
ASPIRIN
• ↑ BIOAVAILABILITY OF SEROTONIN IN RATS
• EXACT MECHANISM YET UNKNOWN

10. COMPARISON WITH NSAID’S
• NOT MENBER OF NSAID’S LIKE IBUPROFEN &
ASPIRIN DUE TO LITTLE ANTI-INFLAMMATORY
EFFECT
• NO GASTRIC IRRITAION,BLOOD COAGULATION OR
EFFECT ON KIDNEYS
• SAFE IN PREGNANCY
• SAFE IN CHILDREN WITH NO RISK OF REYE’S
SYNDROME
• COMBINATION WITH OPIODS HAS MORE CHNACES
OF REBOUND HEADACHE THAN ASPIRIN

11. SIDE EFFECTS
• COMMON SIDE EFFECTS LIKE NSAID’S
• MAJOR SIDE EFFECT IS HEPATOTOXICTY
• RENAL TUBULAR NECROSIS & HYPOGLYCEMIC
COMA ON PROLONGED USE(RARE)
• DIZZINESS,EXCITEMENT & DISORIENTATION WITH
LARGER DOSES
• MINOR ALTERATION IN LEUKOCYTE COUNT BUT
TRANSISTANT
• HEMOLYTIC ANEMIA & METHEMOGLOBINEMIA BY
PHENACETIN & NOT BY PARACETAMOL

12. INDICATIONS/USES
• EFFECTIVE ANALGESIC & ANTIPYRETIC
• ALSO USED IN MYALGIA & POSTPARTUM PAIN
• ADJUNCT THERAPY IN ”RA”
• COUPLE OF PREFERANCES OVER ASPIRIN
• MAJOR INGREDIENTS IN FLUE & COLD
MEDICATIONS
• ALSO USED IN MIGRAINE IN COMBINATIONS
• MAY PROTECT HARDENING OF ARTERIES
• PROTECTIVE ACTION AGAINST OVARY CANCER

13. USE WITH CAUTION
• ANEMIA
• DRINKING MORE THAN 3 ALCOHOL DRINKS
• INFECTIONS
• KIDNEY DISEASES
• LIVER DISEASE,CIRRHOSIS & HEPATITIS
• AN UNUSUAL ALLERGIC REACTION TO
DRUG
• PHENYLKETONEURIA

14. DRUG INTERACTIONS
• ALCOHOLS
• ANTACIDS,CIMITIDINE AND RIFAMPICIN ↓
EFFECT
• BARBITURATES,CARBAMAZIPINE,HYDANTOI
N,SULPHINPYRAZONE & ORAL
ANTICOAGULANTS ↑ EFFECT
• MEDICINED FOR SEIZURES
• MEDICINES FOR MENTAL PROBLEMS &
PSHCYOTIC DISTURBANCES

15. DOSAGE REGIMEN
• TWO 500 Mg TABS EVERY 4-6 HRS, NOT
EXCEEDING MORE THAN 8 TABS IN 24 HRS
• CHILDREN DOSAGE USUALLY ON BASE OF AGE
AND BODY WEIGHT
• UNDER 3 MONTHS,10MG/KG BODY WEIGHT
• 3MONTHS-1YEAR,60-120MG,MAY BE REPEATED
EVERY 4-6HRS
• 1-5 YEARS,120-250MG WITH SAME STATUS
• 6-12 YEARS,250-500 MG WITH SAME STATUS
• FOR HIGHER DOSAGE IN HOSPITAL,POD &
CHRONIC USER SHOULD MONITOR LIVER
FUNCTION

16. USE IN PREGNANCY
• USE OF NSAID’S AT TIME OF CONCEPTION HAS 80%
↑ RISK OF MISCARRIAGE
• USE DURING PREGNANCY HAS ALSO SAME
EFFECTS
• PARACETAMOL USE SAFE IN PREGNANCY
• NSAID’S WORK BY INHIBITING PG SYNTHESIS &
INVOLVED IN IMPLANTATION OF EMBRYO IN WOMB
LININ G
• RESEARCH CARRIED ON 1055 WOMEN IN USA

17. STRUCTURE ACTIVITY RELATIONSHIP
OH
HN
C
O
CH3

18. TOXIC ASPECTS OF PARACETAMOL
• HEPATIC INJURY BY TOXIC METABOLITE
• RENAL DAMAGE BY SAME MECHANISM
• OVERDOSE IN PREGNACY;FETAL DEATH &
SPONTANEOUS ABORTION
• DELAYED ABSORPTION BY SUSTAINED RELEASE
OR COINGESTION OF OPIODS& CHOLINERGICS
• TOXIC DOSE IN CHILDREN 150-200 mg & 6-7g ADULT
• CHILDREN YOUNGER THAN 10-12 YEARS BIT SAFE
• ↓MARGIN OF SAFETY IN P-450 INDUCED PATIENTS
• ALCOHOLIC,ANTICONVULANT USER &
MALNUTRITIIONED AT HIGH RISK

19. CLINICAL PRESENTATION & DIAGNOSIS
• AFTER ACUTE OVERDOSE,ANOREXIA, NAUSEA,
VOMITING
• 24-48 hrs, AST & ALT ↑ & HEPATIC NECROSIS
EVIDENT
• ENCEPHALOPATHY,METABOLIC ACIDOSI, ↑IN PT
TIME INDICATE POOR PROGNOSIS
• RENAL FAILURE WITH OR WITHOUT LIVER FAILURE
• DIAGNOSIS POSSIBLE IS TOXICITY SUSPECTED &
SERUM LEVEL GOT.
• GET LEVELS AFTER ACUTE INGESTION&CHECK BY
NOMOGRAM

20. TREATMENT
• SPONTANEOUS VOMITING MAY DELAY ANTIDOTE OR
CHARCOAL (METOCLOPRAMIDE )
• EMERGENCY LIVER TRANSPLANT IN FAILURE
• ENCEPHALOPATHY,METABOLIC ACIDOSIS
• HYPOGLYCEMIA & ↑PT ;SEVERE LIVER INJURY
• ANTIDOTAL TREATMENT BY NAC(MUCUMYST®)
• IF VOMITING INTERFERES,USE GASTRIC TUBE OR I/V NAC OR
MRTOCLOPRAMIDE ( 1-2mg/kg I/V)
• EXTENDED RELEASE TABS,REPAEAT SERUM LEVELS
• NAC DOSE 140 mg/Kg ORALLY FOLLOWED BY 70 mg/Kg 4 HRS
• CURRENT PROTOCOL IS 17 DOSES OF ORAL NAC IN 72 HRS
• CANADA,UK & EUROPE FOR 20 HRS BY I/V (BETTER 36 HRS)

21. FORMULATION OF PARACETAMOL ELIXIR
• ACETAMINOPHEN = 24 g
• BENZOIC ACID = 1g
• PROPYLENE GLYCOL = 150ml
• ALCOHOL = 150 ml
• SOLULEE SACCAHRIN = 1.8 g
• WATER = 200 ml
• FLAVOUR = q.s
• SORBITAL SOLN. TO MAKE 1000ml

22. RIBOFLAVIN(VIT B2, LACTOFLAVIN)
NH2
Me
Me
+
CH
C
C
C
CH2OH
O
OH
OH
OH
CH2OH
C
H OH
C
C
H OH
CH
H OH
N
Me
Me
CH2OH
C
H OH
C
C
H OH
CH2
H OH
H
H
H
NH
Me
Me N N NO2
H2/Pd N+
NO2
NCl-

23. CH2OH
C
H OH
C
C
H OH
CH2
H OH
NH
Me
Me NH2
H2/Ni
Under pressure
Alloxan
NH
H
N O
O
O
O CH2OH
C
H OH
C
C
H OH
H2C
H OH
N
N
NH
N
O
O
Me
Me
H3BO3
RIBOFLAVIN

24. DEFICEINCY DISEASES
• SYMPTOMS CONFINED TO MUCOUS MEMBRANE &
SKIN
• ANGULAR STOMATITIS,
GLOSSITIS,CHEILOSIS,SEBORRHOIC DERMATITIS &
PERIPHERAL NEPHROPATHY CAN OCCUR
• CONDITION REFERRED AS “ARIBOFLAVIN”
• DRUGS LIKE BARBITURATES CAN CAUSE
RIBOFLAVIN DEFICIENCY

25. MODE OF ACTION(OR APPLICATION)
• CENTRAL ROLE IN ENERGY YEILDING METABOLISM
• PROVIDES REACTIVE MOIETIES OF COENZYMES
FMN & FAD
• SOME STUDIES SUGESST ITS IMPORTANT ROLE IN
ENERGY PRODUCTION IN BODY
• ALSO ACTS AS ANTIOXIDANT
• ALSO PROVIDES CELL GROWTH(ESPE.SKIN,NAILS
& HAIRS NEED ITS ADEQUATE AMOUNT)

26. NICOTINIC ACID(VIT B5 OR NIACIN)
N
SO3H
N
CN
N
COOH
NACN
200C
HOH
Nicotinic Acid

27. MODE OF ACTION & DEFIECENCY
• ACTS AS ELECTRON CARRIER AS NAD+ & NADP+ IN
REDOX REACTION IN METABOLISM
• IMPORTANT ROLE IN SYNTHESIS OF SEX
HORMONES,ASSISTS IN ENERGY PRODUCTION
• ENHANCES CIRCULATION, ↓ CHOLESTROL
• DEFICIENCY CAUSES “PELLAGRA” INVOLVING
SKIN,GIT & CNS
• SYNPTOMS OF DISEASE PROGRESS THROUGH
DERMATITIS,DIARRHEA
• IF NO TREATMENT, DEATH ! ! ! !

28. THANKS A LOT FOR
LISTENING
QUESTION OR COMMENTS
WELCOMED