Paracetamol

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