DETOXIFICATION OF IBUPROFEN

BY: HERMAN NDJAMENGROUP: 205

STRUCTURE OF

IBUPROFEN

CHEMICAL SYNTHESIS

USES OF IBUPROFEN

MECHANISM OF ACTION

MECHANISM OF

DETOXIFICATION

ADVERSE EFFECTS AND

OVERDOSE

CONCLUSION

OUTLINE

STRUCTURE OF IBUPROFENIBUPROFEN ALSO KNOWN CHEMICALLY AS 2-(4-isobutylphenyl)propanoic acid OR 2-(4-(2-methylpropyl)phenyl)propanoic acid (IUPAC ID) is a non-steroidal anti-inflammatory drug which is widely used nowadays as pain relief. It exist chemically in two forms:

- R-2-(4-(2-METHYLPROPYL)PHENYL)PRAPANOIC ACID

- S-2-(4-(2-METHYLPROPYL)PHENYL)PROPANOIC ACID.

THEY ARE JUST ENANTIOMERS OF EACH OTHER, THE S FORM BEING MORE ACTIVE THAN THE R.

INDUSTRIAL PREPARATION (CHEMICAL SYNTHESIS)

Ibuprofen is produced industrially as a racemate mixture of the R&S forms but since the S form is more active, there is a need of converting the R into S form. For this purpose an enzyme is used;alpha-methylacyl-CoA racemase (Isomerase).

R-IBUPROFEN (levibuprofen)

S-IBUPROFEN(DEXIBUPROFEN)

SYNTHESIS

THE IMPROVED SYNTHESSIS OF IBUPROFEN OCCURS IN THREE MAIN STEPS:

I. FRIEDEL-CRAFTS ACETYLATION OF ISOBUTYLBENZENE (FORMS ISOBUTYLPHENYL ETHANONE

II. HYDROGENATION WITH RANEY NICKEL PRODUCES (ISOBUTYLPHENYLETHANOL)

III. CARBONYLATION USING PALLADIUM AS CATALYST ( FORMS IBUPROFEN)

USES OF IBUPROFEN

• IBUPROFEN IS PRIMARILY USED FOR FEVER, PAIN, DYSSMENORRHEA (MENSTRUAL PAIN)

• IT IS ALSO USED DURING INFLAMMATORY DISEASES LIKE RHEUMATOID ARTHRITIS

• IT IS USED FOR PERICARDITIS AND PATENT DUCTUS ARTERIOSUS

MECHANISM OF ACTION• Nonsteroidal anti-inflammatory drugs such as

ibuprofen work by inhibiting the enzyme cyclooxygenase (COX), which converts arachidonic acid to prostaglandin H2 (PGH2). PGH2, in turn, is converted by other enzymes to several other prostaglandins (which are mediators of pain, inflammation, and fever) and to thromboxane A2

(which stimulates platelets aggregation leading to blood clots formation.

• They may also inhibit chemotaxis, alter lymphocyte activity and inhibit neutrophil aggregation.

DETOXIFICATION

• THE GENERAL PRINCIPLE UNDERLYING DETOXIFICATION OF DRUGS BY THE LIVER IS A SERIES OF REACTIONS WHICH WILL RENDER THE HYDROPHORBIC TOXIC DRUG MORE HYDROPHILIC.

• DETOXIFICATION BY THE LIVER GENERALLY OCCURS IN TWO STEPS:

PHASE 1: OCCURS IN THE RIGHT LOBE PHASE 2: OCCURS IN THE LEFT LOBE

MECHANISM OF DETOXIFICATION

• IBUPROFEN IS PROCESSED IN THE LIVER IN TWO DIFFERENT WAYS; OXIDATION & CONJUGATION WITH GLUCURONIC ACID (GLUCURONIDATION)

• THE SERUM HALF-LIFE OF IBUPROFEN IS 1.8 TO 2.0 HOURS.

OXIDATION

* 25 PERCENT IS OXIDIZED BY THE LIVER TO FORM 2 HYDROXY IBUPROFEN AND 37 PERCENT TO CARBOXYIBUPROFEN USING MONOXYGENASES AS ENZYMES.

GENERAL EQUATION

RH+ O2 + NADPH + H+ R-OH + H2O + NADP

* OXIDATION OF IBUPROFEN IN THE LIVER OCCURS MAINLY BY ADDITION OF OXYGEN MOLECULE TO IBUPROFEN. THIS REACTION IS CATALYSED BY MONOXYGENASES AND USES NADPH AS Co-ENZYME, REASON FOR WHICH THE REACTION IS USUALLY TERMED A HYDROXYLATION REACTION

CONJUGATIONTHE PRINCIPLE OF CONJUGATION IS THE SAME AS THAT SEEN DURING BILIRUBIN CONJUGATION. THIS INVOLVES THE REACTION OF IBUPROFEN WITH UDP-GLUCURONIC ACID IN THE PRESENCE OF THE ENZYME GLUCURONYLTRANSFERASE TO FORM THE IBUPROFEN GLUCURONIDE.

14% OF IBUPROFEN IN THE LIVER IS BEING EXCRETED AS IBUPROFEN GLUCURONIDE IN URINE AND FAECES.

ADVERSE EFFECTS Adverse effects that may arise due to frequent usage (long-term) of ibuprofen are divided into common and infrequent. * common adverse effects include: nausea, dyspepsia, gastrointestinal ulceration/bleeding, raised liver enzymes, diarrhea, constipation, epistaxis, headache, dizziness, priapism, rash, salt and fluid retention, and hypertension. * Infrequent adverse effects include: heart failure, hyperkalemia, renal impairment, confusion, and bronchospasm and sometimes allergy.

CARDIOVASCULAR RISK• chronic ibuprofen use has been found correlated

with risk of hypertension and myocardial infarction (heart attack), particularly among those chronically using high doses.

EFFECT ON THE SKIN• Along with other NSAIDs, ibuprofen has been associated

with the onset of bullous pemphigoid or pemphigoid-like blistering. This is because Ibuprofen has been reported to be photosensitising although weaker than other NSAID’s

NB: DRINKING ALCOHOL WHEN TAKING IBUPROFEN INCREASES RISK OF STOMACH BLEEDING.

OVERDOSE This is the term used to describe a more than normal intake of a drug.NORMAL DOSAGE: In medical practice the maximum amount for an adult is 800mg per dose or 3200mg per day but preparations generally advice a maximum of 1200mg per day. Human response in cases of overdose ranges from absence of symptoms to fatal outcome despite intensive-care treatment.

• Most symptoms are an excess of the pharmacological action of ibuprofen, and include:

- abdominal pain, nausea, vomiting, drowsiness, dizziness, headache, tinnitus, and nystagmus.

- Rarely, more severe symptoms, such as gastrointestinal bleeding, seizures, metabolic acidosis, hyperkalaemia, hypotension, bradycardia, tachycardia, atrial fibrillation, coma, hepatic dysfunction, acute renal failure, cyanosis,respiratory depression, and cardiac arrest have been reported.

Some new medical terms used• DYSPEPSIA: A painful, difficult or disturbed digestion

accompanied by symptoms of nausia, vomiting and heartburn.

• EPISTAXIS: Bleeding from the Nose.• PRIAPISM: Presence of a persistent, usually painful, erection

of the penis unrelated to sexual stimulation or desire.• TINNITUS: Hearing ringing, buzzing, or other sounds

without an external cause.• BULLOUS PEMPHIGOID: An acute or chronic autoimmune

skin disease, involving the formation of blisters at the space between the skin layers epidermis and dermis.

• PHOTOSENSITIZATION: development of abnormally heightened reactivity of the skin or eyes to sunlight.

CONCLUSION

• Doctors should always take time to prescribe the appropriate drug with it’s appropriate dosage.

• Patients should always seek for the advice of a medical personnel before beginning any treatment.

THANKS FOR YOUR ATTENTIO

N