Transcript D.2 Aspirin and Penicillin

ASPIRIN AND PENICILLIN
ASPIRIN
• THE SENSATION OF PAIN – OUR ABILITY TO PERCEIVE PAIN IS ONE OF OUR BEST DEFENSE
MECHANISMS.
• PAIN ALLOWS US TO ACT IN A WAY THAT REDUCES FURTHER DAMAGE TO OUR BODIES. FOR
EXAMPLE, REMOVING THE HAND FROM A HOT PLATE OR NOT BEING ABLE TO CONTINUE
RUNNING AFTER PULLING A MUSCLE.
ASPIRIN
• PAIN CAN BE ACUTE OR CHRONIC.
• PAIN IS UNPLEASANT, IRRITATING, DEBILITATING, AND CAN BECOME UNBEARABLE.
• PAINKILLERS CAN BE TAKEN TO REDUCE PAIN. PAINKILLERS BELONG TO GROUP OF DRUGS CALLED
ANALGESICS.
• PAINKILLERS TREAT THE SYMPTOMS (PAIN), NOT THE UNDERLYING CAUSE.
ASPIRIN
• PAIN IS DETECTED AS A SENSATION BY THE BRAIN WHEN NERVE MESSAGES ARE SENT
FROM VARIOUS PAIN RECEPTORS LOCATED AROUND THE BODY.
• THESE RECEPTORS ARE STIMULATED BY CHEMICALS KNOWN AS PROSTAGLANDINS .
• PROSTAGLANDINS ARE SUBSTANCES MADE AT THE SITES OF TISSUE DAMAGE OR
INFECTION AND ARE INVOLVED IN THE HEALING PROCESS.
• PROSTAGLANDINS CONTROL PROCESSES SUCH AS INFLAMMATION, BLOOD FLOW,
THE FORMATION OF BLOOD CLOTS, AND THE INDUCTION OF LABOUR.
ASPIRIN
• ONCE RELEASED, PROSTAGLANDINS PRODUCE THE INFLAMMATORY RESPONSE.
• THE INFLAMMATORY RESPONSE IS THE BODY'S NATURAL RESPONSE THAT OCCURS
IMMEDIATELY FOLLOWING TISSUE DAMAGE. IT'S MAIN FUNCTIONS ARE TO DEFEND THE BODY
AGAINST HARMFUL SUBSTANCES, DISPOSE OF DEAD OR DYING TISSUE AND TO PROMOTE THE
RENEWAL OF NORMAL TISSUE.
• THE INFLAMMATORY RESPONSE LEADS TO SWELLING, PAIN AND INCREASED TEMPERATURE
(FEVER).
ASPIRIN
• ASPIRIN AND NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAID) SUCH AS IBUPROFEN ARE
MILD ANALGESICS.
• THEY ACT BY INHIBITING THE PRODUCTION OF PROSTAGLANDINS FROM THE SITE OF INJURY,
WHICH LOWERS THE INFLAMMATION, THE FEVER AND THE PAIN.
• BECAUSE THE ANALGESICS DO NOT INTERFERE WITH THE FUNCTIONING OF THE BRAIN, THEY
ARE NON-NARCOTICS.
ASPIRIN
Mechanism of action of the drug aspirin. Aspirin works by
preventing the production of prostaglandin: aspirin molecules
(blue hexagons) enter the cell and chemically modify the
cyclooxygenase enzyme (purple) to prevent prostaglandin
synthesis
ASPIRIN
 SINCE ABOUT 400 B.C. IT WAS KNOWN THAT CHEWING WILLOW BARK REDUCED PAIN AND
FEVER.
 IN THE EARLY 1800'S, IT WAS SHOWN THAT THE ACTIVE INGREDIENT IN THE BARK IS SALICIN,
WHICH IS CONVERTED TO SALICYLIC ACID IN THE BODY.
 ALTHOUGH SALICYLIC ACID WAS EFFECTIVE FOR TREATING PAIN, IT TASTED AWFUL AND
CAUSED VOMITING.
SALICYLIC ACID (2-HYDROXYBENZOIC ACID)
ASPIRIN
• IN 1890, THE BAYER COMPANY IN GERMANY MADE AN ESTER DERIVATIVE OF SALICYLIC ACID
WHICH WAS MORE PALATABLE AND LESS IRRITABLE TO THE BODY; IT WAS CALLED ASPIRIN.
• TODAY, ASPIRIN CONTINUES TO BE THE MOST WIDELY USED DRUG IN THE WORLD.
• ASPIRIN IS EFFECTIVE IN REDUCING FEVER (ANTIPYRETIC) AND IN PROVIDING PAIN RELIEF.
ASPIRIN
• TO PRODUCE ASPIRIN, SALICYLIC ACID (2-HYDROXYBENZOIC ACID) IS CONVERTED INTO ASPIRIN
THROUGH AN ESTERIFICATION PROCESS, IN WHICH THE –OH GROUP OF THE SALICYLIC ACID IS
CONVERTED INTO THE ESTER GROUP.
• THE PROCESS IS CARRIED OUT WITH ETHANOIC ANHYDRIDE AND CONCENTRATED SULFURIC ACID
OR PHOSPHORIC ACID AS A CATALYST. ADDITIONALLY, THE MIXTURE IS WARMED GENTLY.
• THE ASPIRIN PRODUCT MUST THEN BE ISOLATED AND PURIFIED FROM THE MIXTURE.
ASPIRIN
• AFTER THE REACTION IS COMPLETE, THE PRODUCT IS COOLED TO CAUSE CRYSTALS TO FORM.
• THEN, THE PRODUCT IS SUCTION FILTERED AND WASHED WITH CHILLED WATER. SINCE THE ASPIRIN
HAS A VERY LOW SOLUBILITY IN WATER AT LOW TEMPERATURE, THIS PROCESS ALLOWS THE
SOLUBLE ACIDS TO BE REMOVED WITHOUT REMOVING THE ASPIRIN PRODUCT.
• THE PRODUCT IS THEN PURIFIED. THE PURIFICATION INVOLVES A TECHNIQUE KNOWN AS
RECRYSTALLIZATION.
• RECRYSTALLIZATION INVOLVES DISSOLVING THE IMPURE CRYSTALS IN HOT ETHANOL, WHICH
DISSOLVES THE IMPURE CRYSTALS. THIS FORMS A SATURATED SOLUTION OF ASPIRIN.
• THIS SOLUTION IS THEN COOLED SLOWLY. THIS DECREASES THE SOLUBILITY OF THE ASPIRIN, SO
THE ASPIRIN CRYSTALLIZES OUT OF THE SOLUTION AND CAN BE SEPARATED BY FILTRATION.
ASPIRIN
• THE PURITY CAN BE CONFIRMED BY MELTING POINT DETERMINATION.
• PURE SUBSTANCES HAVE WELL-DEFINED MELTING POINTS, WHICH ARE ALTERED BY THE
PRESENCE OF IMPURITIES. PURE ASPIRIN HAS A MELTING POINT OF 138O C - 140O C, AND
SALICYLIC ACID HAS A MELTING POINT OF 159O C. A MIXTURE WOULD HAVE A LOWER
MELTING POINT.
• THE YIELD OF THE REACTION CAN BE CALCULATED FROM THE MASS OF THE SALICYLIC ACID
USED AND THE MASS OF THE PRODUCT OBTAINED.
• AS WE LEARNED IN TOPIC 11, INFRARED SPECTROSCOPY CAN BE USED TO IDENTIFY THE PRESENCE
OF CERTAIN FUNCTIONAL GROUPS IN A MOLECULE.
•
•
SIMILARITIES:
DIFFERENCES:
ASPIRIN
• AS MENTIONED BEFORE, ASPIRIN WORKS BY BLOCKING THE SYNTHESIS OF PROSTAGLANDINS. THIS
EXPLAINS THE ANALGESIC EFFECTS OF ASPIRIN, AS WELL AS ITS EFFECTIVENESS IN REDUCING FEVER
AND INFLAMMATION.
• ASPIRIN CAN ALSO HAVE SIDE EFFECTS. THE SIDE EFFECTS CAN BE POSITIVE AND NEGATIVE.
• ASPIRIN IS AN ANTICOAGULANT- THIS MEANS THAT IT REDUCES THE ABILITY OF THE BLOOD TO CLOT.
THIS MAKES IT USEFUL IN THE TREATMENT OF PATIENTS AT RISK FOR HEART ATTACKS AND STROKES.
THIS SIDE EFFECT IS ALSO POTENTIALLY DANGEROUS IF IT IS TAKEN BY A PERSON WHOSE BLOOD
DOESN’T CLOT EASILY.
• NEGATIVE SIDE EFFECTS OF ASPIRIN INCLUDE IRRITATION AND EVEN ULCERATION OF THE STOMACH
AND THE DUODENUM, WHICH CAN LEAD TO BLEEDING. ADDITIONALLY, ASPIRIN IS NOT
RECOMMENDED FOR CHILDREN UNDER 12 BECAUSE IT HAS BEEN LINKED TO REYE’S SYNDROME, A
POTENTIALLY FATAL LIVER AND BRAIN DISORDER.
• THE EFFECTS OF ASPIRIN ARE MORE ACUTE WHEN IT IS TAKEN WITH ETHANOL IN ALCOHOLIC DRINKS.
THE SYNERGISTIC EFFECTS OF ETHANOL AND ASPIRIN CAN CAUSED INCREASED BLEEDING OF THE
STOMACH LINING AND INCREASED RISK OF ULCERS.
ASPIRIN
• ASPIRIN CAN BE MODIFIED FOR BETTER ABSORPTION AND BETTER DISTRIBUTION (INCREASED
BIOAVAILABILITY)
• ASPIRIN IS TAKEN ORALLY AND TRANSPORTED IN THE PLASMA OF THE BLOOD IN AQUEOUS
SOLUTION, HOWEVER, IT HAS A LOW SOLUBILITY IN WATER SINCE IT A LARGELY NON-POLAR
MOLECULE.
• IN ORDER TO INCREASE ITS BIOAVAILABILITY, ITS SOLUBILITY IN WATER NEEDS TO INCREASE.
THIS CAN BE ACCOMPLISHED THROUGH CHEMICAL MODIFICATION. THIS INVOLVES REACTING
THE ASPIRIN WITH AN ALKALI SUCH AS NaOH OR NaHCO3, SO THAT IT FORMS AN IONIC
SALT.
PENICILLIN
• PENICILLIN IS AN ANTIBIOTIC, WHICH IS A MEDICINE THAT INHIBITS THE GROWTH OF OR
DESTROYS MICROORGANISMS.
• PENICILLIN REVOLUTIONIZED MODERN MEDICINE.
• PENICILLIN WAS DISCOVERED BY ALEXANDER FLEMING IN 1928 WHILE WORKING ON BACTERIAL
CULTURES. FLEMING PUBLISHED HIS FINDINGS, BUT DID NOT ISOLATE OR IDENTIFY THE ACTIVE
INGREDIENT.
PENICILLIN
• IN THE EARLY 1940'S, HOWARD FLOREY AND ERNST CHAIN ISOLATED PENICILLIN AS THE
ANTIBACTERIAL AGENT PRODUCED BY THE PENICILLIUM MOLD.
• IN 1941, PENICILLIN WAS USED IN HUMAN TRIALS. PENICILLIN SAVED THE LIVES OF MANY
SOLDIERS IN WORLD WAR II.
• IN 1945, DOROTHY HODGKIN DETERMINED THE STRUCTURE OF PENICILLIN G, THE MAJOR
CONSTITUENT OF THE PENICILLIUM MOLD.
PENICILLIN
• THE PENICILLIN MOLECULE CONTAINS A FIVE MEMBERED RING, CONTAINING A SULFUR ATOM,
ATTACHED TO A FOUR MEMBERED RING CONTAINING A CYCLIC AMIDE GROUP, KNOWN AS A
BETA–LACTAM.
• THE BETA-LACTAM RING CONTAINS ONE NITROGEN ATOM AND THREE CARBON ATOMS. THIS IS
THE PART OF THE MOLECULE RESPONSIBLE FOR ITS ANTIBACTERIAL PROPERTIES.
PENICILLIN
• THE BETA-LACTAM ANTIBIOTICS WORK BY DISRUPTING THE FORMATION OF THE CELL
WALLS OF BACTERIA BY INHIBITING A KEY BACTERIAL ENZYME CALLED TRANSPEPTIDASE.
• AS THE DRUG APPROACHES THE ENZYME, THE HIGH REACTIVITY OF THE AMIDE GROUP IN
THE RING CAUSES IT TO BIND TO AND DEACTIVATE THE TRANSPEPTIDASE ENZYME.
• WHEN THE TRANSPEPTIDASE ENZYME IS DEACTIVATED, THE BACTERIA IS UNABLE TO
CONSTRUCT A CELL WALL AND IT DIES.
PENICILLIN
• INACTIVATION OF THE ENZYME BLOCKS THE PROCESS OF CELL WALL CONSTRUCTION IN
THE BACTERIUM BY PREVENTING THE FORMATION OF POLYPEPTIDE CROSS-LINKS.
• WITHOUT THE CROSS-LINKS, THE CELL WALL IS UNABLE TO SUPPORT THE BACTERIUM, SO IT
BURSTS AND DIES.
PENICILLIN
• A DISADVANTAGE OF PENICILLIN G IS THAT IT IS BROKEN DOWN BY STOMACH ACID, SO IT
HAS TO BE INJECTED INTO THE BLOOD.
• DIFFERENT FORMS OF PENICILLIN HAVE BEEN DEVELOPED BY MODIFYING THE SIDE CHAIN (THE
R GROUP) AND THIS ENABLES THE DRUG TO RETAIN ITS ACTIVITY WHEN INGESTED IN PILL
FORM.
• THE USE OF PENICILLIN IS ALSO LIMITED BY THE SIGNIFICANT NUMBER OF PEOPLE WHO
SUFFER FROM ALLERGIC RESPONSES TO IT.
BACTERIAL RESISTANCE TO PENICILLIN
• BACTERIAL RESISTANCE TO PENICILLIN AND OTHER ANTIBIOTICS HAS BECOME A MAJOR PROBLEM
IN MODERN MEDICINE.
• AS EARLY AS THE 1940S PENICILLIN PROVED TO BE INEFFECTIVE AGAINST SOME POPULATIONS OF
BACTERIA.
• THESE RESISTANT BACTERIA PRODUCE AN ENZYME KNOWN AS PENICILLINASE OR BETALACTAMASE, WHICH CAN OPEN PENICILLIN'S FOUR-MEMBERED RING AND RENDER IT INACTIVE.
• AS NON-RESISTANT STRAINS OF BACTERIA HAVE BEEN WIPED OUT BY ANTIBIOTICS, THE
POPULATION OF THE RESISTANT BACTERIA HAVE BEEN ABLE INCREASE BECAUSE THEY HAVE LESS
COMPETITION.
RESPONSES TO THE CHALLENGE OF ANTIBIOTICS
RESISTANCE
• 1. PRODUCE DIFFERENT FORMS OF PENICILLIN THAT CAN WITHSTAND THE ACTION OF
PENICILLINASE. TWO PENICILLIN DERIVATIVES THAT STILL CONTAIN THE BETA-LACTAM RING
ARE OXACILLIN AND METHICILLIN. THEY HAVE MODIFIED SIDE CHAINS (R GROUP) THAT
PREVENTS THE PENICILLINASE ENZYME FROM BINDING.
• 2. BETTER CONTROL AND RESTRICTIONS FOR THE USE OF ANTIBIOTICS.
• 3. ENCOURAGE DOCTORS TO AVOID OVER PRESCRIPTION OF ANTIBIOTICS WHEN OTHER
TREATMENTS ARE EFFECTIVE.
• 4. EDUCATE PATIENTS IN THE IMPORTANCE OF COMPLETING THE FULL COURSE OF
ANTIBIOTICS.