Antibiotics&analgesics (3).pptxvvvvvvvvvvvvv

GUIDED BY:
DR. RANA K. VARGHESE, PROFESSOR AND HOD.
DR. MALWIKA SISODIYA, READER.
DR. RAUNAK SINGH, READER.
DR. NAVEEN KUMAR GUPTA, READER.
DR. NITIN AGRAWAL, SENIOR LECT.
DR. ANITA CHANDRAKAR, SENIOR LECT.
DR. CHANDRABHAN GENDLY, SENIOR LECT.
PRESENTED BY:
DR SWATYI PRIYA
POST GRADUATE STUDENT
DEPT. OF CONSERVATIVE
DENTISTRY
AND ENDODONTICS

Introduction
• Tools for the control of infections in modern dentistry
are usually provided by antibiotics.
• However, because endodontic therapy now emphasizes
the importance of debridement procedures and the
elimination or reduction of microorganisms and their
substrate, infections of serious nature rarely occur.

• A common error in antibiotic therapy is to prescribe too
short of a duration.
• Unfortunately such a schedule will kill off the weaker
organisms, thus leaving more substrate available for those
with greater virulence to become entrenched.

• The decision to use an antimicrobial or antibiotic agent in
managing infection is based on several factors.
• The clinician must first diagnose the cause of infection and
determine the appropriate dental treatment that may include
multiple modalities, including initiation of endodontic
therapy or mechanical disruption of the infectious
environment.
• The determination as to whether conjunctive therapy is
indicated is based on several factors including host defense
mechanisms, severity of infection, magnitude of the
extension of the infection and expected pathogen.

History
• Term antibiosis- Jean Paul Vuillemin 1877
• Renamed antibiotics - Selman Waksman,1942.
• 1928 Alexander Fleming - penicillin
• Gerhard Domaqk in 1932 in Germany- first sulfonamide &
received Noble Prize the 1939.
• Florey and Chain purifying penicillin,in 1942
• Chemical structure of penicillin - Dorothy Crowfoot
Hodgkin in 1945.

• The first reported local use of an antibiotic in endodontic
treatment was in 1951 when Grossman used a
polyantibiotic paste known as PBSC.
• PBSC contained penicillin to target Gram-positive
organisms, bacitracin for penicillin-resistant strains,
streptomycin for Gram-negative organisms, and caprylate
sodium to target yeasts – these compounds were all
suspended in a silicone vehicle.

• Although clinical evaluation suggested that the paste
conferred a therapeutic effect, the composition was
ineffective against anaerobic species which are now
appreciated as being the dominant organisms responsible
for endodontic diseases.
• In 1975, the USA Food and Drug Administration banned
PBSC for endodontic use primarily because of the risks of
sensitization and allergic reactions attributed to penicillin.

• The two most common antibiotic-containing commercial
paste preparations currently available are Ledermix™
paste (Lederle Pharmaceuticals, Wolfsratshausen,
Germany) and Septomixine Forte™ paste (Septodont,
Saint-Maur, France).
• Both of these preparations also contain corticosteroids as
anti inflammatory agents.

• Septomixine Forte contains two antibiotics – neomycin
and polymixin B sulphate.
• Neither of these can be considered as suitable for use
against the commonly reported endodontic bacteria
because of their inappropriate spectra of activity.
• Neomycin is bactericidal against Gram-negative bacilli
but it is ineffective against Bacteroides and related
species, as well as against fungi. Polymyxin B sulphate
is ineffective against Gram-positive bacteria.

Definition
ANTIBIOTICS
• These are substances produced by microorganism, which
suppress the growth of or kill other microorganisms at
very low concentrations.

Classification of antibiotics
• Based on spectrum of activity:
1. Narrow spectrum- Penicillin G ,Streptomycin,
Erythromycin.
2. Broad spectrum- Tetracyclines, Chloramphenicol.
• Type of action:
1. Bacteriostatic- Sulfonamides, Tetracyclines,
Chloramphenicol, Erythromycin.
2. Bactericidal- Penicillins, Aminoglycosides,
Cephalosporins, Vancomycin, Ciprofloxacin.

Mechanism of action
• Inhibition of bacterial cell wall synthesis .
penicillins, cephalosporins, vancomycin.
• Inhibition of cytoplasmic membrane function.
polymyxin, gramicidin.
• Inhibition of nucleic acid synthesis.
rifampicin.
• Inhibition of protien synthesis.
Streptomycin, gentamycin.

Classification of antibiotics
• A. Chemical structure
1.Sulfonamides and related drugs- Sulfadiazine
2.Diaminopyrimidines- Trimethoprim, Pyrimethamine
3.Quinolones- Nalidixic acid, Ciprofloxacin
4.Tetracycline- Oxytetracycline, Doxycycline
5.Nitobenzene derivative-Chloramphenicol
6.Aminoglycosides- Streptomycin,Neomycin
7.Macrolide antibiotics- Erythromycin, Azithromycin
8.Polypeptide-Polymyxin B, Bacitracin
9.Glycopeptides-Vancomycin
10.Nitroimidazoles-Metronidazole, Tinidzole
11.Polyene antibiotics- Nystatin
12.Azole derivatives- Ketoconazole , Fluconazole

• B. Mechanism of action
Inhibition of bacterial cell wall synthesis .
penicillins, cephalosporins, vancomycin.
• Inhibition of cytoplasmic membrane function.
polymyxin, gramicidin.
Inhibition of nucleic acid synthesis.
rifampicin.
Inhibition of protien synthesis.
Streptomycin, gentamycin

• C. Types of organism against which
primarily active
1. Antibacterial- Penicillins, Aminoglycosides
2. Antifungal- Amphotericin B, Ketoconazole
3. Antiviral- Acyclovir, Zidovudine
4. Antiprotozoal- Chloroquine, Metronidazole
5. Antihelmintic- Mebendazole

• Based on spectrum of activity:
1. Narrow spectrum- Penicillin G ,Streptomycin, Erythromycin.
2. Broad spectrum- Tetracyclines, Chloramphenicol.
• Type of action:
1. Primarily bacteriostatic- Sulfonamides, Tetracyclines,
Chloramphenicol, Erythromycin.
2. Primarily bactericidal- Penicillins, Aminoglycosides,
Cephalosporins, Vancomycin, Ciprofloxacin

Antibiotic combinations
• The result may be additive, potentiative or
antagonistic.
• Additive response :one in which the antimicrobial
effect of the combination is equal to the sum of the
effects of the two drugs alone.
• Potentiative interaction :one in which the effect of
the combination is GREATER than the sum of the
effects of the individual agents.

• Antagonistic response : in certain cases the combination
of two antibiotics may be less effective than one of the
agents by itself (ie combination of a bacteriostatic with a
bactericidal drug)

• Disadvantages of antibiotic combinations
1) Increased risk of toxic and allergic reactions
2) Possible antagonism of antimicrobial effects.
3) Increased risk of suprainfection
4) Selection of drug resistant bacteria.
5) Increased cost.

Problems that arise with the use of AMAs
1. Toxicity:
A. Local irritancy- gastric irritation, pain, thromboflebitis.
B. Systemic toxicity- kidney toxicity, bone marrow
depression, neurological toxicity.
2. Hypersensitivity reaction: drugs involved are penicillins,
cephalosporins, sulfonamides.

3. Drug resistance- it refers to unresponsiveness of a
microorganism to an AMAs. It can be-
A. Natural: always been resistant to AMAs
B. Acquired: it is the development of resistance by an
organism due to the use of an AMA over a period of time.

• Resistance may be developed by mutation or gene
transfer:
1. Mutation: it is a stable and heritable genetic change that
occurs spontaneously and randomly among
microorganism.
• Not induced by the AMA.
• Microbe contains few mutant cells require higher
concentration of AMA for inhibition.
• They proliferate when the sensitive cells are eliminated by
AMA.
• In time the sensitive strain are replaced by a resistant one.

• Mutation and resistance may be:
1. Single step: high degree of resistance, emerges rapidly
eg. Enterococci to streptomycin.
2. Multistep: sensitivity decreases gradually in a stepwise
manner.
eg. Resistance to erythromycin, tetracycline is developed
by many organism in this manner.

Gene transfer
• From one organism to another can occur by:
1. Conjugation: Bacterial conjugation is the transfer of
genetic material (plasmid) between bacterial cells by
direct cell-to-cell contact or by a bridge-like connection
between two cells. Conjugation is a mechanism of
horizontal gene transfer as are transformation and
transduction although these two other mechanisms do not
involve cell-to-cell contact.

• Transformation: is the genetic alteration of a cell
resulting from the direct uptake, incorporation and
expression of exogenous genetic material (
exogenous DNA) from its surroundings and taken up
through the cell membrane.
• Transformation occurs naturally in some species of
bacteria, but it can also be effected by artificial means in
other cells. For transformation to happen, bacteria must
be in a state of competence, which might occur as a time-
limited response to environmental conditions such as
starvation and cell density.

• Transduction: is the process by which DNA is
transferred from one bacterium to another by a virus. It
also refers to the process whereby foreign DNA is
introduced into another cell via a viral vector.
Transduction does not require physical contact between
the cell donating the DNA and the cell receiving the DNA
(which occurs in conjugation), and it is DNase resistant (
transformation is susceptible to DNase).

cross-resistance
• Resistance to a particular antibiotic that often results in
resistance to other antibiotics, usually from a similar
chemical class, to which the bacteria may not have been
exposed.
• Cross-resistance can occur, for example, to both colistin
and polymyxin B or to both clindamycin and lincomycin.

superinfection
• The act or process of superinfecting a cell or organism.
• An infection following a previous infection, especially
when caused by microorganisms that have become
resistant to the antibiotics used earlier.
• infection that occurs while you are being treated for
another infection

The Nature and treatment of Endodontic Infections
• The vast majority of infections of endodontic origin can be
effectively managed with the use of antibiotics.
• Systemically administered antibiotics are not a substitute
for proper endodontic treatment.
• Chemomechanical debridement of the infected root canal
system with drainage through the root canal or by incision
and drainage of soft tissue will decrease the bio burden so
that a normal healthy patient can begin the healing process.

• Antibiotics are not recommended for
healthy patients with symptomatic pulpitis,
symptomatic apical periodontitis, drainage
sinus tract, localized swelling of
endodontic origin.

• An antibiotic regimen should be prescribed in
conjunction with proper endodontic therapy
when there are systemic signs and symptoms or a
progressive spread of infection.
o Presence of fever >100F
o Malaise
o Cellulitis
o Unexplained trismus
o Progressive swelling

• Under these circumstances, an antibiotic is indicated in
addition to debridement of root canal harboring the
infection and drainage of any accumulated prevalence.
• Patients with serious endodontic infections should be
closely followed on a daily basis. The patients condition
will usually improve once the source of the infection is
removed.

• Because of the lack of circulation, systemically
administered antibiotics are not effective against a reservoir
of microorganisms within an infected root canal system.
• Likewise, a minimum inhibitory concentration of an
antibiotic may not reach a space filled with pus because of
poor circulation.
• The antibiotics moves via diffusion gradient through the
edematous fluid and purulent exudates that accumulates in
an anatomic space.

• An incision for drainage will allow drainage
of the purulent material and improve
circulation of the area.
• Empirical selection of an antibiotic must be based on one’s
knowledge of which bacteria are most commonly associated
with endodontic infections and their antibiotic susceptibility.
• The clinician must be thoroughly familiar with antibiotic
and inform the patient of the benefits, possible side effects
and possible sequelae of failing to take the proper dosage.

• The antibiotic should be generally be continued for 5-7
days following resolution of the major clinical signs and
symptoms of the infection.
• Following treatment of the source of the infection and
adjunctive antibiotic therapy, significant improvement in
the patient’s status occurs in 24 – 48 hours.
• A loading dose is important to provide an initial adequate
therapeutic level of antibiotic. An adequate maintenance
dose is recommended to prevent the selection of resistant
bacteria.

GUIDELINES FOR PRESCRIBING ANTIBIOTICS:
1. Make an accurate diagnosis which is based on thorough
history both medical and dental to reveal or avoid adverse
reactions such as allergies and drug Interactions.
2. Use appropriate antibiotics and dosing schedules.
3. Consider using narrow spectrum antibacterial drugs in
simple infections to minimize disturbance of the normal
microflora, and preserve the use of broad spectrum for
more complex infections.

4. Obtain thorough knowledge of side effects and drug
interactions of antibacterial drugs before prescribing it.
5. Educate the patient regarding the proper use of drug and
stress the importance of completing the full course of
therapy.

Selection of an antibiotic regimen:
• There are different types of endodontic infections, which
are usually associated with different clinical conditions.
• Most commonly found are facultative and strict
anaerobes.
• The primary root canal infection is caused by M.O.
colonizing, the necrotic pulp tissue.
• Primary infections are mixed infections and predominated
by anaerobic bacteria.
• These are bacteroids, porphyromonas, prevotella,
fusobacterium, peptostreptococcus etc.

• Facultative or micro aerophilic streptococci are also
commonly found in primary infections.
• Current evidence suggests that Gram negative anaerobic
bacteria are closely associated with the etiology of
symptomatic periradicular lesions.
• Under ideal conditions, susceptibility testing would be
undertaken before the prescription of antimicrobial drugs.
• Unfortunately with the polymicrobial nature of
endodontic infections, it may take several days to weeks
to obtain a complete susceptibility profile of the bacteria.

• Therefore by necessity, the initial antibiotic prescription is
empirical.
• Penicillin VK remains the first antibiotic of choice
because it has remained effective against most of the
facultative and strict anaerobes commonly found in
polymicrobial endodontic infection.
• Bacterial sensitive to penicillin includes anaerobes like
Porphyromonas, Prevotella, Peptostreptococcus,
Fusobacterium, Actinomyces.

Indications for culturing:
• Culturing is undertaken when the patient is not responding
to the first antibiotic prescribed after 48 hrs and
appropriate dental treatment has been completed.
• The infection is progressing to other facial spaces.
• The patient is immunocompromised or has a history of
bacterial endocarditis and is not responding to antibiotic
therapy.

Collection of a microbial sample:
• An aseptic microbial sample from a root canal is
accomplished by first isolating the tooth with a rubber
dam and disinfecting the tooth surface and rubber dam
with sodium hypochlorite or other disinfectant.
• Sterile burs and instruments must be used to gain access
to root canal system.
• Antimicrobial solution should be used until after the
microbial sample has been taken.

• If there is drainage from the canal it may be sampled with a
sterile paper point or aspirated into a syringe with a sterile
18-25 gauge needle.
• The aspirate should either be taken immediately to a
microbiology lab in syringe or in transport media provided
by the lab.
• To sample a dry root canal, a sterile syringe should be used
to place some pre-reduced transport medium into canal.
• A sterile endodontic instrument is then used to scrape the
walls of the canal to suspend microorganisms in the medium.

• To obtain sample from a soft swelling after the profound
anaesthesia has been achieved, the surface of the mucosa
should be dried and disinfected with an iodophor swab.
• A sterile 16-20 gauge is then used to aspirate the exudates.
The aspirate should be handled as described above.
• If purulence cannot be aspirated, a sample can be
collected on a swab after incision for drainage.

Mechanism of action:
• Antibiotics have various effects on bacterial based on their
pharmacologic action.
• The most commonly used antibiotics in dentistry are
Penicillins, Cephalosporins. These are bactericidal.
• They work by attacking the cellular processes necessary
for bacterial cell wall synthesis while having no effect on
host cells.
• Macrolides like Azithromycin and Clarithromycin are the
drugs of choice in cases where patients are allergic to
Penicillin.

• Erythromycins (bactericidal) – they inhibit the
translation needed for bacterial protein synthesis.
• Metronidazole (bactericidal) – it is mainly indicated for
anaerobic infections and directly degrades DNA in
bacteria.
• Newer synthetic antibiotics like fluoroquinolones have
limited role in endodontics and are only indicated in cases
where culture and sensitivity prove their use. They
interfere with replication of DNA.

• Tetracyclines kill the broadest spectrum of microbes of
all antibiotics.
• They have recently found a place in periodontal infection
fighting and should be included in endodontist’s
armamentarium since periodontal pathogens frequently
invade the root canal and periapical tissues.
• The sample should be gram stained to demonstrate which
types of m.o. predominate.
• Antibiotics can usually be chosen to treat endodontic
infections based on identification of micro-organism.

Types of Antibiotics and
Recommended Dosages
• Penicillins
• Mechanism of action : the drugs weaken the cell
wall ,causing the bacterium to take up excessive amounts
of water and then rupture.

Classification :
• 1) Narrow-spectrum (penicillinase sensitive)
• 2) Narrow-spectrum that are penicillinase resistant
(antistaphylococcal)
• 3) Broad-spectrum penicillins (aminopenicillins)
• 4) Extended-spectrum penicillins
(antipseudomonal )

• Cephalosporins
• The drugs are beta-lactamic antibiotics similar in structure
and actions with penicillins.
• Broadspectrum antibiotics with low toxicity.
• Mechanism of action :
Disruption of cell wall synthesis and consequent lysis of
the cell.

• Classification:
• a) First generation :highly active against gram positive
bacteria (staphylococci)
- Cefadroxil, Cephradine
• b)Second-generation : enhanced activity against gram-
negative bacteria
- Cefuroxime axetil, Cefaclor
• c)Third-generation : more active against gram negative
aerobes (important activity against Pseudomonas Aeruginosa).
- Cefixime, Cefpodoxime proxetil
• d)Fourth generation : highly resistant to betalactamases.
Broad spectrum antibiotics.
- Cefepime , Cefpirome

• ADVERSE EFFECTS
1)Allergic reactions :rash that develops after days of
treatment .Severe immediate reactions are rare.
2) Bleeding :Five cephalosporins cause bleeding tendencies
(cefamandole, cefmetazole, cefoperazone, cefotetan and
moxalactam).Two mechanisms involved: reduction of
prothrombin levels and impairment of platelet aggregation
(only with moxalactam).
3)Thrombophlebitis :it may develop during IV infusion (--
>change the infusion site).
4) Pain at sites of IV infusion.

• Tetracycline
• Broad spectrum antibiotics.
• Mechanism of action : suppression of bacterial growth
by inhibiting protein synthesis.
• Absorption: the drugs should NOT be administered
together with calcium supplements, milk products, iron
supplements, magnesium-containing laxatives, antacids
(formation of chelates reduces absorption).

• Adverse Effects
1)Gastrointestinal irritation (burning, nausea, vomiting,
diarrhea)
2) Effects on bones and teeth (teeth discoloration in
children under 5 years old. The drugs can also suppress
long-bone growth in premature infants. The effect is
reversible).
3) Suprainfection (C. difficile pseudomembranous
colitis ,fungus infections usually with Candida albicans)

4) Hepatotoxicity (fatty infiltration of the liver)
5) Renal toxicity (the drugs may exacerbate renal
dysfunction in patients with pre-existing kidney
dysfunction )
6) Photosensitivity (the drugs increase sensitivity of skin to
UV radiation).

Penicillin VK
• Based on recent antibiotic susceptibility tests, penicillin
VK is the drug of choice for periradicular abscesses.
• It is effective against facultative and anaerobic
microorganisms associated with endodontic infections.
• Penicillin VK remains the antibiotic of choice because
of its effectiveness, low toxicity and low cost.
• However, about 10 percent of the population will give a
history of allergic reactions to penicillin

• To achieve a steady serum level with penicillin VK, it
should be administered every four to six hours.
• A loading dose of 1,000 mg of penicillin VK should be
orally administered, followed by 500 mg every four to six
hours for five to seven days.
• Following debridement of the root canal system and
drainage of facial swellings, significant improvement of
the infection should be seen within 48-72 hours.

Amoxicillin
• Amoxicillin is an analogue of penicillin that is rapidly
absorbed and has a longer half-life.
• This is reflected in higher and more sustained serum
levels than penicillin VK.
• Because of these traits, amoxicillin is often used for
antibiotic prophylaxis of patients that are medically
compromised .

• Amoxicillin may be used for serious odontogenic
infections, however, its extended spectrum may select for
additional resistant strains of bacteria.
• The usual oral dosage for amoxicillin is 1,000 mg
loading dose followed by 500 mg every eight hours for
five to seven days.

• The combination of amoxicillin with clavulanate
(Augmentin) was the most effective antibiotic combination
in recent susceptibility tests.
• Clavulanate is a competitive inhibitor of the beta
lactamase enzyme produced by bacteria to inactivate
penicillin.
• The usual oral dosage for amoxicillin with clavulanate
is 1,000 mg loading dose followed by 500 mg every
eight hours for five to seven days.

Clindamycin
• Clindamycin is effective against gram-positive
facultative microorganisms and anaerobes.
• Clindamycin is a good choice if a patient is allergic to
penicillin or a change in antibiotic is indicated.
• Penicillin and clindamycin have been shown to produce
good results in treating odontogenic infections.

• Clindamycin is well distributed throughout most body
tissues and reaches a concentration in bone approximating
that of plasma.
• The oral adult dosage for serious endodontic infections
is a 600 mg loading dose followed by 300 mg every six
hours for five to seven days.

Metronidazole
• Metronidazole may be used in combination with
penicillin or clindamycin.
• If a patient’s symptoms worsen 48-72 hours after initial
treatment and the prescription of either penicillin or
clindamycin, metronidazole may be added to the original
antibiotic.
• Metronidazole is a synthetic antimicrobial agent that is
bactericidal and has activity against anaerobes, but lacks
activity against aerobes and facultative anaerobes.

• Susceptibility tests have shown significant numbers of
bacteria resistant to metronidazole.
• It is important that the patient continue to take penicillin
or clindamycin, which are effective against the facultative
bacteria and those resistant to metronidazole.
• The usual oral dosage for metronidazole is a 1,000 mg
loading dose followed by 500 mg every six hours for
five to seven days.

Erythromycin
• Erythromycin is a macrolide that has traditionally
been prescribed for patients allergic to penicillin
• However, it is not effective against anaerobic bacteria.
• Erythromycin is no longer recommended for treatment of
endodontic infections because of this poor spectrum of
activity and significant gastrointestinal upset.

Clarithromycin and Azithromycin
• Clarithromycin and azithromycin are macrolides that
have a spectrum of activity that includes some anaerobes
involved in endodontic infection and offer improved
pharmacokinetics.
• Food slows down but does not affect the bioavailability of
clarithromycin.
• Food and heavy metals may inhibit the absorption of
azithromycin.

• The oral dosage for clarithromycin is a 500 mg loading
dose followed by 250 mg every 12 hours for five to seven
days.
• The oral dosage for azithromycin is a 500 mg loading
dose followed by 250 mg once a day for five to seven
days.

Cephalosporins
• Cephalosporins are usually not indicated for the
treatment of endodontic infections.
• First-generation cephalosporins do not have activity
against the anaerobes usually involved in endodontic
infections.
• Second-generation cephalosporins have some efficacy for
anaerobes, however, there is a possibility of cross
allergenicity of cephalosporins with penicillin.

Doxycycline
• Doxycycline occasionally may be indicated when the
above antibiotics are contraindicated.
• However, many strains of bacteria have become resistant
to the tetracyclines.

Ciprofloxacin
• Ciprofloxacin is a quinilone antibiotic that is not
effective against anaerobic bacteria usually found in
endodontic infections.
• With a persistent infection it may be indicated if culture
and sensitivity tests demonstrate the presence of
susceptible organisms.

Pulp revascularisation- triple antibiotic paste
• A new area which has received a lot of interest recently is
pulp revascularisation.
• This can only be performed in teeth with a very good
blood supply (open apices).
• The theory of the procedure is that if the pulp which is
infected coronally is removed then the stem cells in the
apical region of the root sheath and pulp will be allowed to
multiply and differentiate causing apical formation.

• The first stage of the procedure involves use of a triple
antibiotic paste to ‘sterilise’ the canal.
• The antibiotics used are ciprofloxacin, metronidazole and
minocycline.
• These are ground up and mixed with distilled water to
create a paste which is placed within the root canal for 4
weeks.
• After this time the dressing is removed and a blood clot is
created within the canal by intentionally instrumenting
through the apex.

• Mineral trioxide aggregate (MTA) is then gently placed
onto this clot and the tooth is restored.
• Discolouration of the teeth can be a problem with this
treatment.
• So far the treatment has been limited to case reports and
there are no studies showing long term of success.
However it may become an area where the use of local
antibiotics becomes essential.

Analgesics
“Analgesics are drugs that selectively
relieve pain by acting in the CNS or
on the peripheral pain mechanisms,
without altering consciousness”

History of Analgesics
• BC: Ancient Greeks and Romans used salicylate
extracts derived from willow leaves as analgesics
and antipyretics
• Middle Ages: Medicinal herb gardens featured salicylate
containing wintergreen and meadowsweet plants
• 1763: Edward Stone reported on use of willow bark
powder as an anti-inflammatory agent.
• 1853: Von Gerhardt synthesized a crude form of aspirin
(acetylsalicylic acid)
• 1860: Felix Hoffman synthesized pure aspirin

• Opiates are one of the oldest types of drugs
in history
• Opium is extracted from poppy seeds (Paper
somniforum)
• Use of Opium was first recorded in China
over 2000 years ago
• Greeks dedicated the Opium poppy to the
Gods of Death (Thanatos), Sleep (Hypnos),
and Dreams (Morpheus)
• Sixteenth Century is the first reported use of
Opium for its Analgesic qualities

• 1949: The NSAID Phenylbutazone was introduced
• 1963: Indomethacin was introduced
• 1971: Vane and Piper demonstrated that NSAIDs
inhibit prostaglandin production
• 1974: Ibuprofen was introduced
• 1976: Miyamoto et al identified the COX-1 enzyme
• 1989: Simmons et al identified the COX-2 enzyme
• 1999: The COXIBs celecoxib and rofecoxib were
introduced
• 2004: Rofecoxib was banned in india due to its
cardiotoxic effect

Classification of NSAIDs
• Non selective COX inhibitors (conventional
NSAID’s)
– Salicylates: Asprin
– Propionic acid derivatives: Ibuprofen,
Naproxen,
Ketoprofen,
– Anthranilic acid derivative: Mephenamic acid
– Aryl-acetic acid derivatives: Diclofenac
– Oxicam derivatives: Piroxicam, Tenoxicam
– Pyrrolo-pyrrole derivative: Ketorolac
– Indole derivative: Indomethacin
– Pyrazolone derivatives: Phenylbutazone,

• Preferential COX-2 inhibitors
– Nimesulide, Meloxicam, Nabumetone
• Selective COX-2 inhibitors
– Celecoxib, Rofecoxib, Valdecoxib, Etoricoxib
• Analgesics-antipyretics with poor anti inflammatory
action
– Para aminophenol derivative: Parcetamol
(Acetaminophen)
– Pyrazolone derivatives: Metamizol (Dipyrone),
– Benzoxazocine derivative: Nefopam

NSAIDs and prostaglandin (PG) synthesis inhibition
• Prostaglandins, prostacyclin (PGI2) and
thromboxane A2(TXA2) are produced from
arachidonic acid by the enzyme cyclo oxygenase
which exists in 2 forms
– (COX-1) - Cyclo oxygenase -1
– (COX-2) - Cyclo oxygenase -2
• Most NSAID’s inhibit COX-1 and COX-2
non selectively

Cellular Arachidonic Acid Metabolism
Inflammatory
Leukotrienes

Beneficial actions due to PG synthesis inhibition
• Analgesia
• Anti pyresis
• Anti inflammatory

Toxicities due to PG synthesis
inhibition
• Gastric mucosal damage
• Bleeding: inhibition of platelet function
• Limitation of renal blood flow: sodium and water
retention
• Delay / prolongation of labour

Adverse effects of NSAID’s
• Gastrointestinal
– Gastric irritation, erosions, peptic ulceration,
gastric bleeding / perforation, esophagitis
• Renal
– Sodium and water retention, chronic renal failure,
interstitial nephritis, papillary necrosis (rare)
• Hepatic
– hepatic failure (rare)

Adverse effects of NSAID’s
• CNS
– Headache, mental confusion, behavioral
disturbances, seizure precipitation
• Haematological
– Bleeding, thrombocytopenia, hemolytic
anaemia,
• Others
– Asthma exacerbation, nasal polyposis, skin
rashes, pruritis, angioedema

Salicylates -Asprin
• Is acetylsalicylic acid
• Pharmacological actions
– Analgesic, antipyretic, anti inflammatory actions
• Analgesic action is due to prevention of PG
mediated sensitization of nerve endings
• Resets the hypothalamic thermoregulatory centre
• Anti inflammatory at high doses
– Blood
• Irreversibly inhibits TXA2 synthesis thus
interferes with platelet aggregation and BT is
prolonged
• Long term use of large doses decreases
synthesis of clotting factors in liver

Aspirin
– Respiration
• Anti inflammatory doses – stimulates respiration
• Hyperventilation in salicylate poisoning, in
doses higher than this there is respiratory
depression

Aspirin
– GIT
• Aspirin irritates gastric mucosa & causes
epigastric pain, nausea and vomiting
• ‘Ion trapping’ in gastric mucosa increases
gastric toxicity
• Acute ulcers, erosive gastritis, congestion and
microscopic hemorrhages
– Metabolic effects
• Chronic use can cause negative nitrogen
balance by increased conversion of protein to
carbohydrate.

Aspirin
• Precautions and contraindications
– Contraindicated in patients sensitive to it
and in peptic ulcer, bleeding tendencies, & in
children suffering from chicken pox or
influenza. (due to risk of Reye’s syndrome)
– In chronic liver disease
– Asprin should be stopped 5 days before
elective surgery, dental extraction
– Pregnancy and lactating mothers

Asprin
• Adverse effects
– Most important – gastric mucosal damage
and peptic ulceration
– Acute salicylate poisoning
• Uses
– As analgesic
– As antipyretic
– Acute rheumatic fever
– Rheumatoid arthritis
– Osteoarthritis

Propionic acid derivatives
Ibuprofen –
• first introduced member of this class
• Anti inflammatory efficacy is lower than asprin
• Inhibit Prostaglandin synthesis
• Doses-400-600mg TDS
• Adverse effects
– Milder and better tolerated than asprin
– GI disturbances are present
– Precipitate asprin-induced asthma

Propionic acid derivatives
• Uses
– Analgesic and Antipyretic and anti-
inflammatory
– Soft tissue injuries, tooth extraction,
fractures, post operative pain.
– Rheumatoid arthritis, osteoarthritis and
musculoskeletal disorders… where pain is
more prominent than inflammation

Aryl-acetic acid derivative
• Diclofenac sodium
– Inhibits PG synthesis
– Has short lasting anti platelet action
– Adverse effects are mild
– Dose- 50mg TDS
• Uses
– Toothache
– Post operative and post traumatic inflammatory conditio
– Rheumatoid arthritis and osteoarthritis

Pyrrolo-pyrrole derivative
Ketorolac
– Potent analgesic and moderate anti inflammatory
activity
– Used in post operative pain after surgery and
acute dental pain

Preferential COX-2 inhibitors
• Nimesulide
– Newer NSAID
– Completely absorbed orally
– Used in patient with history of asthma and anaphylactic
reactions to other NSAIDs.
– Used for short-lasting painful inflammatory conditions like -
- sports injuries,
- sinusitis and other ENT disorders
- fever and low back pain
Adverse effect – Hepatotoxic in pediatric patients .
• Recently instances of hepatic failure have been reported

Para-amino phenol derivatives
• Paracetamol (Acetaminophen) -
– Central analgesic action similar to asprin, i.e it
raises pain threshold
– Has weak peripheral anti inflammatory
component
– Promptly acting antipyretic
• Adverse effects
– Acute paracetamol poisoning – children

Paracetamol (Acetaminophen)
• Uses –
– Most commonly used drug & One of the
best antipyretic drugs
– Can be used in all age groups, also in
pregnant and lactating women
Clinical studies have found paracetamol
and asprin to be equally effective in
relieving pain after 3rd
molar extraction
And it is more safer than asprin – lesser GI
disturbances and bleeding tendencies

Classification of opioids
• Natural opium alkaloids
– Morphine, codeine
• Semi synthetic opiates
– Diacetylmorphine (heroin), pholcodeine
• Synthetic opioids
– Pethidine (meperidine), fentanyl, methadone,
dextropropoxyphene, tramadol

Morphine
– Alkaloid of opium
– Widely used
• Pharmacological actions
• CNS
– Analgesia
• Strong analgesic
• Nociceptive pain arising from peripheral pain
receptors is better relieved than neuritic pain
• Reactions associated with intense pain –
apprehension, fear are also depressed

Morphine
– CNS
– Sedation
• Drowsiness and indifference to surroundings
as well as to own body , ataxia and apparent
excitement also occur
• Higher doses produce sleep and coma
– Mood and subjective changes
• Calming effect
• feeling of detachment,mental clouding and
inability to concentrate

Morphine
– Respiratory and cough centres
• Depresses Repiration and Cough centre
– Temperature regulating and vasomotor centre
• Depressed
– CTZ, vagal centre & certain cortical areas are
stimulated
– GIT
• Constipation is a prominent feature

Morphine
• Neuro-endocrine
– Enhances ADH release and so urine volume is
reduced
– Causes sympathetic stimulation – mild
hypoglycemia
• CVS
– Causes vasodilation
– Cardiac work is consistently reduced due to
decrease in peripheral resistance

Codeine
• Is methyl morphine
• Less potent than morphine (1/10th
as analgesic)
• Is more selective cough suppressant

Tramadol
• Centrally acting analgesic
• It is believed to work through modulation of serotonin
and norepinephrine in addition to its relatively-weak μ-
opioid receptor agonism
• 100mg tramadol IV is equally analgesic to 10mg
morphine IM
• Uses
– Mild to moderate intensity short lasting pain due to
surgery, dental procedures, injury etc

Opioids in dental pain
• Opioids are less effective and suitable than
NSAID’s for dental pain
• Mostly used as additional drugs with NSAID’s to
boost their analgesic effect
• Among opioids oral codeine is most suitable
• Oral tramadol and pentazocine are alternatives
• Injectable opioids like morphine, pethidine are
limited to intra-operative use to supplement
anaesthesia and to allay apprehension

Analgesics & Medical conditions
• NSAIDs should be given in 2nd
triemister of
pregnancy and opioids should be avoided .
• Paracetamol is the safest drug to use in
pregnancy
• Aspirin & Ibuprofen should not be given in
asthmatic patients
• Aspirin & Paracetamol should not be given
in nephropathy.
• Codein should not be used in renal
dysfunction while fentanyl & methadone are
safe .

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