ANALGESICS IN DENTISTRY.pptx

ANALGESICS IN DENTISTRY
Moderator: Dr. Kumuda Rao
Presenter: Dr. Anand Shankar Sarkar, PG

CONTENTS
• INTRODUCTION
• WHAT IS PAIN?
• MECHANISM (PAIN PATHWAY)
• CLASSIFICATION OF ANALGESICS
SOURCE
PHARMACOKINETICS
PARMACODYNAMICS
MODE OF ACTION
HALF LIFE AND INFLUENCE
INDICATIONS & CONTRAINDICATIONS
DRUG DOSAGE
ADVERSE EFFECTS
SUMMARY
• STANDARD APPLICATION IN
DENTISTRY
• OTC ANALGESICS- A MENACE?
• RECENT ADVANCEMENTS
• CONCLUSION

INTRODUCTION
• Pain broadly known as “An unpleasant emotional experience usually initiated
by a noxious stimulus and transmitted over a specialized neural network to the
central nervous system where it is interpreted as such”.
• Pain can be classified into two broad categories: acute and chronic pain.
• Effective and safe pain management is a primary goal in dental practice.
Control of pain associated with dental or periodontal disease is a main reason
that patients seek care from dentists. In addition, many dental procedures are
painful, and postoperative pain may persist for days.

• Analgesics are “the drugs that selectively relieve pain by acting on the central nervous
system (CNS) or on peripheral pain mechanism, without significantly altering
consciousness”.
• Sodium salicylate was used for fever and pain in 1875 and led to the introduction of
acetyl salicylic acid (Aspirin) in 1899, which remains one of the most common
remedies for pain till date. Opioid use has been known from the earliest times.
• Serturner isolated the active principle of opium (morphine) in 1806 and gave clinicians
for the first time a chemically pure, highly effective analgesic.
• In 1971, Vane and coworkers made first observation that NSAIDS blocked PGs
Generation.

WHAT IS PAIN?
• “An unpleasant sensory and emotional experience associated
with, or resembling that associated with, actual or potential
tissue damage,” – IASP(1979)
• According to IASP Published paper on 16th july, 2020, the
earlier definition is expanded upon by the addition of six key
Notes and the etymology of the word pain for further valuable
context
Pain is always a personal experience that is influenced to
varying degrees by biological, psychological, and social
factors.
Pain and nociception are different phenomena. Pain cannot be
inferred solely from activity in sensory neurons.
Raja SN, Carr DB, Cohen M, Finnerup NB, Flor H, Gibson S, Keefe FJ, Mogil JS, Ringkamp
M, Sluka KA, Song XJ, Stevens B, Sullivan MD, Tutelman PR, Ushida T, Vader K. The revised
International Association for the Study of Pain definition of pain: concepts, challenges, and
compromises. Pain. 2020 Sep 1;161(9):1976-1982.

Through their life experiences, individuals learn the concept of pain.
A person’s report of an experience as pain should be respected.
Although pain usually serves an adaptive role, it may have adverse effects on
function and social and psychological well-being.
Verbal description is only one of several behaviors to express pain; inability to
communicate does not negate the possibility that a human or a nonhuman animal
experiences pain.
Raja SN, Carr DB, Cohen M, Finnerup NB, Flor H, Gibson S, Keefe FJ, Mogil JS, Ringkamp
M, Sluka KA, Song XJ, Stevens B, Sullivan MD, Tutelman PR, Ushida T, Vader K. The revised
International Association for the Study of Pain definition of pain: concepts, challenges, and
compromises. Pain. 2020 Sep 1;161(9):1976-1982.

PAIN TRANSMISSION
• Nociceptive pathway
Diagrammatic outline of the major neural structures relevant to pain. The sequence of events leading to pain perception begins in the transmission system
with transduction (lower left), in which a noxious stimulus produces nerve impulses in the primary afferent nociceptor. These impulses are conducted to the
spinal cord, where the primary afferent nociceptors contact the central pain-transmission cells. The central pain-transmission cells relay the message to the
thalamus either directly via the spinothalamic tract or indirectly via the reticular formation and the reticulothalamic pathway. From the thalamus, the
message is relayed to the cerebral cortex. (DRG: dorsal root ganglion.) The pain-modulation system has inputs from the frontal association cortex and the
hypothalamus (H). The outflow is through the midbrain and medulla to the dorsal horn of the spinal cord, where it inhibits pain-transmission cells, thereby
reducing the intensity of perceived pain.

The experience of pain as we currently understand it can be broadly divided
into four steps: transduction, transmission, modulation, and perception.
• Transduction involves the stimulation of nociceptors at tissue sites by
various noxious stimuli.
• Transmission carries the induced action potentials via fast A-delta and
slower C fibres to the dorsal horn of the spinal cord, and further on to the
thalamus and finally the cerebral cortex.

• Modulation of nociceptive signals occurs by stimulation of
descending inhibitory pathways from the brain and
brainstem, thereby altering afferent signals that eventually
reach the brain to be interpreted.
• Perception of nociceptive signals is very complex, and
occurs primarily in the somatosensory, prefrontal, insular,
and cingulate cortices.

PAIN PATHWAY
• According to the International Association for the Study of Pain (IASP), pain can be classified,
based on the region of the body involved (e.g., head, visceral), pattern of occurrence’s duration
(acute and chronic), or the system of which dysfunction that may cause the pain (e.g.,
gastrointestinal, nervous). However, it is suggested for pain to be classified based on only three
characteristics: symptoms, mechanisms and syndromes. Thus, internationally pain has been
classified into three major classes—nociceptive pain, neuropathic pain and inflammatory pain.

• Primarily, both the CNS and PNS are involved in the mechanism and pathways of all
variations of pain perception. The PNS comprises nerves and ganglia that are located
outside the brain and spinal cord, mainly functioning to connect the CNS to organs and
limbs in our body. On the other hand, the CNS is composed of the spinal cord and the
brain, which is mainly responsible for integrating and intepreting the information sent
from the PNS, and subsequently coordinating all the activities in our bodies, before
sending response towards the effector organs.

1.Nociceptive Pain
• Nociception used interchangeably with nociperception is the response of our bodies’sensory nervous
systems towards actual or potentially harmful stimuli. The sensory endings that are activated by such
stimuli are known as nociceptors,which are mainly responsible for the first stage of pain sensations.
Fundamentally, the A- and C-fibers are two types of primary afferent nociceptors responding to
noxious stimuli presented in our bodies’.
• Both these nociceptors have specialized free nerve endings that are widely located in the skin,
muscle, joint capsule, bone and some major internal organs.
• They are functionally used to detect potentially damaging chemical ,mechanical and thermal stimuli
that might put us in harm’s way.

2.Neuropathic Pain
• Neuropathic pain is commonly described as a nerve injury or nerve impairment and is often
associated with allodynia. Alloydnia is a central pain sensitization that is a result of repetitive non-
painful stimulation of the receptors. It triggers a pain response from a stimulus that is deemed as non-
painful in normal conditions, due to sensitization process from said repetitive stimulation. This
condition can be described as “pathologic” pain, because neuropathic pain actually serves no purpose
in terms of defense system for our body, and the pain could be in the form of continuous sensation or
episodic incidents. The major causes of this type of pain could be primarily due to inflammation or
metabolic diseases, such as diabetes, trauma,toxins, tumors, primary neurological diseases and herpes
zoster infection. The central sensitization plays a rather important role in this process. Neuropathic
pain can be caused by the damage of the nerve, affecting the somatosensory nervous system, and may
be generated by the disorders of the PNS or CNS.

3.Inflammatory Pain
• Inflammation is a natural biological response produced by the tissues within our body
as a reaction to the harmful stimuli in order to eradicate the necrotic cells and initiate
the tissue repairing process.
• Neutrophils are usually the first respondents of an inflammatory response and gather at
the site of injury via the bloodstream, followed by the release of other chemical
mediators. Inflammation may lead to three major responses: hyperalgesia, allodynia
and sympathetic maintained pain.
• An inflammation can also induce mast cell degranulation, which subsequently leads to
the release of platelet activating factor (PAF) and stimulates the release of 5-HT from
the circulating platelet.

• The localized inflammatory response then induce the release of free arachidonic acid
(AA) from the phospholipids, which are converted into prostaglandins (PG) via the
cyclooxygenase (COX) pathways.
• Pain from inflammation can be further classified into two types: chronic and acute pain.
• Acute inflammatory pain is normally intense and occurs for a short period of time, which
is initiated as a response to harmful stimuli that are normally mediated by the A-fibers.
Leukocytes and plasma from the bloodstream are accumulated at the site of the injury to
assist in the inflammatory process.
• However,prolonged inflammation, better known as chronic inflammatory pain, lasts
beyond the expected period of healing, which is typically mediated by C-fibers.

T H E S IG N A LIN G M E C H A N IS M PAT H WAY S O F PA IN - A S S O C IAT E D
N E U R O T R A N S M IT T E R S A N D T H E IR C O G N AT E R E C E P TO R S IN V O LV E D IN P R E -
A N D P O S T- S Y N A P T IC LO C AT IO N S F O R PA IN T R A N S M IS S IO N . :
A C T IVAT E / E N H A N C E P R O D U C T IO N ; : IN H IB IT / R E D U C E P R O D U C T IO N ; :
G E N E R AT E / LE A D TO .

PAIN TRANSMITTERS
• There are varieties of neurotransmitters involved in the pain sensation.
• All the major types of neurotransmitters (inflammatory mediators: PGE2, PGI2,
LTB4, NGF, proton, BK, ATP, adenosine, SP, NKA, NKB, 5-HT, histamine,
glutamate, NE and NO; non-inflammatory mediators: CGRP, GABA, opioid peptides,
glycine and cannabinoids) etc, are responsible for pain mediation through CNS or
PNS pathway.

Yam MF, Loh YC, Tan CS, Khadijah Adam S, Abdul Manan N, Basir R. General Pathways of Pain Sensation and the
Major Neurotransmitters Involved in Pain Regulation. Int J Mol Sci. 2018 Jul 24;19(8):2164.

NON –OPIOD ANALGESICS(NSAIDS)

NSAIDS(NON OPIODS)
• NSAIDs decrease the production of prostaglandins, an effect that is attributed to the inhibition of
COX. tNSAIDs inhibit both COX-1 and COX-2 to different degrees.
• These drugs have common therapeutic actions, including anti-inflammatory, analgesic, and
antipyretic actions that are mainly due to the inhibition of COX-2, the expression of which is
induced by inflammation.
• In contrast, the inhibition of COX-1 is generally responsible for NSAID-induced gastropathy,
nephropathy, and prolonged bleeding time.
• Acetaminophen similarly has analgesic and antipyretic activities via the inhibition of COX enzymes,
but it is technically not classified as an NSAID because it has only minimal anti-inflammatory
activity, although its exact mechanism of action is still unclear

• NSAIDs are one of the most commonly prescribed classes of medication for pain
and inflammation. They are responsible for approximately 5-10% of all
medications prescribed each year. The prevalence of NSAID use in patients over
65 years old is as high as 96% in the general practice setting. Approximately
7.3% of elderly patients over 60 years old filled at least one NSAID prescription
in one year period.
• In addition to their anti-inflammatory effect, NSAIDs have antipyrexic and
analgesic properties. These medications inhibit Cyclooxygenases (COXs)
enzymes, which are rate-determining enzymes for prostaglandins and other
prostanoids synthesis, such as thromboxanes.

PHARMACODYNAMICS &
PHARMACOKINETICS
• The major therapeutic actions of NSAIDs are primarily enacted by their ability to
block certain prostaglandins (PGs) synthesis through the cyclooxygenase enzymes
(COX-1 and COX-2) inhibition.
• COX-1 produces prostaglandins and thromboxane A2 which control mucosal barrier
in GI-tract, renal homeostasis, platelet aggregation and other physiological functions.
• COX-2 produces PGs that related to inflammation, pain and fever. COX-1 is
expressed in normal cells, while COX-2 is induced in inflammatory cells.
• COX-2 inhibition most likely represents the desired effect of NSAIDs’ anti-
inflammatory, antipyretic and analgesic response; while COX-1 inhibition plays a
major role in the undesired side effects such as GI and renal toxicities.

• Most NSAIDs are well absorbed in the gastrointestinal tract and have high
bioavailability. Some drugs such as diclofenac undergo hepatic first-pass
metabolism which resulted in the reduction in bioavailability.
• While some drugs such as sulindac and parecoxib are prodrugs and need hepatic
metabolism to become their active metabolites (sulindac sulfide and valdecoxib,
respectively).
NSAIDs are highly bound to plasma proteins. NSAIDs are usually
metabolized in the liver and excreted in the urine. Common
NSAIDs drug have a variable half-life; they can be anywhere from
0.25-0.3 hours such as aspirin or 45-50 hours such as piroxicam.
All these pharmacokinetics parameters can change with aging since
the elderly have low body water compared with adults. Protein
binding may be reduced and volumes of distribution may be altered.

CURRENT GUIDELINE AND THE USE OF
NSAIDS
• In 1986, The World Health Organization (WHO) developed the analgesic ladder
for the treatment of cancer pain with the three-step sequential approach for pain
medication administration depending on the severity of pain. NSAIDs are
considered group one medications, recommended for mild pain and are the first
step in treating pain.
Balding L. The World Health Organisation analgesic ladder: its place in modern Irish medical
practice. Ir Med J. 2013 Apr;106(4):122-4.

• Professional societies, including American Geriatric Society, American College of
Rheumatology, and the European League Against Rheumatism, recommend using NSAIDs
with caution and limit their use to the lowest effective dose and shortest duration. They
recommend that, when used, common gastrointestinal, renal and cardiovascular side effects
should be routinely monitored.
• Considering this recommendation, the prevalence of inappropriate use of NSAIDs is
concerning.
• In 2015, Ussai et al., did a retrospective study of 3,050 subjects with chronic pain. They
found that 97% of chronic pain subjects took NSAIDs for more than 21 consecutive days.

SUMMARY – PART I
• “An unpleasant sensory and emotional experience associated with, or resembling that associated
with, actual or potential tissue damage,” – IASP(1979).
• Howeverly recent 2020 Guidelines have added six points in pain classification.
• The experience of pain as we currently understand it can be broadly divided into four steps:
transduction, transmission, modulation, and perception.
• All the major types of neurotransmitters (inflammatory mediators: PGE2, PGI2, LTB4, NGF,
proton, BK, ATP, adenosine, SP, NKA, NKB, 5-HT, histamine, glutamate, NE and NO; non-
inflammatory mediators: CGRP, GABA, opioid peptides, glycine and cannabinoids) etc, are
responsible for pain mediation.
• Analgesics broadly been classified as Opioid and Non opioid analgesics.

ANALGESICS IN DENTISTRY P-II

ACETAMINOPHEN(PARACETAMOL)
• The tNSAIDs currently available on the market include aspirin, diflunisal, ibuprofen,
naproxen, ketoprofen, flurbiprofen, indomethacin, sulindac, etodolac, diclofenac,
ketorolac, piroxicam, mefenamic acid, and nabumetone.
• Acetaminophen (also known as paracetamol) is one of the most widely used analgesic
antipyretic drugs and has minimal anti-inflammatory activity.
INTRODUCTION

• It has also been placed on all three steps of pain treatment intensity of the WHO
analgesic ladder for the treatment of cancer pain.
• Acetaminophen does not possess any anti-inflammatory activity, because it is a very
weak inhibitor of COX and does not inhibit neutrophil activation.

SOURCE
• Paracetamol is the deethylated active metabolite of phenacetin,
introduced in last century came into use by 1950s.

PHARMACOKINETICS
• Acetaminophen has a very high oral bioavailability of 60–88% (Bertolini et al.,
2006), and after oral administration of 1,000 mg acetaminophen, the plasma
maximum concentration (Cmax) is 12.3 μg/ml, area under the curve over 6 h
(AUC0–6) is 29.4 μg/h/ml, and AUC extrapolated to infinity (AUC0–∞) is
44.4 μg/h/ml.
• Metabolism: Conjugation with Glucoronic acid and sulfate, excretion Urine.

MODE OF ACTION
• The main analgesic mechanism of acetaminophen is its metabolization to N-
acylphenolamine (AM404), which then acts on the transient receptor potential vanilloid 1
(TRPV1) and cannabinoid 1 receptors in the brain.

• *AM404, N-acylphenolamine; FAAH, fatty acid
amide hydrolase; COX, cyclooxygenase; CB1,
cannabinoid 1; TRPV1, transient receptor potential
vanilloid 1.

• The time to maximal concentration (Tmax) is 1.0 h, and the elimination half-life (t1/2) is
2.53 h.
• In contrast, after intravenous administration of 1,000 mg acetaminophen, the
plasma Cmax is 21.6 μg/ml, AUC0–6 is 42.5 μg/h/ml, and AUC0–∞ is 50.0 μg/h/ml.
The Tmax is 0.25 h, and the t1/2 is 2.17 h (Singla et al., 2012).
• Intravenous administration of acetaminophen shows earlier and higher peak plasma
levels than oral administration.
• Effects:3-5 hrs.

• OTC Analgesic for headache, dental originating pain.
• Antipyretic use in fever.
• Mild migraine
• Musculoskeletal pain
• Dysmenorrhea etc
• Osteoarthritis(first choice)

ROUTES OF ADMINISTRATION
• Acetaminophen is administered by oral, transanal, and intravenous routes.
• Few Drug Combinations available in Market as :
• CROCIN 500mg, 1 gm; METACIN, PARACIN 500mgtab;CALPOL 500mg tab,
125 mg/5ml syrup; FEVASTIN 300mg/2ml inj; CROCIN PAIN RELIEF 650
mg+caffeine 50mg tab etc; JUNIMOL –RDS 80,170,250 mg suppository(fro
children) etc.

DRUG DOSAGE
• The maximum single-dose of acetaminophen for the treatment of
pain or fever is 1,000 mg every 4 h as needed, up to a
recommended maximum daily dose of 4 g.
• These therapeutic concentrations range from 5 to 20 mg/ml.

ADVERSE EFFECTS
• Nausea,stomach pain (upper right side);
• loss of appetite;
• tiredness, itching;
• dark urine, clay-colored stools; or
• jaundice (yellowing of the skin or eyes).
• Acute paracetamol poisioning, followed by COMA.

SUMMARY
• Acetaminophen acts not only on the brain but also the spinal cord and
induces analgesia.
• Moreover, the most possible analgesic mechanism is that the acetaminophen
metabolite AM404 acts by activating TRPV1 and/or CB1 receptors.
• Acetaminophen>>Aspirin

DICLOFENAC/ACECLOFENAC
(PREFERENTIAL COX 2 INHIBITORS)
• An Analgesic-Antipyretic-Antiinlammatory drug, inhibits PG
synthesis , antiplatelet action action is not appreciable.
• A moderately COX-2 selective congener of diclofenac having similar
properties
• Enhancement of GAG synthesis may confer chondroprotective
property to aceclofenac.

PHARMACOKINETICS
• Diclofenac is rapidly and efficiently absorbed after conventional oral,
rectal, or intramuscular administration.
• After intramuscular administration peak plasma concentrations are
attained after 10-30 min. With the enteric-coated formulation peak
concentrations are reached after 1.5-2.5 h, and this is delayed by food to
2.5-12 h
• Well absorbed orally ,99% protein bounded metabolized and excreted
both in urine an bile.

MODE OF ACTION
• Diclofenac is a potent inhibitor of cyclooxygenase in vitro and in
vivo, thereby decreasing the synthesis of prostaglandins, prostacyclin,
and thromboxane products.
• Whereas aceclofenac is an orally administered phenyl acetic acid
derivative with effects on a variety of inflammatory mediators.

• Plasma t1/2 life is about of 2 hours
• Tissue penetrability and concentration in the synovial fluid is
maintained for 3 time longer than in plasma , extended therapeutic
action on joints.

INDICATIONS AND CONTRAINDICATIONS
• Dental related pain, headache,musculoskeletal
• inflammatory conditions: Acute soft tissue injuries, including sprains, strains, tendinitis
and sports injury; Localised forms of soft tissue rheumatism, eg. tendinitis (e.g. tennis
elbow) and bursitis.
• Short term (up to 3 weeks) relief of pain in non-serious arthritis (i.e. mild and localised
forms of osteoarthritis) of the knee and fingers.
• Established congestive heart failure (NYHA II-IV), ischemic heart disease, peripheral
arterial disease and/or cerebrovascular disease.

• It is available in oral, rectal and topical, i.m forms.

DRUG DOSAGE
• Dose: 50mg TDS, then BD orally ;75mg deep i.m
• Aceclofenac; Dose: 100mg BD.

ADVERSE EFFECTS
• Mild epigastric pain
• nausea, headache
• Dizziness, rashes
• Gastric ulcerationand bleeding are less common.
• Might increase the risk of heart attack and stroke.
• Reversible elevation of serum AT , kidney damage is rare.

DRUG COMBINATIONS
• VOVERAN 50mg Tab; 100mg S.R tab, 25mg/ml in 3ml amp. Or i.m inj.
• DICLOMAX 25,50mg TAB.
• Diclofenac potassium; VOLTAFLAM 25,50mg tab, ULTRAK 50mg Tab;
VOVERAN 1% topical gel. Etc
• Aceclofenac; ACECLO, DOLOKIND 100mg Tab, 200mg SR Tab.

SUMMARY
• Diclofenac and aceclofenac are nonsteroidal antiinflammatory drugs (NSAIDs).
Diclofenac is advocated for the treatment of painful and inflammatory rheumatic
and certain non rheumatic conditions such as rheumatoid arthritis,
osteoarthritis,etc.
• Gastrointestinal (GI) problems are the most frequent effects, which are caused by
diclofenac and include dyspepsia and abdominal pain.
• The initial dosage of conventional or enteric-coated tablets of diclofenac is 150 mg
daily in two or three divided doses with meals, and in most patients therapeutic
control can be maintained on 100 mg daily.

ASPIRIN(SALICYLATES)
• Salicylates have been derived from the willow tree bark.
• The Sumerians were noted to have used remedies derived from the willow tree for
pain management as far back as 4000 years ago.

• In a 1763 clinical trial, the first of its kind, Reverend Edward Stone
studied the effects of willow bark powder for treating fever.
• Even though it has been available since the early 1900s, its real
mode of action was not known until the late 1970s.

SOURCE
• In 1828, Professor Johann Buchner used salicin, the Latin word for
willow. Henri Leroux used it to treat rheumatism after isolating it in a
crystalline form in 1829. In the 1800s, the Heyden Chemical Company
was the first to mass-produce salicylic acid commercially. It was not until
1899 when a modified version named acetylsalicylic acid was registered
and marketed by Bayer under the trade name aspirin.
Arif H, Aggarwal S. Salicylic Acid (Aspirin) [Updated 2021 Jul 15]. In: StatPearls [Internet].
Treasure Island (FL): StatPearls Publishing; 2021

MODE OF ACTION
• Aspirin is a cyclooxygenase-1 (COX-1) inhibitor. It is a modifier of the enzymatic
activity of cyclooxygenase-2 (COX-2).(Irreversible binding).
• It also blocks thromboxane A2 on platelets in an irreversible fashion preventing
platelet aggregation

PHARMACOKINETICS
• Aspirin absorption from the gastrointestinal (GI) tract depends on the formulation state.
• When consumed as a liquid preparation, it is rapidly absorbed as opposed to tablets. Its
hydrolysis yields salicylic acid.
• Aspirins absorption is pH sensitive at the level of the small intestine. At pH 3.5 or 6.5,
aspirin's intestinal absorption is greater than the gastric absorption of the compound. The
stomach does not absorb aspirin at pH 6.5.
• Salicylate elimination occurs through two pathways via the creation of salicyluric acid and
salicyl phenolic glucuronide.

• Plasma t1/2 life is 15-20 minutes
• Orally: 3-5 hours
• Elimination is dose dependent.

INDICATION AND CONTRAINDICATIONS
• As Analgesics; Headache,myalgia,joint pain,toothache,neuralgias,Angina pectoris.
• Ankylosing spondylitis, Cardiovascular risk reduction ; Colorectal cancer ;Fever.
• Ischemic stroke: Prophylaxis; Myocardial infarction; Osteoarthritis
• Dental Related pain, Oromucosal Pain; Pain Revascularization procedures;
Rheumatoid arthritis ;Systemic lupus erythematosus etc.

• Aspirin can be administered via the oral, rectal, and intravenous
(IV) route.

DRUG DOSAGE
• It is available in different doses, the lowest being 81 mg,
also called a baby aspirin.
• Tablet: 325 mg, 500 mg
• Delayed-release tablet: 81 mg, 325 mg, 500 mg, 650 mg
• Chewable: 81 mg
• Suppository: 60 mg, 120 mg, 200 mg, 300 mg, 600 mg
• Intravenous: 250 mg, 500 mg

DRUG COMBINATIONS
• ASPIRIN 350mg Tab ; COLSPRIN 100, 325 mg Tab,
ECOSPRIN 75, 150,325 mg Tabs, DISPRIN 350mg Tab(
with cal. Carbonate 105mg+citric acid 35mg)
• BIOSPIRIN : Lysine acetylsalicylate 900 mg+ glycine
100mg/ 5ml and i.v

ADVERSE EFFECTS
• The most common side effect of aspirin is gastrointestinal upset ranging from
gastritis to gastrointestinal bleed.
• Hypersensitivity ;Reye Syndrome ;Intracerebral Hemorrhage;hypersensitivity
• Aspirin increases the risk of GI bleeding in patients who already suffer from peptic
ulcer disease or gastritis.
• Patients who have G6PD deficiency are at risk of acute intravascular hemolytic
anemia. Many factors can precipitate these hemolytic episodes. Aspirin is one such
know cause.

SUMMARY
• Aspirin is acetylsalicycic acid. Aspirin is a cyclooxygenase-1 (COX-1) inhibitor.
• Plasma t1/2 life is 15-20 minutes
• Orally: 3-5 hours
• As Analgesics; Headache, myalgia, joint pain, toothache, neuralgias,Angina
pectoris, etc.
• ASPIRIN 350mg Tab ; COLSPRIN 100, 325 mg Tab,etc
• The most common side effect of aspirin is gastrointestinal upset ranging from
gastritis to gastrointestinal bleed.

ANALGESICS IN DENTISTRY P-III

IBUPROFEN(PROPIONIC ACID
DERIVATIVE)
• Ibuprofen, a 2-proprionic acid derivative discovered by the research arm of the British
Boots Group in the 1960s.
• The disease was the initial impetus for creating what would eventually become known
as ibuprofen; Dr. Stewart Adams OBE was the researcher.
• Initially patented as 2-(4-isobutylphenyl) propionic acid in 1961 by Dr. Adams and
Dr.John Nicholson, ibuprofen became and remains one of the most widely used
NSAIDs worldwide.

SOURCE
• Chemically produced : 2-(4-isobutylphenyl) propionic acid
Ngo VTH, Bajaj T. Ibuprofen. [Updated 2021 May 31]. In: StatPearls [Internet]. Treasure Island
(FL): StatPearls Publishing; 2021

MODE OF ACTION
• The primary mechanism of Ibuprofen, an NSAID, is through the inhibition
of prostaglandin precursors.
• Inhibition of COX-1 and COX-2 pathways decreases the expression of
prostaglandin precursors;
• For ibuprofen specifically, COX-1 is inhibited approximately 2.5 times more
potently than COX-2

PHARMACOKINETICS
• All are well absorbed orally , highly bound to plasma protein(90-99%).
• Likely to decrease the action of diuretic and antihypertensive action of
thiazides, furosemide and beta blockers.
• All derivatives enter brain, synovial fluid and crosses placenta.
• Metabolized by hydroxylation and glucuronide conjugation and excreted in
urine and bile

• Plasma t ½ life: 2-4 hours,Flurbiprofen: 4-6 hours.,Naproxen: 12-16 hours.

INDICATIONS AND
CONTRAINDICATIONS
• Ibuprofen is indicated and FDA-approved for use in the treatment of inflammatory
diseases and rheumatoid disorders.
• FDA-approved for use in mild to moderate pain and as an antipyretic used for fever
reduction in both adults and children.
• Ibuprofen and other NSAIDs are also FDA-approved to treat osteoarthritis,
pericarditis,dysmennorhea, prevent PDA, Prevent colorectal carcinoma.
• It is contraindicated in patients with a known history of hypersensitivity or allergic
reactions to the drug itself, other NSAIDs, or aspirin, CHD, bronchospasm.

DENTAL CONSIDERATION
• Most commonly used in Pre and post endodontic therapy.
• Wisdom tooth extraction
• Pediatric dentistry(4-10mg/kg) used in combination with paracetamol for moderate to
severe pain.
• Post implant surgeries
• Orthodontic pain management
• Periodontal pain management
• Tooth whitening

• A study comparing COX-2 inhibitors with ibuprofen after third molar removal
showed no statistically significant differences in pain relief after 6, 8, and 12 hours,
but a significant increase in rescue analgesia was used in the ibuprofen group 24
hours.
Jain N, Maria A. Randomized double blind comparative study on the efficacy of Ibuprofen and
aceclofenac in controlling post-operative sequelae after third molar surgery. J Maxillofac Oral
Surg. 2011 Jun;10(2):118-22.

• Orally, parenterally as i.m

DRUG DOSAGE
• Dose: 400-800 mg
• oral capsule (200 mg); oral suspension (100 mg/5 mL; 50
mg/1.25 mL); oral tablet (100 mg; 200 mg; 400 mg; 600
mg; 800 mg); oral tablet, chewable (100 mg; 50 mg)

DRUG COMBINATIONS
• IBUGESIC PLUS (400mg/325mg), IBUFLAMAR ;REBUFEN 400mg OCUFLUR,
FLUR, FLURBIN etc.

ADVERSE EFFECTS
• Gastrointestinal bleeding is a well-known adverse effect
of ibuprofen usage and can lead to gastritis, ulceration, hemorrhage,
or perforation.
• Nausea, vomiting, dizziness, tinnitus, deppression., itching etc.
• Diminished renal function,rashes, DRESS syndrome, impaired
hepatic function.

SUMMARY
• The discovery of ibuprofen was spurred by finding an alternative non-corticosteroid treatment
for rheumatoid arthritis.
• 2-(4-isobutylphenyl) propionic acid in 1961 by Dr. Adams and John Nicholson.
• The primary mechanism of Ibuprofen, an NSAID, is through the inhibition of prostaglandin
precursors.Metabolized by hydroxylation and glucuronide conjugation and excreted in urine
and bile, Plasma t ½ life: 2-4 hours.
• Ibuprofen is also FDA-approved for use in mild to moderate pain & as antipyretics used for
fever reduction in both adults and children.
• Gastrointestinal bleeding is a well-known adverse effect of ibuprofen.

MEPHENAMIC ACID(MEFANAMATE)
• Mefenamic acid is a nonsteroidal anti-inflammatory drug (NSAID) exhibiting a
wide range of anti-inflammatory, antipyretic and analgesic activities, which
inhibits the synthesis of PGs as well as antagonizes some of their actions.
• It is a derivative of N-phenylanthranilic acid and is a member of the ‘fenamate’
family of NSAIDs.
• It exerts peripheral as well as central analgesic action.

MODE OF ACTION
• NSAIDs like mefenamic acid exhibit their primary effect by inhibiting
the COX enzyme or prostaglandin H synthase (PGHS), thereby
impairing the conversion of arachidonic acid to its metabolites,
including PGs, prostacyclin and thromboxane.
• ability to block the E-type prostanoid (EP) receptors, thereby blocking
the pre-formed PGs as well.

PHARMACOKINETICS
• Oral absorption is slow but almost complete.
• It is highly bounded to plasma proteins-displacement interactions
can occur;partly metabolized and excreted in urine as well as bile.

• Plasma t1/2 life is about for 2-4 hours.

• Analgesic in muscle,joint and soft tissue pain,effective in dysmenorrhea.
• Helpful in RA and osteoarthritis.
• Anti-inflammatory and analgesic action
• Postpartum pain;Menorrhagia;migraine;Headache;Musculoskeletal injuries;Low
back pain;Osteoarthritis ;Rheumatoid arthritis;Post-COVID myalgia.
• Endodontic pain ;Preoperative pain particularly dental procedures;Postoperative
pain,etc.

DENTAL CONSIDERATION
• Post 3rd Molar Surgeries.
• Pre and post extraction pain management
• Post endodontic therapy.

DRUG DOSAGE
• Dose: 250-500mg TDS

DRUG COMBINATIONS
• MEDOL 250,500mg cap;MEFTAL 250,500mg
tab,100mg/5ml susp.
• PONSTAN 125,250,500mg tab,50 mg/ml syrp.

ADVERSE EFFECTS
• Diarrhoea
• Epigastric distress
• Skin rashes, dizziness,and other CNS
manifestations, hemolytic anemia.

SUMMARY
• Analgesic, anti-inflammatory and antipyretic effects of mefenamic acid
have been utilized in the clinical use of the drug.
• Mefenamic acid has been a promising agent in treating several
inflammatory conditions, including fever, inflammatory diseases such
as arthritis, pain relief in dysmenorrhea and myalgia.

KETOROLAC
(ACETIC ACID DERIVATIVE)
• Arylacetic acid is a potent analgesic but with modest anti-
inflammatory agent.
• It is an FDA –approved medication used in the treatment of moderate
to severe acute onset pain.

SOURCE
• Ketorolac is a pyrrolizine carboxylic acid derivative,
• structurally and pharmacologically related to tolmetin, zomepirac,
and indometacin.
• The trometamol salt of ketorolac enhances its solubility and allows
parenteral administration.

MODE OF ACTION
• It inhibits PG synthesis and relieves pain primarily by a peripheral
mechanism.

PHARMACOKINETICS
• Rapidly absorbed after Oral and I.m administration
• It is highly plasma protein bound and 60% excreted unchanged in
urine.
• Major metabolic pathway is glucoronidation ;
• plasma t1/2 life is 5-7 hours.

INDICATONS AND CONTRAINDICATIONS
• moderate or severe postoperative pain, dental pain,
musculoskeletal pain.
• Renal colic,migraine and pain due to bony metastasis.
DENTAL CONSIDERATION:
Indicated in cases of post implant surgery, pre and post endodontic therapy, Third
molar surgery as well as post disimpaction surgeries.

• ketorolac is contraindicated as a preemptive analgesic before
any major surgery and is contraindicated intraoperatively
when hemostasis is critical because of the increased risk of
bleeding.

ADVERSE EFFECTS
• Nausea, admonial pain, dyspepsia.
• ulceration, loose stools, drowsiness, headache, dizziness,
nervousness, pruritis.
• pain at injection site, rise in serum transaminase and fluid retention.
• Anticoagulants (contraindicated)

DRUG DOSAGE
• Dose: 10-20mg 6 hourly , moderate pain.
• Drug combinations available as KETOROL,
ZOROVON,KETANOV,TOROLAC 10mg tab, 30mg in 1ml amp.
• KETLUR, ACULAR 0.5% eye drops, 1-2 drops 2-4/ day

PIROXICAM
• Enolic Acid Derivative
• A long acting NSAID, with anti-inflammatory potency similar to
indomethacin and good analgesic- antipyretic action.
• It is a non selective, reversible inhibitor of COX pathway hence lowers
PG concentration in synovial fluid and inhibits the platelet aggregation.

• It also decreases the production of IgM RF and leukocyte
chemotaxis.
• 99% plasma protein bound,in liver by hydroxylation and
glucuronide conjugation, excretion urine & bile.
• Plasma t1/2 is 2 days.

• Uses: Long term anti-inflammatory drug in RA &
OA,Ankylosing spondylitis etc.
• Treating acute gout , musculoskeletal injuries and dental pain.
• Dose: 20mg BD for two days followed by 20 mg OD
• Drug combinations: DOLONEX;PIROX 10,20mg cap, 20 mg
DT, 20mg/ml in 1 &2 amp inj.

• piroxicam 20 mg and 40 mg, however, produced
significantly longer durations of analgesia than
aspirin 648 mg, and
• It appears that the analgesic effect of piroxicam
may extend for up to 24 hours in a substantial
proportion of patients.
Desjardins PJ. Analgesic efficacy of piroxicam in postoperative dental pain. Am J
Med. 1988 May 20;84(5A):35-41

ADVERSE EFFECTS
• Adverse effects includes GI side effects>> ibuprofen
• Causes less fecal blood loss than aspirin.
• Rashes and pruritis are seen in <1% of patients.
• Edema & reversible azotaemia .

SELECTIVE COX II INHIBITORS
• Past 2 decades; In general
classification, selective COX2
inhibitors belong to two major
structural classes:
• 1) Tricyclics (also known as
ortho-diaryl heterocycles or
carbocycles);
• 2) Non-tricyclics

• All of the compounds in this class possess 1,2-diarylsubstitution
on a central hetero or carbocyclic ring system
• with a characteristic methanesulfonyl, sulfonamido, azido,
methanesulfonamide or pharmacophore-based tetrazole group on
one of the aryl rings.
• Coxibs such as Celecoxib, Rofecoxib, Valdecoxib and etc, belong
to this common structural class.

ANALGESICS IN DENTISTRY P-IV

CONTINUED
• Celecoxib
• Etoricoxib
• Parecoxib
• Rofecoxib
• Valdecoxib
• Lumiracoxib
DISCONTINUED
SELECTIVE COX II INHIBITORS
(COXIBS)

CELECOXIB,ETORICOXIB,PARECOXIB
• Celecoxib: similar to diclofenac; exerts anti-inflammatory, analgesic and
antipyretic actions with low ulcerogenic potential.
• Indications and contraindication
• Dental considerations:As effective as naproxen or diclofenac, Pain relief
aftercomplicated extractionor third molar surgery,post-surgical andalveolitis
• Abdominal pain, dyspepsia and mild diarrhoea,Rashes ,edema,and a small
rise in B.P.
• It is slowly absorbed ,97% plasma protein bound and CYP2C9 with a t1/2 life
of ~10 hours.
• Available as : CELACT, REVIBRA,COLCIBRA 100,200mg Caps.

• Etoricoxib:
• Highest COX-2 selective inhibitor.
• Dental considerations:It is suitable for acute dental surgery pain,pain caused by
mandibular or maxillary dislocation, postsurgical pain treatment and pulpitis
• ankylosing spondylitis, acute gouty arthritis, osteoarthritis, dysmenorrhea, less
affecting the platelet function/damaging gastric mucosa.
• Side effects are dyspepsia, abdominal pain, pedal edema, rise in BP, dry mouth,
apthous ulcers, taste disturbances and paresthesias.
• Dose: 60-120mg OD
• Available in market as ETOSHINE,TOROCOXIA,
ETOXIB,NUCOXIA,60,90,120mg tabs.

• Parecoxib:
• Prodrug: Valdecoxib
• Efficacy to ketorolac,same reaction of serious cutaneous reactions as
valdecoxib
• Rash, stop use.
• Dose: 40mg oral/i.m i.v repeated after 6-12hours.
• Available as: REVALDO,VALTO P-40mg/vial inj., PAROXIB 40mg tab.

OPIOID ANALGESICS
• Eber’s papyrus(1500 BC), name morphine(greek god of
dreams,Morpheus),Opioids produce the majority of their
therapeutic and adverse effects by acting as agonists at mu
and/or kappa opioid receptors.
• These side effects include sedation, respiratory depression,
dependence, nausea, miosis, Constipation and miosis.

CLASSIFICATION • Two types:
• 1.Phenanthrene derivative:
• Morphine(10%in
opium),codene(0.5%) in
opium,Thebaine(0.2% in
opium){nonanalgesic}.
• 2.Benzoisoquinolone derivative:
• Papaverine(1%),
Noscapine(6%){nonanalgesic}
1.Natural opium alkaloids:
Morphine, Codeine
2.Semisynthetic opiates:
Diacetylmorphine, pholcodeine,
Ethylmorphine.
3.Synthetic opioids:
Pethidine(Meperidine), Fentanyl,
Methadone, Dextropropoxyphene,
Tramadol.

MORPHINE
• Morphine, principal alkaloid
• Morphine was first isolated between 1803 and 1805
by German pharmacist Friedrich Sertürner.
• This is generally believed to be the first isolation of an
active ingredient from a plant called opium.
• Merck began marketing it commercially in 1827.
• Morphine was more widely used after the invention of
the hypodermic syringe in 1853–1855

PHARMACOKINETIC AND HALF LIFE
• High variable first pass metabolism, Oral bioavailability: 1/6th -14th of drug.
• About 30% bound to plasma proteins
• Distribution is wider and crosses placenta.
• Metabolized in liver by glucuronide conjugation, morphine 6 – glucuronide.
• Plasma t1/2 life: 2-3 hours.
• Elimination completes in 24 hours.

INDICATIONS AND
CONTRAINDICATIONS
• Dental considerations:Post operative medication combined with
NSAIDS, mostly in post major surgeries.
• Contraindicated in infants/elderly with respiratory insufficiency,
bronchial asthma,head injury, hypotensive and hypovolemic,
undiagnosed acute abdominal pain, elderly male,hypothyroidism,
kidney or liver diseases.

DRUG DOSAGE AND COMBINATIONS
• Dose: 10-50mg Oral, 10-15mg i.m or s.c , 2-3mg
epidural/ intrathecal;children 0.1 to0.2 mg/kg i.m or s.c.
• MORPHINE SULPHATE 10 mg /ml inj; MORCONTIN
10,30,60 ,100mg CR tab,30-100mg BD, RILLIMORF
60mg SR tab.

ADVERSE EFFECTS
• Side effects; sedation, mental clouding,vomiting,blurring of vision,
respiratory depression, urinary retention etc.
• Idiosyncrasy and allergy
• Apoea of newborn
• Acute morphine poisioning
• Tolearance and dependence

HYDROCODONE
• Hydrocodone and Oxycodone
• Hydrocodone and oxycodone are attractive analgesics
because they have an oral bioavailability:60%.
• Additionally, their greater potency reduces the portion of an
administered dose of the parent drug that contributes to
nausea and constipation.

• Like codeine, oxycodone and hydrocodone are methylated
molecules having little or no analgesic efficacy.
• Presumably, 10% of a dose administered parenterally is
demethylated to its respective morphine counterparts,
hydromorphone and oxymorphone.
• This implies that the oral dose for codeine is approximately 20
times the IM dose of morphine (200 mg vs 10 mg).

TRAMADOL
• Tramadol is a centrally-acting analgesic with binary action. This resembles the action
of tricyclic antidepressants and potentiates descending inhibitory pathways.
• Tramadol’s principal metabolite, M1, demonstrates agonist action on mu receptors,
providing analgesic efficacy approximating that of codeine 60 mg.

• Tramadol is marketed as an effective and safe analgesic for moderate to moderately
severe pain.
• Nausea, vomiting, and dizziness may occur with the use of tramadol.
contraindicated;seizure disorder.
• Tramadol is not recommended for patients with a tendency to opioid abuse or
dependence.

PHARMACOKINETICS AND HALF LIFE
• Oral bioavailability is high
• T1/2 life: 5-6 hours.
• Parenteral dose ratio is 1.4
• SSRI therapy-serotonin syndrome

DRUG DOSAGE AND COMBINATION
• Dose: 50-100mg oral/i.m slow i.v
infusion(children 1-2mg /kg 4-6 hourly)
• CONTRAMAL ,DOMADOL,TRAMAZAC 50mg
cap, 100mg SR tab,50mg/ml inj in 1 & 2ml
ampoule.

INDICATIONS
1. As analgeics(pre and post operative)for dental related pain
2. Preanesthetic medication
3. Balanced anesthesia and surgical analgesia
4. Relief of anxiety and apprehension
5. Acute left ventricular failure (cardiac asthma)
6. Cough
7. diarrhoea

PETHIDINE(MEPERIDINE)
• Meperidine 75–100 mg is equianalgesic to morphine 10 mg following intramuscular
(IM) administration.
• A significant portion of an IM dose of meperidine is converted to normeperidine, a
metabolite that has no analgesic properties, but is a noted central nervous system
stimulant.

PHARMACOKINETIC AND HALF LIFE
• Parenteral activity os higher at 1/3 to ½ ratio. Liver
metabolization
• Plasma t1/2 life is 2-3 hours.

INDICATIONS AND
CONTRAINDICATIONS
• Primary as analgesic and in preanesthetic medication
• Dental consideration includes: post extraction medication and post
surgical
• i.v infusion, recovery anesthesia.
• All other indications as of morphine.
• Overdose causes delirium, myoclonus, mydriasis, tremors etc.

DRUG DOSAGE AND COMBINATIONS
• Dose: 50-100mg i.m, s.c orally or i.v
• PETHIDINE HCl 100mg/2ml inj;50,100mg tab.

• Furthermore, this metabolite has a 15–20 hour elimination
half-life, compared to 3 hours for the parent drug.
• For hospitalized patients, meperidine is used only for a day
or two; otherwise, normeperidine can accumulate.The oral
bioavailability for meperidine is approximately 25%, which
requires a 300 mg dose to be equianalgesic to its IM dose of
75 mg.

DEL MURO, C. F. E.; GÓMEZ, C. K.; RODRÍGUEZ, G. N. A.; VARELA-PARGA, M.;
LUENGO, F. J. A. & MEDRANO, R. J. C. COX-2 inhibitors in dental pain management. Int. J.
Odontostomat., 12(3):225-227, 2018.

STANDARD APPLICATION IN DENTISTRY

Becker DE, Phero JC. Drug therapy in dental practice: nonopioid and opioid analgesics. Anesth
Prog. 2005 Winter;52(4):140-9.

Huynh MP, Yagiela JA. Current concepts in acute pain management. J Calif Dent Assoc. 2003
May;31(5):419-27

OTC DRUGS: A MENACE?
• 3 different kinds of use are discussed.
• The first is persisting use of higher-than-
recommended doses without medical advice.
• The second is use to treat symptoms for which the
drug is not indicated.
• The third is use to produce intoxication.

ANALGESIC :ABUSE
• phenacetin was abused., Patients continued,kidney damage; they engaged in drug-
seeking behaviour suggestive of dependence; association with the abuse of other
psychoactive agents; and phenacetin;alleviate psychological symptoms.
• There is also evidence suggesting that the drug was used to produce intoxication.
• currently available OTC analgesics abused to treat mood states, anxiety, sleep problems
and stress may be in need of treatment with more specific and efficacious agents.
Perrot S, Cittée J, Louis P, Quentin B, Robert C, Milon JY, Bismut H, Baumelou A. Self-
medication in pain management: The state of the art of pharmacists' role for optimal Over-The-
Counter analgesic use. Eur J Pain. 2019 Nov;23(10):1747-1762.

RECENT ADVANCEMENTS
• Food and Drug Administration (FDA) allowed continued marketing of
celecoxib, but mandated a cardiovascular safety trial.
• In the Prospective Randomized Evaluation of Celecoxib Integrated Safety
versus Ibuprofen or Naproxen trial, they sought to assess cardiovascular,
gastrointestinal, renal, and other outcomes with celecoxib as compared with two
nonselective NSAIDs (Ahmed et al., 2014)
• It is of importance the pharmacotherapeutic management of dental pain,
particularly of severe intensity pain, which is also accompanied by
inflammation.

DEVELOPMENT OF NEW ANALGESICS
• Capsaicin, Ketamine, Dronabinol, and Ziconotide Analgesic drugs with completely new
mechanisms of action directed at the novel molecular targets belong to 4 types.
• Each type is usually represented by 1 drug with an analgesic effect confirmed by FDA
approval (ziconotide) or by meta-analysis (capsaicin, ketamine, and dronabinol).
• Three of these subgroups were identified some time ago in plants (chili peppers for
capsaicin and cannabis for dronabinol) or snail venom (Conus magus for ziconotide)
• Discovered relatively recently (TRPV1 ion channel for capsaicin, CB1 and CB2
receptors for dronabinol, and N-type voltage-sensitive calcium channel for ziconotide).
Kissin I. The development of new analgesics over the past 50 years: a lack of real breakthrough
drugs. Anesth Analg. 2010 Mar 1;110(3):780-9.

REFERENCES
• Kim SJ, Seo JT. Selection of analgesics for the
management of acute and postoperative dental pain: a
mini-review. J Periodontal Implant Sci. 2020 Mar
19;50(2):68-73.
• Priya SL, Shubashini RJ. Analgesics In Dentistry-A
Review. Indian Journal of Research in Pharmacy and
Biotechnology (IJRPB). 2020 May;8(3).
• Perrot S, Cittée J, Louis P, Quentin B, Robert C,
Milon JY, Bismut H, Baumelou A. Self-medication in
pain management: The state of the art of pharmacists'
role for optimal Over-The-Counter analgesic use. Eur
J Pain. 2019 Nov;23(10):1747-1762.
• Wood H, Dickman A, Star A, Boland JW. Updates in
palliative care - overview and recent advancements in
the pharmacological management of cancer pain.
Clin Med (Lond). 2018 Feb;18(1):17-22.
• Textbook of pharmacology,KD tripathi ,8th edition

• Kissin I. The development of new
analgesics over the past 50 years: a lack
of real breakthrough drugs. Anesth
Analg. 2010 Mar 1;110(3):780-9.
• Huynh MP, Yagiela JA. Current concepts
in acute pain management. J Calif Dent
Assoc. 2003 May;31(5):419-27.
• Zarghi A, Arfaei S. Selective COX-2
Inhibitors: A Review of Their Structure-
Activity Relationships. Iran J Pharm Res.
2011 Fall;10(4):655-83.

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