Analgesics / dental implant courses

ANALGESICS
INDIAN DENTAL ACADEMY
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PAIN- IS A SUBJECTIVE EXPERIENCE WHICH CAN NOT
BE OBJECTIVELY DEFINED OR QUANTIFIED
SATISFACTORILY.
ALGESIA (pain) is an ill-defined, unpleasant sensation, usually
evoked by an external or internal noxious stimulus.
Classification-
1. Supeficial/ cutaneous pain.
2. Deep non-visceral pain
3. Visceral pain
4. Reffered pain
5. Psychogenic or functional pain

Classification of pain
PAIN
Somatic Visceral
DeepSuperficial
(from skin and SC tissue) (from bones& joints)

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Somatic pain arises from stimulation of receptors in the skin, in
which case it is called superficial somatic pain.
From stimulation of receptors in skeletal muscles, joints, tendons
and fascia it is called deep somatic pain.
In most cases of visceral pain, sensation is not projected back to point of
stimulation. Pain may be felt in a surface area far from stimulated organ. This
phenomenon is called referred pain.

ANALGESICS are drugs which relieve pain without loss of
consciousness.
ANALGESICS selectively relives pain by acting in the CNS or on
peripheral pain mechanisms with out significantly altering
consciousness.
Classification:
 OPIOIDS
 NON-OPIOIDS (NSAID’s)

OPIOID ANALGESICS / NARCOTID /
MORPHINE LIKE ANALGESICS:
 The word opiates refers to the products from the opium
poppy.
 The term opioid (opoiate – like) is used to denote all
naturally occurring, semi synthetic and synthetic drugs
which have a morphine like action viz relief from pain
and depression of the CNS, both of which are reversed by
naloxone.
 These drug formerly called ‘narcotic’ analgesics because
some of them induce sleep. The word ‘narcotic’ is derived
from the greek prefix ‘Narco’ which means to deaden.
 Opioids are capable of producing drug dependencies.

Sub classification of opioid
analgesics1. AGONISTS : such as morphine and compounds
which resemble it in most of their actions, viz,
derivatives of morphine, codeine and its
derivatives, synthetic compounds such as
pethidine, methadone, propoxyphine,
levorphonol and tramadol.
2. PARTIAL AGONISTS: Ex:Buprenorphine and
meptazinol They have partial agonist action only
on the mu receptors.
3. MIXED AGONIST – ANTAGONISTS: which act
as agonists at one type of opioid receptors and
as competitive antagonists at another type of
receptors. Eg: Nalburphine,
pentazocine and butorphanol.

Peptides with strong opiate-like analgesic &
mu receptor binding activity are now known
to present in CNS & other tissues. In CNS,
they act as endogenous analgesics, as NTs
& behaviour modulators. They are:
1.Beta-endorphin
2.Enkephalins
3.Dynorphins
4.Nociceptin/orphanin
5.Endomorphins 1 & 2

Opioids – Mechanism of action:
1. The opioid drugs produce their effects by binding to opioid receptors which
are widely distributed in the CNS and other tissues.
2. Opioid receptors are part of the family of G-protein complex receptors and
act to open K+ channels and prevent opening of voltage- grated Ca++
channels.
3. They their by inhibit the release of other neurotransmitters. The opioid
receptors have been classified into
i. Mu
ii. Delta
iii. Kappa(k1 and k2) and
iv. Nociceptin (orphanin ) types.
Apart from the 4 major classes, several other sub types have been
identified. The pharmacological effects associated with these receptors
subtypes and the selectivity of the various opioid drugs for these
receptors are as follows.

PHARMACOLOGICAL EFFECTS ASSOC WITH OPIOID RECEPTOR TYPES:
RECEPTOR EFFECTS
Mu • Supraspinal/ spinal A
• Euphoria, resp dep, sedation, miosis, decreased
GI motility, Sm mus spasm.
• Physical dependece, release of prolactin & GH, N
& V, feeding.
Kappa • Supraspinal/ spinal A, euphoria, resp dep,
sedation, miosis,
• Decreased GI motility,less phy dep,
dysphoria,psychomimetic effects, diuresis,
Delta • Supraspinal/ spinal A, less resp depn, dec GI motility, realese
GH, feeding.
Nocciceptin/orph
hanin FQ
• Drug reward & reinforcement
• Stress responsiveness
• learning & memory

Selectivity of common opioid analgesic drugs 3 for
different receptors
Compounds Receptor type
Mu Kappa Delta
1. Pure agonists
morphine
methadone
codeine
+++
+++
+
+
0
+
+
0
0
2. Partial agonists
buprenorphine
butorphanol
propinam
(+++)
(++)
(++)
-
+++
0
0
0
3. Agonist/ anatagonists
pentazocine
nalbuphine
-
-
++
(++)
+
+
+ agonist (++) partial agonist - antogonist 0 no action

Opium alkaloids:
Divided in to:
1. Phenanthrene group
-morphine, codeine, thebaine
2. Benzyl iroquinoline group
- papaverine, noscapine, narcine
(it is devoid of Analgesic activity, but act as smooth m relaxants)
MORPHINE: is the most important alkaloid of opium & is used as sulphate or
hydrochloride; both salts are soluble in water.
Pharmacological actions-
- periaqueductal gray matter of the brain stem & thalamus: high opioid
receptor density.
- Analgesic actions- seletive action on mu receptors situated both in higher
centers & in S.C

- Opiate receptors are also found in the area postrema which contains
the CTZ & the solitary nuclei which receive visceral sensory fibers
from the vagus & the 9 th C.N
- Opiate receptors have also been identified in the amygdala & it is
possible that they are assoc with influences of opiates on emotional
reaction.
- Within the spinal cord, opiate receptors are localized in the substantia
gelatinosa, which is the first site in the CNS for the integration of
sensory information.
- Opioids & endogenous opioid like peptides have been shows to
modify the release of acetylcholine, noradrenaline, dopamine & sub-
p.
On CNS:
1) analgesia: M produces relief of pain in a dose that usually does not
cause motor incoordination.
-in subanaesthetic doses-has little effect on pinprick sensation &
withdrawal reflex, though pain arising from tissues is well suppresed.
- in moderate doses- releaves cont dull pain.
- In largr doses- releaves sharp intemittant pain & visceral pain.

-Dose just short of causing toxicity- in treatment of terminal cancer.
-M raises the pain theshold, there by reducing the perception of pain.
2) Euphoria, sedation & hypnosis:
-in therapeutic doses, M produces a sense of emotional well being
termed euphoria( this makes this drug one of the worst drugs of abuse)
- rarely, it may produce a sense of anxiety/fear termed dysphoria
particularly in pain free individuals.
- Causes sedation
- larger doses induce sleep with EEG changes similar to those
observed during natural sleep.
- psychological effects of M lasts longer than its analgesic effect.
3) Respiration- depresses the respiratory center. Therapeutic doses
acts by * direct depression action on the respiratory center &
* reducing its sensitivity to increased plasma CO2 conc.
-causes broncho constriction as a result of histamine release.
-Toxic doses – breathing maintained by hypoxic drive mediated through
carotid and aortic body chemo receptors – chyne stokes resp.

4. Pupils- M stimulates occulomotor centre
5. Nausea and emesis – M stimulates CTZ and produces vomitting
-this is abolished by Nalorphin and Prochlorperazine (5-10mg 4-8
hrly), metoclopramide)10mg 4-8 hrly), haloperidol(1-2mg daily) but
not by antihistamines.
-In larger doses- depresses the vomiting centre.
6. Cough supression
7. Vagal stimulation
8. Spinal cord: M increases the reflex excitability of SC.
-this is masked by depression of higher centres in CNS.
-therapeutic doses produce significant increase in CSF pressure.
9. GIT – induces vigorous spasm of smooth muscle of gut, ileocolic
and anal spinchters while at same time it reduces peristaltic
movements.
-spasmogenic actoin in duodenum of large intestine
-Reduces salivary, gastric and intestinal secretions

-Dessication of feaces , abolision of peristaltic movements, spasm of
sphinctres and in attention to normal sensory stimuli from a loaded
rectum as a result of psychololgical effect of M, all lead to constipation
-Atropine antagonists spasmodic action of M
-M increases the intrabililary pressure
10. Smooth muscles – M produces increased in the tone of uterus and
deturus muscle of bladder – reults in urinary retention.
-produces increase in the tone of bronchi and bronchioles.
-larger doses has effect on human uterus at full term.
11. CVS - therapeutic doses of M have negligible effect on
myocardium ,BP, HR.
-Produces dilatation of B.V, this may reduce the pre load on the heart.
-pruritis , sweating and flushing often accompany cutaneous cappilary
dilatation.
-toxic doses of M may produce hypotension.

12.Neuro endocrine system- M acts in the hypothalamus and
inhibits the release of GnRH & CHR.It thus decreases plasma
concentration of FSH, LH & ACTH.
-Plasma conc of prolactin increases .
13.Immune system – opioid suppresses various immune functions
and increses the susceptibility to infections.
14. Metabolism- M decreases the metabolic rate resulting in slight
fall in body temp , reduced RR ,reduced muscular activity and
peripheral vasodilatation.
ABSORPTION, FATE AND EXCERTION-
-adequately absorbed when given orally, but extensively
metabolised during first pass through the liver ( oral bioavailability
20 to 40%)
-Sustained release prep have longer duration of action
- can also be given rectally
-Given subcutaneously it prouces analgecic effect within 15 to 20
mins with peak effect at 60 to 90 mins , persisting for 3-5 hrs
-Given IV, produces immediate effect

-M circulates in plasma partly bound to plasma proteins and partly in
free form.
-crosses placental barrier readily
-metabolised by liver and kidney readily
-M is congugated with glucouronic acid to form M-6-glucoronide
(more potent than M)
-in adults plasma half life of M is 2 hrs
-small amounts of free M and large amounts of congugted M are
excreted in urine (90% within 24hrs)
-biliary excretion of congugated form – 7-10%
PREPARATIONS & DOSAGE-
1.Tincture opium- is a hydro alcoholic solution of 10% opium and 1%
M . Dose – 0.3 – 2ml
2.Chlorodyne- is a cloroform and M tincture containing 0.22gm % of
morphine hydrocholride.Dose 0.3 – 0.6ml
3.M solution(2 to 20 mg/ml for oral use)-
10-30mg for adults , upto 200 mg in terminal cancer

4.M hydrochloride and sulphate injection-
Dose – 10-20mg SC/IM
2.5- 5mg IV slowly over 5 mins
5.Controlled release tablets (10,30 and 60mg) of morphine sulphate
ADVERSE REACTIONS-
1.Intolerence
2.effects on CNS
3.Resp depression
4.Constipation
5.hypotension
6.urinary retention
7.A/E on foetus
8.Tolerence
9.Drug dependence
10.Acute M poisoning
11.Drug interactinons

TOLERANCE: Repeated admn of M results in the development of
tolerance. With intermittant use of M, however, it is possible to obtain the
desired analgesic effect & sedative effects.
-tolerance develops to the resp depressant, analgesic, sedative &
euphoriant effects of M as well as to urinary retention, but the pupils &
GIT do not share the tolerance.
-A morphine addict thus has chaly
pin-point pupil & is habitually
constipated.
-Tolerance to M is attributed primarily to the ability of the cells of the
CNS to withstand the larger doses of the drug.
-Persons tolerant to M exhibits cross tolerance to other opioid drugs &
even to compounds like barbiturates & alcohol.

DRUG DEPENDENCE-
-is a major drawback of M therapy.
-Mainly due to its euphoriant effects.
-Morphine addicts are usually malnourished & debilitated.
-A/E of self injections
-Depression of libido
-withdrawal syndrome manifestations are as follows

ABSTINENCE PERIOD MANIFESTATIONS
6-12 hrs Intense craving for the drug,
lethargy & weakness
12 hrs Yawning, lacrimation,
perspiration, rhinorrhoea,
tremors ,anorexia
48 hrs Peak of withdrawal S, fever,
increase in BP, inc in HR,
dilatation of previously
constricted pupils,intestinal
cramps.
7-10 days Symptoms clear up but pt
c/o restlessness, insomnia,
weakness, back & leg pain
for several weaks

- Prevention of morphine dependence
-Treatment for morphine dependence
Principles of treatment of drug dependence
1. Hospitalization of pt.
2. Gradual or sudden withdrawal of drug
3. Substitution therapy- methadone
4. Psychotherapy & occupational therapy
5. Specific drug therapy
6. Correction of nutritional deficiency
7. Community treatment & rehabilitation.
- in acute opiate withdrawal symptoms & signs drugs like
chlorpromazine, propranolal & clonidine are given(which counter the
nor-adr over activity).

ACUTE MORPHIN POISONING
-may occur from clinical overdose , accidental over ingestion in an
addict or suicidal or homicidal intention
-a dose of 60mg is usually toxic but rarely fatal in a normal adult who
is not in pain.A dose of 250mg is usually fatal.
-In addicts the toxic as well as fatal doses are much higher.
-M poisoning is charecterised by resp dep, pin point pupils,
cyanosis ,reduced body temp and urinary output, hypotension, shock
and coma.Convulsions may occur in infants.death is usually due to
resp dep or shock , pulmonary edema & secondary infection.
-Naloxone & Nalorphine are the specific M antagonist.

THERAPEUTIC USES OF MORPHINE:
1.For relief of pain – in acute MI , fracture of long bones, burns,
terminal stage of cancer, pulmonary embolism, acute pericarditis,
pleurisy and spontaneos pneumothorax
-in sudden excruciating pain – IV M given, this also minimises shock
-SC administration of M is not advocated in the presence of shock.
-used for relief of pain in renal and biliary colic
-Post operatively parenteral M is given
-intrathecal and epidural M has also used to produce analgesia.
-deafferentiation pain is relatively resistant to M gp of drugs
2.In acute left ventricular failure and pulmonary edema
3.As sedative
4.As pre anesthetic medication
5.To produce constipation
6.As an anesthetic

Precautions with M therapy
1.COPD
2.Myxoedema
3.old people and infants
4.head injuries
5.acute abdomen
6.IV M may produce hypotension if administered during hypovolumeic
shock.
7.In sever impairment of kidney or liver infection

Other Phenantherin alkaloids of opium
1.Codine
-is a weak agonist, less potent than M.
-does not produce significant dep of respiration & has a low
dependence liability.
-in toxic doses, may produce excitement convulsions.
-It enhances the analgesic effect of aspirin.
-Better absorbed when given orally, oral bio-avl is 50%
-About 10% codeine is converted to M in liver
-Used as antitussive.
-Available as codeine phosphate(for oral & I.m use)
-Main disadv is constipation, used as antidiarrhoeal
-Dihydrocodiene & oxycodone.

2.Tramadol:it is weak synthetic opioid, acts seletively on mu receptors.
-absorbed & metabolized in liver.
-t1/2 is 6hrs.
-actions are similar to those of codiene & it has low addiction potential.
-causes less resp dep.
-causes dizziness, sedation & nausea.
-it is expensive.
BENZYLISOQUINOLINE ALKALOIDS OF OPIUM
1. Papaverine
2. Noscapine

SEMISYNTHETIC DERIVATIVES OF NATURAL OPIUM ALKALOIDS
-the M derivatives are
1.Heroin(diacetyl morphine, diamorphine):
-more potent analgesic than M, produces greater euphoria & has
higher dependence liability.
-Rarely employed therapeutically, (cos- drug abuse)
-Withdrawal syndrome in newborns- mothers who are heroin addicts.
-Treatment for addiction is simillar to that of M- 1mg of methadone.
-Their toxicity is similar to that of Morphine.
2. Apomorphine-
-It is a stimulant of CTZ, acts as a potent emitic
-effect is blocked by cholorpromazine
-Steriotyped behaviour syndrome
- acts both on pre & post synaptic DA receptors & thus produces a
variety of behavioural, neuropharmacological & endocrine effects.
-A/E- N,V, dizziness, hypotension & bradycardia.

SYNTHETIC MORPHINE SUBSTITUTES
1. PETHIDINE & ITS CONGENERS
2. METHADONE & ITS CONGENERS
3. MORPHINAN COMPOUNDS & CONGENERS. Eg: LEVOPHANOL
& BUTORPHANOL
4. BENZOMORPHAN DERIVATIVES.Eg: PENTAZOCINE
5. MISCELLANEOUS- NABBUPHINE,BUPRENORPHINE
PETHIDINE( Meperidine, Demerol)
-ph actions are similar to morphine.
-devoid of significant antitussive activity.
-the incidence of N & V is higher.
-has vagolytic action.
- may occasionally produce hypotension & syncope due to peripheral
vasodilatation.

ABSORPTION, FATE & EXCRETION:
-50% bio-avai on oral administration, the analgesic effects appears
with in 10-15 min.
- on parental admn the action lasts for 2-4 hrs
- Crosses placental barrier & also secreted in milk
- Metabolized by liver, norpethidine possesses significant excitatory
action on the CNS.
- norpethidine tends to accumulate during chronic use.
- Small portion of pethidine is excreted unchanged in urine, the
urinary excreation is enhanced when urine is acidic.
PREPARATION & DOSAGES:
1. Pethidine hydrochloride tablets
dose- 25-100mg
2. Pethidine hydrochloride inj 2ml amp containing 50mg/ml of the salt.
Dose- im/sc 25-100mg
iv- 25-50mg to be repeated, if necessary after 4 hrs.

A/E-
-local irritation on parenteral admn,sweating, euphoria, dizziness,
drymouth, vomiting,dysphoria, visual disturbances, weakness
&palpitation.
-Anaphylactoid reaction
- admn to mothers produces significant depression of foetal respiration.
-Causes bronchospasm,Decreases secretion
-Pethidine overdosage causes resp depn, coma or tremors myoclonus
& convulsions.
-Drug tolerance & dependence
DRUG INTERACTIONS: with
-Phenytoin
-cimitidine
-imipramine or an MAOI
C/I ARE SIMILAR TO MORPHINE

THERAPEUTIC USES:
1.as analgesic
2.preanaesthetic medication
3.obsterical analgesia
4.epidural & intrathecal analgesia
PETHEDINE CONGENERS:
Eg Priminodine,
Phenopridine,Fentanyl,Aifentanil,Remifentanyl,Anileridine &
Alphaprodine.
-used mainly as anesthetic adjuncts
-Alphaprodine has shorter duration of action , used for relief of pain in
first stage of labour
-Diphenoxylate is used in treatment of diarrhoea.

Methadone(Physeptone)
-Analgesic potency >/= to M.
-Pharmocological actions similar to M but less hypnotic
-Resp dep is same degree as M , and has marked antitussive
effect
-Methadone inhibits the reuptake of nor adrenaline and 5-HT and
blocks the action of NMDA receptors
ABSORPTION FATE AND EXCRETION
-80% Oral bio availability
-analgesic effect occurs within 10-15 mins following parenteral and
20-30 mins following oral medication
-highly bound to plasma & tissue proteins
-plasma half life is 24 – 36 hrs
-crosses placental barrier
-metabolized in liver
-< 10% is excreted unchanged in kidneys

PREPARATIONS AND DOSAGE
1.Methadone hydrochloride tablet 5 – 10 mg
2.Methadone hydrochloride inj , 5-10mg IM/SC
ADVERSE EFFECTS
-Similar to those of morphine
-acute intoxication responds to naloxone
-tolerance and withdrawal syndrome develops more slowly
-codeine is often used as substitute during treatment of methadone
addiction
USES
1.In chronic pain, visceral pain
2.Drug of choice in treatment of opioid withdrawal sydrome
3.Anti-tussive
METHADONE CONGENERS-levomethadyl acetate and propoxane

MORPHINIAN COMPOUNDS
Levorphanol-
-More potent analgesic than M
-better absorbed on oral administration
-produces less constipation
-can cause drug dependence
-can be given orally or IM/SC in the dose of 2-3 mg
Pentazocine(Fortral, Fortvin, Talwin)
-is a benzo morphine derivative
-acts on kappa receptors in S.C
-weak opiod antagonist at mu receptors
-less analgesic activity, shorter duration of action , do not cause
euphoria.
-has lower dependence liability, constipation is uncommon, less
resp dep, raises systemic and pulmonary artetrial BP(not
recommended in MI).

Absorption fate and excretion
-well absorbed when given orally
-metabolised in liver
-excreted as glucornide
-Smokers metabolise 40% > than non smokers
Dose-
25mg tab &30mg (lactate) per ml inj
-oral dose 25mg –100mg every 3-4 hrs
-SC or IM or IV –30-60mg every 3-4 hrs
Adverse effects-
1.CNS- sedation sweating dizziness and nausea
2.Psychomimetic reactions, hallucinations and unpleasent dreams
3.precipitation of acute withdrawal syndrome in a morphine addict
4.tolerence and physical dependence (low)
-Naloxone -antidote

BUTORPHANOL-
NALBUPHINE-
MEPTAZINOL-
BUPETNORPHIN( BUPRINE, NORPHINE, TIDIGESIC)-
Actions
Adverse effects
Dose 0.2 –0.4 mg sublingually every 8hrs
0.3-0.6 mg IM/slow IV every 6-8hrs

NON ANALGESIC USES OF OPIODS
1.Anti diarrheal eg; diphenoxylate, loperamide
2.central cough suppresant eg: codiene
3.emetic eg: apomorphine
4. In acute LVF eg;morphine

OPIOD ANTAGONISTS
-Acts mainly by competitive antagonism
Classification-
1.Pure antagonists eg: naloxone ,naltrexone
2.Partial agonists of Nalorphine type eg: nalorphine, levallorphan and
cyclazocine
3.Partial agonists of morphine type eg: propiran , profadil
NALOXONE(Narcan)- N-allyl analogue of oxymorphone, a pure
antagonist, selectively antagonizes the resp depressant action of
morphine & other opioids.
-when given orally, only 1/50 as potent as when given parenterally
cos of its metabolism in liver.
-1mg given I.v completely blocks the action of 25mg of heroin. Its
duration of action is 3-4hrs.
-it is almost completely metabolized in liver.
- tolerance to the opioid antagonist properties does not occur.

-available in 1 ml vials containing 0.4mg/ml & is the antagonist of choice
in treatment of opioid poisoning.
-it is administered as iv bolous in the dose of 0.8-2mg every 2-3min to a
total max of 10mg.
-in children iv 10mg/kg, if no response then inject 100mcg/kg(bolous)
-it is used to reverse the residual resp dep effect of opioid at the end of
op. procedure.
NALTREXONE(Nalorex):Orally administered, long acting, opioid
antagonist.
-well tolerated & has no euphoric effect
-available as 50mg scored tablets
-For treating heroin addiction, small doses 25mg/day is used initially,
followed by 50mg/day.
- it is given in former opioid addicts to prevent re-addiction.
-Also used in alcohol addiction.
-A/E; GI dist, nervousness, sleeping difficulty & muscular pains. Rarely
thrombocytopenia & liver function abnormalities may occur.

NALORPHINE(N-allyl-normorphine)
-semisyntetic congener of morphine.
-for treatment of acute M poisoning.
Actions-
1. When administered without prior medication with morphine
2. When administered after morphine
3. When administered to a morphine addict
-oral-poor absorption
-subcutaneous- rapid a
- metabolized in liver by conjugation
Dose-10mg/ml-sc or iv in dose of 3-10mg(total of 40mg)

Uses-
1. Acute poisoning due to M & related compounds.
2. Diagnosis of M addiction.
3. Used in M addicts along with M.
LEVALLORPHAN-
CYCLOZOCINE-

Analgesic- antipyretics & non-steroidal anti inflammatory drugs:
Non-opoid analgesics:
- relieve pain wihout interacting with opioid receptors
- reduce elevated body temp.
- posses anti-inflammatory property.
- have antiplatelet activity.
- do not cause sedation or sleep
-are non addicting drugs
TEMPARATURE REGULATION:
INFLAMMATION:

CLASSIFICATION: A. Analgesic & anti inflmmatory
1. Salicylates- aspirin
2. Pyrazolone derivatives- phenybutazone
3. Indole derivatives- indomethacin, sulindac
4. Propionic acid derivatives- ibuprofen
5. Antranalic acid derivatives- mephenamic acid
6. Aryl acetic acid derivatives- diclofenac
7. Oxicam derivatives- piroxicam
8. Pyrrole-pyrrole derivatives- ketorolac
9. Sulfonanilide derivatives- nimesulide
10. Alkanones- nabumetone
B. Analgesic but poor anti inflammatory
1. Para amino phenol derivative- paracetamol
2. Pyrazollone derivative- metamizol 3. Benzoxazocaine-
nefopam

A. Non-selctive COX inhibitors
1. Salicylates
2. Paraamino phenol derivatives
3. Pyrazolone derivatives
4. Indole derivatives
5. Hetro cyclic arylacetic acid derivatives
6. Propionic acid derivatives
7. Fenamates
8. Oxicams
B. Selective COX-2 inhibitors-
- nimesulide, meloxicam, nabumetone, celecoxib, rofecoxid &
valdecoxib.

MECHANISM OF ACTION:
- During inflammation, pain & fever, arachidonic acid is
liberated from phospholipid fraction of the cell membrane.
- AA is then converted via cyclo-oxygenase(COX-1&2)
pathways to PGs. The steps are
1. Oxidation of AA to the endoperoxide PGG2 &
2. Its subsequent reduction to hydroxy endoperoxide PGH2- this
is transformed in to the primary prostanoids PGE2, PGF2,
PGD2, PGI2 & TXA2
- COX-1 activity is constitutively present in nearly all cell types
at a constant level & is involved in tissue homeostasis
- COX-2 activity is normally absent from cells(except those of
kidney & brain) but is induceble by bacterial liposaccharides
IL2 & TNF in activated leucocytes & other inflammatory cells
- Thus, COX-1 is physiological & COX-2 is usually pathological

- Actions of PGs
- most NSAIDs inhibit COX-1 & COX-2 nonselectively, but
now some selective COX-2 inhibitors have been produced
- aspirin inhibits COX irreversibly by acetylating one of its
serine residues, return of COX activity depends on synthesis
of fresh enzyme.
- others- competative & reversible inhibition of COX
BENIFICIAL ACTIONS DUE TO PG SYN INHIBITION:
1. Analgesia, Antipyresis, Anti-inflammatory
2. Antithrombotic
3. Closure of ductus arteriosus
SHARED TOXICITIES:
1. Gastric mucosal bleeding, inh of platelet function
2. Limitation of renal blood flow- Na & water retention
3. Asthma & anaphylactoid reactions in suceptible individuals

SALICYLATES(esters of salicylic acid)
Eg: methyl S& sodium S & aspirin(acetyl S acid)
Pharmcological action-
1. Local actions:
- salicylic acid & methyl S are irritants, salicylic acid also
has keratolytic,antiseptic & fugistatic action.
- Salts of salicylic acid do not irritate unbroken skin but
when ingested, may release free salicylic acid in
stomach causing local irritation.
2. CNS-
• Analgesia-act predominantly peripheral.
• Can be combined with codeine

•Aspirin Inhibits the biosynthesis of PG’s by irreversible
acetylation & consequent inactivation of COX in contrast to
other NSAID’s which cause its revesible inhibition.
• not usefull in deaffrenation & visceral pain.
• in smaller dose-only analgesic action, larger doses- anti
inflammatory activity, releive vascular congestion & edema.
Antipyretic action-
•By inhibiting brain PG synthesis & release.
• do not reduce heat production but increase dissipation of
heat by producing cutaneous vasodilatation.
Respiration-
•Stimulate resp as a result of direct & indirect actions.

Acid base balance & electrolytes-
•Compensated resp alkalosis
• hypokalemia
• dehydration & hypernatremia
• in a.toxic doses-metabolic acidosis.
3. GIT- salicylates may produce
•dyspepsia, N & V- gastric irritation
• peptic ulceration, GI bleeding, hematemisis, malena.
•decrease in PGE2 & PGI2-loss of protective effect of PGon
stomach
• also reduce motility of stomach & increase gastric emptying
time.
• alkalies reduce gastric irritation & absorption of salicylates.
•To avoid gastric irritation:

4. Anti inflammatory & anti rheumatic effect-
•By inhibiting PG synthesis
• by reducing capillary permiability
• by inhibition of neutrophil aggregation & activation
• inhibit the formation of activated kallikerin from inactive
plasma & leucocyte kallikerin
• inhibit mucopolysac bio-synthesis
5. Immunologic phenomenon-
•Prevent release of histamine as a result of Ag-Ab reaction.
• do not significantly interfere with the development of
agglutinins following typhoid inoculation
• may reduce CMI.

6. Blood & Platelets:
•Does not affect normal leucocyte count
• reduce leucocytosis & reduce the high ESR in acute rh fever
• inhibit platelet aggregation(suppersion of TXA2 in platelets)-
irreversible, other NSAID’s- reversible
•non acetylated salicylates such as sodium S do not posses
antiplatelet action.
7. Hepatic & renal effects
8. Uricosuric effects
9. On CVS
10. Endocrine effects
11. Metabolic effects- uncoupling of oxidative phosphorylation
- on sugar level
- reduce lipogenisis

INR values and its importance in dentistry
Absorption, fate & excretion-
• absorbed from intact skin, given orally, absorbed in stomach & upper
small intestine.
• plasma ½ life- 2-8 hrs
• after absorption, 80% of salicylate is bound to P.P(aspirin-50%)
• aspirin ½ life 15 min
• Dose dependent pharmacokinetics
1. Lower dose- 300-600mg- Ist order kinetics.
2. Higher dose- 1-2g- zero order kinetics
• Mainly excreted in urine

Adverse effects-
1. Intolerance
2. On GIT
3. On hemopoietic system
4. On kidneys
5. Rey’s syndrome
6. Pregnant women & infants
7. Salicylism
8. Acute salicylate intoxication

S
s
a
SALICYLISM
-High doses of salicylates may produce a condition of mild salicylate
intoxication termed salicylism.
-syndrome usually developes when the plasma salicylate levels
>25mg%
-charecterised by headcahe, dizziness, vertigo, tinitus, difficulty in
hearing n sight, drowsiness, lethargy, mental confusion, nausea,
vomitting & diarrhoea may occur
-may also be associated with tachypneoa & resp alkalosis
-signs & symptoms are reversible on cessation of drug.

ACUTE SALICYLATE INTOXICATION
-overzealous therapy in infants or accidental ingestion
-50mg% mild toxicity & > 75mg% potentially fatal
-charecterised by acid base electrolyte disturbances, hypoglycemia,
hyperpyrexia, GI irritation, restlessness, vertigo, tremors ,
convulsions ,coma
-moderate doses cause resp alkalosis, with higher doses the resp
centre is depressed leading to metabolic acidosis
-treatment : correction of acidosis & urinary alkalinization using 2%
dextrose & 2% sodium bicarbonate, at the rate of 2 lt/hr with frequent
determination of blood ph & plasma bicarbonate to prevent metabolic
alkalosis.
-sedatives like barbiturates are dangerous in these cases

Principles of management of salicylate poisoning
1. Hopitalization
2. Gastric lavage
3. Correct hyperthermia, de/overhydration, hypokalemia, acid-base
disturbances, ketosis.
4. Increase elimination by alkalinization, potential dialysis &
hemoperfusion.
5. Vit-K, blood transfusion.
6. Exchange transfusion in very small children.

Preparations & dosage-
1. Acetyl salicylic acid(aspirin- 300mg tab)
2. Soluble aspirin tab contain aspirin 300mg, citric acid 30mg,
CaCo3- 3mg.
3. Buffered aspirin tab – aspirin & antacid like MgOH, AlOH, AL
glycinate.
4. Sodium salicylate- 500mg tab.
5. Methyl salicylate(oil of wintergreen): Methyl salicylate 25% in
peanut oil, Methyl salicylate ointment 50% in bees wax &
hydrous wool fat.
6. Salicylic acid: ointment contains 2-6% Salicylic acid, while
whitfields ointment contains 6% benzoic acid,& Salicylic acid
3%.
7. Lysine acetyl salicylate(injisprin, biosprin) iv infusion
preparations.

Uses-
1. Local application
2. As analgesic antipyretic
3. As anti-inflammatory
4. As anti-rheumatic
5. As anti platelet agent
6. Miscellaneous- Indomethacin in persistant patent ductus, barters
syndrome, food intolerence , diarrhoea, sun burns , ocular
inflammation etc…
DIFLUNISAL-

PARA AMINOPHENOL DERIVATIVES-
Eg- Paracetamol, Acetanilid, Phenacetin
PARACETAMOL-
-Aanlgesic & antipyrectic
-less antiinflammatory effects
-< GI irritation, acid base imbalance , electrolyte disturbances
as compared to salicylates
ABSORPTION , FATE & EXCRETION-
-Oral administration rapidly absp
-reaches plasma levels in ½ to 1 hr
-metabolised in liver and excreted in urine as conjugate
products of glucuronic & sulfuric acid
-Infants have poor ability for glucuronidation thus causes
enhanced toxicity of drugs in neonates

ADVERSE EFFECTS
-Hepatic & renal toxicity (7-10gm)
-liver toxicity due to N-acetyl-p-benzoquinoneimine
-may cause fever , neutropenia, thrombocytopenia, nephropathy &
skin reaction
-rarely produces anemia as a result of hemolysis &
methhemoglobinaemia
PREPARATION AND DOSAGE
1.250-500MG TAB analgesic & antipyrectic(adult 2.5g)
2.liquid dosage form in children
3.inj Febrinil- 150mg/ml

PYRAZOLONE DERIVATIVES
-Aminopyrine & antipyrine (not well tolerated no longer used)
-phenylbutazone & oxyphenbutazone
-others phenyl dimethyl pyrazalone(analgin, dipyrone)
PHENYLBUTAZONE
-Potent antiinflammatory drug
-poorly tolerated as it causes various GI ,hepatic , renal ,
fetal, heamatologic toxic effects
-gives rise to various drug interactions
-hence rarely used

OXYPHENABUTAZONE(Phenabid,Oxyin)
-metabolic degradation product of Phenylbutazone
-claimed to cause less gastric irritation
ANALGIN (Dipylone, Novalgin)
-potent analgesic & antipyretic but no uricosuric effect
-has no advantage over aspirin except that it can be injected
-toxic effect are similar to those of phenylbutazone & include fatal blood
dyscrasias
INDOLES & RELATED DRUGS
Indomethacin(Indocid)
-anti inflammatory, analgesic , antipyretic
-used in Rheumatoid Arthritis

-used in treatment of acute attack of gout
-acts as an analgesic even in the absence of obvious inflammation
eg- osteoarhtritis, ankylosing spondylitis
ABSORPTION ,FATE ,EXCRETION
-oral admist completely absorbed reaching a peak plasma con. In
1-2hrs
-metabolised in liver & excreted in kidneys as glucuronide
-t1/2 is 2hrs
ADVERSE EFFECTS
-Headache, mental confusion, giddiness, blurring of vision,
depression & psychotic disturbances

-neuropsychiatric adverse effects are common
-less common adverse effects are nausea, vomitting,
dyspepsia, diarrhoea , skin rashes and rarely blood
dyscariasis.
-peptic ulceration associated with bleeding & liver damage is
reported
-may cause sodium retention , oedema
-may aggrevate renal disease
PREPARATION AND DOSAGE
25mg CAP : 50-150mg/day in divided doses
USES
-acute gout attacks,ankylosing spondylitis
-it does not interfere with the uricosuric effect of probenecid
-not a drug of choice in rheumatoid a, due to side effects.

HETROCYCLIC ARYLACETIC ACID DERIVATIVES:
DICLOFENAC(Voveran):
-has greater activity than other NSAIDs.
-50% of sodium salt is metabolised during first pass through the
liver.
-It is extensively bound to plasm proteins, t1/2 is 1-2 hrs.
-It accumulates in the synovial fluid, which probably is
responsible for its longer duration of action than its plasma half
life.
A/E:
- 20% incidence
-similar to propionic acid derivatives.
-GI symptoms & elevation of liver enzymes occur more
frequently
- other side effects include CNS effects & fluid retention

USES:
-Rheumatoid arthritis, severe osteoarthritis, ankylosing spondalitis
-75-100mg/day in divided doses, im/oral
-also used as 0.1% eye drops for inhibition of intraoperative
miosis & to prevent postop inflammation in cataract surgery.
-for postop analgesia,75-100mg in divided doses, intrarectal
route.
KETOROLAC:
-Moderately effective analgesia
-Dose: 20-30mg(single dose)
-T1/2 is 5hrs
-Like other NSAIDs, it also has antiplatelet activity
-Initial dose of 20-30mg I.m may be followed by 10-15mg by the
same route 6-8hrly(max-80-120mg)
- I.V doses is simillar to im dose

TOLMETIN(Tolectin):
-pyrrole acetic acid derivative
- resembles ibuprofen in its action & toxicity
-Less potent than indomethacin.
PROPIONIC ACID DERIVATIVE:
Eg- ibuprofen, naproxen, fenoprofen, flurbiprofen & ketoprofen
-have analgesic-antipyretic & anti-inflammatory properties similar
to aspirin
-Better tolerated orally
-Highly bound to plasma albumin(92-99%) & like aspirin, can
displace drugs such as hydantoins, sulfonylureas &
waraferin.They, however, differ in their Pharmacokinetics &
hence, in their duration of action following single dose.

A/E:
-GI disturbances such as epigastric pain, nausea, sensation of
fullness in the stomach & heartburn.
-Occult blood loss is less common.
-Less frequently, they may cause CNS symptoms such as
headache, dizziness, blurred vission & tinitus.
-In a few cases, fluid retntion & edema may occur
-Jaundice, impairment of renal function, thrombocytopenia are
rare
USES:
-Rheumatoid arthritis, osteoarthritis, ankylosing spondalitis
-flurbiprofen eye drops for eye inflammation.

FENAMATES:
Eg: Mefenamic acid( meftal,pontstan)
-anthranilic acid derivative
-used in chronic & dull aching pains.
-Mefenamic acid is a weaker analgesic than aspirin
-A/E- D, gastric upset, dizziness, headache, skin rashes,
hemolytic anemia & blood dyscrasias
-Dose: 500mg 2-3 times a day
-USES:in dysmennorhoea
-Flufenamic acid has similar properties.

OXICAMS:Eg- piroxicam(feldene, pirox)
-this is structurally different from other agents
-well absorbed when given orally
-longer half life(38-45hrs)-hence administred once a day
-doses- 10-20mg(antipyretic & analgesic)
20-40(anti-inflammatory)
-causes GI & CNS disturbances
-USES: Rheumatoid arthritis,osteoarthritis, ankylosing
spondalitis, acute gout
-has no advantage except a longer duration of action
- other oxicams are tenoxicam, meloxicam & lornoxicam

SELECTIVE COX-2 INHIBITOR NSAID’S:
- Selectively block COX-2 activity more than COX-1 activity, thus
interfering less with the protective action of COX-1 in the
stomach, BV & kidneys.
-Eg: nimesulide, meloxicam, nabumetone, celecoxib, rofecoxid &
valdecoxib.
- given orally, their absorption is complete.
- effective analgesic-anti inflmmatory action(single dose)
- effective in treatment of osteoarthritis & rheumatoid arthritis.
ADVANTAGES:
-fewer gastric ulcers
- do not inhibit platelet aggregation
DISADVANTAGES:
- have prothrombotic effect, leading to a higher incidence of
cardiovascular events.

A/E:-N, V, dyspepsia, abdominal pain, diarrhoea & edema of
lower extrimities
- renal A/Es like decrease renal blood flow
- edema & dose releated worsening of hypertension
- studies in animals suggest that inhibiting COX-2 may interfere
with wound(ulcer) healing, bone remodeling, ovulaton & prenatal
renal development.
C/I:
-children, pregnant women, lactating mothers
-Celecoxib is contraindicated in pts allergic to sulfonamides.
- nimesulide causes nephrotoxicity & hepatotoxicity. So drug
should be avoided in children & old people.
- recently, the use of rofecoxib & valdecoxib has been reported
to be associated with icrease incidence of MI & stroke. Hence,
COX-2 inhibitors are under suspicion regarding their long term
toxicity.

DRUG ½ LIFE(Hrs) DOSE-mg
NABUMETONE(
RELIFEX)
24 500-1000 OD
NIMUSULIDE
(NIMULID, NISE)
<5 100 TID
MELOXICAM(M
UVERA, MOBIC)
20 7.5-15 OD
CELECOXIB
(CELEBREX)
11 200-400 OD/BID
ROFECOXIB
(VIOXX)
17 12.5-15 OD
VALDECOXIB
(BEXTVA)
8 10 OD

NSAID & RENAL DAMAGE:
- All NSAIDs can cause acute or chronic renal damage
following repeated use, sometimes as short as 2 wks.
- drugs with a long half life(naproxan & piroxicam) are more
likely to cause renal damage than those with shorter half
life(ibuprofen)
- clinically the renal injury can present it self in several forms
1. Acute renal failure
2. Mild asymptomatic renal impairment
3. Chronic renal impairment due to papillary necrosis/interstitial
fibrosis
4. Serious hyperkalemia
- first 3 are releated to the action of NSAIDs to inhibit
intrarenal PG synthesis by blocking COX-1

- Locally produced PGE act as intrarenal vasodilators to
counter act the vasoconstriction effect of Angiotensin II & nor
adrenaline(as in shock), they also influence the tubular
transport of ions & water.
- in normal young individuals the renal perfusion is not
dependent upon the locally produced PGs, in old people & in
individuals with diseases such as DM, it is.
- effects of inhibition of PG synthesis within kidney are:
1. The protective intrarenal vasodilator effect is lost
2. Renal blood flow & GFR are reduced in people with pre-
existing renal impairment
3. The natriuretic effect of PFE2 on renal medulla is lost with
consequent sodium retension
- hyperkalemia is due to diminished aldosterone synthesis
secondary to inhibition of renin synthesis by NSAID-
hyporeninimic hypoaldosteronism

- hyperkalemia is particularly likely to occur in pts with DM,
renal disease & in those on potassium sparing diuretics
- mechanism of NSAID induced renal damage include
1. Analgesic Nephropathy
2. Allergic type of intestitial nephritis &
3. Urate nephropathy.
- increased risk for this is seen in- pts of old age, cirrhosis of
liver, diabetic nephropathy, gout, renal & renovascular
disease & salt or volume depletion.
- NSAID enhance the effects of vasopressin on the kidneys &
can diminish excretion of free water

REFERENCES:
1.
2. Pharmacology & pharmacotherapeutics- 19th
edition, R.S.
Satoskar.
3. Essentials of medical Pharmacology – 4th
edition, K.D.Tripathi.

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