Analg /prosthodontic courses

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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
Pain pathways-

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:
1. OPIOIDS
2. NON-OPIOIDS (NSAID’s)

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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 analgesics
1. 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 actionwww.indiandentalacademy.com

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 secretionswww.indiandentalacademy.com

-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 cancerwww.indiandentalacademy.com

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.www.indiandentalacademy.com

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 propoxanewww.indiandentalacademy.com

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-

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