The document discusses various types of analgesics, including opioids and non-opioid analgesics. It provides details on morphine, including its mechanism of action, uses, side effects, and toxicity. It also covers non-steroidal anti-inflammatory drugs (NSAIDs) like aspirin and acetaminophen. NSAIDs work by inhibiting prostaglandin synthesis and reducing inflammation. The document outlines their mechanisms, classifications, uses, and potential side effects.

1. ANALGESICS
SUJIT KARPE
PRINCIPAL
SOJARCOLLEGE OF PHARMACY, KHANDVI

2. What is pain?
Pain is an unpleasant experience associated with acute tissue damage.
Experienced:
1) following injury,
2) organic diseases such as advanced cancer,
3) its origin within the CNS itself (not associated with tissue damage)
Accompanied by
1) emotional reaction (fear or anxiety)
2) autonomic responses such as sweating and an increase BP and HR.
 Sherrington “Pain is the physical adjunct of an imperative protective reflex."
Painful stimuli generally initiate potent withdrawal and avoidance responses.

3. Functions of Pain
•  Protects body against further injury
•  Guides functional recovery
•  May enhance disability

4. Classification

6. The structures that take
part in perception of
pain: thalamus,
hypothalamus,
reticular formation,
limbic system,
occipital and frontal
areas of cortex
System which
conducts and
perceives pain -
nociceptive

7. Modulation Pain

8. • Every day the world nearly 4 million
patients suffer from pain of different
intensity: 10-15% of moderate pain,
30-40% of the average pain intensity,
60-80% of severe pain.
• Studies show that more than 30
million people in the world take
NSAIDs daily , and that the
complications of their reception,
primarily gastrointestinal, constantly
growing

9. Types of pain

10. Referred Pain
Often a person feels pain in a
part of the body that is fairly
remote from the tissue
causing the pain is called
referred pain

11. Narcotic analgesic

12. • Opium is extracted from poppy seeds (Papaver
somniferum)
• Used for thousands of years to produce:
• Euphoria
• Analgesia
• Sedation
• Relief from diarrhea
• Cough suppression
History of Opioids

13. •Used medicinally and
recreationally from early Greek
and Roman times
•Opium and laudanum (opium
combined with alcohol) were
used to treat almost all known
diseases
History of Opioids
Morpheus
is the Greek god of dreams and sleep.
Friedrich Wilhelm Adam Sertürner, a
German pharmacist, isolated
Morphine from opium, in 1805.

14. • Invention of the hypodermic needle
in 1856 produced drug abusers who
self administered opioids by injection
• Controlling the widespread use of
opioids has been unsuccessful
because of the euphoria, tolerance
and physiological dependence that
opioids produce
History and
background

15. • group of G-protein coupled
receptors with opioids as ligands.
• The endogenous opioids are
dynorphins, enkephalins,
endorphins, endomorphins and
nociceptin.
Subtypes of opioid receptors:
mu, delta, kappa, epsilon, sigma
Opioid Receptor

16. Mechanism of
action

17. Mechanism of
action

18. Mechanism
of action

19. Response Mu-1 Mu-2 Kappa Delta Sigma
Analgesia
Respiratory
depression
Euphoria
Dysphoria
Decrease GI
motility
Physical
Dependence
Mania,
hallucination
Opioid Receptor
Activation

20. Morphine CNS Action
Depressant effects
• Analgesia
• Indifference to surroundings
• Mood and subjective effects
• Depression of respiration
• Cough centre
• Temperature regulating
centre
• Vasomotor centre
Stimulate effects
• CTZ (nausea, vomiting)
• Edinger Wesphal nucleus
(III nerve –producing
miosis)
• Vagal centre
(bradycardia)
• Certain cortical areas
and hippocampal

21. Morphine can be used as an analgesic
to relieve:
pain in myocardial infarction
pain associated with surgical conditions, pre- and postoperatively
(pre-anesthetic medication, balanced anesthesia, surgical
analgesia)
pain associated with trauma, burns
severe chronic pain, e.g., cancer
pain from kidney stones, renal colic, ureterolithiasis, etc (pain may
be valuable for diagnosis: should not be relived by analgesic unless proper
assessment of the patient has been done)
traumas of thorax accompanied by cough (morphine depresses
central links of coughing reflexes)

22. Acute left-ventricular cardiac failure
(cardiac asthma)
 Reduce preload on heard due to vasodilatation
 Tending to shift blood from pulmonary to systemic
circuit; relieves pulmonary congestion and edema
 Allays air hunger by depressing respiratory centre
 Cuts down sympathetic stimulation by calming the
patient

23. Applications in Dentistry
• Narcotic (opioid) analgesics are extremely effective
in reducing acute dental and postoperative pain.
• The narcotic analgesics have established for the
treatment of pain in those situations where the
NSAIDs are less effective.
• Hydrocodone, oxycodone, codeine, and
occasionally meperidine are the narcotics used to
treat dental pain.

24. MORPHINE HYDROCHLORIDE
routes of administration
 subcutaneously and intramuscularly
(analgesic action after 10-15 min)
 oral administration – presystemic elimination
( 20-60 % enters general blood circulation)
 sublingually – quick absorption
 i.v. is indicated even in emergency
 Epidural or intrathecal ( into the spinal canal ) injection produces
segmental analgesia lasting 12 hours without affecting other
sensory, motor or autonomic modalities
Duration of analgesic action – 4-6 hours
Maximum single dose of morphine is 0.02 g,
maximum daily dose – 0.05 g

25. Side effects of morphine
 Respiratory depression
 Euphoria, Mental clouding
 Vomiting (excitation of starting zone of vomiting
center)
 bradycardia (increasing of tone of vagus nuclei)
 spasm of sphincters of gastro-intestinal tract
accompanied by constipation
 increasing of tone of smooth musculature of
urinary and bile-excreting tracts (retentions of
urination, bile stasis)
 Decreasing of BP

26. CONTRAINDICATIONS FOR ADMINISTRATION
OF MORPHINE
acute respiratory depression
renal failure (due to accumulation of the metabolites
morphine-3-glucuronide and morphine-6-glucuronide)
chemical toxicity (potentially lethal in low tolerance
subjects)
raised intracranial pressure, including head injury (risk of
worsening respiratory depression)
Biliary colic
Precaution
pain that accompanies chronic inflammatory pain
children before the age of 2 years

27. Toleranc
e
• Tolerance is a diminished responsiveness to the drug’s
action that is seen with many compounds
• Tolerance can be demonstrated by a decreased effect from a
constant dose of drug or by an increase in the minimum
drug dose required to produce a given level of effect
• Physiological tolerance involves changes in the binding of a
drug to receptors or changes in receptor transductional
processes related to the drug action
• This type of tolerance occurs in opioids

28. Addiction
• Physical dependence
• Physiological
dependence
• Withdrawal reactions

30. Withdrawal
Reactions
Acute Action
• Analgesia
• Respiratory Depression
• Euphoria
• Relaxation and sleep
• Tranquilization
• Decreased blood pressure
• Constipation
• Pupillary constriction
• Hypothermia
• Drying of secretions
• Reduced sex drive
• Flushed and warm skin
Withdrawal Sign
• Pain and irritability
• Hyperventilation
• Dysphoria and depression
• Restlessness and insomnia
• Fearfulness and hostility
• Increased blood pressure
• Diarrhea
• Pupillary dilation
• Hyperthermia
• Lacrimation, runny nose
• Spontaneous ejaculation
• Chilliness and “gooseflesh”

31. Acute poisoning with opioid
analgesics
• Respiratory
Depression
• Euphoria
• Relaxation and sleep
• Tranquilization
• Decreased blood
pressure
• Constipation
• Pin point pupil
• Hypothermia
• Drying of secretions
• Flushed and warm
Cause
s
• Clinical overdose
• Accidental or
intentional overdosing
during addiction by
addicts
Symptom
s

32. Triad in case poisoning with morphine
deep tendon reflexes
increased
Cheyne Stokes
respiration
Acute miosis
(Pinpoint pupils)

33. Treatment of acute poisoning
 Naloxon (antagonist of opioid receptors)
intravenously – 0.4-1.2 mg
general dose of naloxone should not overcome 10
mg
 stomach lavage (for morphine enter hepatic
circulation is typical) with 0.05-0.1% solution of
potassium permanganate and 0.5 % tannin solution
 suspension of 20-30 g of activated charcoal
 salt laxative agents (sodium sulfate)
 forced diuresis
 atropine sulfate
 inhalation of carbogen (5-7 % СО2 and 93-95 % O2)

34. NON-OPIOID ANALGESICS
NONSTEROIDAL ANTI INFLAMMATORY
AGENT
NSAIDS

35. Pharmacodynamic Effects
•Analgesic
•Antipyretic
•Anti-inflammatory
(except Paracetamol)

36. Antipyretic Effects
• "normal" temperature: slightly affected
• "elevated" temperature: reduced
• The higher temperature, the more potent action
• Mechanism of action
Blocks pyrogen-induced prostaglandin
production in thermoregulatory center (CNS)

37. NSAIDs
Pyrogen
Prostaglandins
pGE2
thermoregulatory
center
heat production ↑
Heat dissipation ↓
set point ↑
Fever
• Antipyretic Mechanism
Block prostaglandins
production
• Sites of action: Central
Nervous System

38. Heat production and heat dissipation . In
fever associated with an infection ,increased
oxidative processes enhance heat
production .
Aspirin causes cutaneous vasodilation,
prompts perspiration, and enhance heat
dissipation.

39. Analgesic Effects
• Effective to mild to moderate pain
0.5g of aspirin is a weak or mild analgesic that is
effective in short, intermittent types of pain as
encountered in neuralgia, myalgia, toothache.
• Pain may arise from:
Musculature, dental work , vascular , postpartum
conditions, arthritis , bursitis
• Sites of action:
peripherally -- sites of inflammation
subcortical sites

40. NSAIDs
Prostaglandins
pGE2 pGF2
Nerve ending of
pain
Pain
Bradrkinin
histamine
factors
+
• block prostaglandins
production
• Sites of action:
peripheral tissue

41. Anti-inflammatory Effects
• NSAIDs only inhibit the symptoms of inflammation
• But they neither arrest the progress of the disease nor do they
induce remission
• Reduced synthesis:
--eicosanoid mediators
• Interference:
--kallikrein system mediators
--inhibits granulocyte adherence
--stabilizes lysosomes
--inhibits leukocyte migration

44. • PGE2 vasodilatation, pain sensitization, gastric
cytoprotection [mucous/HCO3 secretion], fever
• PGF2 bronchoconstriction, uterine contraction
• PGI2 inhibition of platelet aggregation, gastric
cytoprotection
• TXA2 platelet aggregation

45. The principal pharmacological effect of NSAIDs is due to their
ability to inhibit prostaglandin synthesis by blocking the
cyclooxygenase （COX） activity of both COX-1 and COX-2.
NSAIDs----- acetylation of COX
(reversible or irreversible)
Mechanism of action

46. NSAIDs
Prostaglandins
pGE2 pGF2
Symptoms of
inflammation
Red, swelling,
Heating, Pain
Bradrkinin
Histamine
5-HT
Inflammatory
factors
+
• block prostaglandins
production
• Sites of action:
peripheral tissue

47. Classification of NSAIDS
1. Salicylic acid derivative
• Acetyl salicylic acid
• Sodium salicylate
2. Para amino Phenol derivative
• Paracetamol
• Phenacetin
3. Pyrazolon derivative
• Phenylbutazone
• oxyphenbutazone
4. Indole derivative
• Indomethacin
5. Propionic acid derivative
• Ibuprofen
• Ketoprofen

48. Salicylates
• Acetylsalicyclic acid (Aspirin)
• Sodium Salicylate

49. Pharmacokinetics
• Rapidly absorbed: stomach and upper small intestine
• Distribution through the body
rapidly hydrolyzed --------- acetic acid + salicylate, catalyzed by
tissue/blood esterase
• metabolite in liver
dose ＜1g/day：one-order elimination T1/2: 3--5 hrs
dose ＞1g/day：zero-order elimination
• Excretion: kidney, influenced by pH of urine

50. Pharmacodynamics
1. Analgesic Effects (300-600mg)
2. Antipyretic Effects (300-600mg)
3. Anti-inflammatory Effects (3-6g)
do not influence the progress of disease
4. Effects on Platelets (40-100mg)
Reduced platelet aggregation
reduces thromboxane A2 (TXA2) formation

51. 5. Other effects
• Immune inhibition
• Effect on metabolism of connective tissue
• Effects on metabolism of glucose, fat, protein ----
catabolism ↑
• ACTH release ↑
Pharmacodynamics

52. Clinical Uses
1. Commonly used for management of mild to moderate
pain (300-600mg)
2. Combination agents (cold)
3. Used for reducing fever (300-600mg)
4. Useful in treatment of:
(high doses 3-6g) T1/2 > 12 hours
 rheumatic fever
 rheumatoid arthritis
 other inflammatory joint diseases

53. Clinical Uses
5. Antiplatelet: (low doses) 40-100mg
 reduce incidence of transient ischemic attacks
(prophylaxis)
 reduce incidence of unstable angina (prophylaxis)
 may reduce incidents of coronary artery thrombosis
6. Hypertension in pregnancy : (low doses) 60-100mg
TXA2↓
7. Local indication
GI inflammation : 5-amido-salicylic acid

54. SIDE EFFECTS
1. CNS: excitation----inhibition
salicylic acid reaction: Headaches; confusion;
hallucinations; tremors; vertigo; behavior
disturbance
2. GI effects: direct stimulation
PGE2 & PGI2 ↓
Esophagitis; gastric ulcerations; GI hemorrhage

55. SIDE EFFECTS 3. Liver & renal toxicity
 Dose dependence toxicity
 Reye's syndrome
a potentially fatal disease that causes numerous detrimental
effects to many organs, especially the brain and liver.
The disease causes hepatitis with jaundice and
encephalopathy
4. Other reaction
Hematologic: decreased platelet aggregation; prolonged
bleeding time.
Exacerbations of asthma
Hypersensitivity: rashes
Acid-base Imbalance

56.  Cause
• Prolonged administration of salicylates in treatment of
rheumatic fever or rheumatoid arthritis
Symptoms
• Headache - tinnitus - dizziness – hearing impairment – dim vision
• Confusion and drowsiness
• Sweating and hyperventilation
• Nausea, vomiting
• Marked acid-base disturbances
• Hyperpyrexia
• Dehydration
• Cardiovascular and respiratory collapse, coma convulsions and
death
Salicylism (Aspirin toxicity)

57. Salicylism (Aspirin toxicity)
Treatment
• Prompt hospitalization
• Decrease absorption - activated charcoal, emetics,
gastric lavage
• Enhance excretion – ion trapping (alkalinize urine),
forced diuresis, hemodialysis
• Supportive measures - fluids, decrease temperature,
bicarbonate, electrolytes, glucose, etc…

58. Acetaminophen (Paracetamol)
• Rapidly absorbed from GI
• Similar antipyretic, analgesia to aspirin
• Weak anti-inflammatory properties
• used to reduce fever and pains (a major ingredient in
numerous cold and flu medications) (choice for child)
• used appropriately, side effects are rare

59. More potent than aspirin
• As an anti-inflammatory agent
• More adverse reaction
• More analgesia
• Fewer adverse reaction
• Brufen；Benzeneacetic acid； Fenbid； Emodin；
Motrin
Indomethacin
Ibuprofen

60. Phenylbutazone
• Powerful anti-inflammatory effects
• Weak analgesic & antipyretic activities
• Promote excretion of uric acid
• Used for acute gout, rheumatic & rheumatoid
arthritis
• More adverse reaction
• Can induce activities of drug metabolize-E
• Can displace other drugs from plasma proteins

61. Anti
pyretic
analges
ic
Anti-
inflam-
matory
Side
Effect
Acetaminophen ++ ++ +
Indomethacin ++++ ++++
sulindac ++++ ++
tolmetin + + ++ ++
diclofenac ++ ++ ++
Ibuprofen + +++ + +
meloxicam ---- cox2
Phenylbutazone +++ +++
ketorolac +++ i.m

62. Gout and anti gout agent
• Gout is a disorder of purine metabolism and is characterized by
deposition of Na urate crystals in the joint (Hyperuricaemia)
painful arthritis.
• Acute attacks treated with indomethecin, naproxen, or other
NSAIDs, but not with aspirin (increase plasma urate levels at low
doses by inhibiting uric acid secretion in the renal tubules).
• Colchicine – bonds tubulin in leukocytes  prevents polymerization
in microtubules  inhibits the phagocytic activity and migration of
leukocytes to the area of uric acid deposition  decrease
inflammatory response.

63. Treatment of Gout
• Allopurinol lowers plasma urate by
inhibiting xanthine oxidase
(xanthine  uric acid).
• Uricosuric drugs (sulfinpyrazone,
probenicid) inhibit renal tubular
reabsorption of uric acid 
increase excretion.
• Should drink plenty of water to
prevent crystallization of urate in
the urine.
• These drugs less effective and more
toxic than allopurinol.

67. NSAIDS
• Non-selective COX
inhibitors
– Ibuprofen
– Diclofenac sodium
• COX–2 inhibitors
– celecoxib
DMARDS
Synthetic
• Methotrexate
• Sulphasalazine
• Chloroquine
• Hydroxychloroquine
• Leflunomide
 Biologic
• Monoclonal Antibodies to TNF
– Infliximab
– Adalimumab
• Soluble Receptor Decoy for TNF
– Etanercept
• Receptor Antagonist to IL-1
– Anakinra
• Monoclonal Antibody to CD-20
– Rituximab