ANALGESICS
DEFINITION
1. Analgesics are drugs that relieve pain.
2. An agent that relieves pain without causing loss
of consciousness
CLASSIFICATION OF ANALGESICS
Non-Opioid analgesics
Used in mild to moderate pain
•
•
Non-Steroidal Anti-inflammatory drugs
Paracetamole
Opioid analgesics
Used in moderate to severe pain
- Morphine
- Pethidine
NON-STEROIDAL ANTI-INFLAMMATORY DRUGS
AND PARACETAMOL
• NSAIDs are a group of agents that share in common the capacity to
induce Anti-inflammatory, Analgesic and Antipyretic effects.
• Paracetamol is an Analgesic-Antipyretic with No Anti-inflammatory
action.
MECHANISM OF ACTION OF NSAIDs
AND PARACETAMOL
• NSAIDs act by inhibiting cyclo-oxygenase enzyme which is
responsible for conversion of arachdonic acid. This results in
inhibition of production of prostaglandins and leucotrines which
are pain mediators and inflamatory agents.
• Acetyl Salicylic acid (Aspirin), the prototype NSAID induces
irreversible inhibition of both COX-1 and COX-2 enzymes.
• Other NSAIDs cause competitive reversible inhibition of COX
enzymes.
• Paracetamol inhibits PG synthesis in CNS resulting in Analgesic and
Antipyretic effects but is a weak inhibitor of PG in periphery. Thus,
Paracetamol has NO Anti-inflammatory effect.
Classification of NSAIDs
NSAIDs are classified according to their Cox
specificity as follows;
i) Cox 2 selective: celecoxib, rofecoxib,
melocoxib
ii) Non-Cox-2 selective: All other NSAIDs
ACETYL SALICYLIC ACID (ASPIRIN)
Therapeutic uses of Aspirin
1) Anti-inflammatory:
• Uses: Rheumatic fever, Rheumatoid arthritis
2) Analgesic effect:
• Uses: Mild to moderate pain especially secondary
to inflammation; Arthritis, Dental pain, Headache
(decreases cerebral vasodilator effect of PGs),
Dysmenorrheal and Postpartum pain.
Cont`d
3) Antipyretic effect:
• Uses: Antipyretic (Lowers body temperature)
in fever.
4) Anti-platelet effect:
• Uses: Prophylaxis against transient ischemic
attacks, Myocardial infarction and Unstable
Angina.
ASPIRIN
Dosages:
• Antiplatelets: 150 (75 – 325) mg/day.
• Analgesic and Antipyretic: 0.3 gram, 1-2 tablets when
necessary.
• Anti-inflammatory: 4-8 grams/ day.
Contra-indications
1) History of peptic ulcer
2) Hemophilia or other bleeding disorders
3) Liver disease
4) Patient receiving anticoagulant therapy
ASPIRIN
Adverse drug effects
• GI. side effects: - Dyspepsia, nausea, vomiting,
gastritis, ulceration with risk of hemorrhage
(due to direct irritant effect on the mucosa
and decreased protective PGs).
• Renal damage (Analgesic nephropathy): due
to decreased renal vasodilator PGs.
Adverse effects cont`d
• Hypersensitivity reactions: Skin rash, Rhinitis,
Asthma.
 Since blockade of the synthesis of PG, leukotriene
and other lipoxygenase metabolites from arachidonic
acid are increased. They are endogenous bronchial
smooth muscle constrictors and may result in
bronchospasm and asthma.
• Hyper-uricemia in patients with Gout (in low doses):
Competes with uric acid for excretion by organic acid
secretory mechanism in renal tubules.
ASPIRIN
Adverse drug effects
• Reye’s syndrome: encephalopathy, liver injury
in adolescents and children recovering from
febrile viral infections.
• Attention: hepatic coma!
• Paracetamol is preferred for such febrile
illnesses in children under 12 years.
Adverse Effects
• Chronic toxicity (Salicylism): Large doses
(>5g/d) used for long periods lead to dizziness,
tinnitus, deafness and gastric upset
• Acute toxicity: Respiratory alkalosis
(hyperpnoea and washing out of CO2)
followed by respiratory acidosis due to
respiratory depression and metabolic acidosis
(due to accumulation of acidic metabolites).
Adverse effects
• Coagulation disorders: Aspirin prolongs bleeding
time.
 Contraindication in patients with bleeding diseases.
 Aspirin should be avoid in patients receiving
anticoagulants such as coumarin and heparin
 Inhibiting platelet Prostaglandin syntheses and TXA2
production.
Drug interactions
• Alcohol- Likely to cause gastritis
• Anticoagulants- Increases bleeding
• Antacids- Excretion of aspirin increased in
alkaline urine
• Anti-epileptics- Phenytoin, valproate effect
enhanced.
• Corticosteroids- Increased risk of bleeding and
peptic ulceration.
OTHER NSAIDs
1) Ibuprofen (Brufen);
• Anti-pyretic, anti-inflammatory , anti-rheumatic
• Effect less than aspirin
• Effective and better tolerated (decreased
incidence of side effects than other NSAIDs). First
choice in inflammatory joint disease.
2) Naproxen;
• It is related to Ibuprofen, more potent with
moderate risk of side effects. It is longer acting
(given twice daily).
3) Piroxicam;
• Potent and long acting, given once daily.
• No accumulation in the elderly or in patients with
renal impairment. 20% of patients develop side
effects e.g. GIT bleeding.
• Used in long-term treatment of chronic inflammatory
musculoskeletal disorders e.g.:
 Rheumatoid arthritis,
 Osteoarthritis and Ankylosing Spondylitis,
 Renal colic and Post-operative pain.
 An ophthalmic solution is used for post-operative
inflammation.
4) Diclofenac;
• It is very potent
• Used in long-term treatment of chronic
inflammatory musculoskeletal disorders e.g.:
Rheumatoid arthritis,
Osteoarthritis and
Ankylosing Spondylitis,
Renal colic and Post-operative pain.
An ophthalmic solution is used for postoperative inflammation.
5) Indomethacin
• It has stronger anti-pyretic, anti-inflammation, antirheumatic effect and more side effects than aspirin
• Due to its serious adverse effects, its use is limited
to: Acute Gouty arthritis, Rheumatoid arthritis,
ankylosing Spondylitis, Post-operative pain, Patent
ductus arteriosus (inhibits PG synthesis closing the
ductus).
• It can be used to prevent premature labour. Because it
can prolong gestation and labour time. (but it causes
transient constriction of ductus arteriosus in some
fetuses).
Adverse effects of Indomethacin
• GIT: Nausea, vomiting, ulcer, bleeding.
• CNS: Dizziness, confusion, ataxia, severe
headache (cerebral vasodilatation).
• Salt and water retention (antagonize
antihypertensives) and hyperkalemia. It
aggravates pre-existing renal failure.
• Aplastic anemia.
Selective COX-2 inhibitors
Colecoxib and Rofecoxib
• Colecoxib and Rofecoxib are selective COX-2
inhibitors that spare COX-1, thus they do not
inhibit synthesis of protective PGs in the GIT.
Hence they have less GIT side effects.
PARACETAMOL
CHARACTERISTICS:
• The intensity of anti-Antipyretic and analgesic
effect is equal to aspirin, but slow and lasting.
• It inhibits PG synthesis in the brain but hardly
at all in the periphery.
• I t has no Gastrointestinal tract reaction
• Anti-inflammation effect is weak, it has no
practical use.
PARACETAMOL
• Mainly used to treat patients who can’t sustain
the therapy of aspirin such as:
a) Patients allergic to Aspirin.
b) Peptic ulcer (No GIT disturbances).
c) Gout (Aspirin may cause hyper-uricemia).
d) Viral infection in children (to avoid Reye’s
syndrome with Aspirin).
e) Bleeding disorders (does not affect platelet
function).
PARACETAMOL
• Paracetamol is ineffective in high fever because excess
free radicals generated by leucocytes antagonize
antipyretic effect of Paracetamol.
• Dose: It is usually given orally (500mg to 1g, 3-4 times
daily)
Paracetamole
Side effects
It causes liver damage in case of overdose. Toxic doses
(15 grams or more) cause nausea and vomiting,
followed in 24-48hrs by potentially fatal liver damage.
Interactions
1) Anticoagulants-enhances the effect of warfarin after
regular use.
2) Metoclopramide & Domperidone- absorption of
paracetamole is enhanced.
OPIOID ANALGESICS
are also called narcotic analgesics
Opioid are natural or synthetic
compounds that produce morphine-like
effect.
Opiate is the generic term for drugs
obtained from opium
Sources of Opioid analgesics:
• Plant: - Morphine, Codeine (natural products of
Opium poppy)
• Synthetic: - Fentanyl, Methadone, Pethidine,
Heroin.
• Endogenous: - Endorphins, Encephalins and
Dynorphins (Opiopeptides) released in the body,
acting on Opioid receptors and producing
Morphine-like effects.
Opium:A dried exudate of fruit
capsule of the poppy(Papaver
Somniferum)
Mechanism of action
• The brain contains chemical substances called
encephalins and endophins which act on opioid
receptors in the brain, and spinal cord. When
these receptors are stimulated, transmission of
nerve impulses related to pain and the
appreciation of pain are inhibited
• Opioid analgesics also react with these receptors
and thus relieve pain
• Opioid receptor include Mu, Kappa and delta.
Classification of Opioid analgesics
Pure agonists: examples include:
• Morphine.
• Fentanyl.
• Methadone.
• Pethidine.
• Heroin.
• Codeine
Partial Agonists: examples include:
• Buprenorphine
• Tramadol
• nalbuphine.
Antagonists
• Naloxone
• Naltrexone
Pharmacological actions of Opioids:
Main effects:
• Analgesia: - Decreases pain perception and
emotional response to pain.
• Sedation.
• Euphoria (sometimes dysphoria).
Pharmacological actions of Opioids:
Inhibitory effects:
• Vasomotor centre: causing venular and arterial dilatation.
• Respiratory depression.
• Inhibition of the cough centre.
• Inhibition of uterine muscle.
Pharmacological actions of Opioids:
Stimulatory effects:
• Stimulation of the oculomotor nucleus producing miosis.
• Stimulation of CTZ producing nausea and vomiting.
• Increases smooth muscle tone but inhibit peristalsis leading to
constipation.
• Stimulation of the release of anti diuretic hormone.
• Histamine release producing hypotension, itching and
bronchospasm.
• Tolerance develops to all effects except constipation and
miosis.
THERAPEUTIC USES OF OPIOIDS
• Analgesics in:
– Acute pain (trauma).
– Chronic dull pain (visceral).
– Post-operative pain and Cancer pain.
• Anesthesia (Morphine or Fentanyl).
• Myocardial infarction and acute pulmonary
edema (Morphine): Decreases pain and anxiety,
arteriolar and venodilator (decreases venous
congestion and pulmonary edema).
• Antitussive (Codeine and Dextromethorphan).
Adverse effects of Opioids
•
•
•
•
•
•
•
•
Sedation and narcosis.
Drug dependence.
Respiratory depression.
Nausea and vomiting.
Miosis.
Constipation and urine retention.
Hypotension, itching and bronchospasm (due to Histamine release).
Delay labor and Asphyxia neonatorum (Respiratory depression in
the newborn).
• Mask the diagnosis of acute abdomen (mask pain).
• Biliary spasm
Contraindications of Opioids
• Acute undiagnosed abdomen (mask pain).
• Head injury (Opioids cause respiratory depression leading to increased
CO2 resulting in cerebral vasodilatation with increased intracranial
tension).
• Bronchial asthma (Opioids cause Histamine release).
• Biliary colic (Opioids increase intra-biliary pressure and aggravate the
colic).
• Patients with enlarged prostate (Opioids decrease motility of the bladder
wall and cause urine retention).
• Extremes of age, Hypothyroidism and liver dysfunction (decreased Opioid
metabolism).
Drug interactions of Opioids:
• Addictive CNS depression with other CNS
depressants e.g. Sedative-hypnotics, Alcohol,
Antidepressants, Antipsychotics.
• Pethidine + MAOIs results in Hyper-pyrexic
coma, Respiratory depression and
Convulsions.
Morphine
• Pharmacokinetics
－often given parenterally (sc, im, iv)
－ t1/2 : 2-3 hr; duration:3-6 hr.
－can pass though blood-placenta
barrier
－can secrete in milk of breast-feeding
mothers.
 Pharmacological Effects
－ CNS
－ Cardiovascular system
－Smooth muscle
1. CNS
a. Analgesia
• － relieve moderate to severe pain
• － relieve continuous, dull pain >
•
intermittent sharp pain
• －produce sedation and Euphoria
• at the same time
b. Respiratory depression
• － decrease respiratory rate,
respiratory failure, death
• － direct inhibition of respiratory
•
center
• － decreased sensitivity of
•
respiratory center to carbon
dioxide.
c. Emesis(vomiting) and nausea
－ caused by direct stimulate the
chemoreceptor trigger zone(CTZ).
－ also a direct vestibular component.
d. Depression of cough reflex
－ inhibition of the cough center
e. Miosis : “pinpoint pupils”
• － characteristic symptom of opioids
poisoning
2. Cardiovascular system
Hypotension
peripheral
vasodilation
－ inhibition of the vasomotor center
－increase histamine release
increased intracranial pressure
Cerebral vasodilation
－the result of the increased Pco2
caused by respiratory depression
3. Smooth muscle
Constipation:
Urinary retention
Increased biliary pressure
Constipation:
－ increased tone, decreased motility in
many parts of the gastrointstinal tract.
Urinary retention
－increase urethral sphincter tone
Increased biliary pressure
－ constrict biliary smooth muscle and the
sphincter of oddi
－may result in biliary colic
 Clinical uses
• － Analgesia
• － Cardiogenic asthma
• － Diarrhea
1. Analgesia
－ severe pain only when other
analgesics are useless
• Trauma, burn, acute myocardial
infarction, postoperative pain
• renal or biliary colic, use
morphine+ atropine
• cancer (long term use)
2. Cardiogenic asthma
• dyspnea from acute pulmonary edema
caused by left ventricular failure.
• sedation ( relieves anxiety)
• vasodilation (reduction cardiac
preload and afterload )
• respiratory depression
breathing more slowly , deeply and
effectively
3. Diarrhea
－ usually use tincture camphor
compound.
Adverse Effect
• 1. Side Effects
－Dizziness, nausea, vomiting ，
constipation
•
•
－ respiratory depression
－increased biliary tract
pressure,urinary retension
2. Tolerance and dependence
Tolerance
Dependence
－ psychic dependence
－ physical dependence
－withdrawal syndrome:
lacrimation, yawning, sweating,
restlessness, dilated pupils, anorexia,
irritability, tremor, diarrhea, flushing,
cramps, muscle spasms.
3. Toxicity
 symptoms
－Coma
－respiratory depression
－pinpoint pupil
Treatment
- Support respiration
- Opioid antagonist: Naloxone I.V.
- Gastric lavage.
4. Contraindications
• －delivery, breast-feeding women
• －bronchial asthma, pulmonary
•
heart disease
• － high intracranial pressure
• － impaired hepatic function
•
patients.
Codeine
• Antitussive （cough suppression）
equal to 1/4 morphine
• Analgesia：equal to 1/12 morphine.
• adverse effects：lower than morphine
－ tolerance and addition
－ respiratory depression
－ ...
Pethidine
• Artificial synthetic analgesic
• Routes: I.M S.C., and Oral.
 potency: equal to 1/8 morphine
• －less adverse effects
•
constipation, respiratory depression,
tolerance ,dependence
• － Clinical Uses
•
analgesia, cardiogenic asthma,
premedication
Pethidine differs from Morphine in the
following ways:
• Less potent.
• Less spasmogenic: Less biliary spasm, less constipation,
less urine retention (due to short duration of action).
• Less respiratory depression in neonates
• Shorter duration of analgesia
• Little hypnotic effect
• It does not delay labour therefore preferred during
labour with less risk of Asphyxia neonatorum.
• Does not usefully suppress cough
• Atropine-like action: - Dry mouth, Blurring of vision,
tachycardia.
Natasha mukwai!
Life is precious
Be good and be careful