Analgesics.pptx

Analgesics
Sewasew Amsalu (MD) Analgesics 1

• Analgesics – Are drugs that selectively relieves pain by acting on the CNS
or on the peripheral pain mechanism with out significantly altering
consciousness.
• Two types
1. NSAIDs or Anti Inflammatory
2. Opioid analgesics

Opioid Analgesics & Antagonists

OPIOIDS
• Are natural or semisynthetic and synthetic compounds that produce
morphine like effects.
• Morphine is the standard against which all drugs that have strong
analgesic action are compared
• Morphine is obtained from the poppy, Papaver somniferum and P album.
• Although the Opioids have a broad range of effects their primary use is to
relive intense pain.

Fig: summary o
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• Three receptors mediate the main pharmacological effects of opiates
• mu receptors (Mu ()) are responsible for the analgesic and major unwanted
effects (respiratory depression, sedation and dependance).
• Delta () for analgesia and peripheral effects of opiates and
• Kappa (Kappa ()) contribute to analgesia at spinal level and dysphoria.
• The analgesic properties of the opioids are primarily mediated by the μ
receptors that modulate responses to thermal, mechanical, and chemical
nociception.
• The kappa receptors also contribute to analgesia by modulating the response
to chemical and thermal nociception.

Classification of opioids
•May be classified in several ways
• Strength of Analgesia
• Strong, moderate, and weak
•Fentanyl
•Hydrocodone
•Morphine
•Pethidine
•Oxycodone
•Codeine
• Heroin?

Pharmacokinetics
• Most well absorbed when taken orally,
• Also available in parenteral & sustained release forms
• They cross the placental barrier and exert effects on the fetus
• result in both respiratory depression and, with continuous exposure, physical
dependence in neonates.

A. Morphine
• Is the major analgesic drug contained in crude opium.
• The principal effects of the opioid analgesics with affinity for mu receptors
are on the central nervous system; the more important ones include
analgesia, euphoria, sedation, and respiratory depression.
• With repeated use, a high degree of tolerance occurs to all of these effects
except respiratory depression.
• They also cause addiction and dependence.

Morphine cont’d…
• Pharmacological Actions:
• Analgesia: causes relief of pain.
• Euphoria: produces a powerful sense of wellbeing, over confidence & over optimism.
• a typical patient in pain experiences a pleasant floating sensation and freedom from
anxiety and distress.
• Respiratory depression: by reduction of the sensitivity of respiratory center neurons to
CO2.
Most common cause of death in acute opioid overdoses: tolerance develop quickly with repeated
dosing, which allows the safe use of morphine for the Rx of pain when the dose is correctly titrated.

• Action…
• Depression of cough reflex: morphine & codeine have antitussive
properties.
• Miosis: pin point pupil (PPP): Dx purpose
• Emesis: directly stimulate CRT zone.
• Labor: prolong the 2nd stage of labor by transiently decreasing the strength,
duration, and frequency of uterine contractions.

Picture: unlike other compounds that cause respiratory depression and coma, morphine
causes ppp. Sewasew Amsalu (MD) Analgesics 12

Therapeutic Uses:
• Analgesic: severe pain
• Rx of diarrhea
• Relief of cough

 Adverse effects
 Respiratory depression
 Constipation
 Orthostatic hypotension
 Urinary retention
 Emesis,
 Cough suppression
 Biliary colic caused by morphine
 Euphoria/dysphoria, sedation, and
miosis

B. Codeine
• Much less potent analgesic than morphine but it has a higher oral efficacy.
• Shows good antitussive activity.
• Has a lower abuse potential & rarely produce dependency.
• Produce less euphoria than morphine.
• It's used as antitussive, but now widely replaced by dextrometorphan, a
synthetic cough depressant that has low potential for abuse.

c. Meperidine (Pethidine)
• Lower-potency synthetic opioid structurally unrelated to morphine
• A predominant κ-receptor agonist.
• Used as analgesic and not used for the treatment of cough or diarrhea.
Diphenoxylate and Loperamide
• Are derivatives of meperidine devoid of central effects.
• Slow GI motility and used as antidiarrheals.

D. Tramadol
• A synthetic μ opioid receptor agonist.
• is a centrally acting analgesic that binds to the µ-opioid receptor.
• In the treatment of mild to moderate pain tramadol is as effective as morphine or
meperidine. However it is less effective in severe and chronic pain.
• Respiratory depression is less than morphine and constipation is less than equivalent
doses of morphine.
• Has less abuse potential but should never be used in patients with a history of addiction.

Nonsteroidal Anti-
inflammatory Drugs
(NSAIDs)

Anti-inflammatory drugs
 Non-steroidal anti-inflammatory drugs (NSAIDs)
 Steroids (corticosteroids)

Anti-inflammatory drugs cont’d…
 Inflammation: is a complex protective reaction caused by endo- and exogenous
stimuli.
 Classic inflammatory symptoms include: warmth, pain, redness, and swelling
 Inflammatory response is characterized mechanistically by a transient local
vasodilation and increased capillary permeability, infiltration of leukocytes and
phagocytic cells, tissue degeneration and fibrosis.
• Prostaglandins and related compounds are produced in minute quantities by
virtually all tissues.
• They generally act locally on the tissues in which they are synthesized, and they
are rapidly metabolized to inactive p
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Analgesics
20

• All of the NSAIDs act by inhibiting the synthesis of prostaglandins.

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Therapeutic uses of Prostaglandins
 Abortion
• Systemic or intravaginal administration
mifepristone (PR antagonist)
• PGE2 or PGF2 can induce labor at term
of the PGE2 analog misoprostol in combination with
 Gastric protection - Misoprostol, a PGE2 analogue
• used for prevention of ulcers after long-term treatment with NSAIDs
 Impotence
• PGE1 causes erection which lasts for 1 to 3 hours
• Its use has been replaced by the use of PDE5 inhibitors, such as sildenafil,

Prostaglandin antagonists
Corticosteroids
• Blocks all the known pathways of eicosanoid synthesis
NSAIDs (eg, Aspirin, Indomethacin, Ibuprofen)
 Inhibit COX activity and hence synthesis of both prostaglandins and thromboxanes
Leukotriene receptor antagonists
 Montelukast and Zafirlukast
 Use- treatment of asthma

Analgesic, Antipyretic
and
Anti-inflammatory
agents

Non-steroidal anti-inflammatory drugs
(NSAIDs)
Antipyretic, analgesic, & anti-inflammatory agents
 As antipyretics
Reduce body temperature in febrile states
 As analgesics
Relieve mild to moderate pain such as dental pain, dysmenorrhea, and headache.
Unlike the opioid analgesics, they do not cause neurological depression or
dependence.
 As anti-inflammatory agents
Used to treat conditions such as musculo-skeletal inflammatory condition

Classification of NSAIDs
 Reversible/irreversible action
All inhibit COX reversibly, except aspirin
 COX2 selective/ COX nonselective
Note: Acetaminophen (paracetamol) is not
considered as NSAID.
COX nonselective
• Diclofenac
• Indomethacin
• Meloxicam
• Ibuprofen
• Aspirin
COX2 selective
• Celecoxib

MOA (NSAIDs)
Anti-inflammatory
 Inhibits cyclooxygenase (COX) enzyme and hence prostaglandin synthesis
 COX-1 is a primarily constitutive in most normal cells and tissues
 COX-2 is induced isoform but is also constitutively expressed in certain areas of
kidney and brain.
 Involved in normal renal development and vascular prostacyclin production.
 NSAIDs do not inhibit the lipoxygenase pathways of AA metabolism and hence do
not suppress Leukotriene formation.
 All NSAIDs, with the exception of Aspirin, are reversible competitive inhibitors of
COX.

Analgesic
 Pain that accompanies inflammation and tissue injury results from local
stimulation of pain fibers and enhanced pain sensitivity (hyperalgesia) : PG-
mediated sensitization of nerve endings.
Antipyretic
 Formation of cytokines such as IL-1b, IL-6, interferons, and TNF-
 Later increase the synthesis of PGE2
 Triggers the hypothalamus to elevate body temperature

Therapeutic uses (NSAIDs)
All NSAIDs are antiinflammatory, antipyretic and analgesic,
with the exception of acetaminophen, which is largely devoid of
anti-inflammatory activity
Analgesic
 Effective only in pain of low-to-moderate intensity
 Have less maximal efficacy than opiates but lack the
unwanted adverse effects of opiates
• Not useful in pain arising from visceral organs (exception to this
is menstrual pain)

 Antipyretic
• Reduce fever in most situations
• not the circadian variation in temperature or the rise in response to exercise or
increased ambient temperature
 Anti-inflammatory
• In the treatment of musculoskeletal disorders, such as rheumatoid arthritis and
osteoarthritis, gout
• Generally provide only symptomatic relief from pain and inflammation associated
with the disease, do not arrest the progression of pathological injury

Adverse Effects of NSAID Therapy
Gastrointestinal
 Anorexia, nausea, dyspepsia, abdominal pain, and diarrhea
 Normally, prostacyclin (PGI2) inhibits gastric acid secretion, whereas PGE2 and
PGF2α stimulate synthesis of protective mucus in both the stomach and small
intestine.
 In the presence of aspirin (NSAIDS), these prostanoids are not formed, resulting in
increased gastric acid secretion and diminished mucus protection
Related to the induction of gastric or intestinal ulcers

Adverse Effects of NSAID Therapy (cont’d)
Cardiovascular
 Aspirin is associated with cardioprotection.
 Use of COX-2-Selective inhibitors: celecoxib, is associated with ↑ed CVS hazards
(increase incidence of myocardial infarction, stroke, and thrombosis)
Renal & renovascular adverse events
 NSAIDs causes : Retention of salt and water

Salicylates (ASPRIN)
Salicylic acid is irritating  only used externally
Derivatives synthesized for systemic use
 Esters of salicylic acid (SA). E.g., Aspirin is ester of acetic acid
• It is also the standard against which all anti-inflammatory agents are compared.
MOA : Inhibit synthesis of PGs and thromboxanes
 Irreversibly acetylates COX-1 and COX-2 :
New enzyme synthesis is needed
Can take as long as 10 days (the life of platelets)

pharmacodynamics
Analgesic Effects (300-600mg)
• mild to moderate pain
• Headache, joint and muscle pain, and dysmenorrhea.
Antipyretic Effects (300-600mg)
Anti-inflammatory Effects (3-6g)
• do not influence the progress of disease
• At higher doses aspirin is an effective antinflammatory in rheumatoid arthritis

Pharmacodynamics cont’d ……
Effects on Platelets (40-100mg)
 T X A2 enhances platelet aggregation, whereas PGI2 decreases it.
 Low doses (81 to 325 mg daily) of aspirin can irreversibly inhibit thromboxane
production in platelets via acetylation of cyclooxygenase
• Decrease incidence of blood clots, myocardial infarction, unstable angina and transient ischemic
attacks (prophylaxis)

Therapeutic uses
Systemic uses
 Antipyresis
 Analgesia
 Rheumatoid Arthritis.
 Acute rheumatic fever
 Postmyocardial infraction & poststroke pateints – at low doses, aspirin 40-100mg/day.
 0thers : patent ductus arteriosus, familial colonic polyposis, prevention of colon cancer.
Local use
 Inflammatory bowel syndrome (sulfasalazine)

Adverse effects
 Salicylism: usually occurs with repeated administration of
large doses.
Mild form of ASA toxicity
headache, mental confusion, and drowsiness.
tinnitus and difficulty in hearing, vertigo.
hyperthermia, sweating, thirst, hyperventilation, vomiting, and
diarrhea.

Adverse effects cont’d…
 Gastrointestinal disturbances
• PGE2 & PGI2 ↓
• Gastric ulcerations and/or GI hemorrhage
 Reye's syndrome
A potentially fatal disease that causes numerous detrimental effects to many organs,
especially the brain and liver in childrens having viral infections (varicella, influenza).
Disease causes hepatitis with jaundice and encephalopathy
 Hematologic: decreased platelet aggregation→ prolonged bleeding time.

Salicylates and Pregnancy
 Avoid administration during the third trimester as they may cause
Prolonged gestation and complicated deliveries
Postpartum hemorrhage
Premature closure of the ductus arteriosus
Low birth weight babies.

Acetaminophen (Paracetamol)
Pharmacologic effects:
 It has analgesic and antipyretic actions similar to those of asprin but only weak anti-
inflammatory
 It appears to be an inhibitor of PG synthesis in the brain which explains its analgesic
and antipyretic activity.
 Acetaminophen has less effect on cyclooxygenase in peripheral tissues, which accounts
for its weak anti-inflammatory activity.
 Acetaminophen does not affect platelet function or increase blood-clotting time.
Acetaminophen is not considered to be an NSAID

Acetaminophen cont’d…
 Indication: used as substitute for the analgesic and antipyretic effects of NSAIDs
for patients with
Gastric complaints/risks
Prolongation of bleeding time is not desirable
Anti-inflammatory action of NSAIDs is not required
Analgesic/antipyretic of choice for children with viral infections (due to the
risk of Reye syndrome with aspirin)

Adverse effects
 At normal therapeutic doses, it is virtually free of significant adverse effects.
 With large doses of, →hepatic necrosis.
 Hepatic necrosis: a very serious and potentially life threatening condition, can result.
 High dose acetaminophen may results in an increased risk of gastrointestinal toxicity
equivalent to NSAIDs.
 It is hepatotoxic (contraindicated in patients with known liver diseases),

 Especially in small children's.
 Toxic doses cause nausea,vomiting, abdominal pain, liver tenderness,
hypoglycaemia, jaundice.
 After 24-48 hours, potentially fatal liver damage
Management
• Oral N-acetyl cysteine (NAC) is an Antidote

Indomethacin
Anti-inflammatory, analgesic, and antipyretic
Analgesic effects distinct from its anti-inflammatory properties (central and
peripheral actions)
Pharmacologic effects: (10-40 time more potent anti-inflammatory than aspirin)
Despite its potency as an anti-inflammatory agent, the toxicity of
indomethacin limits its use to the treatment of acute gouty arthritis,
Ankylosing spondylitis and in osteoarthritis of the hip

Indomethacin
Therapeutic uses
 Medical closure of persistent patent ductus arteriosus
 Rheumatoid arthritis when Aspirin is ineffective
 Ankylosing spondylitis
 Osteoarthritis
 Acute gout
Note: Because of its toxicity and side effect, it is not routinely used for
analgesia or antipyresis.

Indomethacin
Adverse effect
 Gastrointestinal complaints :
 CNS effects: 25%-50%
• light-headedness, Seizures, confusion, psychosis, hallucinations, and
suicidal tendency.
 Hematologic reactions
• Neutropenia, thrombocytopenia, and aplastic anemia.

Diclofenac
• is the most commonly used NSAID
• Pharmacological Properties
• Its potency against COX-2 is greater than that of several NSAIDs.
• Diclofenac is a potent cyclooxygenase inhibitor with antiinflammatory,
analgesic, and antipyretic properties.
• Diclofenac is more potent than indomethacin or naproxen.
• Pharmacokinetics
• Substantial first-pass effecSt
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Diclofenac Cont’d…
 Therapeutic Uses
• Long-term symptomatic treatment of rheumatoid arthritis, osteoarthritis,
and ankylosing spondylitis.
• Short-term treatment of acute musculoskeletal pain, postoperative pain,
and dysmenorrhea.
• In combination with misoprostol (to reduce the frequency of GI ulcers)
 Common Adverse Effects
• GI (20%): Mild
Sewasew Amsalu (MD) Analgesics
51

Ibuprofen
Include: Ibuprofen, naproxen
Pharmacological Properties
• nonselective COX inhibitors
• Gastrointestinal irritation and bleeding occur, though less frequently than with aspirin.
Therapeutic uses
• Rheumatoid arthritis, Osteoarthritis, ankylosing spondylitis
• Acute gouty arthritis , dysmenorrhea
 Apply to long-term treatment because they are better tolerated.

Ibuprofen
 Adverse Effects
• Better tolerated than aspirin and indomethacin
• Concomitant administration of ibuprofen and aspirin antagonizes the
irreversible platelet inhibition induced by aspirin :
• Thus, treatment with ibuprofen in patients with increased cardiovascular
risk may limit the cardioprotective effects of aspirin.
• use of ibuprofen concomitantly with aspirin may decrease the total anti-
inflammatory effect.

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