Analgesics

Pain
What is pain ?
• A protective mechanism to warn of damage or the
presence of disease
• Part of the normal healing process

What are analgesics

• A group of drug that selectively relieves pain by acting
in CNS or peripheral pain mechanism, without
significantly altering consciousness.
Analgesics
• Are largely classified as
Opioid
• Morphine, Codeine, Tramadol
NSAIDs( Non Steroidal Anti Inflammatory Drugs)
• Aspirin, Ibuprofen, Diclofenac
Opioid Analgesics
• Drugs that relieve pain without causing loss of
consciousness.
• Opioid
• Any drug, natural or synthetic, similar
action as morphine
• opiate
• Reserved for drugs, morphine and
codeine, obtained from the juice of the
opium poppy
Opioid receptors

• All opioid drugs act by binding to specific opioid

receptors (μ, κ, & δ) in CNS
• To produce effects that mimic action of
endogenous peptide NTs
• Found in dorsal horns of S. cord
• GPCRs-Gi
• Opening of K+ channels- hyperpolarization
• Inhibit the openings of Ca++ channel- decrease
glutamete release
Contd..
• Mu receptors
• Most analgesic effect and major unwanted effects
• Respiratory depression
• Euphoria
• Sedation
• Physical dependence
• Decrease GI motility
• Delta receptors
• Periphery, analgesia
• Kappa receptors
• Analgesia, sedation, constipation,
dysphoria, no dependence
Classification of Opioid Drugs

• Based on opioid receptor actions, 3 groups:

1. Pure opioid agonists
2. Opioid antagonist
3. Partial opioid agonists
4. Nonopioid Centrally Acting Analgesics
1. Pure Opioid Agonists

• Activate mu receptors and kappa receptors

• Can produce:
 Analgesia
 Euphoria
 Sedation
 Respiratory depression
 Physical dependence
 Constipation, and other effects
• Subdivided into two groups:
1. Strong opioid agonists- morphine
2. Moderate to strong opioid agonists- codeine
Basic Pharmacology of the Opioids

 Morphine
• Extracted from opium
• Strong opioid analgesics
• Multiple pharmacologic effects
 Therapeutic uses
• Analgesia- relief of pain [moderate- severe]
• Postoperative
• Cancer
• Labor & delivery
• Diarrhea
• Cough
Adverse effects
• Respiratory depression
• Constipation-Rx-methylnaltrexone
• Orthostatic hypotension-histamine-VD
• Urinary retention
• Cough suppression
• Biliary colic
• Emesis
• Elevation of intracranial pressure- by supp. resp.—CO2
• Euphoria/dysphoria
• Sedation
• Miosis
• Neurotoxicity
• Physical & psychological dependence
 Meperidine
• A synthetic opioid structurally unrelated to morphine.
• Used for acute pain
• Not clinically useful in treatment of diarrhea or cough
 Methadone
• A synthetic, orally effective opioid
• Equal in potency to morphine
• Induces less euphoria
• Longer duration of action
• Used as an analgesic & in controlled withdrawal of dependent
abusers from heroin and morphine
 Fentanyl
• Chemically related to meperidine
• 100-fold the analgesic potency of morphine
• Used in anesthesia
• Highly lipophilic
• Rapid onset and short duration of action
• Causes papillary constriction
 Heroin
• Produced by diacetylation of morphine
• A 3-fold increase in its potency
• No accepted medical use
 Moderate to Strong Opioid Agonists
 Codeine
• Prodrug of morphine
• Antitussive effects
• Much less potent analgesic than morphine
• But with a higher oral effectiveness
• Produces less abuse & euphoria than morphine
• Used in combination with aspirin or acetaminophen
 Oxycodone
• A semisynthetic derivative of morphine.
• Orally active
• Formulated with aspirin or acetaminophen
• Used to treat moderate to severe pain
 Propoxyphene
• A derivative of methadone
• A weaker analgesic than codeine
• Used in combination with acetaminophen
2. Agonist-Antagonist Opioids

• Alone, produce analgesia

• With pure agonists, antagonize analgesia produced by pure
agonists
 Pure Opioid Antagonists
• Act as antagonists at mu and kappa receptors
• Not produce analgesia
• Reversal of respiratory & CNS depression caused by
overdose with opioid agonists
• Naloxone, naltrexone, nalmefene
Agonist-Antagonist Opioids

 Pentazocine
• Promotes analgesia by activating receptors in the
spinal cord
• Used to relieve moderate pain
• Administered either orally or parenterally
• Produces less euphoria compared to morphine.
 Buprenorphine
 Nalbuphine
 Butorphanol
3. Pure analgesic antagonists

 Naloxone
• Used to reverse coma and respiratory depression of opioid
overdose
• Rapidly displaces all receptor-bound opioid molecules
• Able to reverse the effect of a heroin overdose
 Naltrexone
• Longer duration of action than naloxone
• Hepatotoxic
 Nalmefene
• A parenteral opioid antagonist
• Similar actions to naloxone and naltrexone
• Longer duration of action
4. Nonopioid Centrally Acting Analgesics

1. Clonidine- α2 agonist
• blocks nerve traffic from periphery to brain in S. cord
2. Ziconotide- n-type CCBs [nociceptive afferent
neurons in s. cord]
3. Dexmedetomidine- α2 agonist
• Do not cause
• Respiratory depression
• Physical dependence
• Abuse
4. Tramadol

• A centrally acting analgesic

• Analogs of codeine
• Binds to the µ-opioid receptor
• Blocks reuptake of NE & 5-HT
• Activating mono-aminergic spinal
inhibition of pain
• Used to manage moderate to moderately severe
pain
NSAIDS
Autacoids
• Chemical mediators of inflammation
• Derived from exogenous & endogenous
• Actions:
1. Vasodilation
• Histamine, NO, PGs
2. Increase vascular permeability
• Histamine, serotonin, LTs
3. Fever
• Interleukins, TNF, PGs
4. Pain
• PGs, bradykinin, serotonin, histamine, subs. P
5. Tissue damage
• Neutrophil & macrophage products
• Lysosomal enzymes, ROS, NO
 Prostaglandins(PGs)
• All of NSAIDs act by inhibiting synthesis of PGs
• Synthesis of PGs
• From arachidonic acid-primary
precursor
• Two major pathways in eicosanoids
synthesis
Cyclooxygenase (COX) pathway
• Produces prostanoids
• PGs, TXs, & PCs
 Two isoforms:
COX-1
• For physiologic production of prostanoids
• Housekeeping enzyme = good COX
• Found in all tissues as constitutiant
• Regulates normal cellular processes:
• Gastric cytoprotection (PGE2&I2)
• Platelet aggregation (TXA2)
• Kidney function(PGE2&I2)
COX-2
• Bad COX, at sites of tissue injury
• Promote inflammation & sensitize receptors to painful
stimuli via production of PGE2 & I2
• Inducible by cytokines & other inflammatory stimuli
• Injured tissue(PGE2)
• Brain- mediates fever & perception of pain
• Kidney (PGE2&I2)- RBF
• Blood vessels (PC)- VD
• Colon/rectum- cancer
Non-Steroidal Anti-inflammatory
Drugs (NSAIDs)
• Block PG production By inhibition of COX
 Medical uses
• Anti-inflammatory
• Analgesic
• Antipyretic
• Anticoagulant
 Produce analgesia- CNS & peripheral
• Reducing capillary permeability
• Stabilizing mast cell
• Inhibit PG production
• Inhibit BK from stimulating pain receptors
Antipyretic- CNS effect (on thermoregulatory center’s set point)
• Inhibit effect of PGs on TRC set point
• Lowering it
Anti-inflammatory
• PG inhibition
Anticoagulants
• Inhibit platelet aggregations (TXA2)

Common Adverse effects

• Platelet dysfunction
• ↓TXA2
• Gastritis & peptic ulceration with bleeding
• ↓[PGE2 & PGI2]
• Acute renal failure
• Sodium & water retention & edema
• Analgesic nephropathy
• Prolongation of gestation & inhibition of labor
• ↓PGE2
• Hypersensitivity rxn
• ↑LXN
First-Generation NSAIDs

• Conventional/traditional NSAIDs
• Inhibit both COXs
• Large & widely used family of drugs
• Clinically used to:
1. Treat inflammatory disorders
2. Alleviate mild to moderate pain
3. Suppress fever
4. Relieve dysmenorrhea
Aspirin, ASA

• Derivatives of salicylic acid

• Commonly used
• Most Irreversible acetylates & inactivates COXs
• Nonselective inhibitor
• Beneficial effects on COX-2 inhibition
• Anti-inflammatory
• Analgesia
• Antipyretic
• Beneficial effect on COX-1 inhibition
• Protection from MI & CAD
• AEs
• Gastric ulceration, bleeding & renal impairment
Dose dependent effect of aspirin
Adverse effects

• GI effects- ulceration, perforation, & bleeding

• Bleeding
• Renal impairment
• Salicylism
• Overdose or toxic level
• Tinnitus, sweating, headache, dizziness &
acid-base disturbance (respiratory alkalosis)
• Reye's syndrome
• Rare but serious illness of childhood
• Cerebral edema, encephalopathy & fatty
liver degeneration
• Children (˂ 16 yrs) with influenza or
chickenpox
Other NSAIDs

• Analgesic, anti-inflammatory & antipyretic

• Reversible COXIs
• Non-selective
• Analgesic ceiling
• High risk of MI & stroke
Ibuprofen
• Propionic acid derivative
• Possess anti-inflammatory, analgesic, and antipyretic
activity
• Alter platelet function & prolong bleeding time
• For chronic treatment of RA & osteoarthritis
Indomethacin

• Acetic acid derivative

• Anti-inflammatory, analgesic, & antipyretic activity
• For acute gouty arthritis, ankylosing spondylitis, and
osteoarthritis of hip

Diclofenac
• For long-term use in the treatment of RA,
osteoarthritis, and ankylosing spondylitis
• Similar toxicities to other NSAIDs
Second-Generation NSAIDs

• COX2Is
• Coxibs
• Selectively inhibit COX-2
• Suppress pain & inflammation
• Little or no risk of gastric ulceration
• Increase risk of MI & stroke
• Celecoxib
• Rofecoxib
• Valdecoxib
Celecoxib

• More selective for inhibition of COX-2

• For treatment of RA, osteoarthritis, and pain
• Not inhibit platelet aggregation
• Does not increase bleeding time
• Less GI bleeding & dyspepsia
• Avoided in patients with severe hepatic & renal Ds
• Common side effects
 Headache
 Dyspepsia
 Diarrhea
 Abdominal pain
Acetaminophen/ paracetamol

• Inhibits PG synthesis in CNS

• Antipyretic and analgesic properties
• Devoid of anti-inflammatory effect
• But it does not:
 Suppress platelet aggregation
 Cause gastric ulceration
 Decrease RBF or cause renal impairment
• Large doses- severe liver injury
 Avoid in severe hepatic impairment