Analgesics and Anti-inflammatories

Pharmacology 49.222Bill Diehl-Jones RN, PhD

Faculty of Nursing and Department of Zoology

Major Drug Classifications

Agenda

• A Zen Review

• Analgesia in general– Mediators of pain, pain pathways– Arachidonic Acid metabolites

• Narcotics and Non-Narcotics

• NSAIDS

Drugs Used to Alleviate Pain and Inflammation

• Analgesics

• Opioid Analgesics

• Co-Analgesics

• NSAIDS

Analgesics(Drugs to Treat Pain)

• What is pain?– Sensory stimuli comes from

release of prostaglandins, NO, bradykinins, histamine from damaged tissue

– Substance P released from sensory nerves, causes spread of pain

– Stimuli carried by sensory fibres to Thalamus & Cerebrum

Sensory Cortex

Thalamus

SpinothalamicNerveTract

A Few Word About Prostglandins

Arachidonic Acid

ProstaglandinsLeukotrienes

Lipoxygenase Cyclooxygenase

Phospholipase A2

Cell Membrane

(What’s the significance? We’ll talk later …)

So How do Non-Narcotic Analgesics Work?

• Acetaminophen– inhibits PG synthesis in CNS

– good substitute for aspirin• why?

– Good stuff!• Relatively few side effects

• LARGE doses can damage liver

• Phenacetin– more toxic

How About Narcotic Analgesics?

• Mainly, affect opioid receptors, – opiate agonists

– mixed agonists/antagonists

– antagonists

• Important opium receptors:– mu (), kappa (), delta ()– each is specific for

different drugs

Excitatory Neurotransmitters(Eg: Substance P)

OpioidReceptors

Examples of Opiate Agonists:Morphine

• Acts at mu receptors in spinal cord• inhibits substance P release (and others)• Clinical effects:

– Raises pain threshold in spinal cord– produces euphoria– DECREASES RESPIRATORY DRIVE, cough– pupillary constriction, CV depression

• What are some other effects? Why?

Examples of Opiate Agonists:Meperidine

• Synthetic, not related to morphine

• binds to kappa receptors

• causes respiratory depression, pupillary dilation, impedes GI motility

Two More Opioid Narcotics:

• Methadone– works on mu receptors– synthetic, produces less euphoria– What is it a substitute for?

• Fentanyl– works like meperidine– where used?

Morphine, Meperidine, Methadone and Fentanyl are STRONG Opioid Agonists

What does that mean?

Moderate Opioid Agonist:Codeine

• Produces less euphoria

• Antitussive

• But …. Also has antimotility effects

Mixed Agonist-Antagonist:Pentazocine

• Agonist for kappa receptors

• Antagonist for mu, delta receptors

• for moderate pain

• produces less euphoria

Opioid Antagonist:Naloxone (Narcan)

• Used to reverse opioid overdose

• displaces receptor-bound opioids

• Good for overcoming respiratory/CV depression

Opioid Receptor

Naloxone

Morphine

Just beat it!

Clinical Pearls on Narcotics

Morphine• Brand Names :

– Astramorph, Epimorph, MS Cantin, Roxanol• Uses:

– Acute or chronic pain relief; relieves dyspnea of L. ventricular failure

• Watch:– Caution with respiratory depression, increased

intracranial pressures, acute asthma– Look for “morphine eyes” (pin-point pupils, glazed)– ALWAYS KEEP NARCAN ON HAND. Works in 2

minutes– Antidiarrheic, antitussive

Meperidine• Brand Names :

– Demerol, Pethadol, Pethidine• Uses:

– Similar to morphine; controls moderate to severe pain– Often used for obstetric analgesia

• Watch:– No miosis at usual dose (but will with overdose)– Little or no antidiarhheic or antitussive effect– Patients using St. John’s Wort may have increased

sedation

Codeine• Brand Names :

– Paveral• Uses:

– Similar to morphine; less potent (about one sixth)• Watch

– Can cause more histamine effects than morphine– Less antitussive effect than morphine– Check older men – prostatic hypertrophy– Less risk of abuse than morphine– Give with milk if possible

And Now, NSAIDs ….

How Do They Work?

• Inhibit prostaglandin synthesis

• Aspirin is the prototype

• These differ from acetaminophen:

Anti-inflammatory

Analgesic

Antipyretic

Analgesic

Antipyretic

NSAIDs

ACETAMINOPHEN

Where do NSAIDs Work?

Arachidonic Acid

ProstaglandinsLeukotrienes

Lipoxygenase Cyclooxygenase

Phospholipase A2

Cell Membrane

Steroids works here: NSAIDs

NSAIDs We Know And Love:

• Salicylates – Aspirin

• Propionic Acid Derivatives– Ibuprofen, naproxen

• Indolacetic Acids– Indomethacin

Clinical Pearls on NSAIDS

Aspirin• Brand Names :

– A.S.A., Alka-Seltzer, Entrophen, Novasen

• Uses:– Low to moderate pain, RA and osteoarthritis, reduce

risk of TIA and MI

• Watch:– Not for use in children with chickenpox or influenza

due to Reye’s syndrome– Risk of GI bleed– Take with lots of water

Ibuprofen

• Brand Names : – Advil, Motrin, Ibuprin, Medipren

• Uses:– Chronic RA, gout

• Watch:– Caution with bleeding abnormalities, renal failure

– Can cause hyponatremia

– A larger loading dose is often used (400-600 mg in adults), followed by 200 mg

Indomethacin

• Brand Names : – Indameth, Indocid, Indocin

• Uses:– Also used with rheumatoid, gouty arthrits– Closes PDAs in premature infants

• Clinical Pearls:– Dizziness, hallucinations not uncommon

Naproxen

• Brand Names : – Apo-Naproxen, Naprosyn, Naxen, Walprox

• Uses:– Also used with rheumatoid, gouty arthrits

• Clinical Pearls:– An OTC drug in Canada, can be purchased without a

script in the US

– More sustained duration of action than ibuprofen

And now, a word aboutVIOXX

Vioxx

• A new type of analgesic that is used in the treatment of pain from osteoarthritis, rheumatoid arthritis, dysmenorrhea, and other sources of acute pain.

• Other examples of COX-2 inhibitors include Celebrex and Bextra.

So, what happened …?

• Vioxx, was voluntarily withdrawn on September 30, 2004 due to mounting evidence linking it to increased risk of cardiovascular problems.

• Following a three-year study involving the drug, researchers concluded that withdrawing Vioxx from the market would be in the best interest of the patients.

• The drug has also been connected with higher incidences of respiratory and liver and kidney dysfunction.

Some Clinical Pointers on NSAIDS

• New evidence suggests that Ibuprofen may interfere with anticoagulatory effects of aspirin