CPPS 306 Non-Narcotic analgesics

What are the two classes of Non-narcotic analgesics?

Non Steroidal Anti-inflammatory drugs (NSAIDS)

Acetaminophen

What is the prostanoid synthesis

A pathway that converts: arachnoid acid → prostanoids (prostaglandins, prostacyclin, and thromboxane), which regulate pain, sensitization, inflammation, blood flow, platelet aggregation, and fever

Explain the prostanoid synthesis pathway

• Begins with membrane phospholipids — Phosphoplipase A → Arachnoid Acid

• AA — cyclooxygenase activity COX → PGG2

• PGG2 — perioxdase activity COX → PGH2

• PGH2 → PROSTANOIDS

How do NSAIDs affect prostanoid synthesis and what does this lead to?

NSAIDs inhibit cyclooxyrgenase of the COX enzymes, block the first step of prostanoid biosynthesis

• Blocking the first step reduces PG production → decreased pain sensitization, inflammation, and fever

What is the primary role of COX-1 in the body

A constitutive (present or active under normal conditions) enzyme that produces PG used for

• GI cytoprotections

• Platelet aggregation

• Renal electrolyte homeostasis

• Renal blood flow maintenance

What is the main role of COX-2 in the body

has a constitutive role in:

• Renal electrolyte homeostasis

• Renal blood flow maintenance

Inducible (turned on in certain times) role in:

• Pain

• Fever

• Inflammation

How do non-selective NSAIDs affect COX enzymes and what does this cuase?

Non-selective NSAIDs inhibit both COX1 and COX2, reducing pain and inlfammation but also causing

• GI irritation

• Increasing bleeding risks

• Renal side effects

How do selective COX inhibitors differ from non selective NSAID’s

Selective COX inhibitors primarily block COX-2 mediated pain, fever and inflammation while sparring COX 1, resulting in less GI side effects and no inhibition of platelet aggregation

Why does selectively inhibitting COX-2 still affect renal funciton despite sparing COX-1

Because COX-2 still has a constitutive role which maintains

• renal blood flow maintenance

• renal electroylte homeostasis

so inhibition can still impact kidney function

What role do Prostaglandins play in pain and inflammation

Sensitize nociceptors to chemical mediators, thermal, and physical stimuli

Increase blood flow and leukocyte in injured sites → edema + inflammation

How does peripheral inflammation increase pain signaling in the CNS

Peripheral inflammation increases COX-2 expression in the dorsal horn enhancing central pain processing

What are the two NSAIDs mentioned in class and what are their half lives

Aspirin = 0.5 hrs

Ibuprofen = 2 hrs

What are the roles of Aspirin and Ibuprofen

• inhibit COX 1 + 2 → reduced PG and thromboxane

• Inhibit pain sensory transmission in PNS and CNS

• Reduce elevated body temperature (keeps normal body temperature)

Are NSAIDs required for mild to moderate fever?

NO, Seldom necessary

Compare and contrast the severity of side effects from taking Ibuprofen vs Aspirin

Ibuprofen has less adverse GI effects compared to Aspirin

What are the adverse effects of NSAIDs

• GI effects:

  • NSAIDs recrease PGI12/PGE2 (which normally protects stomach) leading to GI irritaiton and ulceration

• Decrease blood coagulation, cant form blood clots → more bleeding

• Kidney

  • Decreased renal blood flow

  • Intersitital nephritis (inflammation of the spaced between renal tubules)

Compare and contrast low dosage vs high dosage of aspirine

• Low dosage → analgesic affect → first order kinetics → dug elimination rate = [concentration] therefore safer

• High dosage = anti inflammatory dose → zero order → so increasing the dose causes drug accumulation and increased risk of toxicity/overdose

What are the NSAID COX II selective inhibitors and what are its effects

Celecoxib

• Selectively inhibits COX II

  • prevents iflammatory mediators but doesnt alter GI mucosal defense or platelet aggregation

Describe the inhibition affects of Acetaminophen

• Weak inhibition of prostaglandin formation in peripheral tissues, so it lacks anti-inflammatory and antiplatelet action, but this also causes less GI irritation and no increased bleeding risk

• Meaning acetaminophen is ideal for pain and fever but not for inflammation

What is the first metabolite of Acetaminophen and what does this do

AM404

• Act on TRPV1 receptors on termincal C-fibers in dorsal horn and endocannabinoids in the brain to exert analgesic effects

What is neuropathic pain

Pain that reults form injury or dysfunction of peripheral or central sensory nerves, rather than from tissue damage and inflammatory mediator release

What sensory abnormalities happen due to neurpathic pain

Hyperalgesia = painful stimulus more painful than they really are

Allodynia = pain caused by stimulus that are not normally painful

Paresthesias = tingling, pins and needles, burning sensation

Dysthesias = burning, shooting, electric shock like sensation

What happens pathophysioloigcally in neuropathic pain

• Primary afferent sensory neurons become hyperactive and discharge randomly.

• This causes neurons in dorsal root ganglia and dorsal horn to:

  • Show increased Na and Ca channel activity making them more excitable

• Descending inhibitory pathways using 5-HT and NE are less effecting

Together these result in enhanced pain transmission

Which drugs are used to counter the effects of neuropathic pain and how do they work

• Carbamazepine/Lamotrigine = Block Na channels

• Pregabalin/Gabapentine = Block Ca channels

• Serotonin and NE reuptake inhibitors

  • Amitriptilyn/Nortriptyline (TCA)

  • Deluxetine/Venlaxetine

What is trigeminal neuralgia

Disabling neuropathic pain disorder where the person feels a sudden, shooting pain, along the trigeminal nerve in the face form chewing, brushing teeth, or wind on the face

What are the main causes of trigeminal neuralgia in younger vs older patients

In younger patients = multiple sclerosis

In older patients = a pulsating vascular loop touching the trigeminal nerve causing demyelination

What is the fist line of trating trigeminal neuralgia?

Na channel-blocking drugs

• Carbamazepine

• Phenytoin

  • Lamotrigine

If no pharmacoligcal drug works in treating trigeminal neuralgia, what should be done

Surgical comrpession of vasucalr loop of trigeminal nerve

What is Fibromyalgia and what is it caused by?

Neuropathic pain characterized by tender joints, allodynia (pain from non painful stimuli), increased pain response to pressure

• Caused by central sensitization where neurotransmitter signalling is altered and increased sensitivity of pain receptors

Which drugs are used to treat fibromyalgia

Pregabalin

Amitriptyline

What is gout and what causes it

An inlfammatory join disease caused by elevated uric acid levels (INCREASED production / DECREASED excretion) leading to deposition of uric acid crystals in joints, inflammation, and joint damage

What is the goal of treating acute gout and which drugs are used

• Goal is to reduce inflammation

• Using:

  • NSAIDs

  • prednisone

  • Cholchicine

What is the goal of long-term gout treatment and which drugs are used

• Aims to lower uric acid levels

• Using:

  • Allopurinol → blocks hypoxanthine oxidase

  • Probenecid → increase urate excretion