Pain Medications and Anti-Arthritis Medications

Extra Notes

1. How Salonpas works is that the “heat” busies receptors and “distracts” them from the pain

2. If something is a factor it is generally a polypeptide

Pain and Classifications

• complex sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage

• even without pathological/tissue damage, it’s still pain

Can be classified based on:

1. Pathophysiology

2. Duration

3. Etiology

4. Location

Types of Pain Based on Pathophysiology

Nociceptive Pain: activation of nociceptors in response to noxious stimuli

• ex: headache, back pain

• involves inflammation

Neuropathic Pain: due to central sensitization or neuronal damage

• ex: phantom pain, burning, tingling, numbing, sitting on hand, cancer, etc.

Nociplastic Pain:

• changes in nociceptive pathway without evidence of nerve or tissue damage

• due to oversensitization/Central Sensitization

• ex: cancer pain; phantom pain (even if not there)

Mixed Pain: nociceptive and neuropathic origin

• pain caused by mixture of various pathologies

Peripheral Pain: can be Nociceptive or Neuropathic

Central Sensitization: can be Nociplastic or Mixed, some Neuropathic

Types of Pain Based on Duration

Acute Pain: immediate short term effect upon exposure to stimuli

• few seconds to less than six months

Chronic Pain: sensitization at the level of spinal neurons via multiple mechanisms

• can be episodal (not all the time, when triggered or seasonal, every night, etc.)

• lasts for 6 or more months

Breakthrough Pain: pain in an already-treated patient due to movement, spontaneous or resulting from weaning off drugs or drug effects

• ex: cancer pain, withdrawal

• “breaks through” the current pain medication

Types of Pain Based on Etiology

Cancer Pain:

• cause due to cancer itself, drug treatment for cancer, or associated disease

Chronic Non-Cancer Pain (CNCP): 

• may have multiple etiologies

• ex: rheumatoid arthritis

Types of Pain Based on Location

Lower Back Pain:

• ex: due to posture, strains, underlying disease, referred pain

Neck and Shoulder Pain: 

• due to strains, sprains, posture, spinal cord compression, injuries

Headaches: 

• due to posture, stress, migraines, underlying disease (ex: tumors)

Referred Pain: 

• visceral pain that radiates to surrounding region

• pain is felt somewhere else other than the actual damaged part

Pain Pathways

1. Transduction

• sensory nerve picks up noxious stimulus via nociceptor

  • pseudo-unipolar, single axon that branches to two (soma is to the side)

• stimulus is picked up at the peripheral end

2. Transmission

• signal is transmitted via peripheral axons (primary afferent fibers)

• signal travels to somas in Dorsal Root Ganglion

3. Relay

• central end axons of DRG neurons release chemical neurotransmitters

• received by Spinal Cord Dorsal Horn Neurons (SCDH) (secondary neurons)

• secondary neurons carry signal to Central Nervous System

• also beginning point of Central Sensitization

4. Integration & Interpretation/Perception

• signal is brought to higher brain and is processed

• pain is actually perceived

5. Modulation

• brain sends response signal through descending pathway

• can either facilitate or inhibit pain

• descending neurons synapse with Dorsal Horn, release neurotransmitters

  • ex: opioids, enkephalin, endorphins

Peripheral Sensitization up until Dorsal Root Ganglion (before Dorsal Column)

Central Sensitization starts in spinal cord

Drug that Target Specific Steps in Pain Pathway

Transduction:

• Paracetamol

• NSAIDs

• Antihistamines

• Opioids

• Local Anesthetics

Transmission:

• Opioids

• Local Anesthetics

Integration & Interpretation:

• Opioids

• α2 Agonists

• General Anesthetics

Modulation:

• Opioids

• α2 Agonists

• NMDA Antagonists (N-methyl-D-Aspartate)

Peripheral Sensitization

• due to inflammation

• Chemokines

  • released by Neutrophils, Mast Cells, Macrophages, Vessels, etc.

  • ex: TNF-α, 5-HT, Histamine, Prostaglandins, Interleukins, etc.

• or other noxious stimuli (ex: Capsaicin/Heat, acid, ATP, etc.)

• bind to neuron, cause action potential (depolarization)

• Potential spreads all the way to spinal neuron

Peripheral Receptors

Refer to note in previous card

Acid-Sensing Ion Channel:

• senses protons

• if too acidic, will signal for pain

P₂X₃: 

• ATP-Gated Ion Channel

Tyrosine Receptor Kinase B:

• responds to BDNF (brain-derived neurotropic factor)

TRPV1:

• responds to heat or capsaicin

Can be targeted by Paracetamol, NSAIDS, Antihistamines, Opioids, Local Anesthetics, Steroids

Central Sensitization

• from peripheral nerve that reaches spinal neuron

• leads to release of Substance P and BDNF (in pre-synapse)

  • have receptors in post-synapse in spinal column

• Glial cells (brain) also release Interleukins and Tumor Necrosis Factor-α

• Descending Pathway Neuron can also release glutamate

• all receptors lead to release in Calcium

• Calcium propagates signal until it reaches brain

Central Receptors

NMDA:

• activated by glutamate

AMPA:

• activated by glutamate

NK₁: 

• Neurokinin-1

• activated by Substance P

Tyrosine Receptor Kinase B: 

• activated by BDNF

Sodium and Calcium Channels:

• allow for influx of cations

• cause depolarization due to positive charge

• also Ca-Channels increase intracellular calcium

Can be targeted by Paracetamol, Opioids, α2 Agonists, NMDA Antagonists

NSAIDS

Nonsteroidal Anti-Inflammatory Drugs

Pharmacophore:

• generally have aromatic acid portion with other group attached

• phenolic acid part confers activity

Types:

• Salicylic Acid Derivatives

• Aryl and Heteroaryl Acetic Acid Derivatives

  • generally Propionates

• Indol and Indene Acetic Acid Derivatives

• Anthranilic Acid Derivatives

• Enolic Acid Derivatives

NSAIDS Mechanism

Arachidonic Acid:

• Cell membrane contains C¹⁸ unsaturated fatty acid residues

  • phospholipase A2, removes phosphoglycerol head

  • triggered by various stimuli

  • converted into C₂₀ arachidonic acid

• main substrate for COX-I and COX-II, and 5-lipoxygenase 

  • COX form prostaglandins

  • 5-lipoxygenase forms leukotrienes

NSAIDS target COX-I, COX-II, and 5-lipooxygenase

• prevent synthesis of pain-related eicosanoids 

• ideally selective for COX-II (inducible) and not COX-I (always expressed) (ex: celecoxib)

COX-I and COX-II Selective Binding

• main substrate is arachidonic acid

• COX-I is always expressed, maintains homeostasis

• COX-II is only inducible

• COX-II has a larger hydrophobic binding pocket

  • Valine residue instead of COX-I Isoleucine (one less C)

  • COX-II selective drugs have an extra protruding hydrophobic part to hook into that gap; and to prevent fitting into COX-I space

NSAIDS Toxicity

Due to effect over long-use

• induced mitochondrial dysfunction and apoptosis

• Intracerebral Hemorrhage

  • Aspirin decreases platelet aggregation, promotes microbleeding

• Respiratory Complications

  • decreases PGI₂ and increased inflammation (aspirin exacerbated respiratory disease)

  • Community Acquired Pneumonia - decrease in neutrophil recruitment due to chemokine decrease

• Heart Injury

  • prevention of thrombosis (aspirin)

  • mitochondrial dysfunction, apoptosis

• GI Mucosal Injury:

  • due to reactive prooxidants, apoptosis

• Liver Injury

  • apoptosis, ROS

• Kidneys

  • renal injury, hypertension, decreased water & sodium retention

Specific Mechanism:

• NSAID Overdose → loosens tight junction of epithelial cells (due to acidity of drug)

• makes paracellular transport easier

  • LPS (endotoxin) entry = inflammation

  • increase in toxic bile salt micelles = membrane disruption = apoptosis

  • disrupts proton gradient (due to acidity/H⁺ flowing back in) = decreases ATP Production

    • picks up proton in matrix, releases it in cell

  • increased ROS = DNA damage

Paracetamol

• also acetaminophen (acetyl amine + phenol)

• technically not anti-inflammatory

• analgesic (less effective than NSAIDs), antipyretic

• targets COX-3 which is more in Central Nervous System

• is both central and peripheral acting (more central; can exist as molecular form, not charged = permeation)

• main metabolite is aminophenol, which is also central acting

• can be used for acute and chronic pain (but not as effective)

• maximum dose: 4g/day

  • recommended dose: 500-1000 mg; q 4-6 hours

Paracetamol MOA

• targets COX-1 protein variant in central

• targets COX-2 in central

  • COX1/2 inhibition leads to antipyretic effect

• can also activate TRPV1 and T-Type Calcium Channels

  • might lead to analgesic effect

Paracetamol Toxicity

• can occur even at regular doses, also occurs as toxic doses

Regular Dose Toxicity Examples:

• GI Complaints

• Hypersensitivity, Angioedema (swelling)

• Kidney damage

• GI Bleeding (doses taken >2g/day continuously)

• Stevens-Johnson Syndrome & Toxic Epidermal Necrolysis

• Agranulocytosis, Anemia, Thrombocytopenia

• Small increased Systolic BP, hypertension

Toxic Dose Toxicity Examples:

• serious liver damage, acute liver failure

• nausea, vomiting, sweating

• pain in right hypochondrium (due to liver)

• increase in aminotransferases (due to liver damage releasing)

• acute kidney injury

• skeletal muscle cytosis

• hepatic encephalopathy (brain problem due to liver problem)

Paracetamol Metabolism and Toxicity

• 95% is metabolized by conversion to glucuronide sulfates (Phase II) → excretion in urine

• 5% is converted to NAPQI (Quinone Intermediate) via Phase I

  • intermediate is toxic

  • Rescued by Glutathione, conjugates to form non-toxic product, excreted in urine

  • but those that it misses can cause hepatoxicity (due to electrophilicity)

  • ex: attacked by SH of cysteine residues

• Regular Continuous Consumption = run out of glutathione = NAPQI will cause hepatoxicity

  • also because so much is taken, that 5% becomes a lot

Opioid Analgesics

• can be natural, semi-synthetics, and fully synthetic

• can hit almost all steps in pain pathway

• Endogenous: Endorphins and Enkephalin

Mechanism:

• inhibition of presynaptic neuron release (ex: Substance P) due to preventing Calcium influx

• activation of opioid receptor 

  • are inhibitory G-Protein Coupled Receptors

  • lowers intracellular calcium in pre-synaptic neuron

  • prevents cAMP as well by inhibiting adenylyl cyclase

• associated receptor with analgesia: MOR (μ-opioid receptor

• promotes K-Channel, inhibits Ca-Channel, prevents action potential propagation/depolarization

Opioid Pharmacophore

• due to similarity to enkephalin

• side from OH to NH portion

μ-opioid receptor

Inactivated State:

• closed state

• G protein is not activated, so no overall inhibition of process

• state promoted by antagonists

Activated State:

• open state

• activates G protein, causes inhibitory effect

• state promoted by agonists

Opioid Toxicity

Common Effects:

• constipation

• nausea, vomiting

• sedation

• pruritus (itch)

Less Common Effects:

• dry mouth

• urinary retention

• respiratory depression

• mental confusion

Tramadol:

• also has somnolence (drowsiness)

Adjuvant Analgesics

• agents not initially meant for pain, but also do inhibit pain

• ex: Antiepileptic, Tricyclic Antidepressants, SNRIs, etc.

• aid in the slowing down of pain, or affect perception of pain

Antiepileptic Agents (GABA Receptors Agonists)

• ex: gabapentin

• GABA Receptors are also inhibitory G-Protein receptors

• open chloride channels, allow chloride to flow in

• causes cell hyperpolarization, prevents depolarization for signal transduction

• causes inhibitory effect

  • sedation, analgesic effect

Kohane VA Struck by MizuEna Beams

Arthritis Types

• Rheumatoid Arthritis

  • thinned cartilage

  • synovial area is highly inflamed

  • immune system attacks joints

• Osteoarthritis

  • shortened cartilage, no synovial insulation

  • bone ends rub together, causing pain

  • DMARDs do not work (due to not being caused by inflammation)

• Gouty Arthritis

  • due to monosodium urate crystal buildup (from uric acid)

  • unable to be excreted, builds up at joints

  • crystals cause inflammation and pain

Rheumatoid Arthritis Pathophysiology

• unknown trigger promotes inflammation in synovial membrane

  • attracts leukocytes

• Autoreactive CD4 T Cells activate macrophages → pro-inflammatory chemokine production

• Chemokines induce MMPs and RANK ligand production by fibroblasts

• RANK ligand activates osteoclast and MMP destroys tissue

Treatment: prevention of release/production of chemokines

Antirheumatoid Drugs

1. DMARDs (Disease Modifying Anti-Rheumatoid Drugs)

   • split into biological

     • TNF-a inhibitors

     • IL-1 antagonists

     • generally monoclonal antibodies (bind the chemokines)

   • and nonbiological

     • immunosuppressant

2. Adjuvant Drugs

Methotrexate (MTX) and Sulfasalazine

MTX:

• originally anticancer agent

• enters cell as prodrug

• converted into MTX-PG (added glutamate)

• folic acid analog

  • affects DNA synthesis (decreases thymine)

  • but for this pathway, inhibits ATIC enzyme

  • causes buildup of AICAR

  • inhibits Adenosine Deaminase, leads to increased adenosine

  • which is exported and binds to extracellular receptors, causing anti-inflammatory effects

Sulfasalazine:

• inhibits AICAR conversion to IMP

• this increases adenosine and also increases AICAR

• AICAR may promote anti-inflammatory response

Note: inhibited DNA synthesis also prevents rapid cell proliferation (which limits immune cells)

Longer effect; but does end up modifying disease (as opposed to just symptom inhibition)

Gold Compounds

• contain gold

• work by inhibiting thioredoxin reductase

• prevents DNA replication which prevents leukocyte attack, and eventually, ends inflammation

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Drug Targets for Gout

can either attack: 

• Acute Gout Attack:

  • increase in uric acid and decrease in PH → crystal deposits forming

• Purine Metabolism: 

  • Uric acid a product of purine breakdown

  • can inhibit xanthine oxidase (prevents formation of xanthine and uric acid)

  • can also inhibit reabsorption

Can be treated by:

• NSAIDs

• Corticosteroids

• Colchicine (caution in kidney disease, may cause bone marrow suppression)