Pharmacology Unit 2

Common MSK health conditions

Osteoarthritis, Rheumatoid arthritis/Autoimmune disorders, Injuries/Surgical procedures

MSK symptoms

pain, inflammation, muscle spasm

MSK typical routes of administration

Oral, topical, injectable

Why use skeletal muscle relaxants?

address hyperexcitable skeletal muscle, spasticity, acute spasm (pain)

Skeletal muscle relaxants: goal

reduce hyperexcitability/normalize excitability, not eliminate muscle activity

Where do skeletal muscle relaxants work?

Spinal cord, neuromuscular junction, skeletal muscle fiber

What does the site of action of skeletal muscle relaxants determine?

effects and side effects

Spasticity

results from CNS condition such as CVA, Cerebral Palsy, multiple sclerosis. Loss of supraspinal inhibition

Acute muscle spasm

associated with MSK injury such as muscle strain, Tonic, involuntary contraction. Painful and localized

Centrally Acting Antispasm Drugs (Polysynaptic Inhibitors): MOA

Global decrease in CNS excitability results in sedative effect (not well defined)

Centrally Acting Antispasm Drugs (Polysynaptic Inhibitors): Adverse effects

Drowsiness, Dizziness, Nausea, & Lightheadedness, Tolerance, Withdrawal symptoms

Centrally Acting Antispasm Drugs (Polysynaptic Inhibitors): Drugs

cyclobenzaprine (Flexiril) / carisoprodol (Soma) / metaxalone (Skelaxin)

Centrally Acting Antispasm Drugs (Polysynaptic Inhibitors): often prescribed with

NSAIDs

Benzodiazepine

Enhances GABA-mediated inhibition, reduces alpha motor neuron activity, reduces spasticity

Benzodiazepine: adverse effects

Sedation limits long-term use, can produce tolerance, physical dependence, and withdrawal

Two uses of diazepam (Valium)

antispasm & antispasticity

Centrally-acting Antispasticity Drugs: MOA

Increase GABA activity in CNS

Centrally-acting Antispasticity Drugs: drugs

Baclofen, Gabapentin, Diazepam

Alpha 2-adrenergic agonists: MOA

inhibit excitatory neurotransmitter reducing transmission to alpha motor neurons

Alpha 2-adrenergic agonists: drugs

tizanidine (Zanaflex)

Baclofen (Lioresal) ORAL

GABAB receptor agonist › Inhibits spinal reflex transmission › Most effective for spinal cord lesions › Often drug of choice for multiple sclerosis Causes less generalized muscle weakness than other drugs

Baclofen (Lioresal) ORAL: adverse effects

Transient drowsiness, disappearing in a few days, confusion/hallucinations in the elderly or those who have had a CVA

Intrathecal Baclofen

Delivered via pump For sever, intractable spasticity Delivered directly into subarachnoid space › Lower doses, higher specificity

Intrathecal Baclofen: adverse effects

Pump malfunction (Increased delivery: --> Overdose, respiratory distress, decreased cardiac function, coma / Decreased delivery: --> Withdrawal: fever, confusion, delirium, seizures) & Tolerance

Peripherally Acting Antispasticity Drugs (Direct Acting)

Botulinum Toxin Dantrolene Sodium

Peripherally Acting Antispasticity Drugs (Direct Acting): MOA

Direct Acting at the NM Junction or Muscle directly

dantrolene sodium (Dantrium): MOA

Only muscle relaxant that acts directly on skeletal muscle › Inhibits Ca2+ release from SR › Less Ca2+ available for actin and myosin crossbridge formation

dantrolene sodium (Dantrium): causes

weakness and hepatotoxicity

dantrolene sodium (Dantrium): uses

to treat severe spasticity, regardless of underlying pathology (not prescribed for muscle spasms due to MSK injury)

dantrolene sodium (Dantrium): adverse effects

Causes weakness (sometimes counterproductive to therapy) & Hepatotoxicity

Botulinum Toxin (botox): MOA

blocks acetylcholine release, Targeted muscle injection (EMG/US guided). Effects last ~3 months (repeated injections required) (Often combined with therapy)

Botulinum Toxin: Spasticity management

CP, stroke, TBI, SCI › Enhances ADLs: Enables UE extension in flexor spasticity, Improves hygiene, dressing, etc

Botulinum Toxin: improves movement

Reduces spastic dominance → better gait and task performance › Facilitates voluntary motor control during rehab

Botulinum Toxin: supports orthopedic intervention

Enhances stretching and serial casting › Prevents contractures, reduces surgical need › Improves orthotic tolerance (e.g., AFO fit)

Botulinum Toxin: adverse effects

muscle weakness, can become systemic, potentially could even cause death

Salicylate Analgesic Drugs: drugs

Aspirin is also known as acetylsalicylic acid (ASA)

Salicylate Analgesic Drugs: therapeutic actions

analgesic, anti-inflammatory, reduce fever

Salicylate Analgesic Drugs: adverse effects

may produce stomach ulcers, can't be used for children because of reye's syndrome

Aspirin is the original...

NSAID

Mystery as to why aspirin could affect so many systems

analgesic and anti-inflammatory, fever reducer, blood thinner

Aspirin mystery solved in 1970s

Discovered that aspirin interfered with the biosynthesis of prostaglandins

NSAIDs block...

cyclooxygenase (cox enzyme)

Prostaglandins are created when:

1. cells experience damage

2. disruption of homeostasis

How are prostaglandins created?

1. Cell membrane phospholipids are converted to arachadonic acid

2. The cyclooxygenase (COX) enzyme converts arachidonic acid to prostaglandins and thromboxane

What are the effects of prostaglandins?

inflammation, increase sensitivity of nociceptors, fever, clotting

Aspirin and other NSAIDs are potent...

inhibitors of the COX enzyme

Inhibition of COX blocks the formation of prostaglandins, resulting in...

Decreased inflammation, decreased pain, decreased fever, decreased clotting

COX-1 enzyme:

Component of normal cell activity (produces generally benign prostaglandins)

COX-2 enzyme

Produced in emergency situations (produces prostaglandins that tend to mediate pain and be associated with inflammation)

NSAIDs either...

1. Effect both COX forms (non-selective)

2. Selectivity inhibit COX-2

Aspirin and most NSAIDs are...

non-selective

Primary beneficial effect is due to inhibition of...

COX-2

Most side effects are due to inhibition of...

COX-1

Nonselective NSAIDs: drugs

acetylsalicylic acid (Aspirin), ibuprofen (Advil, Motrin), naproxen (Aleve)

Non-Selective NSAIDs: primary adverse effect

GI damage due to loss of protective COX-1 prostaglandins

Non-Selective NSAIDs: other adverse effects

can increase blood pressure, POSSIBLY delay bone healing (controversial), Reye syndrome (aspirin), risk of renal disease

COX-2 Selective NSAIDs: MOA

selectively inhibit COX-2, COX-2 drugs inhibit a specific prostaglandin that promotes vasodilation and inhibits clotting

COX-2 Selective NSAIDs: drugs

celecoxib (Celebrex)

T/F: acetaminophen (Tylenol) is an NSAID

False

acetaminophen (Tylenol): uses

pain relief, fever reduction

acetaminophen (Tylenol) is preferred for...

patients with GI risk or ulcer history (no gastric irritation)

acetaminophen (Tylenol) is widely used for...

noninflammatory conditions

Opioid Analgesics: MOA

Relieve pain by binding with opiate receptor sites in the brain to block pain impulses from ascending neural pathways

Opioid Analgesics: Uses

Treat moderate-to-severe pain, preop/postop pain relief, sedation, maintain general anesthesia (strong Agonists, mild to Moderate Agonists, mixed Agonists-Antagonists, antagonists)

Opioid Analgesics: adverse effects

tolerance/dependence

Opioid Analgesics: tolerance

Need to progressively increase the dosage of a drug to achieve a therapeutic effect when the drug is used for prolonged periods

Opioid Analgesics: physical dependence

› Defined as the onset of withdrawal symptoms when the drug is abruptly removed › Severe cases: withdrawal symptoms occur within 6-10 hours of last dose › Withdrawal symptoms typically last around 5 days, peaking at day 2-3

Opioid Analgesics: spinal cord MOA

Opioid receptors are concentrated neurons in the dorsal horn (Presynaptic terminals of specific first order nociceptive afferents & Postsynaptic terminals of secondary afferents)

Opioid Analgesics: brain MOA

Disinhibits (activates) descending pain pathways from the periaqueductal gray matter

Opioid Analgesics: brain MOA (3 steps)

1. Opioids bind to specific receptors in the midbrain and remove inhibition of descending pathways that decrease nociception 2. Increased activity of descending pathways travels through the ventromedial medulla (VMM) to reach the dorsal horn of the spinal cord. 3. Neurons in descending pathways release serotonin and norepinephrine onto dorsal horn synapses and inhibit the ability of these synapses to transmit nociceptive impulses to the brain

Opioid Analgesics: peripheral tissues MOA

Opioid receptors have been identified on the distal (peripheral) ends of primary afferent (sensory) neurons (binding an opioid to these receptors decreases the cell's excitability, resulting in decreased nociceptive signaling to the spinal cord)

Opioid: agonist

Binds to the opioid receptor and activates it, producing a biological response

Opioid: antagonist

Binds to the opioid receptor but does not activate it, thereby blocking agonists from producing a response

Types of opioids

1. Strong agonists

2. Mild-to-moderate agonists

3. Mixed agonist-antagonists

4. Antagonists

Strong Agonists: adverse effects

Sedation, respiratory depression, constipation

Strong Agonists: uses

Treat severe pain

Strong Agonists: drugs

Morphine sulfate Fentanyl (Duragesic-25) (Hydromorphone (Dilaudid) Tramadol (Ultram)

Strong Agonists: MOA

High affinity for opioid receptors: primarily Mu

Mild to Moderate Agonists: Uses

Treat moderate pain

Mild to Moderate Agonists: Drugs

Codeine Hydrocodone Oxycodone (OxyContin)

Mild to Moderate Agonists: MOA

Opioid Receptors - not as great an affinity or efficacy as strong agonists

Mixed Agonist-Antagonist: adverse effects

Cause greater psychotropic effects (hallucinations) / Not commonly used due to hallucination/vivid dreams

Mixed Agonist-Antagonist: uses

Provide adequate analgesia with less risk of side effects such as resiratory depression

Mixed Agonist-Antagonist: drugs

Butorphanol (Stadol) Buprenorphine (Buprenex) (used for opioid use disorders / withdrawal)

Mixed Agonist-Antagonist: MOA

Binds and activates Kappa blocks or partially activates Mu & Partially activates Mu receptor and antagonist at Kappa

Antagonists: Uses

Used to treat overdose Used for opioid use disorder Control side effect of constipation

Antagonists: Drugs

Naltrexone (ReVia) Naloxone (Narcan) Naloxegol (Movantik)

Antagonists: MOA

Opioid Receptors - knock agonists off of receptors - used for opiate overdose & Opioid induced constipation

Rheumatoid Arthritis (RA)

Chronic, systemic disorder, autoimmune response Affects 0.5 to 1% of the population worldwide Occurs 3 times as often in women compared to men

RA is characterized by...

Synovitis, destruction of articular tissue and bone erosion, periods of exacerbation and remission, progressive in nature

RA is associated with...

pain, stiffness, inflammation, increased incidence of CVD

RA joint affected

Small synovial joints of hands and feet, large joint like the knee

RA is...

systemic (autoimmune response)

Two goals of drug treatment of RA

1. Decrease joint inflammation 2. Arrest progression of disease

3 categories of RA drugs

NSAIDs, glucocorticoids, disease-modifying antirheumatic drugs (DMARDs)

T/F: NSAIDs for RA used to play a primary role, but now are secondary to DMARDs

True

T/F: NSAIDs for RA still play long-term role in reducing inflammation

False, short-term

T/F: Acetaminophen is optimal for RA due to lack of anti-inflammatory properties

False, it is NOT optimal

Glucocorticoids for RA: Powerful anti-inflammatory drugs

Glucocorticoids (e.g., prednisone) reduce joint inflammation and pain in rheumatoid arthritis

Glucocorticoids for RA: Potential disease-modifying effects

Early use may slow joint erosion and damage, but high doses are often required if used alone