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MSK/Rheum > Pharm-Fibromyalgia, Sk M Relaxers, Spasticity > Flashcards

Pharm-Fibromyalgia, Sk M Relaxers, Spasticity Flashcards

1
Q

What 3 drugs are used to treat Fibromyalgia (FM)? For which of these is this an off-label use?

A 
DAM Pain Feels Crappy
1. Duloxetine
3. Pregabalin
6. Cyclobenzaprine
Off-label use for 6
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2
Q

What is the suggested etiology of fibromyalgia?

A

↑’d nt function in ascending pathways of spinal cord + ↓’d levels in descending, modulatory pathways→amplification of all nociceptive signals arriving in brain from peripheral tissues (A+B leads to C)

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3
Q

What drugs have been historically used to treat FM? Why?

A

NSAIDs, Muscle relaxants, Narcotic analgesics, Sedative Hypnotics, Antidepressants; these were used to Rx the symptoms of FM (pain, sleep disturbance, mood disorders)

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4
Q

Which two of these drugs are in the same class? What is it?

A

Duloxetine and Milnacipran (both are oral); they belong to Serotonin-Norepinephrine Reuptake Inhibitor (S/NERI) class of Antidepressants

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5
Q

MoA of Duloxetine and Milnacipran? How do they differ? What is there affect on receptors? How do they affect dopamine reuptake?

A

Both inhibit reuptake of Serotonin and NE.
Duloxetine: Ser>NE blockade
Milnacipran: NE> Ser blockade (3-fold)
NEITHER HAS ACTS ON ANY RECEPTORS OR AFFECTS REUPTAKE OF DOPAMINE

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6
Q

Metab/Elim of Duloxetine?

A

M: extensive CYP metabolism, including CYP2D6. It moderately inhibits 2D6→potential for d-d interxns. (D in duloxetine and 2D6)
E: metabolites eliminated in urine

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7
Q

Metab/Elim of Milnacipran?

A

M: metabolism does NOT involve CYPs
E: eliminated in urine as mix of parental drug and metabolites

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8
Q

ADEs/CIs/BBW of Duloxetine and Milnacipran? (5)

A
  1. Mild ↑ in HR and BP; caution for pt’s w/ pre-existing CV issues
  2. CI’d in Glaucoma (closed-angle)
  3. CI’d w/ concurrent MAOIs
  4. SIADH leading to Hyponatremia
  5. BBW for suicidal ideation
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9
Q

Pregabalin is structurally related to what drug?

A

the anti-seizure drug Gabapentin (they share the same MoA, but Gabapentin is not approved/labeled for FM)

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10
Q

MoA of Pregabalin?

A 
Acts on PREsynaptic alpha-2-delta subunits of L-type calcium channels→inhibition of excitatory glutamate transmission
It's all in the Name Pregabalin:
PRE=presynaptic
Gaba=glutamate
L=L-type calcium channel
IN=inhibition of excitatory transmission
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11
Q

What are the effects of Pregabalin action?

A

Allevation of neuropathic pain, anxiety, and pain syndromes

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12
Q

Is Pregabalin a controlled substance?

A

Yes, it’s a Schedule V drug

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13
Q

Absorption/Elimination/Metabolic effects of Pregabalin? D

A

Rapid absorption
Renal elimination w/ evidence renal tubular reabsorption; reduce dose in renal failure
No known drug-metabolism interxns

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14
Q

ADEs/Cautions of Pregabalin?

A

BASS= Blurred vision/xerostomia + Additive sedation + Suicide + Schedule 5

  1. Rebound worsening of symptoms upon withdrawal; dependence w/ continued use (Schedule 5)
  2. Additive sedation w/ other Rx affecting CNS
  3. Worsening depression or suicidal thoughts/behavior
  4. Blurred vision, Xerostomia, Dizziness, Sedation, esp in elderly
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15
Q

What needs to be monitored w/ use of Pregabalin?

A

Serum Creatinine

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16
Q

What type of drug is Amitriptyline? Fluoxetine? How do these aid in the Rx of FM?

A

Amitriptyline→TCA (tricyclic antidepressant)
Fluoxetine→SSRI (selective serotonin reuptake inhibitor)
These both appear to redress the imbalance of transmission in ascending vs descending spinal pain pathways.

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17
Q

What are the Skeletal Muscle Relaxer agents? (2)

A

“sit back, RELAX and watch a TCM (Copyright)

  1. Cyclobenzaprine
  2. Tizanidine
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18
Q

What is the indication/route of Carisoprodol?

A

Oral for musculoskeletal pain (older drug less frequently used than newer agents; not scheduled by FDA but concerns about abuse)

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19
Q

MoA/Effects of Carisoprodol?

A

Acts in reticular activation system of CNS (brain and spinal cord)→leads to sedation and reduced perception of pain.

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20
Q

How does Carisoprodol effect neuronal conduction, neuromuscular transmission, and muscular excitability?

A

it has NO DIRECT EFFECT on neuronal conduction, nm transmission, or muscular excitability

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21
Q

Metab/Elim of Carisoprodol? Importance?

A

M/E: extensive hepatic metabolism by CYP2C19 to several less active compounds; ultimate elim in urine (renal).
Renal or hepatic dysfunction→increased retention→increased toxicity

22
Q

ADEs/Cautions of Carisoprodol? (3 types)

A

Most are related to Sedation

  1. CNS Effects (4): Drowsiness/Dizzinnes (most common); also agitation, insomnia, vertigo, ataxia)
  2. Systemic Sedative Effects (4): Asthenia, Vision loss (temporary), Mydriasis, Orthostatic Hypotension
  3. Additive sedation if combined with other sedative agents
23
Q

Cyclobenzaprine indications?

A

Oral drug for muscle spasm or FM (off-label)

24
Q

What drug is Cyclobenzaprine closely related to?

A

Closely related to Amitriptyline (TCA). They have comparable actions and side effects. (Cylob is TCA)

25
Mechanism of Cyclobenzaprine? (2)
a. Acts CENTRALLY, possibly at brain stem. b. Also has ANTICHOLINERGIC activity (these are both like amitriptyline)
26
Metab/Elim of Cyclobenzaprine? Reduced clearance in what types of pt's? (2)
a. Enterohepatic recirculation and extensive hepatic metabolism (CYP3A4, 1A2, 2D6) b. Reduced clearance in elderly and with hepatic impairment.
27
ADEs/Cautions of Cyclobenzaprine?
SQP 1. S(edation): Additive CNS depression (Sedation) w/ depressant drugs and alcohol 2. P(aralytic ileus/GI): Anticholinergic effects (opposite of DUMBELLS; especially Drowsiness/Dizziness, Xerostomia, more on handout). Additive with other anticholinergics. MOST significant effect→**GI PROBLEMS→PARALYTIC ILEUS** 3. Q: possible QT prolongation; use w/ caution in presence of anti-arrhythmics or other drugs that prolong QT
28
What type of pt's are most at risk to ADEs of cyclobenzaprine? What can this lead to?
Elderly→confusion and cardiac effects leading to falling
29
Route/MoA/Effects of Methocarbamol?
Route: Oral, IM, or IV MoA: Generalized sedation and altered pain perception (**No direct effect on muscle or excitation-contraction coupling**) Effect: Pain relief
30
Indications for Rx w/ Methocarbamol?
Muscle Spasm, Tetanus
31
Metab/Elim of Methocarbamol? Importance?
M/E: Hepatice dealkylation and hydroxylation with renal (urinary) elimination. Imp: hepatic or renal dysfunction→increased toxicity
32
ADEs/Cautions of Methocarbamol?
a. Additive CNS depression (sedation) w/ alcohol or depressant drugs b. Common: drowsiness/dizziness, lightheadedness, blurred vision, N/V, headache, irritability
33
Route/MoA of Tizanidine? Effect? Indications:
Oral agent; Central, pre-synaptic alpha-2 receptor AGONIST→decreased activation of polysynaptic spinal cord motor neurons→concomitant decrease in MUSCLE TONE but NOT MUSCLE STRENGTH. Indications: Multiple Sclerosis, Spasticity, and Spinal cord trauma
34
Tizanidine is related to what other drug? How are they similar? Different?
Clonidine→also and alpha-2 agonist leading to decreased sympathetic outflow and decreased BP. Tizanidine has only weak (2-10%) anti-HTN (SNS) activity compared to clonidine.
35
Metab/Elim of Tizanidine?
M/E: extensive hepatic first-pass metabolism; short t1/2; extensive renal excretion of long-lasting metabolites
36
Dose adjustment of Tizanidine in what types of pt's? (2) Why?
Reduced renal clearance with increased toxicity in: | a. elderly b. renal dysfunction
37
ADEs/Cautions with Tizanidine?
"High LFTs and Depression" H: additive Hypotension w/ clonidine, methyldopa, guanfacine, guanabenz L: (Liver) Hepatocellular toxicity→monitor LFTs F: Features resulting from central alpha-2 blockade→asthenia, xerostomia, dizziness, sedation, hypotension T: Tapered cessation of Rx to avoid REBOUND hypertonicity, tachycardia, HTN (esp after high doses) D: (Depression) Additive CNS depression with CNS depressants
38
What four drugs are used in Rx of Spasticity?
BBDT 1. Baclofen (GABA-B) 2. Botulinum toxin 3. Dantrolene (SR of sk m) 4. Tizanidine (alpha-2 agonist)
39
MoA of Baclofen? (2, kinda a 3rd)
Complex: a. GABA-B receptor AGONIST at multiple levels in the spinal cord→either inhibitory or hyperpolarizing signals→reduced excitatory (aspartate&glutamate) polysynaptic pathways→reduced spastic mvmts b. Inhibition of Substance P→ pain relief c. Only at high doses→sedation (supraspinal action)
40
Indications for Baclofen?
Multiple sclerosis, muscle spasm, spasticity, spinal cord trauma
41
Elimination of Baclofen? Importance?
Extensive renal elimination. | Imp: Caution w/ renal dysfunction
42
What side effects of Baclofen are seen in pt's w/ renal failure?
Decreased clearance→drug accumulates→encephalopathy, abdominal pain, seizures, respiratory depression
43
ADE/Cautions w/ Baclofen? (6)
"Taper High Gaba" (1,2, and 3 below) 1. TAPERed dosing; **BBW** for abrupt discontinuation→REBOUND NEURAL ACTIVITY→seizures, confusion, hallucinations, psychiatric disturbances, and increased spasticity 2. H: additive Hypotension w/ antihypertensives and MAOIs 3. G: increased blood Glucose→dose adjustment of antidiabetic agents 4. Additive CNS depression with other depressants 5. Common ADEs: drowsiness/dizziness, asthenia, confusion, fatigue, headache 6. More severe CNS effects in renal failure (see previous slide)
44
MoA of Dantrolene?
Direct inhibition of Ryanodine Receptor (RyR)→decreased Ca2+ release from SR of sk m cells→decreased muscle contraction. This effectively UNCOUPLES the Excitation-Contraction process
45
Important use of Dantrolene other than spasticity?
Malignant hyperthermia
46
What does Dantrolene NOT do (2)? How does it effect cardiac/smooth muscle and CNS?
a. It does not act like a CCB b. It does not block Ach release from endplate c. It has little or no effect on cardiac or smooth m at doses used for sk m relaxation d. Extent of CNS effect is unknown
47
How is dantrolene administered?
Oral or IV
48
What two things are important regarding IV administration of Dantrolene?
a. It's very alkaline (basic)→solubulized w/ surfactant+water→can cause THROMBOPHLEBITIS. So have to infuse it into Fast-Running or Large vein. b. Need for Reconstitution delays immediate administration!!!
49
Metab/Elim of Dantrolene?
M/E: hepatic metabolism to inactive metabolites, which are renally excreted
50
ADEs/Cautions with Dantrolene?
1. Additive CNS depression w/ other CNS depressants 2. IV dantrolene+CCBs (in Rx of malignant hyperthermia)→V-fib and CV collapse 3. Crosses placenta during C-section→Floppy Child Syndrome 4. Possible hepatotoxicity (get LFTs)→esp in MS, females>35 yo, and in pt's w/ concurrent multiple drug therapy (esp Estrogen)
51
Why is Diazepam (and other benzodiazepines) not used for spasticity?
They cause muscle relaxation, but at doses that produce significant sedation

MSK/Rheum (7 decks)

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