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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
Q

Mechanism of Cyclobenzaprine? (2)

A

a. Acts CENTRALLY, possibly at brain stem.
b. Also has ANTICHOLINERGIC activity
(these are both like amitriptyline)

26
Q

Metab/Elim of Cyclobenzaprine? Reduced clearance in what types of pt’s? (2)

A

a. Enterohepatic recirculation and extensive hepatic metabolism (CYP3A4, 1A2, 2D6)
b. Reduced clearance in elderly and with hepatic impairment.

27
Q

ADEs/Cautions of Cyclobenzaprine?

A

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
Q

What type of pt’s are most at risk to ADEs of cyclobenzaprine? What can this lead to?

A

Elderly→confusion and cardiac effects leading to falling

29
Q

Route/MoA/Effects of Methocarbamol?

A

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
Q

Indications for Rx w/ Methocarbamol?

A

Muscle Spasm, Tetanus

31
Q

Metab/Elim of Methocarbamol? Importance?

A

M/E: Hepatice dealkylation and hydroxylation with renal (urinary) elimination.
Imp: hepatic or renal dysfunction→increased toxicity

32
Q

ADEs/Cautions of Methocarbamol?

A

a. Additive CNS depression (sedation) w/ alcohol or depressant drugs
b. Common: drowsiness/dizziness, lightheadedness, blurred vision, N/V, headache, irritability

33
Q

Route/MoA of Tizanidine? Effect? Indications:

A

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
Q

Tizanidine is related to what other drug? How are they similar? Different?

A

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
Q

Metab/Elim of Tizanidine?

A

M/E: extensive hepatic first-pass metabolism; short t1/2; extensive renal excretion of long-lasting metabolites

36
Q

Dose adjustment of Tizanidine in what types of pt’s? (2) Why?

A

Reduced renal clearance with increased toxicity in:

a. elderly b. renal dysfunction

37
Q

ADEs/Cautions with Tizanidine?

A

“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
Q

What four drugs are used in Rx of Spasticity?

A

BBDT

  1. Baclofen (GABA-B)
  2. Botulinum toxin
  3. Dantrolene (SR of sk m)
  4. Tizanidine (alpha-2 agonist)
39
Q

MoA of Baclofen? (2, kinda a 3rd)

A

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
Q

Indications for Baclofen?

A

Multiple sclerosis, muscle spasm, spasticity, spinal cord trauma

41
Q

Elimination of Baclofen? Importance?

A

Extensive renal elimination.

Imp: Caution w/ renal dysfunction

42
Q

What side effects of Baclofen are seen in pt’s w/ renal failure?

A

Decreased clearance→drug accumulates→encephalopathy, abdominal pain, seizures, respiratory depression

43
Q

ADE/Cautions w/ Baclofen? (6)

A

“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
Q

MoA of Dantrolene?

A

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
Q

Important use of Dantrolene other than spasticity?

A

Malignant hyperthermia

46
Q

What does Dantrolene NOT do (2)? How does it effect cardiac/smooth muscle and CNS?

A

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
Q

How is dantrolene administered?

A

Oral or IV

48
Q

What two things are important regarding IV administration of Dantrolene?

A

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
Q

Metab/Elim of Dantrolene?

A

M/E: hepatic metabolism to inactive metabolites, which are renally excreted

50
Q

ADEs/Cautions with Dantrolene?

A
  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
Q

Why is Diazepam (and other benzodiazepines) not used for spasticity?

A

They cause muscle relaxation, but at doses that produce significant sedation

MSK/Rheum (7 decks)

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