spas-pharmacology

Pharmacology
Sites of Action:

all pharmacologic agents work by influencing the stretch reflex
this is true for all central and peripheral acting agents

Classes of Commonly used PO Medications
- benzodiazepines
- baclofen
- dantrolene sodium
- tizanidine
- clonidine
Important Signal Pathways
Segmental
- Reticulospinal Tract
- Rubrospinal Tract
- Vestibulospinal Tract
Neurotransmitters & Signal Pathways
Glycine - Segmental
GABA - Segmental & diffuse Central effect
Norepinephrine - Reticulospinal (inhibitory)
Serotonin - Reticulospinal (excitatory)
Excitatory Amino Acids - Rubrospinal, Vestibulospinal
Opiates - diffuse Spinal & Cerebral
Acetycholine - Presynaptic @ neuromuscular junction (NMJ)
Calcium - muscle contraction (peripheral)

Physiological Basis of Drug Treatment

Medication	System Action
Baclofen	GABA-beta
Diazepam	GABA-alpha
Tizanidine	alpha-2-adrenergic agonist
Botulinum	acetylcholine
Dantrolene	calcium
Cyproheptadine	serotonin

Benzodiazepines
- Diazepam most commonly studied
- Oldest medication that is still in use
- Action in the central nervous system
- Binds in brainstem, reticular formation, spinal poly-synaptic pathways
- Potentiates presynaptic effect of GABA-a
- Dosing - Diazepam
  - initial dose 2mg BID
  - increase by 2mg weekly (or as tolerated)
  - maximum dose 60mg/day
  - rapid increase of medication may increase side effects
- Side Effects
  - sedation, decreased memory, weakness, ataxia, decreased coordination, depression, drug dependence
- Benzodiazepine Options
  - Valium
  - Klonopin
  - Ativan
  - Xanax
  - Tranxene
Baclofen
- Action of Baclofen
  - centrally acting agent
  - GABA-b analogue
  - acts on poly-synaptic inhibitory pathways
- Parameters Effected by Baclofen
  - reduction in resistance to ROM
  - reduction in sudden painful spasms and clonus
  - resistance to stretch
  - not ADL’s and ambulation
- Dosing of Baclofen
  - starts at 5mg BID - TID
  - increase 5mg every 5 - 7 days
  - maximum dose 80mg (PDR) - can go much higher, as tolerated and effective
- Side Effects of Oral Baclofen
  - sedation, fatigue, weakness, nausea, dizziness, paresthesias, lowering seizure threshold, hallucination and seizures from too rapid withdrawal
Dantrolene Sodium
- Action of Dantrolene Sodium
  - action is in the periphery
  - by inhibiting release of Ca+ from sarcoplasmic reticulum it uncouples muscle contraction from excitation
  - this occurs in both extrafusal and intrafusal fibers
  - the effect on intrafusal fibers may change sensitivity of spindle action
- Dosing & Use of Dantrium
  - first check LFT’s
  - start @ 25mgBID
  - increase by 25 - 50mg/week
  - 100 - 200mg dose usually appropriate
  - maximum dose ~ 400mg/day
- Side Effects
  - drowsiness, lethargy, dizziness, weakness, paresthesias, nausea, diarrhea, liver damage
  - liver damage (rare)
    - result from long term high dose use
    - repeated therapy
    - women > 30yo
    - 1.8% over 60 days - but usually reversible
Tizanidine
- Newest agent available
- Imidazole derivative that exhibits central muscle relaxant activity
- Limited sedation or cardiovascular effects
- Demonstrates myotonolytic activity
- Reduces tonic response with less effect on phasic response
- Pharmacology & Site of Action for Tizanidine
  - alpha-2 agonist:-
    - decreases release of excitatory amino acids in spinal cord
    - facilitatory effect of coerulospinal pathways
  - poly-synaptic reflex arc only
  - potent imidazole affinity - ?significance
  - antinociceptive activity
  - anticonvulsant activity
    - not GABA or NMDA
    - possibly glycine or alpha-2
- Comparison with other Antispasticity Agents
  - better side effect profile than baclofen and diazepam, with less weakness and sedation
  - as effective as baclofen and diazepam
- Dosing
  - begin 2mg BID - TID
  - increase by 4mg every 4 - 7 days
  - maximum dose of 36/mg/day in TID - QID
- Side Effects
  - dry mouth, somnolence, asthenia, dizziness
Other, Less Common Medications for Spasticity Reduction That Have Been Reported to be Effective
- Alpha agents: clonidine, phenothiazines, thymoxamine
- GABA: piractem, progabide
- Glycine, Threonine
- Dilantin, Phenobarbital
- Morphine
- Cyclobenzaprine
- Cyproheptadine
- Tetrahydrocannabinol (THC)
Initial and Maximum Dosages of Medications for Spasticity
- General First-Line Use
  - diazepam: 2mg BID to 15mg QID
  - dantrolene: 25mg BID to 100mg QID
  - baclofen: 5mg BID to 40mg QID
    For Spasms
  - clonidine: 0.05mg QID to 0.2mgTID
  - tizanidine: 2mg BID to 12mg TID
- Second-Line or Supplementary Use
  - phenytoin: 10 - 20mg/dl
  - phenobarbital: 10 - 30mg/dl
  - threonine: 500mg to 2.5g TID
  - cyproheptadine: 4mg BID to 8mg QID
  - chlorpromazine: 10mg QD to 50mg TID
  - cannabinoids: 5mg THC QD to 10mg TID
- Miscellaneous
  - Piracetam - chemically related to gaba, used in europe -(Nootropyl), not yet FDA approved
  - Orphenadrine - Norflex, NMDA-antagonist, 60mg iv - action within 30’, can use in preparation for PT joint ranging & stretching
  - Cannabis (Cesamet, Marinol)
    10 mg superior to 5mg
    peak 3 hours, 1/2 life 20-44 hours
    Dronabinol - 2.5, 5, 10mg capsules
    Nabilone - 1mg bid
    - Dunn etal, Paraplegia 1974;12:175
    - Petro etal, J Clin Pharmacol 1981; 21:413