pharmacology of skeletal muscle

Question 1

Classification of drugs acting on the

skeletal muscles

Answer 1

1. Drugs causing contractions
    Tetanus toxin – strong spastic contraction.
    Activators of the mutated ryanodine receptors – halothan, succynylcholine, probably antipsychotics (see neurolpetic malignant syndrome)
    Sympathomimetics – increase muscle strength
   Centrally acting – any convulsive agent

2.  Relaxants
A. Centrally acting – „spasmolytics”-
B. Peripherally acting
 Blockers of the neuromuscular junction
 Botulinum toxin
 Tetracyclines, aminoglycosides

Question 2

spasmolytic goal

Answer 2

therapy goal in both chronic (cerebral palsy, multiple sclerosis, strokes) and acute forms is to reduce the excessive skeletal muscle tone without reduction of strength-> reduction of pain.

Question 3

neuromuscular junctions blockers

Answer 3

usually have no CNS activity and have an important role in induction of muscle paralysis as part of a preoperative general anesthesia.

Question 4

spasmylytic agent

Answer 4

usually work by either enhancing the level of inhibition or reduction of level of excitation of descending motor neurons

Question 5

drugs- general

Answer 5

Drugs for spasticity only:
baclofen – GABAB agonist, highly sedative

Drugs for acute muscle spasm (unknown
mechanism)
mephenesine, guaiphenesin
chlorzoxazone

Question 6

Centrally acting skeletal muscle

relaxants

Answer 6

Drugs for both acutely and for spasticity
diazepam – benzodiazepine
tizanidine – 2 agonist, structural relative of
clonidine (imidazoline)
tolperisone – unknown mechanism
carisoprodol (its metabolite is meprobamate) –
it has abuse potential, meprobamate is
hepatotoxic

Question 7

Diazepam (a benzodiazepine)

Answer 7

Mechanism: interacts with GABA-A (ionotropic channel) and agonist of it-> less muscle spams (postsynpase).

Indication:
1/cervical and lumbar syndromes (transection?).
2/ multiple sclerosis, myelopathys etc..

Kinetics
Oral and IV

adverse effects:
marked sedation.
hypotonia.
rebound effects at withdrawl.

Question 8

tizanidine

Answer 8

Mechanism:
presynaptic inhibition via alpha 2 agonist.

Indication
Muscle spasm.
Cervical and lumbar syndrome.

Kinetics
Taken orally.

Adverse
asthenia.
Drowsiness.
Dry mouth
Hypotension.

Question 9

baclofen

Answer 9

Mechanism:
GABA B agonist

1) Presynaptic: GABA B exicted-> Less glutamate (excitatory) released.
2) Postsynpatic (gaba B)- K influx-> less excitation (hyperpolarization)

Indications:
MS, Spacicity, Alcoholics.
kinetics:
admin: Oral and intrathecal)

Adverse:
1. Sedative (less than diazapam).
2. enhancement of sedative and respiratory depressive 3/ effects of opiates and alcohol.
4/ Hallucinogenic.

Question 10

Rilozole

Answer 10

orally taken
inhibition of glutamatergic tramission.
indication: ALS.
adverse: hepatotoxicity, neutropenia, GI.

Question 11

other centrally acting spasmolytics

Answer 11

tolperisone – unknown mechanism
carisoprodol (its metabolite is meprobamate) –
it has abuse potential, meprobamate is
hepatotoxic.
mephenesin and guaiphenesin (parentally)- unknown mechanism.

Question 12

dantrolene

Answer 12

Mechanism: Acts on the skeletal muscle cells to reduce the release of Ca from the SR by interacting with the RyR1 receptor channel (Ca channel in skeletal muscle)-> less actin myosin interaction.

Cardiac and SMC use RyR2.

Pharmacokinetics: orally about 1/3 of dose is absorbed and elimination half life is about 8 hours.

Indication:

1. Malignant hyperthermia.
2. spinal injury and
3. after stroke.

adverse:
1. hepatotoxic (1-2% chance occuring, lethal if does).
2. generalized muscle weakness.
3. Sedation.

Question 13

botulinum toxin

Answer 13

exotoxin of clostridium botulinum.
Theraputic use:
opthalmic-
1. plepharospasm (uncontrolled movements of eye lid)
2. strabismus (eyes are not pointing in the same direction)
3. generalized spastic disorders (cerebral palsy)
4. dystonia
5. cosmetics.

Mechanism: inhibits release of ACh by binding to synaptobrevin.