Medical Pharmacology Chapter 20:  Neuromuscular Blocking Agents and Muscle Relaxants

• Diazepam (Valium)

  •  Enhances CNS GABA inhibitory activity; active at most (all) GABA_A synapses.

  •  Anti-spasmolytic effect in part due to action in the spinal cord (effective in patients with cord transection)

  •  Tends to be sedating

• Baclofen (Lioresal)

  • Mechanism: GABA agonist at GABA_B receptors

    • Receptor activation causes increased K⁺ conductance (hyperpolarization) in the brain and spinal cord

    • Spinal cord effects probably occur following increased presynaptic inhibition which reduces transmitter released by reducing calcium influx.

  • Similar anti-spasticity compared to diazepam (Valium) but with less sedation

  • Pharmacokinetics:

    • Orally active;well absorbed

    • half-life: 3-4 hours

  •   Adverse Effects:

    • Drowsiness

    • Increased seizure activity in patients with epilepsy

  • Intrathecal Baclofen (Lioresal) use:

    • Management of severe spasticity/pain when nonresponsive to medication by other routes of administration.

      •  Few peripheral symptoms; higher concentrations may be used

      •  Partial tolerance may develop

      •  Major disadvantage: maintaining the integrity of the delivery catheter.

      •  Advantage: significant improvement of quality of life in some patients

• Tizanidine (Zanaflex)

  • Overview

    • Tizanidine (Zanaflex) is related to clonidine (Catapres)

    • Enhances both pre-and postsynaptic inhibition in the spinal cord

      • Also inhibits nociceptive transmission (dorsal horn)

  • Clinical Use

    • Probably a significant benefit for patients with spasticity (several types)

    • Comparable efficacy compared to: diazepam (Valium), baclofen (Lioresal), and dantrolene (Dantrium)

    • Dosage must be carefully titrated for each patient

  • Adverse Effects:

    • Drowsiness, dry mouth, asthenia, hypotension

• Dantrolene (Dantrium)

  • Overview

    •  Unique mechanism:  acts outside the CNS

    •  Interferes with muscle fiber excitation-contraction coupling

  •  Mechanism of action

    • Blockade of sarcoplasmic reticulum calcium channel (ryanodine channel)

    • Reduced calcium concentration diminishes actin-myosin interaction

    • Motor units contracting more rapidly are more sensitive to dantrolene (Dantrium)

      • Cardiac muscle and smooth muscle are only slightly affected (different calcium release mechanism)

  • Pharmacokinetics

    • Bioavailability: about 33% of oral dose absorbed

  •  Adverse Effects:

    • Muscle weakness

    • Sedation

    • Hepatitis (occasional)

   

  • Malignant hyperthermia, is associated with hereditary abnormality in sarcoplasmic reticulum calcium sequestration affecting probably, in some cases affecting the ryanodine receptor (calcium channel in the SR) is triggered by:

    •  General anesthesia

    •  Neuromuscular blocking drugs

       

      • "Malignant Hyperthermia"

        Attribution:  Litman RS Malignant Hyperthermia (5/19) https://www.youtube.com/watch?v=ZMX6040YSS4 Case Western Reserve University YouTube Channel:  https://www.youtube.com/channel/UCQ7jir4mIfQx3_DJsmVbwqA

    • Malignant Hyperthermia Clinical Presentations:

      • Significant muscle contractions

      • Sudden and prolonged calcium release

      • Increased lactic acid production

      • Increased body temperature

    • Dantrolene (Dantrium) reduces calcium release

      •  Other interventions are required to reduce body temperature and manage acidosis.

       

• Calcium Channel Structure

  "The open and closed states of the Ca2+-release channel are shown side by side in three different views: top, side and bottom. Important details are marked: the clamp-shaped domain (C), the handle (H) which connects the clamp shaped domain to the central part of the cytoplasmic side (CY) of the tetramer. The putative transmembrane (TM) part of the assembly resembles the stem of the mushroom-shaped protein. In the open-state reconstruction the transmembrane region of the channel appears open towards the SR, whereas in the closed state a central opening is not seen in this region. As is clearly visible in these images, the clamp-shaped domains (C) are open in the open-state reconstruction whereas the fingers of the clamps touch in the closed state reconstruction."  From Orlova, E. et al. Nature Structural Biology v3(6) 547-52. 1996.