Page 502 - Basic _ Clinical Pharmacology ( PDFDrive )

488 SECTION V Drugs That Act in the Central Nervous System

2+
2+
from its stores in the sarcoplasmic reticulum (see Figures 13–1 have a hereditary alteration in Ca -induced Ca release via the
and 27–10). This activator calcium brings about the tension- RyR1 channel or impairment in the ability of the sarcoplasmic
2+
generating interaction of actin with myosin. Calcium is released reticulum to sequester calcium via the Ca transporter (Figure
from the sarcoplasmic reticulum via a calcium channel, called the 27–10). Several mutations associated with this risk have been
ryanodine receptor (RyR) channel because the plant alkaloid identified. After administration of one of the triggering agents,
ryanodine combines with a receptor on the channel protein. In there is a sudden and prolonged release of calcium, with massive
the case of the skeletal muscle RyR1 channel, ryanodine facilitates muscle contraction, lactic acid production, and increased body
the open configuration. temperature. Prompt treatment is essential to control acidosis
and body temperature and to reduce calcium release. The latter
O is accomplished by administering intravenous dantrolene, starting
with a dose of 1 mg/kg IV, and repeating as necessary to a maxi-
HN N N CH NO 2
mum dose of 10 mg/kg.
O
O Dantrolene
ANTISPASMODICS: DRUGS USED TO
Dantrolene interferes with the release of activator calcium TREAT ACUTE LOCAL MUSCLE SPASM
through this sarcoplasmic reticulum calcium channel by binding
to the RyR1 and blocking the opening of the channel. Motor units A large number of less well-studied, centrally active drugs
that contract rapidly are more sensitive to the drug’s effects than (eg, carisoprodol, chlorphenesin, chlorzoxazone, cycloben-
are slower-responding units. Cardiac muscle and smooth muscle zaprine, metaxalone, methocarbamol, and orphenadrine) are
are minimally depressed because the release of calcium from their promoted for the relief of acute muscle spasm caused by local
sarcoplasmic reticulum involves a different RyR channel (RyR2). tissue trauma or muscle strains. It has been suggested that these
Treatment with dantrolene is usually initiated with 25 mg drugs act primarily at the level of the brainstem. Cyclobenzap-
daily as a single dose, increasing to a maximum of 100 mg four rine may be regarded as the prototype of the group. Cycloben-
times daily as tolerated. Only about one third of an oral dose of zaprine is structurally related to the tricyclic antidepressants and
dantrolene is absorbed, and the elimination half-life of the drug produces antimuscarinic side effects. It is ineffective in treating
is approximately 8 hours. Major adverse effects are generalized muscle spasm due to cerebral palsy or spinal cord injury. As a
muscle weakness, sedation, and occasionally hepatitis. result of its strong antimuscarinic actions, cyclobenzaprine may
A special application of dantrolene is in the treatment of cause significant sedation, as well as confusion and transient
malignant hyperthermia, a rare heritable disorder that can be visual hallucinations. The dosage of cyclobenzaprine for acute
triggered by a variety of stimuli, including general anesthetics (eg, injury-related muscle spasm is 20–40 mg/d orally in divided
volatile anesthetics) and neuromuscular blocking drugs (eg, succi- doses. This drug class carries risks of significant adverse events
nylcholine; see also Chapter 16). Patients at risk for this condition and abuse potential.

SUMMARY Skeletal Muscle Relaxants

Subclass, Mechanism Pharmacokinetics,
Drug of Action Effects Clinical Applications Toxicities, Interactions
DEPOLARIZING NEUROMUSCULAR BLOCKING AGENT
• Succinylcholine Agonist at nicotinic Initial depolarization causes Placement of endotracheal tube Rapid metabolism by plasma
acetylcholine (ACh) transient contractions, followed at start of anesthetic procedure cholinesterase • normal duration
receptors, especially at by prolonged flaccid paralysis • rarely, control of muscle ~5 min • Toxicities: Arrhythmias
neuromuscular junctions • depolarization is then followed contractions in status epilepticus • hyperkalemia • transient increased
• depolarizes • may by repolarization that is also intra-abdominal, intraocular
stimulate ganglionic accompanied by paralysis pressure • postoperative muscle
nicotinic ACh and cardiac pain
muscarinic ACh receptors
(continued)