Action potential muscle relaxants

Isoflurane is a respiratory depressant (71). At concentrations which are associated with surgical levels of anesthesia, there is Htde or no depression of myocardial function. In experimental animals, isoflurane is the safest of the oral clinical agents (72). Cardiac output is maintained despite a decrease in stroke volume. This is usually because of an increase in heart rate. The decrease in blood pressure can be used to produce "deHberate hypotension" necessary for some intracranial procedures (73). This agent produces less sensitization of the human heart to epinephrine relative to the other inhaled anesthetics. Isoflurane potentiates the action of neuromuscular blockers and when used alone can produce sufficient muscle relaxation (74). Of all the inhaled agents currently in use, isoflurane is metabolized to the least extent (75). Unlike halothane, isoflurane does not appear to produce Hver injury and unlike methoxyflurane, isoflurane is not associated with renal toxicity. 

Verapamil. Verapamil hydrochloride (see Table 1) is a synthetic papaverine [58-74-2] C2qH2 N04, derivative that was originally studied as a smooth muscle relaxant. It was later found to have properties of a new class of dmgs that inhibited transmembrane calcium movements. It is a (+),(—) racemic mixture. The (+)-isomer has local anesthetic properties and may exert effects on the fast sodium channel and slow phase 0 depolarization of the action potential. The (—)-isomer affects the slow calcium channel. Verapamil is an effective antiarrhythmic agent for supraventricular AV nodal reentrant arrhythmias (V1-2) and for controlling the ventricular response to atrial fibrillation (1,2,71—73). 

When the action potentials in the alpha motor neuron cease, stimulation of muscle fiber is ended. Ca++ ions are pumped back into the sarcoplasmic reticulum and troponin and tropomyosin return to their original positions. As a result, the myosin-binding sites on the actin are covered once again. The thin filaments return passively to their original positions, resulting in muscle relaxation. 

As mentioned previously, a single action potential lasting only 2 msec causes a muscle twitch that lasts approximately 100 msec. If the muscle fiber has adequate time to completely relax before it is stimulated by another action potential, the subsequent muscle twitch will be of the same magnitude as the first. However, if the muscle fiber is restimulated before it has completely relaxed, then the tension generated during the second muscle twitch is added to that of the first (see Figure 11.3). In fact, the frequency of nerve impulses to a muscle fiber may be so rapid that there is no time for relaxation in between stimuli. In this case, the muscle fiber attains a state of smooth, sustained maximal contraction referred to as tetanus. 

Figure 11.3 Muscle twitch summation and tetanus. A single action potential (represented by A) generates a muscle twitch. Because duration of the action potential is so short, subsequent action potentials may restimulate the muscle fiber before it has completely relaxed, leading to muscle twitch summation and greater tension development. When the frequency of stimulation becomes so rapid that no relaxation occurs between stimuli, tetanus occurs. Tetanus is a smooth, sustained, maximal contraction.

Neuromuscular transmission (B) of motor nerve impulses to the striated muscle fiber takes place at the motor endplate. The nerve impulse liberates acetylcholine (ACh) from the axon terminal. ACh binds to nicotinic cholinocep-tors at the motor endplate. Activation of these receptors causes depolarization of the endplate, from which a propagated action potential (AP) is elicited in the surrounding sarcolemma. The AP triggers a release of Ca from its storage organelles, the sarcoplasmic reticulum (SR), within the muscle fiber the rise in Ca concentration induces a contraction of the myofilaments (electromechanical coupling). Meanwhile, ACh is hydrolyzed by acetylcholinesterase (p. 100) excitation of the endplate subsides. if no AP follows, Ca + is taken up again by the SR and the myofilaments relax. 

Cydobenzaprine (Flexeril) [Skeletal Muscle Relaxant/ANS A nt] Uses Relief of muscle spasm Action Centrally acting skeletal muscle relaxant reduces tonic somatic motor activity Dose 5-10 mg PO bid-qid (2-3 wk max) Caution [B, ] Shares the toxic potential of theTCAs urinary hesitancy, NAG Contra Do not use concomitantly or w/in 14 d of MAOIs hyperthyroidism heart failure arrhythmias Disp Tabs SE Sedation anticholinergic effects Interactions t Effects of CNS d ression W/ CNS dqjressants, TCAs, barbiturates, EtOH t risk of HTN convulsions W/MAOIs EMS Use caution w/ other CNS depressants concurrent EtOH use can t CNS d ession OD May cause N/V,... 

Inhalation anesthetics, such as isoflurane, enflurane, halothane, and nitrous oxide, potentiate the action of nondepolarizing blockers, either through modification of end plate responsiveness or by alteration of local blood flow. The extent of potentiation depends on the anesthetic and the depth of anesthesia. The dose of muscle relaxant should be reduced when used with these anesthetics. 

Mechanism of Action A benzodiazepine that potentiates the effects of gamma-aminobutyric acid and other inhibitory neurotransmitters by binding to specific receptors in the CNS. Therapeutic Effect Produces sedative effect and skeletal muscle relaxation. 

Release. Certain drugs will increase synaptic activity by directly increasing the release of neurotransmitter from the presynaptic terminal. Amphetamines appear to exert their effects on the CNS primarily by increasing the presynaptic release of catecholamine neurotransmitters (e.g., norepinephrine). Conversely, other compounds may inhibit the synapse by directly decreasing the amount of transmitter released during each action potential. An example is botulinum toxin (Botox), which can be used as a skeletal muscle relaxant because of its ability to impair the release of acetylcholine from the skeletal neuromuscular junction (see Chapter 13). 

The only muscle relaxant available that exerts its effect directly on the skeletal muscle cell is dantrolene sodium (Dantrium).40,102 This drug works by impairing the release of calcium from the sarcoplasmic reticulum within the muscle cell during excitation (Fig. 13 -3).56,89 In response to an action potential, the release of calcium from sarcoplasmic storage sites initiates myofilament cross-bridging and subsequent muscle contraction. By inhibiting this release, dantrolene attenuates muscle contraction and therefore enhances relaxation. 

By stimulating p-receptors, and hence cAMP production, catecholamines augment all heart functions including systolic force, velocity of myocyte shortening, sinoatrial rate, conduction velocity, and excitability. In pacemaker fibers, cAMP-gated channels ( pacemaker channels ) are activated, whereby diastolic depolarization is hastened and the firing threshold for the action potential is reached sooner (B). cAMP activates protein kinase A, which phosphorylates different Ca2+ transport proteins. In this way, contraction of heart muscle cells is accelerated, as more Ca2 enters the cell from the extracellular space via L-type Ca2 channels and release of Ca2 from the sarcoplasmic reticulum (via ryanodine receptors, RyR) is augmented. Faster relaxation of heart muscle cells is effected by phosphorylation of troponin and phospholamban. 

Normally, a single nerve Impulse in a terminal motor axon liberates enough ACh to produce a localized depolarization (the endplate potential) that initiates a propagated muscle action potential. The liberated ACh is rapidly hydrolyzed by AChE, and the muscle relaxes. Therefore, each motor-nerve Impulse initiates only one muscle contraction. After oartial inhibition of AChE. however. 

To understand the physiological nature of muscle contractions, it is helpful to examine muscles microscopically. Muscle fibers have an outside membrane called the plasmalemma, an interior structure called a sar-colemma, transverse tubules across the fibers, and an inner network of muscle tissue called sarcoplasma. When a nerve impulse reaches the muscle, an action potential is set up and the current quickly travels in both directions from the motor end plate through the entire length of the muscle fiber. The whole inside of the muscle tissue becomes involved as the current spreads and, aided by calcium, the contractile protein called actin causes the muscle component (myosin) to contract. An enzyme, ATP-ase, helps provide the energy needed for the muscular filaments to slide past each other. Relaxation occurs promptly when Ca flows into the muscle tissue and the cycle is completed. The muscle fiber is now ready to be stimulated again by a nerve impulse. 

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