Motor disorders and spastfcity When you consider the complexity of the notor systen there is little wonder at. the potential for dysfunction.A command for nowement may be corrupted anywhere in its path frou the notor cortex to the skelelal uuscle that brings it aboul.Specific clinical defects of moverent such as parkinsonism and epilepsy are dealt with elsewbere.but there are a variety of conditions that involve an increase in nuscle tone that is disubling and painful.This hypertomia,usually accoupunied by an increased resistance to stretching.is called spasticity and may result from birth injury,traura to the spinal cord,cerebrovascular disease or the local irritation of'arthritis.This spasticily can be treated with drues tbat uct at different points in the motor cbain. Benxodiaxepine tranquillixers are minly used to reduoe anxiety and produce sedation.They do,however.have a sigmificant muscle relaxant effect and in hich ecough doses are anticonvulsants.Their relaxant effect is particularly useful in pticnts whose anxiety produces nainful musele tension.The action is nt spinal and supraspinal lovels where they depress polysynaptic transnission in an interesting if sonewhat complex way.Benzadiaxepines bind (and can therefore he supposed to act) nost strongly at the cerebral sartex,less in the hrainsten and spinal card and hardly at all in other tissue.The specific binding site is one of the farily of GABA reeeptors that produce the increase in chloride perneahility which is the hasis of GABA's inhibitory effect as a nsturally cccurring neurotransuitler.Benzodiazepines do not bind at the sane site as GABA but on the sane receptor,where they in sone vay Increase its affinity for CABA and consequently the cpening of chloride chanels in nerve perbranes. Benzodiazepines are usually given by nouth but can be given intravenously when rapid action is required as when controlling an epileptic fit. The inhibitory effects of the neurotransnitter GABA inbue it with potentially potent therapeatic effects.Much work has therefore gone into modifying its nolecule to assist its penetration of the blood-brain harrier.Cne of the nany suhstances
Motor disorders and spasticity When you consider the complexity of the motor system there is little wonder at the potential for dysfunction. A command for movement may be corrupted anywhere in its path from the motor cortex to the skeletal muscle that brings it about. Specific clinical defects of movement such as parkinsonism and epilepsy are dealt with elsewhere, but there are a variety of conditions that involve an increase in muscle tone that is disabling and painful. This hypertonia, usually accompanied by an increased resistance to stretching, is called spasticity and may result from birth injury, trauma to the spinal cord, cerebrovascular disease or the local irritation of arthritis. This spasticity can be treated with drugs that act at different points in the motor chain. Benzodiazepine tranquillizers are mainly used to reduce anxiety and produce sedation. They do, however, have a significant muscle relaxant effect and in high enough doses are anticonvulsants. Their relaxant effect is particularly useful in patients whose anxiety produces painful muscle tension. The action is at spinal and supraspinal levels where they depress polysynaptic transmission in an interesting if somewhat complex way. Benzodiazepines bind (and can therefore be supposed to act) most strongly at the cerebral cortex, less in the brainstem and spinal cord and hardly at all in other tissue. The specific binding site is one of the family of GABA receptors that produce the increase in chloride permeability which is the basis of GABA's inhibitory effect as a naturally occurring neurotransmitter. Benzodiazepines do not bind at the same site as GABA but on the same receptor, where they in some way increase its affinity for GABA and consequently the opening of chloride channels in nerve membranes. Benzodiazepines are usually given by mouth but can be given intravenously when rapid action is required as when controlling an epileptic fit. The inhibitory effects of the neurotransmitter GABA imbue it with potentially potent therapeutic effects. Much work has therefore gone into modifying its molecule to assist its penetration of the blood-brain barrier. One of the many substances
produced during this work is baclofen which acts on a different subset of GABA receptors than do the benzudiaxepines.Baclofen appears to act by reducing excessive Y-rotoneurone activity and because of this action Is used to treat the spasticity ol wltiple sclerosis.Its inabilily to relieve spusticity of cerebral oricin denonstrates that its site of actioa is the spinal cord. The ratiocale of stimulating inhibitory pathways to reduce excessive nuscle tone as in the case of benzodiazepines and Gn)is also utilixed in treatnent with the drug tizanidine.This is an c:agonist which inhibits supraspinal and spinal polysynaptic reflexes.It has the great advantage of reducing excessive tone vithout reducing the pticnt's muscular strength. The drugs carisoprodol and nethocarbarol are of the sane cheaical fanily and cause selective inhibition of polysynaptic excitation of motoneurones.Thus the polysyaptic flexor reflex is inhihited while the tendon icrk reflex is unaffected. It has been suggested that this distinction hetveen poly-and monosynaptic pathways is the result of the drug altering the refractory period of neuroces.The nonasynaptic pathway would carry a single synchronous burst of activity which would be less affected than the trains of action potentials in the polysynaptic pathay. An alternative.cntirely peripheral.tethod of roducing msele tone is demonstrated by the drug dantrolene which acts directly on the sarcoplasnic reticulun ta inpair the Ca"release that is essential for the initiation of contraction.Doantrolcne is nch less cffective in prevent.ing contraction of cardiac and snooth nuscle because these utilize external Ca"for their contraction rather than that stored in their sarcoplasmic reticulun Ohe of the tost dramatic pharscolopical muscle relaxants must be the toxin of the nicroorganisn Cfostridiuo botu/inue.This is ooe of the nost toxic substances kmxoan.The organisn lives in soil and its spores can contaninate food and survive heating to 100"C.Unlike the toxins of rost hacteria,C boru/inuo toxin is active by mouth.It has two very unpleasant actions: .acclutination of red blood cells
produced during this work is baclofen which acts on a different subset of GABA receptors than do the benzodiazepines. Baclofen appears to act by reducing excessive γ-motoneurone activity and because of this action is used to treat the spasticity of multiple sclerosis. Its inability to relieve spasticity of cerebral origin demonstrates that its site of action is the spinal cord. The rationale of stimulating inhibitory pathways to reduce excessive muscle tone (as in the case of benzodiazepines and GABA) is also utilized in treatment with the drug tizanidine. This is an α2 agonist which inhibits supraspinal and spinal polysynaptic reflexes. It has the great advantage of reducing excessive tone without reducing the patient's muscular strength. The drugs carisoprodol and methocarbamol are of the same chemical family and cause selective inhibition of polysynaptic excitation of motoneurones. Thus the polysynaptic flexor reflex is inhibited while the tendon jerk reflex is unaffected. It has been suggested that this distinction between poly- and monosynaptic pathways is the result of the drug altering the refractory period of neurones. The monosynaptic pathway would carry a single synchronous burst of activity which would be less affected than the trains of action potentials in the polysynaptic pathway. An alternative, entirely peripheral, method of reducing muscle tone is demonstrated by the drug dantrolene which acts directly on the sarcoplasmic reticulum to impair the Ca2+ release that is essential for the initiation of contraction. Dantrolene is much less effective in preventing contraction of cardiac and smooth muscle because these utilize external Ca2+ for their contraction rather than that stored in their sarcoplasmic reticulum. One of the most dramatic pharmacological muscle relaxants must be the toxin of the microorganism Clostridium botulinum. This is one of the most toxic substances known. The organism lives in soil and its spores can contaminate food and survive heating to 100°C. Unlike the toxins of most bacteria, C. botulinum toxin is active by mouth. It has two very unpleasant actions: • agglutination of red blood cells
preventicn of transmission at poripheral cholinergic junctions,a property which is used as a mascle relaxant. Poisoning by C boto/ioueis called dorol/ss and the overall mortality is of the order of 70k.Death results from paralysis of the respiratory muscles with consequent suffocation.The action of the toxin is to bind to presynaptic nerve mesbranes where it inactivates actin,a protein involved in the exocytosis of acetylcholine transaitter.The binding is so powerful that antitoxin administration is no use once the symptons appear and the effects persist for weeks,until the affected regions of pembrane are replaced i norral process of nerbrane turnover. This powerful binding means that the toxin does not spread and enables it to be used therapeutically by close local injection to treat blepharospasn (a persistent and disabling eyelid spasm),hemifacial spasn and equinus due to spasticity in cerehral palsy.The persistent action of botulinon toxin is useful in these comditions but as one would imagine its use is highly specialized. A few other suhstances such as 8-bungnrotoxin inhibit release of acetylcholine at the neuromscular junetion but this constituent of'cobra venoa understandably has little clinical application.The naority of neurouscular blockers of clinical importance exert their effect at the next step in the chain fron brain to muscle the postsynaptic muscle neabrane.These clinically useful drugs exert their action by blocking muscle receptors to acetylcholine or persistently depolarizing them Their major use is not in the treatment of spasticity but in surgery because their actions are usefully brief.They are described in Chapter 3.3 in the context of the neuromuscular junction,which is where they act
• prevention of transmission at peripheral cholinergic junctions, a property which is used as a muscle relaxant. Poisoning by C. botulinumis called botulism and the overall mortality is of the order of 70%. Death results from paralysis of the respiratory muscles with consequent suffocation. The action of the toxin is to bind to presynaptic nerve membranes where it inactivates actin, a protein involved in the exocytosis of acetylcholine transmitter. The binding is so powerful that antitoxin administration is no use once the symptoms appear and the effects persist for weeks, until the affected regions of membrane are replaced in the normal process of membrane turnover. This powerful binding means that the toxin does not spread and enables it to be used therapeutically by close local injection to treat blepharospasm (a persistent and disabling eyelid spasm), hemifacial spasm and equinus due to spasticity in cerebral palsy. The persistent action of botulinum toxin is useful in these conditions but as one would imagine its use is highly specialized. A few other substances such as β-bungarotoxin inhibit release of acetylcholine at the neuromuscular junction but this constituent of cobra venom understandably has little clinical application. The majority of neuromuscular blockers of clinical importance exert their effect at the next step in the chain from brain to muscle - the postsynaptic muscle membrane. These clinically useful drugs exert their action by blocking muscle receptors to acetylcholine or persistently depolarizing them. Their major use is not in the treatment of spasticity but in surgery because their actions are usefully brief. They are described in Chapter 3.3 in the context of the neuromuscular junction, which is where they act