Color Atlas of Pharmacology (Part 17): Drugs Acting on Motor Systems

Chia sẻ: Big Big | Ngày: | Loại File: PDF | Số trang:12

lượt xem

Color Atlas of Pharmacology (Part 17): Drugs Acting on Motor Systems

Mô tả tài liệu
  Download Vui lòng tải xuống để xem tài liệu đầy đủ

Drugs Acting on Motor Systems spinal disorders. Benzodiazepines enhance the effectiveness of the inhibitory transmitter GABA (p. 226) at GABAA receptors. Baclofen stimulates GABAB receptors. !2-Adrenoceptor agonists such as clonidine and tizanidine probably act presynaptically to inhibit release of excitatory amino acid transmitters. The convulsant toxins, tetanus toxin (cause of wound tetanus) and strychnine diminish the efficacy of interneuronal synaptic inhibition mediated by the amino acid glycine (A). As a consequence of an unrestrained spread of nerve impulses in the spinal cord, motor convulsions develop. The involvement of respiratory muscle groups endangers life. Botulinum toxin from Clostridium botulinum is the...

Chủ đề:

Nội dung Text: Color Atlas of Pharmacology (Part 17): Drugs Acting on Motor Systems

  1. 182 Drugs Acting on Motor Systems Drugs Affecting Motor Function spinal disorders. Benzodiazepines en- hance the effectiveness of the inhibitory The smallest structural unit of skeletal transmitter GABA (p. 226) at GABAA re- musculature is the striated muscle fiber. ceptors. Baclofen stimulates GABAB re- It contracts in response to an impulse of ceptors. !2-Adrenoceptor agonists such its motor nerve. In executing motor pro- as clonidine and tizanidine probably act grams, the brain sends impulses to the presynaptically to inhibit release of ex- spinal cord. These converge on !-moto- citatory amino acid transmitters. neurons in the anterior horn of the spi- The convulsant toxins, tetanus tox- nal medulla. Efferent axons course, bun- in (cause of wound tetanus) and strych- dled in motor nerves, to skeletal mus- nine diminish the efficacy of interneu- cles. Simple reflex contractions to sen- ronal synaptic inhibition mediated by sory stimuli, conveyed via the dorsal the amino acid glycine (A). As a conse- roots to the motoneurons, occur with- quence of an unrestrained spread of out participation of the brain. Neural nerve impulses in the spinal cord, motor circuits that propagate afferent impuls- convulsions develop. The involvement es into the spinal cord contain inhibit- of respiratory muscle groups endangers ory interneurons. These serve to pre- life. vent a possible overexcitation of moto- Botulinum toxin from Clostridium neurons (or excessive muscle contrac- botulinum is the most potent poison tions) due to the constant barrage of known. The lethal dose in an adult is ap- sensory stimuli. prox. 3 10–6 mg. The toxin blocks exo- Neuromuscular transmission (B) of cytosis of ACh in motor (and also para- motor nerve impulses to the striated sympathetic) nerve endings. Death is muscle fiber takes place at the motor caused by paralysis of respiratory mus- endplate. The nerve impulse liberates cles. Injected intramuscularly at minus- acetylcholine (ACh) from the axon ter- cule dosage, botulinum toxin type A is minal. ACh binds to nicotinic cholinocep- used to treat blepharospasm, strabis- tors at the motor endplate. Activation of mus, achalasia of the lower esophageal these receptors causes depolarization of sphincter, and spastic aphonia. the endplate, from which a propagated A pathological rise in serum Mg2+ action potential (AP) is elicited in the levels also causes inhibition of ACh re- surrounding sarcolemma. The AP trig- lease, hence inhibition of neuromuscu- gers a release of Ca2+ from its storage or- lar transmission. ganelles, the sarcoplasmic reticulum Dantrolene interferes with electro- (SR), within the muscle fiber; the rise in mechanical coupling in the muscle cell Ca2+ concentration induces a contrac- by inhibiting Ca2+ release from the SR. It tion of the myofilaments (electrome- is used to treat painful muscle spasms chanical coupling). Meanwhile, ACh is attending spinal diseases and skeletal hydrolyzed by acetylcholinesterase muscle disorders involving excessive (p. 100); excitation of the endplate sub- release of Ca2+ (malignant hyperther- sides. If no AP follows, Ca2+ is taken up mia). again by the SR and the myofilaments relax. Clinically important drugs (with the exception of dantrolene) all inter- fere with neural control of the muscle cell (A, B, p. 183 ff.) Centrally acting muscle relaxants (A) lower muscle tone by augmenting the activity of intraspinal inhibitory interneurons. They are used in the treat- ment of painful muscle spasms, e.g., in Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  2. Drugs Acting on Motor Systems 183 Antiepileptics Antiparkinsonian drugs Myotonolytics Dantrolene Muscle relaxants Myotonolytics Convulsants Increased Attenuated inhibition inhibition Inhibitory Inhibitory neuron interneuron Benzodiazepines Tetanus e.g., diazepam GABA Glycine Toxin Strychnine Inhibition Receptor of release Agonist Baclofen antagonist (GABA = "-aminobutyric acid) A. Mechanisms for influencing skeletal muscle tone Motor Mg2+ Muscle relaxants neuron Botulinum toxin inhibit generation inhibit of action ACh-release potential Sarcoplasmic reticulum Action potential t-Tubule ACh Depola- Dantrolene rization inhibits Ca2+ release Membrane potential Motor endplate Myofilaments Muscle tone Ca2+ ACh receptor (nicotinic) Contraction ms 10 20 B. Inhibition of neuromuscular transmission and electromechanical coupling Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  3. 184 Drugs Acting on Motor Systems Muscle Relaxants pressing anything. For this reason, care must be taken to eliminate conscious- Muscle relaxants cause a flaccid paraly- ness by administration of an appropri- sis of skeletal musculature by binding to ate drug (general anesthesia) before us- motor endplate cholinoceptors, thus ing a muscle relaxant. The effect of a sin- blocking neuromuscular transmission (p. gle dose lasts about 30 min. 182). According to whether receptor oc- The duration of the effect of d-tubo- cupancy leads to a blockade or an exci- curarine can be shortened by adminis- tation of the endplate, one distinguishes tering an acetylcholinesterase inhibitor, nondepolarizing from depolarizing such as neostigmine (p. 102). Inhibition muscle relaxants (p. 186). As adjuncts to of ACh breakdown causes the concen- general anesthetics, muscle relaxants tration of ACh released at the endplate help to ensure that surgical procedures to rise. Competitive “displacement” by are not disturbed by muscle contrac- ACh of d-tubocurarine from the recep- tions of the patient (p. 216). tor allows transmission to be restored. Unwanted effects produced by d-tu- Nondepolarizing muscle relaxants bocurarine result from a nonimmune- mediated release of histamine from Curare is the term for plant-derived ar- mast cells, leading to bronchospasm, ur- row poisons of South American natives. ticaria, and hypotension. More com- When struck by a curare-tipped arrow, monly, a fall in blood pressure can be at- an animal suffers paralysis of skeletal tributed to ganglionic blockade by d-tu- musculature within a short time after bocurarine. the poison spreads through the body; Pancuronium is a synthetic com- death follows because respiratory mus- pound now frequently used and not cles fail (respiratory paralysis). Killed likely to cause histamine release or gan- game can be eaten without risk because glionic blockade. It is approx. 5-fold absorption of the poison from the gas- more potent than d-tubocurarine, with trointestinal tract is virtually nil. The cu- a somewhat longer duration of action. rare ingredient of greatest medicinal Increased heart rate and blood pressure importance is d-tubocurarine. This are attributed to blockade of cardiac M2- compound contains a quaternary nitro- cholinoceptors, an effect not shared by gen atom (N) and, at the opposite end of newer pancuronium congeners such as the molecule, a tertiary N that is proto- vecuronium and pipecuronium. nated at physiological pH. These two Other nondepolarizing muscle re- positively charged N atoms are common laxants include: alcuronium, derived to all other muscle relaxants. The fixed from the alkaloid toxiferin; rocuroni- positive charge of the quaternary N ac- um, gallamine, mivacurium, and atra- counts for the poor enteral absorbabil- curium. The latter undergoes spontane- ity. ous cleavage and does not depend on d-Tubocurarine is given by i.v. in- hepatic or renal elimination. jection (average dose approx. 10 mg). It binds to the endplate nicotinic cholino- ceptors without exciting them, acting as a competitive antagonist towards ACh. By preventing the binding of released ACh, it blocks neuromuscular transmis- sion. Muscular paralysis develops with- in about 4 min. d-Tubocurarine does not penetrate into the CNS. The patient would thus experience motor paralysis and inability to breathe, while remain- ing fully conscious but incapable of ex- Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  4. Drugs Acting on Motor Systems 185 Arrow poison of indigenous South Americans d-Tubocurarine Pancuronium (no enteral absorption) ACh Blockade of ACh receptors No depolarization of endplate Artificial Antidote: Relaxation of skeletal muscles ventilation cholinesterase necessary inhibitors (Respiratory paralysis) (plus general e.g., neostigmine anesthesia!) A. Non-depolarizing muscle relaxants Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  5. 186 Drugs Acting on Motor Systems Depolarizing Muscle Relaxants AP through the entire cell. If the AP fails, the muscle fiber remains in a relaxed In this drug class, only succinylcholine state. (succinyldicholine, suxamethonium, A) The effect of a standard dose of suc- is of clinical importance. Structurally, it cinylcholine lasts only about 10 min. It can be described as a double ACh mole- is often given at the start of anesthesia cule. Like ACh, succinylcholine acts as to facilitate intubation of the patient. As agonist at endplate nicotinic cholino- expected, cholinesterase inhibitors are ceptors, yet it produces muscle relaxa- unable to counteract the effect of succi- tion. Unlike ACh, it is not hydrolyzed by nylcholine. In the few patients with a acetylcholinesterase. However, it is a genetic deficiency in pseudocholineste- substrate of nonspecific plasma cholin- rase (= nonspecific cholinesterase), the esterase (serum cholinesterase, p. 100). succinylcholine effect is significantly Succinylcholine is degraded more slow- prolonged. ly than is ACh and therefore remains in Since persistent depolarization of the synaptic cleft for several minutes, endplates is associated with an efflux of causing an endplate depolarization of K + ions, hyperkalemia can result (risk of corresponding duration. This depola- cardiac arrhythmias). rization initially triggers a propagated Only in a few muscle types (e.g., action potential (AP) in the surrounding extraocular muscle) are muscle fibers muscle cell membrane, leading to con- supplied with multiple endplates. Here traction of the muscle fiber. After its i.v. succinylcholine causes depolarization injection, fine muscle twitches (fascicu- distributed over the entire fiber, which lations) can be observed. A new AP can responds with a contracture. Intraocular be elicited near the endplate only if the pressure rises, which must be taken into membrane has been allowed to repo- account during eye surgery. larize. In skeletal muscle fibers whose mo- The AP is due to opening of voltage- tor nerve has been severed, ACh recep- gated Na-channel proteins, allowing tors spread in a few days over the entire Na+ ions to flow through the sarcolem- cell membrane. In this case, succinyl- ma and to cause depolarization. After a choline would evoke a persistent depo- few milliseconds, the Na channels close larization with contracture and hyper- automatically (“inactivation”), the kalemia. These effects are likely to occur membrane potential returns to resting in polytraumatized patients undergoing levels, and the AP is terminated. As long follow-up surgery. as the membrane potential remains in- completely repolarized, renewed open- ing of Na channels, hence a new AP, is impossible. In the case of released ACh, rapid breakdown by ACh esterase al- lows repolarization of the endplate and hence a return of Na channel excitabil- ity in the adjacent sarcolemma. With succinylcholine, however, there is a per- sistent depolarization of the endplate and adjoining membrane regions. Be- cause the Na channels remain inactivat- ed, an AP cannot be triggered in the ad- jacent membrane. Because most skeletal muscle fibers are innervated only by a single endplate, activation of such fibers, with lengths up to 30 cm, entails propagation of the Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  6. Drugs Acting on Motor Systems 187 Acetylcholine Succinylcholine Depolarization Depolarization ACh Propagation of Succinylcholine action potential (AP) Skeletal Contraction muscle Contraction cell 1 Rapid ACh cleavage by Succinylcholine not degraded acetylcholine esterases by acetylcholine esterases 2 Repolarization of end plate Persistent depolarization of end plate ACh New AP and contraction New AP and contraction can be elicited cannot be elicited 3 Membrane potential Na+-channel Membrane potential Membrane potential Open Closed (opening not possible) Persistent depolarization Repolarization No repolarization, renewed opening of Closed Na+-channel (opening possible) impossible A. Action of the depolarizing muscle relaxant succinylcholine Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  7. 188 Drugs Acting on Motor Systems Antiparkinsonian Drugs Inhibitors of monoamine oxi- dase-B (MAOB). This isoenzyme breaks Parkinson’s disease (shaking palsy) and down dopamine in the corpus striatum its syndromal forms are caused by a de- and can be selectively inhibited by se- generation of nigrostriatal dopamine legiline. Inactivation of norepinephrine, neurons. The resulting striatal dopa- epinephrine, and 5-HT via MAOA is un- mine deficiency leads to overactivity of affected. The antiparkinsonian effects of cholinergic interneurons and imbalance selegiline may result from decreased of striopallidal output pathways, mani- dopamine inactivation (enhanced levo- fested by poverty of movement (akine- dopa response) or from neuroprotective sia), muscle stiffness (rigidity), tremor mechanisms (decreased oxyradical for- at rest, postural instability, and gait dis- mation or blocked bioactivation of an turbance. unknown neurotoxin). Pharmacotherapeutic measures are Inhibitors of catechol-O-methyl- aimed at restoring dopaminergic func- transferase (COMT). L-Dopa and dopa- tion or suppressing cholinergic hyper- mine become inactivated by methyla- activity. tion. The responsible enzyme can be L-Dopa. Dopamine itself cannot blocked by entacapone, allowing higher penetrate the blood-brain barrier; how- levels of L-dopa and dopamine to be ever, its natural precursor, L-dihydroxy- achieved in corpus striatum. phenylalanine (levodopa), is effective in Anticholinergics. Antagonists at replenishing striatal dopamine levels, muscarinic cholinoceptors, such as because it is transported across the benzatropine and biperiden (p. 106), blood-brain barrier via an amino acid suppress striatal cholinergic overactiv- carrier and is subsequently decarboxy- ity and thereby relieve rigidity and lated by DOPA-decarboxylase, present tremor; however, akinesia is not re- in striatal tissue. Decarboxylation also versed or is even exacerbated. Atropine- takes place in peripheral organs where like peripheral side effects and impair- dopamine is not needed, likely causing ment of cognitive function limit the tol- undesirable effects (tachycardia, ar- erable dosage. rhythmias resulting from activation of Amantadine. Early or mild parkin- !1-adrenoceptors [p. 114], hypotension, sonian manifestations may be tempo- and vomiting). Extracerebral produc- rarily relieved by amantadine. The tion of dopamine can be prevented by underlying mechanism of action may inhibitors of DOPA-decarboxylase (car- involve, inter alia, blockade of ligand- bidopa, benserazide) that do not pene- gated ion channels of the glutamate/ trate the blood-brain barrier, leaving NMDA subtype, ultimately leading to a intracerebral decarboxylation unaffect- diminished release of acetylcholine. ed. Excessive elevation of brain dopa- Administration of levodopa plus mine levels may lead to undesirable re- carbidopa (or benserazide) remains the actions, such as involuntary movements most effective treatment, but does not (dyskinesias) and mental disturbances. provide benefit beyond 3–5 y and is fol- Dopamine receptor agonists. Defi- lowed by gradual loss of symptom con- cient dopaminergic transmission in the trol, on-off fluctuations, and develop- striatum can be compensated by ergot ment of orobuccofacial and limb dyski- derivatives (bromocriptine [p. 114], lisu- nesias. These long-term drawbacks of ride, cabergoline, and pergolide) and levodopa therapy may be delayed by nonergot compounds (ropinirole, prami- early monotherapy with dopamine re- pexole). These agonists stimulate dopa- ceptor agonists. Treatment of advanced mine receptors (D2, D3, and D1 sub- disease requires the combined adminis- types), have lower clinical efficacy than tration of antiparkinsonian agents. levodopa, and share its main adverse ef- fects. Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  8. Drugs Acting on Motor Systems 189 Normal state Selegiline H H Dopamine Acetylcholine Amantadine N N CH CH3 NMDA CH3 receptor: Dopamine deficiency Blockade of ionophore: Inhibition of attenuation dopamine degradation of cholinergic by MAO-B in CNS neurons Predominance of acetylcholine Parkinson´s disease Blood-brain barrier Dopa- COMT decarboxylase 200 mg Carbidopa Dopamine Entacapone O H3 C NH2 HO C2H5 N N C2H5 2000 mg H Stimulation of CN HO COOH peripheral dop- amine receptors NO2 Inhibition of dopa- Inhibition of decarboxylase catechol- Adverse effects O-methyltransferase Dopamine substitution Bromocriptine L-Dopa H3 C Benzatropine N CH3 H 3C OH O O N H H N HO N N O H O H O N CH3 COOH H H3C CH3 HO N Dopamine-receptor Br H agonist Dopamine precursor Acetylcholine antagonist A. Antiparkinsonian drugs Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  9. 190 Drugs Acting on Motor Systems Antiepileptics second-line drug or combined use (“add on”) be recommended (B), provided Epilepsy is a chronic brain disease of di- that the possible risk of pharmacokinet- verse etiology; it is characterized by re- ic interactions is taken into account (see current paroxysmal episodes of uncon- below). The precise mode of action of trolled excitation of brain neurons. In- antiepileptic drugs remains unknown. volving larger or smaller parts of the Some agents appear to lower neuronal brain, the electrical discharge is evident excitability by several mechanisms of in the electroencephalogram (EEG) as action. In principle, responsivity can be synchronized rhythmic activity and decreased by inhibiting excitatory or ac- manifests itself in motor, sensory, psy- tivating inhibitory neurons. Most excit- chic, and vegetative (visceral) phenom- atory nerve cells utilize glutamate and ena. Because both the affected brain re- most inhibitory neurons utilize !-ami- gion and the cause of abnormal excit- nobutyric acid (GABA) as their transmit- ability may differ, epileptic seizures can ter (p. 193A). Various drugs can lower take many forms. From a pharmaco- seizure threshold, notably certain neu- therapeutic viewpoint, these may be roleptics, the tuberculostatic isoniazid, classified as: and "-lactam antibiotics in high doses; – general vs. focal seizures; they are, therefore, contraindicated in – seizures with or without loss of con- seizure disorders. sciousness; Glutamate receptors comprise – seizures with or without specific three subtypes, of which the NMDA modes of precipitation. subtype has the greatest therapeutic The brief duration of a single epi- importance. (N-methyl-D-aspartate is a leptic fit makes acute drug treatment synthetic selective agonist.) This recep- unfeasible. Instead, antiepileptics are tor is a ligand-gated ion channel that, used to prevent seizures and therefore upon stimulation with glutamate, per- need to be given chronically. Only in the mits entry of both Na+ and Ca2+ ions into case of status epilepticus (a succession of the cell. The antiepileptics lamotrigine, several tonic-clonic seizures) is acute phenytoin, and phenobarbital inhibit, anticonvulsant therapy indicated — among other things, the release of glu- usually with benzodiazepines given i.v. tamate. Felbamate is a glutamate antag- or, if needed, rectally. onist. The initiation of an epileptic attack Benzodiazepines and phenobarbital involves “pacemaker” cells; these differ augment activation of the GABAA recep- from other nerve cells in their unstable tor by physiologically released amounts resting membrane potential, i.e., a de- of GABA (B) (see p. 226). Chloride influx polarizing membrane current persists is increased, counteracting depolariza- after the action potential terminates. tion. Progabide is a direct GABA-mimet- Therapeutic interventions aim to ic. Tiagabin blocks removal of GABA stabilize neuronal resting potential and, from the synaptic cleft by decreasing its hence, to lower excitability. In specific re-uptake. Vigabatrin inhibits GABA ca- forms of epilepsy, initially a single drug tabolism. Gabapentin may augment the is tried to achieve control of seizures, availability of glutamate as a precursor valproate usually being the drug of first in GABA synthesis (B) and can also act as choice in generalized seizures, and car- a K+-channel opener. bamazepine being preferred for partial (focal), especially partial complex, sei- zures. Dosage is increased until seizures are no longer present or adverse effects become unacceptable. Only when monotherapy with different agents proves inadequate can changeover to a Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  10. Drugs Acting on Motor Systems 191 Drugs used in the treatment of status epilepticus: Benzodiazepines, e.g., diazepam Waking state EEG Epileptic attack µV µV 150 150 100 100 50 50 0 0 1 sec 1 sec Drugs used in the prophylaxis of epileptic seizures H Cl H O N C2H5 H3C O Cl N O O N N H5C2 N N N H N H O O C O H O NH2 H2N N NH2 Carbamazepine Phenytoin Phenobarbital Ethosuximide Lamotrigine CH3 H3C O H3C COOH O O H2N COOH H3C CH2OCNH2 H2C CH O CH2OCNH2 O H2N COOH O O H 3C OSO2NH2 CH3 Valproic acid Vigabatrin Gabapentin Felbamate Topiramate A. Epileptic attack, EEG, and antiepileptics Focal I. II. III. Choice seizures Simple seizures Carbam- Valproic acid, Primidone, azepine Phenytoin, Phenobar- Clobazam bital Complex + Lamotrigine or Vigabatrin or Gabapentin or secondarily generalized Generalized Tonic-clonic Valproic acid Carbam- Lamotrigine, attacks attack (grand mal) azepine, Primidone, Phenytoin Phenobarbital Tonic attack Clonic attack + Lamotrigine or Vigabatrin or Gabapentin Myoclonic attack alternative Absence Ethosuximide addition seizure + Lamotrigine or Clonazepam B. Indications for antiepileptics Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  11. 192 Drugs Acting on Motor Systems Carbamazepine, valproate, and prevent neural tube developmental de- phenytoin enhance inactivation of volt- fects. age-gated sodium and calcium channels Carbamazepine, phenytoin, pheno- and limit the spread of electrical excita- barbital, and other anticonvulsants (ex- tion by inhibiting sustained high-fre- cept for gabapentin) induce hepatic en- quency firing of neurons. zymes responsible for drug biotransfor- Ethosuximide blocks a neuronal T- mation. Combinations between anticon- type Ca2+ channel (A) and represents a vulsants or with other drugs may result special class because it is effective only in clinically important interactions in absence seizures. (plasma level monitoring!). All antiepileptics are likely, albeit to For the often intractable childhood different degrees, to produce adverse epilepsies, various other agents are effects. Sedation, difficulty in concentrat- used, including ACTH and the glucocor- ing, and slowing of psychomotor drive ticoid, dexamethasone. Multiple encumber practically all antiepileptic (mixed) seizures associated with the therapy. Moreover, cutaneous, hemato- slow spike-wave (Lennox–Gastaut) syn- logical, and hepatic changes may neces- drome may respond to valproate, la- sitate a change in medication. Pheno- motrigine, and felbamate, the latter be- barbital, primidone, and phenytoin may ing restricted to drug-resistant seizures lead to osteomalacia (vitamin D prophy- owing to its potentially fatal liver and laxis) or megaloblastic anemia (folate bone marrow toxicity. prophylaxis). During treatment with Benzodiazepines are the drugs of phenytoin, gingival hyperplasia may de- choice for status epilepticus (see velop in ca. 20% of patients. above); however, development of toler- Valproic acid (VPA) is gaining in- ance renders them less suitable for creasing acceptance as a first-line drug; long-term therapy. Clonazepam is used it is less sedating than other anticonvul- for myoclonic and atonic seizures. sants. Tremor, gastrointestinal upset, Clobazam, a 1,5-benzodiazepine exhib- and weight gain are frequently ob- iting an increased anticonvulsant/seda- served; reversible hair loss is a rarer oc- tive activity ratio, has a similar range of currence. Hepatotoxicity may be due to clinical uses. Personality changes and a toxic catabolite (4-en VPA). paradoxical excitement are potential Adverse reactions to carbamaze- side effects. pine include: nystagmus, ataxia, diplo- Clomethiazole can also be effective pia, particularly if the dosage is raised for controlling status epilepticus, but is too fast. Gastrointestinal problems and used mainly to treat agitated states, es- skin rashes are frequent. It exerts an pecially alcoholic delirium tremens and antidiuretic effect (sensitization of col- associated seizures. lecting ducts to vasopressin water in- Topiramate, derived from D-fruc- toxication). tose, has complex, long-lasting anticon- Carbamazepine is also used to treat vulsant actions that cooperate to limit trigeminal neuralgia and neuropathic the spread of seizure activity; it is effec- pain. tive in partial seizures and as an add-on Valproate, carbamazepine, and oth- in Lennox–Gastaut syndrome. er anticonvulsants pose teratogenic risks. Despite this, treatment should continue during pregnancy, as the po- tential threat to the fetus by a seizure is greater. However, it is mandatory to ad- minister the lowest dose affording safe and effective prophylaxis. Concurrent high-dose administration of folate may Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  12. Drugs Acting on Motor Systems 193 Na+ Ca++ Excitatory neuron NMDA- receptor Inhibition of glutamate Glutamate release: NMDA-receptor- antagonist phenytoin, felbamate, lamotrigine valproic acid phenobarbital Ca2+-channel T-Type- calcium channel blocker Voltage ethosuximide, dependent (valproic acid) Na+-channel Enhanced inactivation: GABAA- carbamazepine receptor valproic acid GABA phenytoin CI– Gabamimetics: benzodiazepine barbiturates vigabatrin Inhibitory tiagabine neuron gabapentin A. Neuronal sites of action of antiepileptics Benzodiazepine GABAA- receptor Tiagabine Allosteric " Inhibition of enhance- # # GABA ment of ! " # " # Chloride reuptake GABA ! " channel action Barbiturates Progabide GABA- GABA- GABA transaminase mimetic Vigabatrin Glutamic acid Inhibitor of decarboxylase Succinic GABA- semialdehyde transaminase Succinic acid Glutamic acid Gabapentin Improved utilization Ending of of GABA precursor: inhibitory glutamate neuron B. Sites of action of antiepileptics in GABAergic synapse Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
Đồng bộ tài khoản