Section Three Drugs thatact on the central nervous system In this section we will introduce you to studying a series of drugs having different pharmacological effects by mainly acting on the particular regions of central nervous system(CNS). All these drugs are very important because they are widely used in the inical practice. Chapter 10 Sedative-Hypnotic Drugs Anxiety and sleep disordersare easily taken place in the ordinary people,owing to many factors The mechanisms causing these symptoms have not been quite clear as vet.Sedative-hypnotic drugs are widely used to relieve the sufferings of patients with anxiety and insomnia.Some of them have strong anti-convulsive effects. 【Sleep phases】 1.Non-rapid eye movement sleep(NREM)It represents 70-75%of total sleep tim (1)Drowsy stage The time that people take to fall asleep. (2)Light sleep stage Itoccupies about 5%ofNREM (3)Deep sleep stage(slow wave sleep,SWS)In this stage somnambulism (sleep walker)and night terror may occur NREM sleep may help people to recover the physical capacity and promote growth as well as development of body 2.Rapid eye movement sleep (REM)The characteristics of REM include that people are dreaming with un-stabilization of automatic nervous system (irregular heart rate,respiration,blood pressure as well as relaxant skeletal muscle). REM sleep may help people to sustain and/or develop intelligence NREM and REM occur cyclically several times over the night.The shortage of REM sleep induced by any factors will cause anxiety and nervousness followed by rebound increase in REM sleep. Benzodiazepines[](BZs) 【Chemistry and history】 The first compound of the benzodiazepines,chlordiazepoxide,was found by accident at the laboratories of Hoffiman la Roche in 1961.Its unexpected pharmacological activity was recognized as a result of a routine screening procedure.This series of compounds quite soon became the most widely prescribed drugs in the world.The core chemical structure of these drugs isa7-membered heterocyclic ring combined with aromatic ring. 【Actions and uses】 1.Anti-anxiety BZshave a significant anti-anxiety action at the level less than sedative dose Animal experiments showed that BZs were able to release punishment-suppressed behavior,which was quite different from other sedative-hypnotics This disinhibitive efect is considered as anti- 26
26 Section Three Drugs that act on the central nervous system In this section we will introduce you to studying a series of drugs having different pharmacological effects by mainly acting on the particular regions of central nervous system (CNS). All these drugs are very important because they are widely used in the clinical practice. Chapter 10 Sedative-Hypnotic Drugs Anxiety and sleep disorders are easily taken place in the ordinary people, owing to many factors. The mechanisms causing these symptoms have not been quite clear as yet. Sedative-hypnotic drugs are widely used to relieve the sufferings of patients with anxiety and insomnia. Some of them have strong anti-convulsive effects. 【Sleep phases】 1. Non-rapid eye movement sleep (NREM) It represents 70-75% of total sleep time. (1) Drowsy stage The time that people take to fall asleep. (2) Light sleep stage It occupies about 50% of NREM. (3) Deep sleep stage (slow wave sleep, SWS) In this stage somnambulism (sleep walker) and night terror may occur. NREM sleep may help people to recover the physical capacity and promote growth as well as development of body. 2. Rapid eye movement sleep (REM) The characteristics of REM include that people are dreaming with un-stabilization of automatic nervous system (irregular heart rate, respiration, blood pressure as well as relaxant skeletal muscle). REM sleep may help people to sustain and/or develop intelligence . NREM and REM occur cyclically several times over the night. The shortage of REM sleep induced by any factors will cause anxiety and nervousness followed by rebound increase in REM sleep. Benzodiazepines[benzdaizepins] (BZs) 【Chemistry and history】 The first compound of the benzodiazepines, chlordiazepoxide, was found by accident at the laboratories of Hoffman la Roche in 1961. Its unexpected pharmacological activity was recognized as a result of a routine screening procedure. This series of compounds quite soon became the most widely prescribed drugs in the world. The core chemical structure of these drugs is a 7-membered heterocyclic ring combined with aromatic ring. 【Actions and uses】 1. Anti-anxiety BZs have a significant anti-anxiety action at the level less than sedative dose. Animal experiments showed that BZs were able to release punishment-suppressed behavior, which was quite different from other sedative-hypnotics. This disinhibitive effect is considered as anti-
anxiety action of BZs.Therefore,BZs are widely used for treatment of anxiety symptoms including ,worry,and phobia 2.Sedative and hypnotic actions In the range of much wide dosage BZs exhibit very excellent sedative-hypnotic effects without the marked respiratory,and ervous systems.They shorten sleep latency,reduce awaken times,and prolong sleep time.Therefore,BZs have already replaced barbiturateson thisaspect inthe practice 3.Muscle relaxation action BZs have a skeletal muscle relaxant effect by mainly inhibiting polysynaptic reflexesat the spinal level.They can be used to relieve skeletal muscle spasms caused by some specific neuromuscular and central disorders. 4.Anticonvulsant action BZs exert anticonvulsant effects without marked CNS depression. They inhibit the development and spread of epileptiform activity in CNS and can be used to deal with the generalized tonic status epilepticus(iv),myoclonic seizures,absence seizures,as well as other from a variety of reasons 5.Anesthetic action Some of BZs.such as diazepam.midazolam.lorazepam.can be used as intravenous anesthetics.They are usualy given 10-15min before induction of general anesthesia They also cause amnesia(temporary loss of memory),which is useful for patients being receiving Table 10-1 Pharmacokinetic characteristics of benzodiazepines Tpeak(hr) Tin of parents (hr) metabolite(hr) Alprazolam[pm] 1.5 9 Chlordiazepoxide[k:daizepou'ksaid] 3.0 40 15 30 60 Flurazepam [flur 'zep m 1 60 Lorazepamor'zep m] 3.5 10 15 Triazolam[traim] 1.0 3 35 【Mechanism of action】 BZs activate BZ receptors that exist in the particular regions of brain,enhance the binding of GABA with GABA receptors,and facilitate the process of chloride channel opening on the membrane of neurons.As a result,BZs intensify GABAergic inhibition at all levels of neuraxis. 【Properties of pharmacokinetics】 Except triazolam,nearly all the BZs have high lipid solubility.The absorption from gastrointestinal tracts after given orally is much better than intramuscular injection.Theyare metabolized in the liver and most of metabolites from them still have pharmacological activities and much onger half lives than that of the parents 【Adverse reactions】 27
27 anxiety action of BZs. Therefore, BZs are widely used for treatment of anxiety symptoms including restlessness, stress, worry, and phobia. 2. Sedative and hypnotic actions In the range of much wide dosage BZs exhibit very excellent sedative-hypnotic effects without the marked troubles from the circulatory, respiratory, and nervous systems. They shorten sleep latency, reduce awaken times, and prolong sleep time. Therefore, BZs have already replaced barbiturates on this aspect in the clinical practice. 3. Muscle relaxation action BZs have a skeletal muscle relaxant effect by mainly inhibiting polysynaptic reflexes at the spinal level. They can be used to relieve skeletal muscle spasms caused by some specific neuromuscular and central disorders. 4. Anticonvulsant action BZs exert anticonvulsant effects without marked CNS depression. They inhibit the development and spread of epileptiform activity in CNS and can be used to deal with the generalized tonic status epilepticus (iv), myoclonic seizures, absence seizures, as well as other convulsions from a variety of reasons. 5. Anesthetic action Some of BZs, such as diazepam, midazolam, lorazepam, can be used as intravenous anesthetics. They are usually given 10-15 min before induction of general anesthesia. They also cause amnesia (temporary loss of memory), which is useful for patients being receiving electric defibrillation. Table 10-1 Pharmacokinetic characteristics of benzodiazepines Tpeak(hr) T1/2 of parents (hr) T1/2 of metabolite (hr) Alprazolam[lprz’lm] Chlordiazepoxide[kl:daizepou’ksaid] Diazepam[dai’zepm] Flurazepam[flur’zepm] Lorazepam[lr’zepm] Triazolam[traiz’lm] 1.5 3.0 1.5 1.5 3.5 1.0 9 - 30 1 10 3 14 40 60 60 15 3.5 【Mechanism of action】 BZs activate BZ receptors that exist in the particular regions of brain, enhance the binding of GABA with GABA receptors, and facilitate the process of chloride channel opening on the membrane of neurons. As a result, BZs intensify GABAergic inhibition at all levels of neuraxis, including the spinal cord, hypothalamus, substantia nigra, cerebellar cortex, and cerebral cortex. 【Properties of pharmacokinetics】 Except triazolam, nearly all the BZs have high lipid solubility. The absorption from gastrointestinal tracts after given orally is much better than intramuscular injection. They are metabolized in the liver and most of metabolites from them still have pharmacological activities and much longer half lives than that of the parents. 【Adverse reactions】
All BZs are low toxicity with high therapeutic index(T).When therapeutic doses are taken during the period of short time they nearly no side reactions.However,when they are used for a long time,they may cause tolerance,dependence,and addiction. Barbiturates[bbitjureit] The sedative,hypnotic,and anesthetic properties of barbiturates were discovered arlyin the last century.Hundreds of the derivatives were synthesized and among them more than twenty compounds had been put in clinical practice until 1960s Because of their much smaller therapeutic indices(strongly respiratory and circulatory depressions)and significantly tolerance,dependence.as well as addiction,they were nearly replaced by benzodiazepines,except for a few drugs,which have specific as Phenobarbital pentobarbital,secobarbital,and thiopental. 【Actions and uses】 1.Sedative and hypnotic actions Barbiturates have distinct sedative and hypnotic effects without significantly anxiolytic action and muscle relaxation when small doses are taken.Besides, they may shorten the time of REM and induce "rebound phenomenon of sleep".They are now little usedassedative and 2.Anticonvulsant and epileptic effects Phenobarbital has an excellent anticonvulsant effect and can beused symptoms caused by different factors.It sutable for treatment of partial seizures and generalized tonic-clonic seizures. 3.Anesthetic effect Thiopental is an inravenous anesthetics.However,owing to the severe respiratory depression and unsatisfactory analgesic effect,it is used for inductive anesthesia in combnation with inhaled anesthetics. 4.Inductive effect of hepatic drug metabolic enzymes Barbiturates are typical inducers of hepatic drug metabolic enzymes In clinical practice Phenobarbital is used to deal with the hyperbilirubinemia and kernicterus of neonates 【Adverse reactions】 Barbiturates have marked respiratory,dependence,and addiction,aswel as narrow margin of safety.They have more chance to cause drug interactions Buspirone buspirn] Buspirone is a new anxiolytic drug without distinctly sedative,hypnotic,anticonvulsant,and muscle relaxant effects.It is a partial agonist of 5-HTLA receptor.Buspirone is rapidly absorbed but undergoes extensive first-pass effect after given orally.The half-life is4 hours.Buspirone is used totreat generalized anxiety disorders and has similar effect to benzodiazepines.The patients with buspirone do not show rebound anxiety or withdrawal signs on abrupt discontinuance of the drug It also causes less impairment of psychomotor than BZs,and does not affect driving skills.It was reported that buspirone might cause tachycardia palpitation,nervousness,gastrointestinal distress. and paresthesias
28 All BZs are low toxicity with high therapeutic index (TI). When therapeutic doses are taken during the period of short time they nearly no side reactions. However, when they are used for a long time, they may cause tolerance, dependence, and addiction. Barbiturates[b:bitjureit] The sedative, hypnotic, and anesthetic properties of barbiturates were discovered early in the last century. Hundreds of the derivatives were synthesized and among them more than twenty compounds had been put in clinical practice until 1960s. Because of their much smaller therapeutic indices (strongly respiratory and circulatory depressions) and significantly tolerance, dependence, as well as addiction, they were nearly replaced by benzodiazepines, except for a few drugs, which have specific properties, such as Phenobarbital, pentobarbital, secobarbital, and thiopental. 【Actions and uses】 1. Sedative and hypnotic actions Barbiturates have distinct sedative and hypnotic effects without significantly anxiolytic action and muscle relaxation when small doses are taken. Besides, they may shorten the time of REM and induce “rebound phenomenon of sleep”. They are now little used as sedative and hypnotic drugs. 2. Anticonvulsant and epileptic effects Phenobarbital has an excellent anticonvulsant effect and can be used to control convulsive symptoms caused by different factors. It is also suitable for treatment of partial seizures and generalized tonic-clonic seizures. 3. Anesthetic effect Thiopental is an intravenous anesthetics. However, owing to the severe respiratory depression and unsatisfactory analgesic effect, it is used for inductive anesthesia in combination with inhaled anesthetics. 4. Inductive effect of hepatic drug metabolic enzymes Barbiturates are typical inducers of hepatic drug metabolic enzymes. In clinical practice Phenobarbital is used to deal with the hyperbilirubinemia and kernicterus of neonates. 【Adverse reactions】 Barbiturates have marked respiratory depression, tolerance, dependence, and addiction, as well as narrow margin of safety. They have more chance to cause drug interactions. Buspirone[buspirn] Buspirone is a new anxiolytic drug without distinctly sedative, hypnotic, anticonvulsant, and muscle relaxant effects. It is a partial agonist of 5-HT1A receptor. Buspirone is rapidly absorbed but undergoes extensive first-pass effect after given orally. The half-life is 4 hours. Buspirone is used to treat generalized anxiety disorders and has similar effect to benzodiazepines. The patients with buspirone do not show rebound anxiety or withdrawal signs on abrupt discontinuance of the drug. It also causes less impairment of psychomotor than BZs, and does not affect driving skills. It was reported that buspirone might cause tachycardia, palpitation, nervousness, gastrointestinal distress, and paresthesias
Other sedative-hypnotic drugs Chloral hydrate,meprobamate,glutethimide,paraldehyde They had been used widely for hypnotics and anticonvulsants before,but now hardly used in the clinical practice. (J-Q Yang.Q-X Zhou) 29
29 Other sedative-hypnotic drugs Chloral hydrate, meprobamate, glutethimide, paraldehyde They had been used widely for hypnotics and anticonvulsants before, but now hardly used in the clinical practice. (J-Q Yang, Q-X Zhou)
Chapter 11 Anti-seizure drugs Epilepsy is a common disease,which has been bothering about 1%population in the world isa heterogeneous,which is nto several groups(table 11-1).The causes of epilepsy are extremely diverse,including genetics,developmental defects,as well as postnatal factors,such as infective,traumatic,neoplastic,degenerative disease processes The pathophysiological mechanism is unclear.It is known that epileptic seizure involves in the abnormal discharges from the neurons in the particular regions and the abnormal electric waves spread to the normal regions.Antiepileptic drugs may act either through suppressing abnormal discharges or blocking the abnormal electric waves to spread by following mechanisms:(1) Enhancement of GABAergic transmission,(2)Diminution of excitatory (esp.gutamatergic) transmission,(3)Modification of ionic conductances. 【Description of seizure classification】 Partial seizures The attacks begin in the particular loci of the brain and the locican be ascertained Simple partial seizure It has a minimal spread of the abnormal discharge.Thus,the normal consciousness and awareness of the patients are preserved.Clinical symptoms a sudden onset of clonic jerking of extremities lasting 60-90 sec;residual weakness may continue for 15-30 min after an attack Complex partial seizure Discharge is more widespread (usually bilateral)and almost always involves in the limbic system.Clinical symptoms:most show fragments of integrated motor behavior called automatisms,such as lip smacking.swallowing.fumbling.scratching.or even walking about,patients may have a brief warning followed by an alteration of consciousness during which some patients may stare and others may fall. Secondarily generalized attack A partial seizure immediately precedes a generalized tonic- Generalized seizures No evidence of localized onset Generalized tonic-n (grand mal)seizures They are characterized by tonic rigidity of all extremities,followed in 15-30 sec by a tremor that is actually an interruption of the tonus by relaxation. Absence (petit mal)seizure It is characterized by both sudden onset and abrupt cessation.The duration is usually less than 10 sec.Consciousness is altered.The attack may also be associated with mild clonic jerking of eyelids,or extremities.Absence attacks begin in the childhood adolescence. Mvoclonic ierking It can be seen in a wide variety of seizures.including generalized tonic- clonic seizures,partial seizures,absence seizures,and infantile spasms. Atonic sizres Atonic seen in the children very ofen.Patients have sudden oss ofpostural tone. 30
30 Chapter 11 Anti-seizure drugs Epilepsy is a common disease, which has been bothering about 1% population in the world. Epileptic seizure is a heterogeneous complex symptom, which is classified into several groups (table 11-1). The causes of epilepsy are extremely diverse, including genetics, developmental defects, as well as postnatal factors, such as infective, traumatic, neoplastic, degenerative disease processes. The pathophysiological mechanism is unclear. It is known that epileptic seizure involves in the abnormal discharges from the neurons in the particular regions and the abnormal electric waves spread to the normal regions. Antiepileptic drugs may act either through suppressing abnormal discharges or blocking the abnormal electric waves to spread by following mechanisms: (1) Enhancement of GABAergic transmission; (2) Diminution of excitatory (esp. glutamatergic) transmission; (3) Modification of ionic conductances. 【Description of seizure classification】 Partial seizures The attacks begin in the particular loci of the brain and the loci can be ascertained either by clinical observation or by electroencephalographic recording. Simple partial seizure It has a minimal spread of the abnormal discharge. Thus, the normal consciousness and awareness of the patients are preserved. Clinical symptoms: a sudden onset of clonic jerking of extremities lasting 60-90 sec; residual weakness may continue for 15-30 min after an attack. Complex partial seizure Discharge is more widespread (usually bilateral) and almost always involves in the limbic system. Clinical symptoms: most show fragments of integrated motor behavior called automatisms, such as lip smacking, swallowing, fumbling, scratching, or even walking about; patients may have a brief warning followed by an alteration of consciousness during which some patients may stare and others may stagger or even fall. Secondarily generalized attack A partial seizure immediately precedes a generalized tonicclonic seizure. Generalized seizures No evidence of localized onset Generalized tonic-clonic (grand mal) seizures They are characterized by tonic rigidity of all extremities, followed in 15-30 sec by a tremor that is actually an interruption of the tonus by relaxation. Absence (petit mal) seizure It is characterized by both sudden onset and abrupt cessation. The duration is usually less than 10 sec. Consciousness is altered. The attack may also be associated with mild clonic jerking of eyelids, or extremities. Absence attacks begin in the childhood or adolescence. Myoclonic jerking It can be seen in a wide variety of seizures, including generalized tonicclonic seizures, partial seizures, absence seizures, and infantile spasms. Atonic seizures Atonic seizures are seen in the children very often. Patients have sudden loss of postural tone