Section 3 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 (BZs)

【Chemistry and history】

 The first compound of the benodiazepines, 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 hetereocyclic 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 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 1.5 9 14

Chlordiazepoxide 3.0 - 40

Diazepam 1.5 30 60

Flurazepam 1.5 1 60

Lorazepam 3.5 10 15

Triazolam 1.0 3 3.5

【Mechanism of action】

BZs activate BZ receptors that exist in the particular regions of brain, enhance the binging

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 trizolam, 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 (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

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 benzodiazipines, except of 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

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 4hour.

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, gastrointenstinal 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.

【preparation and usuage】

地西泮（diazepam，安定）：片剂（tablets）：2.5mg，5mg; 2.5～5mg hs for sedation or insomnia,

or tid for anxiety。注射剂(injection)：10mg/2ml; 5～20mg iv injection for the generalized tonic

status epilepticus.

氯氮卓(chlordiazepoxide，利眠宁)：片剂（tablets）：5mg; 5～10mg tid for sedation or anxiety,

or 10～20mg hs for insomnia.

氟西泮(flurazepam)：胶囊剂(capsules)：15mg，15～30mg hs for insomnia.

阿普唑仑(aprazolam)：片剂（tablets）：0.25mg，0.4mg，0.5mg，0.4～0.8mg hs for insomnia.

三唑仑(trizolam)：片剂（tablets）：0.25mg，0.5mg；0.25～0.5mg hs for insomnia.

苯 巴 比 妥 钠 (sodium phenobarbital) ： 注 射 剂 (injection) ： 100mg ， 0.1 ～ 0.2mg im for

anti-convulsion，or iv injection slowly for the generalized tonic status epilepticus.

苯巴比妥(phenobarbital)：片剂（tablets）：15mg，30mg，100mg；15～30mg bid or tid for sedation

or anti-epilepsy. 60～100mg hs for insomnia.

硫喷妥钠(sodium thiopental)：注射剂(injection)：500mg，mix into 1.25%～2.5% solution with

5% GS normal saline solutin, iv injection slowly.

(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.

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 tonic-clonic 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

tonic-clonic 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.
Generalized tonic-clonic sustained seizures They are grand mal seizures with a sustained

attack.

Infantile spasms These are epileptic symptoms, and not a seizure type.

Table 11-1 Classification of seizures and choice of drugs

Classification Choice of drugs
Partial seizures
Simple partial seizures Phenytoin, Carbamazepine, Valproate
Complex partial seizures Phenytoin, Carbamazepine, Valproate
Partial seizures secondarily generalized Phenytoin, Carbamazepine, Valproate
Generalized seizures
Generalized tonic-clonic (grand mal) seizures Phenytoin, Carbamazepine, Phenobarbital
Absence (petit mal) seizures Ethosuximide, Valproate
Tonic seizures Clonazepam,
Atonic seizures Phenytoin
Clonic and myoclonic seizures Valproate,
Generalized tonic-clonic sustained seizures Diazepam, Lorazepam, Phenobarbital, Phenytoin
Infantle spasms1 Phenobarbital, clonazepam
1 An epileptic syndrome rather than a specific seizure type.
Phenytoin(Diphenylhydantoin)

Phenytoin is the oldest nonsedative antiepileptic drugs found in 1938. It has still been

one of the most important drugs used for control of the epileptic seizures as yet.

【Pharmacological actions and clinical uses】

At the therapeutic concentrations (10-20ng/ml), the major action of phenytoin is to block

sodium channels on the cell membrane and suppress the generation of repetitive action potentials.

1. Antiepilepsy Phenytoin is very effective for nearly all kinds of epileptic seizures

except absence (petit mal) seizures.

2. Peripheral neural pains It can be used to relieve trigeminal neuralgia,

glossopharyngeal neuralgia, and sciatic neuralgia.

3. Antiarrhythmia Phenytoin is especially effective for treatment of arrhythmias

caused by digitalis intoxications.

【Adverse reactions】

1. Acute toxic reactions They occur when the serum concentration of phenytoin is over

than 20ng/ml. The symptoms include nystagmus, loss of smooth extraocular pursuit movements,

diplopia, ataxia, and sedation.

2. Chronic toxic reactions They occur after the drug is given chronically, including

coarsening of facial features, diminished deep tendon reflexes in the lower extremities,

abnormalities of vitamin D metabolism and osteomalacia, low folate levels and megaloblastic

anemia, gingival hyperplasia, and hirsutism.

3. Other adverse reactions Skin rash, fever, and agranulocytosis are

relatively rare to be seen. Local irritations can also be seen after administrations
orally or parentally.

Carbamazepine

This drug has a similar mechanism of action to phenytoin. At the thearapeutic

concentrations of 4-8 ng/ml it also inhibits uptake and release of noradrenaline from brain

synaptosomes.

It can be used to treat the generalized tonic-clonic seizure, partial seizures like phenytoin.

It is also used for trigeminal neuralgia and mania.

 Carbamazipine is easily absorbed by bowel, destroyed by liver, and is an inducer of

hepatic microsomal enzymes. Its plasma protein bound rate is 70% and plasma elimination

half-life is 36 hours.

The adverse reactions of this drug include: diplopia, ataxia, drowsiness, and unsteadiness,

which are dose-related responses. Idiosyncratic blood dyscrasias (aplastic anemia and

agranulocytosis), allergic reactions (skin rash and hepatic dysfunction) are unsual.

Phenobarbital

It is used for treatment of partial seizures and generalized tonic-clonic seizures, especially

for epilepsy of infants and children. It is also chosen when seizure attacks are difficult to control

by other antiepileptic drugs.

It is extremely rare for Phenobarbital to cause hematologic disorders.

Ethosuximide

Ethosuximide was introduced in 1960. It is a ‘pure’ petit mal drug for treatment of

absence seizure. The effective levels are 50-100ng/ml. The mechanism of it may involve in

the inhibition of T-type calcium channels in neurons.

Ethosuximide is easily absorbed after given orally without significantly plasma protein

bound rate. The concentration of it in the CSF is equal to that in the blood plasma. It is

completely metabolized by liver and elimination half life is about 40 hours.

The adverse reactions are: gastric distress (upper abdomen pain, nausea, vomiting),

transient lethargy or fatigue, headache, dizziness, hiccup, and euphoria. Skin rashes and decrease

of blood cells are very rare.

Benzodiazepines

Several benzodiazepines play prominent roles in the therapy of epilepsy. They are

diazepam, lorazepam, clonezepam, and nitrazepam. Diazepam and lorazepam are very effective

drugs to control generalized tonic-clonic status epilepticus when given intravenously.

Clonazepam and nitrazepam are often used for contrl absence seizure and myoclonic seizure.
Valproic acid and sodium valproate

Valproic acid was found to have a strong anticonvulsant when it was used as a solvent in

the search for other drugs effective against seizures. France in 1969 and USA in 1978 were

allowed its salt, sodium valproate for clinical uses.

Valproate is a broad spectrum antiepileptic drug. The molecular mechanism of actions

has not been clear as yet. However, because of the severe idiosyncratic hepatotoxicity of it, the

drug is not first choice drug for treating epilepsy. It may be preferred if the patients have

concomitant absence seizure and generalized tonic-clonic attacks.

Besides the severe idiosyncratic hepatotoxicity, valproate may cause dose-related

gastro-intestinal reactions, such as nausea, vomiting, heartburn, as well as teratogenicity (spina

bifida, cardiovascular, orofacial, and digital abnormalities).

Table 1-2 Effective plasma levels of some antiseizure drugs

Drugs Effective levels (g/ml) Emax levels* (g/ml) Toxic levels (g/ml)

Carbamazepine 4-12 7 8

Ethosuximide 50-100 80 100

Phenobarbital 10-40 35 40

Phenytoin 10-20 18 20

Primidone 5-15 10 12

Valproate 50-100 80 100

* The level should be achieved in the patients with the refractory seizures.

【preparation and usuage】

苯妥英钠（sodium phenytoin）：片剂（tablets）：50mg，100mg；50～100mg bid after meal for

anti-epilepsy; maximum dose: 300mg each time，600mg per day. 注射剂(injection)：100mg，

250mg；150～250mg ad to 5% GS 20～40ml，iv injection slowly for the generalized tonic-clonic

status epilepticus.

乙琥胺（ethosuximide）：胶囊剂（capsules）:0.25g; 糖浆剂（syrupus）:5%; 500mg qd, for the

patients with absence seizure.

酰胺咪嗪（carbamazipine）：片剂（tablets）：100mg，200mg；糖衣片（sugar coated tablets）:50mg；

100mg bid.

丙戊酸钠（sodium valproate）：片剂 (tablets): 200mg；糖浆剂（sugar syrupus）:50mg/ml；

200～400mg, bid for adults or 30～60mg per day for children.

(J-Q Yang ，

Q-X Zhou)

Chapter 12 Antiparkinsonism drugs

Parkinsonism is an idiopathic disorder, which is characterized by a combination of rigidity,

bradykinesia, tremor, and postural instability, that can occur for a wide variety of reasons. The

pathophysiologic basis of the Parkinsonism may involve in both of dopaminergic and cholinergic

activities in substantia nigra and striatum of brain (Fig 12-1). When the level of dopamine is

reduced or the dopamine receptors are blocked in basal ganglia of brain, the cholinergic activity in

the striatum will relatively increase. As a result, the parkinsonsm is indu

Fig 12-1 Schematic representation of the sequence of neurons

At present the therapeutic strategy of Parkinsonism is to either enhance dopaminergic

activity or inhibit the cholinergic activity in substantia nigra-striatum system of brain.

Levodopa (L-dopa)
【Properties of pharmacology】

1. L-dopa is rapidly absorbed after given orally, and easily penetrate blood brain barrier.

But most amount of oral dose is metabolized by peripheral dopa decarboxylase, only about 1-3%

administrated levodopa actually enters the brain as unaltered.

2. Concomitant administration of a peripheral dopa decarboxylase inhibitor, carbidopa,

with L-dopa (carbidopa : L-dopa=1:4) may significantly reduce the metabolism of L-dopa in

peripheral tissues and reduce the adverse effects of L-dopa.

3. L-dopa can ameliorate all of the clinical features of Parkinsinism, but is particular

effective in relieving bradykinesia. However, the benefits of L-dopa treatment often begin to

diminish after 3 or 4 years of therapy irrespective of the initial therapeutic response.

4. Mainly unwanted reactions of L-dopa include: gastrointestinal reactions (anorexia,

nausea, and vomiting), techycardia and ventricular extrasystoles, dyskinesias, and behavioral side

reactions (depression, anxiety, hallucinations, nightmares, euphoria).

Bromocriptine and pergolide

Both are ergot-derivatives and directly stimulate dopamine receptors. They have an

important role as the first line therapy for the parkinson’s disease with a lower incidence of

response fluctuations and dyskinesias. However, in order to minimize adverse effects and

improve the tolerance, the dose should be built up slowly over 2 or 3 months from a starting level

of 1.25mg twice daily for bromocriptine and 0.05mg daily for pergolide.

The common adverse reactions are: anorexia, nausea, vomting, dyspepsia, delusions, and

postural hypotension.

Amantadine

Amentadine is an antiviral drug. Its mode of action in Parkinsonism is unclear, but it may

potentiate dopaminergic function by influencing the synthesis, release, or reuptake of dopamine.

Its thearapeutic effect is less potent than levodopa and sustains short time. Its efficacy of

antiparkinsonism often disappears after a few weeks of treatment.

The adverse effects include restlessness, depression, irritability, insomnia, agitation,

excitement, hallucination, and confusion.

Acetycholine receptor blockers  Trihexyphenidyl (Artane)

Artane is a selective central action cholinergic receptor blocker with less peripheral

anticholinergic effects.

All antimuscarinic drugs may improve the tremor and rigidity of Parkinsonism, but have little

effect on bradykiniesia.

【preparation and usuage】

左旋多巴（levodopa）：片剂（tablets）：50mg，100mg，250mg；胶囊剂（capsules）：

100mg，125mg，250mg. 0.5～1.0g per day, after meals: maximum dose：8g per day.

卡比多巴（carbidopa）：片剂（tablets）：25mg，25mg tid.

盐酸金刚烷胺（amantadine hydrochloride）：片剂（tablets）：0.1g，0.1g bid.

甲磺酸溴隐亭（bromocriptine mesylate）：片剂（tablets）：2.5mg，1～5mg bid；maximum

dose：100mg per day.

甲磺酸培高利特（pergolide mesylate）：片剂（tablets）：0.25mg，0.25mg bid；maximum

dose：5mg per day.

盐酸苯海索（trihexyphenidyl hydrochloride）：片剂（tablets）：2mg，1～2mg bid，

or tid，or qid，after meals；maximum dose：20mg per day.

(J-Q

Yang, Q-X Zhou)

Chapter 13 Drugs used for treatment of psychosis

Psychosis, usually said “mental problems” denotes a variety of mental disorders. It includes

schizophrenia, mania, depression, and anxiety. The pathophysionlogical mechanism of

psychosis has not been clear as yet. Genetic tendency is undoubted. However, the extra-stress

factors (conditions) are also necessary.

І. Antipsychotic drugs
 Antipsychotic drugs are such a kind of drugs that are used to treat schizophrenia. They

are also called as ‘major tranquilizers’, compared with benzodiazipines that are called as ‘minor

tranquilizers’ and used to treat the patients with anxiety.

About more than 50 years ago, the treatments of patients with schizophrenia were not

inhuman. The measures of therapy included electric shock, insulin-induced hypoglycemia, and

injection of reserpine or scopolamine, even though the patients were fastened. In the early 1950s,

the discovery of chlorpromazine and its derivatives initiated the new era of the therapy of

schizophrenic patients.

Chlorpromazine and its derivatives of phenothiazipines

Phenothiazipines are widely used for dealing with psychosis. They are chlorpromazine,

fluphenazine, perphenazine, thioridazine, and trifluoperazine.

【Properties of pharmacokinetics】

After given orally, phenothiazipines undergo significantly the first-pass elimination in the

liver and bioavailabilities are less than 35%. They are highly lipid-soluble and highly protein

bound (92-99%). The volumes of distribution are usually more than 7L/kg. They are nearly

completely metabolized by liver, and metabolites are mainly excreted through kidneys. The

serum elimination half lives vary from 10 to 24h. However, because of high lipid-solubility,

their actions in the central nervous system may sustain very long time.

【Properties of pharmacodynamics and clinical uses】

Phenothiazines have many effects, which involve in their blocking actions on a variety of

receptors.

1. Blocking actions on dopamine receptors It is now recognized that there at least

exist five important dopaminergic pathways in CNS: the first is mesolimbic-mesocortical pathway,

the most related to behaviors; the second is nigrostriatal pathway, involved in coordination of

voluntary movement; the third is tuberoinfundibular pathway, connecting with secretions of

endocrines; the fourth is medullary-perventricular pathway, probably involved in eating behavior;

the fifth is incertohypothalamic pathway, which function has not been defined.
 At present, at least five different dopamine receptors (D-R) have been described, among

which, D2-R is the most closely related with psychotic activities, motor and stereotyped behavior,

as well as the efficacy of antipsychotic drugs.

1) Antipsychotic effects They are relative to blocking action of drug on D2-R of

dopaminergic meso-limbic and meso-cortical pathway. After given, phenothiazipines make the

patients tranquil (quiet, peaceful, and indifferent to the changes of circumstances) and induced

into the light sleep state. After that, the clinical symptoms of schizophrenia are improved:

hallucination and fancy are slowly eliminated, logical thinking begins to recover, and daily life of

patients can be taken care of by themselves. However, these drugs can cause unpleasant

objective effects in the health person, such as sleepiness, restlessness, impaired performance, etc.

2) Body temperature-regulating effects They blunt the roles of temperature-regulating

center in the hypothalamus, make the body temperature fluctuation with the variation of

temperature in the circumstance. This effect can be used for artificial hibernation to deal with

some emergency situations. The drug usually taken is chlorpromazine with pethidine and

promethazine.

3) Antiemetic effects Phenothiazines have a strong antiemetic effect, except

thioridazine. This action is due to D-R blockage, both centrally (in the chemoreceptor trigger

zone of the medulla) and peripherally (on receptors in the stomach). At the high doses, they also

inhibit vomiting center of medulla. This effect can be used to prevent nausea and vomiting from

some chemotherapeutic drugs, radiations, renal failure, pregnancy, etc. But they are ineffective

for prevention of motion sickness.

4) Influence on the endocrines They promote releases of prolactin and

melanocyte-stimulating hormone, and inhibit the releases of corticotropine and growth hormone

through blocking D2-R in the tuberoinfundibular area.

5) Enhancing effects of some central inhibitors They enhance the central inhibitions of

sedative-hypnotics, analgesics, and anesthetics. But they could induce the attack of seizures.

2. Blocking action on -receptor Chlorpromazine and thioridazine have a strong -R

blocking action. As a result, when given at high doses or by injection, they may cause orthostatic

hypotension and nasal congestion.

 3. Blocking action on M-receptor Again, chlorpromazine and thioridazine have a

strong M-R blocking action. They cause the symptoms like atropine, such as dry mouth, urinary

retetion, vision blur, and increase of intraocular pressure.

【Adverse reactions】

1. The side reactions from blocking receptors

1) D-R block It may cause many central reactions, such as mental depression, endocrine

irregulation (amenorrhea, galactorrhea, false pregnancy, retardation of growth and development of

children), extrapyramidal reactions (Parkison’s syndrom, acute dystolic reactions, akathisia and

tardive dyskinesia; the first three symptoms can be improved with antimuscarinic receptor drugs,

the last is difficult to be treated.)

2) -R block It may cause orthostatic hypotension and nasal congestion.

3) M-R block dry mouth, vision blur, increasing intraocular pressure, urinary retetion.

2. General side reactions They may include local stimulation reactions (local pain,

inflammation, cholestatic jaundice, agranulocytosis, skin eruptions, etc.).

Butyrophenones  haloperidol, droperidol

【Properties of pharmacology】

This group drugs have the strongest affinity for D2-R and less other effects. Therefore,

they have much more potent effects than phenothiazines on the psychotic activities, temrature

control, endocrine regulation, and CTZ as well as vomiting center.

Haloperidol can be used to treat the patients with schizophrenia refractory to other drugs.

It is also an effective drug for treatment of patients with uncontrolled hiccup.

Doperidol is often useful in combination with opioid compounds, such as fentanyl in the

neuroleptic anesthesia.

The main side reactions are very high incidence of extrapyramidal symptoms (about 40%).

Rarely, a life threatening disorder  neuroleptic malignant syndrom may occur, the characteristic

signs of which include markedly muscle rigidity, very high fever, increasing serum creatine kinase

isoezymes, etc. It is believed that the symptoms are resulted from an excessively rapid blockage

of post-synaptic dopamine receptors.

 Other antipsychotic drugs

Chlorprothixene (Taractan, Tardan)

Chlorprothixene is a derivative drug of thiothixene with wide spectum antipsychotic activities.

It is suitable to treat schizoaffective disorders with both schizophrenia and depression.

Clozapine

Clozapine is a drug with quite different properties from other drugs above in chemical

structure and receptor affinity. It shows much stronger affinity to D4-R than D2-R and D1-R.

Clozapine is used for some patients who are refractory to the classic antipsychotic drugs. The

advantage is that it nearly has no extrapyramidal toxicity. However, it causes much more high

incidence of agranulocytosis than other antipsychotic drugs.

II. Antimanic drugs

In many parts of the world, antimanic drugs are considered as “mood-stabilizing drugs”,

because they have a primary action of preventing mood swings in patients with bipolar affective

(manic-depressive) disorder.

Lithium carbonate

Lithium is monovalent cation, which has been used for dealing with patients with manic

symptom since earlier 1950s. However, its mechanism of action still is unclear.

Recently, it was shown that the action of lithium on metabolism of inositol phosphates appears to

be the most relative with its antimanic effects. It is well known that inositol-1,4,5-triphosphate

(IP3) and diacylglycerol (DAG) are very important second messengers for  - and  -adrenergic,

muscarinic-, dopaminergic, etc transmissions. Lithium inhibits several important enzymes in the

normal recycling of membrane phosphoinositides, including coversion of IP2 to IP (inositol

monophosphate) and the conversion of IP to inositol (figure13-1). This block leads to a

depletion of phosphatidylinositol-4,5-bis-phosphate (PIP2), the membrane precursor of IP3 and

DAG. Thus, the effects of transmitters, such as NA, DA, 5-HT, or Ach, may diminish.
 Fig 13-1 Effect of lithium on the IP3 and DAG second-messager system

【Properties of clinical use】

1. Lithium carbonate is effective to control mania and prevent attacks of both mania and

depression, but it has no obvious effect on health person when the therapeutic dose is used.

2. The combination of lithium and antipsychotic drugs for treatment of severe mania

patients is suitable. After mania is controlled, the antipsychotic drugs may be stopped, lithium

salt continues as maintenance therapy.

3. Lithium at the therapeutic concentration is devoid of autonomic blocking effects and of

activating or sedating effects.

4. Lithium has a very narrow safe range of doses for individuals. The doses for majority

required are between 1000mg/d and 1800mg/d.

5. Lithium causes many adverse reactions, including tremor, vomiting, interfering thyroid

function, polydipsia and polyuria, even chronic interstitial nephritis, edema (causing Na+ retetion),

bradycardia-tachycardia-syndrom. It may have teratogenic effect.

III. Antidepressant drugs

Depression is one of the most common psychiatric disorders, and is a hetereogenous

disorder that has been classified in a variety of ways. A simplified classification is as follows:

(1) reactive or secondary depression (most common); (2) endogenous depression; (3) depression

associated with bipolar affective disorders.

 The pathophysiological mechanism of depression is not clear, even though an amine

hypothesis had been suggested in 1950s.

Antidepressant drugs can be divided into five groups considering their chemical structures

and active mechanisms.

A. Tricyclic antidepressants (TCAs)

This group includes imipramine, despramine, amitriptyline, etc. They inhibit the uptake of

both noradrenaline and serotonin by the ends of nerves. They also have markedly antimuscarinic

activity, sedative action, and -R blocking action.

B. Tetracyclics

They belong to the second generation antidepressants, including amoxapine, maprotilline, etc,

and have a similar pharmacological effects to tricyclines.

C. Heterocyclics

They belong to the third generation antidepressants, including trazodone and bupropion

and seem to have small inhibition of uptake of noradrenaline and serotonin.

D. Selective serotonin reuptake inhibitors (SSRI)

They were approved to go into clinical practice in 1990s, including fluoxetine, paroxetine,

sertraline, and fluvoxamine. The properties of their pharmacology are that they have the much

higher selective action than other drugs on the uptake of serotonin and lack many of the toxicities

of tricyclics, tetracylics, and heterocylics, such as the influences on the automatic nervous

activaties. However, they may cause sexual function disorders.

F. MAO inhibitors

They belong to one of the oldest antidepressants, including phenelzine, isocarboxazid, and

tranylcypromine. They inhibit both MAO-A and MAO-B activities and interfere with the

metabolism of tyramine, serotonin, dopamine, noradrenaline, and adrenaline.

【Clinical uses】
 1. The major indication for these drugs above is to treat the patients with depression.

The actions of these drugs on the transmitters and receptors are prompt, but complete

antidepressant effects require several weeks to be manifest.

2. Panic disorder Panic disorder is an acute episode of anxiety. MAO inhibitors

and SSRI are effective to control the symptom.

3. Obsessive-compulsive disorder SSRI have been shown to be uniquely effective

for treatment of this disorder.

4. Chronic pain Tricyclics and tetracyclics are especially useful for treating a variety

of chronically painful states that caused often by terminal cancers, or disease not being

definitively diagnosed.

【Adverse reactions】

Different antidepressants have different adverse reactions. Here is sum as follows.

Tricyclics: Sleepiness, tremor, insomnia, confusion, sexual disturbance, aggravation of

psychosis, weight gain, seizure, withdrawal syndrom; blurred vision, consitipation, urinary

retention, sweating, orthostatic hypotension, conduction defects, arrhythmias.

Tetracyclics: Similar to tricylics.

Heterocyclics: Drowsiness, dizziness, nausea, agitation, and sweating.

SSRI: Insomnia, tremor, sexual dysfunction, and acute anxiety.

MAOI: Sleep disturbance, weight gain, postural hypotension, and sexual disturbance.

【preparation and usuage】

盐酸氯丙嗪（chlorpromazine hydrochloride）：片剂（tablets）：12.5mg，25.0mg，50mg；

注射剂（injection）：10mg/ml，25mg/ml，50mg/2ml；30～100mg per day，po or im; Sustaining

dose: 400mg per day for treating the patients with schizophrenia. 12.5～25mg, po or im for

vomit or hiccup.
奋乃近（perphenazine）：片剂（tablets）：2mg，4mg；6～60mg per day for schizophrenia.

2～4mg for vomit or hiccup.

氟奋乃近葵酸酯（fluphenazine decanoate）：注射剂（injection）：25mg/ml；12.5～25mg im,

every other week for chronic schizophrenia.

盐酸三氟拉嗪（trifluopherazine hydrochloride）: 片剂（tablets）：1mg，2mg，5mg；2～5mg

bid po，; moximum dose：30mg per day; sustaining dose: 15～20mg per day.注射剂（injection）：

2mg/ml； 1～2mg bid im deeply.

盐酸硫利哒嗪（thioridazine hydrochloride）：片剂（tablets）：10mg，25mg，50mg，100mg；

50～100mg tid；maximum dose: 800mg per day; sustaining dose: 100～500mg.

氯普噻吨（chlorprothixene）：片剂（tablets）：10mg，；10～40mg qd or bid po; sustaining dose：

10～40mg. 注射剂（injection）：50mg/ml； 50～100mg im deeply，two times per week.

盐酸替沃噻吨（tiotixene hydrochloride）：胶囊剂（capsules）：2mg，5mg，10mg；2mg tid;

maximum dose: 30mg per day. 注射剂（injection）：2.5mg/ml，2～4mg tid im.

氟哌啶醇（haloperidol）：片剂（tablets）：2mg，4mg；1～2mg bid or tid；maximum dose：

30mg per day. 注射剂（injection）：5mg/ml；5～10mg im bid.

氟哌利多（droperidol）：注射剂（injection）：5mg/ml；2.5～5mg plus fetanyl 0.1mg im or iv

for neurolept analgesia ； 2.5 ～ 5mg im or iv 30 ～ 60 min before operation for neuroleptic

anesthesia.

氯氮平（clozapine）：片剂（tablets）：25mg，50mg；125mg qd or bid.

(J-Q Yang,

Q-X Zhou)

Chapter 14 Opioid Anagesics and Antagonists

About 3 thousands ago, the documents from ancient Egypt, Greek, and Roman, recorded the

actions of opium from opium poppy, Papaver Somniferum. Opioid anagesics imply that these

drugs can relieve severe pain without loss of other senses and consciousness. Sertŭrner from

German isolated a pure active substance from opium in 1803. He named the compound

‘Morphine’ similar pronunciation to Morpheus, the Greek god of dreams. Since than, many

opioid compounds have been found and used for clinical practice. In 1970s opioid receptors and

endogenous opioid peptides (endorphin, enkephin, dynorphin) were found in the bodies.

I. Morphine and codeine

 They belong to opioid alkaloids with distinct central pharmacological activities. The

anagesic and relieving cough potency of morphine are 12 times and 4 times more than that of

codeine, respectively.

【Pharmacokinetics】

After orally given, morphine undergoes widely hepatic metabolism, only less than 25%

amount is absorbed. However, the absorption of codeine from intestine is much better than

morphine and about 10% administered is transformed into morphine in the liver. The binding

rates of morphine and codeine to serum protein are 35% and 7%, and the half lives are 2.0h and

3.0h, respectively. They are mainly eliminated by urine.

【Phamacodynamics】

1. Effects on central nervous system Morphine and opioid analgesics exhibit important

central effects by mainly stimulating -R in the special cerebral regions.

1) Analgesia Morphine has a strong analgesic action with sedation (drowsiness and

clouding mentality) and euphoria. It is more effective on chronic dull pain than acute sharp pain.

The painful sense of patients still exists, but the sensitivity of patients to pain is clearly reduced

and emotional response of patients to pain is improved.

The analgesic mechanism of morphine has not been completely understood. It stimulates

opioid receptor existing on presynaptic terminal of primary afferent nerves and reduces the release

of transmitters, which involves in the conduction of pain pulse. It also stimulates -R existing on

GABAergic interneurons, and diminishes the control on pain inhibitory neurons from GABAergic

interneurons and indirectly excites the pain inhibitory neurons.

2) Respiratory depression Morphine significantly inhibits the sensitivity of

respiratory center to carbon dioxide at the therapeutic dose.

3) Antitussive effect Morphine clearly suppresses cough center at the dose less than

that for its analgesia.

4) Mitosis Morphine distinctly constricts pupils by parasympathetic mechanism,

which can be blocked by opioid antagonists and atropine.

5) Nausea and vomiting Morphine activates the chemoreceptor trigger zone and

vestibular component to cause nausea, vomiting, and dizziness.

2. Peripheral effects
 1) Postural hypotension Injection of morphine causes orthostatic hypotension,

which comes from the dilation of peripheral blood vessels induced by both inhibitions of

vasomotor center and release of histamine from mast cells.

2) Gastrointestinal effects A. Morphine reduces stomach motility and enhances the

stomach tone (persistent contraction). B. Morphine increases resting tone of small intestine. C.

Morphine diminishes propulsive peristaltic waves of large intestine and increases its tone, thus

delays the passage of the fecal mass and increases absorption of water; in addition, morphine

makes patients obtuse sense of stool excretion. The extensive effects of morphine lead to

constipation.

3) Other effects Morphine constricts biliary smooth muscle and sphincter of Oddi.

It also constricts urethral smooth muscle and bladder sphincter and makes the tones increase and

urinary retention.

【Clinical uses】

1. Analgesia Morphine can be used to treat acute sharp pain or severe pains from variety of

causes, such as operations, terminal cancers, bone fracture, etc. But it should be combined with

atropine for controlling the biliary or kidney colic.

2. Acute pulmonary edema This is the symptoms induced by acute left ventricular failure of

heart. As an assistant drug, intravenous injection of morphoine can markedly improve the

clinical symptoms of left ventricular failure through following mechanisms: 1) reduce the

sensitivity of respiratory center to carbon dioxide; 2) relieve patient’s anxiety; 3) decrease

resistance of the peripheral vessels and preload and afterload of the heart.

3. Antitussive Codeine usually uses to control severe cough, which may cause threatening

complications.

4. Treatment of diarrhea Tinctura opium is occasionally used to control simple diarrhea.

5. Other uses opioids are frequently used as premedicant drugs before anesthesics and

surgery because of their sedative, anxiolytic, and analgesic properties. They are also used to

enhance analgesic efficacy of anesthetic drugs during the operation.

【Adverse reactions】

Morphine has extensively adverse reactions, including respiratory depression, nausea,

vomiting, constipation, urinary retention, orthostatic hypotension, inducing attack of asthma,

increasing pressure of biliary tract, dysphoria, etc. Chronic administration of morphine will

induce tolerance and dependence (addiction), as well as abstinence syndrome (withdrawal

syndrome) when drug is suddenly taken away.

Overdose of morphine may cause severe repiratory depression, which can be antagonized by

morphine receptor antagonist naloxone or naltrexone.

【Contraindications】

Morphine is forbidden to give the patients with head injuries, elevating intracranial pressure,

bronchial asthma, severe pulmonary function damage, pregnancy, delivery and lactation.

II. Synthetic analgesics

Meperidine (Pethidine)

【Chemistry and history】

Pethidine is a phenylpiperidine derivative and was occasionally found in studying

atropine-like substances 67 years ago (1937).

【Propeties and pharmacology】

1. The oral bioavailability of pethidine is much higher than morphine.

2. It has similar pharmacological effects to morphine, and mainly stimulates  -R and

produces analgesia, euphoria, sedation, nausea, vomiting, and depression of breathing; but the

potencies of analgesia and respiratory depression are only a seventh of morphine. It can be

used for replacement of morphine in clinical practice, except antitussive and stopping diarhea.

3. The half-life of pethidine is much shorter than morphine. Therefore, it less causes

constipation.

4. It has some atropine-like actions. When overdose is used, it may causes some

atropine-like symptoms and convulsion.

5. It still has tolerance, dependence, and addiction, when chronically given. It also

induces asthma attack and causes orthostatic hypotension when parenterally given.

Fentanyl

Fentanyl has a similar chemical structure to pethidine. However, its analgesic potency is

80-100 times more than morphine, and its half-life is much shorter. Fentanyl is usually used as
an adjunct to general anesthesia and as a primary component of anesthetic regimen in

cardiovascular surgery or other types of high-risk surgery.

Methadone

【Properties of pharmacology】

1. Methadone given orally has much higher bioavailability than morphine, but half life is

similar to morphine.

2. Methadone has similar potency and efficancy of analgesia to morphine, but patients feel

less euphoria to it and physical dependence develops much slower than morphine. Therefore,

patients do not like methadone, compared with morphine.

3. It is very useful drug for detoxification and for maintenance of chronically relapsing

heroin and morphine addict. For detoxification: 5-10mg per os, bid or tid; for maintenance

terapy: 50-100mg/d, per os.

Pentazocine

Pentazocine is a  receptor agonist with weak  receptor partial agonist properties. Its

analgesic potency is only a third of morphine, the suppressive effect on respiratory center is also a

third of morphine with a ‘ceiling effect’. The cardiovascular effect of pentazocine is excitatory.

Because it is a weak -R agonist, it can accelerate appearance of withdrawal syndrome of opioid

drugs.

III The opioid receptor antagonists

Naloxone and nal’trexone are pure opioid antagonists. The former has a poor

bioavailability with short half-life when given orally. The later is well absorbed after oral

administration and a much longer half-life (10h) than naloxone. They are used to treat acute

opioid overdose, reverse the effects of opioid drugs, such as respiration, pupil size, and

consciousness. They are also used for dealing with alcoholism.

【preparation and usuage】

盐酸吗啡（morphine hydrochloride）：注射剂（injection）：10mg/ml；5～10mg sc 1～3 times

per day；maximum dose：20mg，60mg per day.

磷酸可待因（codeine phosphate）：片剂（tablets）：15mg，30mg；15～30mg tid；maximum

dose 100mg，250mg per day.

盐酸哌替啶（pethidine hydrochloride）：片剂（tablets）：25mg，50mg；50～100mg po prn；

maximum dose：200mg each time，600mg per day. 注射剂（injection）：10mg/ml，100mg/2ml；

50～100mg sc prn；maximum dose：150mg each time，600mg per day.

盐酸美沙酮（methadone hydrochloride）：片剂（tablets）：2.5mg，10mg；注射剂（injection）
：

5mg/ml；5～10mg po or sc tid.

枸橼酸芬太尼（fentanyl citrate）：注射剂（injection）：0.1mg/ml；0.1mg im.

盐酸喷他佐辛（pentazocin hydrochloride）：片剂（tablets）：25mg，50mg；25～50mg q4h if

necessary.

盐酸纳洛酮（naloxone hydrochloride）：注射剂（injection）：0.4mg/ml；0.4～0.8mg im or iv.

(Q-X

Zhou)

Chapter 15 Non-steroidal anti-inflammatory drugs (NSAID)

【Introduction】

In this chapter, the drugs introduced have same mechanism of actions, which involve in

inhibition of cyclooxygenases that catalyze the biosynthesis of prostaglandins (PGs), and have

similar pharmacological properties including antipyretic action, analgesic action, and

anti-inflammatory effect.

1. Antipyretic action NSAID make high fever of patients lower to the normal level

temporarily through inhibiting PGs synthesis in temperature–regulating center, lowering the point
of the thermostat, and increasing the heat dissipation. But they have no influence on the normal

temperature of health person, compared with phenothiazine derivatives.

2. Analgesic action NSAID have markedly analgesic effect on the mild and moderate

pains from nervous, muscular, tendon, as well as arthritic tissues; especially pain caused by

inflammation. PGs not only cause mild pain but also facilitate the sensitivity of receiver of pain

to bradykinin which stimulates the pain receiver on the afferent nervous terminals and causes pain.

NSAID inhibit PGs synthesis, therefore, they have certain analgesic effect.

Compared with opioid drugs, the advantages of NSAID are that they have no respiratory

suppression and addiction.

3. Anti-inflammatory action NSAID decrease the sensitivity of vessels to bradykinin

and histamine, inhibit vascular permeability, and relieve the sign of inflammation by inhibiting

PGs synthesis. PGs not only cause vesodilation, increase permeability, and promote the

chemotaxis of inflammation cells, but also have synergistic actions with bradykinin and histamine.

It is known that there exist two isoenzymes of COX, COX-1 and COX-2 in the body.

Inhibition of COX-1 is responsible for gastrointestinal side reactions. Thus, selective COX-2

inhibitors are very suitable to patients who need to avoid gastrointestinal side reactions or take

these drugs for a long period.

I. Salicylates

Salicylatic acid known as plant hormone exists widely in many plants. It was first

used as antipyretic and anti-inflammatory drugs to treat rheumatic fever and arthritis in 1763.

Because of severe gastrointestinal adverse reactions, it was replaced by acetylsalicylate (aspirin)

in 1899. Aspirin as an ‘over the counter’ drug, is very famous in the history of NSAID

development and clinical practice.

【Properties of pharmacokinetics】

Aspirin is easily and rapidly absorbed from the stomach and upper small intestine. It is

also rapidly hydrolyzed to acetic acid and salicylate by esterase with serum half-life 15 minutes in

the blood and tissues. Salicylate is excreted by urine with half-life 3-5 hours. When total load

of salicylate in the body exceeds 600mg per day, its half-life may increase to 12-16 hours.
【Pharmacodynamics】

Aspirin is non-selective COX inhibitor, and has more potent inhibiton on COX-1 than

COX-2.

1. Antipyretic effects Aspirin reduces elevated temperature by inhibiting both COX-1

and COX-2 in CNS when 0.3-0.5g is used. The fall of temperature is related to increasing

dissipation of heat through vasodilation of superficial blood vessels and profuse sweating. It can

be used to treat the patients with high fever.

2. Analgesic effects Aspirin is quite effective in reducing the mild or moderate pains,

especially pain caused by inflammation at the dose of 0.5g. It is used for treating headache,

And other pain from nerve, arthritis, muscle, tendon, teeth, as well as uterus.

3. Anti-inflammatory effects When used with large dose (600mg per day), aspirin has

significantly and fast anti-inflammatory effects. Permeability of vessels is decreased, adherence

of granulocytes to damaged vasculature is inhibited, and migration of polymorphonuclear

leukocytes and macrophages into the sites of inflammation is prevented. It can be used in

treatment of rheumatic arthritis, and other inflammatory joint conditions.

4. Anti-platelet aggregation Small dose of aspirin (50-100mg per day) can irreversibly

inhibit COX-1activity of platelets for 8-10day, reduce the TXA2 level, and prevent platelet

aggregation. So it can be used for prevention of the thrombosis formation.

5. Other uses Aspirin is given chronically at low dosage may lower the incidence of

Alzeimer’s disease and colon cancer.

【Adverse effects】
 Fig 14-1 Approximate relationship between plasma salicylate levels and pharmacodynamics

Figure 14-1 shows the approximate relationship of plasma salicylate levels to

pharmacodynamic responses of body. It is clear that when usual doses are used the adverse

reactions of aspirin are less important and mild, including gastric upset and bleeding (it means that

aspirin tablets must be given in pieces and after or with meal, and not given the patients with

alimentary ulcers.) Some persons may have hypersensitive reactions, and skin rashes and

urticaria may happen in some persons. As increasing dose of aspirin the incidences of adverse

reactions increase, and symptoms are more serious, even the side reaction of CNS occurs,

including nausea, vomiting, tinnnitus, renal and respiratory failures. Sodium bicarbonate

infusion may make urine alkalinized and promote the excretion of salicylate and its metabolites

from kidney.

II. Acetaminophen

Acetaminophen has excellent antipyretic and analgesic effects, but has no significantly

anti-inflammatory action, and less causes the gastrointenstinal trobles. Acetaminophen is the
active metabolite of phenacetin, the later is one of the oldest antipyretic and analgesic drugs and

has been discarded because of severe side effects.

Acetaminophen is absorbed well after given orally. It is partially metabolized in liver

and converted into acetaminophen sulfate and glucuronide and excreted mainly by kidneys. The

half-life is 2-3 hours.

As an OTC drugs, acetaminophen is widely used to deal with mild and moderate pains

and high fever, such as headache, myalgia, tooth pain, nervous pain, and postpartum.

When therapeutic doses are used, acetaminophen is very safe, and rare cases of renal

damage are reported. However, if large dose (more than 15g) is taken it can cause severe fatal

hepatotoxicity with centrilobular necrosis.

III. Indomethacin

Indomethacin is an indole derivative, and introduced in clinical use in 1963. It is a potent

non-selective COX inhibitor. It may also inhibit phospholipase A and C, and prevent PMN

migration, and decrease T cell and B cell proliferation.

Indomethacin is absorbed well orally. As a NSAID, it is used for treatment of

rheumatic symptoms, gout, ankylosing spondylitis, pleurisy, and so on.

Unfortunately, indomethacin has a high incidence of adverse reactions. More than a

third of patients have to discontinue taking this drug because of severe adverse effects including

gastrointenstinal troubles (epigastric pain, anorexia, vomiting, diarrhea, hemorrhage), CNS

symptoms (dizziness, confusion, hallucination, tinnitus, vertigo.), hepatic abnormalities, and

seriously hematological disorders.

V. Propionic acid derivatives

Propionic acid derivatives include ibuprofen, fenoprofen, flurbiprofen, ketoprofen,

naproxen, and so on. They are non-selective COX inhibitors with good anti-inflammatory,

analgesic, and antipyretic effects. Compared with aspirin, they have less adverse reactions,

especially gastrointestinal responses when ordinary doses are used chronically. Therefore, they

replace aspirin to treat rheumatoid arthritis, osteoarthritis, gout, dysmenorrhea, and other painful

conditions.
 All propionic acid derivatives are well absorbed after given orally and have very high

binding rate with albumen. They undergo hepatic metabolism and excreted by the kidney.

The most common adverse reaction is still gastrointestinal responses including dyspepsia and

bleeding. Headache, tinnitus, dizziness have also been reported.

VI. Selective COX-2 inhibitors

Gastrointestinal responses are the most common adverse reactions of non-selective COX

inhibitors. Many efforts were done to find COX-2 selective inhibitors to avoid the GI adverse

effects. Celecoxib and rofecoxib were introduced into the clinical practice to treat chronically

osteoarthritis and rheumatoid arthritis.

Celecoxib

Celecoxib is about 375 times more selective to COX-2 than COX-1. It was approved

for clinical use in United States in 1998. Celecoxib is readily absorbed orally and has highly

protein bound. It is extensively metabolized by hepatic cytochrome P450 and excreted in the

feces and urine. The half-life is about 11 hours.

The main adverse reactions are abdominal pain, diarrhea, and dyspepsia, although the

incidences of GI side reactions are only a third or a fifth of ibuprofen and naproxon. It has no

obvious effect on platelet aggregation. As a sulfonamide compound, celecoxib may cause

cross-allergic reaction with other sulfonamide drugs.

Rofecoxib

Rofencoxib is also a highly selective potent COX-2 inhibitor and was approved for

clinical use in USA in 1999. It is well absorbed after given orally. The protein bound (87%) is

less than celecoxib. Rofecoxib is metabolized by enzymes in liver as well as in intestinal wall,

and excreted by kidney. The half-life is 17 hours.

Rofencoxib has been approved only for treating osteoarthritis as yet. Its potency is much

higher than celecoxib, but has still similar pharmacological properties to celecoxib, including little

effects on GI and platelet aggregation.

【Preparations of NSAIDs】
 In order to increase antipyretic, analgesic, or anti-inflammatory effects of NSAIDs, many

preparations for special purposes were made. These preparations usually consist of NSAIDs,

antihistamine drugs, sedatives, and drugs contracting vessels. APC and other OTC drugs are

classic preparations among them. When needed, we must choose them carefully.

【preparation and usuage】

阿司匹林（aspirin）：片剂（tablets）：0.5g; 0.5g po prn for high fever and mild pain. 肠溶片

（enteric-coated tablets）：25mg，50mg; 75～150mg per day.

复方阿司匹林（aspirin compound）：Tt is composed of asprin，phenacetin, and caffein. 1# po

prn for high fever and mild pain.

对乙酰氨基酚：（paracetamol）：片剂（tablets）：0.5g; 0.5g po prn for high fever and mild pain.

吲哚美辛（indomethacin）：片剂（tablets）：25g; 100～150mg per day, po for rheumatic symptoms

and gout.

布洛芬（ibuprofen）：片剂（tablets）或胶囊剂（capsules）：0.1g，0.2g，0.3g; 0.4～0.8g tid

or qid for rheumatic diseases; 0.2～0.4g q6h for analgesia.

酮 洛 芬 （ ketoprofen ） ： 肠 溶 胶 囊 （ enteric-coated capsules ） ： 20mg ， 40mg; 控 释 胶 囊

（sustained-release capsules）：0.2g；缓释片（extended-release tablets）：75mg; 50mg tid after

meals.

芬布芬（fenbufen）：片剂（tablets）：0.15g，0.3g; 胶囊剂（capsules）：0.5g; 0.6g per day;

maximum dose: 0.9g per day.

美罗昔康（meloxicam）：片剂（tablets）：7.5mg，15mg; 7.5mg～15mg per day for osteoarthritis

and rheumatoid arthritis.

塞来昔布（celecoxib）：胶囊剂（capsules）：100mg；100mg bid for osteoarthritis and rheumatoid

arthritis.

尼美舒利（nimesulide）：片剂（tablets）：50mg，100mg; 100mg bid for osteoarthritis and

rheumatoid arthritis.

(Q-X Zhou)
 Chapter 16 CNS stimulants
In this chapter we introduce three groups of drugs that primarily stimulate the central nervous

system. The first group is respiratory stimulants, which stimulate respiratory center and

vasomotor center in medullary bulb. The second group is psychomotor stimulants, which cause

excitement and euphoria, decrease feeling of fatigue, and increase motor activity. The third is

notropic drugs, which may help brain to recover some functions that are damaged by diseases or

accidents.

I. Respiratory stimulants
Nikethamide (Coramine)

【Properties】

When respiratory failure occurs, nikethamide makes respiration excitatory through

directly stimulating respiratory center and indirectly exciting respiratory center―stimulating

chemoreceptors in carotid body and then making respiratory center reflex excitation. It also

excites vasomotor center.

Nikethamide is used in treatment of the patients with respiratory failure caused by

variety of factors, especially opioids.

Lobeline

Lobeline is an alkaloid with an effect of reflex respiratory excitement by stimulating

chemoreceptors in carotid and artic bodies. It is used in treatment of carbon monoxide

intoxication, respiratory failure, and asphysia of newborn babies.

Caffeine

Caffeine is also an alkaloid usually extracted from caffee, a common beverage.

Caffeine can stimulate cerebral cortex, respiratory center, vasomotor center in medullus bulb and

even spinal cord, as its dose increases. It also has positive inotropic and chronotropic effects on

the heart, diuretic effect, and promotes gastric acid secretion. The preparation of caffeine is

benzoic caffeine, which is used for treatment of respiratory failure.

II. Psychomotor stimulants

Amphetamine

Amphetamine is a sympathemimetic drug with CNS actions. It promotes the releases

of catecholamines from neurons in special areas and leads to increased alertness, decreased fatigue,

and suppressing appetite and insomnia. At high doses used it causes convulsion. Amphetamine

has strong psychological and physiological dependence when given chronically. It is easy to

cause amphetamine addiction and lead to the health damage.

Methylphenidate

Methylphenidate is structurally related to amphetamine with more prominent effects on

mental than on motor activities. Its pharmacological properties are essentially the same as those

of amphetamine. Methylphenidate is effective in the treatment of narcolepsy and

attention-deficit hyperactivity disorder.

Methylphenidate is readily absorbed after oral administration and reaches peak concentration

in plasma in about 2 hours with a half-life of 4-6 hours. The main metabolite is a deesterified

product, ritalinic acid, which is excreated through kidneys. The use of methylphenidate is

contraindicated in patients with glaucoma.

Cocaine

Cocaine is a highly addictive drug, which is currently abused daily by more than three

million people in the United States. Cocaine blocks the re-uptake of noradrenaline, serotonine,

and adrenaline into nervous terminals and prolongs the actions of mono- amine transmitters and

produces the intense euphoria, alertness, feeling of well being, even produces hallucinations,

delusions, and paranoia.

Suitable dose of cocaine is a local anesthetic drug and used as topical anesthesia in eyes, ears,

nose, as well as throat surgery practice.

III. Nootropic drugs

Nootropic drugs are such drugs that help patients to overcome the congenital and acquired

recognization disorders and improve the functions of learning and memory. Among them
pyrrolidones, circular GABA derivatives are a famous group, including piracetam,

pramiracetam, oxiracetam, aniracetam, and nefiracetam. It was reported that pyrrolidones

were effective against learning and memory disoders caused by inhibitors of protein synthesis,

scopolamine, alcohol, and Librium and improved the capacity of learning and memory from eld or

ischamic animals. The mechanism has not been clear as yet. However, it is said that they may

promote the express of substances related to recognization functions in the body.

Pyrrolidones are well absorbed after given orally. They undergo widely metabolism in the

liver and are excreated through kidneys.

【preparation and usuage】

苯甲酸钠咖啡因（coffeine and sodium benzoate）：注射剂（injection）：0.25g/ml，0.5g/2ml;

0.25～0.5g im prn; maximum dose: 0.8g each time; 3g per day.

尼可刹米（nikethamide）：注射剂（injection）：0.375g/1.5ml；0.375g im or iv prn.

盐酸山梗菜碱（lobeline hydrochloride）：注射剂（injection）：3g/ml，10mg/ml; 3～10mg sc

or im for adults; maximum dose: 20mg each time, 50mg per day.

盐酸哌醋甲酯（methylphenidate hydrochloride）：片剂（tablets）：5mg，10mg; 20～60mg per

day for narcolepsy. 5mg bid first, then gradually increase dose upto 60mg per day for children

with attention-deficit hyperactivity disorder.

匹莫林（pemoline）：片剂（tablets）：18.75mg，37.5mg，75mg; 37.5mg qd every morning;

maintence maximum dose: 112.5mg per day.

吡拉西坦（piracetam）：片剂（tablets）：0.4g；0.8～1.2g bid.

(Q-X Zhou)