AGENTS ACTING ON THE CENTRAL NERVOUS SYSTEM. Liu Juntian ( 刘俊田 ) (Pharmacol Dept, Med School of XJTU). CHAPTER 13 General consideration. 1.composition of nervous system (1)central and peripheral nervous systems (2)neuron and synapse *. 2.function of CNS: regulating body functions.
Liu Juntian (刘俊田)
(Pharmacol Dept, Med School of XJTU)
1.composition of nervous system
(1)central and peripheral nervous systems
(2)neuron and synapse*
3.activity of neuron(conduction of nervous impulse)
(1)AP: sodium, calcium, kalium, chloride
ion channel: voltage-gated, ligand-gated
①NA, ACh, DA, GABA, glutamate, glycine,
5HT, histamine, opioid peptides, tachykinins
②biosynthesis, storage, release, degradation,
neurotransmitter interacts with receptor
neurotransmitter-receptor complex initiates a sequence of events (open ion channel)
modulate the electrical activity of the postsynaptic neuron (depolarization/ hyperpolarization). *
slow/block axonal electrical conduction
(2)synapse: most drugs
synthesis, storage, release, reuptake.
②affect receptor: activation/inhibition(block)
e.g. benzodiazepines, antipsychotics
③directly act on ion channels
barrier between blood and brain cell;
3 parts barrier between blood and cerebrospinal
barrier between brain cell and cerebrospinal
(2)function: restrict passage of polar compounds and macromolecules from blood into brain
(3)Pharmacological significance: prerequisite
3.other agents: e.g. chloral hydrate.
anxiety, insomnia, convulsion, epilepsy etc.
chlordiazepoxide (t1/2 5~10h)
oxazepam (t1/2 5~10h)
diazepam (t1/2 30~60h)
flurazepam (t1/2 50~100h)
There are benzodiazepine receptors (BZR1, BZR2) in CNS,
which are separate from but adjacent to receptor for GABAA.
Benzodiazepines activate BZR
promote GABA binding to GABAA receptors
The binding opens Cl— channel
Cl— influx to neurons
The influx causes a small hyperpolarization
inhibits formation of action potentials
inhibitory effect on neuronal conduction.*
antianxiety small dose
respiratory depression large dose
All sedative-hypnotic drugs are capable of relieving anxiety at sedative doses, but benzodiazepines exert antianxiety action at the lowest effective doses that do not cause sedation.
anxiety states: restlessness
common drug: chlordiazepoxide, diazepam
(temporary loss of memory, i.v.)
common drug: diazepam
P.O. / i.v. /small dose
to reduce awaking times,
to prolong sleep time
to shorten sleep latency.
insomnia, especially insomnia with anxiety
common drug: flurazepam, temazepam,
to inhibit development and spread of epileptiform activity in CNS.
(2)use: convulsion and status epilepticus, injection/large dose.
(3) common drug:
①clonazepam for chronic treatment of epilepsy;
②diazepam for terminating grand mal epileptic seizures and status epilepticus;
③chlordiazepoxide, clorazepate, diazepam and oxazepam for alcohol withdrawal.
inhibitory effects on polysynaptic reflexes and internuncial transmission in CNS, leading to muscle relaxation
relaxing muscle spasm induced by cerebral palsy
common drug: diazepam
Benzodiazepines have a low toxicity and wide margin of safety (therapeutic index).
1. central inhibitory effect
dizziness, asthenia, drowsiness.
2. tolerance, dependence and addiction.
3. acute toxication
flumazenil--competitively BZR blocker.
thiopental (action of duration：0.25h)
secobarbital (action of duration：2~3h)
pentobarbital and amobarbital
(action of duration：3~6h)
phenobarbital (action of duration：6~8h)
①to enhance effects of GABA.
②to interfere with sodium and potassium transport across cell membrane that leads to inhibition of mesencephalic reticular activating system.
③todirectly activate chloride channel,
to prolong opening time of chloride channel,
to increase influx of Cl- to enlarge membrane potential in large dose.
1. to depress CNS at all levels
sedation small dose
depression of vasomotor center large dose
3.to shorten amount of time in REMS
4.induce hepatic microsomal drug-metabolizing enzymes
(1) to increase degradation of the barbiturates,
ultimately leading to barbiturate tolerance.
(2)to increase inactivation and decreased action of other compounds in drug interaction.
1.sedation and hypnosis:
intermediate and long-acting barbiturates
① narrow therapeutic-to-toxic dosage range;
② suppressing REMS;
③ tolerance ;
④ high potential for physical dependence and abuse
⑤ drug interaction secondary to microsomal enzyme
phenobarbital, pentobarbital or amobarbital
phenobarbital for epileptism in infant and children
4. intravenous anesthetics or intravenous adjunct to
Barbiturates, especially in anesthetic doses, significantly decrease oxygen utilization by brain, which may be of value in lessening cerebral edema caused by surgery or trauma and in protecting against cerebral infarction duration cerebral ischemia.
6. Hyperbilirubinemia (jaundice) and kernicterus in the neonate.
1.CNS depressant effects
physiologic and psychological dependence.
Withdrawal of barbiturates may result in grand mal seizures, severe tremors, vivid hallucinations, and psychoses.
Abrupt withdrawal should be avoided.
(1) clinical menifestations
severe respiratory depression,
① supporting respiration and circulation;
② alkalizing gastric juice, body fluids and
dose lower than same dose as
one for sedation. for sedation.
2. shortening REMS : weak obvious
3. central muscular have no
4. anaesthesis: no have
5. hepatic micro- no have
6. margin of safety: wide narrow
7. depression of weak strong
1. a relatively safe hypnotic drug, inducing sleep in a half hour and lasting about 6 hours.
2. relatvely small reduction in REM sleep.
3. use: children and the elderly with
insomania, most effective for 1-3 nights.
4. bad-tasting and irritating to the gastro-
intestinal tract, administered by enema in
5. addiction can occur.
1. CNS depressant activity of paraldehyde resembles that of alcohol, chloral hydrate and barbiturates.
exclusively for patients undergoing withdrawal from alcohol and for patients with hepatic or renal failure.
1. main effects
2. main uses
3.main adverse reactions
5.dose and administration
Agents used in the treatment of seizures
(1) primary epilepsy: inherited abnormality.
(2) secondary epilepsy: such as brain tumors, head injury, hypoglycemia, meningeal infection, rapid withdrawal of alcohol from an alcoholic.
sudden, excessive and abnormal discharge of cerebral neurons which diffuses to local or whole brain in short time over-excitement.
regional or whole brain dysfunction:
①grand mal epilepsy (tonic-clonic)
epilepticism (status epilepticus)
②absence epilepsy(petit mal)
③ myoclonic epilepsy
②Complex partial *
(1) primary epilepsy
(2) secondary epilepsy
+ against primary cause
Mechanisms of action of drugs:
【mechanism of action】
to decrease Na+ conductance in neurons to stabilize nervous cellular membranes to reduce the influx of calcium ions during depolarization suppresses high-frequency repetitive firing halts seizure activity.
effective for tonic-clonic and partial seizures
2. Anti-peripheral neuralgia
2. peripheroneural pain. trigeminal neuralgia, glossopharyngeal neuralgia and sciatic neuralgia etc..
3. arrhythmia (see antiarrhythmic drugs)
1. gastrointestinal irritation
administration with or after meal.
2. depression of CNS
3. blood dyscrasias
(arrhythmia, calcium antagonism)
5. gingival hyperplasia
6. hepatitis in the long administration
7. allergic reaction
8. fetal malformation
9. to induce the P-450 system
(1)mechanism of action is unknown but involves potentiation of inhibitory effects of GABA neurons.
(2)dose required for antiepileptic action is lower than dose that causes pronounced CNS depression for the patient. More selectivity in anticonvulsant action than in sedative effect.
(1) 50% effective rate for simple partial seizure.
(2) not effective for complex partial seizure.
(3) first-choice drug for epilepticism in infant and children.
(4) effective for recurrent tonic-clonic seizures, especially inpatients who do not respond to diazepam plus phenytoin.
Intravenous diazepam is used for epilepticism in adults.
Clonazepam is used for absence and myoclonic seizure in children.
1.The actions and mechanism are similar to those of phenytoin.
2.More adverse effects, especially serious liver toxicity.
1.effective for absence seizure,
no effective for other seizures.
2.more adverse effects.
Other new agents: gabapenitin in 1993
lamotrigine in 1994
tiagabine in 1998*
1. choice of drugs for different patterns of
2. effects and uses of phenytoin
2. anticonvulsant drugs
laxative effect and promoting bile excretion
2. injection administration
inhibiting ACh release
(2)hypotensive: direct vasodilation
2. convulsion and hypertensive emergencies
1. drugs used for convulsion
2. effects, mechanism of action, and uses of magnesium sulfate
Agents Used in the Treatment of Parkinsonian Disorders
1.classification of Parkinsonian disorders
(D2R) DA Ach(MR)
motor neurons in anterior horn of spinal cord
skeletal muscle contraction
tremor, muscular rigidity, bradykinesia etc.
reestablish dopamine/ acetylcholine balance.
(1) To increase function of dopaminergic neurons in nigrostriatum.
(2) To decrease function of cholinergic neurons.
Clinical effect: reliefing symptoms, not stoping progress
(2) anticholinergic drug: trihexyphenidyl
【mechanism of action】
L-dopa is transformed to dopamine via dopa decarboxylase in brain and corrects dopamine deficiency in nigrostriatum.???
1. Dopamine does not cross BBB, thus L-dopa (precursor of dopamine) is given instead and is readily transported into CNS.
2.L-dopa is well absorbed from small intestine; however, 99% is rapidlydecarboxylated in periphery, resulting in peripheral side effects. So, large dose of L-dopa is required.*
1.Improvement of bradykinesia and rigidity is more rapid and complete than of tremor.
2. L-dopa is more effective for young and mild patients or early disease than old and severe patients.
3. L-dopa is ineffective for Parkinsonian syndrome induced by antipsychotic drug phenothiazides.
4. Tolerance to both beneficial and adverse effects from L-dopa occurs with time. L-dopa is more effective in the first 2-5 years of therapy.
tachycardia, arrhythmias etc.
2.central nervous side effects
vivid dream, delusion etc. mental disturbances.
3.gastrointestinal reaction: nausea, vomiting.
4.no Vit B6 during therapy.
augmenting beneficial effects of L-dopa
reducing dose and adverse effects of L-dopa.
2. action mechanisms
restlessness, agitation, confusion and hallucination.
blocking M receptors in CNS reducing function of cholinergic nerves in nigrostriatum restoring balance between dopaminergic and cholinergic neurons.
patients of discontinuation of L-dopa due to adverse effects, Parkinsonian syndrome induced by phenothiazides
similar to those of atropine.
1. mechanisms of action of all drugs.
2. characteristics of drugs.
3. uses of drugs.
4. main adverse reactions of L-dopa.
5. combination of drugs.
Agents used in the Treatment of Psychiatric Disorders
2.antimanic and antidepressive agents lithium carbonate，imipramine
(antischizophrenic drugs, major tranquilizers, neuroleptic drugs)
schizophrenia, manic states of other psychiatric disorders.
delusions, hallucinations, thinking or speech disturbances.
Based on the structure of the drug:
chlorpromazine, fluphenazine, promethazine, thioridazine etc.
2. benzisoxazoles: risperidone
Relevance of pathogenesis of schizophrenia to dopaminergic nerve in CNS:
1.DA increases in the brain of the patient.
2.DR increases in the brain of the patient.
3.functions of dopaminergic neurons increase.
4.promotion of DA release induces episode of schizophrenia.
5.blocking DR inhibit episode of schizophrenia.
1.limbic system- mesencephalic pathway
2.cortico- mesencephalic pathway
thinking and motion
antagonism of dopaminergic receptors (D2) in CNS.
1.to block dopamine receptors in limbic system -mesencephalic pathway to improve emotion
2.to block dopamine receptor in cortico- mesencephalic pathway to restore thinking and motion
3.to block dopamine receptor in nigrostriatum pathway to cause extrapyramidal symptoms
4.to bock dopamine receptor in hypothalamo-hypophysis pathway to cause endocrine dysfunction
Drug Major use Frequency of Adverse Effects
chlorpromazine antipsychotic moderate moderate
clozapine antipsychotic low low
thioridazine antipsychotic moderate low
triflupromazine antipsychotic moderate high
fluphenazine antipsychotic low high
prochlorperazine antiemetic low low~moderate
promethazine antihistaminic moderate low
1.effects on CNS
(1) antipsychotic effect
(2) sedation and synergism with other
(3) antiemetic effects
(4) effects on temperature-regulating
1) antipsychotic effects
in few days.
(2) intellect restoration, emotional quieting, reducing psychomotor excitement of the patient
in few weeks.
(3) to eliminate hallucination and illusion of the patient
in few months.
blocking dopamine D2 receptor in limbic system- mesencephalic and cortico-mesencephalic pathways.
2) sedation and synergism with other CNS depressives (analgesics, sedative-hypnotics, anesthetics).
3) antiemetic effects:
to block D2 receptors in medullary CTZ. In high doses, the agents may directly depress medullary vomiting center.
4)effect on temperature-regulating mechanism
to inhibit temperature-regulating center in hypothalamus to induce poikilothermia (hypothermia, hyperthermia).
to depress hypothalamus by blocking dopamine receptors to induce endocrine alteration
2.most phenothiazines except thioridazine
4.antipruritics: promethazine (H1 blocking).
5. intractable hiccup: chlorpromazine.
body temperature↓+ central depression(sleep)
irritability to pathologic reaction↓;
basal metabolism↓→ O2 consumption↓;
vasodilation→to improve microcirculation
to protect the important organs from damage to gain enough time for effective etiological treatment by other drugs.
Artificial hibernation therapy can be used in serious patients with toxic infection, toxication and trauma etc.
1.general adverse effects
central depression, M-receptor blockage
pathogenesis: blocking DR in the nigrostriatum.
3. cardiovascular effects: orthostatic hypotension (NA), syncope and reflex tachycardia.
4. allergic reactions.
1. blocking 3 types of receptors
2. effect on 3 systems
3. 3 main clinical uses
4. 3 main adverse reactions
Use: affective disorder(mania, depression)
【mechanism of action】
Mechanism of action is unknown. It is currently proposed that lithium acts by altering the cellular concentration of inositol triphosphate (IP3).
1.mania, manic episodes of bipolar disorder
2.useful in reducing the intensity of
high toxic and low therapeutic index, to maintain serum concentration between 0.8 and 1.5mmol/L.
diarrhea, excessive thirst and polyuria, somnolene,
confusion and psychomotor disturbances,
cardiovascular anomalies in the newborn,
hypotension and cardiac arrhythmias.
Chronic lithium use results in thyroid enlargement.
Lithium toxication can usually be reversed by
osmotic diuresis or, in more severe cases, by
1. NA and 5-HT reuptake inhibitors (tricyclic or polycyclic antidepressants)
imipramine, amitriptyline, desipramine, nortriptyline, doxepin, trimipramine.
2. MAO inhibitors
(1) hydrazides: isocarboxazid, phenelzine
(2) nonhydrazides: tranylcypromine
3.selective 5-HT reuptake inhibitors
fluoxetine, sertraline, paroxetine, bupropion, venlafaxine etc.
【mechanism of action】
of variable first pass metabolism in the liver.
Therefore the patient response is used to adjust dose.The initial treatment period is typically 4 to 8 weeks.The dose can be gradually reduced unless relapse occurs.
All tricyclic antidepressants have similar therapeutic efficacy.
1. effects on CNS
3. effects on autonomic nervous system
(1)A nondepressed person experiences sleepiness after administration. In addition, anxiety and toxic anticholinergic effects may be experienced.
(2)In depressed patient, tricyclic antidepressants elevate mood, improve mental alertness, increase physical activity and reduce morbid preoccupation. Onset of mood elevation is slow and requires 2 to 3 weeks after administration.
Latency period can be as long as 4 weeks.
(3)Tricyclic antidepressants can cause extrapyramidal symptoms and ataxia. Highdoses of tricyclic antidepressants are capable of producing seizures and coma.
slow atrioventricular conduction.
3. effects on autonomic nervous system anticholinergic effect.
1. severe endogenous depression.
2. enuresis(bed-wetting): imipramine.
3. obsessive-compulsive neurosis accompanied by depression, and phobic anxiety syndromes, chronic pain, and neuralgia may respond to tricyclic agents.
Adverse effects of tricyclic anti-depressants resemble to phenothiazines.
ataxia, dizziness and muscle tremor; manic excitement and delirium can occur in the patients with bipolar illness.
3. cardiovascular effects
cardiac arrhythmias and hypotension
drug t1/2(h) inhibition of reuptake sedation anticholinergic
imipramine 9~24 ++ ++ ++ ++
desipramine14~76 0 +++ + +
amitriptyline17~40 +++ + +++ +++
doxepin 8~24 weak weak +++ +++
MAO inhibitors inhibit MAO activity to increase store of noradrenaline, serotonin and dopamine within the neuron.
MAO inhibitors are indicated for depression patients who are unresponsive or allergic to tricyclic antidepressants or who experience strong anxiety.
The selective 5-HT reuptake inhibitors specially inhibit serotonin reuptake. Compared with tricyclic antidepressants, these drugs cause fewer anticholinergic effects and lower cardiotoxicity.
(anxiolytic drugs or minor tranquilizers)
1.anxiety: symptom, anxiety sydrome
2.use: anxiety or neurosis