AGENTS ACTING ON THE CENT

RAL 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.

3.activity of neuron(conduction of nervous impulse)

(1) AP: sodium, calcium, kalium, chloride

ion channel: voltage-gated, ligand-gated

(2) neurotransmitter:

①NA, ACh, DA, GABA, glutamate, glycine,

5HT, histamine, opioid peptides, tachykinins

(excitatory/ inhibitory).

②biosynthesis, storage, release, degradation,

reuptake.*

(3)receptor *

(4)conduction of impulse cross synapse: presynaptic neuron

release neurotransmitter

synaptic cleft

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). *

4.mechanism of drugs on CNS(1)axon: slow/block axonal electrical conduction e.g. antiepileptics anaesthetics(2)synapse: most drugs ①affect transmitter: synthesis, storage, release, reuptake. e.g. antidepressants ②affect receptor: activation/inhibition(block) e.g. benzodiazepines, antipsychotics ③directly act on ion channels e.g. phenytoin

5.BBB(1) structure barrier between blood and brain cell;3 parts barrier between blood and cerebrospinal fluid barrier between brain cell and cerebrospinal fluid.

endothelial cells(2)function: restrict passage of polar compounds and

macromolecules from blood into brain(3)Pharmacological significance: prerequisite e.g. penicillin/SD----meningitis

CHAPTER 14 Sedative-Hypnotics

【 classification 】 1. benzodiazepines.

2. barbiturates.

3.other agents: e.g. chloral hydrate.

【 general use 】 anxiety, insomnia, convulsion, epilepsy etc.

Benzodiazepines 【 classification 】1.short-acting

triazolam (t1/2 2~4h) 2.intermediate-acting

chlordiazepoxide (t1/2 5~10h)

oxazepam (t1/2 5~10h) 3.long-acting

diazepam (t1/2 30~60h)

flurazepam (t1/2 50~100h)

【 pharmacokinetics 】• Benzodiazepines are lipophilic and are rapi

dly and completely absorbed after oral administration and are distributed throughout body.

• Most benzodiazepines are metabolized by hepatic microsomal metabolizing system to compounds that are also active.

• The benzodiazepines are excreted in urine as glucuronides or oxidized metabolites.

【 mechanism of action 】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.*

【 pharmacologic effects and uses 】 antianxiety small dose sedation hypnosis

anticonvulsion

respiratory depression large dose

DOSE, ADMINISTRATION

【 pharmacologic effects and therapeutic uses 】 1. antianxiety (1) effect All sedative-hypnotic drugs are capable of relie

ving anxiety at sedative doses, but benzodiazepines exert antianxiety action at the lowest effective doses that do not cause sedation.

(2) use anxiety states: restlessness worry stress phobia states common drug: chlordiazepoxide, diazepam P.O./small dose

2. sedation(calming effect) use:• general anaesthesis • tracheoscopy examination electric defibrillation (temporary loss of memory, i.v.)

common drug: diazepam P.O. / i.v. /small dose

3. hypnosis (1) effect to reduce awaking times, to prolong sleep time to shorten sleep latency. (2) use insomnia, especially insomnia with anxiety common drug: flurazepam, temazepam, triazolam, P.O./middle dose

4. anticonvulsant effect(1) effect to inhibit development and spread of epile

ptiform activity in CNS. (2)use: convulsion and status epilepticus, inje

ction/large dose.(3) common drug: ①clonazepam for chronic treatment of epil

epsy; ②diazepam for terminating grand mal epile

ptic seizures and status epilepticus; ③chlordiazepoxide, clorazepate, diazepam

and oxazepam for alcohol withdrawal.

5. muscle relaxation (1) effect inhibitory effects on polysynaptic refle

xes and internuncial transmission in CNS, leading to muscle relaxation

(2) use relaxing muscle spasm induced by cere

bral palsy

common drug: diazepam injection/large dose

【 adverse effects 】 Benzodiazepines have a low toxicity a

nd 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.

Barbiturates【 history 】 【 classification 】1. ultra-short-acting thiopental (action of duration ： 0.25h)2. short-acting secobarbital (action of duration ： 2~3h)3.intermediate-acting pentobarbital and amobarbital (action of duration ： 3~6h)4. long-acting phenobarbital (action of duration ： 6~8h)

【 pharmacokinetics 】• Duration of action depends on rate of meta

bolic degradation, degree of lipid solubility, extent of binding to serum proteins. Ultra-short-acting barbiturates are highly lipid-soluble, whereas long- acting barbiturates are lowly lipid-soluble.

• redistribution: e.g. thiopental.

• excretion via kidney. Alkalinization of urine profoundly promotes excretion of barbiturates.

【 mechanism of action 】①to enhance effects of GABA.

②to interfere with sodium and potassium transport across cell membrane that leads to inhibition of mesencephalic reticular activating system.

③to directly activate chloride channel,

to prolong opening time of chloride channel,

to increase influx of Cl- to enlarge membrane potential in large dose.

【 pharmacologic effects 】1. to depress CNS at all levels sedation small dose hypnosis anticonvulsion

anesthesia

respiratory depression

depression of vasomotor center large dose

2.to augment action of other CNS depressants3.to shorten amount of time in REMS4.induce hepatic microsomal drug-metabolizin

g enzymes clinical significance: (1) to increase degradation of the barbiturates, ultimately leading to barbiturate tolerance. (2)to increase inactivation and decreased acti

on of other compounds in drug interaction.

【 therapeutic uses 】 DOSE, ADMINISTRATION1.sedation and hypnosis: intermediate and long-acting barbiturates P.O. small dose

disadvantages: 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 induction.

2. Anticonvulsion phenobarbital, pentobarbital or amobarbital injection large dose3. Antiepileptism phenobarbital for epileptism in infant and children injection large dose4. intravenous anesthetics or intravenous adjunct to surgical anesthetics thiopental intravenous injection large dose

5.cerebral edema, cerebral infarction

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.

【 adverse effects 】1.CNS depressant effects• Oversedation• nightmare.

2. dependence:

physiologic and psychological dependence.

Withdrawal of barbiturates may result in grand mal seizures, severe tremors, vivid hallucinations, and psychoses.

Abrupt withdrawal should be avoided.

3. acute barbiturate overdosage

(1) clinical menifestations

coma,

diminished reflexes,

severe respiratory depression,

cardiovascular collapse,

renal failure.

(2) treatments

① supporting respiration and circulation;

② alkalizing gastric juice, body fluids and

urine(sodium bicarbonate),

③ diuresis.

Differentiation of barbiturates with benzodiazepines benzodiazepines barbiturates1. antianxiety: dose lower than same dose as one for sedation. for sedation.2. shortening REMS : weak obvious3. central muscular have no4. anaesthesis: no have5. hepatic micro- no have some induction:6. margin of safety: wide narrow7. depression of weak strong respiration:

Chloral hydrate 1. a relatively safe hypnotic drug, inducing sl

eep 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 children. 5. addiction can occur.

Paraldehyde

1. CNS depressant activity of paraldehyde resembles that of alcohol, chloral hydrate and barbiturates.

2. use

exclusively for patients undergoing withdrawal from alcohol and for patients with hepatic or renal failure.

Summary for this chapter

1. main effects

2. main uses

3.main adverse reactions

central inhibition

dependence

toxic effects

4.common drugs

5.dose and administration

CHAPTER 15

Agents used in the treatment of seizures

1.etiology

(1) primary epilepsy: inherited abnormality.

(2) secondary epilepsy: such as brain tumors, head injury, hypoglycemia, meningeal infection, rapid withdrawal of alcohol from an alcoholic.

2.pathogenesis

sudden, excessive and abnormal discharge of cerebral neurons which diffuses to local or whole brain in short time over-excitement.

3. clinic manifestation regional or whole brain dysfunction: • motor • vegetative and mental episodes • loss of consciousness etc.

4. classification (1)generalized ①grand mal epilepsy (tonic-clonic) epilepticism (status epilepticus) ②absence epilepsy(petit mal) ③ myoclonic epilepsy ④febrile seizures (2)Partial

①Simple partial

②Complex partial *

5.treatment (1) primary epilepsy antiepileptic drugs (2) secondary epilepsy antiepileptic drugs + against primary cause

Mechanisms of action of drugs:• Inhibiting sodium influx• Potentiating GABA-neuronal function

Phenytoin 【 pharmacokinetics 】 • high concentrations in brain,• high plasma albumin binding,• half-life: 24 hours. 【 mechanism of action 】 to decrease Na+ conductance in neurons t

o stabilize nervous cellular membranes to reduce the influx of calcium ions during depolarization suppresses high-frequency repetitive firing halts seizure activity.

【 pharmacologic effects 】1.antiepileptic effect

effective for tonic-clonic and partial seizures

2. Anti-peripheral neuralgia

3. antiarrhythmia

【 therapeutic uses 】1. epilepsy.

• highly effective for all partial seizures, tonic-clonic seizures and status epilepticus.

• not effective for absence seizure.

2. peripheroneural pain. trigeminal neuralgia, glossopharyngeal neuralgia and sciatic neuralgia etc..

3. arrhythmia (see antiarrhythmic drugs)

【 adverse effects 】1. gastrointestinal irritation administration with or after meal.2. depression of CNS 3. blood dyscrasias4.cardiovascular collapse (arrhythmia, calcium antagonism)5. gingival hyperplasia6. hepatitis in the long administration7. allergic reaction8. fetal malformation9. to induce the P-450 system

Barbiturates1.characteristics (1)mechanism of action is unknown but involves pot

entiation of inhibitory effects of GABA neurons. (2)dose required for antiepileptic action is lower tha

n dose that causes pronounced CNS depression for the patient. More selectivity in anticonvulsant action than in sedative effect.

2.use(1) 50% effective rate for simple partial seizure.(2) not effective for complex partial seizure.(3) first-choice drug for epilepticism in infant and child

ren. (4) effective for recurrent tonic-clonic seizures, espec

ially in patients who do not respond to diazepam plus phenytoin.

Benzodiazepines

Intravenous diazepam is used for epilepticism in adults.

Clonazepam is used for absence and myoclonic seizure in children.

Carbamazepine

1.The actions and mechanism are similar to those of phenytoin.

• highly effective for all partial seizure as first-choice drug,

• highly effective for tonic-clonic seizures,

• effective for trigeminal neuralgia etc..

2.More adverse effects, especially serious liver toxicity.

Ethosuximide

1.effective for absence seizure,

no effective for other seizures.

2.more adverse effects.

• Stevens- Johnson syndrome in sensitive individuals

• Urticarria

• leukopenia, aplastic anemia and thrombocytopenia

Sodium valproate• most effective for myoclonic seizure to redu

ce incidence and severity of tonic-clonic seizures,

• effective for absence seizure but second choice because of its hepatotoxicity.

Other new agents: gabapenitin in 1993 lamotrigine in 1994 tiagabine in 1998*

Summary for this chapter

1. choice of drugs for different patterns of

epilepsies

2. effects and uses of phenytoin

CHAPTER 16

Anticonvulsant drugs

1. pathogenesis

2. anticonvulsant drugs

• Barbiturates/ injection, large dose

• Benzodiazepines / injection, large dose

• chloral hydrate/ enema

• magnesium sulfate injection etc.

Magnesium sulfate【 pharmacologic effects 】 ADMINISTRATION, DOSE1.oral administration laxative effect and promoting bile excretion2. injection administration (1)anticonvulsant• inhibiting CNS by Mg2+ (central mechanism)• relaxing skeletal muscle (peripheral mechanism) Ca2+ antagonism inhibiting ACh release(2)hypotensive: direct vasodilation

【 therapeutic uses 】1. constipation, promoting excretion of toxic

substances and parasites in the intestinal tract. P.O/ large dose

2. convulsion and hypertensive emergencies (crisis, encephalopathy): injection【 adverse effects 】• breathe inhibition and hypotention, even

death.• calcium chloride or calcium gluconate sh

ould be administered.

Summary for this chapter

1. drugs used for convulsion

2. effects, mechanism of action, and uses of magnesium sulfate

CHAPTER 17

Agents Used in the Treatment of Parkinsonian Disorders

1.classification of Parkinsonian disorders

Parkinsonian disease

Parkinsonian syndrome

2.Pathogenesis

nigra caudatum

○ ○

(D2R) DA Ach(MR)

striatum

(-) (+)

 

motor neurons in anterior horn of spinal cord

 

skeletal muscle contraction

3.Clinical menifestations

tremor, muscular rigidity, bradykinesia etc.

4.therapy

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

5. classification of drugs

(1) dopaminomimetic

• metabolite precursor: levodopa

• decarboxylase inhibitor: carbidopa

• DA receptor agonist: bromocriptine

• MAO inhibitor: selegiline

• COMT inhibitor: tocapone

• drug releasing dopamine: amantadine

(2) anticholinergic drug: trihexyphenidyl

Levodopa (L-dopa)【 mechanism of action 】 L-dopa is transformed to dopamine via dopa deca

rboxylase in brain and corrects dopamine deficiency in nigrostriatum.???

【 pharmacokinetics 】1. Dopamine does not cross BBB, thus L-dopa (prec

ursor of dopamine) is given instead and is readily transported into CNS.

2.L-dopa is well absorbed from small intestine; however, 99% is rapidly decarboxylated in periphery, resulting in peripheral side effects. So, large dose of L-dopa is required.*

【 pharmacologic effects 】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.

【 therapeutic uses 】• effective for Parkinsonian disease• effective for Parkinsonian syndrome caused

by other causes except phenothiazides (1st choice)

• combination of L-dopa with carbidopa【 adverse effects 】1.cardiovascular effects 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.

Carbidopa

• inhibitor of dopa decarboxylase

• not penetrating BBB

• to reduce peripheral conversion of L-dopa to dopamine

• Use: in combination with L-dopa

augmenting beneficial effects of L-dopa

reducing dose and adverse effects of L-dopa.

• no use alone.

Amantadine1.history

2. action mechanisms• stimulating synthesis and release of dopamine fr

om surviving dopaminergic nerve terminals• delaying its reuptake in nigrostriatum

3. effects• More effective than anticholinergic agents against

rigidity and bradykinesia• Less effective than L-dopa in treatment of Parkins

onian disorders• No effective for tremor

4. uses• Alone for early Parkinsonian disease• Various Parkinsonian diseases in combination wit

h L-dopa

5.adverse effects

restlessness, agitation, confusion and hallucination.

Trihexyphenidyl(Artane)

1.action mechanism

blocking M receptors in CNS reducing function of cholinergic nerves in nigrostriatum restoring balance between dopaminergic and cholinergic neurons.

2.effect: • Less efficious than levodopa.• More effective on tremor, less effective on bradyki

nesia and rigidity.

3.use• alone for:

mild patients

patients of discontinuation of L-dopa due to adverse effects, Parkinsonian syndrome induced by phenothiazides

• all Parkinsonian disorders in combination with L-dopa

4.side effects

similar to those of atropine.

scopolamine

Summary for this chapter

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.

CHAPTER 18

Agents used in the Treatment of Psychiatric Disorders

【 classification 】1.antipsychotic agents

phenothiazines

2.antimanic and antidepressive agents lithium carbonate ， imipramine

3.antianxiety agents

benzodiazepines

I Antipsychotic Agents

(antischizophrenic drugs, major tranquilizers, neuroleptic drugs)

1.use

schizophrenia, manic states of other psychiatric disorders.

2.schizophrenia manifestation

delusions, hallucinations, thinking or speech disturbances.

【 classification of drug 】Based on the structure of the drug: 1.phenothiazines chlorpromazine, fluphenazine, promethazine,

thioridazine etc.2. benzisoxazoles: risperidone3.dibenzodiazepines: clozapine4.butyrophenones: haloperidol5.thioxanthenes: thiothixene*

【 pathogenesis of schizophrenia 】 Relevance of pathogenesis of schizophrenia

to dopaminergic nerve in CNS:

Evidences1.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.

Dopaminergic nervous pathway

1.limbic system- mesencephalic pathway

emotion

2.cortico- mesencephalic pathway

thinking and motion

3.nigrostriatum pathway

motion

4.hypothalamo-hypophysis pathway

endocrine

【 mechanism of action 】 antagonism of dopaminergic receptors (D2)

in CNS.1.to block dopamine receptors in limbic system

-mesencephalic pathway to improve emotion2.to block dopamine receptor in cortico- mesen

cephalic 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

Phenothiazines【 classification 】 Drug Major use Frequency of Adverse Effects

orthostatic extrapyramidal hypotension symptomschlorpromazine antipsychotic moderate moderate(wintermin) antiemeticclozapine antipsychotic low low  anticholinergic  antihistaminicthioridazine antipsychotic moderate lowtriflupromazine antipsychotic moderate high

fluphenazine antipsychotic low high

prochlorperazine antiemetic low low~moderate

promethazine antihistaminic moderate low

【 pharmacologic effects 】1.effects on CNS

(1) antipsychotic effect

(2) sedation and synergism with other

CNS depressives

(3) antiemetic effects

(4) effects on temperature-regulating

mechanisms

2.altering endocrine

3.peripheral effects

1.effects on CNS1) antipsychotic effects(1) tranquilization:• to make animals docile and friendly, rapidly to contr

ol manic states of psychotic patients and make them quiet (calming effect) and peaceful;

• to make patients feel indifferent, then induce sleepin 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.

action mechanism

blocking dopamine D2 receptor in limbic sys

tem- 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 hig

h 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).

2.altering endocrine

to depress hypothalamus by blocking dopamine receptors to induce endocrine alteration

• lactation and gynecomastia,

• abnormal pigmentation,

• decrease of corticotropin release

• decrease of secretion of pituitary growth hormone (for gigantism)

• weight gain

• increased appetite.

3. peripheral effects

• orthostatic hypotension and miosis by α-receptor blocking;

• blurred vision, constipation, dry mouth, decreased sweating, mydriasis and rarely urinary retention by blockade of M receptors.

【 therapeutic uses 】1.psychotic disorders• mania, • paranoid states, • Schizophrenia• psychoses associated with chronic alcoholism (alcoh

olic hallucinosis).2.most phenothiazines except thioridazine • effective for nausea and vomiting,• ineffective for vomiting induced by stimulating vestib

ules of ears (motion sickness).3.artificial hibernation*4.antipruritics: promethazine (H1 blocking).5. intractable hiccup: chlorpromazine.

Lyticcocktail and physical reduction of body temperature↓

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.

【 adverse effects 】1.general adverse effects central depression, M-receptor blockage2.extrapyramidal effects manifestation: • Parkinsonian syndrome, • acute dystonic reaction (facial grimacing and tortic

ollis) • tardive dyskinesia (sucking and macking of the lip

s and other involuntary facial movements). pathogenesis: blocking DR in the nigrostriatum. treatment: artane.3. cardiovascular effects: orthostatic hypotension (N

A), syncope and reflex tachycardia.4. allergic reactions.

Summary1. blocking 3 types of receptors • DR• MR• αR2. effect on 3 systems• CNS• endocrine system• Autonomic nervous system3. 3 main clinical uses• psychotic disorders• nausea and vomiting,• artificial hibernation4. 3 main adverse reactions• central depression• extrapyramidal effects• cardiovascular effects

II Mood-Altering Drugs (Antimanic and Antidepressive Agents)

Use: affective disorder(mania, depression)• Pathogenesis of depression is thought to be relate

d to deficiency of monoamines such as 5- HT and noradrenaline in certain key sites of brain.

• Mania would be induced by an overproduction of these neurotransmitters.

• All clinically useful antidepressant drugs directly or indirectly potentiate noradrenaline, dopamine, and/ or serotonin in brain.

classification of depression:

• major (endogenous)

• reactive

• bipolar(manic-depressive)

Antimanic agents—lithium carbonate

【 mechanism of action 】 Mechanism of action is unknown. It is current

ly proposed that lithium acts by altering the cellular concentration of inositol triphosphate (IP3).

【 therapeutic uses 】1.mania, manic episodes of bipolar disorder2.useful in reducing the intensity of depression?

【 adverse effects 】 high toxic and low therapeutic index, to mainta

in serum concentration between 0.8 and 1.5mmol/L.

toxic effects:ataxia,tremors,convulsion,anorexia, vomiting,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 byosmotic diuresis or, in more severe cases, bydialysis.

Antidepressants agents【 classification 】 *1. NA and 5-HT reuptake inhibitors (tricyclic or polycy

clic antidepressants) imipramine, amitriptyline, desipramine, nortriptyline,

doxepin, trimipramine.2. MAO inhibitors (1) hydrazides: isocarboxazid, phenelzine (2) nonhydrazides: tranylcypromine3.selective 5-HT reuptake inhibitors fluoxetine, sertraline, paroxetine, bupropion, venlafa

xine etc.

Tricyclic/ polycyclic antidepressants

【 mechanism of action 】• to block NA and 5-HT reuptakes into the pr

esynaptic neurons to increase NA and 5-HT level in the synaptic cleft in CNS.

• Monoamine receptor densities in the brain may change over 2 to 4 week with drug use and may be important in the onset of activity.

【 pharmacokinetics 】• well absorbed upon oral administration, • widely distributed,• readily to penetrate into the CNS,• long half-life,• low and inconsistent bioavailability because of variable first pass metabolism in the liver. Therefore the patient response is used t

o adjust dose.The initial treatment period is typically 4 to 8 weeks.The dose can be gradually reduced unless relapse occurs.

【 pharmacologic effects 】 All tricyclic antidepressants have similar

therapeutic efficacy.

1. effects on CNS

2.cardiovascular effects

3. effects on autonomic nervous system

1. effects on CNS(1)A nondepressed person experiences sleepiness a

fter 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 extrapyramid

al symptoms and ataxia. High doses of tricyclic antidepressants are capable of producing seizures and coma.

2.cardiovascular effects orthostatic hypotension, arrhythmias, tachycardia, slow atrioventricular conduction.

3. effects on autonomic nervous system anticholinergic effect.

【 therapeutic uses 】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 】Adverse effects of tricyclic anti-depressants r

esemble to phenothiazines.

1.peripheral effects

anticholinergic actions

2.central effects

ataxia, dizziness and muscle tremor; manic excitement and delirium can occur in the patients with bipolar illness.

3. cardiovascular effects

cardiac arrhythmias and hypotension

Differentiation of tricyclic antidepressantsdrug t1/2(h) inhibition of reuptake sedation anticholinergic

of monoamines

5-HT NA

imipramine 9~24 ++ ++ ++ ++

desipramine14~76 0 +++ + +

amitriptyline17~40 +++ + +++ +++

doxepin 8~24 weak weak +++ +++

MAO inhibitors

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.

Selective 5-HT reuptake inhibitors*

The selective 5-HT reuptake inhibitors specially inhibit serotonin reuptake. Compared with tricyclic antidepressants, these drugs cause fewer anticholinergic effects and lower cardiotoxicity.

III Agents Used in the Treatment of Anxiety(anxiolytic drugs or minor tranquilizers)

1.anxiety: symptom, anxiety sydrome 2.use: anxiety or neurosis3.characteristics• sedative• hypnotic properties• central skeletal muscle relaxant activity• habituation and physical dependence• lower incidence of adverse effects than the antipsychotic agents.*