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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.

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agents acting on the central nervous system

AGENTS ACTING ON THE CENTRAL NERVOUS SYSTEM

Liu Juntian (刘俊田)

(Pharmacol Dept, Med School of XJTU)

chapter 13 general consideration
CHAPTER 13 General consideration

1.composition of nervous system

(1)central and peripheral nervous systems

(2)neuron and synapse*

slide4
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.*

slide7

(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). *

slide9

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

slide10

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
CHAPTER 14 Sedative-Hypnotics

【classification】

1. benzodiazepines.

2. barbiturates.

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

【general use】

anxiety, insomnia, convulsion, epilepsy etc.

slide12

Benzodiazepines

【classification】

1.short-acting

triazolam (t1/22~4h)

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)

slide13

【pharmacokinetics】

  • Benzodiazepines are lipophilic and are rapidly 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 asglucuronides or oxidized metabolites.
slide14

【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.*

slide16

【pharmacologic effects and uses】

antianxiety small dose

sedation

hypnosis

anticonvulsion

respiratory depression large dose

DOSE, ADMINISTRATION

slide17

【pharmacologic effects and therapeutic uses】

1. antianxiety

(1) effect

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.

(2) use

anxiety states: restlessness

worry

stress

phobia states

common drug: chlordiazepoxide, diazepam

P.O./small dose

slide18

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

slide19

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

slide20

4. anticonvulsant effect

(1) effect

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.

slide21

5. muscle relaxation

(1) effect

inhibitory effects on polysynaptic reflexes and internuncial transmission in CNS, leading to muscle relaxation

(2) use

relaxing muscle spasm induced by cerebral palsy

common drug: diazepam

injection/large dose

slide22

【adverse effects】

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.

slide23

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)

slide24

【pharmacokinetics】

  • Duration of action depends on rate of metabolic 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.
slide25

【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.

③todirectly activate chloride channel,

to prolong opening time of chloride channel,

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

slide26

【pharmacologic effects】

1. to depress CNS at all levels

sedation small dose

hypnosis

anticonvulsion

anesthesia

respiratory depression

depression of vasomotor center large dose

slide27

2.to augment action of other CNS depressants

3.to shorten amount of time in REMS

4.induce hepatic microsomal drug-metabolizing enzymes

clinical significance:

(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.

slide28

【therapeutic uses】

DOSE, ADMINISTRATION

1.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.

slide29

2. Anticonvulsion

phenobarbital, pentobarbital or amobarbital

injection

large dose

3. Antiepileptism

phenobarbital for epileptism in infant and children

injection

large dose

4. intravenous anesthetics or intravenous adjunct to

surgical anesthetics

thiopental

intravenous injection

large dose

slide30

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.

slide31

【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.

slide32

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.

slide33

Differentiation of barbiturates with benzodiazepines

benzodiazepines barbiturates

1. antianxiety:

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

some induction:

6. margin of safety: wide narrow

7. depression of weak strong

respiration:

slide34

Chloral hydrate

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

children.

5. addiction can occur.

slide35

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.

slide36

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

slide37

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.

slide38

3. clinic manifestation

regional or whole brain dysfunction:

  • motor
  • vegetative and mental episodes
  • loss of consciousness etc.
slide39

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 *

slide41

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
slide42

Phenytoin

【pharmacokinetics】

  • high concentrations in brain,
  • high plasma albumin binding,
  • half-life: 24 hours.

【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.

slide43

【pharmacologic effects】

1.antiepileptic effect

effective for tonic-clonic and partial seizures

2. Anti-peripheral neuralgia

3. antiarrhythmia

slide44

【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)

slide45

【adverse effects】

1. gastrointestinal irritation

administration with or after meal.

2. depression of CNS

3. blood dyscrasias

4.cardiovascular collapse

(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

slide46

Barbiturates

1.characteristics

(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.

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 children.

(4) effective for recurrent tonic-clonic seizures, especially inpatients who do not respond to diazepam plus phenytoin.

slide47

Benzodiazepines

Intravenous diazepam is used for epilepticism in adults.

Clonazepam is used for absence and myoclonic seizure in children.

slide48

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.

slide49

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
slide50

Sodium valproate

  • most effective for myoclonic seizure to reduce 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*

slide52

Summary for this chapter

1. choice of drugs for different patterns of

epilepsies

2. effects and uses of phenytoin

slide53

CHAPTER 16

Anticonvulsant drugs

1. pathogenesis

2. anticonvulsant drugs

  • Barbiturates/ injection, large dose
  • Benzodiazepines / injection, large dose
  • chloral hydrate/ enema
  • magnesium sulfate injection etc.
slide54

Magnesium sulfate

【pharmacologic effects】

ADMINISTRATION, DOSE

1.oral administration

laxative effect and promoting bile excretion

2. injection administration

(1)anticonvulsant

  • inhibiting CNS by Mg2+ (central mechanism)
  • relaxing skeletal muscle (peripheral mechanism)

Ca2+ antagonism

inhibiting ACh release

(2)hypotensive: direct vasodilation

slide55

【therapeutic uses】

  • 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 should be administered.
slide56

Summary for this chapter

1. drugs used for convulsion

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

slide57

CHAPTER 17

Agents Used in the Treatment of Parkinsonian Disorders

1.classification of Parkinsonian disorders

Parkinsonian disease

Parkinsonian syndrome

slide58

2.Pathogenesis

nigra caudatum

○ ○

(D2R) DA Ach(MR)

striatum

(-) (+)

motor neurons in anterior horn of spinal cord

skeletal muscle contraction

slide59

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

slide60

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

slide61

Levodopa (L-dopa)

【mechanism of action】

L-dopa is transformed to dopamine via dopa decarboxylase in brain and corrects dopamine deficiency in nigrostriatum.???

【pharmacokinetics】

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.*

slide63

【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.

slide64

【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.

slide65

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.
slide66

Amantadine

1.history

2. action mechanisms

  • stimulating synthesis and release of dopamine from 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 Parkinsonian disorders
  • No effective for tremor
slide67

4. uses

  • Alone for early Parkinsonian disease
  • Various Parkinsonian diseases in combination with L-dopa

5.adverse effects

restlessness, agitation, confusion and hallucination.

slide68

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 bradykinesia and rigidity.
slide69

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

slide70

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.

slide71

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

slide72

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.

slide73

【classification of drug】

Based on the structure of the drug:

1.phenothiazines

chlorpromazine, fluphenazine, promethazine, thioridazine etc.

2. benzisoxazoles: risperidone

3.dibenzodiazepines: clozapine

4.butyrophenones: haloperidol

5.thioxanthenes: thiothixene*

slide75

【pathogenesis of schizophrenia】

Relevance of pathogenesis of schizophrenia to dopaminergic nerve in CNS:

Evidences

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.

slide76

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

slide77

【mechanism of action】

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

slide78

Phenothiazines

【classification】

Drug Major use Frequency of Adverse Effects

orthostatic extrapyramidal

hypotension symptoms

chlorpromazine antipsychotic moderate moderate

(wintermin) antiemetic

clozapine antipsychotic low low 

anticholinergic 

antihistaminic

thioridazine antipsychotic moderate low

triflupromazine antipsychotic moderate high

fluphenazine antipsychotic low high

prochlorperazine antiemetic low low~moderate

promethazine antihistaminic moderate low

slide79

【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

slide80

1.effects on CNS

1) antipsychotic effects

  • tranquilization:
  • to make animals docile and friendly, rapidly to control manic states of psychotic patients and make them quiet (calming effect) and peaceful;
  • to make patients feel indifferent, then induce sleep

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.

slide81

action mechanism

blocking dopamine D2 receptor in limbic system- mesencephalic and cortico-mesencephalic pathways.

slide82

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).

slide83

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.
slide84

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.
slide85

【therapeutic uses】

1.psychotic disorders

  • mania,
  • paranoid states,
  • Schizophrenia
  • psychoses associated with chronic alcoholism (alcoholic hallucinosis).

2.most phenothiazines except thioridazine

  • effective for nausea and vomiting,
  • ineffective for vomiting induced by stimulating vestibules of ears (motion sickness).

3.artificial hibernation*

4.antipruritics: promethazine (H1 blocking).

5. intractable hiccup: chlorpromazine.

slide86

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.

slide87

【adverse effects】

1.general adverse effects

central depression, M-receptor blockage

2.extrapyramidal effects

manifestation:

  • Parkinsonian syndrome,
  • acute dystonic reaction (facial grimacing and torticollis)
  • tardive dyskinesia (sucking and macking of the lips and other involuntary facial movements).

pathogenesis: blocking DR in the nigrostriatum.

treatment:artane.

3. cardiovascular effects: orthostatic hypotension (NA), syncope and reflex tachycardia.

4. allergic reactions.

slide88

Summary

1. blocking 3 types of receptors

  • DR
  • MR
  • αR

2. effect on 3 systems

  • CNS
  • endocrine system
  • Autonomic nervous system

3. 3 main clinical uses

  • psychotic disorders
  • nausea and vomiting,
  • artificial hibernation

4. 3 main adverse reactions

  • central depression
  • extrapyramidal effects
  • cardiovascular effects
slide89

II Mood-Altering Drugs (Antimanic and Antidepressive Agents)

Use: affective disorder(mania, depression)

  • Pathogenesis of depression is thought to be related 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.
slide90

classification of depression:

  • major (endogenous)
  • reactive
  • bipolar(manic-depressive)
slide91

Antimanic agents—lithium carbonate

【mechanism of action】

Mechanism of action is unknown. It is currently proposed that lithium acts by altering the cellular concentration of inositol triphosphate (IP3).

【therapeutic uses】

1.mania, manic episodes of bipolar disorder

2.useful in reducing the intensity of

depression?

slide92

【adverse effects】

high toxic and low therapeutic index, to maintain 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 by

osmotic diuresis or, in more severe cases, by

dialysis.

slide93

Antidepressants agents

【classification】*

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.

slide95

Tricyclic/ polycyclic antidepressants

【mechanism of action】

  • to block NA and 5-HT reuptakes into the presynaptic 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.
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【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 to adjust dose.The initial treatment period is typically 4 to 8 weeks.The dose can be gradually reduced unless relapse occurs.

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【pharmacologic effects】

All tricyclic antidepressants have similar therapeutic efficacy.

1. effects on CNS

2.cardiovascular effects

3. effects on autonomic nervous system

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1. effects on CNS

(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.

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2.cardiovascular effects

orthostatic hypotension,

arrhythmias,

tachycardia,

slow atrioventricular conduction.

3. effects on autonomic nervous system anticholinergic effect.

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【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.

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【adverse effects】

Adverse effects of tricyclic anti-depressants resemble 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

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Differentiation of tricyclic antidepressants

drug 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 +++ +++

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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.

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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.

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III Agents Used in the Treatment of Anxiety

(anxiolytic drugs or minor tranquilizers)

1.anxiety: symptom, anxiety sydrome

2.use: anxiety or neurosis

3.characteristics

  • sedative
  • hypnotic properties
  • central skeletal muscle relaxant activity
  • habituation and physical dependence
  • lower incidence of adverse effects than the

antipsychotic agents.*