Transcript PART Ⅳ 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
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
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
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
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
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
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.
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
【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.
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
metabolic degradation, degree of lipid
solubility, extent of binding to serum
proteins. Ultra-short-acting barbiturates
are highly lipid-soluble, whereas longacting 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 depressants
3.to shorten amount of time in REMS
4.induce
hepatic
microsomal
drugmetabolizing 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.
【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.
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
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
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 microno
have
some induction:
6. margin of safety:
wide
narrow
7. depression of
weak
strong
respiration:
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 gastrointestinal 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
to stabilize nervous cellular membranes
to reduce the influx of calcium ions during
depolarization
suppresses highfrequency repetitive firing
halts seizure
activity.
【pharmacologic effects】
1.antiepileptic effect
effective for tonic-clonic
seizures
2. Anti-peripheral neuralgia
3. antiarrhythmia
and
partial
【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 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
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 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
reduce incidence and severity of tonicclonic 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, 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
【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
should 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
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 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. Ldopa 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 Ldopa.
no use alone.
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
4. uses
• Alone for early Parkinsonian disease
• Various Parkinsonian diseases in combination
with 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
bradykinesia 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 Ldopa
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: risperidone
3.dibenzodiazepines: clozapine
4.butyrophenones: haloperidol
5.thioxanthenes: thiothixene*
【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.
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 emotion
2.to block dopamine receptor in corticomesencephalic pathway to restore thinking
and motion
3.to block dopamine receptor in nigrostriatum
pathway to cause extrapyramidal symptoms
4.to bock dopamine receptor in hypothalamohypophysis pathway to cause endocrine
dysfunction
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
【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 CNS
1) antipsychotic effects
(1) 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.
action mechanism
blocking dopamine D2 receptor in limbic
system- mesencephalic and corticomesencephalic 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).
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 αreceptor 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
(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.
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 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.
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
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 5HT 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
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?
【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.
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.
Tricyclic/ polycyclic antidepressants
【mechanism of action】
• to block NA and 5-HT reuptakes into the
presynaptic neurons to increase NA and 5HT 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
to 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
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. 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
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
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
+++
+++
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 neurosis
3.characteristics
• sedative
• hypnotic properties
• central skeletal muscle relaxant activity
• habituation and physical dependence
• lower incidence of adverse effects than the
antipsychotic agents.*