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) Action potential: sodium, calcium, kalium,
chloride ion channel: voltage-gated, ligand-
gated
(2) neurotransmitter:
①NA, ACh, GABA, glutamate, glycine,
5HT, histamine, opioid peptides,
tachykinins
(excitatory/ inhibitory).
②biosynthesis, storage, release, degradation,
reuptake.*
(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 (blood brain barrier)
(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
Kelompok
1. benzodiazepines.
2. barbiturates.
3.other agents: e.g. chloral hydrate.
Indikasi
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/gelisah
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
【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 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
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.
【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 micro- no 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 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
 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 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 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 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

1. choice of drugs for different patterns of

epilepsies
2. effects and uses of phenytoin
 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
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. 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.
 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 L-
dopa
4.side effects
similar to those of atropine.
scopolamine
 Summary

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.