Drugs That Act In The Central Nervous System

2. The central nervous system directs the functions of all tissues of the
body.
The peripheral nervous system receives thousands of sensory inputs
and transmits them to the brain via the spinal cord.
The brain processes this incoming information and discards 99% as
unimportant. After sensory information has been evaluated,
selected areas of the central nervous system initiate nerve impulses
to organs or tissue to make an appropriate response.

3. Chemical influences are capable of producing a myriad of
effects on the activity and function of the central nervous
system.
The known neurotransmitters are: acetylcholine which is
involved with memory and learning; norepinephrine which
is involved with mania-depression and emotions; and
serotonin which is involved with biological rhythms, sleep,
emotion, and pain.

4. A small number of neuropharmacologic agents exert
their effects through direct interactions with
molecular components of ion channels on axons.
Examples include certain anticonvulsants (
carbamazepine, phenytoin),local anesthetics, and
some drugs used in general anesthesia. However the
effects of most therapeutically important CNS drugs
are exerted mainly at synapses.

5. D
R
U
G

6. Sedative-hypnotics are drugs which depress or slow down
the body's functions.
Often these drugs are referred to as tranquilizers and
sleeping pills or sometimes just as sedatives.
Their effects range from calming down anxious people to
promoting sleep. Both tranquilizers and sleeping pills can
have either effect, depending on how much is taken.
At high doses or when they are abused, many of these drugs
can even cause unconsciousness and death.

7. Benzodiazepines
• diazepam (Valium)
• midazolam (Versed)
• clonazepam (Klonopin)
• chlordiazepoxide (Librium)
• clorazepate (Tranxene)
• Alprazolam (Xanax)
• Flurazepam (Dalmane)
• Triazolam (Halcion)
• Lorazepam (Ativan)
• Flumazenil* (Romazicon)
*receptor antagonist
Barbiturates
• Amobarbital (Amytal)
• pentobarbital (Nembutal)
• thiopental (Pentothal)
• secobarbital (Seconal)
• Phenobarbital (Luminal)
Miscellaneous agents
• paraldehyde (Paral)
• meprobamate (Miltown)
• ethchlorvynol (Placidyl)
• chloral hydrate (Noctec)
• methaqualone
(Quaalude)

8. Benzodiazepine
s

9. Derivative of 1,4- benzodiazepines. About 20 are available
for clinical use. They are basically similar in their
pharmacological actions, though some degree of selectivity
has been reported.
It is possible that selectivity with respect to two types of
benzodiazepine receptor may account for these differences.
From a clinical point of view, difference in pharmacokinetic
behaviour are more important than difference in profile of
activity.

10. PHARMACOLOGICAL
EFFECTS

11. 1. Reduction of anxiety and aggression :
• affects the hippocampus and nucleus amygdalae
2. Sedation and induction of sleep:
• (1) the latency of sleep onset is decreased;
• (2) the duration of stage 2 NREM sleep is
increased;
• (3) the duration of slow-wave sleep is decreased.

12. (1) great margin of safety;
(2) little effect on REM sleep;
(3) little hepatic microsomal drug-metabolizing
enzymes;
(4) slight physiologic and psychologic
dependence and withdrawal syndrome;
(5) less adverse effects such as residual
drowsiness and incoordination movement.

13. 3. Anticonvulsant and antiseizure
• They are highly effective against chemically induced convulsions
caused by leptazol, bicuculline and similar drugs but less so against
electrically induced convulsions.
• The can enhance GABA-mediated synaptic systems and inhibit
excitatory transmission.
4. Muscle relaxation
• relax contracted muscle in joint diease or muscle pasm.
5. Other effects
• lead to temporary amnesia
• decrease the dosage of anesthetic;
• depress respiratory and cardiovascular fuction.

14. MECHANISM
OF
ACTION

15. Benzodiazepines act very selectively on GABAA-receptors, which mediate the fast
inhibitory synaptic response produced by activity in GABA-ergic neurons.
The effect of benzodiazepines is to enhance the response to GABA, by facilitating
the opening of GABA-activated chloride channels (an increase in the frequency of
channel opening, but no change in the conductance or mean open time).
Benzodiazepines bind specifically to a regulatory site on the receptor, distinct from
the GABA binding site, and enhanced receptor affinity for GABA.
The GABAA-receptors is a ligand-gated ion channel consisting of a pentameric
assembly of subunits.

16. PHARMACOKINETIC
ASPECTS

17. Well absorbed when given orally;
They bind strongly to plasma protein, and their high lipid solubility
cause many of them to accumulate gradually in body fat. Distribution
volumes is big.
Metabolic transformation in the microsomal drug-metabolizing
enzyme systems of the liver, eventually excreted as glucuronide
conjugates in the urine.
They vary greatly in duration of action, and can be roughly divided
into
• Short-acting compounds: triazolam, oxazepam(15-30min, t1/2 2-3 h)
• Medium-acting compounds: estazolam, nitrazepam (40min, t1/2 5-8 h)
• Long-acting compounds: diazepam, flurazepam(50h)

18. ADVERSE
DRUG
REACTION

19. Acute toxicity
Benzodiazepines in acute overdose are considerably less dangerous than
other sedative-hypnotic drugs. Cause prolonged sleep,without serious
depression of respiration or cardiovascular. The availability of an effective
antagonist, flumazenil.
Side-effects during therapeutic use:
drowsiness, confusion, amnesia, impaired coordination. Main
disadvantages are interaction with alcohol, long-lasting hangover and the
development of dependence.
Tolerance and dependence:
induction of hepatic drug-metabolising enzymes; a change at the receptor
level;

20. Ⅱ.BARBITURATES

21. Classification:
Ultra-short-acting barbiturates:
• act within seconds, and their duration of action is 30min. Therapeutic use of
Thiopental: anesthesia
Short-acting barbiturates:
• have a duration of action of about 2h. The principal use of Secobarbital :
sleep-inducing hypnotics.
Intermediate-acting barbiturates:
• have and effect lasting 3-5h. The principal use of Amobarbital is as hypnotics.
Long-acting barbiturates
• have a duration of action greater than 6h. Such as Barbital and Phenobarbital.
Therapeutic uses: hypnotics and sedative, and antiepileptic agents at low
doses.

22. Barbiturates depress the CNS at all
level in a dose-dependent fashion.
Now it mainly used in anaesthesia
and treatment of epilepsy; use as
sedative-hypnotic agents is no longer
recommended.

23. (1) have a narrow therapeutic-to-toxic dosage
range.
(2) suppress REM sleep.
(3) Tolerance develops relatively quickly.
(4) have a high potential for physical dependence
and abuse.
(5) potent inducers of hepatic drug-metabolising
enzymea.

24. MECHANISM
OF
ACTION

25. (1) Barbiturates share with benzodiazepines the ability to enhance
the action of GABA, but they bind a different site on the GABA-receptor/
chloride channel, and their action seems to prolong the
duration of the opening of GABA-activated chloride channels.
(2) At high doses, barbiturates can inhibit the release of the Ca2+-
dependent neurotransmitter.

26. PHARMACOKINETICS

27. High lipid solubility allows rapid transport across the blood-brain
barrier and results in a short onset.
Removal from the brain occurs via redistribution to the other
tissues results in short duration of action.
Barbiturates and their metabolites the excretion via the renal
route. Alkalinization of the urine expedites the excretion of
barbiturates. Treatment of acute overdosage: Sodium bicarbonate.

28. THERAPEUTIC USES

29. Sedative-hypnotic agents
Be used in the emergency treatment of convulsions as in status
epilepticus.
Anesthetic (or be given before anesthetic)
Combination with antipyretic-analgesic
Treatment of hyperbilirubinemia and kernicterus in the neonate.

30. ADVERSE EFFECTS

31. After effect: hangover---dizzy, drowsiness, amnesia,
impaired judgment, disorientation.
Tolerance: decreased responsiveness to a drug
following repeated exposure because of down-regulation
of receptors and induction of hepatic drug-metabolising
enzymes.
Dependence: including psychologic and physiologic
dependence. Withdrawal symptoms: excitation,
insomnia, tremor, anxiety, hallucinations and
sometimes convulsions.
Depressant effect on respiration: can cross the
placental barrier during pregnancy and secrete to
breast milk.
Others: Skin eruptions and porphyria

32. TREATMENT FOR
ACCUTE OVERDOSE

33. An overdose can result in coma, diminished reflexes,
severe respiratory depression, hypotension leading to
cardiovascular collapse, and renal failure.
Treatment (A.B.C):
• (1) supporting respiration and circulation.
• (2) alkalinizing the urine and promoting diuresis.
• (3) Hemodialysis or peritoneal dialysis.

34. Ⅲ.Nonbarbiturate
sedative-hypnotics

35. Chloral hydrate
(1) relatively safe hypnotic, inducing sleep
in a half hour and lasting about 6h.
(2) used mainly in children and the elder,
and the patients when failed to other
drug.

36. EFFECTS ON CNS
Benzodiazepines
• With increasing doses, benzodiazpines
can progressive cause sedation, then
hypnosis and then stupor.
• do not cause general anesthesia since
awareness persists.
• have anti-anxiety / sedative-hypnotic
properties.
•Some benzodiazepines (clonazepam
(Klonopin)) are effective muscle
relaxants, whereas most others are not.
Barbiturates
• Barbiturates depress respiratory drive
• -At doses somewhat (three times) higher
than required for pharmacological
hypnosis, neurogenic is abolished and
the hypoxic respiratory drive is reduced
and the chemoreceptor drive is
attenuated.
• -At still higher doses, the hypoxic drive is
abolished.

37. THERAPEUTIC USES
Benzodiazepines
• Flurazepam (Dalmane)
• Flurzepam has been prescribed for insomnia.
• Triazolam (Halcion)
• Triazolam is used to induce sleep.
• Flumazenil (Romazicon, benzodiazepine
antagonist*)
• Primary use is for management of
benzodiazepine overdosage.
• Additional use in the reduction of benzodiazepine
effects in general anesthesia or diagnostic
procedures.
• Benzodiazepine-induced electrophysiological and
behavioral effects are antagonized.
• .
Barbiturates
• IV anesthesia: Thiopental
(Pentothal) and methohexital
(Brevital)
• Convulsions: emergency treatment
(eclampsia, tetanus, status
epilepticus), but benzodiazepines
are preferable.
• Epilepsy
• Rarely used as a sedative due to the
availability of safer benzodiazepine
agents

38. Other Abused Sedative-hypnotics
All the other sedative-hypnotics can be abused, including the benzodiazepines.
Diazepam (Valium), chlordiazepoxide (Librium), and chlorazepate (Tranxene)
are examples of benzodiazepines.
These drugs are also sold on the street as downers.
As with the barbiturates, tolerance and dependence can develop if
benzodiazepines are taken regularly in high doses over prolonged periods of
time.
Other sedative-hypnotics which are abused include glutethimide (Doriden),
ethchlorvynol (Placidyl), and methaqualone (Sopor, Quaalude).

39. Sedative – hypnotic
“look-alikes”
These are pills manufactured to look like real sedative-hypnotics
and mimic their effects.
Sometimes look-alikes contain over-the-counter drugs such as
antihistamines and decongestants, which tend to cause
drowsiness.
The negative effects can include nausea, stomach cramps, lack of
coordination, temporary memory loss, becoming out of touch
with the surroundings, and anxious behavior.