2. Introduction to the
Pharmacology of CNS Drugs
Drugs acting in the central nervous system
(CNS) were among the first to be
discovered by primitive humans and are
still the most widely used group of
pharmacologic agents.
In addition to their use in therapy, many
drugs acting on the CNS are used without
prescription to increase one‘s sense of
well-being.
3. The mechanisms by which various drugs
act in the CNS have not always been
clearly understood.
In the last 3 decades, however, dramatic
advances have been made in the
methodology of CNS pharmacology.
It is now possible to study the action of a
drug on individual cells and even single ion
channels within synapses. The information
obtained from such studies is the basis for
several major developments in studies of
the CNS.
4. Major Developments In
Studies Of The CNS
Nearly all drugs with CNS effects act on
specific receptors that modulate synaptic
transmission.
Drugs are among the most important tools
for studying all aspects of CNS physiology.
Unravelling the actions of drugs with known
clinical efficacy has led to some of the most
fruitful hypotheses regarding the
mechanisms of disease
5. Methods for the Study of CNS
Pharmacology
A detailed description of synaptic
transmission was not possible until glass
microelectrodes, which permit intracellular
recording, were developed.
Detailed electrophysiologic studies of the
action of drugs on both voltage- and
transmitter-operated channels were further
facilitated by the introduction of the patch
clamp technique, which permits the
recording of current through single
channels.
6. Histochemical, immunologic, and
radioisotopic methods are widely used to
map the distribution of specific transmitters,
their associated enzyme systems, and their
receptors.
Molecular cloning has had a major impact
on our understanding of CNS receptors
Mice with mutated genes for specific
receptors or enzymes (knockout mice) can
provide important information regarding the
physiologic and pharmacologic roles of these
components.
8. What are sedative-hypnotics?
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
10. Mechanism of Action
Benzodiazepines Barbiturates
•act on GABAA receptors •activate inhibitory GABAA while
•GABA receptor: a pentameric inhibiting excitatory AMPA
protein, consists of several receptors.
subunits designated alpha (mainly •AMPA receptors are the subtype
responsible for the pharmacology of glutamate receptors sensitive to
of the receptor) ,beta and gamma kainate or quisqualate.
which is required for high affinity •The combination of these receptor
benzodiazepine binding. effects may result in the profound
•Electrophysiological Effects: central nervous system depression
Benzodiazepines enhance GABA- that occurs with higher barbiturate
activated hyperpolarizing chloride doses.
currents
11. Effects on CNS
Benzodiazepines Barbiturates
-With increasing doses, -Barbiturates depress respiratory
benzodiazpines can progressive drive
cause sedation, then hypnosis and -At doses somewhat (three times)
then stupor. higher than required for
-do not cause general anesthesia pharmacological hypnosis,
since awareness persists. neurogenic is abolished and the
-have anti-anxiety / sedative- hypoxic respiratory drive is reduced
hypnotic properties. and the chemoreceptor drive is
-Some benzodiazepines attenuated.
(clonazepam (Klonopin)) are -At still higher doses, the hypoxic
effective muscle relaxants, whereas drive is abolished.
most others are not.
12. Effects on Cardiovascular
System
Benzodiazepines Barbiturates
-Except in overdosage, -In sedative or doses for
cardiovascular effects of pharmacological hypnosis,
benzodiazepines in normal barbiturates have minimal
subjects are minor. cardiovascular effects
-If used as preanesthetic -When thiopental is used in general
medication, benzodiazepines anesthesia, following pre-
decrease blood pressure and anesthetic medication:
increase heart rate. *plasma renal flow decreases
*cerebral blood flow decreases
*CSF pressure decreases
-Significant depression of
myocardial contractility occurs in
barbiturate poisoning
13. Effects on Respiratory
System Benzodiazepines
-At pharmacological hypnotic doses, benzodiazepines do not affect respiration
in normal subjects.
-Severely benzodiazepine-intoxicated patients may require assistance in
breathing if other CNS depressant drugs have been taken
-If a patient, however, has a sleep-related breathing syndrome such as
obstructive sleep apnea (OSA), benzodiazepines may be contraindicated.
In patients with obstructive sleep apnea, hypnotic doses of
benzodiazepines may decrease muscle tone in the upper airway and
accentuate or worsen the impact of apneic episodes on alveolar hypoxia,
pulmonary hypertension and cardiac demand.
-At higher doses, such as those used for endoscopy or when given as
preanesthetic medication, benzodiazepines somewhat depress alveolar
ventilation causing a respiratory acidosis secondary to a decrease in hypoxic
drive (rather than hypercapnic drive).
These effects are more severe in patients with COPD (chronic obstructive
pulmonary disease) and maybe sufficiently detrimental to induce alveolar
hypoxia and/or CO2 narcosis.
14. Effects on the Liver
Barbiturates
-Acutely, barbiturates combine with cytochrome P-450 and produce
competitive inhibition of metabolism of a number of drugs and endogenous
agents (such as steroids)
-Chronically, barbiturates increase activities of cytochrome P-450 oxidases
and glucuronyl transferases and therefore increase the metabolism (due
to enzyme induction) of many drugs, steroids, vitamins K & D, cholesterol,
bile salts. The extent of the increase is about two fold
-Part of barbiturate tolerance is due to increased hepatic metabolism of
barbiturates, induced by barbiturates.
-Non-microsomal enzyme system are also induced, including:
*d -aminolevulinic acid (ALA) synthetase. The effect of barbiturates on
ALA *synthetase that produces exacerbation in patients with
intermittent porphyria.
aldehyde dehydrogenase
15. Therapeutic Uses
Benzodiazepines Barbiturates
•Flurazepam (Dalmane) •IV anesthesia: Thiopental
Flurzepam has been prescribed for (Pentothal) and methohexital
insomnia. (Brevital)
•Triazolam (Halcion)
•Convulsions: emergency
Triazolam is used to induce sleep.
treatment (eclampsia, tetanus,
•Flumazenil (Romazicon,
status epilepticus), but
benzodiazepine antagonist*)
benzodiazepines are
Primary use is for management of
preferable.
benzodiazepine overdosage.
•Epilepsy
Additional use in the reduction of
•Rarely used as a sedative
benzodiazepine effects in general
due to the availability of safer
anesthesia or diagnostic procedures.
benzodiazepine agents
Benzodiazepine-induced
electrophysiological and behavioral
effects are antagonized.
16. Can sedative-hypnotics cause
dependence?
Yes. They can cause both physical and
psychological dependence.
Regular use over a long period of time may
result in tolerance, which means people
have to take larger and larger doses to get
the same effects.
When regular users stop using large doses
of these drugs suddenly, they may develop
physical withdrawal symptoms ranging from
restlessness, insomnia and anxiety, to
convulsions and death.
17. Effects combining sedative-
hypnotics with alcohol
Taken together, alcohol and sedative-
hypnotics can kill.
The use of barbiturates and other sedative-
hypnotics with other drugs that slow down
the body, such as alcohol, multiplies their
effects and greatly increases the risk of
death.
Overdose deaths can occur when
barbiturates and alcohol are used together,
either deliberately or accidentally.
18. Barbiturate Adverse Effects
Adverse Effects:
◦ Drowsiness, impaired judgment, impaired motor skills
◦ Significant CNS/respiratory depression with high dosage.
◦ Paradoxical excitement
◦ If barbiturates are given for pain, restlessness, excitement,
or delirium may result
◦ Hypersensitivity: allergic reaction in patients who are
predisposed to angioedema, urticaria, and asthma
◦ Drug interactions: combination with other sedative agents
can result in severe CNS depression.
Untoward effects:
◦ Absolutely contraindicated in acute intermittent porphyria or
porphyria variegata because barbiturates increase
porphyrin synthesis.
◦ i.v. administration can produce cardiovascular collapse;
overdosage can cause severe respiratory depression.
19. Management of barbiturate
poisoning
Severe intoxication is associated with coma
and depressed respiration
Treatment is supportive with CNS
stimulants contraindicated (increases
mortality)
Hemodialysis or hemoperfusion may be
needed
Complicating factors include:
◦ circulatory collapse
◦ shock
◦ dehydration
◦ renal failure.
20. Adverse Effects:
Benzodiazepines
◦ Common: Drowsiness, lethargy
◦ Less common: Muscular incoordination, ataxia
◦ Other: hypotonia, dysarthria, dizziness, behavior
disturbances including hyperactivity, irritability, difficulty in
concentration.
◦ Seizures may occur if drug is discontinued abruptly.
Flurazepam (Dalmane)
◦ Flurazepam has long-acting metabolites.
◦ Adverse Effects:
Presence of long-acting metabolites may cause daytime sedation,
which may be undesirable.
Triazolam (Halcion)
◦ Triazolam is short-acting with no active metabolites
◦ Adverse Effects: Tolerance may develop and rebound
insomnia has been reported.
Reported associations of triazolam with psychotic reactions,
dependency, anterograde amnesia are some factors that
contributed to triazolam removal from the market in some European
21. Flumazenil (Romazicon,
benzodiazepine antagonist*)
Adverse Effects:
◦ in comatose patients, intoxicated with alcohol,
flumazenil may increase risk of seizures.
◦ in comatose patients due to tricyclic
antidepressant agents, flumazenil increases
seizure risk.
22. Effects of Barbiturates When
Abused
Similar to the effects of alcohol.
Small amounts produce calmness and
relax muscles. Somewhat larger doses
can cause slurred speech, staggering
gait, poor judgment, and slow, uncertain
reflexes.
These effects make it dangerous to drive
a car or operate machinery. Large doses
can cause unconsciousness and death.
23. How dangerous are
barbiturates?
Barbiturate overdose is a factor in nearly
one-third of all reported drug-related
deaths.
These include suicides and accidental
drug poisonings.
Accidental deaths sometimes occur when
a user takes one dose, becomes confused
and unintentionally takes additional or
larger doses.
24. With barbiturates there is less
difference between the amount that
produces sleep and the amount that
kills.
Furthermore, barbiturate withdrawal
can be more serious than heroin
withdrawal
25. 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.
26. 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).
27. 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.
28. The negative effects can include nausea,
stomach cramps, lack of coordination,
temporary memory loss, becoming out of
touch with the surroundings, and anxious
behavior.
Editor's Notes
Barbiturates interact differently than benzodiazepines at GABA receptors. For example, the gamma subunit is not required for barbiturate activity
