Drugs That Act In The Central Nervous System

DRUGS

C N S

THAT ACT IN

THE

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.

Introduction to the Pharmacology of

CNS Drugs

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.

Sites & Mechanism Of Drug Action

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.

SEDATIVE –

DRUG

HYPNOTIC

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.

Classification of CNS Deppressants

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)

Benzodiazepines

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.

PHARMACOLOGICAL EFFECTS

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.

Reasons for their extensive clinical use:

(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.

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.

MECHANISM OF

ACTION

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.

PHARMACOKINETICASPECTS

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)

ADVERSE DRUG

REACTION

Acute toxicityBenzodiazepines 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;

Ⅱ.BARBITURATES

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.

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.

REASONS:(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.

MECHANISM OF

ACTION

(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.

PHARMACOKINETICS

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.

THERAPEUTIC USES

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.

ADVERSE EFFECTS

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

TREATMENT FOR ACCUTE OVERDOSE

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.

Ⅲ.Nonbarbiturate sedative-hypnotics

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.

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.

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

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).

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.

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