Neuroactive Agents.pptx

Neuroactive Agents
BY: SWETA MAURYA

Content:
 Antipsychotic agents
 Antianxiety agents
 Stimulants
 Sedatives & Hypnotics
 Anticonvulsants

Neuroactive Agents
Antipsychotic agents
• Phenothiazenes
Antianxiety agents
• Benzodiazepines & Diazepam
CNS Stimulants
• Caffine
• MOA
Sedatives & Hypnotics
• SAR
• MOA
Anticonvulsants
• SAR

General View
The most important types of psychosis are:
 Schizophrenia
 Affective disorders (e.g. depression, mania)
 Organic psychoses (mental disturbances caused by
head injury, alcoholism, or other kinds of organic
disease).

General View
 Classification: anti-schizophrenic drugs (antipsychotic drugs or
neuroleptics), antimanic drug, antidepressants or antianxiolytics.
 Pharmacologically, they are characterised as dopamine receptor
antagonists, though many of them also act on other targets,
particularly 5-HT receptors, which may contribute to their clinical
efficacy.

The Nature of Schizophrenia
 Psychotic illness characterised by hallucinations, delusions and
thought disorder (positive symptoms), together with social
withdrawal and flattening of emotional responses (negative
symptoms).
 Acute episodes (mainly positive symptoms) frequently recur and
develop into chronic schizophrenia, with predominantly negative
symptoms.

The Nature of Schizophrenia
 Incidence is about 1% of population, with a strong, but not
invariable, hereditary component.
 Pharmacological evidence is generally consistent with dopamine
overactivity hypothesis, but most neurochemical evidence is
negative or equivocal. Increase in dopamine receptors in limbic
system (especially in left hemisphere) is consistently found.
 There is some evidence for involvement of 5-HT, and possibly
other mediators, such as glutamate.

Classification of Antipsychotic drugs
Main categories are:
 Typical antipsychotics
Phenothiazines (chlorpromazine, perphenazine, fluphenazine,
thioridazine et al)
Thioxanthenes (flupenthixol, clopenthixol)
Butyrophenones (haloperidol, droperidol)
 Atypical antipsychotics
(e.g. clozapine, risperidone, sulpiride, olanzapine)

Classification of Antipsychotic drugs
Distinction between ‘typical’ and ‘atypical’ groups is not clearly
defined, but rests on:
 Incidence of extrapyramidal side-effects (less in ‘atypical’ group)
 Efficacy in treatment-resistant group of patients
 Efficacy against negative symptoms.

Phenothiazines
Chlorpromazine: wintermine
Pharmacologic effects and mechanism:
CNS: a. neuroleptic effect--- D1, D5---D1-like receptors
D2-4------D2-like receptors
Antipsychotic drugs probably owe their therapeutic effects mainly to
blockade of D2-receptors (lies in midbrain-cortex and midbrain-
limbic system ).
b. antiemetic effect--- inhibit chemoreceptor trigger zone or
directly depress the medullary vomiting center.
c. temperature-regulating effect--- produce hypothermia

Therapeutic uses
 treatment of psychotic disorders: schizophrenia, mania, paranoid
states, alcoholic hallucinosis.
 treatment of nausea and vomiting of certain causes.
 anesthesia in hypothermia and artificial hibernation (used with
pethidine and promethazine).

Adverse Effects
 Extrapyramidal motor disturbances: (1) Parkinson-like symptoms; (2) akathisia; (3)
acute dystonias.
Treatment: anticholinergic
 Tardive dyskinesia comprises mainly involuntary movements of face and tongue,
but also of trunk and limbs, appearing after months or years of antipsychotic
treatment. It may be associated with proliferation of dopamine receptors (possibly
presynaptic) in corpus striatum. Treatment is generally unsuccessful.
 Pseudodepression and Schizophrenia-like syndrome.
 Seizures.
 Cardiac toxicity and endocrine effects.

Adverse Effects
 Other side-effects (dry mouth, constipation, blurred vision,
hypotension, etc.) are due to block of other receptors, particularly
α–adrenoceptors and muscarinic ACh receptors.
 Contact dermatitis, blood dyscrasias, obstructive jaundice
sometimes occurs with phenothiazines.

Thioxanthenes
 Chlorprothixene: mild antipsychotic action, and antianxiety and
antidepressant action.

Butyrophenones
 Haloperidol: control psychomotor excitement.
 Adverse effects: severe extrapyramidal symptoms.

Others
 Clozapine:
(1) be effective in treating some patients with psychosis
unresponsive to standard neuroleptic drug.
(2) blocks D4 receptor and have low affinity for D1 and D2
dopamine receptors.
(3) lacks extrapyramidal side effects.
(4) must monitor the granulocyte counts weekly.
 Risperidone: be used first episode in and chronic schizophrenia.

Clinical Efficacy of Antipsychotic Drugs
 Antipsychotic drugs are effective in controlling symptoms of acute
schizophrenia, when large doses may be needed.
 Long-term antipsychotic treatment is often effective in preventing recurrence
of schizophrenic attacks, and is a major factor in allowing schizophrenic
patients to lead normal lives.
 Depot preparations are often used for maintenance therapy.
 Antipsychotic drugs are not generally effective in improving negative
schizophrenic symptoms.
 Approximately 40% of chronic schizophrenic patients are poorly controlled by
antipsychotic drugs; clozapine may be effective in some of these
‘antipsychotic-resistant’ cases.

Mood altering drug
Ⅰ. Mood-stabilizing: lithium carbonate
Mechanism
(1) effects on electrolyte and ion transport. (2) effects on neurotransmitters---NA, DA. (3) effects on second
messengers— hormone-sensitive adenylate.
Therapeutic uses: prevention of bipolar illness and treatment of acute mania.
Adverse effects:
 Nausea, vomiting and diarrhoea.
 Tremor.
 Renal effect: polyuria (with resulting thirst)
 Various neurological effects, progressing from confusion and motor impairment , to coma, convulsion
and death.
narrow therapeutic limit for the plasma means the monitoring is essential.

antidepressant
Types of antidepressant drug
Tricyclic antidepressant (TCA): imipramine
amitriptyline
Selective 5-HT uptake inhibitors: Fluoxetine
paroxetine
sertraline
NE uptake inhibitors: desipramine
Atypical antidepressant: phenelzine

Therapeutic uses
 Treatment of severe endogenous depression (characterized by
regression and inactivity).
 Treatment of enuresis.
 Treatment of obsessive-compulsive neurosis accompanied by
depression, and phobic-anxiety syndromes, chronic pain and
neuralgia.
Adverse effects: anticholinergic effects

Drugs of Abuse
Drug abuse is the nonmedical, self-administered use of a drug that is harmful
to the user, generally act on the CNS to modify the user’s mental state,
although some are used for enhancing physical performance.
Common abused drugs include:
 CNS stimulants (e.g., cocaine, amphetamines, nicotine),
 hallucinogens (e.g., LSD, mescaline, phencyclidine, and marijuana).
 general CNS depressants (e.g., ethanol),
 sedative–hypnotics (e.g., alprazolam, diazepam),
 opioid analgesics (e.g., heroin),
 inhalants (e.g., toluene, nitrous oxide, amyl nitrate).

CNS stimulants “sympathomimetics”
Few clinical uses, Important as drugs of abuse. A primary motivation
for drug abuse appears to be the anticipated feeling of pleasure
derived from the CNS effects of the drug.
Factors that limit the therapeutic usefulness include:
1. Physiological “Physical” Dependence: .
2. Psychological Dependence “Addiction”
3. Tolerance to the euphoric and anorectic effects

CNS stimulants “sympathomimetics”
are classified according to their action into:
1. Psychomotor stimulants cause: excitement, euphoria, decrease feeling of
fatigue & Increase motor activity
Ex., Methylxanthines (caffeine, theobromine, theophylline), nicotine, cocaine,
amphetamine, atomoxetine, modafinil, methylphenidate.
2. Hallucinogens (psychotomimetic): Affect thought, perception, and mood,
therefore produce
 profound changes in thought patterns & mood,
 little effect on the brain stem & spinal cord
Ex., Lysergic acid diethylamide (LSD), Phencyclidine (PCP), Tetrahydrocannabinol
(THC), Rimonabant.

Psychomotor stimulants
Q. What are Stimulants?
Chemical structure are similar to monoamine neurotransmitters. All are
indirect-acting sympathomimetics:
1. Many CNS stimulants release catecholamines, Therefore, their effects
are abolished by prior treatment with reserpine or guanethidine
Ex: amphetamine, dextroamphetamine, methamphetamine,
methylphenidate (Ritalin), ephedrine, pseudoephedrine (a
stereoisomer of ephedrine), tyramine.
2. Other CNS stimulants block the reuptake of catecholamines (NE and
DA) and serotonin:
EX. Cocaine, sibutramine (reduct)®, modafinil

3. Antidepressants drugs with stimulant effects:
Atomoxetine– a relatively selective NE reuptake inhibitor (ADHD),
Bupropion – blocks the reuptake of both NE and DA.
4. The methylxanthines are adenosine receptor antagonists. Drugs
within this class are NOT generally considered “psychomotor”
stimulants, but they have distinct stimulant effects caffeine,
theophylline.
NB: MAO and COMT inhibitors (indirect-acting adrenergic agonists), but
they are not traditionally considered to be stimulants.

Therapeutic Indications of CNS Stimulants
 Obesity (anorectic agents).
 Attention Deficit Hyperactivity Disorder (ADHD); lack the ability to
be involved in any one activity for longer than a few minutes.
 Narcolepsy: It is a relatively rare sleep disorder, that is characterized
by uncontrollable bouts of sleepiness during the day. It is
sometimes accompanied by catalepsy, a loss in muscle control, or
even paralysis brought on by strong emotion, such as laughter.
Contraindications for CNS Stimulants:
anorexia, insomnia, asthenia, psychopathic personality, a history of
homicidal or suicidal tendencies.

A. methylxanthines
1. Theophylline (found in tea) : long-acting, prescribed for night-
time asthma
2. Theobromine: found in cocoa.
3. Caffeine: (short-acting) the most widely consumed
 found in coffee (200 mg/cup),
 carbonated soft drinks (60 mg/can),
 cocoa and chocolate

B. Nicotine:
 Nicotine is the active ingredient in tobacco.
 Used in smoking cessation therapy,
Nicotine remains important, because it is 2nd only to caffeine as the
most widely used CNS stimulant and 2nd only to alcohol as the most
abused drug.
Actions of Nicotine:
Low dose: ganglionic depolarization
High dose: ganglionic blockade

Actions of Nicotine
I. CNS:
 Low dose: euphoria, arousal, relaxation, improves attention, learning, problem
solving and reaction time.
 High dose: CNS paralysis, severe hypotension (medullary paralysis)
II. Peripheral effects:
 Stimulation of sympathetic ganglia and adrenal medulla→↑ BP and HR
(harmful in HTN patients)
 Stimulation of parasympathetic ganglia→↑ motor activity of the bowel
 At higher doses, BP falls & activating ceases in both GIT and bladder

Adverse effects:
 CNS; irritability and tremors
 Intestinal cramps, diarrhea
 ↑HR & BP
Withdrawal syndrome:
 nicotine is addictive substance,
 physical dependence on nicotine develops rapidly and can be
severe.
 Bupropion: can reduce the craving for cigarettes
 Transdermal patch and chewing gum containing nicotine
 Varenicline

C. Cocaine (highly addictive drug)
1. Mechanism of action: blockade of reuptake of the monoamines (NE, serotonin
and dopamine)Thus, potentiates and prolongs the CNS and peripheral
actions of these monoamines.
 Initially produces the intense euphoria or “rush” by prolongation of
dopaminergic effects in the brain’s pleasure system (limbic system).
 It is this immediate positive reinforcement, followed rapidly by the negative
reinforcement, that makes the drug, particularly in this form, so addictive.
 Chronic intake of cocaine depletes dopamine. This depletion triggers the
vicious cycle of craving for cocaine that temporarily relieves severe
depression.

Cocaine
 Cocaine has minimal bioavailability when taken by the oral route.
 Instead, the cocaine hydrochloride powder is snorted, or
solubilized and injected. The cocaine powder cannot be effectively
smoked, as it is destroyed upon heating.
 However, crack cocaine, an alkaloidal form, can be smoked.

Actions:
a. CNS-behavioral effects result from powerful stimulation of cortex
and brain stem.
 Cocaine acutely increase mental awareness and produces a feeling
of wellbeing and euphoria similar to that produced by
amphetamine.
 Like amphetamine, cocaine can produce hallucinations and
delusions of paranoia or grandiosity.
 Cocaine increases motor activity, and at high doses, it causes
tremors and convulsions, followed by respiratory and vasomotor
depression.

Adverse effects:
 Anxiety reaction that includes: hypertension, tachycardia, sweating, and paranoia.
Because of the irritability, many users take cocaine with alcohol
A product of cocaine metabolites and ethanol is cocaethylene, which is also psychoactive and
cause cardiotoxicity.
 Depression:
Like all stimulant drugs, cocaine stimulation of the CNS is followed by a period of mental
depression.
 Addicts withdrawing from cocaine exhibit physical and emotional depression as well as agitation.
The latter symptom can be treated with benzodiazepines or phenothiazines.
 Toxic effects:
Seizures RX I.V diazepam
fatal cardiac arrhythmias. propranolol

Hallucinogens (psychotomimetic)
 A few drugs have the ability to induce altered perceptual states
reminiscent of dreams, are accompanied by bright, colourful
changes in the environment and by a plasticity of constantly
changing shapes and colour.
 The individual under the influence of these drugs is incapable of
normal decision making, because the drug interferes with rational
thought.

A. Lysergic acid diethylamide
 Multiple sites in the CNS are affected by lysergic acid diethylamide
(LSD).
 The drug shows serotonin (5-HT) agonist activity at presynaptic 5-
HT1 receptors in the midbrain, and also stimulates 5-HT2 receptors.
 Activation of the sympathetic nervous system occurs, which causes
pupillary dilation, increased BP, piloerection, and increased body
temperature.

LSD Adverse effects:
 include hyperreflexia, nausea, and muscular weakness.
 High doses may produce long-lasting psychotic changes in
susceptible individuals.
 Haloperidol and other neuroleptics can block the hallucinatory
action of LSD and quickly abort the syndrome.

B. Tetrahydrocannabinol (THC)
 The main psychoactive alkaloid contained in marijuana is tetrahydrocannabinol (THC),
which is available as dronabinol.
 THC can produce euphoria, followed by drowsiness and relaxation.
 The effects of marijuana on γ-aminobutyric acid (GABA) in the hippocampus diminish
the capacity for short-term memory in users
 decreases muscle strength
 and impairs highly skilled motor activity, such as that required to drive a car.
 Its wide range of effects includes: appetite stimulation, xerostomia, visual
hallucinations, delusions, and enhancement of sensory activity

C. Ethanol (EtOH)
 Alcohol is the most commonly abused substance in modern society.
 Alcoholism decreases life expectancy by 10 to 15 years.
 Ethanol exerts its desired and toxic effects through:
o enhancing the effects of the GABA,
o inducing the release of endogenous opioids,
o and altering levels of serotonin and dopamine.
 Ethanol is a selective CNS depressant at low doses, resulting in decreased inhibitions
and the characteristic drunken behavior.
 At high doses, it is a general CNS depressant, which can result in coma and respiratory
depression.

Ethanol
1. Ethanol is absorbed from the stomach and duodenum, and food slows and decreases
absorption.
2. Peak ethanol levels are generally achieved in 20 minutes to 1 hour of ingestion.
3. Ethanol is metabolized by alcohol dehydrogenase to acetaldehyde and then by aldehyde
dehydrogenase to acetate in the liver.
4. It is metabolized by zero-order elimination at approximately 15 to 40 mg/dL/h.
5. There is a constant blood-to-breath ratio of 2100:1.
6. Medical management of acute ethanol toxicity includes symptomatic supportive care and the
administration of thiamine and folic acid to prevent/treat Wernicke encephalopathy and
macrocytic anemia.

Ethanol:
7. Chronic ethanol abuse can cause profound hepatic, cardiovascular,
pulmonary, hematologic, endocrine, metabolic, and CNS damage.
8. Sudden cessation of ethanol ingestion in a heavy drinker can
precipitate withdrawal manifested by tachycardia, sweating, tremor,
anxiety, agitation, hallucinations, and convulsions.
9. Alcohol withdrawal is a life-threatening situation that should be
medically managed with symptomatic/supportive care,
benzodiazepines, and long-term addiction treatment.

Drugs used in the treatment of alcohol
dependence:
A. Disulfiram blocks the oxidation of acetaldehyde to acetic acid by
inhibiting aldehyde dehydrogenase. This results in the accumulation
of acetaldehyde in the blood, causing flushing, tachycardia,
hyperventilation, and nausea.
B. Naltrexone Naltrexone is a long-acting opioid antagonist that
should be used in conjunction with supportive psychotherapy.
Naltrexone is better tolerated than disulfiram.
C. Acamprosate should also be used in conjunction with supportive
psychotherapy.

Prescription Drug Abuse
 Some commonly abused prescription drugs include opioids,
benzodiazepines, and barbiturates, with opioids outpacing the
other prescription drugs by a large margin.
 Visits to the emergency department related to misuse of
pharmaceuticals now exceed those related to illicit drug use, and
prescription pain relievers also now account for more deaths than
heroin and cocaine combined.

Anxiety
Unpleasant state of tension,
apprehension or uneasiness that seems
to arise from an unknown source.
Usually associated with somatic
symptoms tachycardia, sweating,
tremor, palpitation, hyper apnea, etc

ANXIETY DISORDERS
 Panic Disorder
 Generalized Anxiety Disorder
 Phobic Disorders
 Stress Disorders
 Obsessive-Compulsive Disorder

Anti anxiety drugs
 Mostly mild CNS depressants
 Control the symptoms of anxiety, produce a restful state of mind
without interfering with normal mental or physical functions.

Classification
1. Benzodiazepines: Diazepam ,Chlordiazepoxide
Oxazepam, Lorazepam, Alprazolam, Flurazepam
2) Azapirones :Buspirone ,Gepirone, Ipsapirone
3) Sedative Antihistaminic: Hydroxyzine
4) Beta blockers :Propranolol
5) Others: SSRIs, TCA, MAO- inhibitors,
SNRI (venlafaxine)
Meprobamate , Clonidine,

Benzodiazepines
 Site of action: mid brain ,ascending reticular formation ,&limbic
system
 MOA:
By post synaptic inhibition through BZD receptor

ADR
 Sedation
 Light headedness
 Cognitive impairment
 Vertigo
 Confusion
 Appetite & Wt. gain
 Alt in sexual function
 Dependence

Advantages of BZD
 High therapeutic index
 Do not affect respiration or cardiovascular function
 No microsomal induction
 Low abuse liability
 Specific BZD antagonist Flumazenil is available

CHLORDIAZEPOXIDE
 First BZD used as an antianxiety agent
 Produce smooth long lasting effect
 Preferred in chronic anxiety states
 T1/2 :5-15 hours
 Dose : 20-100 mg

OXAZEPAM
 Hepatic metabolism is less significant
 It is preferred in the elderly and those with liver disease
 Short duration of action
 Used in short lasting anxiety state

LORAZEPAM
 Oral & IM administration
 No active mtb
 Short acting  preferred in elderly
 Used in short lasting anxiety ,Panic, OCD, tension syndrome
 Dose: 1 - 6mg/day

ALPRAZOLAM
 Anxiolytic + antidepressant
 High potency anxiolytic
 Useful in anxiety associated with depression
 Less drowsiness
 Dose : 0.25-0.5mg BD or TDS
 active mtb

AZAPIRONES
 Buspirone , Gepirone, Ipsapirone
MOA:
o Selective agonistic action on 5HT-1A receptor
o Weak D2 blocking action – no antipsychotic or extrapyramidal
S/E
Site of action:
 Dorsal raphe seretoninergic neurones

PK
given orally, rapidly absorbed
Extensive first pass metabolism
Excreted through urine and faeces
ADR
Dizziness ,headache, Nausea
Tachycardia , Pupillary Constriction
DOSE: 5-10mg OD-TDS

Different type of anxiety and its and its
management
Generalized Anxiety Disorder: persistent excessive, unrealistic worry
associated with somatic symptoms.
 Acute phase – Benzodiazepines are preferred
o Rapid onset of action
o Eg: lorazepam, Oxazepam
o Not ideal for long term treatment due to abuse liability &
development of tolerance
 For long term use : Buspirone ,SSRIs.

Obsessive-Compulsive Disorder
Obsessive thoughts and compulsive behaviors that impair everyday
functioning
 Treatment
o TCA (clomipramine) poorly tolerated
o SSRI
• Fluoxetine (5–60 mg/d),
• fluvoxamine (25–300 mg/d),
• sertraline (50–150 mg/d)
o Buspirone
o BZD

Panic Disorder:
Recurrent and unpredictable panic attacks, with intense discomfort
and fear of impending doom or death.
 Treatment
o SSRIs low doses
o Eg: 5–10 mg fluoxetine, 25–50 mg sertraline, 10 mg paroxetine

Phobic Disorders
Persistent fear of objects or situations, exposure to which results in an
immediate anxiety reaction. The patient avoids the phobic stimulus,
and this avoidance usually impairs occupational or social functioning.
 Treatment
o Beta blockers : Propranolol 20–40 mg orally 2 h before the
event (performance anxiety)
o SSRIs
o MAO inhibitors

Stress Disorders
Anxiety following exposure to extreme traumatic events. The reaction
may occur shortly after the trauma (acute stress disorder) or be
delayed and subject to recurrence (PTSD) . In both syndromes,
individuals experience associated symptoms of detachment and loss
of emotional responsivity.
 Treatment
o Benzodiazepines and supportive/expressive psychotherapy
o SSRI
o MAO inhibitors

Normal sleep
Normal sleep consists of
distinct stages,based on three
physiologic measures: the
electroencephalogram, the
electromyogram, and the
electronystagmogram.
Non-rapid eye movement(NREM) sleep:
70%-75%
Stage 1,2
Stage 3,4:slow wave sleep, SWS
Rapid eye movement(REM) sleep

BASIC PHARMACOLOGY OF SEDATIVE-
HYPNOTICS
 An effective sedative (anxiolytic) agent should reduce anxiety and
exert a calming effect with little or no effect on motor or mental
functions.
 A hypnotic drug should produce drowsiness and encourage the
onset and maintenance of a state of sleep that as far as possible
resembles the natural sleep state.
 Hypnotic effects involve more pronounced depression of the
central nervous system than sedation, and this can be achieved
with most sedative drugs simply by increasing the dose.
 Graded dose-dependent depression of central nervous system
function is a characteristic of sedative-hypnotics.

CHEMICAL CLASSIFICATION
1. Benzodiazepines: not to lead general anesthesia, raraly death.
2. Barbiturates: the older sedative-hypnotics, general depression of
central nervous system. With such drugs, an increase in dose
above that needed for hypnosis may lead to a state of general
anesthesia. At still higher doses, it may depress respiratory and
vasomotor centers in the medulla, leading to coma and death.
3. Other classes of drugs: chloral hydrate, buspirone, et al.

Benzodiazepines
 The first benzodiazepine, chlordiazepoxide, was synthesised by
accident in 1961.

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 :
o 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.
3. Anticonvulsant and antiseizure
o They are highly effective against chemically induced convulsions caused by
leptazol, bicuculline and similar drugs but less so against electrically induced
convulsions.
o The can enhance GABA-mediated synaptic systems and inhibit excitatory
transmission.

PHARMACOLOGICAL EFFECTS
4. Muscle relaxation
relax contracted muscle in joint disease or muscle spasm.
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.

PHARMACOKINETIC ASPECTS
 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
o Short-acting compounds: triazolam, oxazepam(15-30min, t1/2 2-3 h)
o Medium-acting compounds: estazolam, nitrazepam (40min, t1/2 5-8 h)
o Long-acting compounds: diazepam, flurazepam(50h)

ADVERSE DRUG REACTION
 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;

BARBITURATES
Classification
(1) Ultra-short-acting barbiturates: act within seconds, and their duration of action is
30min. Therapeutic use of Thiopental: anesthesia
(2) Short-acting barbiturates: have a duration of action of about 2h. The principal use
of Secobarbital : sleep-inducing hypnotics.
(3) Intermediate-acting barbiturates: have and effect lasting 3-5h. The principal use of
Amobarbital is as hypnotics.
(4) 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
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.

BARBITURATES
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.

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 of acute overdosage
 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.

Neuroactive Agents.pptx

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