Sunteți pe pagina 1din 101

By

Pharm. Sheku S. Mansaray


B.Pharm (Hons), M.Sc., MPCPharm., MPSSL
 Identify the major chemical classes of sedative-hypnotics.

 Describe the pharmacodynamics of barbiturates


benzodiazepines (BZDs) and non-BZDs including their
mechanisms of action.

 Compare the pharmacokinetics of commonly used


benzodiazepines and barbiturates and discuss how differences
among them affect clinical use.

 Describe the clinical uses and the adverse effects of sedative-


hypnotics.
Introduction
Def. of sedation, hypnosis
Anxiety disorders
Classification of the SeH & anxiolytics
Chemistry of the SeH & anxiolytics
Pharmacokinetics
Mechanism of action
Pharmacological action
Clinical uses
Side effects
Drug interactions
Other anxiolytics
 Alcohol and opium have been the oldest hypnotics and
continue to be used for this purpose.
 Bromides introduced in 1837 are now obsolete, so are
chloral hydrate (1869) and paraldehyde (1882).
 Fischer and von Mering introduced barbiturates in 1903 and
phenobarbitone in 1912.
 Barbiturates remained supreme till the 1960s when
benzodiazepines started evolving and have now totally
replaced them.
 In the mean time, a number of other sedative-hypnotics
were introduced but none was significantly different from
the barbiturates.
 Some newer non-BZD hypnotics have become available
over the past decades.
 SEDATION: can be defined as a suppression of
responsiveness to a constant level of stimulation, with
decreased spontaneous activity and ideation.

 HYPNOSIS: state of sleep.


SEDATIVES - drugs capable of producing mild depression,
decreased activity, moderate excitement, and emotional calmness

They reduce anxiety (anxiolytic) and exert a calming effect


with little or no effect on motor or mental functions.

HYPNOTICS — drugs are used primarily to induce sleep

The sedatives and hypnotics are more or less general CNS


depressants with somewhat differing time-action and dose-action
relationships.
 Those with quicker onset, shorter duration and steeper dose-
response curves are preferred as hypnotics while more slowly
acting drugs with flatter dose-response curves are employed
as sedatives.

 However, there is considerable overlap; a hypnotic at lower


dose may act as sedative.

 Thus, sedation-hypnosis-general anaesthesia may be regarded


as increasing grades of CNS depression.

 Hypnotics given in high doses can produce general


anaesthesia.
 These are drugs that can depress the CNS in a relatively
nonselective dose-dependent fashion, producing
progressive calmness or drowsiness, sleep,
unconsciousness, surgical anesthesia, coma, fatal
depression of the respiration and cardiovascular
system.

 There major therapeutic use is to cause sedation (with


concomitant relief of anxiety) or to encourage sleep
 Anxiety disorders as recognized clinically include:
 Generalized anxiety disorder (an ongoing state of excessive
anxiety lacking any clear reason or focus)

 Panic disorder (sudden attacks of overwhelming fear that may


occur in association with marked somatic symptoms, such as
sweating, tachycardia, chest pains, trembling and choking).
 Phobic anxiety (strong fears of specific objects or situations,
e.g. snakes, open spaces, flying, social interactions)

 Post-traumatic stress disorder (anxiety triggered by recall of


past stressful experiences)

 Obsessive compulsive disorder (compulsive ritualistic


behaviour driven by irrational anxiety, e.g. fear of
contamination).
 Medical:
a) Respiratory
b) Endocrine
c) Cardiovascular
d) Metabolic
e) Neurologic.
 Drug-Induced:
◦ Stimulants
 Amphetamines, cocaine, TCAs, caffeine

◦ Sympathomimetics
 Ephedrine, epinephrine, pseudoephedrine phenylpropanolamine

◦ Anticholinergics\Antihistaminergics
 Trihexyphenidyl, benztropine, meperidine, diphenhydramine,
oxybutinin

◦ Dopaminergics
 Amantadine, bromocriptine, L-Dopa, carbidopa/levodopa.
◦ Miscellaneous:
 Baclofen, cycloserine, hallucinogens, indomethacin
 Verbal complaints: The patient says he/she is anxious,
nervous, edgy

 Somatic and autonomic effects. The patient is restless


and agitated, has tachycardia, increased sweating,
weeping and often gastrointestinal disorders

 Social effects. Interference with normal productive


activities.
 Chemical structure

 Duration of action
 Benzodiazepines e.g. Diazepam
 Barbiturates e.g Phenobarbital
 Azaspirodecanedione e.g. Buspirone
 Imidazopyridine e.g zolpidem
 Pyrazolopyrimidine e.g . Zaleplon
 Propanediol carbamate e.g. meprobamate
 Melatonin receptor agonist e.g. Ramelteon
 Alcohols e.g. Ethanol, chloral hydrate
 Beta-adrenergic blocking agents e.g, propranolol
 Antipsychotic tranquilizers e.g. Ziprasidone
 Antihistamines e.g. diphenhydramine, hydroxyzine
 Tricyclic antidepressants, SSRIs
Benzodiazepine:
 They are the most important class, used for treating both
anxiety states and insomnia.

 They vary greatly in duration of action, and can be divided


into:

• Short-acting compounds: triazolam, oxazepam, Midazolam (15-30min,


t1/2 2-3 h)
• Medium-acting compounds: estazolam, alprazolam, temazepam,
lorazepam, nitrazepam (40min, t1/2 5-8 h)

• Long-acting compounds: diazepam, halzepam, clorazepate,


chlordiazepoxide, flurazepam (50h)
 Hypnotic: Diazepam, Flurazepam, Nitrazepam, Alprazolam,
Temazepam, Triazolam

 Antianxiety: Diazepam, Chlordiazepoxide, Oxazepam,


Lorazepam, Alprazolam

 Anticonvulsant: Diazepam, Lorazepam, Clonazepam,


Clobazam
Long Acting Barbiturates:
> Phenobarbital
> Barbital
> Mephobarbital
> Metharbital
Intermediate Acting Barbiturates:
> Amobarbital
> Butarbital
Short Acting Barbiturates:
> Pentobarbital
> Secobarbital
Ultra – Short Acting Barbiturates
> Thiopental
> Hexobarbital
> Methohexital
> Thiamylal
 Barbiturates have been popular hypnotics and sedatives
of the last century upto 1960s, but are not used now to
promote sleep or to calm patients.
 However, they are the prototype of CNS depressants.
 Barbiturates are substituted derivatives of barbituric
acid (malonyl urea).
 Barbiturates have variable lipid solubility, the more
soluble ones are more potent and shorter acting.
 They are insoluble in water but their sodium salts
dissolve yielding highly alkaline solution.
 Barbiturates are well absorbed from the GIT.
 They are widely distributed in the body and the rate of entry
into the CNS is dependent on lipid solubility.
 Highly-lipid soluble thiopentone has practically
instantaneous entry, while less lipid-soluble ones
(pentobarbitone) take longer.
 Phenobarbitone enters very slowly.
 Plasma protein binding varies with the compound, e.g.
thiopentone 75%, pentobarbitone 35%, phenobarbitone
20%.
 Barbiturates cross placenta and are secreted in milk; can
produce effects on the foetus and suckling infant.
Redistribution: It is important in the case of highly
lipid-soluble thiopentone and others.
 After their i.v. injection, consciousness is regained in 6-
10 min due to redistribution
 NOTE: Effect of single dose of short acting barbiturate
may last for 6-10 hours due to redistribution,
 Metabolism: Drugs with intermediate lipid-solubility
(short-acting barbiturates) are primarily metabolized in
the liver by oxidation, dealkylation and conjugation.
 Their plasma half life ranges from 12-40 hours.
 Excretion: Barbiturates with low lipid-solubility (long-
acting agents) are significantly excreted unchanged in
urine.
 Alkalinization of urine increases ionization and
excretion.
 Barbiturates induce hepatic microsomal enzymes and
increase the rate of their own metabolism as well as
that of many other drugs.
 Barbiturates appear to act primarily at the GABA:
BZD receptor Cl-channel complex and potentiate
GABAergic inhibition by increasing the lifetime of
Cl-channel opening induced by GABA (contrast
BZDs which enhance frequency of Cl-channel
opening).
 They do not bind to the BZD receptor, but bind to
another site (probably the picrotoxin sensitive site) on
the same macromolecular complex to exert the
GABA-facilitatory action.
 The barbiturate site appears to be located on α or β
subunit, because presence of only these subunits is
sufficient for their response.
 They also enhance BZD binding to its receptor.
 At high concentrations, barbiturates directly increase
Cl-conductance (GABA-mimetic action; contrast to
BZDs which have only GABA-facilitatory action)
 At very high concentrations, barbiturates depress
voltage sensitive Na+ and K + channels as well.
Sedation
> Barbiturates have euphoriant effect
Hypnosis
> Barbiturates alter the stages of sleep in the dose-
dependent manner
> they decrease sleep latency & decrease number of
awakenings and decrease body movements
Anesthesia
> Thiopental and methohexital are very lipid soluble,
penetrating brain tissue rapidly following IV administration
> They are therefore useful in anesthesia practice
Anticonvulsant Effects:
> Phenobarbital and metharbital (converted to
phenobarbital in the body) are effective in the treatment of
generalized tonic-clonic seizures
Respiration:
> Depress both respiratory drive & the mechanisms
responsible for the rhythmic character of respiration
> Diminish neurogenic drive & in higher doses, suppress
hypoxic & chemoreceptor drive
> Laryngospasm – chief complaint of barbiturate
anesthesia
Cardiovascular System
> Cardiovascular reflexes are obtunded by partial inhibition of
ganglionic transmission → slight fall or no change in BP

> Decrease in renal plasma flow and in cerebral blood flow with a
marked fall in CSF pressure
Liver
> Combine with cytochrome 450 & competitively interfere with
the biotransformation of a number of drugs

> Chronic administration causes a marked increase in the protein


and lipid content of the hepatic smooth endoplasmic reticulum
Kidney
> Severe oliguria or anuria in acute barbiturate poisoning, largely
as a result of the marked hypotension
 Except for phenobarbitone in epilepsy and thiopentone
in anaesthesia barbiturates are seldom used now.
 As hypnotic and anxiolytic they have been superseded
by BZDs.
 They are occasionally employed as adjuvants in
psychosomatic disorders.
 The enzyme inducing property of phenobarbitone can
be utilized to hasten clearance of congenital
nonhaemolytic jaundice and kernicterus.
After-effects:
- Drowsiness for only a few hours
- Residual CNS depression up to 10-22 hrs.
- Distortions of mood
- Impairment of judgment & fine motor skills
- Other residual effects: vertigo, nausea, vomiting, diarrhea,
over excitement - awakes slightly intoxicated, euphoric &
energetic
irritability and temper

Paradoxical Excitement:
- Common among geriatric & debilitated patients
- Phenobarbital & N-methylbarbiturates
 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 secreted in
the breast milk.

 Others: Skin eruptions and porphyria


Increased CNS-depressant effects:
1. other CNS depressants (ethanol)
2. isoniazid
3. methylphenidate
4. monoamine oxidase inhibitors
 Induction of microsomal hepatic enzymes -> accelerated
disappearance of drugs & endogenous substances, accelerated
metabolism of vitamins D & K →hamper bone mineralization
& lower Ca`+ absorption (phenobarbital)
 Enhance metabolism of steroid hormones - endocrine
disturbances
 Enhance metabolism of oral contraceptives - unwanted
pregnancy
 Induce hepatic generation of toxic metabolites of
chlorocarbon anesthetics & carbon tetrachloride→ promote
lipid peroxidation & facilitates the periportal necrosis of the
liver
Acute intermittent porphyria:
 Barbiturates enhance porphyrin synthesis
 Chlordiazepoxide and diazepam were introduced
around 1960 as antianxiety drugs.
 Since then, this class has proliferated and has gained
popularity over barbiturates as well as hypnotic
because:
 BZDs have a high therapeutic index. Ingestion of 20
hypnotic doses does not usually endanger life
 there is no loss of consciousness (though amnesia
occurs) and patient can be aroused, respiration is not so
depressed.
 Hypnotic doses do not affect respiration or
cardiovascular functions. Higher doses produce
respiratory depression and hypotension which is
problematic only in patients with respiratory
insufficiency and cardiac/haemodynamic abnormality.
 BZDs have practically no action on other organ
systems. Only on i.v. injection the BP falls may be
marked in an occasional patient) and cardiac
contractility decreases.
 Fall in BP in the case of diazepam and lorazepam is due
to reduction in cardiac output while that due to
midazolam is due to decrease in peripheral resistance.
 BZDs cause less distortion of sleep architecture;
rebound phenomena on discontinuation of regular use
are less marked.
 BZDs do not alter disposition of other drugs
microsomal enzyme induction.
 They have lower abuse liability; tolerance is mild,
psychological, physical dependence and withdrawal
syndrome are less marked
 A specific BZD antagonist; flumazenil is available
which can be used in case of poisoning.
BENZODIAZEPINES
• The Benzodiazepines are the most widely used sedative hypnotics.

 They consists of a benzene ring coupled to a seven-member


heterocyclic structure containing two nitrogens (diazepam) at
positions 1 and 4

 Structures- 1,4, Benzodiazepines-contain a carboxamide group in


the 7 – membered heterocyclic ring structure.

 A substituent in the 7 position, such as a halogen or a nitro group,


is required for sedative-hypnotic activity

 The first member of this group is chlordiazepoxide,

 Triazolam and Alprazolam contain triazole ring at the position 2.


1. Absorption
> to treat anxiety and sleep disorders: given orally
> oral absorption may depend on lipophilicity, with
plasma peak concentration ranging from 0.5 to 8 hours
rapid: triazolam, diazepam, clorazepate
slow : oxazepam, lorazepam temazepam
> with high lipid-water distribution coefficients in the
non-ionized form
> essentially completely absorbed
> Bioavailability : after intramuscular injection unreliable
(except lorazepam and midazolam )
2. Distribution
- some reach the systemic circulation only in the form of
active metabolite (prazepam, flurazepam)
- rate of transport in blood depends on blood flow,
concentration gradients and permeability
- rate of entry into CNS depends on lipid solubility
- plasma protein binding varies from 60% to 95%, they can
cross the placental barrier and secreted into breast milk.
Metabolism
• The BDZs are metabolized extensively by CP450 enzymes
particularly CYP3A4 and CYP2C19.

• Some like oxazepam are conjugated directly and are not


metabolised by these enzymes.

• Macrolides, ritonavir, itraconazole, ketoconazole, nefazodone,


and grapefruit juice are inhibitors of CYP3A4 and can affect
metabolism of BDZs
 Keep in mind that with formation of active metabolites,
the kinetics of the parent drug may not reflect the time
course of the pharmacological effect.

 Estazolam, oxazepam, and lorazepam, which are


directly metabolized to glucuronides have the least
residual (drowsiness) effects

 All of these drugs and their metabolites are excreted in


urine.
 Benzodiazepines act preferentially on midbrain
ascending reticular formation (which maintains
wakefulness) and on limbic system (thought and mental
functions).
 Muscle relaxation is produced by a primary medullary
site of action and ataxia is due to action on cerebellum.
 BZDs act by enhancing presynaptic/postsynaptic
inhibition through a specific BZD receptor which is an
integral part of the GABA-A receptor-Cl- channel
complex.
 The benzodiazepines (BDZs) bind with high affinity to
specific macromolecules within the CNS.
 These BDZ-binding sites (receptors) are closely
associated with the receptors for gamma aminobutyric
acid (GABA)
 GABA is the major inhibitory neurotransmitter in the
mammalian brain.
 BDZs potentiate GABAergic neurotransmission in
essentially all areas of the CNS.
 This enhancement is thought to occur indirectly at the
postsynaptic GABA receptor complex.
 The significance of this drug–receptor interaction is to
regulates the entrance of chloride into the postsynaptic
cells.
 The increase in chloride conductance mediated by
GABA is intensified by the benzodiazepines →
hyperpolarization & diminished synaptic transmission.
 It is noteworthy that the BZDs do not themselves
increase Cl- conductance; have only GABA facilitatory
but no GABA mimetic action.
 This probably explains the lower ceiling CNS
depressant effect of BZDs.
Sedation and induction of sleep
 Benzodiazepines decrease the time taken to get to sleep, and
increase the total duration of sleep.

 The latter effect occurs only in subjects who normally sleep


for less than about 6 hours each night.
Reduction of anxiety and aggression

 BDZs show anxiolytic effects in animal and also exert a


marked 'taming' effect, allowing animals to be handled more
easily.

 BDZs reduce the number of attacks by animals and increase


the number of attacks made on him.

 They do not have antidepressant effects (with the exception of


alprazolam).

 They may paradoxically produce an increase in irritability and


aggression in some individuals (triazolam).
Reduction of muscle tone and coordination
 BDZs reduce muscle tone by a central action that is
independent of their sedative effect.

 Increased muscle tone is a common feature of anxiety states in


humans and may contribute to the aches and pains

 The relaxant effect of benzodiazepines may therefore be


clinically useful.
Anticonvulsant effects
 All the BDZs have anticonvulsant activity

 They are highly effective against chemically induced


convulsions caused by pentylenetetrazol, bicuculline and simila
drugs

 BDZs enhance the action of GABA but not glycine


Anterograde amnesia
 BDZs obliterate memory of events experienced while under
their influence, an effect not seen with other CNS
depressants.

 Minor surgical procedures can thus be performed without


leaving unpleasant memories.
Respiratory System:
 Hypnotic dose→ slight depression of alveolar
ventilation similar to natural sleep changes
Cardiovascular System:
 Minimal decrease in blood pressure, cardiac output and
systemic vascular resistance
 Increased coronary blood flow
Gastrointestinal Tract:
 Improve anxiety related GI disorders

 Decrease nocturnal gastric secretion.


 Anxiety & agarophobia: Alprazolam

 Insomnia: Triazolam, Quazepam, Temazepan, Flurazepam,


Estazolam

 Status epilepticus, anesthetic premedication, muscle


relaxation: Diazepam

 Preanesthetic & intraoperative medication: Midazolam,


Lorazepam

 Seizure, acute mania, movement disorder: Clonazepam


Alcohol and Sedative–Hypnotic Withdrawal:
 BDZs, such as chlordiazepoxide and diazepam are sometimes
used to lessen the intensity of the withdrawal symptoms when
alcohol or sedative–hypnotic drug use is discontinued.
 BDZs are relatively safe drugs. Side effects of
hypnotic doses are dizziness, vertigo, ataxia,
disorientation, amnesia, prolongation of reaction
time-impairment of psychomotor skills (should not
drive).
 Hangover is less common, but may be noted if larger
doses are used, especially of longer acting drugs.
 Weakness, blurring of vision, dry mouth and urinary
incontinence are sometimes complained.
 Like any hypnotic, BZDs can aggravate sleep apnoea.
 Paradoxical stimulation, irritability and sweating may
occur in an occasional patient, especially with
flurazepam.
 Some patients experience increase in nightmares and
behavioral alterations, especially with nitrazepam.
 Additive effect - alcohol, opioid analgesics, anticonvulsants,
and phenothiazines

 Delays hepatic clearance & prolongs elimination half time of


diazepam & metabolites - cimetidine

 Enhanced CNS depression effects -antihistamines,


antihypertensives and tricyclic antidepressants
Flumazenil:
 It is a BZD analogue which has little intrinsic activity
(practically no effect on normal subjects), but competes
with BZD agonists as well as inverse agonists for the
BZD receptor and reverses their depressant or stimulant
effects respectively.
 Flumazenil abolishes the hypnogenic, psychomotor,
cognitive and EEG effects of BZDs.
 At higher doses it has some week BZD agonist-like as well as
inverse agonist-like activity in animal models, but these are of
no clinical significance.

Pharmacokinetics
 Flumazenil is absorbed orally; oral bioavailability is app.16%,
but it is not used orally.
 On i.v. injection, action of flumazenil starts in seconds
and lasts for 1-2 hr; elimination half life is 1 hr, due to
rapid metabolism.
To reverse BZD anaesthesia:
 Patients anaesthetized/sedated with a BZD wakeup, get
oriented and regain motor control within 1 min of an i.v.
injection of 0.3-1 mg of flumazenil

BZD overdose:
 Majority of patients of BZD overdose require only supportive
measures like patent airway, maintenance of BP, cardiac and
renal function, etc.
 In addition, flumazenil 0.2 mg/min may be injected i.v.
till the patient regains consciousness.
 N.B: It cannot reverse the CNS depression of alcohol or
barbiturate overdose.
 Flumazenil is safe and well tolerated.
 Agitation, discomfort, tearfulness, anxiety, coldness
and withdrawal seizures are the occasional side effects.
• These include: Zopiclone, zolpidem and zaleplon (so
called Z-drugs)
• They have shorter half-lives than the BDZs.
• They all have reduced propensity to tolerance and
have less abuse liability.
Zopiclone
 This newer cyclopyrrolone hypnotic is an agonist at a
subtype of BZD receptor.
 It is reported not to disturb sleep architecture or
produce hangover or withdrawal phenomena on
discontinuation
 Zopiclone has been used to weanoff insomniacs taking
regular BZD medication.
Its half life is 5-6 hours.
 Zopiclone is indicated for short term (< 2 weeks)
treatment of insomnia.
Side effects
 Metallic or bitter after-taste
 Impaired judgement and alertness
 Psychological disturbances
 Dry mouth and rarely dependence.
Zolpidem
 An imidazopyridine derivative with hypnotic actions

 Mechanism of action: binds selectively to BZ subtype receptors


and facilitates GABA-mediated neuronal inhibition

 Actions antagonized by flumazenil

 Minimal muscle relaxing and anticonvulsant effect


Short-term treatment of insomnia
Minor effects on sleep patterns but suppress REM sleep at higher
doses.
Less tolerance & dependence with extended use than with
benzodiazepines
Pharmacokinetics
Rapidly metabolized in the liver to inactive metabolites,
elimination half-life ---> 1.5 – 3.5 hours

Precautions
Patients with hepatic dysfunction, elderly

Drug interaction
 Rifampicin — decreases half-life of zolpidem

 Ethanol & other CNS depressants →respiratory depression


Zaleplon

Resembles zolpidem
Mechanism of action: binds selectively to BZ, receptor subtype and
facilitates inhibitory actions of GABA
Decreases sleep latency: Little effect on total sleep time or on sleep
structure.
Pharmacokinetics
Rapidly absorbed from GIT, rapid onset & short duration of action
Elimination half-life is about 1 hour.
Metabolized mainly by hepatic aldehyde oxidase & partly by
cytochrome P450
NOTE: Amnesic effects & next-day psychomotor impairment may
occur
AZAPIRONES
 Buspirone is the first example of a class of anxiolytic
agents that can relieve some symptoms of anxiety in
doses that do not cause sedation.
 Buspirone is well absorbed from the gastrointestinal tract
 Peak blood levels are achieved in 1 to 1.5 hours
 The drug is more than 95% bound to plasma proteins.
 It is extensively metabolized, with less than 1% of the parent
drug is excreted into the urine unchanged.
 It has an elimination half-life of 4 to 6 hours.
 It effects are mediated through interactions at the
serotonin (5-hydroxytryptamine, 5-HT) 5-HT1A
receptor, where it acts as a partial agonist.
 It acts as an antagonist at postsynaptic 5HT1A sites in
the hippocampus (where there is little receptor reserve).
 It has anxiolytic actions in humans.
 In therapeutic doses, buspirone has little or no sedative effect
and lacks the muscle relaxant and anticonvulsant properties of
the benzodiazepines.

 It does not potentiate the central nervous system depression


caused by sedative–hypnotic drugs or by alcohol.

 It is as effective as the BDZs in the treatment of general


anxiety
 Buspirone is effective in general anxiety and in anxiety
with depression.

Side effects
 Dizziness
 Light-headedness
 Headache
• Buspirone has been reported to increase blood pressure
in patients taking monoamine oxidase inhibitors

• It may increase plasma levels of haloperidol if


coadministered.
Paraldehyde
Rapid acting hypnotic —> sleep ensues in 10-15 min
Rapidly absorbed & widely distributed
70-80% metabolized in the liver
> Elimination half-life is 4-10 hrs
> Excreted in expired air & urine
Side effects: acidosis, bleeding gastritis fatty changes in
liver & kidney (toxic hepatitis & nephrosis)
Has little analgesic activity
Decreases sleep latency, awakenings & slow wave sleep
> Metabolized in the liver to trichloroethanol
>Excreted mostly in urine as urochoralic acid

- Side effects:
Irritating to skin & mucous membrane unpleasant taste,
epigastric distress, nausea, occ. vomiting
CNS: lightheadedness, malaise, ataxia, nightmares
"Hangover"
idiosyncratic - disoriented, incoherent, paranoid
behavior
Icterus -acute poisoning Delirium & seizures
Hypnotic-sedative with rapid onset & short duration of action
> has anti-convulsant & muscle relaxant property
acts within 15-30 minutes
> distribution half-life is 1-3 hours > elimination half life is
10-25 hrs.

Side effects:
mint-like aftertaste dizziness, nausea & vomiting hypotension,
facial numbness mild "hangover“
 Hypersensitivity - urticaria, fatal thrombocytopenia,
cholestatic jaundice
 Acute intoxication - severe respiratory depression,
bradycardia
 Idiosyncratic - mild stimulation to marked excitement &
hysteria
 Contraindicated in patients with porphyria
 Drug interaction: enhance metabolism of oral anticoagulants
Gluthetimide
 Rarely recommended for continued use because of its
addiction liability, severity of withdrawal symptoms & certain
features of acute intoxication
 Exhibits pronounced anticholinergic activity
 Absorbed from GIT, 50% bound to plasma proteins, 95%
metabolized in the liver
 Half-life is 5-22 hours
"hangover" excitement blurred vision, gastric irritation,
headache, skin rashes thrombocytopenia, aplastic anemia,
leukopenia

Acute intoxication - less severe respiratory depression

Antimuscarinic actions - xerostomia, ileus, urinary bladder


atony, long lasting mydriasis, hyperpyrexia

Abstinence syndrome - tremulousness, tachycardia, fever,


tonic muscle spasms & generalized convulsions
Hypnotic
Metabolized in the liver & eliminated almost entirely by
urinary excretion

Plasma half-life is 4 hrs > Should be avoided in patients with


intermittent porphyria

Side effects:
"hangover“, nausea, vomiting, diarrhea, esophagitis and
headache, idiosyncratic excitement

Acute intoxication - hypotension, shock, pulmonary edema,


coma - may last up to 5 days
Meprobamate
-Introduced as antianxiety agent in 1955

-Causes widespread depression of CNS but not anesthesia

-Also acts as anticonvulsant

-Well absorbed when administered orally

-Metabolized in the liver & eliminated in the urine

-Half-life is 6-17 hours


Is a urethane

Rapid onset & short duration of action


Inactivated in the liver & excreted as glucuronide in the urine

Side effects:
Nausea, occasional vomiting, rash
Idiosyncratic excitement, fever, thrombocytopenia
Etomidate

 Used as an intravenous anesthetic

 Advantages: lacks pulmonary and vascular depressant activity


Negative inotropic effect

 Used as sedative-hypnotics in ICU's, during intermittent


positive-pressure breathing and in epidural anesthesia
 Has sedative, muscle relaxant and anticonvulsant properties

 Used for hypnosis of elderly & institutionalized patients, for


preanesthetic sedation, management of ethanol withdrawal
For relief of anxiety
For insomnia
For sedation and amnesia before and during medical and
surgical procedures
For treatment of epilepsy and seizure states
As a component of balanced anesthesia (intravenous
administration)
For control of ethanol or other sedative-hypnotic
withdrawal states
For muscle relaxation in specific neuromuscular disorders
As diagnostic aids or for treatment in psychiatry
 Direct Toxic Actions
◦ dose-related depression of the central nervous system
◦ Hypersensitivity reactions
◦ teratogenicity
 Alterations in Drug Response
◦ Tolerance
◦ Cross-tolerance
 Drug Interactions
◦ With other central nervous system depressant drugs
◦ hepatic drug-metabolizing enzyme systems
ANXYOLITICS HYPNOTICS
Alprazolam Chloral hydrate
Chlordiazepoxide Estazolam
Buspirone Flurazepam
Diazepam Pentobarbital
Lorazepam Lorazepam
Oxazepam Quazepam
Triazolam Triazolam
Phenobarbital Secobarbital
Halazepam Temazepam
Prazepam Zolpidem
THANK YOU

S-ar putea să vă placă și