2. Basic pharmacology of
sedative- hypnotics drug
• Sedative- hypnotics drug
– A sedative drug decreases activity, moderates excitement, and calms
the recipient
– A hypnotic drug produces drowsiness and facilitates the onset and
maintenance of a state of sleep that resembles natural sleep
– This effect is sometimes called hypnosis
– Sedation is a side effect of many drugs that are not general CNS
depressants (e.g., antihistamines and antipsychotic agents)
Such agents can intensify the effects of CNS depressants
They usually produce more specific therapeutic effects at concentrations
far lower than those causing substantial CNS depression
2
3. – Although coma may occur at very high doses, neither
surgical anesthesia nor fatal intoxication is produced by
benzodiazepine (BZP)
– An important exception is midazolam, which has been
associated with decreased tidal volume and respiratory rate
– The sedative-hypnotic drugs that do not specifically target
the BZP receptor causes depression of the CNS in a dose-
dependent fashion
– Progressively producing:
calming or drowsiness (sedation)
Sleep (pharmacological hypnosis)
Unconsciousness
Coma
Surgical anesthesia
Fatal depression of respiration and cardiovascular regulation
3
5. • Benzodiazepines
– Promote the binding of neurotransmitter GABA
to the GABAA subtype of GABA receptors
– It constitutes the most commonly used group of
anxiolytics and sedative–hypnotics
– Chlordiazepoxide is the first of the member
– Most of these drugs possess:
Anxiolytic
Sedative–hypnotic
Anticonvulsant properties
5
9. • Mechanism of action
– It potentiates GABAergic neurotransmission in
essentially all areas of the CNS
– This enhancement is thought to occur indirectly at
the postsynaptic GABAA receptor complex
– The increase in chloride conductance mediated by
GABA is intensified by the BZPs
– This facilitation of GABA-induced chloride
conductance results in greater hyperpolarization of
these cells
– Therefore, this leads to diminished synaptic
transmission
9
10. Fig. A model of the GABA A receptor-chloride ion channel macromolecular
complex showing the binding site of BZP and barbiturates 10
11. • Pharmacokinetics
– BZPs are usually given orally and are well absorbed by
this route
– They are weak bases
– They are less ionized in the alkaline environment of the
small intestine
– Therefore, most of their absorption takes place at this
site
– For emergency treatment of seizures or when used in
anesthesia, the BZPs also can be given parenterally
– Diazepam and lorazepam are available for intravenous
administration
11
12. – BZP with a greater lipid solubility tend to enter the CNS
and produce their effects more quickly
– Many BZPs do undergo extensive biotransformation by
hepatic CYPs, particularly CYPs 3A4 and 2C19
– Metabolism takes place both by dealkylation (phase 1)
and conjugation (phase 2) reactions
– Oxazepam, are conjugated directly and are not
metabolized by these enzymes
– Erythromycin, clarithromycin, ritonavir, itraconazole,
ketoconazole, nefazodone, and grapefruit juice are
inhibitors of CYP3A4 and can affect the metabolism of
BZPs
12
13. Fig. Biotransformation of benzodiazepines. (Boldface, drugs available for clinical use in
various countries; *, active metabolite.)
13
14. – Central nervous system effects of BZPs include:
Reduction of anxiety and aggression
Sedation and induction of sleep
Reduction of muscle tone and coordination
Anticonvulsant effects
– CVS
When BZPs are given per orally –no effect on HR and BP
However, after IV route they cause profound hypotension and cardiac arrest
– Respiratory system
• They have little respiratory depression when used alone w/out
CNS depressant
• However, it exacerbate some respiratory disorder such:
Hypoventilation and hypoxemia-in patients with COPD
Apnea (pause in breathing)
14
15. • Clinical uses of BZPs:
– Insomnia
they promote sleep through effect on cortical areas and the sleep-
wakefulness clock
it should be given on an intermittent schedule (3 or 4 days per week)
– Anxiety - at small doses, used as anxiolytics
They reduce anxiety through their effects on the limbic system, a
neuronal network associated with emotionality
– Preoperative medications
Eg . Amnesia – resulted from effect on hippocampus and cerebral
cortex
– Acute alcohol withdrawal- alleviate the withdraw
syndromes
BZPs benefits derived from cross-dependence with alcohol
Eg. Chlordiazepoxide, clorazepate, diazepam, and oxazepam are used
15
16. – As anticonvulsants
inhibit epileptiform activity
used for seizures, status epilepticus (i.v.)
Diazepam, lorazepam,clorazepate, clonazepam are agents used
for seizure
– Chronic muscle spasm and spasticity
relaxing the spasticity of skeletal muscle, probably by
increasing presynaptic inhibition in the spinal cord and
cerebellum
Eg. Diazepam
Spasticity in cerebral palsy, paraplegia, athetosis,
stiff man syndrome
16
17. • Adverse effects
– Hypnotic doses of BZPs can be expected to cause varying
degrees of:
Light-headedness
Lassitude
Increased reaction time
Motor incoordination
Impairment of mental and motor functions
Confusion
Anterograde amnesia
Cognition appears to be affected less than motor performance
– All of these effects can greatly impair driving and other
psychomotor skills, especially if combined with ethanol
17
18. – Other relatively common side effects of BZPs are :
Weakness
Headache
Blurred vision
Vertigo
Nausea and vomiting
Epigastric distress
Diarrhea; joint pains, chest pains, and incontinence are
much rarer
Anticonvulsant benzodiazepines sometimes actually
increase the frequency of seizures in patients with
epilepsy ( Esp. if the dose is missed or abruptly
withdrawn)
18
19. BZPs may cause paradoxical effects
Eg. Flurazepam occasionally increases the incidence of
nightmares—especially during the first week of use
– It causes garrulousness, anxiety, irritability, tachycardia,
and sweating
– Amnesia, euphoria, restlessness, hallucinations, sleep-
walking, sleep-talking, other complex behaviors, and
hypomanic behavior occur during use of various BZPs
– Collectively, these are sometimes referred to as
disinhibition or dyscontrol reactions
19
20. • Drug -interactions
– BZPs interact with: alcohol; cimetidine, ketoconazole, fluvoxamine,
fluoxetine, omeprazole; anticonvulsants; anticholinergics; rifampicin
• Contraindications
– Known hypersensitivity to BZPs
– Chronic obstructive airways disease with incipient respiratory failure
– BZPs are not recommended for the primary treatment of psychotic
illness
– BZPs should not be used alone to treat depression or anxiety associated
with depression as suicide may occur in such patients
– Chlordiazepoxide and diazepam have been reported to increase the
chance of birth defects when used during the first 3 months of
pregnancy
– During nursing diazepam secret into the breast milk and cause
drowsiness and difficulty in feeding of newborn
20
21. • Novel benzodiazepine receptor agonists
– Hypnotics in this class are commonly referred to as "Z compounds“
– They include;
Zolpidem
Zaleplon
Zopiclone
Eszopiclone which is the S(+) enantiomer of zopiclone
– The Z compounds are structurally unrelated to each other and to
benzodiazepines
– However, their therapeutic efficacy as hypnotics is due to agonist effects on
the BZP site of the GABAA receptor
– Compared to BZPs, Z compounds are lack the following effects:
Anticonvulsants
muscle relaxants
Anxiolytic
– This is because Z-compound not bind to all BZP receptors, rather they are
relative selectivity for GABAA receptors containing the ἀ1 subunit
21
22. – Z compounds have largely replaced BZPs in the
treatment of insomnia
– Like BZPs, based on post-marketing clinical
experience with zopiclone and zolpidem,
tolerance and physical dependence can be
expected
– The clinical presentation of overdose is similar to
that of BZPs
– Overdose with Z compounds can be treated with
the BZPs antagonist flumazenil
22
23. • Zaleplon
– It is effective in relieving sleep-onset insomnia
– It has been approved by the FDA for use for up to
7-10 days at a time
– It is used immediately at bedtime or when the
patient has difficulty falling asleep after bedtime
– It has sustained hypnotic efficacy without
occurrence of rebound insomnia on abrupt
discontinuation
–
23
24. • Pharmacokinetics
– It is absorbed rapidly and reaches peak plasma
concentrations in ~1 hour
– Its bioavailability is ~30% because of presystemic
metabolism
– It is metabolized largely by aldehyde oxidase and to a lesser
extent by CYP3A4
– It is eliminated in urine
– None of zaleplon's metabolites are pharmacologically active
– A large or high-fat meals can delay absorption substantially
– Mild rebound may occur first night after discontinuation
•
24
25. • Zolpidem
– It is effective in relieving sleep-onset insomnia
– It has been approved by the FDA for use for up to 7-10
days at a time
– It has sustained hypnotic efficacy without occurrence of
rebound insomnia on abrupt discontinuation
– Zaleplon and zolpidem differ in residual side effects
– Late-night administration of zolpidem has been associated
with morning :
Sedation
Delayed reaction time
Anterograde amnesia
– Whereas zaleplon does not differ from placebo
25
26. • Pharmacokinetics
– It is absorbed readily from the GI tract
– First-pass hepatic metabolism results in an oral
bioavailability of ~70%
– This value is lower when the drug is ingested with
food because of slowed absorption and increased
hepatic blood flow
– Zolpidem has a t1/2 of ~2 hours, which is sufficient
to cover most of a typical 8-hour sleep period
– It is presently approved for bedtime use only
26
27. – It is eliminated almost entirely by conversion to
inactive products in the liver
– Tolerance and physical dependence develop only
rarely and under unusual circumstances
– Zolpidem-induced improvement in sleep time of
chronic insomniacs was sustained during as much
as 6 months of treatment without signs of
withdrawal or rebound after stopping the drug
– Nevertheless, zolpidem is approved only for the
short-term treatment of insomnia
27
28. • Eszopiclone
It is used for the long-term treatment of insomnia and for
sleep maintenance
It is prescribed to patients who have difficulty falling asleep
as well as those who experience difficulty staying asleep
No tolerance was observed, nor were signs of serious
withdrawal, such as seizures or rebound insomnia
– It is absorbed rapidly after oral administration
– Its bioavailability is ~80%
– It is metabolized by CYPs 3A4 and 2E1
– It is believed to exert its sleep-promoting effects through
its enhancement of GABAA receptor function at the BZPs
binding site
28
29. • Benzodiazepine receptor antagonist
• Flumazenil
– It binds with high affinity to specific sites on the GABAA
receptor
– It competitively antagonizes the binding and allosteric
effects of BZPs and other ligands
– It antagonizes both the electrophysiological and behavioral
effects of agonist and inverse-agonist BZPs , β-carboline
– The drug is given intravenously
– Flumazenil is eliminated almost entirely by hepatic
metabolism to inactive products with a t1/2 of ~1 hour
– The duration of clinical effects usually is only 30-60 minutes
29
30. – It is used for the management of suspected BZP
overdose and the reversal of sedative effects
produced by BZPs
– A total of 1 mg flumazenil given over 1-3 minutes
usually is sufficient to abolish the effects of
therapeutic doses of BZPs
– Patients with suspected BZP overdose should
respond adequately to a cumulative dose of 1-5 mg
given over 2-10 minutes
– A lack of response to 5 mg flumazenil strongly
suggests that a BZP is not the major cause of
sedation
30
31. • Benzodiazepine overdose
– May be intentional or secondary to accumulation of
doses
– Symptoms: somnolence, impaired coordination, slurred
speech, diminished reflexes, confusion, respiratory
depression, hypotension
• Treatment options
– Supportive and symptomatic care
– Gastric lavage (removing poison from GIT)
– Activated Charcoal (absorb poisonous substance)
– IV hydration and maintain adequate airway
– IV Flumazenil (Romazicon®): Benzodiazepine antagonist
31
32. • Melatonin Congeners
• Ramelteon
– It is a synthetic tricyclic analog of melatonin
– It was approved in the U.S. in 2005 for the treatment of
insomnia, specifically sleep onset difficulties
– It is the first FDA-approved sleep remedy that is not under
regulatory control of substance act
– Long-term use is permitted
– It is good for inducing sleep but not for maintaining sleep
• Mechanism of action
– Melatonin levels in the suprachiastmatic nucleus rise and fall in
a circadian fashion, with concentrations increasing in the
evening as an individual prepares for sleep
– Ultimately decreasing as the night progresses
32
33. – Two GPCRs for melatonin, MT1 and MT2, are found
in the suprachiasmatic nucleus
– Each of them playing a different role in sleep
– Binding of agonists, such as melatonin, to MT1
receptors promotes the onset of sleep
– However, melatonin binding to MT2 receptors shifts
the timing of the circadian system
– Ramelteon is not known to bind to any other classes
of receptors, such as nicotinic acetylcholine,
neuropeptide, dopamine, or opiate receptors, or
the BZP-binding site on GABAA receptors
33
34. • Clinical pharmacology
– An 8-mg tablet be taken ~30 minutes before bedtime
– It is rapidly absorbed from the GI tract
– In the bloodstream, ~80% of ramelteon is protein bound
– The drug is largely metabolized by the hepatic CYPs 1A2, 2C,
and 3A4, with t1/2 of ~2 hours in humans
– Fluvoxamine, strong inhibitors of Cyp1A2, can increase the
levels of ramelteon
– Of the four metabolites, one, M-II, acts as an agonist at MT1
and MT2 receptors and may contribute to the sleep-promoting
effects of ramelteon
– Very high dose(197 times human dose) causes teratogenic in
rat
– Not recommended for use by nursing mothers
34
35. • Barbiturates
– Once used extensively as sedative-hypnotic drugs
– They have been largely replaced by the much safer
BZPs
– Mainly because barbiturates induce
oTolerance
oDrug-metabolizing enzymes
oPhysical dependence
oVery severe withdrawal symptoms
35
36. – They includes:
Amobarbital – used for insomnia, pre-operative
sedation, emergency management of seizures
Butabarbital – used for insomnia, pre-op
sedation
Mephobarbital –used for Seizure disorders,
daytime sedation
Methohexital –used for induction and
maintenance of anesthesia
Pentobarbital –used for insomnia, pre-op
sedation, emergency management of seizures
36
37. Phenobarbital- used for seizure disorders, status
epilepticus, daytime sedation
Secobarbital -used for insomnia, preoperative
sedation
Thiopental - used for induction/maintenance of
anesthesia, pre-op sedation, emergency
management of seizures
Butabarbital and phenobarbital, are used
sometimes to antagonize unwanted CNS-
stimulant effects of various drugs, such as
ephedrine, dextroamphetamine, and
theophylline
37
38. • Pharmacological properties
– The barbiturates reversibly depress the activity of
all excitable tissues
• Sites and mechanisms of action on the CNS
– Barbiturates act throughout the CNS
– Enhancement of inhibition occurs primarily at
synapses where neurotransmission is mediated by
GABA acting at GABAA receptors
– Barbiturates can produce all degrees of depression
of the CNS, ranging from mild sedation to general
anesthesia
38
39. • Effects on stages of sleep
– Hypnotic doses increase the total sleep time and alter the
stages of sleep in a dose-dependent manner
– Barbiturates decrease sleep latency, the number of
awakenings, and the durations of REM and slow-wave sleep
• Tolerance
– Pharmacodynamic (functional) and pharmacokinetic
tolerance to barbiturates can occur
– During repetitive night administration, some tolerance to the
effects on sleep occurs within a few days
– Tolerance rapidly occur to sedation and its hypnotic effects
but not to toxic effect
39
40. – The effect on total sleep time may be reduced by as
much as 50% after 2 weeks of use
– Discontinuation leads to rebound increases in all the
parameters reported to be decreased by barbiturates
– Pharmacodynamic tolerance to barbiturates confers
cross-tolerance to all general CNS-depressant drugs,
including ethanol
• Abuse and dependence
– Barbiturates are abused, and some individuals develop a
dependence on them
– They may have euphoriant effects
40
41. • Respiration
The barbiturates:
– Slightly depress protective reflexes until the degree of
intoxication is sufficient to produce severe respiratory
depression
– Coughing, sneezing, and laryngospasm may occur when
barbiturates are employed as intravenous anesthetic agents
• Cardiovascular system
– When given orally in sedative or hypnotic doses,
barbiturates do not produce significant overt cardiovascular
effects
– However it causes a slight decrease in blood pressure and
heart rate such as occurs in normal sleep
41
42. – Decreased renal and cerebral blood flow with a marked
fall in CSF pressure occur with IV thiopental
preanesthetic medication
• GI Tract
– The oxybarbiturates tend to decrease the tone of the
GI musculature and the amplitude of rhythmic
contractions
– A hypnotic dose does not significantly delay gastric
emptying in humans
– The relief of various GI symptoms by sedative doses is
probably largely due to the central-depressant action
42
43. • Liver
– Barbiturate causes the microsomal enzyme
induction
– A site at which significant drug-drug interactions
can occur
• Kidney
– Severe oliguria or anuria may occur in acute
barbiturate poisoning largely as a result of the
marked hypotension
43
44. • Pharmacokinetics
– For sedative-hypnotic use, the barbiturates usually are
administered orally
– They are absorbed rapidly and probably completely
– Na+ salts are absorbed more rapidly than the corresponding
free acids
– The onset of action varies from 10-60 minutes, depending on
the agent and the formulation
– High –lipid soluble barbiturates have fast onset of action b/c
they rapidly cross BBB and their effect is terminated by
redistribution to blood and other tissue from the brain
– It is delayed by the presence of food in the stomach
– The intravenous route usually is reserved
for the management of status epilepticus (phenobarbital sodium) or
for the induction and/or maintenance of general anesthesia (e.g.,
thiopental or methohexital)
44
45. – Barbiturates are readily cross the placenta
It can injure the developing fetus
at 3rd trimester may cause drug dependence in the infant
– Except for the less lipid-soluble aprobarbital and
phenobarbital
Nearly complete metabolism and/or conjugation of
barbiturates in the liver precedes their renal excretion
(esp. for polar agents)
– About 25% of phenobarbital and nearly all of
aprobarbital are excreted unchanged in the urine
– Their renal excretion can be increased greatly by
osmotic diuresis and/or alkalinization of the urine
45
46. – The metabolic elimination of barbiturates is more
rapid in young people than in the elderly and
infants
– Its t1/2 are increased during pregnancy partly
because of the expanded volume of distribution
– Chronic liver disease, especially cirrhosis, often
increases the t1/2
– Repeated administration, especially of
phenobarbital, shortens its t1/2
46
47. • Adverse effect
– Distortions of mood
– Impairment of judgment and fine motor skills
– vertigo, nausea, vomiting, or diarrhea, or sometimes
may be manifested as overt excitement
– Because barbiturates enhance porphyrin synthesis
Therefore, they are absolutely contraindicated in patients
with acute intermittent porphyria or porphyria variegata
– Precursors barbiturates stimulates porphyrin Heme
Cyp450
– By increasing the synthesis of porphyrin, barbiturates
increases the production of cyp450 , a key drug-drug
interaction
47
48. • Hypersensitivity
– Allergic reactions occur, especially in persons with
asthma, urticaria, angioedema, or similar
conditions
– Its reaction include localized swellings,
particularly of the eyelids, cheeks, or lips, and
erythematous dermatitis(redness of the skin)
– Exfoliative dermatitis(skin becomes red and
flakes off) may be caused by phenobarbital and
can prove fatal
48
49. • Drug interactions
– Barbiturates combine with other CNS depressants cause
severe depression
ethanol
first-generation antihistamines
Isoniazid-decrease metabolism of barbiturates, so it increases CNS
effect of barbiturates
monoamine oxidase inhibitors- antidepressants have additive effect
on CNS-depressant
– Hepatic enzyme induction enhances metabolism of
endogenous steroid hormones, which may cause endocrine
disturbances
oral contraceptives, which may result in unwanted pregnancy
– The metabolism of vitamins D and K is accelerated
49
50. • Barbiturate poisoning
– Barbiturate poisoning has declined markedly
• Because of decreased their use as sedative-hypnotic
agents
– Poisoning with barbiturates is a significant clinical
problem
– Most of the cases are the result of deliberate
attempts at suicide, but some are from accidental
poisonings in children or in drug abusers
– Severe poisoning is likely to occur when >10 times
the full hypnotic dose has been ingested at once
50
51. – In severe intoxication, the patient is comatose;
respiration is affected early
– Breathing may be either slow or rapid and shallow
– Blood pressure falls because the effect of the drug
and of hypoxia on medullary vasomotor centers
– Depression of cardiac contractility
– Pulmonary complications (e.g., atelectasis, edema,
and bronchopneumonia) and renal failure are
likely to be the fatal complications of severe
barbiturate poisoning
51
52. • The treatment of acute barbiturate intoxication
– It is based on general supportive measures
– Hemodialysis or hemoperfusion is necessary only rarely
– The use of CNS stimulants is contraindicated because they
increase the mortality rate
– If renal and cardiac functions are satisfactory, and the
patient is hydrated
forced diuresis and alkalinization of the urine will hasten the
excretion of phenobarbital
– Measures to prevent or treat atelectasis should be taken,
and mechanical ventilation should be initiated when
indicated
– the blood pressure can be supported with dopamine
– In the event of renal failure, hemodialysis should be
instituted
52
53. • Miscellaneous sedative-hypnotic drugs
– It includes ramelteon, paraldehyde, chloral hydrate, meprobamate,
ethchlorvynol, glutethimide, methyprylon, ethinamate
– With the exception of ramelteon and meprobamate, the
pharmacological actions of these drugs resemble those of the
barbiturates
– All are general CNS depressants that can produce profound hypnosis
with little or no analgesia
– Their effects on the stages of sleep are similar to those of the
barbiturates
– Their chronic use can result in tolerance and physical dependence
– Meprobamate bear some resemblance to those of the
benzodiazepines
– However, meprobamate has a distinctly higher potential for abuse
and has less selective anti-anxiety effects
53
54. • Paraldehyde
– It has a strong odor and a disagreeable taste
– Orally, it is irritating to the throat and stomach
– It is not administered parenterally because of its injurious
effects on tissues
– When given rectally as a retention enema, the drug is
diluted with olive oil
– Oral paraldehyde is absorbed rapidly and distributed
widely
– Sleep usually ensues in 10 to 15 minutes after hypnotic
doses
– About 70% to 80% of a dose is metabolized in the liver
54
55. – Poisoning with the drug include acidosis, gastritis,
and fatty changes in the liver and kidney with
toxic hepatitis and nephrosis
– The clinical uses of paraldehyde include:
Treatment of withdrawal reactions
Psychiatric states characterized by excitement
Convulsions (including status epilepticus) in children
55
56. • Chloral Hydrate
– It is used for hypnotic effect
– In addition the drug has been employed in the past for the
production of sedation in children undergoing diagnostic,
dental, or other potentially uncomfortable procedures
– It is reduced rapidly to the active compound,
trichloroethanol (CCl3CH2OH), largely by alcohol
dehydrogenase in the liver
– Trichloroethanol is conjugated mainly with glucuronic
acid, and the product is excreted mostly into the urine
56
57. – It is irritating to the skin and mucous membranes
– These irritant actions give rise to an unpleasant taste,
epigastric distress, nausea, and occasional vomiting
(esp. if it is not diluted and taken on empty stomach)
– Undesirable CNS effects include lightheadedness,
malaise, ataxia, and nightmares
– Acute poisoning by chloral hydrate may cause jaundice
– Sudden withdrawal from the use of chloral hydrate
may result in delirium and seizures, with a high
frequency of death when untreated
57
