Sedatives are drugs that reduce excitement and calm a person, while hypnotics produce sleep resembling normal sleep. The document discusses several classes of sedatives and hypnotics including barbiturates, benzodiazepines, and newer nonbenzodiazepine hypnotics like zolpidem and zaleplon. It provides details on their mechanisms of action, pharmacokinetics, therapeutic uses, and adverse effects.
2. ïŹ Sedatives: it is a drug that reduces excitement and
calms the person
ïŹ Hypnotics is the drug that produces sleep
resembling the normal sleep
ïŹ The sedatives and hypnotics are more or less
general CNS depressants with some what differing
time- action and dose-action relationships. Those
with quicker onset, shorter duration and steeper
dose response curve are preferred as hypnotics
while more slowly acting drugs with flatter dose
response curves are employed as sedatives
6. MECHANISM OF ACTION
ï Facilitation of GABA action on the brain: Barbiturates bind
at the ÎČ sub unit of GABA-A receptor and increase the
duration of the GABA gated channel opening but in large
dose, they can directly activating chloride channels.
7. SUB-ANAESTHETIC DOSES:
ïdepress excitatory neurotransmitter actions
ANAESTHETIC DOSES:
ï Interfere with Na+
& K+
transport across cell membranes
(reticular activating system inhibition).
8. PHARMACOKINETICS
ï All barbiturates are weak acids
ï lipid soluble
ï absorbed orally.
ï distribute throughout the body
ï Thiopentone is highly lipid soluble (high rate of entry into
CNS- quick onset of action).
9. PHARMACOKINETICS
ï Redistribute in the body from the brain to skeletal muscles-
adipose tissues.
ï Metabolized in the liver to inactive metabolites
ï Excreted in the urine.
ï Alkalinization increases excretion (NaHCO3)
ï Cross the placenta ( pregnancy).
10. PHARMACOLOGICAL
ACTIONS
CENTRAL NERVOUS SYSTEM: In a dose-dependent fashion.
ï Sedative
ï Hypnotic
ï Anesthesia in large dose
ï Anticonvulsant action
ï Coma and death.
RESPIRATORY SYSTEM:
ï suppress hypoxic and chemoreceptor response to CO2
ï Large doses leads to respiratory depression & death.
11. PHARMACOLOGICAL
ACTIONS
CVS:
ï Healthy patient: at low doses, they have insignificant
effects.
ï Hypovolemicstates, CHF: normal doses may cause
cardiovascular collapse.
ï Large dose â circulatory collapse due to medullary
vasomotor depression.
SKELETAL MUSCLE:
ï Anesthetic dose reduce muscle contraction by depressing
excitability of neuromuscular junction
12. Barbiturates poisoning
ïŹ Maintain ABC
ïŹ Maintain electrolyte balance
ïŹ Gastric lavage- after stomach wash, administered activated
charchoal it may enhance the elimination of phenobarbitone.
Endotracheal intubation is performed before gastric lavage to
protect the airway in uncouncious patient.
ïŹ Alkaline diuresis: i.v. NaHCO3
ïŹ Haemodialysis is employed in severe cases.
ïŹ Drug interactions: Barbiturates are potent microsomnal
enzymes and reduces the effectiveness of oral drugs ( e.g.
OCP, oral anticoagulants, oral hypoglycemics etc.)
13. Therapeutic uses
1. Sedation and hypnosis : barbiturates were used in the treatment
of insomnia. At present barbiturates are not recommended.
2. General anesthesia (GA) ultra short acting barbiturates
( thiopentone and methohexitone ) are used in induction of GA.
3. Anticonvulsant: Phenobarbitone has anticonvulsant effect and
used in treatment of status epilepticus and generalized tonic-
clonic seizures ( GTCS , grand mal epilepsy )
4. Neonatal jaundice and non-haemolytic type: phenobarbitone
may be used to reduce serum bilurubin levels. It induces
glucuronyl transferase enzyme and hastens the metabolism of
bilurubin.
5. Diagnostic aid and Psychiatry: i.v. thiopentone in subanesthetic
dose produces a state of deep sedation. The patient becomes
more communative, which helps in diagnostic of psychiatric
disorders like histeria
14. ADVERSE EFFECTS
ï Common side effects are drowsiness, confusion, headache,
ataxia, hypotension and respiratory depression
ï Hangover: residual sedation after awakening.
ï Tolerance
ï Withdrawal symptoms
ï Precipitation of acute attack of porphyria.
ï Allergic reaction: urticaria and skin rash.
Toxicity: drowsiness, Restlessness, hallucinations, hypotension
Respiratory depression, convulsion, Cardiovascular collapse,
coma and death.
15. MECHANISM OF ACTION
ïŹ Benzodiazepines act very selectively on GABAA-receptors, which
mediate the fast inhibitory synaptic response produced by activity
in GABA-ergic neurons.
ïŹ 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
16. MECHANISM OF ACTION
ïŹ Benzodiazepines bind specifically to a regulatory site on the
receptor, distinct from the GABA binding site, and enhanced
receptor affinity for GABA.
ïŹ The GABAA-receptors is a ligand-gated ion channel consisting of a
pentameric assembly of subunits.
25. ZOLPIDEM
ï Acts on benzodiazepine receptors & facilitate GABA mediated
neuronal inhibition.
ï Its action is antagonized by flumazenil.
ï rapidly absorbed from GIT and metabolized to inactive
metabolites via liver CYT P450.
ï Short duration of action ( 2- 4 h).
ï Only hypnotic effect
ï Its efficacy is similar to benzodiazepines.
ï Minor effect on sleep pattern, but high doses suppress REM.
ï Respiratory depression occur at high doses in combination
with other CNS depressant as ethanol.
26. ï§ Has no muscle relaxant effect.
ï§ Has no anticonvulsant effect.
ï§ Minimal psychomotor dysfunction
ï§ Minimal tolerance & dependence.
ï§ Minimal rebound insomnia.
Uses
ïŹ a hypnotic drug for short term treatment of insomnia
Dose should be reduced in hepatic or old patients.
Adverse Effects: GIT upset, Drowsiness Dizziness
27. Zaleplon
ï§Binds to BZs receptors and facilitate GABA actions.
ï§ Rapid absorption
ï§ rapid onset of action
ï§ Short duration of action (1 hr)
ï§ Metabolized by liver microsomal enzymes
ï§Only hypnotic effect
ï§Decreases sleep latency
ï§Little effect on sleep pattern
28. ï§ Potentiates action of other CNS depressants (alcohol).
ï§ Dose reduction as before.
ï§ Used as hypnotic drug
ï§ Advantages
Less impairment of pyschomotor performance than BZs or
zolpidem.
29. Enumerate BZDs. Explain the mechanism of
action, therapeutic use and adverse effect of
them.
Define sedatives and hypnotics. Classify
sedatives and hypnotics drugs.
Why BZDs are preferred to barbiturates as
sedatives and hypnotics ?
Write short notes on : Flumazenil
: Zolpidem
Editor's Notes
A hypnotic at lower dose may act as sedative. Thus sedation-hypnosis-gerneral anestgesia may be regarded as increasing grades of CNS depression. Hypnotics given at the higher doses can produce General Anes. However BZDâS cannot be considered nonslective or general CNS depressants like baribiturates and other
the linear slope for drug A is typical of many of the older sedative-hypnotics, including the barbiturates and alcohols. With such
drugs, an increase in dose higher than th at needed for hypnosis may lead to a state of general anesthesia. At still higher doses, th
ese sedative-hypnotics may depress respiratory and vasomotor centers in the medulla, leading to coma
and death. Deviations from a linear dose-response relationship, as shown for drug B, require proportionately greater dosage increments
to achieve central nervous system depression more profound than hypnosis. This appears to be the
case for benzodiazepines and for certain newer hypnotics that have a similar mechanism of action.
benzodiazepines:
wildly used, not to lead general anesthesia,
or death.
ïą
Barbiturates: (âderivatives of barbituric acid , are non selective CNS depressants and act at many sites , The ARAS being the main site)
the older sedative-hypnotics, general depression of central nervous system. With such drugs, an increase in dose above that needed for hypn
osis may lead to a state of general anesthesia. At still higher doses, it may depress respiratory and vasomotor centers, leading to coma and death.
ïą
Newer Hypnotics:
Several drugs with novel chemical structures have been introduced more recently for use in sleep disorders
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.
Alkaliine diuresis: iv nahco3 alkalinizes urinr. Barbiturates are weakly acidic drygs. In alkaline urine barbiturates exist in inoized form, so they are not reabsorbrd while passing through the renal tubules and are rapidly excreated in urine.
Heamodialysis: highly effective in removing long acting barbiturates.
Tolerance develops on their sedative and hypnotic actions on repeted use
Prolonged use of phenobarbitone may vause megaloblastic anemia by interfing with the absorption of folic acid from the gut
May precipitate aatacks of acute intermittent porphyria by inducing ALA sybthetase that catalyses the production of porphyrias, hence barbiturates are contraindicated in porphyrias.
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.
Advantages of BZD over barbiturates
1. Selective: minimal respiratory and cardiovascular depression.
2. High therapeutic index.
3. Less hangover.
4. Not enzyme inducer.
5. Less dependence with minimal withdrawal symptoms.
6. Has specific antagonist.
Given orally or iv and ocacasionally by rectal route
Absorption of diazepam from im sites is irregular and erratic hence rarely used
Plasma binding variable widely distributed in body
Disadvantages of benzodiazepines
ïą
Dependence
ïą
Depression of central nervous system functions
ïą
Amnestic effects
ïą
To cause depression when administered with
other drugs, including ethanol.
Effects on Pregnancy <ul><li>Benzodiazepines (and their metabolites) can freely cross the placental barrier and accumulate in fetal circulation </li></ul><ul><ul><li>Administration during the first trimester can result in fetal abnormalities </li></ul></ul><ul><ul><li>Administration in third trimester (close to the time of birth) can result in fetal dependence, or âfloppy-infant syndromeâ </li></ul></ul><ul><li>Benzodiazepines are also excreted in the breast milk </li></ul><ul><li>Â </li></ul>
Long term use of bzd are not recommended becoz of tolerance, dependance and hang over effectsâŠ. But for the ocassional use by air travellers, shift workers, these drugs are ideal
BZDS donot cause true geaneral anesthesia, larazeapm, midazolam etc are combined with other cns depressants to produce general anetsheisa
ADIA (ZE) PAM
M- muscle relaxnt
Antianxiety
Preanesthetic medicine
Anticonvulsant
Insomnia
Diagnostic ( endosco[ies) and minor operative procedures
Alchol-withdrawl symptoms
Flumazenil is used in the treatment of BZD overdasge and used to reverse sedative effects of BZD during general anes. âŠâŠâŠâŠâŠâŠ it may precipitate withdrawal symptoms ( anxiety and convulsions) in dependant subjects.
Drug interactions
Rifampicin (decreases half life)
Cimetidine (increases half life)