THIS CLASS IS IN BRIEF FOR UNDERGRADUATE UNDERSTANDING AND EXAMINATION PURPOSE

1. Dr. RAGHU PRASADA M S
MBBS,MD
ASSISTANT PROFESSOR
DEPT. OF PHARMACOLOGY
SSIMS & RC.

2.  An effective sedative (anxiolytic) agent should reduce
anxiety and exert a calming effect with little or no
effect on motor or mental functions.
 Sedation refers to decreased responsiveness to any
level of stimulation and is associated with some
decrease in motar activity and ideation
 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 passive and highly suggestible

3. Awake
Amnesia
sedation
Hypnosis
Coma
Death

4. ACCORDING TO DURATION
OF ACTION :
ULTRA SHORT ACTING
(3-5 HOURS).
TRIAZOLAM, MIDAZOLAM
SHORH ACTING (6-24
HOURS).
ALPRAZOLAM,
NITRAZEPAM
LORAZEPAM
ESTAZOLAM
OXAZEPAM
TEMAZEPAM
LONG ACTING:
( 24-72 HOURS)
CHLORAZEPATE
CHLORDIAZEPOXIDE
DIAZEPAM
FLURAZEPAM.
QUAZEPAM
PRAZEPAM

5. Newer agents(non-benzodiazepines)
ZOLPIDEM, ZALEPLON,
ZOPICLONE, ESZOPICLONE
Barbiturates
PHENOBARBITONE, MEPHOBARBITONE,
SECOBARBITONE,
THIOBARBITONE, PENTOBARBITONE, THIOPENTONE,
HEXOBARBITONE
Miscellaneous
PARALDEHYDE, CHLORAL HYDRATE, GLUTETHEMIDE,
MELATONIN, RAMELTEON, MEPROBAMATE,

7.  GABA –Gamma Amino Butyric Acid is a major
inhibitory neurotransmitter in CNS
 Benzodiazepines potentiate GABA ergic inhibition at
all levels of neuroxis—spinal cord, hypothalamus,
hippocampus, substantia nigra, cerebellar cortex and
cerebral cortex
 Pentameric structure 5 subunits
 Macromolecular complex of ion channel

8. (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.

9. 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 prolong the duration of the opening of GABA-
activated chloride channels.
At high doses, barbiturates can inhibit the release of
the Ca2+-dependent neurotransmitter
 They exhibit a GABA mimetic action
 Depress action of excitatory glutamate
neurotransmitter by binding to AMPA receptor

10.  High lipid solubility allows rapid transport across the
blood-brain barrier and results in a short onset.
 Removal from the brain occurs via redistribution to
the other tissues results in short duration of action.
 Barbiturates and their metabolites excretion via
the renal route.
 Alkalization of the urine expedites the excretion of
barbiturates.
 Treatment of acute over dosage: Sodium
bicarbonate and dialysis

11.  Solution of sodium alkaline Cannot be given by
IM/SC route  necrosis and pain
 Oral and IV Weakly acidic drugs
 Metabolism-phase1- oxidation
Phase 2-glucuronyl conjugation

12.  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 Neonatal jaundice
 Preanaesthetic medication

13. After effect: hangover---dizzy, drowsiness, amnesia,
impaired judgment, disorientation drug automatism
 Tolerance: decreased responsiveness to a drug
following repeated exposure because of down-
regulation of receptors and induction of hepatic drug-
metabolising enzymes.

14. Have a narrow therapeutic-to-toxic dosage range.
Suppress REM sleep.
Tolerance develops relatively quickly.
Have a high potential for physical dependence and
abuse drug automatism
Respiratory depression and hypotension
Potent inducers of hepatic drug-metabolising enzymes.
hyperalgesia

15.  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
 Drug interaction-barbiturates metabolize OCPS
anticoagulants, theophylline, tolbutamide

16.  An overdose can result in coma, diminished reflexes,
severe respiratory depression, hypotension leading
to cardiovascular collapse, and renal failure.
 Treatment
(1) supporting respiration and circulation.
(2) alkalinizing the urine and promoting diuresis.
(3) Hemodialysis or peritoneal dialysis.

17.  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.

18.  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).

19. 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 psychological dependence
and withdrawal syndrome
5) less adverse effects such as residual drowsiness and
incoordination movement.

20. 1. Reduction of anxiety and aggression :
affects the hippocampus and nucleus amygdalae
2. Sedation and induction of sleep:
The latency of sleep onset is decreased;
The duration of stage 2 NREM sleep is increased;
The duration of slow-wave sleep is decreased.

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

22. 4. Muscle relaxation
relax contracted muscle in joint disease
or muscle spasm.
5. Anticonvulsant effect: especially
diazepam, lorazepam, clorazepate,
clonazepam, nitrazepam.
6. Other effects
lead to temporary amnesia
decrease the dosage of anesthetic
depress respiratory and cardiovascular function.
PHARMACOLOGICAL EFFECTS

23. 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.
All Benzodiazepines are metabolized in the liver
Phase I: ( liver microsomal system)
Phase II: glucuronide conjugation and
excreted in the urine.

24. Dose reduction in
Liver disease
Old people.
Synergistic effect with other CNS depressants
Drug interaction
Concurrent with sodium valproate can provoke
psychotic symptoms
Rifampicin (decreases half life)
Cimetidine, isoniazid, OCPs (increases half life)
Contraindication
Alcohol and other CNS depressants, antihistamines

26. TRIAZOLAM
used only for sedation in severe insomnias
It also has amnesic, anxiolytic anticonvulsant, muscle
relaxant properties
Oral-44% sublingual-53%
OXAZEPAM-
Used to relieve anxiety with alcohol withdrawal
Oral bioavailability is 95%
Used in treatment of insomnias
It is a metabolite of Diazepam, Prazepam
It is amnesic, anxiolytic anticonvulsant, hypnotic
Used in Post traumatic stress disorder
Used in pre-menstrual syndrome
10-15mg

27. MIDAZOLAM
Treatment of acute seizures, insomnias
Anxiolytic, hypnotic, anticonvulsant
Induction and maintenance of anaesthesia
Intranasal, buccal route
Used for endoscopy

28. Anxiety disorders: alprazolam
General anxiety disorders
Panic attack - major depressive disorders
Sleep disorders (Insomnia).
Estazolam, Lorazepam, temazepam:
Flurazepam, Quazepam
Long acting drugs can cause hangover.

29. 3.To control withdrawal symptoms of alcohols
diazepam- chlordiazepoxide.
4.Treatment of epilepsy
Diazepam – Lorazepam: Status epilepticus
Clonazepam-Clorazepate: absence , myoclonic
seizures.
5.Muscle relaxation: in spastic states (Diazepam)

30. In anesthesia
1. Preanesthetic medication diazepam
2. Induction of balanced anesthesia(Midazolam)
3. Adjunct therapy during minor surgery
(endoscopy, bronchoscopy, dental surgery).

31.  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 system
 The availability of an effective antagonist, flumazenil
can avert toxicity reactions

32.  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

33.  a selective competitive antagonist of BZD
receptors (Bz1).
 Blocks action of benzodiazepines, zaleplon and
zolpidem but not other sedative /hypnotics.
 Blocks psychomotor, cognitive and memory
impairment of BZs.
Has short duration of action T 1 /2 = 1 hour
Absorbed orally, need to be used repeatedly IV

34. Zopiclone is a cyclopyrrolone in structure.
Acts at the GABAA-benzodiazepine receptor
It has a fairly fast (about 1 h) onset of action
which lasts for 6–8 h, making it an effective drug
both for initial and maintenance insomnia.
Its duration of action is prolonged in the elderly
and in hepatic insufficiency.
The dose is 3.75–7.5 mg orally

35. Zolpidem
It is an immidazopyridine in structure
Fast onset (30–60 min) and short duration of action
Sleep latency is shortened
Sleep duration is prolonged
Relative lack of effect on sleep stages (REM
suppression)
Zolpidem is nearly completely metabolised in liver
Dose-10-20mg

36. Zaleplon
Shortest acting newer non-BZD that inhibits BZD
receptors containing alfa1 subunit
Rapidly absorbed
Oral bioavailability is 30%
Due to first pass metabolism
T1/2-1hr
Dose-5-10mg HS

37. N-acetyl -5 methoxy tryptamine is principal hormone of
pineal gland
High dose-80mg can induce sleep
Low dose-2-10mg donot depress CNS
It has improved sleep quality in elderly insomnias
Melatonin supplements may retard aging
It is tried in cluster headache
Meloset-3mg

38. Buspirone, Ipsapirone, Gepirone
These drugs act through non-GABAergic system
Selective activation of inhibitory presynaptic 5HT1A
Receptor, they suppress 5HT neurotransmission
through neuronal system
BUSPIRONE
Minimal abuse liability and no withdrawal reactions
No rebound anxiety, insomnia
Buspirone causes less impairment of psychomotar
skills

39.  Buspirone does not potentiate the CNS depressant
effect of ethanol (non-sedating anxiolytic drug)
 It has no muscle relaxant, anticonvulsant or hypnotic
action
 It can cause tachycardia nervousness, GIT distress
and parasthesias

40. PROPRANOLOL
Propranolol helps to suppress such performance
anxiety by breaking vicious cycle
Beta –blockers decreases palpitation, tremors, GIT
upset hypertension and blood lactic acid levels
20mg TDS  may have associated CVS effects makes
it unlikely to be used as potential anxiolytic agent

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