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1. BENZODIAZEPINES
CHAIRPERSON:DR H V AIRANI
MODERATOR:DR SHRUTHI
PRESENTER:DR DHARMARAJ

2. General properties of
Benzodiazepines
Benzodiazepines are compounds with sedative, anxiolytic and
anticonvulsant properties.
As the dose is increased the effects observed are first
anxiolytic, followed by sedation, then hypnosis and finally
unconsciousness with respiratory depression.
The dose-response curve for these effects is relatively flat
when compared with the barbiturates which they have
replaced.

3. CLASSIFICATION
Long Acting T1/2 (hrs)
1.Flurazepam 50-100
2.Diazepam 30-60
3.Nitrazepam 30
4.Flunitrazepam 15-25
Short Acting
1.Temazepam 8-12
2.Triazolam 2-3
3.Midazolam 2

4. Potency and pharmacokinetics
Long acting drugs such as nitrazepam, medazepam,
flurazepam, diazepam, chorazepate and chlordiazepoxide have
plasma half-lives of the parent drug plus active metabolite,
which exceed 10hr.
For this reason these drugs are not regarded as suitable long
term treatments for insomnia without anxiety.
The usual route for administration of benzodiazepines is oral,
although some may also be given intravenously &
intramuscular.

5. Below pH 6 it is freely water-soluble and forms a stable
solution, but at physiological pH the ring structure closes and
the drug becomes lipid-soluble, rapidly penetrating the blood-
brain barrier.
In general, benzodiazepines are non polar lipid-soluble drugs
that are not extensively excreted unchanged in the urine.
They are almost entirely eliminated from the body by hepatic
metabolism which usually involves oxidative reactions, by
microsomal enzymes in the hepatic endoplasmic reticulum.

6. Although most of the benzodiazepines are extensively bound
to plasma proteins, it is a free drug, which diffuses across
membranes to produce central nervous system effects.
It is also the free drug that may cross the placenta to affect the
fetus.
The highly lipophilic benzodiazepines cross the placenta
rapidly so that concentrations of diazepam are commonly
greater in the fetus than the mother.
Use of these drugs in late pregnancy leads to accumulation of
active metabolites in fetal tissues that cause early neonatal
depression with hypothermia and hypotonia

7. GABA Receptors
GABA was first proposed as an
inhibitory neurotransmitter in
the mammalian CNS in 1954.
In mammalian CNS GABA is
present in approximately 20-
40% of synapses.
GABA concentrations vary
widely in the CNS.

8. Most GABAnergic neurons are local interneurons with short
local connections.
Their actions are generally inhibitory and the effect is achieved
by an increase in neuronal membrane chloride conductance.
This effect has been shown to occur both pre and post
synaptically.
GABA has been known for a long time to produce presynaptic
inhibition by hyperpolarization of afferent terminals in the spinal
cord.

9. GABAnergic interneurons release GABA onto primary
afferent fibres before they make synaptic contact in the dorsal
horn of the spinal cord.
The subsequent hyperpolarization of primary terminals may be
recorded from the cut central ends of primary afferent fibres as
dorsal root potential.
The effect of this hyperpolarization is to decrease
neurotransmitter release from primary afferent terminals and
inhibit the central propagation of the action potential

10. Anxiety
Anxiolytic effects of GABA are recognised as a reduction in
aggression and increased social behaviour and increased
handlability.
GABA produces this effect by an interaction with 5-
hydroxytryptamine in the limbic system.
Sedation and induction of sleep by GABA were the first
properties.

11. Anticonvulsant effects
Many conventional drugs used in the management of epilepsy
are known to interact with GABA receptors.
Sodium valproate is thought to produce its anticonvulsant
action by reducing the metabolism of GABA.
There are other more recent drugs such as vigabatrin that are
GABA analogues

12. Peripheral-type benzodiazepine
receptor
These sites are located on membranes and have been called
peripheral benzodiazepine binding sites.
It has also been suggested that these are functional receptors-
peripheral benzodiazepine receptors.
Peripheral benzodiazepine receptors are different from central
type because they are not coupled to GABA receptors and they
have different ligand specificity

13. Endogenous benzodiazepines
The demonstration of specific benzodiazepine receptors within
the CNS controlling GABA neurotransmission has an obvious
parallel in the opiate/enkephalin story elucidated in the late
1970s and early 1980s.
Stress may cause concentrations of this substance to vary in
the brain possibly indication that Beta-CCB is an endogenous
inverse agonist active at benzodiazepine receptors, and
perhaps involved in the control of stress.

14. Advantages over barbiturates
Benzodiazepine have a high therapeutic index. Ingestion of
even 50 hyptonic doses does not endanger life-there is no loss
of consciousness and patient can be aroused; respiration is not
so depressed as to need assistance.
Hypnotic doses do not affect respiration or cardiovascular
functions
Benzodiazepines have practically no action on other body
systems. Only on IV injection the BP falls and contractility
decreases. Fall in BP in case of diazepam and lorazepam is due
to reduction in cardiac output while that due to flunitrazepam
and midazolam is due to decrease in peripheral resistance. The
coronary arteries dilate on IV injection of diazepam.

15. Benzodiazepines cause least distortion of sleep architecture
and rebound phenomena on discontinuation of regular use are
less marked.
Benzodiazepines do not alter disposition of other drugs by
microsomal enzyme induction
They have lower abuse liability, tolerance is mild,
psychological and physical dependence and withdrawal
syndrome are less marked.
A specific benzodiazepine antagonist flumazenil is known,
which can be used in case of poisoning.

16. Various actions of
Benzodiazepines
Antianxiety: anxiolytic effects are seen with the lowest doses,
but in severe anxiety and panic attacks, sedative or even
hypnotic doses may have to be used.
Sedation: there is a decreases responsiveness to a constant
level of stimulation, with a decrease in spontaneous activity.
Increasing dosage will eventually produce sleep and the drug
have gained considerable popularity as hyptonics.
Intravenously, BZDs are used extensively to produce
conscious sedation during unpleasant procedures .

17. Diazepam and midazolam have also been used as intravenous
inducing agents.
Cardiovascular stability is a feature of such use, but the drugs
are not as reliable and predictable as thiopental for induction
and there is wide variation between patients in the dose
required to produce the desired effect.
Midazolam, however, potentiates propofol in the technique of
co-induction.

18. Anticonvulsants: like most classes of sedative hypnotics,
BZDs are capable of preventing and terminating convulsive
activity.
Clonazepam and diazepam are effective in status epilepticus,
while the former is also of use in petit mal epilepsy.
Muscle relaxation: benzodiazepines reduce muscle tone and
this is mediated via an interneurons in the spinal cord.

19. Amnesia: Intravenous benzodiazepines will reliably produce
antegrade amnesia. Following midazolam this is very intense
for 20-30 minutes and hence a very useful property when
performing short unpleasant endoscopic procedures. Longer
amnesia, upto 6 hr, has been reported following lorazepam.
The amnesic effects of the benzodiazepines when given
intramuscularly or orally is much more variable. The
mechanism of the amnestic action is not known.

20. Pharmacokinetics of
benzodiazepines
Short acting BZDs such as midazolam may be given
intravenously or intramuscularly as an induction agent: the
onset of action is rapid but the drug is quickly cleared from the
body under most clinical circumstances.
Other relatively short-acting BZDs, such as temazepam or
oxazepam, are used to revive insomnia.
They induced sleep for the first few hours, the patients then
continuing to sleep and awake refreshed and drug free, without
hangover effects.

21. Short-acting BZDs, at lower doses, may also be used to
provide demand relief of acute symptoms of anxiety, such as
panic attacks and phobias.
Long acting BZDs, such as diazepam and chlordiazepoxide
have a slower onset of action following oral administration and
subsequently, a prolonged pharmacological action.
At modest doses, administered just once or twice daily, they
provide sustained relief from persistent symptoms of anxiety,
the expectation being that such treatment may be required
continously over several days or weeks.

22. Benzodiazepines are metabolized in liver by dealkylaytion and
hydroxylation to many metabolites, some of which are active.
The biological half-life of these drugs may be much longer
than the plasma t1/2 of the administered compound.
Benzodiazepines and their phase I metabolites are excreted in
urine as glucoronide conjugates.

23. Other adverse effects
At the time of maximal effect from a hypnotic dose of
benzodiazepines, dizziness, lassitude, vertigo, disorientation,
amnesia, increased reaction time with motor incoordination,
impairment of mental coordination occur.
Weakness, blurring of vision, dry mouth and urinary
incontinence are sometimes complained.
Paradoxical stimulation, irritability and sweating may occur in
an occasional patient, specially with flurazepam.
Increase in nightmares and behavioural alterations are also
seen in some

24. There are a no. of psychological effects that may accompany the
use of short acting benzodiazepines in insomnia.
Normal pattern of sleep, no. of episodes of REM sleep are
frequently disturbed.
Defect in overall production of REM sleep can lead to persistent
tiredness or hangover effect.
With repeated medication, some tolerance to these effects
develops, to the extent that proportion of REM returns to normal.

25. Diazepam
Physical characteristics
•It is insoluble in water
•Solution for injection contains several
organic solvents, mainly propylene
glycol, ethanol & sodium benzoate in
benzoic acid.
•Should not be mixed with other drugs

26. Pharmacology
CNS-Diazepam is a benzodiazepine, which is a potent
tranquilizer, muscle relaxant and anticonvulsant.
These properties are due to its effect on the ascending reticular
activating system and spinal internuncial neurons as well as
the effect on the limbic system.
It can be given in doses that cause a state of extreme
drowsiness but in which the patient is still accessible and there
is marked amnesia.
When combine with other drugs as premedicant, the incidence
of amnesia is increased.

27. Respiratory system: IV injection of 0.15mg/kg depress the
sensitivity of the respiratory centre
CVS: IV injection of 0.2mg/kg at the rate of 10mg/minute, the
only significant change is tachycardia, which may persist for
some time.
There is no effect on cardiac output or any marked effect of
blood pressure

28. Indications
As a premedicant
To induce anaesthesia
Used intravenously in sub-anaesthetic doses as a sedative for
pts with dental phobia to cover unpleasantness in ICU and to
accustom pts to artificial ventilators
Used as a sole agent to cardioversion
As a sedative during carotid angiography
Orally in treatment of psychosomatic illness

29. Reduce fasciculation after scoline.
In radio-diagnostic procedures for pediatric patients.
Reduce hallucination & emergence delirium after Ketamine
anesthesia.
Reduces dose requirement of muscle relaxants.
To treat tachycardia, systolic hypertension & anxiety neurosis.
Used as anti-convulsant in status epilepticus, eclampticus &
tetanus.

30. Dosage and administration
Can be given in tablet form, syrup and by IV
Pre-medication-10 to 20mg, 1-1.5 hr before operation
Acute sedation-0-2mg/kg
To induce unconsciousness-0.6mg/kg
Tetanus treatment-5mg/kg/24hr

31. Midazolam
It is water soluble benzodiazepine whose solubility is pH
dependent.
Chemically designated as 8 chloro 6 (2 fluro-phenyl) 1
methyl-GH-imidazo benzodiazopine.
Mol wt. 325.8
Below 6.0 it is water soluble & forms a stable solution.

32. Pharmacology
CNS: Its actions are qualitatively similar to those of other
benzodiazepines and are exerted by its attachment to
benzodiazepine receptors. It blocks EEG arousal from
stimulation of the brain stem and reticular system.
Effect when given IV varies from mild sedation to full GA,
depending on dosage used.
Drug is highly protein bound and slight variation in plasma
concentration can have a marked influence on the
pharmacodynamically active free drug levels in the plasma

33. CVS: It is less depressant to CVS. It causes a slight fall in
systemic vascular resistance and arterial blood pressure with
little change in cardiac output
RS: In healthy pts, in a dose of 0.075mg/kg IV produces only a
transitory and non-significant depression of the carbon dioxide
response curve

34. Indications
Has largely replaced diazepam in anaesthetic practice.
To produce sedation in unpleasant procedures such as upper
intestinal endoscopy, bronchoscopy, dental work carried out
under local anaesthesia and major surgery performed with the
aid of regional anaesthesia.
When used for sedation it is frequently combined with small
doses of fentanyl & other opioids.
Used for induction of anesthesia

35. Co-induction: combination of sedative drugs with intravenous
anaesthetic agents have a synergic action, although the exact
mechanism is unknown.
Several studies have shown that this also occurs between
midazolam and propofol.

36. Dosage and administration
IM a dose of 0.07-0.08mg/kg produces satisfactory anxiolysis
and sedation when used for pre-medication
For conscious sedation: 0.07-0.1mg/kg
Available for injection either in 1ml ampoules at a
concentration of 5mg/ml or 5ml ampoules containing 1mg/ml.

37. LORAZEPAM
PHYSICAL CHARACTERISTIC
Insoluble in water
Parenteral use-dissolved in polyethylene glycol & propylene
glycol
PHARMACOLOGY
CNS
Similar to diazepam
Produces anterograde amnesia
No analgesic properties

38. RS
Enhanced ventilatory response to CO2 challenge suggesting
stimulant effect on respiration.
CVS
No marked change in BP, PR or SVR.
MUSCULOSKELETAL
Has muscle relaxant property, probably of central origin.

39. FATE IN BODY:
Absorption of orally administered lorazepam is rapid, max
blood concentration occuring 2-4 hrs & it’s action persists for
12-18 hrs.
80% dose recovered in urine as glucuronide

40. INDICATIONS:
For sedation
Relief of anxiety
Post op abolition of emergence reactions when given i.v after
ketamine anaesthesia
DOSAGE & ADMINISTRATION
Intermediate duration of action
5 times as potent as diazepam
Oral dose : for anxiety is 1-3 mg (bd)
Doses upto 5 mg orally or i.v are used for preanaesthetic medication

41. REFERENCES
1.Miller`s Anaesthesia.
2.Stoelting`s Principles of Anesthesiology.
3.K.D Tripathi`s Essentials of Medical
Pharmacology.