SEDATIVE: Ally Anxiety –decreases activity, reduces excitement, calm the individual
HYPNOTICS: produces drowsiness and induces sleep
Discovery began in 1955 by Leo-H. Sternbach
1 s t BDZ Chlodiazepoxide
Pharmacological action revealed by Randal & his
colleagues few years later.
Propert ies Inducing calming
Without ataxia or marked
anticonvulsant propert ies
Mode of action
BDZ having similar pharmacological activity,
therapeutic use, potency and solubil i ty.
Receptors present in the gray matter
BDZs bind the same set of receptors in the CNS as barbiturates but bind to different site of receptors.
BDZs binding to the GABAa receptor increases the frequency of opening of the associated chloride ion channel
For eg:BDZs-receptor binding facilitates binding of GABA to its receptor.
FLUMAZENIL(an imidazobenzodiazepine) is a specific BDZs-receptor antagonist that effectively reverses most of the CNS effect of BDZs
There are number of other drugs bind to GABA-BDZ
receptor complex, notably barbiturates (including
thiopentone) which bind to a separate site, and
some non-benzodiazepine sedative such as
zopiclone and zolpidem which act at the
benzodiazepine site.
CNS :BDZ dose related depression of the CNS.
Amnesia
Anticonvulsant effect
Hypnotic effect
Induction of Anesthesia
AMNESIA: BDZ produce anterograde but not retrograde
Useful Used as sedation for endoscopy or for surgical
procedure under local anaesthesia
Note : It is not produce by Oral or I/M
ANTICONVLSANT:
All BDZ have an anticonvulsant action but not all used for
these purpose due to BDZ1 & BDZ2 receptors differes
HYPNOTIC EFFECT:
Main long term clinical uses of BDZ is as a night time
hypnotics.
It decreases REM sleep
Significant is not fully understood
There is a period of rebound wake full ness
Tolerance & dependence after long term use
INDUCTION OF ANAESTHESIA :
Diazepam, midazolam and flunitrazepam have
been used as induction agents
Claimed advantage is that BDZ having greater
cardiovascular stability and compared with
Thiopentone
Counter balanced by unreliability of effect and
slow recovery
CVS:
Systemic vascular resistance decrease with
peripheral vasodilatation
Decreased cardiac output
Postural hypotension
RESPIRATORY SYSTEM:
Therapeutic doses, Oral administration of BDZ does
not cause respiratory depression.
Intravenous injection as the consciousness lost, so is
sensitive to CO2 decreased tidal volume
compensated by increased respiratory rate (RR)
In patient with chronic obstructive airway disease, the
respiratory depressant effect of BDZ > normal subject.
PHARMACOKINETIC:
CNS AND BLOODBRAIN BARRIER:
Onset and duration of action at psychosedative drug BDZ
depend on capacity to BBB, rate directly proportion to
intrensic lipid solubility at physiological pH
All benzodiazepine are highly liphophilic
e.g. diazepam midazolam – Acts quickly
Lesser liphophilic e.g. lorazepam chlorodizepoxide
DRUGS EQUIVALENT DOSE(mg)
VOLUME OF DISTRIBUTION(li tres/kg)
PROTEINBINDING(%)
CLEARANCE(ml/kg/min)
MIDAZOLAM 0.15-0.3 1.0-1.5 96-98 6-8
DIAZEPAM 0.3-0.5 1.0-1.5 96-98 0.2-0.5
LORAZEPAM
0.05 0.8-1.3 96-98 0.7-1.0
DIAZEPAM:
Colourless crystalline base
Insoluble in water
M.W. 285
Injectable preparation
Contains 5 mg/ml in aqueous vehicle
Consist of mainly propylene glycol, Ethyl alcohol, Sodium Benzoate in Benzoic acid.
pH 6.4 – 6.9
Diazepam is lipid emulsion made up from soya bean similar to the fat emulsion used for parentral nutrition.
MIDAZOLAM:
Nitrogen in the imidazole ring
Water soluble
Shorter duration at action than other
Prepared as a water soluble salt with
hydrochloric, & maleic lactic acid.
Available in stable aqueous solution as hydrochloride salt
Half life is 10 minutes
Must not mixed with acidic solution.
PHARMACOKINETIC OF MIDAZOLAM:
Properties relevant to the fat of relevant diazepam
Increase fraction of free drug
Similar volume of distribution with similar onset time
Quicker & earlier recovery
10 times faster than diazepam
Bio ability 44 % after administration of 15 mg & reduce
with volume of distribution.
Greater dose in women (0.8 to 1.51 / kg)
METABOLISM OF MIDAZOLAM:
Eliminated by hepatic biotransformation
70% eliminated in urine
Half life 2 to 2.4
FLUMAZENIL: It is a BDZs analogue which has l it t le intr insic activity,but competes with BZD agonists as well as inverse agonists for the BZD receptor and reverses their deppresant or stimulant effects respectively
TO REVERSE BZD ANAESTHESIA: Patients anaesthetized/sedated witha BDZ
wakeup,get oriented and regain motor control within 1min of an i.v injection of 0.3-1mg of flumazenil.
BDZ OVERDOSE: Majority of patients of BDZ overdose require
only supportive measures like patent airway,maintenance of BP,cardiac and renal function etc
In addition, FLUMAZENIL 0.2mg/min may be injected i.v till the patient regains consciousness.
Practically all patients intoxicated with BDZ alone respond within 5 mn.
FLUMAZENIL is a safe and well tolerated. Agitation,discomfort,tearfulness,anxiety,coldness
are the occasional side effects...
Use short acting midazolam Dose is 0.15 to 0.3 mg/kg Can be used IV/IM Some have tried oral and nasal rout Antidote is flumanzenile