DR.N.K.AGRAWALPROF. JNMC

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

Elimination half life :Midazolam is 1-4hrs Diazepam-21-37 hrs Lorazepam-10-20 hrs

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