The Ideal Sedative Agent

S.M.A.R.T. Dental Nursing Sedation Day 3

Pharmacology of BenzodiazepinesMr J. Henry

Also see chapter Advanced Dental Nursing

The ideal sedative agent

Alleviate fear and anxiety
Be easy to administer
Be quickly effective
Not suppress protective reflexes
Be free of side effects
Be predictable in both action and duration
Be quickly metabolized and excreted
Not produce active metabolites
Have a half life of approx. 45-60 minutes

Pharmacology of Benzodiazepines

Pharmacodynamics– what the drug dose to the body

Pharmacokinetics– what the body does to the drug

Pharmacodynamically benzodiazepines are all the same.

Differences are due to:

•Affinity for receptors (potency)

•Half Life

•Activity of metabolities

Principle clinical effects:

Anxiolysis

Anticonvulsant

Slight Sedation

Reduced Attention

Amnesia

Intense Sedation

Muscle relaxation

Anaesthesia

Anxiolysis

•Low doses

•Can be subtle

•Basis of oral anxiolysis without sedation

NOT ANALGESIC!

Anticonvulsant

•Prevent and terminate convulsions

•Used in status epilepticus (can give midazolam intramuscularly but not diazepam)

•Local anaesthetic overdose

Sedation

•Slight at low doses

•Intense at higher doses

•Decreased response to a constant stimulus

•Reduced attention

•Will lead to sleep if left un-stimulated

•Disinhibition

Amnesia

•Most intense with iv sedation

•Anterograde amnesia

•Intense for first 20/30 mins

•Variable duration but up to several hours

•Especially good with midazolam

Muscle relaxation

•Central effect

•Depression of spinal reflex activity

•Partly responsible for respiratory depression

•Reduces trismus

Anaesthesia

•Too large or too rapid (bolus) dose

•Very careful in elderly patients

GABA

Gamma aminobutyric acid

•Endogenous inhibitory neurotransmitter

•Mediates pre-synaptic inhibition

•Synthetised and stored in pre-synaptic nerve endings

Action of GABA

GABA attaches to thereceptor site
The chloride channels open
Chlorine Ions enter
Reduced activity of the post synaptic neuron

Benzodiazepine Actions

Benzodiazepines potentate the effect of Gamma Amino Butyric Acid (GABA ) by attaching to adjacent receptor sites in the Brain and CNS.
The resulting increase the influx of inhibitory Chlorine ions into the nerve cells reduces the excitability of the nerve cells.
The Chloride ions entering the cell making the resting membrane potential more negative.
This makes it even more difficult to fire an action potential so reducing:
polysynaptic transmission
depressing the uptake of sensory information

Properties of Benzodiazepines

Rapid absorption from most sites
Onset of sedation is smooth and rapid
Very Lipophilic - readily taken up by the brain, liver and other fatty tissues
Greater volume distribution in obese individuals leading to an increase in half life

Metabolism of Benzodiazepines

Broken down in the liver
Some have metabolites which are biologically active
(des methyl diazepam) a metabolite of diazepam has a longer half life than diazepam
Therefore entero-hepatic recirculation with des methyl diazepam at 9-12 hours may cause resedation

Half Life

Half life Midazolam 2-4 hours
Half life Diazepam 12-24 hours

Phases and Half Life

Elimination half life is the time required for the drug concentration in the blood to half.

Redistribution half-life is the time required for the initial peak level in the tissues to half

Side effects of Benzodiazepines

Respiratory Depression

•CNS depression and muscle relaxation

•Decreased cerebral response to rise in CO2

•Synergism with other CNS depressants

•More common in:

•In patients with pre-existing respiratory disease

•Elderly

•When a second centrally acting drug has been used

Cardiovascular effects

•Reduction of BP by decreasing vascular resistance (15-33% midazolam)

•Compensatory rise in heart rate via baroreceptor response

•Cardiac output is unaffected

•Insignificant in fit patient (within 10% of norm)

•Considered cardiostable for poor risk patients in general anaesthesia.

Drug interactions

•Synergism with other CNS depressants e.g. alcohol, opiates, antihistamines,tranquillisers.

•H2 receptor blockers ( cimetidine “tagamet”) inhibits the metabolism of benzodiazepines

•Cisapride (“Prepulsid”) Motility stimulant

•Baclofen,tizanadine( muscle relaxants) increased sedative effect

Sexual Fantasy

•Males and females

•Usually dentist and patient opposite sex

•Where higher doses of midazolam are given > 0.1 mg/kg

•Chaperone mandatory

Midazolam

Formulation

 IV injection - clear ampoule

Recommended5mg in 5ml. (as per NPSA report)

10mg in 5ml(no longer used )

10mg in 2ml. - too concentrated

Properties

Potent imidazobenzodiazepine
3-4 times as potent as diazepam
Water soluble at pH ,4.0
Lipid soluble at physiological pH (can pass across the blood brain barrier)
No thrombophlebitis or pain on injection
Onset in one arm brain circulation but full clinical effect takes several minutes

Route of administration.

IV,IM, oral, rectal, intranasal, sublingual

High first pass metabolism
97% protein bound (only 3% drug active)
Pregnancy and Aging affects protein binding
Protein binding is proportional to age
Elderly especially sensitive to effects due to decreased protein binding <5mg in >60 year olds

Effect of Aging

Altered drug distribution
Decreased total body water
Increased total body fat
Decreased serum albumin
Altered hepatic metabolism
Decreased mass, flow and enzyme activity
Altered renal excretion
Decreased flow, filtration rate

Side effects ofMidazolam

Hiccoughs
Nausea and vomiting
Coughing
“Over-sedation”
Headache
Drowsiness
Local reactions eg. pain on injection

Midazolam

Elimination half life 1.7 to 2.3 hrs ( 1.9hours)
Broken down in the liver ( hydroxylated)
Clinical working time is ~45 minutes
Excreted by the kidneys (as glucuronide)
Pharmacokinetics may be affected by renal and /or hepatic disease

Midazolam – Drug interactions

The drugs below Inhibit metabolism of midazolam resulting in increased plasma concentration and increased sedation effect

Antibacterials Erythromycin, clarithromycin, quinupristin/dalfopristin and telithromycin
AntifungalsItraconazole, ketoconazole and possibly fluconazole
Antivirals Nelfinavir, Ritonavir ( Anti-HIV drugs)
Ca+ Channel blockers Diltiazem, Verapamil

Midazolam Costs

10 Ampoules£ 9.95

50 Ampoules £48.00

Midazolam overview

+ Good anxyiolsis

+ Good amnesic

+ Good hypnotic

+ Short duration of action ( < 4 hours)

- Risks of respiratory depression

Diazepam

Formulations

Diazemuls 10mg. In 2ml. white lipid emulsion
Maximum dosage 20mg.

Diazepam 10mg. In 2ml. In brown ampoule
Dissolved in Propylene Glycol - painful to inject
Must use large veins in the ACF
Maximum dosage 20mg.

Diazepam

Properties

Mainly historical interest

Non water soluble
Dissolved in organic solvents or emulsified in soya bean oil
Pain on injection and risk of thrombophlebitis
Clinically significant metabolities ( des methyl diazepam half life 56 hours)
Long half life 30 hours

Diazepam

Route of administration. IV, oral
Rebound sedation often seen
(enterohepatic recirculation, broken down in liver, absorbed into gall bladder and secreted into duodenum in the next meal)
Still recommended for termination of convulsions
Oral diazepam useful for anxiolysis night before treatment

Diazepam – Drug Interactions

Antibacterials Isoniazid inhibits metabolism

Rifampicin increases metabolism

Antivirals Ritonavir ( Anti-HIV drugs)
Increases plasma concentration
( risk of extreme sedation )
Ulcer Healing Drugs Omeprazole
metabolism inhibited , increased plasma concentration

Overview

Diazepam

Best anxiolytic, poor amnesic
Minimal CVS depression
Irritant to veins
Long duration of action ( > 12 hours )
Active metabolites which prolong action
Patient can re-sedate

Midazolam

Best amnesic, good hypnotic
Some respiratory depression
Not irritant - small veins
Short duration ( < 2 hours )
No active metabolites
Better recovery
Can produces GA.
Too rapid administration

Temazepam

Formulation

10mg or 20mg tablets

or 10mg in 5ml elixir

Temazepam

Properties

Rapidly acting oral benzodiazepine
Acts in 20-30 minutes
Peak blood levels 2 hours
Useful for night before or light sedation
Controlled Drug (schedule III)

Temazepam

Dosage

12 – 18+ years 20 - 40mg

30 minutes prior to treatment

(10 mg night before treatment)

Temazepam – Drug interactions

Disulfram(used in treatment of Alcohol dependence)

metabolism of temazepam inhibited ,
increased plasma concentration
Increased sedation effect

Overview

Temazepam

+ Good hypnotic

+ Reasonably good anxiolysis

+ Short duration of action ( < 4 hours )

+ Similar 1/2 life to Midazolam

- Some dysphoric reactions in young adults and children

Flumazenil – Anexate

Specific Benzodiazepine antagonist

Essential requirement anywhere Benzodiazepine sedation is used - effective reversal for both oral and IV benzodiazepine sedation.

Flumazenil

Formulation

 IV injection - clear ampoule

0.5mg in 5 ml.

Action of ANNEXATE

Anexate blocks theBenzodiazepine receptor site
This prevents the synergisticeffect
The Chlorine channel reducesto its former dimension
The sedative activity returnsto normal

Flumazenil

Properties

Benzodiazepine antagonist
Reverses the receptor effects of Bzs
No intrinsic activity but high receptor affinity
50 minute half life
IV use but can be administered orally.
Not recommended for routine reversal

Flumazenil

Dosage and Administration

0.2mg IV over 15 seconds then wait 1 min

0.1mg IVevery 60 sec. until recovered.

Maximum dose 1.0mg. - Two ampoules

Flumazenil

Prices

1 Ampoule £ 26.00

5 Ampoules £ 110.00

Flumazenil

Important notes

•Only for use in Emergencies

•Not economic for routine use

•Reawakening is rapid

•Half life short - wears off after approx. 15 min.

•Re-sedation can occur if original sedative was long acting. Must continue to monitor patients.

•Can cause acute withdrawal reaction in habituated patients.

•Can precipitate seizures in epileptic patients on long term benzodiazepine therapy.

Oral Sedation

Midazolam

Formulation

2mg in 1ml Solution

VERSED Syrup Roche *Only licensed and sold in USA

alternative

I.V. preparation

given in oral drink

Dosage

0.5mg / kg body weight

Childs weight easy calculation = ( Age + 4 ) x 2 Kg

( up to maximum dosage 20mg )

30 minutes prior to treatment

Diazepam

Formulation

2mg, 5mg, 10mg tablets

or 2mg in 5ml Solution

or 5mg in 5ml Solution

Dosage

2 – 5 years 2.5 mg

6 – 12 years 5 mg

12 – 18 years10 mg

Given 30mins - 1 hour prior to treatment

Temazepam

Formulation

10mg or 20mg tablets

or 10mg in 5ml elixir

Temazepam

Dosage

12 – 18+ years 20 - 40mg

30 minutes prior to treatment

(10 mg night before treatment)

Intra-Nasal Sedation with midazolam

MAD - Mucosal Atomization device:

Device designed to allow emergency personnel to delivery nasal medications as an atomized spray.

Broad 30-micron spray ensure excellent mucosal coverage.

Dose 1ml in each nostril (5mg in 1ml solution) Midazolam

Compared to oral medications, intranasal medication delivery results in:

Faster delivery to the blood stream
Higher blood levels
No destruction by stomach acid and intestinal enzymes
No destruction by hepatic first pass metabolism

Other Points:

Nasal drug delivery is convenient and easy, but it may not always be effective.
Nasal drug delivery cannot completely replace the need for injections.
Being aware of the limitations and using the correct equipment and drug concentrations will assist you in predicting times when nasal drug delivery may not be effective.

Take away lessons for nasal midazolam:

Dose and volume: Higher concentration required - use 5mg/ml IV solution.
Dosing calculations are difficult: Use a predefined age or weight based table to determine dose.
Deliver immediately on decision to treat: Atomize into nose with MAD, then begin standard care.
Efficacy: No quite 100% effective so failures with nasal may need follow-up with IV therapy.

Adults

10 mg Midazolam
Can be USED ALONE
OR PRE IV SEDATION

Mr J Henry 01/12/2012