Download Benzodiazepines

S.M.A.R.T.
Dental Nursing Sedation
Pharmacology of Benzodiazepines
Day 3
Mr 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
Pharmacokinetics
– what the drug dose to the body
– 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
Mr J Henry 28/11/2015
1
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
Mr J Henry 28/11/2015
2
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 the receptor 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
Mr J Henry 28/11/2015
3

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
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
Mr J Henry 28/11/2015
4
•
•
•
•
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
Recommended
Mr J Henry 28/11/2015
5mg in 5ml.
(as per NPSA report)
10mg in 5ml
(no longer used )
5
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 of Midazolam







Hiccoughs
Nausea and vomiting
Coughing
“Over-sedation”
Headache
Drowsiness
Local reactions eg. pain on injection
Mr J Henry 28/11/2015
6
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
Antifungals
Itraconazole, ketoconazole and possibly fluconazole
Antivirals
Nelfinavir, Ritonavir ( Anti-HIV drugs)
+
Ca Channel blockers
Diltiazem, Verapamil
Midazolam Costs
10 Ampoules
50 Ampoules
£ 9.95
£48.00
Midazolam overview
+
+
+
+
-
Good anxyiolsis
Good amnesic
Good hypnotic
Short duration of action ( < 4 hours)
Risks of respiratory depression
Mr J Henry 28/11/2015
7
Diazepam
Formulations


Diazemuls 10mg. In 2ml. white lipid emulsion




Diazepam 10mg. In 2ml. In brown ampoule
Maximum dosage 20mg.
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
Mr J Henry 28/11/2015
8
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

Antivirals

Ulcer Healing Drugs
Isoniazid inhibits metabolism
Rifampicin increases metabolism
Ritonavir ( Anti-HIV drugs)
 Increases plasma concentration
 ( risk of extreme sedation )
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
Mr J Henry 28/11/2015
9
Temazepam
Formulation
10mg or 20mg
or
10mg in 5ml
tablets
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)
Mr J Henry 28/11/2015
10
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
Mr J Henry 28/11/2015
11
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 the Benzodiazepine receptor site
This prevents the synergistic effect
The Chlorine channel reduces to its former dimension
The sedative activity returns to normal
Flumazenil
Properties



Benzodiazepine antagonist
Reverses the receptor effects of Bzs
No intrinsic activity but high receptor affinity
Mr J Henry 28/11/2015
12



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 IV
every 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.
Mr J Henry 28/11/2015
13
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
( up to maximum dosage 20mg )
Kg
30 minutes prior to treatment
Diazepam
Formulation
2mg, 5mg, 10mg
or
or
2mg in 5ml
5mg in 5ml
tablets
Solution
Solution
Dosage
2 – 5 years
6 – 12 years
12 – 18 years
2.5 mg
5 mg
10 mg
Given 30mins - 1 hour prior to treatment
Mr J Henry 28/11/2015
14
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)
Mr J Henry 28/11/2015
15
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.
Mr J Henry 28/11/2015
16
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 28/11/2015
17