BENZODIAZEPINES Flashcards
Barbiturates compared to Benzodiazepines have ______and less ________
Less tendency for tolerance: potential for abuse
Safe in overdose
Less serious drug interactions
Less addicting than opioids, cocaine, amphetamine, and barbiturates
Benzodiazepines have replaced barbiturates pre-op medications.
Properties of Benzodiazepines
Properties of Benzodiazepines
• Highly lipid soluble
• Highly protein bound
• Hypoalbuminemia
Less binding to the benzodiazepines –>Causes enhanced clinical effect
Due to hepatic cirrhosis or chronic renal failure with protein spillage
Benzodiazepine absorption
Oral absorption-rapid
IV enters brain rapidly
Mechanism of action of Benzodiazepines.
Do they activate GABA?
Mechanism of ACTION
DO NOT activate GABA receptors
• They enhance the affinity of the receptors for GABA
• This leads to enhanced opening of chloride channels, ⇧ chloride conductance and hyper-polarization of the postsynaptic cell membrane, making most post synaptic neurons more resistant to excitation
GABA Receptor
Explain: it is a _________With separate binding sites for __________
Therefore
The basis of _______and why benzo are the
GABA Receptor
• Large macromolecule with separate binding sites for benzodiazepines, barbiturates, Etomidate, propofol,
neurosteroids and alcohol
• Therefore benzodiazepines, barbiturates and alcohol can have synergistic effects by acting on the same receptor by different mechanisms
• Results in ⇧ risk for overdose
• Also the basis for cross tolerance and why benzo’s are the first choice drug for alcohol detoxification
KNow midazolam
CV effects
Pharmacological Effects of Benzodiazepines
SASAA
Anxiolysis Sedation Anticonvulsants Anterograde amnesia Skeletal Muscle Relaxation- spinal cord mediated • Not adequate for surgery, no ⇩NMB dose
Sedative effects of benzo’s reflect
Activation of alpha 1 subunits of GABA
• Anxiolytic, amnesia effect due to
alpha-2 subunit activation
Most abundant receptor subtypes is
Alpha 1 subunits; 60% of GABA receptors in the brain
Less abundant receptor subtypes
Alpha 2 subunits (hippocampus, amygdala)
An important regulator of cardiac function and its physiological effects convey cardioprotection during MI
ADENOSINE
Cannot produce an ISOelectric EEG
Midazolam
Benzos On EEG
Alpha activity decrease
Beta activitiy increase
Side effects on Benzo
Fatigue and drowsiness; most common with chronic use
Benzo Sedation subsides usually
within 2 weeks
Caution of Benzo use in patients with chronic lung disease why ?
characterized by HYPOVENTILATION and DECREASED ARTERIAL OXYGENATION
Acute administration of benzo may cause
Transient Anterograde amnesia especially with alcohol
Benzo dependence occur after
> 6 months
Benzo withdrawal symptoms include TIA ?
When does it begin?
- Tremulousness
- Insomnia
- Agitation
between 1-5 days
Aging and Liver disease affect ________less than ___________ _____pathways
Glucuronidation
Oxidative metabolic pathways.
Preferred in aging and liver disease , why>
LORAZEPAM; because it is metabolized by glucuronidation
Diazepam is metabolized by
Hepatic microsomal enzymes to form ACTIVE METABOLITES
This medication have active metabolites
DIAZEPAM
Midazolam water or lipid soluble
WATER
Midazolam vs Diazepam potency
2-3 Times more POTENT than DIAZEPAM
Midazolam at ph<4 ring is open so it is
WATER SOLUBLE
Midazolam at ph>4 ring is CLOSED so it is
HIGHLY LIPID SOLUBLE
IV administration of Verset
No venous irritation on injection
Midazolam can be mixed with
LR and acidic salts
Midazolam Pharmacokinetics : first pass? lipid solubility
First past effect = 50% of drugs reaches systemic circulation
HIGHLY LIPID SOLUBLE, CROSS BBB
What is the effect equilibration time of midazolam ?
Slow compared to propofol and thiopental (0.9 - 6 minutes)
Protein binding of Midazolam
EXTENSIVE PROTEIN BINDING
Midazolam long acting or short acting and why?
Short acting
Because of REDISTRIBUTION FROM BRAIN TO inactive site and rapid metabolism
Context sensitive half time of MIDAZOLAM ______than diazepam and Lorazepam
LOWER
Elimination Half time is __________; compare to diazepam
1-4 hours;
MUCH SHORTER THAN DIAZEPAM.
2 patients with high Vd, why?
Elderly
Morbidly obese
Due to distribution to adipose tissue
CNS effects of midazolam is ______Than diazepam
SHORTER
Midazolam half time prolonged after
CBP
Metabolism of Midazolam
Undergoes extensive HYDROXYLATION by hepatic and small intestine microsomal enzymes
Midazolam effect prolonged with drugs that
Inhibit CYP450 ;
E-mycin; CCB, fentanyl, cimetidine
Hepatic Clearance of midazolam is 5 times ______ than lorazepan and 10 times _____than diazepam
Greater; Greater
Midazolam on CNS
Decrease CMRO2, and CBF similar to barbiturates and propofol
Cerebral vasomotor responsiveness to CO is preserved
ICP is unchanged
Does not prevent increase ICP ass
Midazolam : Does not prevent
increase ICP that is associated with laryngoscopy
Benzo and Neuroprotective?
Not been shown to be neuroprotective
Midazolam < Can be use to treat seizures ?
Yes, Potent anticonvulsant effect
Can treat Status epilepticus
Midazolam lead to ______in ventilation with _______ equivalent to ___________
decrease; 0.15mg/kg IV ; 0.3mg/kg IV
Midazolam depression in ventilation is greater with
COPD
Rapid administration of Midazolam________ can lead to ______
> 0.15mg/kg; TRANSIENT APNEA
_________Given with fentanyl 2mcg/kg can lead to
0.05 mg/kg
Arterial hypoxemia
Hypoventilation
IMPORTANT : BENZO
can depress the swallowing reflex and DECREASE UPPER AIRWAY activity
Midazolam induction dose
Effect on HR, BP
0.2mg/kg on induction
Decrease systemic BP and INCREASE HR more than diazepam
The hemodynamic changes are similar to
thiopental 3-4mg/Kg IV
What is NOT ALTERED with Benzo?
CARDIAC OUTPUT
Beneficial in Improving CO in patients with CHF
Benzodiazepines.
Midazolam and CV
hypovolemia results in enhanced BP LOWERING EFFECT similar to other agents.
What is the most commonly used Benzo for preop medications?
MIDAZOLAM
Preoperative Medication
Dose of __________ before induction provides reliable ______ and ________ in children without producing delay in awakening
0.5mg/kg PO 30 minutes
Sedation and Anxiolysis
Given with midazolam enhances the anxiolytic and amnestic effects
SCOPOLAMINE
Antegrade amnesia with Midazolam is
Related and parallels the degree of sedation
IV sedation : Midazolam vs Diazepam
More rapid onset
Greater amnesia
Less post op sedation
Depression of ventilation has synergistic effects with
Opioids
Propofol
CNS depressants
Induction of Anesthesia : Midazolam Dose
0.1-0.2 mg/kg over 20-60 seconds
Compared to midazolam: thiopental
50-100% faster induction
Onset of action of midazolam faster with
small dose of opioid
Fentanyl precedes the midazolam onset of action
1-3 minutes
Midazolam require __________ in ________
Smaller doses in elderly
Anesthetic requirements for VA with midazolam are
decrease in a dose dependent manner
Awakening after GA is ___________ than when thiopental is used?
1-2.5 times longer
N/V with emergence with midazolam?
NO
Diazepam is a _________ benzodiazepine with a ______Duration of action compared to midazolam
HIGHLY lipid soluble
Prolonged duration of action
Injection of IV and IM may be painful with
Diazepam
Pharmacokinetics of Diazepam
Peak ______in adult, _______In children
1 hour
15-30 minutes
Diazepam and Brain
Rapid uptake
Volume of Distribution of Diazepam ? women vs men
LArge; LARGER in women than men
Does DIAZEPAM CROSS the placenta?
YES; concentration may be greater in fetus than mother
DIAZEPAM solubility and protein binding
Highly lipid soluble
Bound to plasma proteins
Cirrhosis of liver and renal failure may
Decrease protein binding and INCREASE related adverse events.
Diazepam metabolism is by
Hepatic microsomal enzymes
There are 2 principles Metabolites are
DESMETHYLDIAZEPAM
OXAZEPAM
lesser degree temazepam
Principal is ___________ slightly _______ and is metabolized more slowly half life _______
DESMETHYLDIAZEPAM; 48-96 hours
Ultimately oxidized metabolites are
EXCRETED in urine as Glucuronide conjugated metabolites.
Diazepam and Cimetidine
Cimetidine delays hepatic clearance and prolongs the elimination half life of both DIAZEPAM and DESMETHYLDIAZEPAM due to cimetidine’s induced INHIBITION of MICROSOMAL ENZYMES
Pepcid and diazepam
Pepcid has no effect on diazepam
Half time of Diazepam
21-37 hours
Liver cirrhosis has up to _______folds in ______elimination half time due to
5 ; INCREASE ; increase vd and Decrease hepatic Blood flow
Diazepam and Ventilation effects
Minimal on ventilation
Detectable increase in ventilation not seen up until 0.2mg/kg is given
Sligh increase in PaCO2 due to decrease in TV
Caution with Diazepam
Combined with other CNS depressants or patients with COPD may results in exaggerated or prolonged depression of ventilation
CO2 curve is NOT shifted to the right with
Diazepam
CO2 curve shifted to the right with
OPIOIDS
Diazepam induction dose
0.5mg- 1mg/kg
Effects of Diazepam of BP, CO and SVR
minimal, SIMILAR TO NATURAL SLEEP
What happens with N2O and opioids
Direct myocardial depressant
Decrease in SBP
Diazepam and muscle tone
Decreases skeletal muscle tone
Diazepam overdose
Serious negative outcomes are UNLIKELY if cardiac and pulmonary functions are supported, and other CNS depressant like alcohol are not present
Clinical Use for management of Deliriums Tremors
Diazepam
Diazepam peak is
55 minutes
Diazepam on MAC
Decreases MAC
Diazepam anticonvulsants effects
0.1 mg/kg IV abolishes seizure activity
Explain Diazepam anticonvulsants effects
Due to ability to facilitate the actions of INHIBITORY TRANSMITTER GABA
Lorazepam potency compared to diazepam and midazolam
More potent sedative and amnestic
Metabolism of Lorazepam
Conjugated with glucuronic acid in the liver to form inactive metabolites that are excreted by the kidneys
Elimination half time is
10-20 hours
Metabolism of lorazepam is not
Entirely dependent of microsomal enzymes
less infuences by increasing age, or CYP inhibitors such as cimetidine
Recommended oral dose for pre-op is
50mcg/kg not to exceed 4 mg
Peak level of lorazepam?
Amnesia?
2-4 hours
Maximal ANTEROGRADE amnesia lasting up to 6 hours without excessive sedation
With lorazepam, large doses=
Greater sedation WITHOUT INCREASED AMNESIA
What is the limiting factor when rapid awakening is desired?
Prolonged duration of action
Lorazepam Limitations
Slow onset of action
Effective in limiting emergence reactions after ketamine
Lorazepam
Protein binding of Lorazepam, Diazepam and midazolam
96-98%
Compare doses
Midazolam
Diazepam
Lorazepam
- 15 - 0.3mg
- 3- 0.5
- 05
Flumazenil, Romazicon
Specific and exclusive benzodiazepine receptor GABA antagonist
it binds to specific sites on the GABA-A receptor, where
it competitively inhibits the binding of the neurotransmitter, GABA, to this receptor
Flumazenil effectively antagonizes the benzodiazepine component of
ventilatory depression of combined opioids and benzo
Flumazenil Dosing
0.2mg IV (8-15mcg/kg) usually reverses the CNS effects of Benzo with 2 minutes
Flumazenil if required
0.1mg IV (To a total of 1mg ) can be given at 60 seconds intervals
Flumazenil Doses to decrease the degree of sedation as needed
0.3-0.6mg IV
Flumazenil dose required to ABOLISH the therapeutic effcts of benzodiazepines
0.5 to 1 mg
In patients that have overdose from unknown substance, failure to respond to 5mg indicates
involvement of other substance.
Flumazenil duration of action is
30-60 minutes
Alternative to repeated doses is a continuous low dose infusion of
0.1 - 0.4 mg/hr
Flumazenil Side effects
NO effects on MAC requirements
May precipitate WITHDRAWAL Seizures in patients with seizure disorders , long term benzos or cyclic antidepressants.
NOT associated with LV systolic function or coronary hemodynamics alterations.
EXTRA: Benzo with the fastest onset of acton
Midazolam
BENZO water insoluble in propelene glycol
Diazepam
_____increases the threshold for local anesthetic-induced seizure activity.
DIAZEPAM
Not use for induction anesthesia due to slower onset
LORAZEPAM
