Middlemas - Page 1

Benzodiazepines
David S. Middlemas, Ph.D.
Department of Pharmacology, UNMC
Contact: dmiddlemas@unmc.edu
Sedative and Hypnotic Drugs
Please read your textbook
Read Chapter 22 in your text - Katzung; Basic and Clinical
Pharmacology
If you have questions on lecture material, etc. Use E-mail -
dmiddlemas@unmc.edu
Ill respond within 24 hours.
Sedative and Hypnotic Drugs
Overview of next three
lectures
Benzodiazepines and
Anxiolytics
Barbiturates
Hypnotics
Course Objectives
Differentiate between sedation, hypnosis, and
anesthesia
Understand the Pharmacology of
Benzodiazepines
Barbiturates
Hypnotics
Indications
Mechanism of action (MOA)
Pharmacokinetic properties applicable to clinical
practice
Side effects and adverse effects
Contraindications and drug/drug or drug/food
interactions
Clinical process and use of these drugs
Therapeutic Indication;
Sedative-Hypnotic drugs
Sedatives/anxiolytics: Cause
sedation with the concomitant relief of
anxiety
Hypnotics: Encourage sleep
Benzodiazepines*
Barbiturates
Hypnotics
Ethanol
General Anesthetics
These drugs are CNS Depressants
Sedation
Sleep (Hypnotic state)
Unconsciousness
Anesthesia
Death
Degrees of CNS Depression
CNS Depressants
Middlemas - Page 2
CNS Depression: Dose response Curves for
Sedative-hypnotics
Coma/
Death
Anesthesia
Hypnosis
Sedation
Non-selective
(Ethanol,Barbiturates,
& General Anesthetics)
Selective
(Benzodiazepines)
Dose response - Therapeutic Relevance
Barbiturates and alcohol at higher doses
Induce anesthesia
Coma
Death
Depress respiratory and vasomotor centers
Benzodiazepines require a greater dose increase to
induce CNS depression beyond hypnosis
Margin of safety for anxiety treatment is better
Mechanism of Action:
Biochemical Background information
Ion channels
Membrane spanning protein complexes
Pore or channel for ion conductance
Cation specific ( Na+, K+, or Ca++)
Anion specific (Cl-)
Ligand gated (opened by neurotransmitter
binding)
Voltage gated (opened by membrane
depolarization)
Background: Neurotransmitters and
receptors
Presynaptic terminal
Presynaptic vesicles
Receptors
Mechanism of Action:
Nonselective CNS Depressants
Alter the function of multiple G protein-coupled
neurotransmitter receptors
Alter function of multiple ion channels
Voltage gated ion channels
Ligand gated ion channels
Nicotinic receptor (Acetylcholine - neuromuscular junction)
GABA
A
receptor (GABA is an inhibitory amino acid)
Glutamate receptor (Glutamate is the major CNS excitatory amino
acid)
Alter signal transduction pathways
Specific receptors or ion channels affected varies for the
different depressants
Mechanism of Action:
Selective CNS Depressants
Benzodiazepines Act on the GABA
A
receptor
GABA is the major inhibitory amino acid in the CNS
Inhibitory post-synaptic potentials
Hyperpolarize the membrane
Prevent the axon from reaching threshold for firing
Reduce the synaptic potential produced by excitatory
amino acids
Middlemas - Page 3
Review: Mechanism of Action
Benzodiazepines
Act on the GABA
A
receptor
ligand gated Chloride channel
Cause hyper-polarization of the
membrane (increased polarization)
GABA: ! amino butyric acid
GABA: Major inhibitory neurotransmitter in CNS
NH2-CH2-CH2-CH2-C-OH
Pre-synaptic inhibition mediated by GABA
B
Receptors - (G protein-coupled receptors)
Post-synaptic inhibition mediated by GABA
A
Receptors (Chloride channels)
O
GABA: ! amino butyric acid
GABA: Major inhibitory neurotransmitter in CNS
Pre-synaptic inhibition mediated by GABA
B
Receptors - (G protein-coupled receptors)
Inhibitory synaptic transmission
!Post-synaptic inhibition mediated
!by GABA
A
Receptors
!(Chloride channels)
Types of GABA Receptors
GABA
A
Cl
-
ionophore
Ligand gated ion channel
Major site of action of alcohol, barbiturates,
benzodiazepines and general anesthetics
GABA
B
G protein coupled receptor
Site of action of baclofen (muscle relaxant)
GABA
A
Receptor
Ethanol
Anesthetics
Barbiturate
GABA
Middlemas - Page 4
Ethanol
Anesthetics
Cl-
Cl
-
GABA
GABA
Barbiturate
Chloride channel
Characteristics of GABA receptor
Chloride channel
Family of receptors Chloride channels
There are multiple forms of the subunits
Contains 5 subunits which from a circle
with a hole in the middle (looks like a
donut)
There are usually
2 alpha-subunits
2 beta-subunits and
1 gamma-subunit
Binding sites
GABA binding site
Must be occupied by an agonist for the ion channel to open
Benzodiazepine binding site
On the alpha subunit
Alpha 1 subunit is responsible for sedative and amnesic and part of the
seizure protection effects of the benzodiazepines
Alpha-2 subunit is responsible for the anxiolytic properties of
benzodiazepines
Gamma subunit is required for benzodiazepine activity
Not all GABA
A
receptors contain BNZ-binding sites
Alpha-4, Alpha-6
Barbiturate binding site
Ethanol binding site
Anesthetic binding site
JPET 300:2-8, 2002
Log Dose Response for
GABA
Log Dose Response for
Benzodiazepines
or [Benzodiazapine]
Middlemas - Page 5
Log Dose Response for
GABA + Benzodiazepines
Actions of Benzodiazepines
Greater hyperpolarization than seen with GABA
alone
Potentiate the action of GABA
Are they true agonist of the GABA
A
receptor?
Do not bind to the GABA binding site
Do not open the chloride channel in the absence of
GABA
No, they are not true agonist
Positive allosteric modulators
Detailed Mechanisms:
Changes in Chloride Conductance
Benzodiazipines increase the frequency of
open channels
Barbiturates increase average open time of
channels
(The content of this slide will not be tested)
Primary Mechanisms of Actions of
CNS Depressants
Barbiturates
GABA
A
receptor
Potentiate the action of GABA (Positive
allosteric modulators)
GABA agonist at high concentrations
Inhibit some excitatory neurotransmitter
receptors
Inhibition of voltage dependent Na
+
and K
+
channels
Inhibition of nicotinic receptors
Ethanol
Inhibits voltage gated Ca
++
and K
+
channels
Ligand gated ion channels
Potentiate action of GABA on the GABA
A
receptor
(Positive allosteric modulator)
Nicotinic acetylcholine receptor
Inhibits some excitatory neurotransmitter receptors
Activates Serotonin 5HT
3
receptor
G-protein coupled receptors
Opioid, Noradrenergic, Dopaminergic, Muscarinic
Enzymes in signal transduction pathways
General Anesthetics
Inhibit voltage gated Ca
++
channels
Ligand gated ion channels
Potentiate action of GABA (Positive
allosteric modulators)
Inhibits excitatory neurotransmitter
receptors
Activates Serotonin 5HT
3
receptor
G-protein coupled receptors
Middlemas - Page 6
GABA
A
Receptor
Ethanol
Anesthetics
Barbiturate
GABA
Ethanol is contraindicated
With
Barbiturates!
Benzodiazepines
General anesthetics!
Why? Additive CNS
depressant effects
Rate of Onset of CNS Effects
of CNS Depressants
Based on lipid solubility
More lipid soluble the faster the onset of
action
Benzodiazepines / Contraindications
Antihistamines
Anticholinergics
Duration of Action of
CNS Depressants
After single IV injection or oral dose
Redistribution
The more lipid soluble the drug
The more significant the redistribution
The shorter the duration of action of the drug
Elimination of the drug requires metabolism
After continuous daily usage
Rate of metabolism
Pharmacology of Benzodiazepines
Middlemas - Page 7
Benzodiazepines Structures
CNS Effects of Benzodiazepines
Decrease anxiety
Hypnosis
Muscle relaxation
Anticonvulsant
Anterograde amnesia
Learning and memory
Additive CNS depressant effect
with other drugs which depress the
CNS
Other Effects of
Benzodiazepines
Respiration: Sedative and hypnotic doses
Minimal effect in normal individuals
Suppression with sleep apnea and chronic lung disease
Additive respiratory depressant effect with other CNS
depressants
Cardiovascular system
Low doses: minor
Pre-anesthetic doses:
" Blood pressure
# Heart rate
DSM-IV-diganostic criteria for
Generalized Anxiety Disorder (GAD)
Excessive anxiety - more days than not for 6 months
Worry difficult to control
Anxiety not related to another disorder Anxiety associated with 3 or
more
Restlessness
Easily fatigued
Difficulty concentrating
Irritability
Muscle tension
Sleep disturbance
Not related to another psychiatric disorder
Significant stress and impairment (social, occupational, etc.)
Not related to substance abuse or condition (hyperthyroidism)
GAD
Supportive therapy, cognitive behavioral therapy, biofeedback and
relaxation training
Benzodiazepines
Immediate, stabilization for severe anxiety
Buspirone or antidepressants
Delayed onset
Preferred for long term management
Antidepressants (not covered in this section)
Venlafaxine
Parozetine
GAD is chronic and can relapse
Initial therapy is often 2-6 months
Commonly Used Benzodiazepines
DIAZEPAM (Valium)
Anxiety
Panic attacks
Preanesthetic medication
Skeletal muscle relaxant
Seizures (Status epilepticus)
Withdrawal from alcohol, sedatives and
hypnotics
Middlemas - Page 8
Commonly Used
Benzodiazepines
LORAZEPAM (Ativan)
Anxiety
Antiemetic
Panic attacks
Skeletal muscle relaxant
Seizures (Status epilepticus)
Withdrawal from alcohol, sedatives and
hypnotics
Tremor
Commonly Used
Benzodiazepines
ALPRAZOLAM (Xanax)
Anxiety
Agoraphobia
Panic attacks
CLORAZEPATE (Tranxene)
Anxiety
Commonly Used
Benzodiazepines
Chlordiazepoxide (Librium)
Anxiety
Withdrawal from alcohol, sedatives and hypnotics
Clonazepam (Klonopin)
Anxiety
Panic attack
Seizure disorders
Adjunctive treatment for acute mania and certain
movement disorders
Benzodiazepines Used to Treat Insomnia
FLURAZEPAM (Dalmane) (long acting)
Delayed onset and more prolonged
Patients having difficulty staying asleep
Residual daytime drowsiness
TEMAZEPAM (Restoril) (short half-life)
TRIAZOLAM (Halcion)
Rapid onset and short duration (ultra-short half-life)
Patients having difficulty falling asleep
No daytime sedation
Tolerance develops quickly
Rebound insomnia
Commonly Used Benzodiazepines
MIDAZOLAM (Versed)
Preanesthetic medication
Reference chart:
Benzodiazepams/Approved indications
Muscle Alcochol Induction of Panic
Generic (Trade) Anxiety Insomnia SeizuresSpasm withdrawl Anesthesia disorder
Aprazolam (Xanax) X X
Chlordiazepoxide (Librium) X X
Clonazepam (Klonopin) X
Chlorazepate ( Tranxene) X X X
Diazepam (Valium) X X X X X
Estazolam (ProSom) X
Flurazepam (Dalmane) X
Halazepam (Paxipam) X
Lorazepam (Ativan) X X X X
Midazolam (Versed) X
Oxazepam (Serax) X X
Quazepam (Doral) X
Temazepam (Restoril) X
Triazolam (Halcion) X
* Bold faced drugs are required for exam
Middlemas - Page 9
Pharmacokinetic Properties of
Benzodiazepines
Weak bases
Absorption
Oral: duodenum
IM: irregular
IV: local pain and thrombophlebitis with
diazepam
Metabolism of Benzodiazepines
LORAZEPAM
(Ativan)
OXAZEPAM (Serax)
TEMAZEPAM
(Restoril)
ALPRAZOLAM (Xanax)
MIDAZOLAM (Versed)
TRIAZOLAM (Halcion)
CHLORAZEPATE(Tranxene)
CHLORDIAZEPOXIDE
(Librium)
DIAZEPAM (Valium)
FLURAZEPAN (Dalmane)
Phase II Metabolism
Phase I and II
Metabolism
Short Acting
Long Acting
Phase I and II
Metabolism
Clinical Significance
Decreased phase I reactions for drug
elimination can occur in
Patients with liver disease
Geriatric patients
Metabolism of Benzodiazepines
LORAZEPAM
(Ativan)
OXAZEPAM (Serax)
TEMAZEPAM
(Restoril)
ALPRAZOLAM (Xanax)
MIDAZOLAM (Versed)
TRIAZOLAM (Halcion)
CHLORAZEPATE(Tranxene)
CHLORDIAZEPOXIDE
(Librium)
DIAZEPAM (Valium)
FLURAZEPAN (Dalmane)
Phase II Metabolism
Phase I and II
Metabolism
Short Acting
Long Acting
Phase I and II
Metabolism
Metabolism of
Benzodiazepines
Elimination half-lives (broad range)
3 to 120 hrs
Time to reach steady state plasma
levels
Less than a day to two weeks
Metabolism of Benzodiazepines
Induction of cytochrome P450 enzymes
Not clinically significant
Tolerance is caused by CNS changes
rather than changes in metabolism of
benxodiazepines
Inhibition of drug metabolism by
Cimetidine (Tagamet)
Oral contraceptives
Isoniazid
Middlemas - Page 10
Plasma Protein Binding
70 to 99%
70% alprazolam (Xanax)
99% diazepam (valium)
No drug-drug interactions known at
this time
Adverse Effects of Benzodiazepines
Most common:
Drowsiness
Sedation
Impaired motor function
Confusion
Memory loss
Tolerance develops
Less common but significant
Paradoxical rage reaction
Adverse Effects of Benzodiazepines
Toxic signs
Drowsiness
Ataxia
difficulty with speech (Dysarthria)
Decreased reflexes (Areflexia)
Additive CNS depressant effects with
other CNS depressant drugs including
Antihistamines
Antidepressants
Alcohol
Use of Benzodiazepines During
Pregnancy
Lipid soluble - cross the placenta
Pregnancy category D or X
First trimester - risk of concgenital
malformations
Near term - CNS depression in neonate
Contraindicated
During pregnancy
Labor and deliver
Breast feeding
Benzodiazepine Antagonists
Flumazenil (Romazicon)
Competitive antagonist of
benzodiazepines
Indication
reversal of of sedation caused by
benzodiazepams used for anesthesia
Benzodiazepam overdose
GABA
A
Receptor
Middlemas - Page 11
FLUMAZENIL alone
Flumazenil
Uses
Reverse sedative effect of benzodiazepines after anesthesia
Reverse benzodiazepine overdose
NOT effective in reversing the effects of other CNS
depressants
May precipitate withdrawal
Short half life compared to some benzodiazepines -
repetitive doses are sometimes used
Tolerance to Benzodiazepines
Tolerance
Loss of effectiveness of the drug
Due to changes in the GABA
A
receptor
Subunits present in the receptor
Loss of allosteric modulation of GABA binding
by benzodiazepines
Develops to
Anticonvulsant
Hypnotic effects
Sedative effects
Little tolerance to
Antianxiety effects
Cross tolerance with other CNS depressant drugs
Dependence
Dependence
Physiological state that requires continuous drug
administration to prevent the appearance of an
abstinence or withdrawal symptom
Little tendency to # dosage
Schedule IV drug
Prescription must be rewritten after 6 months or 5
refills
Primary abusers are those who abuse other drugs
Withdrawal effects
Symptom recurrence
Rebound
Withdrawal reaction
Middlemas - Page 12
Withdrawal Effects
General anxiety
Autonomic-like signs
Tachycardia
Trembling (Tremulousness)
Abdominal distress
Mild systolic hypertension
Sweating
Flu-like symptoms
Muscle aches
Malaise
Sensory disturbances
Seizures and Delirium: following long-term, high dosage usage
Treatment of Withdrawal
Treatment
Switch to long acting drug
Gradually decrease the dose
Other Drugs Used to Treat Anxiety
Buspirone (BuSpar)
Use to treat generalized anxiety disorder
Not effective for other types of anxiety disorders
Partial agonist at the 5-HT
1A
receptor
Advantages over benzodiazepines
Little sedation or euphoric effect
No rebound anxiety or withdrawal symptoms
Doesnt potentiate the effects of other CNS
depressants
Takes 1 to 2 weeks to produce an antianxiety
effect
DSM IV Classification of Anxiety Disorders
(Diagnostic and Statistical Manual of Mental Disorders IV)
Generalized anxiety disorder
(GAD): Diazepam
Panic attacks: Alprazolam and
clonazepam
http://anxiety.mentalhelp.net/
Anxiety disorders - Treatment with
Benzodiazepines
Buspirone (BuSpar)
Side effects
Dizziness and lightheadedness
Tachycardia, palpitations
Nervousness or restlessness
GI distress
Tingling or prickling sensation (Paresthesias)
Review: Benzodiazepines
Anxiety treatment
Diazepam (Valium)
Alprazolam* (Xanax)
Clorazepate (Tranxene)
Also: Chlordiazepoxide halazepam, Lorazepam, Oxazepam,
Prazepam
Panic disorder
Alprazolam* (Xanax)
Seizure disorders
Clonazepam (Klonopin)
Also: Chlorazepate, Diazepam
Middlemas - Page 13
Review: Benzodiazepines
Hypnotics (Insomnia treatment)
Flurazepam ( Dalmane)
Temazepam (Restoril)
Triazolam (Halcion)
Muscle spasms
Diazepam (Valium)
Alcohol withdrawl and treatment
Diazepam (Valium)
Oxazepam(Serax)
Clorazepate (Tranxene)
Chlordiazepoxide (Librium)