Anxiolytics
An
effective anxiolytic agent should reduce anxiety with little or no effect on
motor and mental function
·
Benzodiazepines
(BZDs)
·
Barbiturates
(BARBs)
·
5-HT1A
receptor agonists
·
Carbamates
·
Others:TCAs
(fluvoxamine), MAOIs, Antihistaminicagents, B-Adrenoreceptor antagonists, Antipsychotics
(Ziprasidone)
Overdose
effects of an ideal antianxiety/sedative agent should not include generalized
CNS depression. Therapeutic Index, margin of safety is greater for 2nd
generation agents thatn for 1st generation agents. While increasing the dose,
anxiolytics may give effects of sedation to hypnosis and anesthesia
First
generation - eg. barbiturates
2nd
generation - eg. benzodiazepines
3rd
generation - Selective antianxiety, eg.buspirone
GABA
receptors Classification
3
major subtypes of trans-membrane proteins
GABA
A - 5 subunits, coassemble to form an integral, involves ionotropic chloride
channel
GABA
B - it is single, G protein-coupled, metabotropic receptor
GABA
C - ligand-gated chloride channel, function and pharmaco properties are
different from GABA A & B
GABA A
Receptors
GABA
A receptors is a glycoprotein pentamer belonged to of ligand-gated ion
channelfamily
The
GABA A receptor-chloride ionophore complex is made of 5 subunits, alfa, beta
and gamma that co-assemble to form an integral chloride channel
There
are 6 subtypes of alfa, and 3 each of beta and gamma
GABA
binds to a site on the alfa or beta subunit
The
receptor also contains binding sites for benzodiazepines, barbiturates and
steroids such as progesterone (distinct from the GABA-binding site)
Functional
Diversity of the GABA A Receptor Subunits
alfa1
subunit - containing GABA A receptors: sedation
alfa2
subunit - anxiolysis
alfa3
subunit - processing of sensory motor information related to a schizophrenia
endophenotype
alfa4
subunit - sedative, hypnotic and anesthetic effects of some agents in the
thalamus
alfa5
subunit - (extrasynaptic): associative temporal and spatial memory by
inhibitory modulation of activities in the hippocampus
beta3
subunit - sedation, hypnosis, and anesthesia
GABA
Function and Distribution
Inhibitory
neurotransmitter that modulate chloride anion permeability
Widely
distributed thoughout central nervous system
Local
inhibitory action, therefore rapidly alters neuronal output
GABA
is responsible for overall level of inhibitory tone in the brain
GABA
binds to GABA A receptors --> causes conformational changes --> open the
chloride ion channel --> lead to neuronal membraine hyperpolarization -->
inhibitory neurotransmission in the CNS
Barbiturates
Now
largely obsolete as anxiolytic and are mainly used in anesthesia (thiopental)
and epilepsy (phenobarbital)
Taking
BARBs with other CNS depressants can be extremely dangerous and may even lethal
Examples
include: alcohol, tranquillizers, opioids (heroin, morphine, codeine or
methadone), and antihistamines (found in cold, cough, and allergy remedies)
Barbiturate
Mechanism of Action
Enhance GABAnergic Transmission
-increase
opening time of GABAnergic channels both in the presence or absence of GABA
-increase
receptor affinity for GABA
However,
they bind to a different site of the GABA A - receptor / chloride channel. At
high concentrations they may be GABA-mimetic
Barbiturates
are less selective than benzodiazepines, they also:
-depress
actions of excitatory neurotransmitters
-exert
nonsynaptic membrane effects
Disadvantages
of Barbiturates
-increase
toxicity compared to benzodiazepenes
-psychological
dependence
-physiological
tolerance: No tolerance to lethal action of drug
-strongly
induce hepatic CYP450 & conjugating enzymes > increase metabolism of
many other drugs
-flumazenil
not effective
-death
may occur by overdose (often choice to commit suicide)
In
low doses, have a tranquilizing effect. As dose increases, hypnotic or sleep
inducing effect. Even large doses actas anticonvulsants and anesthetics.
Barbiturates has small therapeutic index.
Sedation
> hypnosis > anesthesia > coma > death
Barbiturates
Adverse effects
-excessive
CNS depression
-hypersensitivity
reactions
-excitement
-respiratory
depression and hypotension
-coma
and death in overdose
Benzodiazepines
List of Examples
Chlordiazepoxide
(Benpine, oldest)
Diazepam
(Valium)
Bromazepam
(Lexotan)
Lorazepam
(Ativan)
Chlorazepate
(Tranxene)
Alprazolam
(Xanax)
Clonazepam
Oxazepam
Prazepam
Benzodiazepines
Mechanism of Action
Involvement
of endogenous ligands of the BDZ receptors is suspected.
BDZ
bind selectively to GABA A receptors, in which binding of BDZs to gamma
subunits of GABA A facilitates the process of channel opening
BDZs
enhance the GABAnergic transmission by
-increase
the frequency of openings of GABAergic channels
-increase
receptor affinity for GABA
Serotonergic
effects may result, eg. clonazepam
Benzodiazepines
bind to GABA A receptors (gamma subunit) > act allosterically to increase
the affinity of GABA > facilitate the opening of the Cl- ion channel -
increased chloride permeability. Hence, BDZ potentiate GABA by increasing
neuronal inhibition and CNS depression especially limbic system.
Benzodiazepiens
therapeutic uses
Reduction
of anxiety and agression
Sedation
and induction of sleep
-anxiolysis
(20% receptor occupancy with alfa2)
-sedation
(30-50% receptor occupancy with alfa1)
-hypnosis
(>60% receptor occupancy)
In
addition, BDZ are used in/as:
-alcohol
withdrawal
-pre-anesthetic
medications
-reduction
of muscle tone and coordination
-anticonvulsant
-anterograde
amnesia
Benzodiazepines
Advantages
-higher
therapeutic index
-relatively
safe even if overdose
-have
little effect on respiratory depression
-muscle
relaxation (useful for spasm & back pain)
-can
treat seizures (clonazepam)
Disadvantages
-interaction
with alcohol
-long-lasting
'hangover' effects
-withdrawal
symptoms
-development
of TOLERANCE
Pharmacokinetics of
Benzodiazepines
Pharmacokinetic
properties determine the choice of drug for different clinical conditions
Absorption - BDZs are weak bases, mainly absorbed
from duodenum
- given orally - well
& rapidly absorbed
Distribution - most BDZs extensively protein bound
(85%-95%)
- large volume of
distribution VD - accumulation in body fat (high lipid solubility)
- increase lipid
solubility > high rate of entry into CNS > faster onset
- all BDZ cross placenta
- detectable in breast
milk > may exert depression effects on the CNS of lactating infants
Metabolism - Metabolism: BDZs undergo extensive
metabolism - Oxidation either by N-dealkylation or hydroxylation
- mostly by CYP3A4 or
CYP2C19
- conjugation
(glucuronides)
- conversion to
active/inactive metabolite is an important distinction
- some BDZs are prodrugs
& require metabolism (clorazepate)
- many have active
metabolites with t1/2 greater than parent drug (long duration of action)
Excretion - mostly via urine
- as metabolites
(predominantly glucuronides)
Side effects
of Benzodiazepines
Central
nervous system - headache, drowsiness, excess sedation, impaired coordination,
confusion, anterograde amnesia, euphoria, fatigue
Paradoxical
reactions - increased anxiety, insomnia, hyperexcitability, hallucination
Gastrointestinal
disturbance - nause, vomiting, diarrhea, constipation, dry mouth
Others - BDZs have wide margin of safely if used for
short periods
- prolonged use (beyond several
weeks) may cause Physical Dependence and Psychologic Dependence
- withdrawal syndrome can occur with
BDZs
- tolerance may develop to CNS ADR
and anxiolytic effect upon chronic use
Benzodiazepines
Overdose & Management
Benzodiazepines
is relatively safe in overdose
Acute
Overdose causes -prolonged sleep
-no serious
respiratory depression
-no coma
Fatal
Overdose - incidence is low and more likely to occur when used in combination
with other CNS depressants eg. alcohol, barbiturates
Management
-flumazenil which is benzodiazepines
antagonist
-respiratory function
adequately supported and monitored
Benzodiazepine
Withdrawal Syndrome
High
dose withrawal
-similar
symptoms with alcohol withdrawal
-seizures
-delirium
-tremors
-cramps
-depression
-insomnia
-higher
than therapeutic dose for more than a month
Low
dose withdrawal
-symptoms
different from alcohol withdrawal
-irregular
heart beat
-anxiety
-weight
loss
-muscle
spasms
-impairment
of memory & concentration
-increase
blood pressure
-sensitive
to light/sounds
-tinglign
feeling
-feelings
of unreality
-numbness
-therapeutic
dose longer than 3 months
-should
not be confused with symptom remergence
Benzodiazepine:
Teratogenicity
Pregnancy
category: D
Studies
in pregnant women have demonstrated a risk to the foetus. However, the benefits
of therapy in a life threatening situation or a serious disease, may outweight
the potential risk
Newborn
infants show withdrawal if mother used benzodiazepines
Benzodiazepines
during labor can have effects on newborn
-depressed respiration and feeding
-floppy baby syndrome
-low apgar scores
Benzodiazepines
Drug-Drug Interaction
+
CNS depressants/alcohol > additive > increase CNS depression
+
CYP3A4 inhibitor > increase plasma [benzodiazepiens]
examples
include:
azole
antifungal agents (itraconazole, ketoconazole)
diltiazem
SSRIs
(fluoxetine, fluvoxamine)
grapefruit
juice
isoniazid
erythromycin
nefazodone
non-nucleoside
reverse transcriptase inhibitors (delavirdine, efavirenz)
protease
inhribitors (indinavir)
+
CYP3A4 inducer > decrease plasma [benzodiazepines]
examples
include carbamazepine and rifampin
+
flumazenil = antagonism
*Combination
of anxiolytic drugs should be avoided
Alprazolam
(Xanax)
Pharmacokinetics - oral administration with rapid
absorbed and almost complete oral bioavailability
- crosses placenta &
excreted in breast milk
- metabolisd to alfa-OH
alprazolam (active) & benzophenone der. (inactive)
- excreted in urine
(~20% unchanged)
Side effects
CNS:
drowsiness, fatigue, sedation, memory impairment, cognitive disorder,
somnolence, lightheadness, decreased libido, depression, confusion
CVS:
hypotension, tachycardia
GI:
N/V/D/C, dry mouth
Others:
menstrual disorder, rash
Contraindications:
patients receiving itra/ketoconazole
Drug-drug
interactions
+
cimetidine, disulfiram, oral contraceptive = increase effect of alprazolam
+
theophylline = antagonize sedative effect
+
omeprazole = increase p [alprazolam]
+
imipramine, desipramine = increase p [imi/desipramine]
Diazepam
(Valium)
Administration:
oral, rectal, IM, IV (slow)
Pharmacokinetics - complete oral bioavailability
- highly lipophilic
- crosses placenta &
excreted in breast milk
- metabolised to
desmethyldiazepam (active)
Side effects
CNS:
confusion, dizziness, fatigue, memory impairment, disorientation, headache
CVS:
hypotension, tachycardia
GI:
N/V/D/C, dry mouth
others:
rash, dependency/withdrawal symptoms
Contraindications:
psychoses, lactation
Drug-drug
interactions
+
cimetidine, disulfiram, OC = increse effect of diazepam
+
theophylline = antagonize sedative effect
+
omeprazole = increase p [diazepam]
Lorazepam
Administration:
oral, IM, IV (slow)
Pharmacokinetics - absolute bioavailability ~ 90%
- rapidly conjugated to
lorazepam glucuronide
- t1/2 1-2 hour
(lorazepam)
- t1/2 ~ 18 hours
(lorazepam glucuronide)
Side effects
CNS:
confusion, dizziness, fatigue, memory impairment, disorientation, headache
CVS:
hypotension
GI:
N/V/D/C, dry mouth, dysphagia
Drug-drug
interactions
+
Oral contraceptive = increase clearance rate of lorazepam
+
theophylline = antagonize sedative effect
+
scopolamine = increase incidence of hallucinations, irrational behaviour &
sedation
Clonazepam
Pharmacokinetics
- oral administration
- rapidly absorbed with
bioavailability ~ 90%
- highly metabolised in
liver
- excretion in urine
(<2% unchanged drug) and into breast milk
- t1/2 2-11 hours
Side effects
CNS:
somnolence, dizziness, disorientation, depression, memory disturbance,
decreased libido
CVS:
hypotension
GI:
constipation, decrease appetite
Others:
dysmenorrhoea
Drug-drug
interactions
+
cimetidine, disulfiram, OC = increase clonazepam effect
+
CYP inducer (carbamazepine, barbiturates, phenytoin) = reduce p [clonazepam]
+
digoxin = increase p [digoxin]
+
theophylline = antagonize sedative effect
Carbamates
Meprobamate
-produce
CNS depressant effects
-at
multiple site (including thalamic & limbic system)
-pregnancy
category: D
Pharmacokinetics - well absorbed, 80-92 % liver
metabolised
- excretion through
urine (90%) and feces (10%)
- t1/2 6-14 hours
Side effects
CNS:
drowsiness, ataxia, euphoria, slurred speech, dizziness, headache
CVS:
palpitations, tachycardia, hypertensive crisis
GI:
N/V/D
others:
hypersensitivity, exacerbation of porphyria symptoms
5HT-1A
Agonist
Serotonin
Receptors
5-HT1A
- Anxiety, alcoholism, sexual
function
5-HT1C - Anxiety, migraine pain
5-HT1D - Migraine pain
5-HT2 - Anxiety, depression, schizophrenia
negative symptoms, sexual function
5-HT3 - Migraine pain, emesis, schizophrenia
5-HT4 - Anxiety, schizophrenia?
Stimulation
of 5-HT1A receptors inhibit 5-HT2A, 5-HT2C, and 5-HT3 receptors
5HT1A receptor
There
are 7 different types of serotonin receptor (5-HT1- 5-HT7)
The
5-HT1 receptors are classified into A, B and D subtypes, which are found in the
central nervous system and blood in vessels.
Coupled
to inhibitory G-proteins, the 5-HT1A receptors have an inhibitory effect on
neurotransmission when bound by an agonist.
Buspirone
Buspirone
is non-benzodiazepine anxiolytic which is the most selective anxiolytic
currently
Mechanism of Action
-anxiety
associated with altered serotonin transporters
-partial
agonist at 5-HT 1A receptor presynaptic
-inhibit
serotoin release
-dose
not involve GABA receptors
-delayed
onset (~ 1-2 week)
-pregnancy
category: B
-oral
administration
Advantages
-lack
CNS depressant effect
-no
sedation
-no
impairment of performance
-no
tolerance or withdrawal
-no
cross-tolerance with BDZ
-no
abuse/addiction potential
-minimal
effect on psychomotor functions
Binding
of a partial agonist to the 5-HT1A receptor causes the dissociation of
inhibitory G-proteins. The G-protein alpha sub-unit binds to and inhibits
adenylate cyclase. This prevents the conversion of ATP to cAMP and the
initiation of other secondary messenger signaling mechanisms, hence cell
depolarisation is inhibited.
Pharmacokinetics
-rapidly
absorbed and undergo extensive first pass metabolism
-oxidised
by CYP3A4 to active metabolite
-excretion
through urine (30-60%) and feces (20-40%)
-t1/2
2-11 hours
Side effects
-dizziness,
drowsiness, headache, nervousness
-tachycardia/
palpitations
-parethesia
-GI
distress, N/D
-pupillary
constrition (dose-dependent)
Drug-drug
interactions
+fluoxetine
= reduce buspirone effect
+haloperidol
= increase p [haloperidol]
+CYP3A4
inducer (carbamazepine, barbiturates, phenyton) = reduce p [buspirone]
+CYP3A4
inhibitor (erythromycin, azole, protease, inh) = increase p [buspirone]
+MAOIs
= risk of elevated BP
Other Agents
Antihistamines
(eg. hydroxyzine, promethazine)
Monoamine
oxidase inhibitors
Tricylic/tetracyclic
antidepressants
Beta
blockers
Natural
remedies (eg. melatonin, valerian)
Drug
Treatment of Anxiety
1.
Generalized Anxiety Disorder
Diazepam, lorazepam, alprazolam,
buspirone
2.
Phobic Anxiety
a. simple phobia. BDZs
b. social phobia. BDZs
3.
Panic Disorders
TCAs and MAOIs, alprazolam
4.
Obsessive-Compulsive Behavior
Clomipramine (TCA), SSRI's
5.
Post-traumatic Stress Disorder
Antidepressants, buspirone
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