4. Manifestations of anxiety
• Verbal complaints. The patient says he/she is
anxious, nervous, edgy.
• Somatic and autonomic effects. The patient is
restless and agitated, has tachycardia, increased
sweating, weeping and often gastrointestinal
disorders.
• Social effects. Interference with normal
productive activities.
5
5. Pathological Anxiety
Generalized anxiety disorder (GAD): People suffering
from GAD have general symptoms of motor tension,
autonomic hyperactivity, etc. for at least one month.
Phobic anxiety:
Simple phobias. Agoraphobia, fear of animals, etc.
Social phobias.
Panic disorders: Characterized by acute attacks of fear as
compared to the chronic presentation of GAD.
Obsessive-compulsive behaviors: These patients show
repetitive ideas (obsessions) and behaviors
(compulsions).
6
6. Causes of Anxiety
1). Medical:
a) Respiratory
b) Endocrine
c) Cardiovascular
d) Metabolic
e) Neurologic.
7
11. Anxiolytics
Other Drugs with anxiolytic activity.
TCAs (Fluvoxamine). Used for Obsessive
compulsive Disorder.
MAOIs. Used in panic attacks.
Antihistaminic agents. Present in over the
counter medications.
Antipsychotics (Ziprasidone).
Novel drugs. (Most of these are still on clinical trials).
CCKB (e.g. CCK4).
EAA's/NMDA (e.g. HA966). 12
13. Properties of Sedative/Hypnotics in Sleep
1) The latency of sleep onset is decreased
(time to fall asleep).
2) The duration of stage 2 NREM sleep is
increased.
3) The duration of REM sleep is decreased.
4) The duration of slow-wave sleep (when
somnambulism and nightmares occur) is
decreased.
Tolerance occurs after 1-2 weeks.
15
22. Mechanisms of Action
1) Enhance GABAergic Transmission
frequency of openings of GABAergic
channels. Benzodiazepines
opening time of GABAergic channels.
Barbiturates
receptor affinity for GABA. BDZs and BARBS
2) Stimulation of 5-HT1A receptors.
3) Inhibit 5-HT2A, 5-HT2C, and 5-HT3 receptors.
25
23. Benzodiazepines
PHARMACOLOGY
BDZs potentiate GABAergic inhibition at all levels
of the neuraxis.
BDZs cause more frequent openings of the
GABA-Cl- channel via membrane
hyperpolarization, and increased receptor affinity
for GABA.
BDZs act on BZ1 (1 and 2 subunit-containing)
and BZ2 (5 subunit-containing) receptors.
May cause euphoria, impaired judgement, loss of
cell control and anterograde amnesic effects.
26
24. Pharmacokinetics of Benzodiazepines
Although BDZs are highly protein bound
(60-95%), few clinically significant
interactions.*
High lipid solubility high rate of entry
into CNS rapid onset.
*The only exception is chloral hydrate and
warfarin
27
25. Pharmacokinetics of Benzodiazepines
Hepatic metabolism. Almost all BDZs
undergo microsomal oxidation (N-
dealkylation and aliphatic hydroxylation)
and conjugation (to glucoronides).
Rapid tissue redistribution long acting
long half lives and elimination half lives
(from 10 to > 100 hrs).
All BDZs cross the placenta detectable
in breast milk may exert depressant
effects on the CNS of the lactating infant. 28
26. Pharmacokinetics of Benzodiazepines
Many have active metabolites with half-
lives greater than the parent drug.
Prototype drug is diazepam (Valium), which
has active metabolites (desmethyl-
diazepam and oxazepam) and is long
acting (t½ = 20-80 hr).
Differing times of onset and elimination
half-lives (long half-life => daytime
sedation).
29
28. Biotransformation of Benzodiazepines
• Keep in mind that with formation of active
metabolites, the kinetics of the parent drug
may not reflect the time course of the
pharmacological effect.
• Estazolam, oxazepam, and lorazepam,
which are directly metabolized to
glucoronides have the least residual
(drowsiness) effects.
• All of these drugs and their metabolites are
excreted in urine.
31
29. Properties of Benzodiazepines
• BDZs have a wide margin of safety if used
for short periods. Prolonged use may cause
dependence.
• BDZs have little effect on respiratory or
cardiovascular function compared to BARBS
and other sedative-hypnotics.
• BDZs depress the turnover rates of
norepinephrine (NE), dopamine (DA) and
serotonin (5-HT) in various brain nuclei.
32
30. Side Effects of Benzodiazepines
Related primarily to the CNS depression
and include: drowsiness, excess
sedation, impaired coordination, nausea,
vomiting, confusion and memory loss.
Tolerance develops to most of these
effects.
Dependence with these drugs may
develop.
Serious withdrawal syndrome can
include convulsions and death.
33
32. Toxicity/Overdose with Benzodiazepines
• Drug overdose is treated with flumazenil (a
BDZ receptor antagonist, short half-life), but
respiratory function should be adequately
supported and carefully monitored.
• Seizures and cardiac arrhythmias may occur
following flumazenil administration when BDZ
are taken with TCAs.
• Flumazenil is not effective against BARBs
overdose.
35
33. Pharmacokinetics of Barbiturates
• Rapid absorption following oral
administration.
• Rapid onset of central effects.
• Extensively metabolized in liver (except
phenobarbital), however, there are no
active metabolites.
• Phenobarbital is excreted unchanged.
Its excretion can be increased by
alkalinization of the urine.
36
34. Pharmacokinetics of Barbiturates
• In the elderly and in those with limited
hepatic function, dosages should be
reduced.
• Phenobarbital and meprobamate cause
autometabolism by induction of liver
enzymes.
37
35. Properties of Barbiturates
Mechanism of Action.
• They increase the duration of GABA-gated
channel openings.
• At high concentrations may be GABA-
mimetic.
Less selective than BDZs, they also:
• Depress actions of excitatory
neurotransmitters.
• Exert nonsynaptic membrane effects.
38
36. Toxicity/Overdose
• Strong physiological dependence may
develop upon long-term use.
• Depression of the medullary respiratory
centers is the usual cause of death of
sedative/hypnotic overdose. Also loss of
brainstem vasomotor control and
myocardial depression.
39
37. Toxicity/Overdose
• Withdrawal is characterized by increase
anxiety, insomnia, CNS excitability and
convulsions.
• Drugs with long-half lives have mildest
withdrawal
• Drugs with quick onset of action are most
abused.
• No medication against overdose with
BARBs.
• Contraindicated in patients with porphyria.
40
38. Sedative/Hypnotics
Tolerance and excessive rebound occur in
response to barbiturate hypnotics.
NIGTHS OF DRUG DOSING
SLEEP
PER
NIGHT
(%)
CONTROL WITHDRAWAL
NREM III and IV
REM
1 2 3
41
40. BUSPIRONE
• Most selective anxiolytic currently available.
• The anxiolytic effect of this drug takes
several weeks to develop => used for GAD.
• Buspirone does not have sedative effects
and does not potentiate CNS depressants.
• Has a relatively high margin of safety, few
side effects and does not appear to be
associated with drug dependence.
• No rebound anxiety or signs of withdrawal
when discontinued.
43
41. BUSPIRONE
Side effects:
• Tachycardia, palpitations,
nervousness, GI distress and
paresthesias may occur.
• Causes a dose-dependent pupillary
constriction.
44
42. BUSPIRONE
Mechanism of Action:
• Acts as a partial agonist at the 5-HT1A
receptor presynaptically inhibiting
serotonin release.
• The metabolite 1-PP has 2 -AR
blocking action.
45
43. Pharmacokinetics of BUSPIRONE
• Not effective in panic disorders.
• Rapidly absorbed orally.
• Undergoes extensive hepatic metabolism
(hydroxylation and dealkylation) to form
several active metabolites (e.g. 1-(2-
pyrimidyl-piperazine, 1-PP)
• Well tolerated by elderly, but may have slow
clearance.
• Analogs: Ipsapirone, gepirone, tandospirone.
46
44. Zolpidem
• Structurally unrelated but as effective as
BDZs.
• Minimal muscle relaxing and anticonvulsant
effect.
• Rapidly metabolized by liver enzymes into
inactive metabolites.
• Dosage should be reduced in patients with
hepatic dysfunction, the elderly and patients
taking cimetidine.
47
45. Properties of Zolpidem
Mechanism of Action:
• Binds selectively to BZ1 receptors.
• Facilitates GABA-mediated neuronal
inhibition.
• Actions are antagonized by flumazenil
48
46. Properties of Other drugs
• Chloral hydrate
• Is used in institutionalized patients. It displaces
warfarin (anti-coagulant) from plasma proteins.
• Extensive biotransformation.
49
47. Properties of Other Drugs
2-Adrenoreceptor Agonists (eg. Clonidine)
• Antihypertensive.
• Has been used for the treatment of panic attacks.
• Has been useful in suppressing anxiety during
the management of withdrawal from nicotine
and opioid analgesics.
• Withdrawal from clonidine, after protracted use,
may lead to a life-threatening hypertensive
crisis.
50
48. Properties of Other Drugs
-Adrenoreceptor Antagonists
(eg. Propranolol)
• Use to treat some forms of anxiety, particularly
when physical (autonomic) symptoms
(sweating, tremor, tachycardia) are severe.
• Adverse effects of propranolol may include:
lethargy, vivid dreams, hallucinations.
51
49. Other Uses
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. Posttraumatic Stress Disorder (?)
Antidepressants, buspirone
52
