classifications. pharmacokinetics pharmacodynamics drug interaction precautions drug interactions contraindication side effects

1. Presentation about:
Anxiolytics and
antidepressants
Clinical Pharmacology
Ismail Surchi
General Medicine

2. • The drugs or agents which are used in treatment of anxiety is
called as Anxiolytics, they acts by balancing brain
neurotransmitters level to ease anxiety.
• Psychotherapy, with or without medication, is often
considered a fundamental aspect of treatment for anxiety
disorders.
• CLASSIFICATION OF ANXIOLYTICS
• 1. Benzodiazepines: Alprazolam, Chlordiazepoxide,
,Diazepam, Lorazepam.
• 2. Azapirones: Buspirone, Gepirone.
• 3. Beta blocker: Propranolol
• 4. Sedative antihistamine : Hydroxyzine.
• 5. other : TCA , SSRIs , SNRI : Imipramine, Paroxetine,
Venlafaxine.

3. • Well absorbed orally, can be given IV and IM
• Widely distributed, redistribution from CNS to skeletal
muscles, adipose tissue) (termination of action).
• Cross placental barrier (Fetal depression).
• Excreted in milk (neonatal depression).
• metabolized in the liver to active metabolites (long
duration of action- cumulative effect).
• Half-lives vary widely (4 - 100 hours)
• Excretion throughout urine.

4. • Therapeutic Uses:
• 1 Anxiolytic action in cases of anxiety
• 2 Sedative and Hypnotic action, e.g. preoperative
sedation, and insomnia.
• 3 Anticonvulsant, Antiepileptic action.
• 4 Muscle relaxation can be used in case of Status
epilepticus and Convulsion.

5. • MECHANISM OF ACTION: Benzodiazepines work to
calm or sedate a person, by raising the level of the
inhibitory neurotransmitter GABA in the brain.
• by enhancing the binding of GABA to its receptor. GABA
activates the chloride ion channel, allowing chloride ions to
enter the neuron. The flow of chloride ions into the neuron
hyperpolarizes and inhibits the neuron.
• The mechanism of action of BUSPIRONE: It is a partial
agonist at 5-HT1A receptor. These are the auto receptor in
presynaptic and postsynaptic regions that reduces release
of 5-HT & other mediators. They also inhibits the activity of
noradrenergic locus cerulus neurons & thus interferes with
arousal reaction.
• The mechanism of action of SSRIs, SNRIs : by blocking the
reuptake of serotonin and norepinephrine back into the
nerve cells that released them, which increases the levels

6. Benzodiazepine Half-life
(hr)
Active
metabolites
Anxiolytic dose
range (mg/day)
Approximate dose
equivalency (mg)
Alprazolam (Xanax) 12 Yes 0.5-4 0.25
Chlordiazepoxide (Librium) 100 Yes 15-100 10
Clonazepam (Klonopin) 34 No 0.5-10 0.5
Clorazepate (Tranxene) 100 Yes 7.5-60 7.5
Diazepam (Valium) 100 Yes 2-40 5
Lorazepam (Ativan) 15 No 2-4 1
Oxazepam (Serax) 8 No 30-120 15
Taken from: Kaplan SI, Sadock BJ. Kaplan & Sadock’s Synopsis of Psychiatry, 8th ed.,
Lippincott, Williams & Wilkins, Philadelphia, 1998, p. 996.
Advantages Disadvantages
-Rapid onset of action -Physiologic dependence
-Highly effective -Addicting
-Impaired cognition

7. • Very common : Drowsiness , headache, dizziness, fatigue,
Nausea, Nightmares
• Common : disturbance in attention, ataxia, Sexual
dysfunction, Stomach upset.
• Uncommon : anorexia, flatulence, increase appetite, dry
mouth.
• Dependence, Withdrawal syndrome including rebound
anxiety and tremulousness and twitching.

8. • Pregnancy and breast feeding.
• Myasthenia gravis.
• Sleep apnoea.
• Sever hepatic impairment.
• Allergy to benzodiazepine
• Acute narrow angle glaucoma
• Psychosis, Shock, Coma
• Acute alcohol intoxication

10. Advantages
• High efficacy
• Non-addicting
• Effective for a number
of conditions
Disadvantages
• Can take 2-8 weeks or
longer to be effective
• Side effects
• Drug interactions
• Discontinuation
syndrome

11. • Monoamine oxidase inhibitors (MAOI)
- isocarboxazid, phenelzine, rasagiline, selegiline
• Tricyclic antidepressants (TCA)
- Amitriptyline, Imipramine, Nortriptyline, Desipramine
• Selective Serotonin Reuptake Inhibitors (SSRI)
- Fluoxetine, Sertraline, Escitalopram, Paroxetine.
• Serotonin and Norepinephrine Reuptake inhibitors
(SNRI).
- Duloxetine, Venlafaxine, desvenlafaxine.

12. General features of Anti depressants.
1. Are well absorbed after oral administration, Fairly
rapid oral absorption.
2. Achieve peak plasma level within 2-8 hrs.
3. Undergo hepatic metabolism by cytochrome CYP45
and CYP2D6.
4. Tightly bound to plasma protein.
5. Food has little effect on absorption (except with
sertraline, for which food increases its absorption).
6. The majority of SSRIs have plasma half-lives that
range between 16 and 36 hours.
7. Excreted throughout urine.

13. • They excreted within 24hrs.
• Can take up to 2 weeks to activate.
• The MAOis are well absorbed from the gastrointestinal
tract.
• MAOIs have prominent first-pass effects and tendency to
inhibit MAO in the gut, resulting in tyramine presssor
effects.
• Selegiline is N-demethylated and then hydroxylated.
• Tranylcypromine is ring hydroxylated and N-acetylated.
• Selegiline is available in both transdermal and sublingual
forms that bypass both gut and liver. These routes
decrease the risk of food interactions and provide
substantially incrased bioavailability.

14. • The TCAs tend to be well absorbed and have long half-
lives.
• Most are dosed once daily at night because of their
sedating effects.
• CAs undergo extensive metabolism via demethylation,
aromatic hydroxylation and glucuronide conjugation.
• Only about 5% of TCAs are excreted unchanged in the
urine.
• The TCAs are substrates of the CYP2D6 system.
• Generic polymorphism for CYP2D6 may result in low or
extensive metabolism of the TCAs.
• The secondary amine TCAs, including desipramine and
nortriptyline, lack active metabolites and have fairly linear
kinetics. These TCAs have a wide therapeutic window.

15. • Fluoxetine differs from other SSRIs. Fluoxetine is
metabolized to an active product norfluoxetine, which
may have plasma concentrations greater than those of
fluoxetine.
• The elimination half-life of norfluoxetine is three times
longer than fluoxetine: the longest half-life of all the
SSRIs.
• Fluoxetine has to be discontinued 4 weeks or longer
before an MAOIs can be administered: prevention of
serotonin syndrome.
• Fluoxetine and paroxetine are potent inhibitors of the
CYP2D6 isoenzyme, This contributes to potential drug
interactions.
• Fluvoxamine is an inhibitor of Cyp3A4.

16. • Venlafaxine is extensively metabolized in the liver via the
CYP2D6 isoenzyme to O-desmethyl
venlafaxine(desvenlafaxine).
• Both have similar half-lives of about 11 hours. Despite the
relatively short half-lives, both drugs are available in formulation
that allow once-daily dosing.
• Venlafaxine and desvenlafaxine have the lowest protein binding
of all antidepressants (27-30%).
• Desvenlafaxine is conjugated and does not undergo extensive
oxidative metabolism. At least 45% of desvenlafaxine is
excreted unchanged in the urine compared with 4-8% of
venlafaxine.
• Duloxetine is well absorbed and has a half-life of about 12
hours. It is dosed once daily.
• It is tightly bound to protein* (97%) and undergoes extensive
oxidative metabolism via CYP2D6 and CYP1A2,
• Hepatic impairment significantly alters duloxetine levels unlike
desvenlafaxine.

17. • Therapeutic uses:
• Classified criteria of Diagnostic and Statistical Manual
Mental Disorders (DSM-IV-TR):
• Major Depressive, Manic Depression (Bipolar),
Dysthymia.
• Situational depression, Post partum depression,
Sessional depression disorder.
• They can also be used to treat some other conditions:
• obsessive compulsive disorder (OCD)
• generalised anxiety disorder (GAD)
• post-traumatic stress disorder (PTSD)

18. • Mechanism of action of MAOls: MAO is a
mitochondrial enzyme found in nerve and other
tissues.
• Monoamine oxidase breaks down
norepinephrine, serotonin, and dopamine,
• when monoamine oxidase is inhibited,
norepinephrine, serotonin, and dopamine are
not broken down, increasing the concentration of
all three neurotransmitters in the brain.

19. • Use with other antidepressants
• Cerebrovascular disease
• Hypertension and Congestive Heart Failure.
• Liver disease.
• Drugs containing dopamine.
• Foods containing tyramine.

20. • Mechanism of action of Tricyclic
antidepressants (TCA):
• Inhibit the re-uptake of neurotransmitters.
• They inhibit serotonin, nor epinephrine or dopamine
• reuptake at pre synaptic nerve terminals thus lead to
increased concentration of these transmitters in the
synaptic cleft.
• Takes up to 4 weeks for all TCA antidepressants to
have an effect

21. • Precautions: with DM, seizure HX or thyroid
problems, kidney disease, elderly.
• Drug reactions with CNS depressants,
anticholinergics, MAOIs.
• Contraindications: narrow-angle glaucoma,
BPH, certain heart diseases.

22. MD PMDD OCD PD PTSD GAD SP BN
Sertraline (Zoloft) X X X X X X
Paroxetine (Paxil) X X X X X X X
Fluoxetine (Prozac) X X X X X
Citalopram (Celexa) X
Escitalopram (Lexapro) X X
Fluvoxamine (Luvox) X
Mechanism of Action : Blocks re-uptake of
serotonin thereby increasing serotonin in the
synapse
MD=major depressive , PMDD=peri-menstrual dysphoric disorder,
OCD=obsessive-compulsive disorder, PD = panic disorder, PTSD=post-traumatic
stress disorder, GAD=generalized anxiety disorder, SP=social phobia, BN =
bulimia nervosa,

23. MDD GAD PD SAD FM
Desvenlafaxine (Pristiq) X
Duloxetine (Cymbalta) X X X
Mirtazapine (Remeron) X
Venlafaxine (Effexor-XR) X X X X
MDD = Major depressive disorder, GAD = Generalized anxiety disorder,
PD = Panic disorder, SAD = Social anxiety disorder, FM = Fibromyalgia.
Mechanism of Action : by blocking the reuptake of
serotonin and norepinephrine back into the nerve cells that
released them, which increases the levels of active
neurotransmitters in the brain.

24. • Seizure disorders
• Suicidal ideation
• Hepatic disease (liver clearance can be decreased)
• Anorexia (SSRIs can decrease hunger)
• Concurrent therapy with other antidepressants,
benzodiazepines, beta blockers, methadone, etc.
• Children (about 1 out of 50 children become more
suicidal)
• Pregnancy (only paroxetine is classified in FDA
pregnancy risk category D).

25. • Gastrointestinal
• Anxiety/insomnia
• Flushing/night sweats
• Vivid dreams
• Weight change
• Sexual dysfunction

26. • A 40 years old female visited a psychiatric clinic with
symptoms of depression. She stated that she had daily
weeping spells, anxiety, restlessness, fatigue and low
mood. She reported that her sleeping was disturbed
because it took her several hours to fall asleep. She was
experiencing these symptoms from last three months.
• Past Medical History: Patient was suffering from
Hypertension from last 2 years and Hypercholesterolemia
from last 1 year.
• Past Medication History: She was using Inderal
(Propranolol) 40mg from last 2 years and crestor
(Atorvastatin) 10mg from last 1 year.
• General Examination Weight: 95 Kg Height: 5 foot 6 inches
BMI: 33.7 Kg/ Physical activity: daily work routine home.
• What's The Diagnosis ?? How would you treat the

27. • Diagnosis of Depression Three key symptoms
(low mood, loss of interest, low energy) of
depression were present from last three months
• Patient had three key symptoms (loss of energy,
low mood, and loss of interest) according to
diagnostic criteria; In this case patient was
suffering from fatigue, restlessness, weeping
spells, decreased sleep, numbness and lack of
concentration,
• Based on the symptoms and patients condition
she had major depression.

28. • Psychotherapy should be given to patient for example
cognitive behavior therapy (CBT) and interpersonal
therapy. Patient should be encouraged to try relaxation
techniques and breathing exercises. Talk with family
members and friends and explain how they can be
helpful.
• Regular exercise and walk can reduce symptoms of
depression and also helpful to reduce body weight.
• Dietary modifications are also necessary so choose food
rich in magnesium and zinc content, proteinrich foods,
selenium rich foods and increase dietary intake of vitamin
D, vitamin E and vitamin B6. Psychotherapy should be
given to patient so that patient values herself.
• Suggest patient to do something creative or learn a new
skill

29. • We can use Medications use to treat depression are
which includes :
• Selective serotonin reuptake inhibitors such as
citalopram, escitalopram, fluoxetine, Paroxetine etc,
• Serotonin nor adrenaline reuptake inhibitors such as
desvenlafaxine, venlafaxine duloxetine etc,
• Tricyclic antidepressants such as amitriptyline,
nortriptyline, clomipramine, imipramine etc,
Monoamine oxidase inhibitor such as phenelzine,
selegiline etc.
• Based on the patients history profile and to prevent
interaction best drug is Tricyclic antidepressants.