VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
1
Presented by: Under guidence of: D.Gnana Bhaskar K.V.Santhosh kumar 12AB1R0015 (assistant professor) Dept. of medicinal chemistryVIGNAN PHARMACY
COLLEGE,VADLAMUDI,522213,GUNTUR.(DT),APAFFILATED TO JNTUKAPPROVED BY AICTE
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
2
A CLASS OF PSYCHOTROPICS
ANTIDEPRESSENTS&ANXIOLYTICS
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
3
OVERALL CONTENT VIEW
DEPRESSION
&ANXIETY
1. DEFINITION2.SYMPTOMS3.PATHOPHYSIOLOGY4.TYPES5.TREATMENT
OF
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
4
:DEFINITION:(3)
In Depressed states one who feels exhausted, wrothless, hopeless that immobilizes any kind of people neither poor or rich.it also interfers with the persn’s ability to do daily activities.It mostly comman1 in 4women&1in 10 men
:SYMPTOMS:
sadness Empty moods
Sucidal thoughts
Poor self esteem
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
5
OTHER SYMPTOMS INCLUDE• persistently sad, anxious, or empty moods
• loss of pleasure in usual activities (anhedonia)
• feelings of helplessness, guilt, or worthlessness
• crying, hopelessness, or persistent pessimism
• fatigue or decreased energy
• loss of memory, concentration, or decision-making capability
• restlessness, irritability
• sleep disturbances
• change in appetite or weight
• physical symptoms that defy diagnosis and do not respond to treatment (especially pain and gastrointestinal complaints)
• thoughts of suicide or death, or suicide attempts
• poor self-image or self-esteem (as illustrated, for example, by verbal self-reproach)
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
6
PATHOPHYSIOLOGY(3)
• Different theories are there to explain about various causes of the depression During the late 1960’s a Swiss psychiatrist, proposed that “it is important to select a right anti depressant for the right patient ”. because vast no of classes are available it should properly selected. For that he differentiated TCAs based on whether they possessed ability to sedate or stimulte.
• Eg :sedate :triimpramine, stimulate : nortriptyline1. Mono amine hypothesis2. Receptor sensitivity hypothesis3. Changes in HPA4. Balance between neurotransmitters
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
7
MONO AMINE HYPOTHESIS (NEUROCHEMICAL THEORY)
ANTIDEPRESSENTS
ACT TO CORRECT THOSE DEFFICIENCIES
Deffiiency of 5HT/NE amines likeSERITONIN NOREPINEPHRINE
The mono amine hypothesis proposes thatDepression results from
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
8
CATECHOL AMINE HYPOTHESIS
Decreased concentration ofNeurotransmitters at the synaptic cleft
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
9
RECEPTOR SENSITIVITY HYPOTHESIS• It proposes that it is not the matter involved in the level of
norepinephrine & seritonin in the synapse. the matter involved is sensitivity of post synaptic receptors to the neurotransmitters.
• This is important theory that helps to know about the long delay between administration Of anti depressant drug &its clinical response.
• To desensitize & to increase the no of receptors presence :chronic administration of antidepressant drugs in an gradual increasing concentration there by due to their actions neurotransmitters concentrations will increase in synaptic cleft.it causes post synaptic activity aswell as down regulation of neurotransmitters .
• Supersensitivity and up-regulation of post-synaptic receptors leads to depression
• Suicidal and depressed patients have increased 5HT-α2 receptors
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
10
No of receptors involving
Receptorssensitivity
Optimum good
activity
Not only levels of
neurotransmiters
&
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
11
CHANGES IN HYPO PITUTORY ADRENAL AXIS(HPA)• It suggests that changes in HPA axis can influence the levels of NE, 5HT, released by
nerve cells in the brain there by the activity also get influenced.
NE,5HT,CORTISOL, HYDROCORTISOL
ADH
Enoorphin RF
Stress events
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
12
BALANCE BETWEEN NOR EPINEPHRINE• This theory emphasizing that importance of balance between 5HT&NE in regulating
absolute levels of these neurotransmitters at the synaptic cleft.
• Ex. : If 5HT levels are too low the balanced NE system is lost there by disorders can be happen .
• COGNITIVE SLOWING• HYPER SOMNIA
• DECREASED CONCENTRATION
• ANXIETY• PANIC• PHOBIA• OCD
5HT NE
DEPRESSED
MOOD
DOPAMINE
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
13
TYPES OF DEPRESSION
DEPRESSION
BIPOLAR DISORDER
BIPOLAR1
BIPOLAR2MAJOR
DEPRESSIVE DISORDER
CHRONIC DEPRESSION DYSTHMIA
SEASANOL DEPRESSION
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
14
MAJOR DEPRESSIVE DISORDER(3)
defn.
• Also known as unipolar depression• It changes the brain function where those who persistently think they
are less self esteem themselves among the world
about
• It may also get inheritated for further generations• It lasts for 2 years or more
Psychotherapymedication
• The first line treatment drug is SSRIs• They termed as first drug among 50 drugs prescribed
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
15
CHRONIC ANXIETY(DYSTHIMIA)
Characterized by chronic symptoms
Low self esteem
Anti depressantspsychotherapy
• One from functioning well
• Feeling less value about them selvs
• Just pass through situation without involvement
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
16
BIPOLAR DISORDER
Bipolar1Manichighs
Bipolar2Hypomanic
lows
This is generally because of lows and highs abnormalities of neurotransmitters levels which Causes both depression mania.
This is because of problematic disruption of signaling pathways in hypothalmic pitutory regionGeneral drugs used Lithium, Carbamazepine,Topiramide
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
17
OTHER TYPES OF DEPRESSIVE DISORDERS
occurance
• This disorder involves symptoms of depression during fall&winter season
how
• It is an adjustment disorder with depressed mood • When a person lost his job when the situation location repeat he will
get this sort of depression
additionals.
• Stress at home, work,• It may persists for 6months.
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
18
TREATMENT(1)(7)(4)(5)
Treatment
psychotherapy
medication
SSRI
MAOIs
TCAs/NSRIs
Electro convulsent therapy SNRIs
AAD/DNRIs
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
19
MEDICATION• Antidepressants:
• SSRIs : fluoxetine ,sertraline, citalopram, escitalopram, paroxetine.
• SNRIs : duloxetine, venalfaxine.
• AAD/DNRI : Bupropion, mitrazepine, nefazodone, trazodone.
• TCAs/NSRIs:Amitryptiline,cloimipramine,doxepine,nortryptyline,protryptyline
• Mood stabilizers
PSYCHOTHERAPY(7)COGNITIVEMODELBEHAVIOURAL ACTIVATIONINTER PERSANOL MODEL
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
20
SELECTIVE SEROTONIN REUPTAKE INHIBITOR -SSRIMechanism of actionMost commonly prescribed classCurrent drugsSide effects
Mechanism of action
• They are having 300-3000-fold grater activity towards seritonin transporter rather than nor epinphrine transporter
• They block the reuptake of serotonin from reuptaking, leading to increased concn of serotonin in the synaptic cleft.
• They take at least 2 weeks toproduce significant effects.
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
21
Exact mechanism remains uncertain Ser-438 residue in the human serotonin
transporter (hSERT) appears to be a determining factor in SSRI potency
Antidepressants interact directly with hSERT
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
22
SSRIS IN THE MARKET• citalopram (Celexa)
• dapoxetine (Priligy)
• escitalopram (Lexapro)
• fluoxetine (Prozac)
• fluvoxamine (Luvox)
• paroxetine (Paxil)
• sertraline (Zoloft)
• zimelidine (Zelmid) (discontinued)
• indalpine (Upstene) (discontinued)
fluoxetine
sertraline
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
23
SYNTHESIS OF FLUOXETINE
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
24
SIDE EFFECTS OF SSRIS• Anhedonia• Apathy• Nausea/vomiting• Drowsiness or somnolence• Headache• Bruxism (involuntarily grinding of the teeth)• Extremely vivid and strange dreams• Dizziness• Fatigue• Changes in sexual behavior• Suicidal thoughtsMany disappear within 4 weeks (adaption phase)• Side effects more manageable compared to MAOIs and TCAs• Sexual side effects are common• SSRI cessation syndrome
• Brain zaps• Sexual dysfunction
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
25
THERAPEUTIC USES:Primary indication for depressionThey effective as TCAsOther psychotic disorders also respond for this classThey are also used for GAD, OCD.
PHARMACOKINETICS:All are well absorbed through oral routePeak concentration reach with in 8hoursHalf life16 hr
Caution:Fluoxetine sertraline are potent inhibitors of P450 enzyme system which is responsible for the elimination of TCAs Neuroleptics.Hence they effect the metabolism of other drugs
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
26
TRI CYCLIC ANTI DEPRESSANTS-TCAHistory
ImipramineCurrent DrugsMechanism of ActionSide Effects
TCAs inhibit serotonin, norepinephrine, and dopamine transporters, slowing reuptake
TCAs also allow for the downregulation of post-synaptic receptors by blocking the receptors.
All TCAs and SSRIs contain an essential amino group that appears to interact with Asp-98 in hSERT
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
27
ACTIONS• TCAs elevate mood ,physical activity,improve mental alternesss
• Reduce morbid pre occupation in 50TO 70% of individuals.
• Treat moderate to severe major depression,some panic attacks also respond to this.
PHARMACOKINETICS
• Well absorbed orally because of its lipophilic nature• They widely distributed into CNS.• Dose adjustment done by patient response and plasma levels
Precaution
• Caution in manic depressive patients• 5-6doses of imipramine a lethal dose
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
28
TCA ON MARKET& NEWER ONES• Amitriptyline
• Desipramine (Norpramin)
• Doxepin (Sinequan)
• Imipramine (Tofranil, Tofranil-PM) bed wetting in children
• Nortriptyline (Pamelor) migraine
• Protriptyline (Vivactil)
• Trimipramine (Surmontil)
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
29
SYNTHESIS OF DOXEPIN
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
30
SIDE EFFECT& ADVERSE REACTIONS• Muscarinic M1 receptor antagonism - anticholinergic effects including dry mouth,
blurred vision, constipation, urinary retention and impotence
• Histamine H1 receptor antagonism - sedation and weight gain
• Adrenergic α receptor antagonism - postural hypotension
• Direct membrane effects - reduced seizure threshold, arrhythmia
• Serotonin 5-HT2 receptor antagonism - weight gain (and reduced anxiety )
• Nonselectivity results in greater side effects
• TCAs can also lead to cardiotoxicity
• Increased LDH leakage
• Slow cardiac conduction
• High potency can lead to mania
• Contraindicated with persons with bipolar disorder or manic depression
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
31
MAO INHIBITORS• MAO catalyze deamination of intracellular monoamines
• MAO-A oxidizes epinephrine, norepinephrine, serotonin
• MAO-B oxidizes phenylethylamine
• Both oxidize dopamine nonpreferentially
• MAO transporters reuptake extracellular monoamine
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
32
• They are mitochondrial enzymes pesent in gut&liver tissues of neurons.• They act as saftey valves.• They oxidatively de aminate exessive neurotransmitters present at synaptoc cleft.• Mao inhibitors irreversibly bind to this enzyme and maintain the concentrtion normal.
amines
metabolise
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
33
CURRENT DRUGS
• MAO Inhibitors (nonselective)
• Phenelzine (Nardil)
• Tranylcypromine (Parnate)
• Isocarboxazid (Marplan)
• MAO-B Inhibitors (selective for MAO-B)
• Selegiline (Emsam)
isoniazidiproniazid
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
34
MECHANISM OF ACTION
• MAO contains a cysteinyl-linked flavin• MAOIs covalently bind to N-5 of the flavin residue of the enzyme
• Most MAO inhibitors forms an irreveresible complex with the enzyme.• This results in increase in stores of NE,5HT&dopamine• They not only bind MAO in brain but also in liver &gut• It shows that they are highly prone to drug-food interactions
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
35
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
36
SIDE EFFECTS• Side effects have put MAOIs in the second or third line of defense despite superior
efficacy
• MAO-A inhibitors interfere with breakdown of tyramine
• High tyramine levels cause hypertensive crisis (the “cheese effect”)
• Can be controlled with restricted diet
• MAOIs interact with certain drugs
• Serotonin syndrome (muscle rigidity, fever, seizures)
• Pain medications and SSRIs must be avoided
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
37
SERITONIN NOR EPINEPHRINR RE UPTAKE INHIBITORS- SNRI• It inhibit the re uptake of both NE&5HT
• They are ineffective in relieving pains
• Inhibitor of seritonin mostly then NE&DA
• Side effect are nausea sedation,insomnia.
venalfaxine
• It is also same inhibition effect
• Not prescribed in renal&hepatic failure patients.
duloxetine
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
38
ATYPICAL ANTIDEPRESSENTS• They are mixed group of agents not much effective than others but side
effective profile is different.
• Bupropion: weak reuptaking inhibitor.it have short half life.used for cessation of smoking
• Mitrazapine :enhances the transmission of neurotransmitters.it have sedative property.
• Nefazodone,trazodone:they act by blocking post synaptic autoreceptors.
• nefazodone:pripism trazodone:hepatotoxicity
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
39
PRIORITIES
• Based on:acceptance
SSRITCA
MAO
BASED ON SIDE EFFECTS:
SSRIMAO
TCA
BASED ON DURATION OF ACTION
ssri
mao
tca
ANXIETY-ANNXIOLYTICS
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
41
DEFINITION• It is an adaptive response that prepares a person appropriately to the threatning situation
• Where its over response causes a maladaptive response which is inappropriate to the situation caused by psychological distress
• It interferes with the persons ability to do daily activities morever viscral oegan disfunction
difference
Anxiety required to face the threatning
Over responsive to the situation
Chronic: visceral organ disfunction
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
42
SYMPTOMS
Common Emotional Symptoms of anxiety
• irrational and excessive fear and worry• Irritability • Restlessness • Trouble concentrating • Feeling tense
Common Physical Symptoms of Anxiety
SweatingTachycardia
Stomach upsetShortness of breath
Frequent urination or diarrhea Sleep disturbances (Insomnia)
Fatigue
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
43
PATHOPHYSIOLOGYo Neurotransmitters like GABA, noradrenaline, serotonin abnormalities – anxiety.
o Amygdala, temporal lobe, hippocampus and hypothalamus - involved in anxeity.
1. Nor-adrenaline theory2. Serotonin theory3. GABA receptor theory
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
44
GABA RECEPTOR THEORY
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
45
SERITONIN THEORY
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
46
NOR ADRENALINE THEORY
• In response to threat or fearful situations, the Locus cerulus serves as an alarm center, activating NE release and stimulating the sympathetic and parasympathetic nervous systems.
• In response to threat or fearful situations, the Locus cerulus serves as an alarm center, activating NE release and stimulating the sympathetic and parasympathetic nervous systems.
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
47
TYPES OF ANXIETY
ANXIETY
GAD SAD OCD PHOBIAS
ACUTE ANXIETYPANIC DISORDER
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
48
GAD:GENARALIZED ANXIETY• It is chronic and fills a person’s day with exaggerated worry and tension, even though there is little or
nothing to provoke it, associated with worrying excessively about health, money, family, school or work. Concentration and sleep problems are also common.
• COGNITIVE SYMPTOMS
• Excessive Anxiety
• Worries that are difficult to control
• Poor concentration or mind going blank
•
• PHYSICAL SYMPTOMS
• Sleep disturbance
• Irritability
• Restlessness
•
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
49
PANIC DISORDER• Unexpected panic attacks associated with physiological symptoms of autonomic nervous system without any
warning or apparent reason.
• They can’t predict when an attack will occur, and many develop intense anxiety between episodes, worrying when and where the next one will occur.
• Symptoms include Attacks usually last no more than about 10 minutes.
• Symptoms
• Intensive fear
• Phobias
• Dizziness
• Racing heart
• Perspiring
• Shortness of breath
• Tingling hands
• Fear of dying or going crazy
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
50
SOCIAL ANXIETY DISORDER• Characterized by an intense, irrational, persistant fear of situations, usually social or
performance situations, where risk of embarrassment is present. It can disrupt normal life, interfering with school, work or social relationships.
• Physical symptoms often accompany the anxious feelings.
• Blushing
• Profuse sweating
• Trembling
• Nausea
• Shortness of breath
• Racing heart
• Difficulty talking
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
51
POST TRAUMATIC STRESS DISORDER• Develops subsequent to experiencing or witnessing a traumatic event
• Symptoms (lasting at least 4-6 weeks )
Flash-backs
Disturbing memories
Nightmares
Intrusive images
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
52
PHOBIAS-SPECIFIC DISORDERS Is an intense fear of something that posses little or no actual danger of a object
or situation. Some of the more common specific phobias are Centered around closed-in places Heights Escalators Tunnels Water Flying dogs Injuries involving blood Injection Insects
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
53
OBSESSIVE COMPULSIVE DISORDERS
Obsessions (recurrent, intrusive and generally distressing thoughts, images or feelings).
Compulsions(repetitive,ritualistic behaviors aimed to alleviate obsessions)
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
54
TRETMENT ANXIOLYTICS+ANTIDEPRESSANTS+OTHERS
• Benzodiazepines ( BDZ ).
• 5HT1A agonists.
• 5HT reuptake inhibitors.
• Antidepressants
• beta-adrenergic blockers
• MAO inhibitors
•
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
55
BENZODIAZEPINES• Short acting: (3-5 hours): triazolam
• - Intermediate: (6-24 hours)
• Alprazolam
• Lorazepam
• Oxazepam
• Estazolam
• Temazepam
•
• - Long acting: ( 24-72 hours)
• Clonazepam
• Chlordiazepoxide
• Diazepam
• Flurazepam
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
56
MECHANISM OF ACTIONMechanism of Action Benzodiazepines act by binding to BZ receptors in the brain enhance GABA action on brain chloride channels opening chloride influx to the cell hyper- polarization inhibition of brain.
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
57
SYNTHESIS OF SOME BENZODIAZEPINES
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
58
PHRMACOLOGICAL ACTIONS•Anxiolytic action.
• Depression of cognitive and psychomotor function
• Sedative & hypnotic actions
• Anterograde amnesia.
• Minimal depressant effects on
Cardiovascular system
• Respiratory system
• Some have anticonvulsant effect:
• clonazepam, diazepam
• Treatment of epilepsy
• Diazepam – Lorazepam
• In anesthesia
• Preanesthetic medication (diazepam).
• Induction of anesthesia (Midazolam, IV)
Therapeutic Uses
Anxiety disorders: short term relief of severe anxiety
General anxiety disorderObsessive compulsive disorder
Panic attack with depression Alprazolam (antidepressant effect)
Sleep disorders (Insomnia).
Triazolam, Lorazepam, Flurazepam
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
59
ADR
• Adverse Effects
• Ataxia (motor incoordination)• Cognitive impairment.• Hangover: (drowsiness, confusion) • Tolerance & dependence• Risk of withdrawal symptoms• Rebound Insomnia, anorexia, anxiety, agitation, tremors and
convulsion.
ExamplesCNS
depressants
Alcohol & Antihistaminics
of effect of benzodiazepines
Cytochrome P450 (CYT P450) inhibitors
Cimetidine & Erythromycin
t ½ of benzodiazepines
CYT P450
inducers
Phenytoin & Rifampicin
t 1/2 of benzodiazepines
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
60
BARBITURATES
It was first isolated1864 by adolf Von bayerIt shows diverse effects from small change to obvious effects like sedation,general anesthesia
MechanismThey bind o allosteric site of GABA a receptors makes it easier to openAltering structure of ion channelmaking it easier to open
Short acting:thipental secobarbitrlIntermediate:amobarbital,hexobarbitalLong acting:phenobarbital,mephobarbital
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
61
SYNTHESIS OF PHENO BARBITAL
Therpeutic uses:AnesthesiaAnti cconvulsant
Adr:Droowsiness impaired concentrationTirednessThey induce p450 so sow half life
VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.
62
TCATricyclic AntidepressantsDoxepin- imipramine• act by reducing uptake of 5HT & NA.• Used for anxiety especially associated with depression.• Effective for panic attacks.• Delayed onset of action (weeks).• dry mouth, postural hypotension, sexual dysfunction, weight gain.
)
Fluoxetine acts by blocking uptake of 5HT
Orally Delayed onset of action (weeks).
Used for panic disorder – OCD depression- Generalized anxiety disorders - phobia.
Side Effects:Weight gain, sexual dysfunction, dry mouth
ssri
MONOAMINE OXIDASE INHIBITORSPhenelzine
Acts by blocking the action of MAO enzymes.Used for panic attacks and phobia.Require dietary restrictionAvoid wine, beer, fermented foods as old cheese that contain tyramine.Side effectsDry mouth, constipation, diarrhea, restlessness, dizziness.
mao