Transcript Antidepressants

The Pharmacology of
Antidepressants
Tracy Womble, Ph.D
Florida A&M University, College of Pharmacy and
Pharmaceutical Sciences
Dept. Of Neuroscience
Objectives
 What is depression
 Pathophysiology of Depression
 History
 Classes
 Pharmacology
 Therapeutic use
 Mechanism of action
 pharmacokinetics
 Adverse effects
 toxicity
Depression
 Depression is defined as intense feelings of
sadness, mental slowing, hoplesness, despair,
pessimistic worry, agitation, self-deprecation
and inability to experience pleasure during
usual activities
What is depression?
 Neurological disorder
 Prolonged depression of mood
and impairment of function
 Causes include genetic
predisposition, grief following the
death of a loved one, abuse, major
life changes, serious illness,
personal disputes, and substance
abuse
 Complex illness with many
contributing factors
 Exact biological causes are not yet
fully understood
Types of Depression
 Major Depressive Disorder
 Symptoms interfere with ability to function normally
 10% of people in the US suffer at any one time
 2x more women are diagnosed than men
 Chronic (Dysthymia)
 Less severe, but symptoms linger for longer
 Seasonal Affective Disorder (SAD)
 Psychotic
 Postpartum
Manic Depression
 Mania is characterized by opposing behavior to
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depression; enthusiasim, rapid thought and
speech patterns, extreme self-confidence and
impaired judgement, and elevated “high” mood.
Talkative, go on-and-on about the things they
will do.
Increased self-esteem.
Auditory hallucinations.
Decrease need to sleep.
indiscrete
SuperME
Pathophysiology of
Depression
 Biogenic amine Hypothesis
 Neurotrophic Hypothesis
 Neuroendocrine Factors
Biogenic Amine Hypothesis
 Depression and mania are due to an
alteration in neuronal and synaptic
catecholamine concentration at
adrenergic receptor sites in the brain
 Depression: deficiency of biogenic
amines ( NE, 5-HT)
 Mania: excess amines (NE, 5-HT)
Neurotrophic Hypothesis
 Loss of neurotrophic support or NGF’s
 BDNF (brain-derived neurotrophic factor)
 regulation of neural plasticity, resilience and
neurogenesis.
 Effective therapies increase neurogenesis and
synaptic connectivity in cortical areas
(hypothalamus)
 Activation of tyrosine kinase receptor B in
neurons and glia.
Neuroendocrine Factors
 Abnormalities in HPA axis – hormonal
abnormalities
 Elevated cortisol levels
 Clinical hypothyroidism
 Sex steroids
 Estrogen deficiency (postpartum and
postmenopausal)
 Testosterone deficiency
History of Antidepressants
 Introduction of Reserpine in 1950’s
 Used for hypertension and schizophrenia
 Induced depression in these pts.
 MOA – inhibit storage of NE and 5-HT
 Reasoned that depression is associated with
decrease in amine dependent synaptic
transmission
Clinical Indications of
Antidepressants
 Depression
 Anxiety Disorders
 Pain Disorders
 Premenstrual Dysmoric Disorder
 Smoking Cessation
 Eating Disorders
 Off label usage – urinary stress incontinence,
sexual disorders (premature ejaculation)
Antidepressant (Thymoleptic)
Drugs
 Tricyclic antidepressants (TCA’s)
 Monoamine oxidase inhibitors (MAOIs)
 Newer-generation antidepressants
 Selective serotonin reuptake inhibitors
(SSRIs)
 Selective norepinephrine reuptake
inhibitors (SNRIs)
 5-HT Antagonists
Tricyclic Antidepressants
First-Generation
 mostly replaced as first-line
antidepressant drugs by SSRIs in 80’s
and 90’s.
 Considered second-line
 patients who fail with SSRIs or other
newer-generation antidepressants
 As adjunct therapy with newer
antidepressants
Common TCA’s
 Secondary Amine
 Tertiary Amine
 Amoxapine
 Imipramine*
 Nortiptyline
 Amitriptyline*
 Desipramine
 Clomipramine
 Protriptyline
 Doxepin
 Trimipramine
Tricyclic Antidepressants
TCA’s)
 Characteristic three-ring structure
 Block NE and 5-HT reuptake
 Can not be used with MAOI’s
 No food interactions
 Antagonize 5-HT, α-adrenergic, H1 and
muscarinic receptors
Mechanism of Action of TCA’s
 Block reuptake of neurotransmitters, (NE,
5-HT) causing accumulation at the nerve
endings
 increasing NE and 5-HT will correct the
abnormally low levels that lead to
depression
Tricyclic Antidepressants
 Imipramine
 strong anticholinergic action
 strong NE and 5-HT reuptake inhibitor
 Most likely to cause orthostatic hypotension
 Desipramine
 Metabolite of imipramine
 Less anticholinergic, more potent, more selective
for NET than imipramine
 Nortriptyline
 Least likely to cause orthostatic hypotension
Indications for TCA’s
 Depression
 Childhood enuresis (imipramine)
 Obsessive-compulsive disorders
(clomipramine)
 Adjunctive analgesics for chronic pain
conditions, such as trigeminal neuralgia,
neuropathy
TCA’s (cont’)
 Mode of action – inhibit NE and 5HT reuptake into
presynaptic nerve terminal
 Actions – elevate mood
 Therapeutic uses – severe depression, some panic disorders.
 Pharmacokinetics – well absorbed PO, lipophilic, penetrate
CNS
 Fate – metab. By hepatic microsomal system
Adverse affects of TCA’s
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Antimuscarinic
Cardiovascular
Orthostatic hypotension
Sedation
Precaution
Toxicity
Drugs used for toxicity
Drug Effects
 Blockade of norepinephrine reuptake
 Antidepressant*, tremors, tachycardia
 Blockade of 5-HT reuptake
 Antidepressant*, nausea, headache,
anxiety, sexual dysfunction
*Desired therapeutic effects
Overdose of TCA’s
 Brief excitement and restlessness,
myoclonus, tonic-clonic seizures, coma,
depressed respiration, hypoxia,
hypothermia, hypotension, mydriasis,
urinary retention
 Cardiac toxicity, hypotension
Overdose of TCA’s
 No specific antidote
 Decrease drug absorption with activated
charcoal
 Speed elimination by alkalinizing urine
 Sodium Bicarbonate
 Manage seizures and dysrhythmias
 Lidocaine, propranolol, phenytoin
 Provide basic life support
Overdose of TCA’s
 Lethal—70% to 80% die before reaching
the hospital
 CNS and cardiovascular systems are
mainly affected
 Death results from seizures or
dysrhythmias
Antidepressant (Thymoleptic)
Drugs
 Tricyclic antidepressants (TCA’s)
 Monoamine oxidase inhibitors (MAOIs)
 Newer-generation antidepressants
 Selective serotonin reuptake inhibitors
(SSRIs)
 Selective norepinephrine reuptake
inhibitors (SNRIs)
 5-HT Antagonists
Monoamine Oxidase Inhibitors
 Phenelzine
 Isocarboxazid
 Tranylcypromine
 Selegeline Patch
Monoamine Oxidase Inhibitors
Monoamine Oxidase Inhibitors
 Mitochondrial enzyme, (MAO) regulates
metabolic degradation
 Found in nerve terminal, intestinal mucosa
(gut), liver, etc.
 MAOI irreversibly/reversibly inactivate MAO
 Allow NT to escape degradation
Monoamine Oxidase Inhibitors
 Irreversible MAO inhibitors (Hydrazides)
 Phenelzine, Isocarboxazid
 Reversible MAO inhibitors (non-hydrazide)
 Tranylcypromine
Monoamine Oxidase Inhibitors
 2 forms of monoamine oxidase
 MAO-A - present in both DA and NE neurons
and found mostly in brain, gut, placenta and
liver. (NE, 5-HT)
 Mocolobemide, Clorgyline
 MAO-B - present mainly in serotonergic and
histaminergic neurons, distributed in brain,
liver and platelets. (tyramine, DA)
 Deprenyl, Seligiline
MAOI classification
 Classified according to specificity for MAO-A or MAO-B
and whether they are reversible or irreversible.
 Non-selective
 irreversible- phelnelzine, trancypromine
 Selective
 MAO-A reversible – moclobemide, displaced by
tyramine
 MAO-B irreversible – selegiline (low dose) used in
PD, high dose becomes non-selective
Monoamine Oxidase Inhibitors (MAOI’s)
 Considered second-line treatment for
depression not responsive to TCA’s
 Disadvantage: potential to cause
hypertensive crisis when taken with tyramine
 Use is limited due to dietary restrictions
 Onset time and time to wear off – 2 wks
Wine and Cheese reaction
 Fatal interaction w/ tyramine containing
foods (fermented foods)
 MAO-A breakdown tyramine in body –
MAOI’s cause circulating NE – induces
hypertensive crisis – can lead to
intracranial bleeding, organ damage
Monoamine Oxidase Inhibitors
 Prolong action of drugs metabolized by MAO and
hepatic metabolic P450
 Contraindicated in pts. Using TCA’s
 Drug to drug interaction - use of SSRI’s cause life-
threatening serotonin syndrome.
 Drug to food interaction - hypertensive crisis when
taken with tyramine
Monoamine Oxidase Inhibitors
 Mechanism of action
 inactivate MAO, result in increased stores of 5-
HT, NE and DA.
 Brain and peripheral (high drug-drug, drug-food
interaction)
 Therapeutic use
 Depression not responsive to TCA’s
 Used in phobic states
 Very effective in atypical depression
Monoamine Oxidase Inhibitors
 Pharmacokinetics
 well absorbed p.o.
 antidepressant effect (2-4 weeks)
 wash out period(2 weeks) required when
switching antidepressants
 metabolized, excreted rapidly in urine
Monoamine Oxidase Inhibitors
 Adverse Effects
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drowsiness
orthostatic hypotension
blurred vision
dry mouth
dysuria
constipation
contraindicated w/ SSRI’s – serotonin
syndrome
MAOI Toxicity
 Toxic reactions may occur in hrs, despite
therapeutic response delay
 Agitation, hallucinations, hyperreflexia,
hyperpyrexa and convulsions
 Both hypertension and hypotension
MAOI Toxicity
 Symptoms appear 12 hours after
ingestion
 Tachycardia, circulatory collapse,
seizures, coma
 Treatment: protect brain and heart,
eliminate toxin
 Gastric lavage
 Urine acidification
 Hemodialysis
Antidepressant (Thymoleptic)
Drugs
 Tricyclic antidepressants (TCA’s)
 Monoamine oxidase inhibitors (MAOIs)
 Newer-generation antidepressants
 Selective serotonin reuptake inhibitors
(SSRIs)
 Selective norepinephrine reuptake
inhibitors (SNRIs)
 5-HT Antagonists
Selective Serotonin Reuptake
Inhibitors (SSRI’s)
 Mainly replaced TCA’s and MAOIs as drug
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of choice for depression
Do not affect reuptake of NE
Decreased incidence of anticholinergic
and adrenergic action of TCA’s.
All admin. PO
May interfere with P450 (CYP2Ds)
metabolism of other drugs (enzymes
responsible for metabolism of TCA’s)
Selective Serotonin Reuptake
Inhibitors
 Fluoxetine (Prozac)
 Citalopram (Celexa)
 Fluvoxamine (Luvox)
 Paroxetine (Paxil)
 Sertraline (Zoloft)
Selective Serotonin Reuptake
Inhibitors SSRIs
 Selectively inhibit serotonin reuptake
 Little or no effect on norepinephrine or
dopamine reuptake
 Result in increased serotonin
concentrations at nerve endings
 Advantage over TCA’s and MAOIs: little
or no effect on cardiovascular system,
and no CNS stimulation
Selective Serotonin Reuptake
Inhibitors (SSRI’s)
 Most widely prescribed drugs for
depression, OCD,GAD, PDD, bulimia
 They have few side effects and seem to
be rather safe.
 Adverse effects include: nausea,
decreased libido,anorexia, anxiety,
insomnia, tremors, sleepiness, sweating
 Low threat for overdose. Suicide may be
considered in severe depression.
SSRI’s indications
 Fluoxetine (Prozac) - mental depression,
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OCD, Bulemia
Citalopram (Celexa) – mental depression
Fluvoxamine (Luvox) - OCD
Paroxetine (Paxil) – mental depression,
panic disorder, OCD
Sertraline (Zoloft) - mental depression
Antidepressant (Thymoleptic)
Drugs
 Tricyclic antidepressants (TCA’s)
 Monoamine oxidase inhibitors (MAOIs)
 Newer-generation antidepressants
 Selective serotonin reuptake inhibitors
(SSRIs)
 Selective norepinephrine reuptake
inhibitors (SNRIs)
 5-HT Antagonists
Serotonin-Norepinephrine Reuptake
Inhibitors (SNRI’s)
 2 classes of antidepressants act as combined
NE and 5-HT reuptake inhibitors
 SNRI’s and TCA’s
 SNRI’s
 Venlafaxine - weak inhibitor of NET
 Duloxetine – inhibit both NET and SERT
Serotonin-Norepinephrine
Reuptake Inhibitors (SNRI’s)
 Additional indications
 Major depression, pain disorders, generalized
anxiety, urinary incontinence and vasomotor
symptoms of menopause
 Bind SERT and NET transporters
 Differ from TCA’s - no α-adrenergic blocking,
and anticholinergic effects
Pharmacokinetics of SNRI’s
 Venlafaxine
 extensively metabolized in the liver to Desvenlafaxine
 Both have the lowest protein binding of all
antidepressants
 Desvenlafaxine
 conjugated, does not undergo extensive oxidative metabolism
 about 45% is excreted unchanged in the urine
 Duloxetine
 tightly bound to protein (97%)
 Undergoes extensive oxidative metabolism
 hepatic impairment alters levels, unlike
Desvenlafaxine
Antidepressant (Thymoleptic)
Drugs
 Tricyclic antidepressants (TCA’s)
 Monoamine oxidase inhibitors (MAOIs)
 Newer-generation antidepressants
 Selective serotonin reuptake inhibitors (SSRIs)
 Selective norepinephrine reuptake inhibitors
(SNRIs)
 Tetracyclic and Unicyclic
 5-HT1
and 2 Antagonists
5-HT1 Antagonists
 Trazodone and Nefazodone
 Mechanism of action
 Therapeutic effect related to ability to block
5-HT1
 Weak but selective inhibitors of 5-HT
reuptake
 Little or no effect on NE or DA reuptake
 Increased 5-HT concentrations
 Both are sedating (antihistimine effect)
 Trazodone associated with causing priapism
5-HT2 Antagonists
 Mirtazapine
 Mechanism of action
 Antagonist of 5-HT2/3 – inc. release 5-HT
 Antagonist of α2 receptors-inc. release NE, 5-HT
 Side effects
 sedative due to antihistamine activity
 effective in depressed having difficulty sleeping
 no antimuscarinic (TCA)
 does not interfere w/ sexual function (SSRIs)
 increased appetite, weight gain
Tetracyclic, Unicyclic
 Bupropion
 Mechanism of action – poorly understood
 Release of catocholamines – NE, DA
 No effect on 5-HT
 Decreases cravings for nicotine in tobacco
users
 Side effects – dry mouth, sweating, tremor,
seizure at high dose
 Lower seizure threshold
Tetracyclic, Unicyclic (cont)
 Amoxapne and maprotiline
 Mechanism of action – potent NET inhibitors
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and less potent SERT inhibitors
Side effects – both possess anticholinergic
properties
inhibits D2 receptor
Possess antipsychotic properties
Lower seizure threshold
Conclusion
 Main similarities and differences, which explain
why SSRIs are more commonly prescribed than
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TCAs in the treatment for depression:
SSRIs and TCAs have similar efficacy for the
treatment of depression
SSRIs have fewer anticholinergic and
cardiovascular side effects
TCA have fewer sexual and gastrointestinal side
effects
SSRIs are better tolerated by patients
SSRIs are safer in overdose than TCAs