Pharmocology and Therapeutics of Antidepressant Agents Flashcards
Monoamine Hypothesis
–Depression: due to deficiency in NE and/or 5-HT in the CNS
■Neurotransmitter Receptor Hypothesis
–Changes in the relative density or sensitivity of certain receptor processes (α2 and β adrenergic receptors)
Genetic Component of affective disorders
–related to the circadian abnormalities in depression
–mutations in clock genes have been discovered that accelerate or delay circadian cycles
Glutamate Hypothesis of Depression
■Glutamate
–involved in excitatory transmission that plays a central role in mediating the complex emotional/cognitive changes associated with depression
–also likely represents the actual final common pathway of therapeutic treatments for depression and other mood/anxiety disorders.
N-methyl-D-aspartate receptor (NMDA-R: glutamate-gated cation channels) antagonists possess antidepressant-like action example
–Esketamine
Neuroendocrine Factors in Depression
Dysregulation of the HPA axis
•Hypersecretion of cortisol [adrenal gland]
- Blunted TSH response to TRH
- Blunted GH response to hypoglycemia
■Normally, low blood sugar stimulates the hypothalamus to produce and release hormones that increase growth hormone synthesis and release in the pituitary gland
- Altered 24hr rhythm of prolactin secretion
■elevation of PRL levels during the evening, several hours before sleep; morning PRL levels were slightly higher than normal
- Sex steroids
■Estrogen deficiency states and severe testosterone deficiency-associated with depressive symptoms
Cardio drugs that cause depression
Clonidine
Guanethidine
Metyldopa
Reserpine
Anticonvulsant drugs that cause depression
Phenobarbital
Topiramate
Vigabatrin
Hormonal agents that cause depression
Corticosteroids
Tamoxifen
GnRH agonists
Immunologic agents that cause depression
Interferon-a
Interferon-B
Retinoic acid derivatives that cause depression
Isoretinoin
. Tricyclic Antidepressants
Tertiary Amines (5-HT)
- Imipramine (Prototype)
- Amitriptyline
Secondary Amines (NE)
- Desipramine (Prototype)
- Nortriptyline
Non-selective Monoamine Oxidase Inhibitors
- Phenelzine
- Isocarboxazid
- Tranylcypromine
Selective Monoamine Oxidase Inhibitors
MAO-A: Breaks down 5-HT, DA and NE
•Crorgyline
MAO-B: Breaks down DA:
• Selegiline and Rasagiline
First Generation antidepressants
■TCAs and MAOIs
■Limited efficacy:
–20-30% of patients remain unresponsive
■Delayed onset of therapeutic effects:
–up to 6 weeks
■Troublesome side effects
Second generation antidepressants
- Considered “atypical
- Amoxapine (D2 Blocker)
- Bupropion
■(NE & DA re-uptake inhibitor)
- Mirtazepine
■antagonizes presynaptic α2 presynaptic autoreceptors
- Maprotiline
Third generation antidepressants
SNRIs [Serotonin & Norepinephrine Re-uptake Inhibitors]
- Venlafaxin
- Desvenlafaxin
- Duloxetine
5- HT2 Antagonists
- Trazodone
- Nefazodone
Rebexetine [NE Selective Re-uptake Inhibitor]
Tricyclic Antidepressants (TCAs) mechanism of action
■Inhibit the extra-neuronal re-uptake mechanisms for NE and 5-HT
■Block NE and 5-HT pre-synaptic transporters
■Increases NE and 5-HT in synapse
Also:
–α-1 and α-2 adrenergic
–5-HT2
–Muscarinic cholinergic
–H1
Tricyclic Antidepressants (TCAs) absorption
- Good after oral administration
- Lipophilic Drug
- Highly bound to plasma proteins and tissue
- Large volume of distribution
Tricyclic Antidepressants (TCAs) metabolism
- substrates of the CYP2D6 system
- oxidized in the liver and conjugated with glucuoronic acid
- polar metabolites are excreted in urine
- less than 5% excreted as unchanged compounds
Affect of tricyclic Antidepressants (TCAs) on sleep
- Increases stage 4 sleep
- Increases latency and decreases the total time spent in REM sleep
TCA withdrawal
malaise, chills, muscle aching
TCA CNS side effects
- Confusion (antimuscarinic)
- Insomnia, restlessness, feelings of fatigue and weakness
- Tolerance develops
Sedation, weakness & fatigue
- Increased risk of tonic-clonic seizures
- Increase in ‘switch process’
- transition from depression to hypomania or mania
•Aggravation of psychosis
Desipramine side effects
increased risk of death in patients with a family history of sudden cardiac death, conduction disturbances, and dysrhythmias
. Tricyclic Antidepressants side effects: Image
TCA overdose treatment
■Gastric lavage, early in treatment
–Administration of activated charcoal
■Cardiotoxicity: Phenytoin
■Seizures: Diazepam
■Anticholinergic Effects: Physostigmine
■Hypertension: Short-acting α- adrenergic blockers
TCAs have additive CNS depression with
■ethanol, barbiturates, benzodiazipines, & opiods
TCAs reversal antihypertensive action of __________.
–guanethidine by blocking transport into sympathetic nerve endings
TCAs Increase concentration of _________ because they have a shared metabolic pathway
phenytoin
TCAs Potentiate the pressor effects of __________.
adrenaline
What drugs does TCA interact with?
■Cimethidine - Increases levels of TCAs
■Clonidine - Produces a hypertensive crisis when combined with TCAs
■Oral contraceptives - Increase TCA levels
■Salicylates - Increases TCA levels (Decrease binding of TCAs
■Quinidine - Increase in arrhythmias
■L-dopa - Increases TCA levels
Clinical applications of TCAs
- Major depression unresponsive to other antidepressant drugs
- Chronic pain disorders
- Neuropathic conditions: diabetic neuropathy
- Insomnia
- Obsessive-compulsive disorder
- (clomipramine: selective for SERT transporter)
- Enuresis (imipramine)
- Migranie (Amitriptyline)
•MAOIs mechanism of action
- bind to and inactive the active site of the enzyme inside the pre-synaptic terminal
- block oxidative deamination of NE, DA, and 5-HT
Monoamine Oxidase Inhibitors clinical uses
■Atypical Depression
■OCD
■Panic attacks
■Anxiety
MAO Inhibitor side effects
■Excessive cardiovascular stimulation
- Hepatotoxicity
- Orthostatic hypotension
- Weight gain [over-eating of carbohydrates]
- Fluid retention in lower extremities
- Impaired sexual function
•Anorgasmia (highest of all antidepressant drugs)
- Irreversible, non-selective drugs
- Amphetamine-like properties →
- Activation and restlessness
- Sleep disturbances:
- Insomnia, reduced sleep time
- Decrease in REM sleep with REM-rebound following abrupt withdrawal
- Confusion
- Sedation (phenelzine)
MAO Inhibitor acute overdose
–Agitation, hyperthermia, insomnia and seizures
MAOI withdrawal symptoms
■With sudden discontinuation
–Delirium-like presentation with psychosis, excitement and confusion
MAOI interaction with tyramine
- Increase in blood pressure
- Hyperthermia, tachycardia, arrhythmias, agitation
- Headache, vomiting, chest pain, muscle twitching
Treat with: α-adrenergic blockers, i.v. [Phentolamine]
Serotonin syndrome
Triad of Symptoms (mild to lethal)
•Cognitive Effects:
- Delirium, agitation, and coma
•Autonomic Effects:
- Hypertension, tachycardia, hyperthermia
- Diaphoresis, dilated pupils
- Hyperactive bowel sound, diarrhea
•Somatic Effects:
- Hyper-reflexia, tremor, myoclonus, seizures
Management of serotonin syndrome
- Removal of the precipitating drugs
- Supportive Care:
- Mainstay of Therapy
- administration of intravenous fluids and correction of vital signs
- Control of agitation
- Sedation with benzodiazepines
- Control of autonomic instability and hyperthermia
- Administration of 5-HT2A antagonists
- cyproheptadine
- Administration of 5-HT2A antagonists
Benefits of Second gen antidepressants
- Modify Transmitter Function More Selectively
- Target Specific Symptoms
- Increased Onset of Action
- Reduced Side Effects
- Better than Placebo
- 20-40% Effective in Unipolar Depression
- Safer if Taken in Overdose
Bupropion side effects
–Seizures
–Increase in suicidal ideation
–Less anti-cholinergic activity
–Low cardiotoxicity
–Insomnia. Agitation
–Nausea, Anxiety, Weight loss
Mirtazapine Clinical Indications:
•Beneficial in patients who tolerate sedative effects and do not respond well to SSRIs and cannot tolerate sexual or other adverse effects of other antidepressants
Mirtazapine mechanism of action
■Alpha 2 blocker
–Inhibition of alpha 2 autoreceptor leads to CA release (NE and 5-HT)
■Antagonizes 5-HT 2 and 5-HT3 receptors
Mirtazapine side effects
- Greater sedative effects (strong H1 blockade) than other 2nd and 3rd generations drugs
- Likely to cause weight gain (useful in elderly)
- Minimal inhibitory effects on CYP450 metabolizing enzymes
- Reversible white blood cell disorders (neutropenia and agranulocytosis)
Bupropion metabolized in the liver by ______ to ________.
CYP2B6; hydroxybupropion
Bupropion mechanism of action
■accumulates & contribute to antidepressant activity by blocking NET
- Weak dopamine and NE re-uptake inhibition
- Enhances extracellular dopamine levels in nucleus accumbens
Bupropion side effects
- Headache
- Dry Mouth
- De novo Seizures [especially in high doses]
- More prominent in patients with eating disorders
- Suicidal thoughts or other mood changes
- Tends to have a mild appetite-suppressing effect
- Mild weight loss
- Causes less weight gain than SSRIs
Benefits of buproprion
•Unique among antidepressants
- It does not cause major sexual dysfunction
•No significant cytochrome p450 enzyme interaction
- can be safely co-administered with most medications with the exception of MAOIs
•No significant withdrawal symptoms upon discontinuation
Bupropion contraindications
■Patients with seizures disorders, anorexia nervosa, or bulimia
Buproprion drug interactions
■Carbamazepine reduces blood levels of bupropion
■Some medications with p450 inhibiting properties could increase the blood level of bupropion, raising the risk of seizure
■Interacts with MAOIs, DA precursors and agonists
•Six primary SSRIs
- Fluoxetine (Prozac)
- Sertraline (Zolof)
- Paroxetine (Paxil)
- Fluvoxamine (Luvox)
- Citalopram (Celexa)
- Escitalopram (Lexapro)
SSRIs are all _____ metabolized
Hepatically
SSRIs produce changes in sleep architecture. How?
•decreased REM latency and decreased total REM sleep
•Antidepressant effects of SSRIs often do not appear for __________ after initiation of treatment
3 to 6 weeks
SSRIs advantages
•Broad -spectrum efficacy :
- Depression
- Panic disorder
- OCD
- Social anxiety disorder
- Post-traumatic stress disorder
•Useful in treating the elderly with anxiety or OCD
SSRIs disadvantages
- Reduced efficacy in depressed patients [55 -70%]
- Pharmacokinetic interaction [inhibition of cytochrome P450 liver enzymes]
- SIADH
- Serotonin Syndrome: Due to dangerous high levels of brain 5-HT [May be FATAL]
- Sexual effects: (stimulation of pontine medullary bodies in spinal cord)
- delayed or impaired orgasm in women
- inhibited ejaculation in men
•Changes in sleep architecture
- decreased REM latency and decreased total REM sleep
SSRIs use in preganancy
- Teratogenicity: When taken during first trimester
- Increase in cleft palate, and several types of heart defects
- Paroxetine (Category D)
- Possible postnatal complications: pulmonary hypertension
•Discontinuation Effects of SSRIs
–Headache, nausea, dizziness,
–May include a flu-like reaction and strange sensations of vision or touch
Side Effects of SSRIs
■Anxiety
■Insomnia
■GI Distress
■Sexual Dysfunction
■Syndrome of Inappropriate Antidiuretic Hormones (SIADH)
Most dangerous :
■Suicidal ideation in children and young adults [FDA Warning]
■Serotonin Syndrome
Citalopram side effects
–Prolonged QT interval
■causes arrhythmias such as torsades de pointes (TdP), a potentially life-threatening ventricular arrhythmia.
Paroxetine side effects
–FDA pregnancy Cat D: congenital Heart Defects
■Cardiac septal defects with 1st trimester exposure
–Has a mild affinity for muscarinic receptors and can cause more anticholinergic side effects than the other SSRIs (although much less than the tricyclic antidepressants)
Fluoxetine, Fluvoxamine, Paroxretine side effects
–significant inhibition of Cytochrome P450 enzymes
■SSRIs reduce the rate of elimination of benzodiazepines and cause them to build up in the body
■Fluoxetine: Violence, suicidal behavior
Which SSRI has the lowest risk of drug interactions?
Sertraline
SSRIs compete with other drugs for metabolism by _________ or ______ isoenzymes
CYP2D6; CYP3A4
Side effects of SSRIs Interaction with Dextromethorphan
Drowsiness and Dizziness
Nausea and Vomiting
Hyperactivity
Blurred Vision
Hallucinations (Visual and Auditory)
SNRIs
Venlafaxine, Desvenlafaxine, Duloxetine (Cymbalta)
SNRIs mechanism of action
•Inhibits the presynaptic re-uptake of 5-HT and NE
Venlafaxine extensively metabolized in liver via _____ to _________.
CPY2D6; desvenlafaxine
Which antidepressant has the lowest protein binding of all antidepressants?
Venlafaxine
Clinical use for SNRIs
- Preferred over TCAs for Major Depressive Disorder and
- Pain Syndromes
- GAD
- Stress incontinence in women
Trazodone mechanism of action
- Direct antagonist effect at 5-HT2A postsynaptic receptor
- Inhibits pre-synaptic α1-adrenergic receptor
- Weak inhibitor of SERT
- H1 receptor antagonist [sedation]
Trazadone side effects
- CNS: Dizziness, drowsiness, agitation, sedation
- ANS: Orthostatic hypotension and priapisms
GIT disturbances
Trazadone clinical use
- Insomnia (low doses)
- Not first line treatment for MDD
Reboxetine mechanism of action
•selective NE reuptake inhibitor
Reboxetine clinical use
- Depression
- Panic Disorder
What SSRIs treat premenstrual Dysphoric Disorder?
• fluoxetine & sertraline
■In the first week of March 2019, the FDA approved a drug for treatment-resistant severe depression called ____________.
Esketamine [Spravato]
March 19, 2019, FDA approved Brexanalone [Zulresso], an analog of the endogenous human hormone allopregnanolone, and the first drug specifically approved/designed to treat _________
post partum depression
Esketamine [Spravato] and Brexanalone [Zulresso] work on ________ receptors.
GABA
Brexanalone side effects
headaches, drowsiness, and dizziness
■Sedation and sleep apnea
Esketamine side effects
sedation and dissociation
Potential for abuse and misuse
■Increased risk of suicidal thoughts and behaviors in pediatric and young adult patients taking antidepressants.
Esketamine contraindications
■Aneurysmal vascular disease
–(including thoracic and abdominal aorta, intracranial and peripheral arterial vessels), or
–arteriovenous malformation
■History of intracerebral hemorrhage
■Hypersensitivity to esketamine, ketamine, or any of the excipients
Electroconvulsive Therapy clinical uses
- Severely depressed or suicidal patients
- Treatment resistant bipolar disorder
- Acute but not chronic Schizophrenia
- Acute Manic Episodes
Electroconvulsive Therapy side effects
- Cognitive impairment, confusion and memory loss, stroke
- Nausea, vomiting, headache, muscle ache, jaw pain
Electroconvulsive Therapy drug interactions
•Lithium and ECT: Severs cognitive impairment
ECT and antipsychotic drugs: Increased effectiveness
Disadvantages of TMS
–may cause seizures
