Pharm Unit 5: Psychiarty

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Selective Serotonin Reuptake Inhibitors (SSRIs): Types

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Depression is caused by a deficiency of synaptic neurotransmitters such as serotonin (5-HT), norepinephrine and dopamine. In particular serotonin as associated with mood

fluoxetine; paroxetine; sertraline; citalopram; escitalopram

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Selective Serotonin Reuptake Inhibitors (SSRIs): MOA

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5-HT is released from presynaptic vesicles into the synaptic cleft, where it travels to postsynaptic receptors.

Once released from these postsynaptic recptors, 5-HT is removed from the synaptic cleft by reuptake transporters located on the presynapse.

SSRIs bind to this reuptake transporter preventing the removal of 5-HT and leading to increased 5-HT available to bind to postsynaptic receptors.

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Selective Serotonin Reuptake Inhibitors (SSRIs): Pharm

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Clinical efficacy of antidepressants is delayed a few weeks when compared with their pharmacological actions.
(2-4 week onset, follow-up in 4-8 weeks)

SSRIs typically have long half livers (24 hours or more); allowing for once a day administration.

Fluoxetine has an active metabolite and has the longest half-life (greater then 100 hours).
It is more prone to drug interactions; caution to ensure a proper washout period after fluoxetine discontinuation.

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Selective Serotonin Reuptake Inhibitors (SSRIs): Indications

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-Major depressive disorder

-Obsessive compulsive disorder

-Generalized anxiety disorder

-Bulimia nervosa

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Selective Serotonin Reuptake Inhibitors (SSRIs): Contraindications

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Contra:
SSRIs and monoamine oxidase inhibitors (MAOIs);

-SSRIs and thioridazine (an antipsychotic)

-Thioridazine elicits QT interval prolongation and fluoxetine in particular enhances this effect

-Citalopram and pimozide; greater risk of QT interval prolongation

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Selective Serotonin Reuptake Inhibitors (SSRIs): SE

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SE:
-Sexual dysfunction
-Gastrointestinal distress (GI distress)-(effect GI motility by receptors in the gut)
- Nausea and vomiting
-Agitation, insomnia
-Suicide

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Selective Serotonin Reuptake Inhibitors (SSRIs): Important Notes

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SSRIs increase serotonin concentration whereas MAOIs inhibit the breakdown of serotonin. Concomitant use can lead too much. When switching from an SSRI to an MAOI or vice versa; allow for a washout period of at least 1-2 weeks.

SEROTONIN SYNDROME
SERIOUS SE: elevation of Serotonin.
Symptoms include:
-Hyperthermia
-Muscle rigidity
-Myoclonus
-Rapid fluctuations in vital signs
-Rapid fluctuations in mental status (confusion, irritability, extreme agitation, delirium, coma)

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Tricyclic Antidepressants (TCAs): Types

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Sedating:
1. Doxepin (most sedating)
2. Amitriptyline (Migranes, PC use)
3. Nortriptyline

Activating:
1. Protriptyline (PC use)
2. Desipramine
3. Imipramine

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Tricyclic Antidepressants (TCAs): MOA

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Nortriptyline is a metabolite of amitriptyline

Desipramine is a metabolite of imipramine

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Tricyclic Antidepressants (TCAs): Pharm

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TCAs are metabolized by CYP450 enzymes

TCAs undergo slow absorption; therefore a patient may arrive on his/her own at an emergency department with a fatal dose of TCAs that has not yet been absorbed.

Most TCAs exhibit some degree of CYP450 enzyme inhibition.

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Tricyclic Antidepressants (TCAs): Indications

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Depression

Chronic Pain (as adjunct)

Off label:
IBS
Migraine
Sleep
Fibromyalgia

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Tricyclic Antidepressants (TCAs): Contraindications

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Contra:
Avoid concomitant use of TCAs and MAOIs: (excessive serotonin)

When switching from a TCA to an MAOI, or vice versa, allow for a washout period of at least 2 weeks.

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Tricyclic Antidepressants (TCAs): SE

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Anticholinergic
Dry mouth
Confusion
Urinary retention
Constipation
Blurred visionIncrease intraocular pressure (IOP)
Sedation: via blockade of histamine (H1) receptors

Serious: Cardiovascular toxicities (high doses)
-widening of the QRS complex and heart block, hypotension

Orthostatic hypotension: related to blockade of alpha 1 receptors (most common in teens)

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Tricyclic Antidepressants (TCAs): Important Notes

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TCAs are grouped as a class based on their chemical structure. Although as a class they are considered to be 5-HT or noradrenaline reuptake inhibitors, the degree of reuptake inhibition differs markedly among agents.

Affinities for blockade of receptors that mediate the side effects experienced by patients also differs markedly among the agents.

TCAs should be with caution in conditions that would be exacerbated by cholinergic antagonism: urinary retention, benign prostatic hyperplasia (BPH), glaucoma (closed angle) and increased IOP.

TCAs are potentially fatal in overdose situations:
-Cardiac arrhythmias, -hypotension
-central nervous system (CNS) involvement

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SNRIs (Serotonin Noradrenaline Reuptake Inhibitors): Types

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Venlafaxine
Desvenlafaxine
Duloxetine

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SNRIs (Serotonin Noradrenaline Reuptake Inhibitors): MOA

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They are reuptake inhibitors that increase the concentration of both serotonin (5-HT) and noradrenaline (NA) in the synaptic cleft.

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SNRIs (Serotonin Noradrenaline Reuptake Inhibitors): Pharm

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Compared to SSRIs; SNRIs have shorter elimination half-lives. (SE are greater)

Venlafaxine is available in an extended release (ER) dosage form.

Venlafaxine has an active metabolite

Metabolism varies among patients; due to genetic polymorphisms

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SNRIs (Serotonin Noradrenaline Reuptake Inhibitors): Indications

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Depression

Generalized Anxiety Disorder (GAD)

Social Anxiety Disorder

Panic Disorder

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SNRIs (Serotonin Noradrenaline Reuptake Inhibitors): Contraindications

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SNRIs and MAOIs; allow for at least 2 week wash period between ending one and starting the next

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SNRIs (Serotonin Noradrenaline Reuptake Inhibitors): SE

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Gastrointestinal (GI) distress
-Dizziness
-Somnolence
-Insomnia
(Both length and quality of sleep may be impaired)
-Sexual Dysfunction (such as erections, ejaculation, lubrication and orgasm.)
Sweating
-Dry mouth
Sustained
-hypertension: dose related (patients should have blood pressure monitored)

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SNRIs (Serotonin Noradrenaline Reuptake Inhibitors): Important Notes

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Central as serotonin has an inhibitory effect on dopamine, a neurotransmitter believed to play an important role in arousal.

When discontinuing; dose should be gradually tapered; in order to avoid discontinuation symptoms of:
-Aggression
Agitation
-convulsions
dysphoric mood,
electric shock sensations and others.

All antidepressants carry an FDA warning about increased suicidality, particularly in younger (younger then 25 years of age)

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Noradrenergic and Specific Serotonergic Antidepressants (NaSSAs): Types

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Mirtazapine

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Noradrenergic and Specific Serotonergic Antidepressants (NaSSAs): MOA

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NaSSAs are antidepressants that increase the concentration of noradrenaline and serotonin in the synaptic cleft

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Noradrenergic and Specific Serotonergic Antidepressants (NaSSAs): Pharm

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Clearance is reduce in patients with liver disease (by 30%) or kidney disease (by 30-50%) and in the elderly. Dose reductions should be considered in these populations.

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Noradrenergic and Specific Serotonergic Antidepressants (NaSSAs): Indications

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Depression

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Noradrenergic and Specific Serotonergic Antidepressants (NaSSAs): SE

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Side effects
-Sedation (because of the blockade of histamine receptors at lower dose)

-Increased appetite/Weight gain

Serious, rare effects
Severe neutropenia is rare

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Noradrenergic and Specific Serotonergic Antidepressants (NaSSAs): Important Notes

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May be more useful in elderly patients due to its side effect profile (increase sedation and weight gain) as these patients often have depression accompanied by insomnia and weight loss.

With its distinct mechanism, mirtazapine is seen as an alternative for patients intolerant to SSRIs.

It does have the advantage of lower incidence of sexual dysfunction; but has greater propensity for weight gain then SSRIs.

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Atypical Antidepressants: Type

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Trazodone and nefazodone

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Atypical Antidepressants: Pharm

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Nefazodone was pulled from the market in early 2000s for hepatotoxicity.

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Atypical Antidepressants: Indications

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Sedation (insomnia)

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Atypical Antidepressants: Contraindications

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All antidepressants carry an FDA warning about increased suicidality, particularly in younger (under age 25) patients.

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Atypical Antidepressants: SE

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Similarities to mirtazapine but are not in the same class. They are considered “atypical antidepressants”

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Atypical Antidepressants: Important Note

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Not addictive like benzodiazepines and atypical benzodiazepines

High dose can cause priapism (medical emergency)

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Monoamine Oxidase Inhibitors (MAOIs): Types

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MAO-B: selegiline
MAO-A: moclobemide
Nonselective, irreversible: phenelzine and tranylcypromine

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Monoamine Oxidase Inhibitors (MAOIs): MOA

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MAO degrades catecholamines, serotonin and other endogenous amines in the CNS periphery.

Two key isoenzymes:
MAO-A: degrades epinephrine, norepinephrine and serotonin

MAO-B: degrades phenylethylamine
Both degrade dopamine
The purpose of inhibition is to increase levels of these substances within the body, specifically the CNS

The efficacy of these agents is result of their actions within the CNS

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Monoamine Oxidase Inhibitors (MAOIs): Pharm

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Little MAO-B is found in the gut; therefore an MAO-B selective inhibitor will have minimal effect on the metabolism of dietary tyramine. Although MAO-B selectivity reduces the risk of hypertensive crisis, this selectivity is lost at higher doses.

Reversible MAOIs lead to much less accumulation of tyramine and thus are considered to have minimal risk for hypertensive crisis.

Linezolid , the first in a new class of antibiotics called the oxazolidinones is also an MAOI. Concomitant use of these agents should therefore be avoided.

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Monoamine Oxidase Inhibitors (MAOIs): Indications

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Indications:
• Depression

MAO-B Inhibitors
• Parkinson’s Disease

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Monoamine Oxidase Inhibitors (MAOIs): Contraindications

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Contra:
Drug interaction with sympathomimetics; non selective MAOIs (hypertensive effects) hypertensive crisis that can be fatal.
Methylphenidate, dopamine, epinephrine, norepinephrine and similar agents (methyldopa, L-dop, L-tryptophan, L-tyrosine, phenylalanine should all be avoided.

Foods with tyramine

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Monoamine Oxidase Inhibitors (MAOIs): SE

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-Sleep disturbances (insomnia and reduction in rapid eye movement (REM) sleep.
-Weight gain
-Postural hypotension
-Sexual disturbances

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Monoamine Oxidase Inhibitors (MAOIs): Important Note

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The side effects are largely mediated by their actions outside of the CNS

Hypertensive Crisis- occurs because of a drug-drug or drug-food interaction, leading to increased levels of norepinephrine and subsequent rapid elevation in blood pressure. Before the triggering factors (tyramine rich foods) were identified, this interaction limited the utility of these agents.

MAO-A in the gut breaks down tyramine, a chemical that stimulates the release of norepinephrine. Tyramine is typically found in aged foods such as cheese, wine, beer, yogurt and yeast. Ingestion of these foods leads to increased tyramine and because its breakdown is inhibited, there is increased norepinephrine release; leading to hypertensive crisis.

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Noradrenaline and Dopamine Reuptake Inhibitors (NDRIs): Type

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Bupropion

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Noradrenaline and Dopamine Reuptake Inhibitors (NDRIs): MOA

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Bupropion inhibits the presynaptic reuptake of both dopamine (DA) and noradrenaline (NA) leading to increased levels of both of these neurotransmitters in the synaptic cleft

The NDRIs fall under a broader classification of atypical antidepressants, so named because they do not fit into any of the other antidepressant classes.

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Noradrenaline and Dopamine Reuptake Inhibitors (NDRIs): Pharm

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Increases amount of DA and NA in the synaptic cleft; prevents exogenously administered nicotine from binding to the nicotinic receptor, decreasing reward smokers gain from nicotine

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Noradrenaline and Dopamine Reuptake Inhibitors (NDRIs): Indication

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Depression

Smoking cessation

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Noradrenaline and Dopamine Reuptake Inhibitors (NDRIs): Contraindication

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Seizures: bupropion may lower the seizure threshold,
(patients undergoing drug and alcohol withdrawal; prior diagnosis of bulimia or anorexia nervosa)

MAOIs; co administration could lead to hypertensive crisis

Thioridazine; increase risk of ventricular arrhythmia and sudden cardiac death

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Noradrenaline and Dopamine Reuptake Inhibitors (NDRIs): SE

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• Dry mouth
• Nausea
• Insomnia

Rare, Serious
• Seizures

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Noradrenaline and Dopamine Reuptake Inhibitors (NDRIs): Important Notes

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With respect to smoking cessation; dopamine is believed to be the key neurotransmitter in the reward pathway associated with addiction.

There is some evidence that bupropion is a nicotinic receptor antagonist. By blocking nicotinic receptors, bupropion prevent exogenously administered nicotine from binding to this receptor, decreasing the reward that smokers gain from nicotine

Bupropion lacks serotonergic effects.
As a result, bupropion appears to have a lower propensity for sexual side effects

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Lithium: MOA

Back 48

A chemical element primarily used in the treatment of bipolar disorder

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Lithium: Pharm

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Lithium has a narrow therapeutic index; therefore small increases in lithium levels can lead to toxic effects.

Lithium is almost exclusively excreted in the urine. Renal lithium excretion varies among individuals and is generally decreased in older patients and increased in younger patients.

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Lithium: Indications

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Bipolar Disorder

Treatment refractory depression (adjunctive)

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Lithium: Contraindications

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Contra:
caution in patients:
–with significant renal or cardiovascular disease

-dehydration or sodium depletion

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Lithium: SE

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• Arrhythmia
• Nephrotoxicity
• Weight gain
• Nausea, GI irritation
• Memory disturbances, cognitive dulling

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Lithium: Notes

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Acute lithium toxicity causes nausea, vomiting, diarrhea, renal failure, neuromuscular dysfunction, ataxia, tremor, confusion, delirium and seizures

Lithium is unique among all psychotropic agents in that it lacks sedative, euphoriant or depressive effects in normal individuals who do not suffer from psychiatric illness.

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Second Generation Antipsychotics: Type

Back 54

Olanzapine
Risperidone
Quetiapine

Used to treat disorders of thought

Second generation antipsychotics are also called atypical antipsychotics

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Second Generation Antipsychotics: MOA

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The second generation antipsychotics are believed to antagonize several different receptors; primarily dopamine and serotonin (5-HT)

All antipsychotic drugs are D2 receptor antagonists.

The role of serotonin (specifically 5HT2A) antagonism in the efficacy of antipsychotics is less well understood.

Unlike many of the first generation agents, the second generation agents are potent antagonists of 5 HT2 receptors.

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Second Generation Antipsychotics: Pharm

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Second generation antipsychotics; like first generation antipsychotics antagonize numerous other receptors; including adrenergic and cholinergic as well as histamine H1 receptors.

All are eliminated by hepatic metabolism.

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Second Generation Antipsychotics: Indications

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Schizophrenia

Inappropriate behavior associated with dementia (risperidone)

Acute mania associated with bipolar disorder (risperidone, olanzapine, quetiapine)

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Second Generation Antipsychotics: Contraindications

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All- history of neuroleptic malignant syndrome

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Second Generation Antipsychotics: SE

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Serious: (all agents)
-Increased mortality in elderly patients- mechanism is unclear

-Endocrine- weight gain, exacerbation of diabetes, hyperglycemia, dyslipidemia, hyperprolactinemia

-Neuroleptic malignant syndrome (NMS)

Nonserious adverse effects, common to all agents
• Orthostatic hypotension
• EPS
• Sedation
• Anticholinergic

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Second Generation Antipsychotics: Notes

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Drug interactions: multiple depending on which agent is used.

Run safety profile with other medications patient may be taking before prescribing.