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Chapter 32

Chapter 32. Antidepressants. Antidepressants. Primarily used to relieve symptoms of depression Can also help patients with anxiety disorders Not indicated for uncomplicated bereavement. Antidepressant Groups. Tricyclic antidepressants Selective serotonin reuptake inhibitors (SSRIs)

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Chapter 32

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  1. Chapter 32 Antidepressants

  2. Antidepressants • Primarily used to relieve symptoms of depression • Can also help patients with anxiety disorders • Not indicated for uncomplicated bereavement

  3. Antidepressant Groups • Tricyclic antidepressants • Selective serotonin reuptake inhibitors (SSRIs) • Serotonin/norepinephrine reuptake inhibitors (SNRIs) • Monoamine oxidase inhibitors (MAOIs) • Atypical antidepressants

  4. Depression • Most common psychiatric disorder • 30% of the U.S. population will experience some form during their lifetime • Approximately 5% of adult population is depressed • Incidence in women twice as high as in men • Risk of suicide is high in depression • Often untreated

  5. Clinical Features • Depressed mood • Loss of pleasure or interest • Insomnia (or sometimes hypersomnia) • Anorexia (or sometimes hyperphagia) • Mental slowing and loss of concentration • Feelings of guilt, worthlessness, helplessness • Thoughts of death and suicide • Overt suicidal behavior • Symptoms must be present most of the day, nearly every day, for at least 2 weeks

  6. Pathogenesis • Complex and incomplete • Possible contributing factors • Genetic heritage • Difficult childhood • Chronic low self-esteem • Monoamine hypothesis of depression • Depression is caused by functional insufficiency of monoamine neurotransmitters

  7. Treatment Modalities • Pharmacotherapy • Primary therapy • Depression-specific psychotherapy (eg, cognitive behavioral therapy) • Electroconvulsive therapy (ECT) • When drugs and psychotherapy have not worked • When a rapid response is needed • For severely depressed patients • For suicidal patients • Elderly patients at risk of starving • Vagus nerve stimulation • Only after treatment with at least four drugs has failed

  8. Suicide Risk with Antidepressants • May increase suicidal tendency early in the treatment • Patients should be observed closely for: • Suicidality • Worsening mood • Changes in behavior • Precautions • Prescriptions should be written for the smallest number of doses consistent with good patient management • Dosing of inpatients should be directly observed

  9. Selective Serotonin Reuptake Inhibitors (SSRIs) • Introduced in 1987 • Most commonly prescribed antidepressants • As effective as TCAs, but do not cause hypotension, sedation, or anticholinergic effects • Overdose does not cause cardiac toxicity • Death by overdose is extremely rare

  10. Selective Serotonin Reuptake Inhibitors (SSRIs) • Fluoxetine (Prozac, Sarafem) • Most widely prescribed SSRI in the United States • Other SSRIs

  11. Mechanism of Action • Produce selective inhibition of serotonin reuptake • Produce CNS excitation

  12. Therapeutic Uses • Primarily used to treat major depression • Other uses • Obsessive-compulsive disorder • Bulimia nervosa • Premenstrual dysphoric disorder

  13. Adverse Effects • Serotonin syndrome • 2–72 hours after treatment • Withdrawal syndrome • Neonatal effects when used in pregnancy • Teratogenesis • Extrapyramidal side effects • Bruxism • Bleeding disorders • Sexual dysfunction • Weight gain

  14. Drug Interactions • Monoamine oxidase inhibitors • Risk of serotonin syndrome • Warfarin • Tricyclic antidepressants and lithium • Can elevate levels of these drugs

  15. Other SSRIs • Sertraline (Zoloft) • Blocks uptake of serotonin and dopamine • CNS stimulation • Minimal effects on seizure threshold • Therapeutic uses • Major depression • Panic disorder • Obsessive-compulsive disorder • Post-traumatic stress disorder • Premenstrual dysphoric disorder • Social anxiety disorder

  16. Other SSRIs • Sertraline (Zoloft) (cont’d) • Side effects • Headache • Nausea • Tremor • Diarrhea • Insomnia • Weight gain • Agitation • Sexual dysfunction • Neonatal abstinence syndrome (NAS) and persistent pulmonary hypertension of the newborn (PPHN ) when used late in pregnancy • Nervousness

  17. Other SSRIs • Sertraline (Zoloft) (cont’d) • Drug interactions • MAOIs • Pimozide

  18. Other SSRIs • Fluvoxamine (Luvox) • Inhibition of serotonin reuptake • Used for obsessive-compulsive disorder • Rapidly absorbed from the GI tract • Half-life: about 15 hours • Interacts adversely with MAOIs

  19. Other SSRIs • Fluvoxamine (Luvox) (cont’d) • Side effects • Nausea • Vomiting • Constipation • Weight gain • Dry mouth • Headache • Sexual dysfunction • Abnormal liver function • Sedative effects

  20. Other SSRIs • Paroxetine (Paxil, Paxil CR, Pexeva) • Inhibition of serotonin uptake • Indications • Major depression • Obsessive-compulsive disorder • Social phobia • Panic disorder • Generalized anxiety disorder • Post-traumatic stress disorder • Premenstrual dysphoric disorder

  21. Other SSRIs • Citalopram (Celexa) • Does not block receptors for serotonin, acetylcholine, norepinephrine (NE), or histamine • Used for major depression • Half-life: about 35 hours • Side effects (most common) • Nausea • Somnolence • Dry mouth • Sexual dysfunction • Can cause neonatal abstinence syndrome • Interacts with MAOIs

  22. Other SSRIs • Escitalopram (Lexapro) • S-isomer of citalopram • Better tolerated than citalopram • Side effects • Nausea • Insomnia • Somnolence • Sweating • Fatigue • Interacts with MAOIs

  23. Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) • Venlafaxine (Effexor) • Duloxetine (Cymbalta)

  24. Venlafaxine (Effexor) • Indications • Major depression • Generalized anxiety disorder • Social anxiety disorder (social phobia) • Blocks NE and serotonin uptake • Does not block cholinergic, histaminergic, or alpha1-adrenergic receptors • Serious reactions if combined with MAOIs

  25. Venlafaxine (Effexor) • Side effects • Nausea • Headache • Anorexia • Nervousness • Sweating • Somnolence • Insomnia • Weight loss/anorexia • Diastolic hypertension • Sexual dysfunction • Hyponatremia (in older adult patients) • Neonatal withdrawal syndrome

  26. Desvenlafaxine (Pristiq) • Mechanism of action • Strong inhibitor of 5-HT and NE reuptake • Does not block cholinergic, histaminergic, or alpha1-adrenergic receptors

  27. Desvenlafaxine (Pristiq) • Side effects • Nausea • Headache • Dizziness • Insomnia • Diarrhea • Dry mouth • Sweating • Constipation • Sexual effects, including erectile dysfunction • Decreased libido

  28. Duloxetine (Cymbalta) • Mechanism of action and therapeutic use • Inhibits serotonin and NE reuptake • Weakly inhibits dopamine reuptake • Does not inhibit monoamine oxidase (MAO) • Relieves depression • Relieves pain of diabetic peripheral neuropathy • Pharmacokinetics • Well absorbed following oral administration • Food reduces rate of absorption • Highly bound to albumin in the blood • Half-life:12 hours

  29. Duloxetine (Cymbalta) • Adverse effects • Nausea • Somnolence • Dry mouth • Sweating • Insomnia • Blurred vision • Effects in pregnancy and lactation • Drug interactions • Alcohol • MAOIs • Drugs that inhibit CYP1A2 or CYP2D6 • Preparations, dosage, and administration

  30. Tricyclic Antidepressants • Drugs of first choice for many patients with major depression • Most common adverse effects: sedation, orthostatic hypotension, and anticholinergic effects • Most dangerous adverse effect: cardiac toxicity • May increase risk of suicide early in treatment

  31. Tricyclic Antidepressants • Chemistry • Mechanism of action • Pharmacokinetics • Therapeutic uses • Adverse effects • Drug interactions • Dosage and routes of administration • Preparations and drug selection

  32. Chemistry • Nucleus of the tricyclic antidepressants has three rings • Similar to phenothiazine antipsychotics • Produce varying degrees of: • Sedation • Orthostatic hypotension • Anticholinergic effects

  33. Fig. 32–1. Structural similarities between tricyclic antidepressants and phenothiazine antipsychotics.

  34. Mechanism of Action • Block neuronal reuptake of two monoamine transmitters • Norepinephrine (NE) • Serotonin

  35. Pharmacokinetics • Long and variable half-lives • Usually single daily dose • Requires individualization of dosage

  36. Fig. 32–2. Mechanism of action of tricyclic antidepressants.

  37. Therapeutic Uses • Depression • Bipolar disorder • Other uses • Neuropathic pain • Chronic insomnia • Attention-deficit/hyperactivity disorder • Panic disorder • Obsessive-compulsive disorder

  38. Adverse Effects • Orthostatic hypotension • Anticholinergic effects • Diaphoresis • Sedation • Cardiac toxicity • Seizures • Hypomania • “Yawngasm”

  39. Drug Interactions • Monoamine oxidase inhibitors • Direct-acting sympathomimetic drugs • Indirect-acting sympathomimetic drugs • Anticholinergic agents • CNS depressants

  40. Toxicity • Clinical manifestations • Primarily from anticholinergic and cardiotoxic actions • Dysrhythmias • Tachycardia • Intraventricular blocks • Complete atrioventricular block • Ventricular tachycardia • Ventricular fibrillation

  41. Toxicity • Treatment • Gastric lavage • Ingestion of activated charcoal • Physostigmine • Propranolol, lidocaine, or phenytoin

  42. Dosage and Routes of Administration • Dosage • Initial doses should be low • Routes of administration • All can be administered by mouth

  43. Preparation and Drug Selection • Nine equally effective tricyclic antidepressants (TCAs) • Selection based on side effects

  44. Monoamine Oxidase Inhibitors • 2nd- or 3rd-choice antidepressants for most patients • As effective as TCAs or SSRIs, but more dangerous • Risk of triggering hypertensive crisis if patient eats foods rich in tyramine • Drug of choice for atypical depression

  45. Monoamine Oxidase Inhibitors • Mechanism of action • Convert monoamine neurotransmitters (NE, serotonin, and dopamine) into inactive products • Inactivate tyramine and other biogenic amines • Two forms of MAO in the body • MAO-A and MAO-B

  46. Monoamine Oxidase Inhibitors • Mechanism of action (cont’d) • Affected by antidepressants • Act on MAO in two ways: reversible and irreversible • Reversible:lasts 3 to 5 days • Irreversible:lasts about 2 weeks • All of the MAOIs in current use cause irreversible inhibition

  47. Fig. 32–3. Mechanism of action of monoamine oxidase inhibitors.

  48. Monoamine Oxidase Inhibitors • Therapeutic uses • Depression • Other uses • Bulimia nervosa • Obsessive-compulsive disorder • Panic attacks • Adverse effects • CNS stimulation • Orthostatic hypotension • Hypertensive crisis from dietary tyramine

  49. Monoamine Oxidase Inhibitors • Drug interactions • Indirect-acting sympathomimetic agents • Interactions secondary to inhibition of hepatic MAO • Antidepressants: TCAs and SSRIs • Antihypertensive drugs • Meperidine • Preparations, dosage, and administration • All MAOIs administered orally

  50. Fig. 32–4. Interaction between dietary tyramine and MAOIs.

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