Lecture Notes (19): Antidepressants (Pharmacology) PDF

Prof. Moustafa Mahmoud Hamdy Lecture (19): Antidepressants (Pharmacology) By the end of the lecture the student will be able to: 1- Identify Principles of drug action and pharmacokinetics of drugs used in different...

Prof. Moustafa Mahmoud Hamdy Lecture (19): Antidepressants (Pharmacology) By the end of the lecture the student will be able to: 1- Identify Principles of drug action and pharmacokinetics of drugs used in different CNS diseases e.g., epilepsy, Parkinsonism and depression, etc. 2- Recognize the side effects and interactions of drug used in depression, psychosis, epilepsy and neurodegenerative diseases 3- Choose categories of Individual drugs in each of the following neurological conditions: depression, psychosis, epilepsy and neurodegenerative diseases. Contents: By the end of the lecture the student will be able to: 1. Explain classification of antidepressants. 2. Understand the clinical uses and adverse effects of antidepressants. 3. Explain the pharmacological actions and the mechanism of action of antidepressants. NARS: (1.16, 2.3, 4.7) Ref. books: Kaplan Neuroscience, 2021 pp. 119.121. Kaplan Medical USMLE Step 1 Lecture Notes 2021 Pages: 135-138. Lippincott Illustrated Reviews: Pharmacology, Sixth Edition. Pages: 135-143. Antidepressants Depressed mood may be: Reactive depression: (N.B. reaction to some stressors or adverse life situations like loss of a person by death, divorce, financial crisis or chronic major illness. The symptoms range from mild sadness, anxiety, irritability, worry, and impairment in social and occupational functioning). Endogenous depression (Major depressive disorder, MDD): It may have genetic factors (neurotransmitter dysfunction), physiologic or metabolic disturbances. The patient frequently suffers from lack of interest, withdrawal from activities & feeling of guilt, inability to concentrate, feeling of worthlessness, somatic complaints (e.g. headache, disturbed sleep) thoughts of death and suicidal tendency. (N.B. Episodes may be recurrent (unipolar depression) or alternative with mania (bipolar; manic depressive psychosis). 1 Prof. Moustafa Mahmoud Hamdy Pathophysiology of Major Depression 1- Neurotrophic Hypothesis  (N.B. There is substantial evidence that nerve growth factors such as) brain- derived neurotrophic factor (BDNF) are critical in the regulation of neurons.  Depression is associated with the loss of neurotrophic support. 2- Monoamines & Other Neurotransmitters  The monoamine hypothesis of depression suggests that depression is related to a deficiency in the amount or function of cortical and limbic serotonin (5-HT), norepinephrine (NE), and dopamine (DA).  Reserpine treatment, which is known to deplete monoamines, is associated with depression. 3- Neuroendocrine Factors  Corticosteroids, thyroid hormones and sex steroids, (N.B. all these hormone dysregulations are implicated in the pathophysiology of depression) Genetic: depression run in family Classification of antidepressants: A. Selective Serotonin Reuptake Inhibitor B. Tricyclic Antidepressant C. Selective serotonin-norepinephrine reuptake inhibitors (SNRIs) D. 5-HT2 Receptor Modulators  They act primarily as antagonists at the 5-HT2 receptor: trazodone and nefazodone. The most common use of trazodone in current practice is as hypnotic. E. Tetracyclic and Unicyclic Antidepressants  Among these are bupropion, mirtazapine, amoxapine and maprotiline. F. Monoamine Oxidase Inhibitors (MAOIs)  phenelzine and tranylcypromine  1. Selective Serotonin Reuptake Inhibitors They are the most common antidepressants in clinical use. Examples: Fluoxetine, paroxetine, sertraline, citalopram and fluvoxamine. 2 Prof. Moustafa Mahmoud Hamdy Mechanism of action as antidepressant: - SSRIs are the current first-line treatment for depressive disorders. - (N.B. SSRIs allosterically inhibit the transporter by binding the SERT receptor at a site other than the serotonin binding site). SSRIs block the reuptake of serotonin leading to increased concentration of that neurotransmitter in the synaptic cleft and elevation of the mood (antidepressant effect). - The drugs have greater selectivity for the serotonin transporter than the norepinephrine transporter and (N.B. also in comparison with TCAs, which inhibit the uptake of both norepinephrine and serotonin non-selectively). Pharmacological actions: - The chief advantages of SSRIs compared to TCAs include the following:  do not generally cause significant cardiovascular or anticholinergic side effects.  better tolerated.  wide therapeutic index.  toxic dose is high (difficult to be used by depressed patient as a mean to commit suicide).  they have much lower lethality in overdose compared to TCAs. - Like TCAs, their antidepressant effect, takes at least 2 weeks to manifest and maximum up to 12 weeks or more. Pharmacokinetics of SSRIs - Metabolism by P450-dependent enzymes and glucuronide or sulfate conjugation occur extensively. Fluoxetine and paroxetine are potent inhibitors of CYP2D6, while fluvoxamine is an inhibitor of CYP3A4. - Excretion of the SSRIs is primarily through the kidneys, (N.B. except for paroxetine and sertraline, which also undergo fecal excretion). Adverse effects of SSRIs 1. The most common are nausea, diarrhea, headache, tinnitus, insomnia, nervousness and akathisia. 2. Sexual side effects of erectile dysfunction. 3 Prof. Moustafa Mahmoud Hamdy 3. Serotonin syndrome: High dose of SSRIs or combination with MAOIs especially in elderly cause this syndrome characterized by rigidity, hyperthermia, confusion and autonomic instability. 4. Withdrawal syndrome: Flu-like symptoms, dizziness, paresthesia, agitation & dysphoric mood are common symptoms following abrupt withdrawal. (N.B. So, they must be stopped gradually). 5. Pregnancy: paroxetine associated with cardiac septal defects in first trimester exposures. (N.B. paroxetine is a category D). 2. Tricyclic Antidepressants (TCAs) Examples: Imipramine, desipramine, clomipramine, nortriptyline and amitriptyline Mechanism of action as antidepressant - The primary mechanism was related to their ability to block the reuptake of noradrenaline and / or 5HT (serotonin) following their release and actions as neurotransmitters. (N.B. These drugs also block other receptors (H1, 5-HT2, α1, and muscarinic). Pharmacological action: 1- CNS:  In depressed patients, they elevate the mood, improve mental alertness, and increase physical activity. (N.B. TCAs do not commonly produce CNS stimulation or mood elevation in normal individuals).  It takes usually not less than 2-3 weeks for drug effect to manifest and a full effect needs a maximum daily dose for at least 6 weeks. 2- Autonomic nervous system:  Anticholinergic effects (atropine like action). 3- CVS:  Cardiac effects attributed to anticholinergic effect and (quinidine like effects).  Orthostatic hypotension attributed to apha-1 adrenergic blocking effect. 4 Prof. Moustafa Mahmoud Hamdy Pharmacokinetics:  The TCAs tend to be well absorbed and have long half-lives. As a result, most are dosed once daily at night because of their sedating effects.  The TCAs are substrates of the CYP2D6 system, so CYP2D6 inhibitors affect TCAs levels. (N.B. genetic polymorphism for CYP2D6 may result in low or extensive metabolism of the TCAs). Adverse effects: 1- Anticholinergic: Manifested by blurred vision, dry mouth, urinary retention (in older people with prostatic hyperplasia), constipation, palpitation, tachycardia and aggravation of narrow-angle glaucoma. 2- CVS: Orthostatic hypotension and ECG changes that may lead to life-threatening arrhythmias. (N.B. they should be taken with caution in patients with ischemic heart disease, arrhythmias or conduction disturbances). 3- CNS: Sedation especially in the first weeks of starting treatment. (N.B. They lower the seizure threshold which is of concern in patients) with liability for seizures as head injury and epilepsy. 4- Weight gain & Sexual dysfunction. 5- They have discontinuation syndrome characterized by cholinergic rebound and flu- like symptoms. 5- Physical dependence is sometimes observed. 3. Selective serotonin-norepinephrine reuptake inhibitors (SNRIs) Examples: venlafaxine and duloxetine. Mechanism of action: All SNRIs bind the serotonin (SERT) and norepinephrine (NET) transporters, as do the TCAs. Adverse effects: 1- Increased blood pressure and heart rate. 2- Insomnia, anxiety and agitation. 3- Cardiac toxicity with venlafaxine overdose 4- Duloxetine is rarely associated with hepatic toxicity. 5 Prof. Moustafa Mahmoud Hamdy 5- (N.B. All the SNRIs have been associated with a discontinuation syndrome resembling that seen with SSRI discontinuation). 4. 5-HT2 Receptor Modulators Mechanism of action:  The principle action of both nefazodone and trazodone appears to be blockade of the 5-HT2A receptor. Inhibition of this receptor is associated with substantial antianxiety, antipsychotic, and antidepressant effects.  Nefazodone is a weak inhibitor of both SERT and NET. Trazodone is a selective inhibitor of SERT with little effect on NET.  Trazodone also has a weak-to-moderate presynaptic α-adrenergic–blocking properties and is a modest antagonist of the H1 receptor. Pharmacokinetics:  Trazodone and nefazodone are rapidly absorbed, but have limited bioavailability because of extensive hepatic metabolism. Adverse effects: 1- Sedative effects, particularly with trazodone. (N.B. the treatment of insomnia is currently the primary application of trazodone). 2- Gastrointestinal effects as nausea 3- Trazodone associated with priapism. 4- Both nefazodone and trazodone are α-blocking agents and result in a dose-related orthostatic hypotension. 5- Nefazodone has been associated with hepatotoxicity. 5. Tetracyclic and Unicyclic Agents Mechanism of action:  Bupropion is modest-to moderate inhibitors of norepinephrine and dopamine reuptake. It is also a blocker of the neural nicotinic receptor. 6 Prof. Moustafa Mahmoud Hamdy  Mirtazapine is an antagonist of the presynaptic α2 autoreceptor and enhances the release of both norepinephrine and 5-HT. In addition, mirtazapine is an antagonist of 5-HT2 and 5-HT3 receptors. (N.B. mirtazapine is a potent H1 antagonist).  The actions of amoxapine and maprotiline are potent NET inhibitors and less potent SERT inhibitors. In addition, both possess anticholinergic properties. Pharmacokinetics:  Bupropion is rapidly absorbed and has a mean protein binding of 85%. It undergoes extensive hepatic metabolism. It has three active metabolites including hydroxybupropion. Adverse effects: 1- Amoxapine is associated with a parkinsonian syndrome due to D2-blocking action. 2- Mirtazapine has significant sedative effect. 3- Maprotiline has TCA-like adverse effects and rarely, seizures. 4- Bupropion is associated with agitation, insomnia, and anorexia. 6. Monoamine Oxidase Inhibitors (MAOIs) Mechanism of action:  MAOIs decrease action of monoamine oxidase and increasing monoamine content.  There are two forms of monoamine oxidase. MAO-A is found primarily in the brain, gut, placenta, and liver; its primary substrates are norepinephrine, epinephrine, and serotonin. MAO-B is found primarily in serotonergic and histaminergic neurons and is distributed in the brain, liver, and platelets. MAO-B acts primarily on dopamine and tyramine. Both MAO-A and -B metabolize tryptamine.  Phenelzine and tranylcypromine are irreversible, nonselective MAOIs. Moclobemide is a reversible and selective inhibitor of MAO-A. Selegiline is an irreversible MAO-B–specific agent at low doses (N.B. at higher doses it becomes a nonselective MAOI). Pharmacokinetics:  The MAOIs are well absorbed from the gastrointestinal tract. 7 Prof. Moustafa Mahmoud Hamdy  Because of the prominent first-pass effects and their tendency to inhibit MAO in the gut (resulting in tyramine pressor effects) (N.B. alternative routes of administration are being developed. For example, selegiline is available in both transdermal and sublingual forms that bypass both gut and liver). These routes decrease the risk of food interactions and provide substantially increased bioavailability. Adverse effects: 1- Orthostatic hypotension, tachycardia and weight gain. 2- Sexual dysfunction and anorgasmia. 3- CNS activation, insomnia, and restlessness. Confusion with higher doses of MAOIs. 4- Phenelzine tends to be sedating. 5- interactions with other drugs and food: a. SSRIs with MAOIs produce a serotonin syndrome. b. MAOIs with tyramine-rich diet or with sympathomimetics. An MAOI prevents the breakdown of tyramine in the gut, and this results in high serum levels that enhance peripheral noradrenergic effects with severe hypertension (hypertension crisis). Thus, patients taking MAOIs require a low-tyramine diet and should avoid foods such as aged cheeses, beer, soy products, pickled food and dried sausages, which contain high amounts of tyramine Clinical pharmacology of antidepressants: 1. Depression:  Following initiation of antidepressant drug treatment there is generally a "therapeutic lag" lasting 3-4 weeks before a measurable therapeutic response becomes evident and some patients may require > 8 weeks for an adequate response.  Except TCAs and MAOIs, other drugs as SSRIs and SNRIs considered the 1st line in treatment of depression.  (N.B. If a partial response has been observed, other drugs may be added to the primary SSRI or SNRI medications; these additive medications include the antidepressant drug bupropion, thyroid hormone, or an atypical antipsychotics 8  (olanzapine). After the successful initial treatment phase, a 6-12 months maintenance treatment phase is typical, after which the drug is gradually withdrawn). Anxiety Disorders:  SSRIs and SNRIs have been approved for all the major anxiety disorders.  (N.B. Antidepressants appear to be at least as effective as, and perhaps more effective than, benzodiazepines in the long-term treatment of these anxiety disorders). Furthermore, antidepressants do not carry the risks of dependence and tolerance that may occur with the benzodiazepines.  OCD is known to respond to serotonergic antidepressants (SSRIs). 2. Pain Disorders a. TCAs used in the treatment of neuropathic pain b. Duloxetine approved for the treatment of chronic joint and muscle pain. 3. Premenstrual Dysphoric Disorder (PMDD)  The SSRIs are beneficial to many women with PMDD. 4. Smoking Cessation  Bupropion was approved as a treatment for smoking cessation. (N.B. Bupropion appears to be about as effective as nicotine patches in smoking cessation).  Nortriptyline may have a role in smoking cessation. 5. Eating Disorders  Fluoxetine was approved for the treatment of bulimia.  Bupropion may have some benefits in treating obesity. 6. Other Uses for Antidepressants a. Enuresis in children: imipramine used to control nocturnal enuresis in children (older than 6 years) through atropine like action. b. Duloxetine is approved for the treatment of urinary stress incontinence. c. SSRIs appear to be helpful for treating vasomotor symptoms in perimenopause. d. SSRIs are known to delay orgasm in patients with premature ejaculation. e. Attention Deficit Hyperactivity Disorders in children: TCAs are effective. 1