Antidepressant drugsد. غادة
Mood DisorderThe most common mood disorders are: Major depression (unipolar depression). Manic-depressive illness (bipolar disorder). Major depression and bipolar disorder are pervasive mood altering illnesses affecting energy, sleep, appetite, and the ability to function.
The symptoms of depression are: Intense feelings of sadness. Hopelessness and Despair. The inability to experience pleasure in usual activities. 4. changes in sleep patterns and appetite, loss of energy, and suicidal thoughts. Mania is characterized by the opposite behavior, that is: enthusiasm rapid thought and speech patterns extreme self-confidence impaired judgment the brain. .
Biogenic amine Theory
Depression: is due to a deficiency of monoamines such as norepinephrine and serotonin at certain key sites in the brain. Mania : is caused by an over production of these neurotransmitters. All clinically useful antidepressant drugs potentiate, either directly or indirectly, the actions of norepinephrine, dopamine, and/or serotonin in the brain.Antidepressant Drugs
Tricyclic / polycyclic antidepressants (TCA). Serotonin /Norepinephrine Reuptake Inhibitors. Selective serotonin-reuptake inhibitors (SSRI). Monoamine oxidase inhibitors (MAOI). Drugs used to treat mania: Lithium salts.1- Tricyclic/polycyclic antidepressants
older tricyclic antidepressants Imipramine (the prototype). Amitriptyline . desipramine . Nortriptyline (a demethylated derivative of imipramine). Protriptyline . Doxepin. Amoxapine. Maprotiline second generationTricyclics/Polycyclics
Examples: Amitriptyline, imipramine Mode of Action: 1- Inhibition of neurotransmitter reuptake: Inhibit norepinephrine , serotonin into presynaptic nerve terminals and Dopamine re-uptake It has been suggested that monoamine receptor densities in the brain may change over a 2 to 4 week period with drug use and may be important in the onset of activity.2. Blocking of receptors: TCAs also block serotonergic, α-adrenergic, histaminic, and muscarinic receptors. This is manifested in terms of side effects.
Mode of action
Pharmacokinetics1. Absorption and distribution: Well absorbed upon oral administration. Widely distributed and readily penetrate into the CNS (their lipophilic nature). This lipid solubility also causes these drugs to have long half-lives (4 to 17 hours). These drugs are metabolized by the hepatic microsomal system (and, thus, may be sensitive to agents that induce or inhibit the CYP450 ) and conjugated with glucuronic acid.
Therapeutic uses
1- TCAs are effective in treating moderate to severe depression. 2- Imipramine has been used to control bed-wetting in children (older than 6 years) by causing contraction of the internal sphincter of the bladder. Note: At present it is used cautiously, because of the inducement of cardiac arrhythmias and other serious cardiovascular problems.3- The TCAs, particularly amitriptyline, have been used to help prevent migraine headache. 4- treat chronic pain syndromes (for example, neuropathic pain) in a number of conditions for which the cause of pain is unclear. 5- Low doses of TCAs, especially can be used to treat insomnia.
Adverse effects
Antimuscarinic effects(blurred vision, xerostomia (dry mouth), urinary retention, tachycardia, constipation, and glaucoma)2. Cardiovascular: life-threatening arrhythmias in an overdose situation. 3. Orthostatic hypotension: block α-adrenergic receptors, causing orthostatic hypotension, dizziness, and reflex tachycardia.4. Sedation: may be prominent, especially during the first several weeks of treatment, and is related to the ability of these drugs to block histamine H1 receptors. 5. Weight gain is a common adverse effect of the TCAs.
6. The tricyclic antidepressants have a narrow therapeutic index; for example, 5 to 6 times the maximal daily dose of imipramine can be lethal. 7- Depressed patients : who are suicidal should be given only limited quantities of these drugs and should be monitored closely.
2- Serotonin /Norepinephrine Reuptake Inhibitors. Venlafaxine , duloxetine inhibit the reuptake of both serotonin and norepinephrine . These agents, termed SNRIs, may be effective in treating depression in patients in whom SSRIs are ineffective.
depression is often accompanied by chronic painful symptoms, such as back pain and muscle pain. This pain is, in part, modulated by serotonin and norepinephrine pathways in the central nervous system (CNS). Both SNRIs and the TCAs, with their dual inhibition of both serotonin and norepinephrine reuptake, are sometimes effective in relieving pain associated with diabetic peripheral neuropathy, postherpeutic neuralgia, fibromyalgia, and low back pain.
The SNRIs, unlike the TCAs, have little activity at α-adrenergic, muscarinic, or histamine receptors and, thus, have fewer of these receptor-mediated adverse effects than the TCAs..
3- Selective Serotonin–Reuptake Inhibitors (SSRI Inhibitors) The SSRI are a new group of chemically antidepressant drugs that specifically inhibit serotonin reuptake. Compared with tricyclic antidepressants, the SSRIs cause fewer anticholinergic effects and lower cardiotoxicity. Moreover, the SSRIs have little blocking activity at muscarinic, α-adrenergic, and histaminic H1 receptors.
Therefore, common side effects associated with TCAs, are not commonly seen with the SSRIs. Because they have different adverse effects and are relatively safe even in overdose, the SSRIs have largely replaced TCAs and monoamine oxidase inhibitors (MAOIs) as the drugs of choice in treating depression.
Examples SSRI. : Fluoxetine,
Fluoxetine is effective in the treatment of major depression. The drug is free of most of the troubling side effects of tricyclic antidepressants. Fluoxetine is preferred over tricyclic antidepressantsMechanism of action The SSRIs block the reuptake of serotonin, leading to increased concentrations of the neurotransmitter in the synaptic cleft. Antidepressants, of SSRIs, typically take at least 2 weeks to produce significant improvement in mood, and maximum benefit may require up to 12 weeks or more.
Therapeutic uses
effective in treating depression, Fluoxetine is effective in treating obsessive-compulsive disorder. The drug has been used for a variety of other indications, including: anorexia nervosa, panic disorder, pain associated with diabetic neuropathy.Adverse affects:
Gastrointestinal symptoms. Sleep disturbance (insomnia and somnolence ) anxiety (acutely), tremor. Overdoses of fluoxetine do not cause cardiac arrhythmias but can cause seizures. For example, in a report of patients who took an overdose of fluoxetine (up to 1200 mg compared with 20 mg/day as a therapeutic dose) about half of the patients had no symptoms.
4- MAO Inhibitors Monoamine oxidase Inhibitors
(MAO) is a mitochondrial enzyme found in nerve and other tissues, such as the gut and liver. In the neuron, MAO functions as a “safety valve” to oxidatively deaminate and inactivate any excess neurotransmitters(for example, norepinephrine, dopamine, and serotonin) that may leak out of synaptic vesicles when the neuron is at rest.MAO Inhibitors
Examples: Phenylzine Mode of Action of MAO enzyme : MAO inactivates excess NE, DO, 5-HT Inhibitors (MAO enzyme) increase the amounts of these neurotransmittersThe MAO inhibitors may irreversibly or reversibly inactivate the enzyme (MAO enzyme), permitting neurotransmitter molecules to escape degradation and therefore to both accumulate within the presynaptic neuron and to leak into the synaptic space. This causes activation of norepinephrine and serotonin receptors, and may be responsible for the antidepressant action of these drugs.
These drugs inhibit not only MAO in the brain but also MAO in the liver and gut that catalyzes oxidative deamination of drugs and potentially toxic substances, such as tyramine, which is found in certain foods. The MAOIs, therefore, show a high incidence of drug–drug and drug–food interactions.
Therapeutic uses
To depressed patients who are unresponsive or allergic to tricyclic antidepressants or who experience strong anxiety. Patients with low psychomotor activity may benefit from the stimulant properties of MAO inhibitors. Treatment of phobic states. Atypical depression, may respond to MAOIs. Atypical depression is characterized by labile mood, rejection sensitivity and appetite disorders.Adverse effects
Tyramine, contained in certain foods, such as aged cheeses, chicken liver, beer, and red wines, is normally inactivated by MAO in the gut. Individuals receiving a MAO inhibitor are unable to degrade tyramine obtained from the diet. Tyramine causes the release of large amounts of stored catecholamines from nerve terminals, resulting in headache, tachycardia, nausea, hypertension, cardiac arrhythmias, and stroke.Patients must therefore be educated to avoid tyramine-containing foods. Phentolamine or prazosin are helpful in the management of tyramine-induced hypertension. Use of MAO inhibitors is now limited because of the complicated dietary restrictions required of patients taking MAO inhibitors.
Clinical uses to treatment with tricyclic antidepressants, MAO inhibitors, or SSRIs;
Several psychosomatic disorders may respond at least partly to treatment with tricyclic antidepressants, MAO inhibitors, or SSRIs; among these are: Chronic pain disorders, including diabetic and other peripheral neuropathic syndromes Fibromyalgia; chronic fatigue.
3- Peptic ulcer and irritable bowel syndrome. 4- Hot flashes of menopause. 5- cataplexy and sleep apnea. 6- migraine. These disorders may have some psychobiological relationship to mood or anxiety disorders.