| mao inhibitor action | Although MAO is fully inhibited after several days of treatment, the antidepressant action of the MAOIs, like that of the SSRIs and TCAs, is delayed several weeks. Selegiline and tranylcypromine have an amphetamine-like stimulant effect that may produce agitation or insomnia. |
| depression | The symptoms of depression are intense feelings of sadness, hopelessness, and despair as well as the inability to experience pleasure in usual activities, changes in sleep patterns and appetite, loss of energy, and suicidal thoughts. Mania is characterized by the opposite behavior: enthusiasm, rapid thought and speech patterns, extreme self-confidence, and impaired judgment. |
| antidepressant use | Most clinically useful antidepressant drugs potentiate, either directly or indirectly, the actions of norepinephrine and/or serotonin in the brain. This, along with other evidence, led to the biogenic amine theory |
| therupetic use moai | The MAOIs are indicated for depressed patients who are unresponsive or allergic to TCAs or who experience strong anxiety. Patients with low psychomotor activity may benefit from the stimulant properties of the MAOIs. These drugs are also useful in the treatment of phobic states. A special subcategory of depression, called atypical depression, may respond preferentially to MAOIs. Atypical depression is characterized by labile mood, rejection sensitivity, and appetite disorders. Because of their risk for drug-drug and drug-food interactions, the MAOIs are considered to be last-line agents in many treatment venues. |
| monoamine hypothesis problem | However, the amine theory of depression and mania is overly simplistic. It fails to explain why the pharmacologic effects of any of the antidepressant and anti-mania drugs on neurotransmission occur immediately, whereas the time course for a therapeutic response occurs over several weeks. Furthermore, the potency of the antidepressant drugs in blocking neurotransmitter uptake often does not correlate with clinically observed antidepressant effects. This suggests that decreased uptake of the neurotransmitter is only an initial not be directly responsible for the antidepressant effects. It has been proposed that presynaptic inhibitory receptor densities in the brain decrease over a 2 to 4 week period with antidepressant drug use. This down-regulation of inhibitory receptors permits greater synthesis and release of neurotransmitters into the synaptic cleft and enhanced signaling in the postsynaptic neurons, presumably leading to a therapeutic response. effect of the drugs, which may not be directly responsible for the antidepressant effects. It has been proposed that presynaptic inhibitory receptor densities in the brain decrease over a 2 to 4 week period with antidepressant drug use. This down-regulation of inhibitory receptors permits greater synthesis and release of neurotransmitters into the synaptic cleft and enhanced signaling in the postsynaptic neurons, presumably leading to a therapeutic response.Difficulties with this hypothesis include the facts that (1) postmortem studies of patients do not reveal decreases in the brain levels of NE or 5-HT; (2) although antidepressant drugs may cause changes in brain amine activity within hours, clinical response requires weeks; (3) most antidepressants ultimately cause a downregulation of amine receptors; (4) bupropion has minimal effects on brain NE or 5-HT; (5) Brain-derived neurotrophic factor (BDNF) is depressed in the brains of depressed patients. |
| pharmacokinetics maoi | These drugs are well absorbed after oral administration, but antidepressant effects require at least 2 to 4 weeks of treatment. Enzyme regeneration, when irreversibly inactivated, varies, but it usually occurs several weeks after termination of the drug. Thus, when switching antidepressant agents, a minimum of 2 weeks of delay must be allowed after termination of MAOI therapy and the initiation of another antidepressant from any other class. MAOIs are metabolized and excreted rapidly in urine. |
| amine hypothesis of mood | The amine hypothesis of mood postulates that brain amines, particularly norepinephrine (NE) and serotonin (5-HT), are neurotransmitters in pathways that function in the expression of mood. According to the hypothesis, a functional decrease in the activity of such amines is thought to result in depression;
a functional increase of activity results in mood elevation. |
| III. SELECTIVE SEROTONIN REUPTAKE INHIBITORS | are a group of chemically diverse antidepressant drugs that specifically inhibit serotonin reuptake, having 300- to 3000-fold greater selectivity for the serotonin transporter, as compared to the norepinephrine transporter. it exhibit little ability to block the dopamine transporter muscarinic, α-adrenergic, and histaminic H1 receptors. |
| ssri adverse effect comparison | Because they have fewer 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. |
| seizures | Because the convulsive threshold is lowered by TCAs and MAOIs, seizures may occur with overdoses of these agents. Overdoses of maprotiline and the SSRIs have also caused seizures. |
| ssris include | SSRIs include fluoxetine (the prototypic drug), citalopram escitalopram fluvoxamine paroxetine and sertraline. Both citalopram and fluoxetine are racemic mixtures, of which the respective S-enantiomers are the more potent inhibitors of the serotonin reuptake pump. Escitalopram is the pure S-enatiomer of citalopram. |
| other uses of tca | As alternative agents, tricyclic drugs continue to be most useful in patients with psychomotor retardation, sleep disturbances, poor appetite, and weight loss. TCAs are also used in the treatment of bipolar affective disorders, acute panic attacks, phobic disorders , enuresis, attention deficit hyperkinetic disorder, and chronic pain states. |
| action ssri | The SSRIs block the reuptake of serotonin, leading to increased concentrations of the neurotransmitter in the synaptic cleft and, ultimately, to greater postsynaptic neuronal activity. |
| antidepressant time period | Antidepressants, including SSRIs, typically take at least 2 weeks to produce significant improvement in mood, and maximum benefit may require up to 12 weeks or more. However, none of the antidepressants are uniformly effective. Approximately 40 percent of depressed patients treated with adequate doses for 4 to 8 weeks do not respond to the antidepressant agent. Patients who do not respond to one antidepressant may respond to another, and approximately 80 percent or more will respond to at least one antidepressant drug. [Note: These drugs do not usually produce central nervous system (CNS) stimulation or mood elevation in normal individuals.] |
| other uses of moai | MAOIs are thought to be most useful in patients with significant anxiety, phobic features, and hypochondriasis. Selegiline, the MAO type B inhibitor used
in parkinsonism is now available in a skin-patch formulation for treatment of depression. |
| therupetic use ssri | The primary indication for SSRIs is depression, for which they are as effective as the TCAs. OCD gad ptsd panic disorder social anxiety disorder, premenstrual dysphoric disorder, and bulimia nervosa (only fluoxetine is approved). |
| snri other uses | The SNRIs (eg, duloxetine, venlafaxine) are effective in patients with neuropathic pain and fibromyalgia; duloxetine is also approved for the pain of diabetic neuropathy. |
| pharmacokinetics ssri | All of the SSRIs are well absorbed after oral administration. Peak levels are seen in approximately 2 to 8 hours on average. Food has little effect on absorption (except with sertraline, for which food increases its absorption). Only sertraline undergoes significant first-pass metabolism. The majority of SSRIs have plasma half-lives that range between 16 and 36 hours. Metabolism by cytochrome P450 (CYP450)-dependent enzymes and glucuronide or sulfate conjugation occur extensively. [Note: These metabolites do not generally contribute to the pharmacologic activity.] |
| pharmacokinetics fluoxetine | Fluoxetine differs from the other members of the class in two respects. First, it has a much longer half-life (50 hours) and is available as a sustained-release preparation allowing once-weekly dosing. Second, the metabolite of the S-enantiomer, S-norfl uoxetine, is as potent as the parent compound. The half-life of the metabolite is quite long, averaging 10 days. |
| ssri hepatic enzyme inhibitor | Fluoxetine and paroxetine are potent inhibitors of a hepatic CYP450 isoenzyme (CYP2D6) responsible for the elimination of TCAs, neuroleptic drugs, and some antiarrhythmic and β-adrenergic antagonist drugs. [Note: About 7 percent of the Caucasian population lacks this P450 enzyme and, therefore, metabolize fluoxetine and other substrates of this enzyme very slowly. These individuals may be referred to in the literature as “poor metabolizers.”] Other cytochrome enzymes (CYP2C9/19, CYP3A4, CYP1A2) are involved with SSRI metabolism and may also be inhibited to various degrees by the SSRIs. Thus, they may affect the metabolism of multiple medications. Fluoxetine inhibits CYP2D6 and to a lesser extent CYP3A4 isoforms; fluvoxamine inhibits CYP1A2 and paroxetine CYP2D6. Through its inhibition of CYP2D6, fluoxetine can increase plasma levels of several drugs including dextromethorphan, propranolol, tamoxifen, and the TCAs. Citalopram causes fewer drug interactions than other SSRIs. |
| ssri other uses | Clomipramine and the SSRIs are effective in obsessive-compulsive disorders. SSRIs are approved for patients who suffer from generalized anxiety disorders, panic attacks, social phobias, post-traumatic stress disorder, bulimia, and premenstrual dysphoric disorder, and they may also be useful in the treatment of alcohol dependence. |
| execretion ssri | Excretion of the SSRIs is primarily through the kidneys, except for paroxetine and sertraline, which also undergo fecal excretion (35 and 50 percent, respectively). Dosages of all of these drugs should be adjusted downward in patients with hepatic impairment. |
| adverse effect ssri | headache, sweating, anxiety and agitation, gastrointestinal (GI) effects (nausea, vomiting, diarrhea), weakness and fatigue, sexual dysfunction, changes in weight, sleep disturbances (insomnia and somnolence), and the above-mentioned potential for drug-drug interactions. Sleep disturbances: Paroxetine and fluvoxamine are generally more sedating than activating, and they may be useful in patients who have difficulty sleeping. Sexual dysfunction: Loss of libido, delayed ejaculation, and anorgasmia are underreported side effects often noted by clinicians, but these are not prominently featured in the list of standard side effects.Extrapyramidal effects early in treatment may include akathisia, dyskinesias, and dystonic reactions. Seizures are a consequence of gross overdosage. Cardiac effects of citalopram overdose include QT prolongation. A withdrawal syndrome has been described for SSRIs, which includes nausea, dizziness, anxiety, tremor, and palpitations. |
| Jitteriness ssri treatment | Jitteriness can be alleviated by starting with low doses or by adjunctive use of benzodiazepines. |
| serotonin syndrome | A serotonin syndrome was first described for an interaction between fluoxetine and an MAOI. This life-threatening syndrome includes severe muscle rigidity, myoclonus, hyperthermia, cardiovascular instability, and marked CNS stimulatory effects, including seizures. Drugs implicated include MAOIs, TCAs st johns wort dextromethorphan, meperidine and possibly illicit recreational drugs such as MDMA (“ecstasy”). Antiseizure drugs, muscle relaxants, and blockers of 5-HT receptors (eg, cyproheptadine) have been used in the management of the syndrome. |
| ssri sexual dysfunction | One option for managing SSRI-induced sexual dysfunction is to replace the offending antidepressant with an antidepressant having fewer sexual side effects, such as bupropion or mirtazapine. Alternatively, the dose of the drug may be reduced. In men with erectile dysfunction and depression, treatment with sildenafil, vardenafil, or tadalafil may improve sexual function. |
| 3. Use in children and teenagers: | 3. Use in children and teenagers: Antidepressants should be used cautiously in children and teenagers, because about 1 out of 50 children report suicidal ideation as a result of SSRI treatment. Pediatric patients should be observed for worsening depression and suicidal thinking whenever any antidepressant is started or its dose is increased or decreased. Fluoxetine, sertraline, and fluvoxamine are approved obsessive-compulsive disorder, and fluoxetine is approved to treat childhood depression. |
| 4. Overdoses: | seizures are a possibility because all antidepressants may lower the seizure threshold. All SSRIs have the potential to cause a serotonin syndrome that may include the symptoms of hyperthermia, muscle rigidity, sweating, myoclonus (clonic muscle twitching), and changes in mental status and vital signs when used in the presence of a MAOI or other highly serotonergic drug. Therefore, extended periods of washout for each drug class should occur prior to the administration of the other class of drugs. |
| 5. Discontinuation syndrome: | Whereas all of the SSRIs have the potential for causing a discontinuation syndrome after their abrupt withdrawal, the agents with the shorter half-lives and having inactive metabolites have a higher risk for such an adverse reaction. Fluoxetine has the lowest risk of causing an SSRI discontinuation syndrome. Possible signs and symptoms of such a serotonin-related discontinuation syndrome include headache, malaise and flu-like symptoms, agitation and irritability, nervousness, and changes in sleep pattern. |
| snri uses | Venlafaxine desvenlafaxine and duloxetine inhibit the reuptake of both serotonin and norepinephrine. SNRIs may be effective in treating depression in patients in whom SSRIs are ineffective. Furthermore, depression is often accompanied by chronic painful symptoms, such as backache and muscle aches, against which SSRIs are also relatively ineffective. This pain is, in part, modulated by serotonin and norepinephrine pathways in the CNS. Both SNRIs and TCAs, with their dual actions of inhibiting both serotonin and norepinephrine reuptake, are sometimes effective in relieving physical symptoms of neuropathic pain such as diabetic peripheral neuropathy. |
| snri activity | However, the SNRIs have little activity at adrenergic, muscarinic, or histamine receptors and, thus, have fewer of these receptor-mediated adverse effects than the TCAs. Venlafaxine, desvenlafaxine, and duloxetine may precipitate a discontinuation syndrome if treatment is abruptly stopped. |
| venlafaxine | Venlafaxine is a potent inhibitor of serotonin reuptake and, at medium to higher doses, is an inhibitor of norepinephrine reuptake. It is also a mild inhibitor of dopamine reuptake at high doses. Venlafaxine has minimal inhibition of the CYP450 isoenzymes and is a substrate of the CYP2D6 isoenzyme.Venlafaxine has less affinity for the NE transporter than desvenlafaxine or duloxetine. |
| venlafaxine pharmacokinetics | The half-life of the parent compound plus venlafaxine active metabolite is approximately 11 hours. Desvenlafaxine is the active, demethylated, metabolite of the parent compound venlafaxine. |
| venlafaxine side effects | The most common side effects of venlafaxine are nausea, headache, sexual dysfunction, dizziness, insomnia, sedation, and constipation. At high doses, there may be an increase in blood pressure and heart rate. Desvenlafaxine is not considered to have a significantly different clinical or adverse effect profile compared to venlafaxine.There have been reports of cardiotoxicity with overdose of venlafaxine. Venlafaxine causes a dose-dependent increase in blood pressure and has CNS stimulant effects similar to those of the SSRIs. Severe withdrawal symptoms can occur, even after missing a single dose of venlafaxine. |
| duloxetine | Duloxetine inhibits serotonin and norepinephrine reuptake at all doses. It is extensively metabolized in the liver to numerous metabolites.Duloxetine should not be administered to patients with hepatic insufficiency. Metabolites are excreted in the urine, and the use of duloxetine is not recommended in patients with end-stage renal disease. Food delays the absorption of the drug. The half-life is approximately 12 hours. GI |
| duloxetine side effect | side effects are common with duloxetine, including nausea, dry mouth, and constipation. Diarrhea and vomiting are seen less often. Insomnia, dizziness, somnolence, and sweating are also seen. Sexual dysfunction also occurs along with the possible risk for an increase in either blood pressure or heart rate. Duloxetine is a moderate inhibitor of CYP2D6 and CYP3A4 isoenzymes.Duloxetine is also reported to cause liver dysfunction. |
| V. ATYPICAL ANTIDEPRESSANTS | The atypical antidepressants are a mixed group of agents that have actions at several different sites. they include bupropion mirtazapine nefazodone and trazodone. They are not any more efficacious than the TCAs or SSRIs, but their side effect profiles are different. |
| bupropion | This drug acts as a weak dopamine and norepinephrine reuptake inhibitor to alleviate the symptoms of depression. Its short half-life may require more than once-a-day dosing or the administration of an extended-release formulation. Bupropion also assists in decreasing the craving and attenuating the withdrawal symptoms for nicotine in tobacco users trying to quit smoking.The mechanism of antidepressant action of bupropion is unknown—the drug has no effect on either 5-HT or NE receptors or on amine transporters. |
| bupropion side effect | Side effects may include dry mouth, sweating, nervousness, tremor, a very low incidence of sexual dysfunction, and an increased risk for seizures at high doses. Bupropion is metabolized by the CYP2B6 pathway and is considered to have a relatively low risk for drug-drug interactions. The daily dose of bupropion should be within the manufacturer’s recommendations to minimize the risk of seizures that may occur in above recommended doses. Its use should also be avoided in patients at risk for seizures or who have eating disorders (such as bulimia).Adverse effects of bupropion include anxiety, agitation, dizziness aggravation of psychosis |
| B. Mirtazapine mechanism | This drug enhances serotonin and norepinephrine neurotransmission via mechanisms related to its ability to block presynaptic α2 receptors. Additionally, it may owe at least some of its antidepressant activity to its ability to block 5-HT2 receptors. It is a sedative because of its potent antihistaminic activity, but it does not cause the antimuscarinic side effects of the TCAs, or interfere with sexual functioning, as do the SSRIs. Increased appetite and weight gain frequently occur. Mirtazapine is markedly sedating, which may be an advantage in depressed patients having difficulty sleeping. |
| mirtazapine side effects | Mirtazapine causes weight gain and is markedly sedating, as is trazodone. |
| C. Nefazodone and trazodone | These drugs are weak inhibitors of serotonin reuptake. Their therapeutic benefit appears to be related to their ability to block postsynaptic 5-HT2A receptors. With chronic use, these agents may desensitize 5-HT1A presynaptic autoreceptors and, thereby, increase serotonin release. They are sedating, probably because of their potent H1-blocking activity. they are weak inhibitors of NE and 5-HT transporters their half-lives are short and usually require administration 2 or 3 times daily. |
| C. Nefazodone and trazodone side effect | Trazodone has been associated with causing priapism causes weight gain and is markedly sedating and nefazodone has been associated with the risk for hepatotoxicity. Both agents also have mild to moderate α1-receptor antagonism contributing to orthostasis and dizziness. |
| nefazodone hepatic effect | Through its inhibitory action on CYP3A4, nefazodone enhances the actions of several drugs including carbamazepine, clozapine, HMG-CoA reductase inhibitors (“statins”), and TCAs. Though rare, nefazodone has caused life-threatening hepatotoxicity requiring liver transplantation. |
| VI. TRICYCLIC ANTIDEPRESSANTS | The TCAs block norepinephrine and serotonin reuptake into the neuron. The TCAs include the tertiary amines imipramine (the prototype drug), amitriptyline clomipramine doxepin trimipramine. The TCAs also include the secondary amines desipramine and nortriptyline (the respective N demethylated metabolites of imipramine and amitriptyline) and protriptyline. Maprotiline and amoxapine are related “tetracyclic” antidepressant agents and are commonly included in the general class of TCAs.These drugs are a valuable alternative for patients who do not respond to SSRIs. |
| VI. TRICYCLIC ANTIDEPRESSANTS moa | Inhibition of neurotransmitter reuptake: TCAs and amoxapine are potent inhibitors of the neuronal reuptake of norepinephrine and serotonin into presynaptic nerve terminals. At therapeutic concentrations, they do not block dopamine transporters. By blocking the major route of neurotransmitter removal, the TCAs cause increased concentrations of monoamines in the synaptic cleft. Maprotiline and desipramine are relatively selective inhibitors of norepinephrine reuptake. 2. Blocking of receptors: TCAs also block serotonergic, α-adrenergic, histaminic, and muscarinic receptors. It is not known if any of these actions produce TCAs’ therapeutic benefit. However, actions at these receptors are likely responsible for many of the adverse effects of the TCAs. Amoxapine also blocks 5-HT2 and D2 |
| tca actions | The TCAs elevate mood, improve mental alertness, increase physical activity, and reduce morbid preoccupation in 50 to 70 percent of individuals with major depression. The onset of the mood elevation is slow, requiring 2 weeks or longer. These drugs do not commonly produce CNS stimulation or mood elevation in normal individuals. Physical and psychological dependence has been rarely reported, however, this necessitates slow withdrawal to minimize discontinuation syndromes and cholinergic rebound effects. These drugs, like all of the antidepressants, can be used for prolonged treatment of depression. |
| Imipramine use | Imipramine has been used to control bed-wetting in children (older than age 6 years) by causing contraction of the internal sphincter of the bladder. At present, it is used cautiously because of the inducement of cardiac arrhythmias and other serious cardiovascular problems. |
| therupetic use tca | The TCAs are effective in treating moderate to severe depression. Some patients with panic disorder also respond to TCAs. The TCAs, particularly amitriptyline, have been used to treat migraine headache and chronic pain syndromes (for example, neuropathic pain) in a number of conditions for which the cause of the pain is unclear. Low doses of TCAs, especially doxepin, can be used to treat insomnia. |
| tca pharmacokinetics | TCAs are well absorbed upon oral administration. Because of their lipophilic nature, they are widely distributed and readily penetrate into the CNS. This lipid solubility also causes these drugs to have variable halflives (for example, 4 to 17 hours for imipramine). As a result of their variable first-pass metabolism in the liver, TCAs have low and inconsistent bioavailability. Therefore, the patient’s response and plasma levels can be used to adjust dosage. The initial treatment period is typically 4 to 8 weeks. The dosage can be gradually reduced to improve tolerability, unless relapse occurs. These drugs are metabolized by the hepatic microsomal system (and, thus, may be sensitive to agents that induce or inhibit the CYP450 isoenzymes) and conjugated with glucuronic acid. Ultimately, the TCAs are excreted as inactive metabolites via the kidney. They have high volumes of distribution and are not readily dialyzable. Extensive hepatic metabolism is required before their elimination; plasma half-lives of 8–36 h usually permit once-daily dosing. |
| maoi adverse effects | Other possible side effects of treatment with MAOIs include drowsiness, orthostatic hypotension, blurred vision, dry mouth, dysuria, and constipation. MAOIs and SSRIs should not be coadministered due to the risk of the life-threatening “serotonin syndrome.” Both types of drugs require washout periods of at least 2 weeks before the other type is administered, with the
exception of fluoxetine, which should be discontinued at least 6 weeks
before a MAOI is initiated. Combination of MAOIs and bupropion can produce seizures. CNS stimulation leading to agitation and convulsions. In the absence of indirect sympathomimetics, MAOIs typically lower blood pressure; overdosage with these drugs may result in shock, hyperthermia, and seizures. |
| tca adversa effects | Blockade of muscarinic receptors leads to blurred vision, xerostomia (dry mouth), urinary retention, sinus tachycardia, constipation, and aggravation of narrow-angle glaucoma. These agents also affect cardiac conduction similarly to quinidine, which may precipitate life-threatening arrhythmias should an overdose of one of these drugs be taken. The TCAs also block α-adrenergic receptors, causing orthostatic hypotension, dizziness, and reflex tachycardia. In clinical practice, this is the most serious problem in elderly adults. Imipramine is the most likely, and nortriptyline the least likely, to cause orthostatic hypotension. 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. Weight gain is a common adverse effect of the TCAs. Sexual dysfunction, as evidenced by erectile dysfunction in men and anorgasmia in women, occurs in a significant minority of patients, but the incidence is still considered to be lower than the incidence of sexual dysfunction associated with the SSRIs. excessive sedation, lassitude, fatigue, and, occasionally, confusion; electrocardiogram (ECG) abnormalities, and cardiomyopathies tremor and paresthesias; and weight gain. Overdosage with tricyclics is extremely hazardous, and the ingestion of as little as a 2-week supply has been lethal. Manifestations include (1) agitation, delirium, neuromuscular irritability, convulsions, and coma; (2) respiratory depression and circulatory collapse; (3) hyperpyrexia; and (4) cardiac conduction defects and severe arrhythmias. The “3 Cs”—coma, convulsions, and cardiotoxicity— are characteristic. |
| tca drug interactions | Tricyclic drug interactions include additive depression of the CNS with other central depressants, including ethanol, barbiturates, benzodiazepines, and opioids. Tricyclics may also cause reversal of the antihypertensive action of guanethidine by blocking its transport into sympathetic nerve endings. Less commonly, tricyclics may interfere with the antihypertensive actions of methylnorepinephrine (the active metabolite of methyldopa) and clonidine. |
| tca precautions | 1. Precautions : TCAs should be used with caution in patients with bipolar disorder, even during their depressed state, because antidepressants may cause a switch to manic behavior. The TCAs have a narrow therapeutic index (for example, five- to sixfold the maximal daily dose of imipramine can be lethal). Depressed patients who are suicidal should be given only limited quantities of these drugs and be monitored closely. The TCAs may exacerbate certain medical conditions, such as unstable angina, benign prostatic hyperplasia, epilepsy, and preexisting arrhythmias. Caution should be exercised with their use in very young or very old patients as well. |
| maoi hypertensive crisis | Severe and often unpredictable side effects, due to drug-food and drug-drug interactions, limit the widespread use of MAOIs. For example, tyramine, which is contained in certain foods, such as aged cheeses and meats, chicken liver, pickled or smoked fish (such as anchovies or herring), and red wines, is normally inactivated by MAO in the gut.
Individuals receiving a MAOI are unable to degrade tyramine obtained from the diet. Tyramine causes the release of large amounts of stored catecholamines from nerve terminals, resulting in what is termed a “hypertensive crisis,” with signs and symptoms such as occipital headache, stiff neck, tachycardia, nausea, hypertension, cardiac arrhythmias, seizures, and, possibly, stroke. Patients must, therefore, be educated to avoid tyramine-containing foods. Phentolamine and prazosin are helpful in the management of tyramine-induced hypertension.
[Note: Treatment with MAOIs may be dangerous in severely depressed patients with suicidal tendencies. Purposeful consumption of tyramine-containing foods is a possibility.] |
| maoi types | are structurally related to amphetamines and are orally active. The older, standard drugs inhibit both MAO-A (monoamine oxidase type A), which metabolizes NE, 5-HT, and tyramine, and MAO-B (monoamine oxidase type A), which metabolizes dopamine. Tranylcypromine is the fastest in onset of effect but has a shorter duration of action (about 1 week) than other MAOIs (2–3 weeks). In spite of these prolonged actions, the MAOIs are given daily. They are inhibitors of hepatic drug-metabolizing enzymes and cause drug interactions. Selegiline, a selective inhibitor of MAO type B, was recently approved for treatment of depression |
| mao | MOA 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 neurotransmitter molecules (norepinephrine, dopamine, and serotonin) that may leak out of synaptic vesicles when the neuron is at rest. The MAO inhibitors (MAOIs) may irreversibly or reversibly inactivate the enzyme, permitting neurotransmitter molecules to escape degradation and, therefore, to both accumulate within the presynaptic neuron and leak into the synaptic space. This is believed to cause activation of norepinephrine and serotonin receptors, and it may be responsible for the indirect antidepressant action of these drugs. |
| MAOI IN USE | Four MAOIs are currently available for treatment of depression: phenelzine tranylcypromine isocarboxazid and the agent that was prior-approved for Parkinson disease, but is now also approved for depression, selegiline, which is the first antidepressant available in a transdermal delivery system. Use of MAOIs is now limited due to the complicated dietary restrictions required of patients taking them |
| ssri snri hetrocyclic toxicity | Amoxapine, maprotiline, mirtazapine, and trazodone cause some autonomic effects. Amoxapine is also a dopamine receptor blocker and may cause akathisia, parkinsonism, and the amenorrhea-galactorrhea syndrome.
Seizures and cardiotoxicity are prominent features of overdosage with amoxapine and maprotiline. |
| maoi moa | Most MAOIs, such as phenelzine, form stable complexes with the enzyme, causing irreversible inactivation. This results in increased stores of norepinephrine, serotonin, and dopamine within the neuron and subsequent diffusion of excess neurotransmitter into the synaptic space. These drugs inhibit not only MAO in the brain, but also MAO in the liver and gut that catalyze 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. |
| selegine pharmacokinetics | Selegiline administered as the transdermal patch may produce less inhibition of gut and hepatic MAO at low doses because it avoids first-pass metabolism. |
