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214 Cards in this Set
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- Back
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Lamotrigine was approved by the US Food and Drug Administration (FDA) for maintenance treatment of bipolar X disorder in ?.
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one, 2003
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Compare Li to Lamotrigine
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Although comparatively new when compared with lithium, the gold standard of bipolar maintenance therapy, lamotrigine has very real advantages compared with that agent in terms of tolerability, safety, and convenience.
For example, lamotrigine treatment is associated with no significant metabolic or neurologic effects, and does not require laboratory testing of plasma concentrations. In contrast to lithium however, lamotrigine does not have any acute antimanic effect |
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Lamotrigine half-life? excretion?
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Lamotrigine is completely absorbed, has bioavailability of 98 percent, and has a steady-state plasma half-life of 25 hours. The rate of lamotrigine's metabolism varies, however, over a sixfold range, depending on which other drugs are administered concomitantly. Dosing is escalated slowly to twice-a-day maintenance dosing. Food does not affect its absorption, and it is 55 percent protein bound in the plasma; 94 percent of lamotrigine and its inactive metabolites are excreted in the urine
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Lamotrigine MOA?
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Among the better-delineated biochemical actions of lamotrigine are blockade of voltage-sensitive sodium channels, which in turn modulate release of glutamate and aspartate, and a slight effect on calcium channels. Lamotrigine modestly increases plasma serotonin concentrations, possibly through inhibition of serotonin reuptake, and is a weak inhibitor of serotonin 5-HT3 receptors.
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Lamotrigine modestly increases plasma serotonin concentrations, possibly through inhibition of serotonin reuptake, and is a weak inhibitor of serotonin receptors
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5-HT3
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Lamotrigine indications in BP1 Ds?
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Lamotrigine is indicated in the maintenance treatment of bipolar disorder and may prolong the time between episodes of depression and mania. It is more effective in lengthening the intervals between depressive episodes than manic episodes. It is also effective as treatment for rapid-cycling bipolar disorder.
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Lamotrigine side fx most common?
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The most common adverse effects—dizziness, ataxia, somnolence, headache, diplopia, blurred vision, and nausea—are typically mild. Cognitive impairment and joint or back pain may occur
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Lamotrigine concerning side fx?
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The appearance of a rash, which is common and occasionally very severe, is a source of concern. About 8 percent of patients started on lamotrigine develop a benign maculopapular rash during the first 4 months of treatment, and the drug should be discontinued if a rash develops. Although these rashes are benign, concern is that in some cases, they may represent early manifestations of a Stevens-Johnson syndrome or toxic epidermal necrolysis. Nevertheless, even if lamotrigine is discontinued immediately on development of rash or other signs of hypersensitivity reaction, such as fever and lymphadenopathy, this may not prevent subsequent development of a life-threatening rash or permanent disfiguration.
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Lamotrigine rash rates?
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Estimates of the rate of serious rash vary, depending on the source of the data. In some studies, the incidence of serious rashes was 0.08 percent in adult patients receiving lamotrigine as initial monotherapy and 0.13 percent in adult patients receiving lamotrigine as adjunctive therapy. German registry data, based on clinical practice, suggest that the risk of rash may be as low as 1 of 5,000 patients. The appearance of any type of rash necessitates immediate discontinuation of drug administration
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What increases risk of rash?
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It is known that the likelihood of a rash increases if the recommended starting dose and speed of dose increase exceed what is recommended.
Concomitant administration of valproic acid also increases risk, and should be avoided if possible. If valproate is used, a more conservative dosing regimen is followed. Children and adolescents under 16 years of age appear to be more susceptible to rash with lamotrigine. If patients miss more than four consecutive days of lamotrigine treatment, they need to restar |
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Lamotrigine starting dose?
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Week 1&2: 12.5mg or 25mg
Week 3&4: 25 to 50mg Week 5: 100mg Increase then by 50mg Target dose: up to 200mg In the clinical trials leading to the approval of lamotrigine as a treatment for bipolar disorder, no consistent increase in efficacy was associated with doses above 200 mg per day |
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Lamotrigine and pregnancy drug risk?
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Pregnancy registry data suggest a possible association between lamotrigine and an increased risk of nonsyndromic oral clefts in infants exposed to lamotrigine during the first trimester of pregnancy.
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Lamotrigine drug Intx?
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The most potentially serious lamotrigine drug interaction involves concurrent use of valproic acid, which doubles serum lamotrigine concentrations.
Lamotrigine decreases the plasma concentration of valproic acid by 25 percent. Sertraline (Zoloft) also increases plasma lamotrigine concentrations, but to a lesser extent than does valproic acid. Lamotrigine concentrations are decreased by 40 percent to 50 percent with concomitant administration of carbamazepine, phenytoin, or phenobarbital. Combinations of lamotrigine and other anticonvulsants have complex effects on the time of peak plasma concentration and the plasma half-life of lamotrigine |
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Lamotrigine concentrations are decreased by 40 percent to 50 percent with concomitant administration of ?
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carbamazepine, phenytoin, or phenobarbital.
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Lamotrigine should not be taken by anyone under the age of ?? years
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16
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Appearance of any type of rash necessitates ?(slow, gradual, immediate) discontinuation of lamotrigine administration
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immediate.
Lamotrigine should usually be discontinued gradually over 2 weeks unless a rash emerges, in which case it should be discontinued over 1 to 2 days. |
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Lithium main uses?
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Until recently, it was the only drug approved for both acute and maintenance treatment. It is also used as an adjunctive medication in the treatment of major depressive disorder.
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Lithium pharmacologic properties including half life
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Lithium does not bind to plasma proteins, is not metabolized, and is excreted through the kidneys.
The plasma half-life is initially 1.3 days and is 2.4 days after administration for more than 1 year. The blood–brain barrier permits only slow passage of lithium, which is why a single overdose does not necessarily cause toxicity and why long-term lithium intoxication is slow to resolve. The elimination half-life of lithium is 18 to 24 hours in young adults, but is shorter in children and longer in the elderly. |
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Renal clearance of lithium is decreased with ?
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renal insufficiency.
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The excretion of lithium is complex during pregnancy; excretion ? during pregnancy, but ? after delivery
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increases
decreases |
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Theories of Lithium mood stabilization?
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Theories include alterations of ion transport and effects on neurotransmitters and neuropeptides, signal transduction pathways, and second messenger systems.
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Lithium controls acute mania and prevents relapse in about XX percent of persons with bipolar I disorder and in a somewhat smaller percentage of persons with mixed (mania and depression) episodes, rapid-cycling bipolar disorder, or mood changes in encephalopathy
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80%
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Lithium has a relatively ? onset of action when used and exerts its antimanic effects over ?
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Lithium has a relatively slow onset of action when used and exerts its antimanic effects over 1 to 3 weeks.
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Which patients respond less well to lithium?
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Patients with mixed or dysphoric mania, rapid cycling, comorbid substance abuse, or organicity respond less well to lithium than those with classic mania
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When a depressive episode occurs in a person taking maintenance lithium, the differential diagnosis should include
Tx approach to poor lithium response? |
lithium-induced hypothyroidism, substance abuse, and lack of compliance with the lithium therapy.
Possible treatment approaches include increasing the lithium concentration (up to 1 to 1.2 mEq/L), adding supplemental thyroid hormone (e.g., 25 µg a day of liothyronine [Cytomel]) even in the presence of normal findings on thyroid function tests, augmentation with valproate or carbamazepine, the judicious use of antidepressants, or electroconvulsive therapy (ECT). |
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Lithium provides relatively more effective prophylaxis for ? (dep/man) than for (dep/man)?, and supplemental antidepressant strategies may be necessary, either intermittently or continuously
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Lithium provides relatively more effective prophylaxis for mania than for depression, and supplemental antidepressant strategies may be necessary, either intermittently or continuously
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Lithium maintenance is almost always indicated after the ?# episode of bipolar I disorder depression or mania and should be considered after the first episode for
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Lithium maintenance is almost always indicated after the second episode of bipolar I disorder depression or mania and should be considered after the first episode for adolescents or for persons who have a family history of bipolar I disorder.
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Other people who benefit from lithium?
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Others who benefit from lithium maintenance are those who have poor support systems, had no precipitating factors for the first episode, have a high suicide risk, had a sudden onset of the first episode, or had a first episode of mania.
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Clinical studies have shown that lithium reduces the incidence of suicide in patients with bipolar I disorder ?
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sixfold or sevenfold
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Why start Li after 1st manic episode?
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First, each episode of mania increases the risk of subsequent episodes.
Second, among people responsive to lithium, relapses are 28 times more likely after lithium use is discontinued. Third, case reports describe persons who initially responded to lithium, discontinued taking it, and then had a relapse but no longer responded to lithium in subsequent episodes. |
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The most common role for lithium in major depressive disorder is as
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an adjuvant to antidepressant use in persons who have failed to respond to the antidepressants alone.
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About? percent of antidepressant nonresponders do respond when lithium, 300 mg three times daily, is added to the antidepressant regime
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50 percent to 60
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Persons with prominent ? symptoms—either bipolar type or depressive type—with schizoaffective disorder are more likely to respond to lithium than are those with predominant ? symptoms
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Persons with prominent mood symptoms—either bipolar type or depressive type—with schizoaffective disorder are more likely to respond to lithium than are those with predominant psychotic symptoms
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Lithium role in aggression?
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Lithium has antiaggressive activity that is separate from its effects on mood. Aggressive outbursts in persons with schizophrenia, violent prison inmates, and children with conduct disorder, and aggression or self-mutilation in persons with mental retardation can sometimes be controlled with lithium.
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More than ? percent of patients taking lithium experience side effects
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More than 80 percent of patients taking lithium experience side effects
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Excessive sodium intake (e.g., a dramatic dietary change) ? lithium concentrations.
Conversely, too little sodium (e.g., fad diets) can lead to ? concentrations of lithium. |
Excessive sodium intake (e.g., a dramatic dietary change) lowers lithium concentrations.
Conversely, too little sodium (e.g., fad diets) can lead to potentially toxic concentrations of lithium. |
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Decreases in body fluid (e.g., excessive perspiration) can lead to dehydration and lithium?
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Decreases in body fluid (e.g., excessive perspiration) can lead to dehydration and lithium intoxication
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Lithium Side Fx?
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Neurologic
Benign, nontoxic: dysphoria, lack of spontaneity, slowed reaction time, memory difficulties Tremor: postural, occasional extrapyramidal Toxic: coarse tremor, dysarthria, ataxia, neuromuscular irritability, seizures, coma, death Miscellaneous: peripheral neuropathy, benign intracranial hypertension, myasthenia gravis-like syndrome, altered creativity, lowered seizure threshold Endocrine Thyroid: goiter, hypothyroidism, exophthalmos, hyperthyroidism (rare) Parathyroid: hyperparathyroidism, adenoma Cardiovascular Benign T-wave changes, sinus node dysfunction Renal Concentrating defect, morphologic changes, polyuria (nephrogenic diabetes insipidus), reduced GFR, nephrotic syndrome, renal tubular acidosis Dermatologic Acne, hair loss, psoriasis, rash Gastrointestinal Appetite loss, nausea, vomiting, diarrhea Miscellaneous Altered carbohydrate metabolism, weight gain, fluid retention |
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The lithium preparation least likely to cause diarrhea is lithium ?
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The lithium preparation least likely to cause diarrhea is lithium citrate
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GI Sx of Li?
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N/V, Less Appetite, Diarrhea
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Lithium mech of weight gain?
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Weight gain results from a poorly understood effect of lithium on carbohydrate metabolism. Weight gain can also result from lithium-induced hypothyroidism, lithium-induced edema, or excessive consumption of soft drinks and juices to quench lithium-induced thirst.
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Describe Li tremor including hertz
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A lithium-induced postural tremor can occur that is usually 8 to 12 Hz and is most notable in outstretched hands, especially in the fingers, and during tasks involving fine manipulations.
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Tx of Li tremor?
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The tremor can be reduced by dividing the daily dosage, using a sustained-release formulation, reducing caffeine intake, reassessing the concomitant use of other medicines, and treating comorbid anxiety. β-adrenergic receptor antagonists, such as propranolol, 30 to 120 mg a day in divided doses, and primidone (Mysoline), 50 to 250 mg a day, are usually effective in reducing the tremor. In persons with hypokalemia, potassium supplementation may improve the tremor. When a person taking lithium has a severe tremor, the possibility of lithium toxicity should be suspected and evaluated.
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Li cognitive effects? DDx Li cog side fx?
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Lithium use has been associated with dysphoria, lack of spontaneity, slowed reaction times, and impaired memory. The presence of these symptoms should be noted carefully, because they are a frequent cause of noncompliance. The differential diagnosis for such symptoms should include depressive disorders, hypothyroidism, hypercalcemia, other illnesses, and other drugs. Some, but not all, persons have reported that fatigue and mild cognitive impairment decrease with time.
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The most common adverse renal effect of lithium is ?
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polyuria with secondary polydipsia
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The polyuria primarily results from lithium
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antagonism to the effects of antidiuretic hormone, which thus causes diuresis
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Tx of Li polyuria?
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When polyuria is a significant problem, the person's renal function should be evaluated and followed up with 24-hour urine collections for creatinine clearance determinations. Treatment consists of fluid replacement, the use of the lowest effective dosage of lithium, and single daily dosing of lithium. Treatment can also involve the use of a thiazide or potassium-sparing diuretic—for example, amiloride (Midamor), spironolactone (Aldactone), triamterene (Dyrenium), or amiloride-hydrochlorothiazide (Moduretic). If treatment with a diuretic is initiated, the lithium dosage should be halved, and the diuretic should not be started for 5 days because the diuretic is likely to increase lithium retention
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The most serious renal adverse effects, which are rare and associated with continuous lithium administration for X years or more, involve
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The most serious renal adverse effects, which are rare and associated with continuous lithium administration for 10 years or more, involve appearance of nonspecific interstitial fibrosis, associated with gradual decreases in glomerular filtration rate and increases in serum creatinine concentrations, and rarely with renal failure
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It is prudent for persons taking lithium to check their ??? at X-month intervals
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It is prudent for persons taking lithium to check their serum creatinine concentration, urine chemistries, and 24-hour urine volume at 6-month intervals
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Lithium and thyroid effects?
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Lithium causes a generally benign and often transient diminution in the concentrations of circulating thyroid hormones
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Li, Thyroid and gender?
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Lithium-induced hypothyroidism is more common in women (14 percent) than in men (4.5 percent). Women are at highest risk during the first 2 years of treatment.
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Persons taking lithium to treat bipolar disorder are twice as likely to develop hypothyroidism if they develop
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rapid cycling.
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In lithium-treated persons, TSH concentrations should be measured every
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6 to 12 months
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Li and Cardiac effects?
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The cardiac effects of lithium resemble those of hypokalemia on the electrocardiogram (ECG).
They are caused by the displacement of intracellular potassium by the lithium ion. The most common changes on the ECG are T-wave flattening or inversion. The changes are benign and disappear after the lithium is excreted from the body |
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Lithium treatment, therefore, is contraindicated in persons with heart condition?
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sick sinus syndrome
Lithium depresses the pacemaking activity of the sinus node, sometimes resulting in sinus dysrhythmias, heart block, and episodes of syncope |
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Lithium cardiotoxicity is more prevalent in persons
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on a low-salt diet, those taking certain diuretics or angiotensin-converting enzyme (ACE) inhibitors, and those with fluid-electrolyte imbalances or any renal insufficiency
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Li and derm effects?
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Dermatologic effects may be dose dependent. They include acneiform, follicular and maculopapular eruptions; pretibial ulcerations; and worsening of psoriasis. Occasionally, aggravated psoriasis or acneiform eruptions may force the discontinuation of lithium treatment. Alopecia has also been reported. Many of those conditions respond favorably to changing to another lithium preparation and the usual dermatologic measures. Lithium concentrations should be monitored if tetracycline is used for the treatment of acne, because it can increase lithium retention.
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Signs and sx of mild to mod Li intox? give level?
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(lithium level = 1.5 to 2.0 mEq/L)
GI Vomiting Abdominal pain Dryness of mouth Neurologic Ataxia Dizziness Slurred speech Nystagmus Lethargy or excitement Muscle weakness WANDS Weakness, Ataxia, Nystagmus, Dizziness, Slurred Speech, |
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Signs and Sx of Mod to Severe Li Intoxication?
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Moderate to severe intoxication (lithium level = 2.0 to 2.5 mEq/L)
GI Anorexia Persistent nausea and vomiting Neurologic Blurred vision Muscle fasciculations Clonic limb movements Hyperactive deep tendon reflexes Choreoathetoid movements Convulsions Delirium Syncope Electroencephalographic changes Stupor Coma Circulatory failure (lowered BP, cardiac arrhythmias, and conduction abnormalities) 2SICKINBED=Stupor, Syncope,Clonic movements, Convulsions, Coma,eKG, Increased reflexes, Nausea, Blurred Vision, EEG changes, Delirium |
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Signs and Symptoms of severe Lithium intoxication
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Severe lithium intoxication (lithium level >2.5 mEq/L)
Generalized convulsions Oliguria and renal failure Death |
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The early signs and symptoms of lithium toxicity include
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neurologic symptoms, such as coarse tremor, dysarthria, and ataxia; GI symptoms; cardiovascular changes; and renal dysfunction.
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The later signs and symptoms of Lithium intoxication include
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impaired consciousness, muscular fasciculations, myoclonus, seizures, and coma.
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Li intox risk factors?
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Risk factors include exceeding the recommended dosage, renal impairment, low-sodium diet, drug interaction, and dehydration. Elderly persons are more vulnerable to the effects of increased serum lithium concentrations.
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Management of Lithium Toxicity?
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1. The patient should immediately contact his or her personal physician or go to a hospital emergency room.
2. Lithium should be discontinued and the patient instructed to ingest fluids, if possible. 3. Physical examination should be completed, including vital signs and a neurologic examination with complete formal mental status examination. 4. Lithium level, serum electrolytes, renal function tests, and ECG should be obtained as soon as possible. 5. For significant acute ingestion, residual gastric contents should be removed by induction of emesis, gastric lavage, and absorption with activated charcoal. 6. Vigorous hydration and maintenance of electrolyte balance are essential. 7. For any patient with a serum lithium level greater than 4.0 mEq/L or with serious manifestations of lithium toxicity, hemodialysis should be initiated. 8. Repeat dialysis may be required every 6 to 10 hours, until the lithium level is within nontoxic range and the patient has no signs or symptoms of lithium toxicity. |
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For any patient with a serum lithium level greater than ? mEq/L or with serious manifestations of lithium toxicity, hemodialysis should be initiated.
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Lithium and dialysis?
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In severe cases, hemodialysis rapidly removes excessive amounts of serum lithium. Postdialysis serum lithium concentrations may rise as lithium is redistributed from tissues to blood, so repeat dialysis may be needed. Neurologic improvement may lag behind clearance of serum lithium by several days, because lithium crosses the blood–brain barrier slowly.
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Main teen concerns with Li?
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The serum lithium concentrations for adolescents are similar to that for adults. Weight gain and acne associated with lithium use can be particularly troublesome to an adolescent.
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Elderly Li considerations?
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Elderly persons should initially be given low dosages, their dosages should be switched less frequently than are those of younger persons, and a longer time must be allowed for renal excretion to equilibrate with absorption before lithium can be assumed to have reached its steady-state concentrations.
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Li and pregnancy?
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Lithium should not be administered to pregnant women in the first trimester because of the risk of birth defects. The most common malformations involve the cardiovascular system, most commonly Ebstein's anomaly of the tricuspid valves. The risk of Ebstein's malformation in lithium-exposed fetuses is 1 of 1,000, which is 20 times the risk in the general population.
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How manage pt on Li while preg?
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The possibility of fetal cardiac anomalies can be evaluated with fetal echocardiography.
A woman who continues to take lithium during pregnancy should use the lowest effective dosage. The maternal lithium concentration must be monitored closely during pregnancy and especially after pregnancy, because of the significant decrease in renal lithium excretion as renal function returns to normal in the first few days after delivery. Adequate hydration can reduce the risk of lithium toxicity during labor. Lithium prophylaxis is recommended for all women with bipolar disorder as they enter the postpartum period. Lithium is excreted into breast milk and should be taken by a nursing mother only after careful evaluation of potential risks and benefits |
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Li vs Valproate and carb during pregnancy compare?
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The teratogenic risk of lithium (4 percent to 12 percent) is higher than that for the general population (2 percent to 3 percent), but appears to be lower than that associated with use of valproate or carbamazepine.
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Signs of infant lithium toxicity?
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Signs of lithium toxicity in infants include lethargy, cyanosis, abnormal reflexes, and sometimes hepatomegaly
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Which drugs can increase Li conc
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NSAIDS, Diuretics, ACE
Metronidazole The coadministration of lithium and carbamazepine, lamotrigine, valproate, and clonazepam may increase lithium concentrations and aggravate lithium-induced neurologic adverse effects |
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Li and Aspirin?
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Aspirin and sulindac (Clinoril) do not affect lithium concentrations.
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Li and ECT?
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A person taking lithium who is about to undergo ECT should discontinue taking lithium 2 days before beginning ECT to reduce the risk of delirium.
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Potentially fatal neurotoxicity possible with Li and which drug?
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The coadministration of lithium and calcium channel inhibitors should be avoided because of potentially fatal neurotoxicity.
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Pre Lithium start lab workup?
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All patients should have a routine laboratory workup and physical examination before being started on lithium.
The laboratory tests should include serum creatinine concentration (or a 24-hour urine creatinine if the clinician has any reason to be concerned about renal function), electrolytes, thyroid function (TSH, T3, and T4), a complete blood count (CBC), ECG, and a pregnancy test in women of child-bearing age. |
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Lithium Dosing?
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The starting dosage for most adults is 300 mg of the regular-release formulation three times daily. The starting dosage for elderly persons or persons with renal impairment should be 300 mg once or twice daily. After stabilization, dosages between 900 and 1,200 mg a day usually produce a therapeutic plasma concentration of 0.6 to 1 mEq/L, and a daily dose of 1,200 to 1,800 mg usually produces a therapeutic concentration of 0.8 to 1.2 mEq/L. Maintenance dosing can be given either in two or three divided doses of the regular-release formulation or in a single dosage of the sustained-release formulation equivalent to the combined daily dosage of the regular-release formulation. The use of divided doses reduces gastric upset and avoids single high-peak lithium concentrations. Discontinuation of lithium should be gradual to minimize the risk of early recurrence of mania and also to permit recognition of early signs of recurrence.
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Lithium levels should be obtained every ?
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Lithium levels should be obtained every 2 to 6 months
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Baseline ECGs are essential and should be repeated?
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Baseline ECGs are essential and should be repeated annually.
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Lithium concentrations 12 hours postdose in persons treated with sustained-release preparations are generally about XX percent higher than the corresponding concentrations obtained from those taking the regular-release preparations
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30%
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When obtaining blood for lithium levels, patients should be at steady-state lithium dosing (usually after 5 days of constant dosing), preferably using a twice- or three-times daily dosing regimen, and the blood sample must be drawn X hours (PM 30 minutes) after a given dose
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12
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Factors that can cause fluctuations in lithium measurements include :
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dietary sodium intake, mood state, activity level, body position, and use of an improper blood sample tube.
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Once the daily dose has been set, it is reasonable to change to
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the sustained-release formulation given once daily.
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Effective serum concentrations for mania are X mEq/L, a level associated with 1,800 mg a day. The recommended range for maintenance treatment is Y mEq/L, which is usually achieved with a daily dose of 900 to 1,200 mg
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Effective serum concentrations for mania are 1.0 to 1.5 mEq/L, a level associated with 1,800 mg a day. The recommended range for maintenance treatment is 0.4 to 0.8 mEq/L, which is usually achieved with a daily dose of 900 to 1,200 mg.
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Li and patient Advice categories?
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Dosing, BLood Tests, Other Rx, Diet and Fluid Intake, Intox warning signs
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Li and dosing advice to patients
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Dosing
Take lithium exactly as directed by your doctor—never take more or less than the prescribed dose. Do not stop taking without speaking to your doctor. If you miss a dose, take it as soon as is possible. If it is within 4 hours of the next dose, skip the missed dose (about 6 hours in the case of extended- or slow-release preparations). Never double up doses. |
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Li and Blood tests
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Blood Tests
Comply with the schedule of recommended regular blood tests. Despite their inconvenience and discomfort, your lithium blood levels, thyroid function, and kidney status need to be monitored as long as you take lithium. When going to have lithium levels checked, you should have taken your last lithium dose 12 hours earlier. |
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Li and other rx?
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Use of Other Medications
Do not start any prescription or over-the-counter medications without telling your doctor. Even drugs such as ibuprofen (Advil, Motrin) or naproxen (Aleve) can significantly raise lithium levels. |
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Li and Diet and Fluid Intake?
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Diet and Fluid Intake
Avoid sudden changes in your diet or fluid intake. If you do go on a diet, your doctor may need to increase the frequency of blood tests. Caffeine and alcohol act as diuretics and can lower your lithium concentrations. During treatment with lithium, it is recommended that you drink about 2 or 3 quarts of fluid daily, and use normal amounts of salt. Inform your doctor if you start or stop a low-salt diet. |
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Lithium and potential problems
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Recognizing Potential Problems
If you engage in vigorous exercise or have an illness that causes sweating, vomiting, or diarrhea, consult your doctor, because these might affect lithium levels. Nausea, constipation, shakiness, increased thirst, frequency of urination, weight gain, or swelling of the extremities should be reported to your doctor. Blurred vision, confusion, loss of appetite, diarrhea, vomiting, muscle weakness, lethargy, shakiness, slurred speech, dizziness, loss of balance, inability to urinate, or seizures could indicate severe toxicity, and should prompt immediate medical attention. |
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Lithium: If no response occurs after 2 weeks at a concentration that is beginning to cause adverse effects, then the person should
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taper off lithium use over 1 to 2 weeks and should try other mood-stabilizing drugs.
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What is Ramelteon?
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Ramelteon (Rozerem) is a melatonin receptor agonist used to treat sleep onset insomnia. Unlike benzodiazepines, ramelteon has no appreciable affinity for the γ-aminobutyric acid (GABA) receptor complex.
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Ramelteon MOA?
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Ramelteon essentially mimics melatonin's sleep-promoting properties. It has high affinity for melatonin MT1 and MT2 receptors in the brain. These receptors are believed to be critical in the regulation of the body's sleep-wake cycle.
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Melatonin (N-acetyl-5 methoxytryptamine) is a hormone mainly produced at time of day in what gland?
Its secretion is ? by the dark and ? by light. |
night in the pineal gland.
Its secretion is stimulated by the dark and inhibited by light. |
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Melatonin It is naturally synthesized from
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the amino acid tryptophan
Tryptophan is converted to serotonin and finally converted to melatonin. |
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Where are the melatonin receptors?
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The suprachiasmatic nuclei (SCN) of the hypothalamus have melatonin receptors and melatonin may have a direct action on SCN to influence “circadian” rhythms.
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Where is melatonin produced along with the gland?
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Melatonin is also produced in the retina and gastrointestinal (GI) tract.
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Ramelteon peak absorption time, half life?
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Peak absorption occurs between 30 and 90 minutes after ingestion. The half-life of ramelteon is between 1 and 2.6 hours
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Ramelteon indication?
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Ramelteon mainly shortens latency to sleep onset and, to a lesser extent, increases total duration of sleep
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Ramelteon side fx?
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Headache is the most common side effect. Other adverse effects of ramelteon may include somnolence, fatigue, dizziness, worsening insomnia, depression, nausea, and diarrhea. This drug should not be used in patients with severe hepatic impairment. It is also not recommended in patients with severe sleep apnea or severe chronic obstructive pulmonary disease (COPD).
Ramelteon has been found to sometimes decrease blood cortisol and testosterone and to raise prolactin. Female patients should be monitored for cessation of menses or galactorrhea, decreased libido, or fertility problems. Safety and effectiveness of ramelteon in children has not been established. Its use is not recommended during lactation. |
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Ramelteon dosage?
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The usual dose of ramelteon is 8 mg within 30 minutes of going to bed. It should not be taken with or immediately after high fat meals.
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Melatonin side fx?
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Melatonin can cause severe headaches, mental impairment, and mood changes
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Melatonin relation to MAOI?
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Melatonin concentrations are increased when taken in combination with monoamine oxidase inhibitors (MAOIs) because MAOIs inhibit the breakdown of melatonin by the body
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Melatonin relation to sexual fxn?
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Melatonin can suppress libido by inhibiting secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gland
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Melatonin elim half life?
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The elimination half life of melatonin is 32 to 40 minutes.
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What is Agomelatine and it's indication? dose?
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Agomelatine (Valdoxan) is structurally related to melatonin and is being investigated as a treatment of major depressive disorder. It acts as an agonist at melatonin (MT1 and MT2) receptors. It is also an antagonist at serotonin-2C (5-HT2C) receptors. It is hypothesized that the antidepressant-like activity agomelatine most probably involves a combination of both its melatonin agonist and 5-HT2C receptor antagonist properties.
The effective dose in clinical trials is 25 mg/day |
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Mirtazepine MOA unique properties?
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Mirtazapine (Remeron) is unique among drugs used to treat major depression in that it increases both norepinephrine and serotonin through a mechanism other than reuptake blockade (as in the case of tricyclic agents or selective serotonin reuptake inhibitors [SSRIs]) or monoamine oxidase inhibition (as in the case of phenelzine or tranylcypromine).
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Mirtazapine is (reduce/increase) nausea and diarrhea, the result of its effects on ? receptors.
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Mirtazapine is also more likely to reduce rather than cause nausea and diarrhea, the result of its effects on serotonin 5-HT3 receptors.
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Mirtaz key side fx?
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Characteristic side effects include increased appetite and sedation
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Mirtaz half life, peak, what impairs clearance?
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Mirtazapine is administered orally and is rapidly and completely absorbed. It has a half-life of about 30 hours. Peak concentration is achieved within 2 hours of ingestion and steady-state is reached after 6 days. Plasma clearance may be slowed up to 30 percent in persons with impaired hepatic function, up to 50 percent in those with impaired renal function, up to 40 percent slower in elderly males, and up to 10 percent slower in elderly females.
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Explain MOA of mirtaz (this might take awhile)
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The mechanism of action of mirtazapine is antagonism of central presynaptic α2-adrenergic receptors and blockade of postsynaptic serotonin 5-HT2 and 5-HT3 receptors. The α2-adrenergic receptor antagonism causes increased firing of norepinephrine and serotonin neurons. The potent antagonist of serotonin 5-HT2 and 5-HT3 receptors serves to decrease anxiety, relieve insomnia, and stimulate appetite. Mirtazapine is a potent antagonist of histamine H1 receptors and is a moderately potent antagonist at α1-adrenergic and muscarinic-cholinergic receptors.
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Mirtaz well suited for what kind of depressed patient?
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Combined with the tendency to cause a sometimes ravenous appetite, mirtazapine is well suited for depressed patients with melancholic features such as insomnia, weight loss, and agitation. Elderly depressed patients, in particular, are good candidates for mirtazapine, whereas young adults are more likely to object to this side-effect profile.
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Mirtazapine's blockade of ?receptors, a mechanism associated with medications used to combat the severe gastrointestinal (GI) side effects of cancer chemotherapy agents, has led to use of the drug in a similar role
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5-HT3
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Mirtazapine is often combined with SSRIs or venlafaxine (Effexor) because?
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Mirtazapine is often combined with SSRIs or venlafaxine (Effexor) to augment antidepressant response or counteract serotonergic side effects of those drugs, particularly nausea, agitation, and insomnia.
Mirtazapine has no significant pharmacokinetic interactions with other antidepressants. |
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?, the most common adverse effect of mirtazapine, occurs in over XX percent of person
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Somnolence, over 50%
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Caution with mirtaz?
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Persons starting mirtazapine, thus, should exercise caution when driving or operating dangerous machinery, or even when getting out of bed at night. This adverse effect is why mirtazapine is almost always given before sleep. Mirtazapine potentiates the sedative effects of other central nervous system (CNS) depressants, so potentially sedating prescription or over-the-counter drugs and alcohol should be avoided during use of mirtazapine.
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Mirtaz second most common side fx?
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7% dizzy
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Mirtazapine increases appetite in about
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one third of patients
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Mirtaz effects on metabolic pare
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Mirtazapine may also increase serum cholesterol concentration to 20 percent or more above the upper limit of normal in 15 percent of persons and increase triglycerides to 500 mg/dL or more in 6 percent of persons. Elevations of alanine transaminase (ALT) levels to more than three times the upper limit of normal were seen in 2 percent of mirtazapine-treated persons, as opposed to 0.3 percent of placebo controls.
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Mirtaz and hemotology?
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In limited premarketing experience, the absolute neutrophil count dropped to 500/mm3 or less within 2 months of onset of use in 0.3 percent of persons, some of whom developed symptomatic infections. This hematologic condition, which was reversible in all cases, was more likely to occur when other risk factors for neutropenia were present. Increases in the frequency of neutropenia, however, have not been reported during the extensive postmarketing period. Persons who develop fever, chills, sore throat, mucous membrane ulceration, or other signs of infection should nevertheless be evaluated medically. If a low white blood cell (WBC) count is found, mirtazapine should be immediately discontinued, and the infectious disease status should be followed closely.
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A few persons experience low or high bp while taking mirtazapine.
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orthostatic hypotension
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Mirtaz and pregancy?
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Mirtazapine use by pregnant women has not been studied; because the drug may be excreted in breast milk, it should not be taken by nursing mothers.
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Mirtaz and ranking of side fx?
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Problem and %
Somnolence 54 Dry mouth 25 Increased appetite 17 Constipation 13 Weight gain 12 Dizziness 7 Myalgias 5 Disturbing dreams 4 |
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Mirtaz and drug Intx?
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Drug Interactions
Mirtazapine can potentiate the sedation of alcohol and benzodiazepines. Mirtazapine should not be used within 14 days of use of a monoamine oxidase inhibitor. |
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Mirtaz dosing?
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If persons fail to respond to the initial dose of 15 mg of mirtazapine before sleep, the dosage may be increased in 15-mg increments every 5 days to a maximum of 45 mg before sleep
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The monoamine oxidase inhibitors (MAOIs), which were introduced as antidepressants in 1957, are effective in treating
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both depression and panic disorde
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MAOI discovery?
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The first of these drugs were hydrazine derivatives developed as treatments for tuberculosis. Their antidepressant properties were discovered by chance, when some of the patients were observed to experience elevation of mood during treatment.
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Despite their effectiveness, prescription of MAOIs as first-line agents has always been limited by concern about the development of
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potentially lethal hypertension and the consequent need for a restrictive diet.
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What are the available MAOIs?
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The currently available MAOIs include phenelzine (Nardil), isocarboxazid (Marplan), tranylcypromine (Parnate), and selegiline (Eldepryl). Oral Selegiline is a selective inhibitor of MAOB used for the treatment of parkinsonism.
Reversible inhibitors of MAOA (RIMAs), which are not available in the United States (e.g., moclobemide [Manerix] and befloxatone), require few dietary restriction |
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Because they irreversibly inactivate MAOs, the therapeutic effect of a single dose of irreversible MAOIs may persist for as long as
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2 weeks.
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The RIMA moclobemide is rapidly absorbed and has a half-life of ?. Because it is a reversible inhibitor, moclobemide has a much briefer clinical effect following a single dose than do irreversible MAOIs.
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0.5 to 3.5 hours
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MAOI MOA?
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The MAO enzymes are found on the outer membranes of mitochondria where they degrade cytoplasmic and extraneuronal monoamine neurotransmitters, such as norepinephrine, serotonin, dopamine, epinephrine, and tyramine.
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MAOI site of action?
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MAOIs act in the central nervous system (CNS),
the sympathetic nervous system, the liver, and the gastrointestinal (GI) tract. |
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MAO A metabolizes what?
MAO B metabolizes what? |
MAOA primarily metabolizes norepinephrine, serotonin, and epinephrine; dopamine and tyramine are metabolized by both MAOA and MAOB.
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MAOI's especially good in what type of depression?
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Some research indicates that phenelzine is more effective than tricyclic antidepressants (TCAs) in depressed patients with mood reactivity, extreme sensitivity to interpersonal loss or rejection, prominent anergia, hyperphagia, and hypersomnia—a constellation of symptoms conceptualized as atypical depression.
Evidence also indicates that MAOIs are more effective than TCAs as a treatment for bipolar depression |
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MAOI's help with which anxiety ds?
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Patients with panic disorder and social phobia respond well to MAOIs
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MOst frequent side fx of MAOIs?
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The most frequent adverse effects of MAOIs are orthostatic hypotension, insomnia, weight gain, edema, and sexual dysfunction
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Management of MAOI side fx?
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Orthostatic hypotension can lead to dizziness and falls. Thus, cautious upward tapering of the dosage should be used to determine the maximal tolerable dosage. Treatment for orthostatic hypotension includes avoidance of caffeine, intake of 2 L of fluid per day, addition of dietary salt or adjustment of antihypertensive drugs (if applicable), support stockings, and, in severe cases, treatment with fludrocortisone (Florinef), a mineralocorticoid, 0.1 to 0.2 mg a day.
Orthostatic hypotension associated with tranylcypromine use can usually be relieved by dividing the daily dosage. Insomnia can be treated by dividing the dose, not giving the medication after dinner, and using trazodone (Desyrel) or a benzodiazepine hypnotic, if necessary. Weight gain, edema, and sexual dysfunction often do not respond to any treatment and may warrant switching to another agent. When switching from one MAOI to another, the clinician should taper and stop use of the first drug for 10 to 14 days before beginning use of the second drug. |
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MAOIs and muscle side fx?
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Paresthesias, myoclonus, and muscle pains are occasionally seen in persons treated with MAOIs.
Paresthesias may be secondary to MAOI-induced pyridoxine deficiency, which may respond to supplementation with pyridoxine, 50 to 150 mg orally each day. |
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RIMA moclobemide side fx?
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The most common adverse effects of the RIMA moclobemide are dizziness, nausea, and insomnia or sleep disturbance
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RIMAs cause ? GI adverse effects than do SSRIs.
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fewer
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Moclobemide and cardiovasc? sexual fxn?
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Moclobemide does not have adverse anticholinergic or cardiovascular effects, and it has not been reported to interfere with sexual function
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Persons with ? diseases, should use the MAOIs with caution
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renal disease, cardiovascular disease, or hyperthyroidism
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MAOIs may alter the dosage of a ? agent required by diabetic persons.
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hypoglycemic
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MAOIs in BP1 depression? Sz?
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MAOIs have been particularly associated with induction of mania in persons in the depressed phase of bipolar I disorder and triggering of a psychotic decompensation in persons with schizophrenia.
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MAOIs and preg?
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MAOIs are contraindicated during pregnancy, although data on their teratogenic risk are minimal. MAOIs should not be taken by nursing women because the drugs can pass into the breast milk.
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Most worrying side effect of MAOI?
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The most worrisome side effect of MAOIs is the tyramine-induced hypertensive crisis.
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MAOI and MAOI HTN?
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The amino acid tyramine is normally transformed via GI metabolism. MAOIs, however, inactivate GI metabolism of dietary tyramine, thus allowing intact tyramine to enter the circulation. A hypertensive crisis may subsequently occur as a result of a powerful pressor effect of the amino acid. It is to allow resynthesis of adequate concentrations of MAOs that tyramine-containing foods be avoided until 2 weeks after the last dose of an irreversible MAOI.
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What should be avoided with MAOIs?
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Accordingly, foods rich in tyramine or other sympathomimetic amines, such as ephedrine, pseudoephedrine (Sudafed), or dextromethorphan (Trocal), should be avoided by persons who are taking irreversible MAOI
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Sx of HTN crisis?
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In addition to severe hypertension, other symptoms may include headache, stiff neck, diaphoresis, nausea, and vomiting. A patient with these symptoms should seek immediate medical treatment.
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Tyramine Rich foods?
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Fish, EtOH, Marmite, Sauerkraut, Age Cheese
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An MAOI-induced hypertensive crisis should be treated with
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α-adrenergic antagonists—for example, phentolamine (Regitine) or chlorpromazine (Thorazine).
These drugs lower blood pressure (BP) within 5 minutes. Intravenous (IV) furosemide (Lasix) can be used to reduce fluid load and a β-adrenergic receptor antagonist can control tachycardia. A sublingual 10-mg dose of nifedipine (Procardia) can be given and repeated after 20 minutes |
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MAOIs should not be used by persons with
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thyrotoxicosis or pheochromocytoma.
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The risk of tyramine-induced hypertensive crises is relatively low for persons who are taking RIMAs, such as moclobemide and befloxatone. These drugs have relatively little inhibitory activity for MAOB and, because they are reversible, normal activity of existing MAOA returns within ? hours of the last dose of a RIMA.
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16 to 48
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A reasonable dietary recommendation for persons taking RIMAs is
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not to eat tyramine-containing foods for a period from 1 hour before to 2 hours after taking a RIMA.
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MAOI overdose sx and tx?
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Often, an asymptomatic period of 1 to 6 hours occurs after an MAOI overdose before the occurrence of the symptoms of toxicity. MAOI overdose is characterized by agitation that progresses to coma with hyperthermia, hypertension, tachypnea, tachycardia, dilated pupils, and hyperactive deep tendon reflexes. Involuntary movements may be present, particularly in the face and the jaw. Acidification of the urine markedly hastens the excretion of MAOIs, and dialysis can be of some use. Phentolamine or chlorpromazine may be useful if hypertension is a problem. Moclobemide alone in overdosage causes relatively mild and reversible symptoms.
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MAOI Drug Intx?
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Antidepressants and precursors,
MAOIs may potentiate the action of CNS depressants, including alcohol and barbiturates. MAOIs should not be coadministered with serotonergic drugs, such as SSRIs and clomipramine (Anafranil), because this combination can trigger a serotonin syndrome. Use of lithium or tryptophan with an irreversible MAOI may also induce a serotonin syndrome. Initial symptoms of a serotonin syndrome can include tremor, hypertonicity, myoclonus, and autonomic signs, which can then progress to hallucinosis, hyperthermia, and even death |
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MAOI and fatal reaction?
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Fatal reactions have occurred when MAOIs were combined with meperidine (Demerol) or fentanyl (Sublimaze).
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When switching from an irreversible MAOI to any other type of antidepressant drug, persons should wait at least X days after the last dose of the MAOI before beginning use of the next drug to allow replenishment of the body's MAOs.
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14
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When switching from an antidepressant to an irreversible MAOI, persons should wait ? days (or ? weeks for fluoxetine [Prozac]) before starting use of the MAOI to avoid drug–drug interactions
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When switching
P.1069 from an antidepressant to an irreversible MAOI, persons should wait 10 to 14 days (or 5 weeks for fluoxetine [Prozac]) before starting use of the MAOI to avoid drug–drug interactions |
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MAO activity recovers completely ? hours after the last dose of a RIMA.
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MAO activity recovers completely 24 to 48 hours after the last dose of a RIMA.
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Drugs never to use with MAOIs
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Antiasthmatics
Antihypertensives (methyldopa, guanethidine, reserpine) Buspirone Levodopa Opioids (especially meperidine, dextromethorphan, propoxyphene, tramadol; morphine or codeine may be less dangerous) Cold, allergy, or sinus medications containing dextromethorphan or sympathomimetics SSRIs, clomipromine, venlafaxine, sibutramine Sympathomimetics (amphetamines, cocaine, methylphenidate, dopamine, epinephrine, norepinephrine, isoproterenol, ephedrine, pseudoephedrine, phenylpropanolamine) L-tryptophan |
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MAOI P450 fx?
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Tranylcypromine inhibits CYP 2C19. Moclobemide inhibits CYP 2D6, CYP 2C19, and CYP 1A2, and is a substrate for 2C19
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The MAOIs may ? blood glucose concentrations
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The MAOIs may lower blood glucose concentrations
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Phenelzine dosing?
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Phenelzine use should begin with a test dose of 15 mg on the first day. The dosage can be increased to 15 mg three times daily during the first week and increased by 15 mg a day each week thereafter until the dosage of 90 mg a day, in divided doses, is reached by the end of the fourth week.
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Hepatic transaminase serum concentrations should be monitored periodically because of the potential for hepatotoxicity, especially with
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phenelzine and isocarboxazid
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Elderly persons (more or less or equally ) sensitive to MAOI adverse effects than are younger adults. MAO activity (decreases, increases, does not change) with age, so that MAOI dosages for elderly persons are (lower, higher, same) as those required for younger adults
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Elderly persons may be more sensitive to MAOI adverse effects than are younger adults. MAO activity increases with age, so that MAOI dosages for elderly persons are the same as those required for younger adults
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Moclobemide dosing? dietary restriction? give after or before tyramine meal?
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Moclobemide use is initiated at 300 to 450 mg a day, divided three times per day, and may be increased to a maximum of 600 mg a day after several weeks. Dietary restrictions consist of avoidance of only large quantities of tyramine-containing foods and the administration of moclobemide after, rather than before, tyramine-containing meals. .. let the enzyme do it's work
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Selegiline use?
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Oral selegiline is approved only as an adjunct to levodopa or carbidopa for patients with Parkinson's disease, but some studies have found it to be effective for treating depression
Antidepressant doses are above 30 mg per day, a level that results in loss of selective inhibition of MAOB and consequent risk of the same tyramine reactions seen with the older MAOIs. So, rarely used as antidepressant. A transdermal formulation of selegiline was approved in 2006 for treating major depressive disorder. |
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Why is selegiline patch ok for tx depression?
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Being absorbed through the skin eliminates first-pass hepatic metabolism and, thus, alters the mix of available medication. At the lowest (6 mg) strength, transdermal selegiline delivers more selegiline to the bloodstream than does low-dose oral selegiline but without inhibiting gut MAOA. By selectively inhibiting MAOB, it appears to have a lower risk of potentially fatal hypertensive reaction seen with other MAOIs.
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Selegiline patch dosing?
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The 6-mg patch provides the brain MAOA and MAOB inhibition necessary for an antidepressant effect while eliminating the need for dietary restrictions at this lowest dosage. At higher doses, 9 mg per day and 12 mg per day, transdermal selegiline may inhibit too much gastrointestinal MAOA to clear tyramine from foods.
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Compared with oral selegiline, transdermal delivery results in ? plasma selegiline concentrationswith much lower exposure to metabolites.
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Compared with oral selegiline, transdermal delivery results in higher plasma selegiline concentrations (1,500 pg/mL with the 6-mg patch) with much lower exposure to metabolites.
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Selegiline patch drug Intx?
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As with oral selegiline, the transdermal patch should not be used concurrently with SSRIs, Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs), tricyclic antidepressants, mirtazapine, or bupropion. Other contraindicated drugs include carbamazepine or oxcarbazepine, meperidine, tramadol, methadone, and propoxyphene, St. John's wort, cough syrups containing dextromethorphan, amphetamines, cyclobenzaprine, and drugs containing pseudoephedrine, phenylephrine, phenylpropanolamine, or ephedrine
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Selegiline patch dosing?
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ransdermal selegiline is started at 6 mg per day. The patch is applied to the upper torso (chest, back, or stomach) where vascularity is richer than the buttocks and legs. The patch is changed daily and is applied to a different spot each day to prevent inflammation. The dosage can be increased after 2 or 3 months if response is inadequate. Transdermal selegiline patches contain 1 mg/cm2 of selegiline and deliver approximately 0.3 mg/cm2 of selegiline over 24 hours. Available dosing forms are 6-, 9-, and 12-mg patches. Patches should not be cut.
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Nefazodone: side fx it does not cause, side fx does cause?
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Nefazodone (Serzone) is indicated for the treatment of major depression. It is an analog of trazodone (Desyrel). When nefazodone was introduced in 1995, expectations were that it would become widely used because it did not cause the sexual side effects and sleep disruption associated with the selective serotonin reuptake inhibitors (SSRIs). Although it was devoid of these side effects, it was nevertheless found to produce problematic sedation, nausea, dizziness, and visual disturbances. Consequently, nefazodone was never extensively adopted in clinical practice. This fact, as well as reports of rare cases of sometimes fatal hepatotoxicity, led the original manufacturer to discontinue production of branded nefazodone in 2004
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Why nefazodone d/c
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fatal hepatotoxicity
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Nefazodone and MOA?
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Although nefazodone is an inhibitor of serotonin uptake and, more weakly, of norepinephrine reuptake, its antagonism of serotonin 5-HT2A receptors is thought to produce its antianxiety and antidepressant effects. Nefazodone is also a mild antagonist of theα1-adrenergic receptors, which predisposes some persons to orthostatic hypotension, but is not sufficiently potent to produce priapism.
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Nefazodone indications?
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Therapeutic Indications
Nefazodone is effective for the treatment of major depression. The usual effective dose is 300 to 600 mg a day. In direct comparison with SSRIs, nefazodone is less likely to cause inhibition of orgasm or decreased sexual desire. Nefazodone is also effective for treatment of panic disorder and panic with comorbid depression or depressive symptoms, of generalized anxiety disorder, and of premenstrual dysphoric disorder, and for the management of chronic pain. It is not effective for the treatment of obsessive-compulsive disorder. Nefazodone increases rapid eye movement (REM) sleep and increases sleep continuity. Nefazodone is also of use in patients with posttraumatic stress disorder and chronic fatigue syndrome. It may also be effective in patients who have been treatment resistant to other antidepressant drugs. |
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Commonly abused opioids include
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heroin, hydromorphone (Dilaudid), codeine, meperidine (Demerol), butorphanol (Stadol), and hydrocodone (Robidone)
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Methadone half life?
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The peak plasma concentrations of oral methadone are reached within 2 to 6 hours, and the plasma half-life initially is 4 to 6 hours in opioid-naïve persons and 24 to 36 hours after steady dosing of any type of opioid
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Methadone MOA?
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Methadone and levomethadyl act as pure agonists at µ-opioid receptors and have negligible agonist or antagonist activity at κ- or δ-opioid receptors
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Buprenorphine MOA?
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Buprenorphine is a partial agonist at µ-receptors, a potent antagonist at κ-receptors, and neither an agonist nor an antagonist at δ-receptors.
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Advantages of methadone program?
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Enrollment in a methadone program reduces the risk of death by
70 percent reduces (1) illicit use of opioids and other substances of abuse; (2) criminal activity; (3) the risk of infectious diseases of all types, most importantly HIV and hepatitis B and C infection; and, in pregnant women, (4) the risk of fetal and neonatal morbidity and mortality. |
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Data pooled from many reports indicate that methadone is more effective when taken at dosages in excess of ?? mg a day.
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Data pooled from many reports indicate that methadone is more effective when taken at dosages in excess of 60 mg a day.
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Pregnancy: heroin vs methadone?
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Enrollment of a heroin-addicted pregnant woman in such a maintenance program reduces the risk of malnutrition, infection, preterm labor, spontaneous abortion, preeclampsia, eclampsia, abruptio placenta, and septic thrombophlebitis
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Methadone dosing during preg? teratogenicity
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The dosage of methadone during pregnancy should be the lowest effective dosage, and no withdrawal to abstinence should be attempted during pregnancy. Methadone is metabolized more rapidly in the third trimester, which may necessitate higher dosages. To avoid potentially sedating postdose peak plasma concentrations, the daily dose can be administered in two divided doses during the third trimester. Methadone treatment has no known teratogenic effects
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Neonatal withdrawal sx from methadone?
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Withdrawal symptoms in newborns frequently include tremor, high-pitched cry, increased muscle tone and activity, poor sleep and eating, mottling, yawning, perspiration, and skin excoriation. Convulsions that require aggressive anticonvulsant therapy may also occur. Withdrawal symptoms can be delayed in onset and prolonged in neonates because of their immature hepatic metabolism. Women taking methadone are sometimes counseled to initiate breast-feeding as a means of gently weaning their infants from methadone dependence, but they should not breast-feed their babies while still taking methadone.
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Buprenorphine at a dosage of? mg a day appears to reduce heroin use
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8 to 16
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The most common adverse effects of opioid receptor agonists are
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lightheadedness, dizziness, sedation, nausea, constipation, vomiting, perspiration, weight gain, decreased libido, inhibition of orgasm, and insomnia or sleep irregularities. Opioid receptor agonists can induce tolerance as well as produce physiologic and psychological dependence. Other central nervous system (CNS) adverse effects include depression, sedation, euphoria, dysphoria, agitation, and seizures. Delirium has been reported in rare cases. Occasional non-CNS adverse effects include peripheral edema, urinary retention, rash, arthralgia, dry mouth, anorexia, biliary tract spasm, bradycardia, hypotension, hypoventilation, syncope, antidiuretic hormone-like activity, pruritus, urticaria, and visual disturbances. Menstrual irregularities are common in women, especially in the first 6 months of use. Various abnormal endocrine laboratory indexes of little clinical significance may also be seen.
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The acute effects of opioid receptor agonist overdosage include
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sedation, hypotension, bradycardia, hypothermia, respiratory suppression, miosis, and decreased GI motility.
Severe effects include coma, cardiac arrest, shock, and death |
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The risk of overdosage is greatest in the ? stage of treatment and in persons with?
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The risk of overdosage is greatest in the induction stage of treatment and in persons with slow drug metabolism because of preexisting hepatic insufficiency
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Withdrawal from methadone sx?
|
Abrupt cessation of methadone use triggers withdrawal symptoms within 3 to 4 days, which usually reach peak intensity on the 6th day.
Withdrawal symptoms include weakness, anxiety, anorexia, insomnia, gastric distress, headache, sweating, and hot and cold flashes. The withdrawal symptoms usually resolve after 2 weeks. A protracted methadone abstinence syndrome is possible, however, which may include restlessness and insomnia. |
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Opioid receptor agonists can potentiate the CNS depressant effects of
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alcohol, barbiturates, benzodiazepines, other opioids, low-potency dopamine receptor antagonists, tricyclic and tetracyclic drugs, and monoamine oxidase inhibitors (MAOIs)
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What can induce hepatic enzymes? which can lower the plasma concentration of methadone or buprenorphine and thereby precipitate withdrawal symptoms
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Carbamazepine (Tegretol), phenytoin (Dilantin), barbiturates, rifampin (Rimactane, Rifadin), and heavy long-term consumption of alcohol
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What helps tx opioid withdrawal?
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These symptoms may be mitigated by use of clonidine, a benzodiazepine, or both.
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Competitive inhibition of methadone or buprenorphine metabolism following short-term use of alcohol or administration of cimetidine (Tagamet), erythromycin, ketoconazole (Nizoral), fluoxetine (Prozac), fluvoxamine (Luvox), loratadine (Claritin), quinidine (Quinidex), and alprazolam (Xanax) can lead to ?(lower or higher) plasma concentrations or (shorten or prolong?) duration of action of methadone or buprenorphine.
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Competitive inhibition of methadone or buprenorphine metabolism following short-term use of alcohol or administration of cimetidine (Tagamet), erythromycin, ketoconazole (Nizoral), fluoxetine (Prozac), fluvoxamine (Luvox), loratadine (Claritin), quinidine (Quinidex), and alprazolam (Xanax) can lead to higher plasma concentrations or prolonged duration of action of methadone or buprenorphine.
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Fatal drug–drug interactions opiod and other drug?
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Fatal drug–drug interactions with the MAOIs are associated with use of the opioids fentanyl (Sublimaze) and meperidine (Demerol)
but not with use of methadone, levomethadyl, or buprenorphine. |
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Methadone induction dosing?
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For induction of opioid detoxification, an initial methadone dose of 15 to 20 mg will usually suppress craving and withdrawal symptoms. Some individuals, however, may require up to 40 mg a day in single or divided doses. Higher dosages should be avoided during induction of treatment to reduce the risk of acute toxicity from overdosage.
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Methadone post-induction dosing?
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Over several weeks, the dosage should be raised to at least 70 mg a day. The maximal dosage is usually 120 mg a day, and higher dosages require prior approval from regulatory agencies. Dosages above 60 mg a day are associated with much more complete abstinence from use of illicit opioids than are dosages less than 60 mg a day.
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What is better in terms of methadone treatment, shorter or longer?
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All studies of methadone maintenance programs endorse long-term treatment (i.e., several years) as more effective than short-term programs (i.e., less than 1 year) for prevention of relapse into opioid abuse
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more than XX percent of persons who terminate methadone maintenance treatment eventually return to illicit drug use within X years
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more than 80 percent of persons who terminate methadone maintenance treatment eventually return to illicit drug use within 2 years
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Buprenorphine dosing?
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Maintenance dosages of 8 to 16 mg three times a week have effectively reduced heroin use. Physicians must be trained and certified to carry out this therapy in their private offices. A number of approved training programs are available in the United States.
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phosphodiesterase (PDE)-5 inhibitor mechanism of action?
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Sexual stimulation causes the release of the neurotransmitter nitric oxide (NO), which increases the synthesis of cyclic guanosine monophosphate (cGMP), causing smooth muscle relaxation in the corpus cavernosum that allows blood to flow into the penis and that results in turgidity and tumescence. The concentration of cGMP is regulated by the enzyme PDE-5, which, when inhibited, allows cGMP to increase and enhance erectile function. Because sexual stimulation is required to cause the release of NO, PDE-5 inhibitors have no effect in the absence of such stimulation, an important point to understand when providing information to patients about their use. The congeners vardenafil and tadalafil work in the same way, by inhibiting PDE-5, thus allowing an increase in cGMP and enhancing the vasodilatory effects of NO. For this reason, these drugs are sometimes referred to as NO enhancers
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PDE--5 metabolism? These drugs are principally metabolized by the cytochrome CYP 3A4 system
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These drugs are principally metabolized by the cytochrome CYP 3A4 system
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PDE--5 elimindation reduced in people ?
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Elimination is reduced in persons over age 65 years, which results in plasma concentrations 40 percent higher than in persons aged 18 to 45 years. Elimination is also reduced in the presence of severe renal or hepatic insufficiency.
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Which PDE-5 has longer half-life?
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tadalafil is about 18 hours. Tadalafil can be detected in the bloodstream 5 days after ingestion, and because of its long half-life, it has been marketed as effective for up to 36 hours—the so-called weekend pill; however, more than once-a-day use can cause excessive accumulation of the drug, and the effects of inhibiting PDE for long periods of time require further investigation.
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half-life of sildenafil and vardenafil?
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mean half-lives of sildenafil and vardenafil are 3 to 4 hours
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PDE-5 onset?
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The onset of sildenafil occurs about 30 minutes after ingestion on an empty stomach; tadalafil and vardenafil act somewhat more quickly.
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Sildenafil vs SSRI?
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Sildenafil has been reported to reverse selective serotonin reuptake inhibitor (SSRI)-induced anorgasmia in men.
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PDE-5 warnings?
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For that reason, any person with a history of MI, stroke, renal failure, hypertension, or diabetes mellitus and any person over the age of 70 years should discuss plans to use these drugs with an internist or a cardiologist
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Use of PDE-5 inhibitors is contraindicated in persons who are
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taking organic nitrates in any form
Also, amyl nitrate (poppers), a popular substance of abuse used by gay men to enhance the intensity of orgasm, should not be used with any of the erection-enhancing drugs. The combination of organic nitrates and PDE inhibitors can cause a precipitous lowering of blood pressure (BP) and can reduce coronary perfusion to the point of causing MI and death. |
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PDE-5 and vision?
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Recently there have been 50 reports and 14 verfied cases of a serious condition in men taking Sildenafil called non arteritic anterior ischemic optic neuropathy (NAION). This is an eye ailment that causes restriction of blood flow to the optic nerve and can result in permanent vision loss. The first symptoms appear within 24 hours after use of Sildenafil and include blurred vision and some degree of vision loss. The incidence of this effect is very rare—one in a million.
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The major route of PDE-5 metabolism is through ? and the minor route is through ?
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The major route of PDE-5 metabolism is through CYP450 (CYP) 3A4, and the minor route is through CYP 2C9
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