Pharm Flashcards

Question

Lithium indications

Answer 1

approved for acute and maintenance treatment of mania in addition to adjunctive treatment for depression. It is less useful in rapid cycling or mixed episodes than valproic acid (VPA). Additionally, data shows reduction in risk of suicide in patients treated with lithium. It can be used in pregnancy and although it has a risk of Ebstein ’ s abnormality when used in the first trimester, this risk is relatively minimal (general population: 1/20,000; Li: 1/1,100, or 0.1%). This risk reduces after the first trimester and must be considered against a 5% risk of neural tube defect with VPA and the risk of danger to the patient and fetus if mania continues untreated. Thus, after the first trimester, lithium is the mood stabilizer of choice for mania in pregnancy.

Answer 2

: it does not bind to proteins, is not metabolized, and is excreted in the kidneys. Half-life is 18 to 24 hours with steady state reached in about 5 days. Dosing should start at 300 mg BID or TID and plasma trough drawn after 5 days of continuous dosing. Formulation includes immediate release lithium carbonate, 450 mg extended release tabs (Eskalith), and liquid lithium citrate. Therapeutic level aims for 0.8-1.2 and can be dosed BID or TID (or once daily with Eskalith). Prior to starting lithium, baseline CBC, Chem 13 (including renal function), TSH, EKG and HCG should be done.

Answer 3

include nausea/vomiting, sedation, weight gain, tremor (treat with propranolol), hypothyroidism (15% female, 4% male; If lithium is helpful, consider use of levothyroxine to treat hypothyroidism), renal tubular damage, bradycardia, AV block, sexual dysfunction (due to increased 5HT), alopecia, acne and neurologic symptoms including confusion, coma, stupor, and death in the case of toxicity. Regarding renal symptoms, lithium is associated with Nephrogenic Diabetes Insipidus where lithium antagonizes the effects of ADH in the distal kidney. The symptoms include polyuria and polydipsia and ultimate renal failure if not resolved. The primary treatment is discontinuation of treatment or addition of HCTZ (thiazide diuretic). This is counterintuitive as thiazides are diuretics and should increase water loss. It is postulated that lithium causes the distal kidney aquaporins to be downregulated and lose sensitivity to ADH. Thiazides, in addition to effects on Na in the proximal kidney, increase expression of distal aquaporins, thus reversing the effects of lithium (Loffing et al). Because HCTZ decreases NA reabsorption, it ultimately leads to increased lithium absorption (a positive ion) and can be associated with lithium toxicity. Thus, lithium coadministered with HCTZ must be decreased in dose.

Answer 4

lithium toxicity is more common in the presence of NSAIDs, diuretics, ACE- Inhibitors, hyponatremia, and dehydration. Treat lithium toxicity with dialysis, gastric lavage or kayexalate, not charcoal. Caffeine is known to decrease lithium by enhancing its renal clearance. Stopping caffeine leads to worse lithium tremor from higher plasma concentration. Lithium combined with SSRIs can cause serotonin syndrome.

Answer 5

acute mania (including rapid cycling and mixed episodes), mania secondary to traumatic brain injury and organic issues, aggression and impulsivity, migraines, general epilepsy. Lithium is better at treating depression and suicidality while VPA is better at treating more severe forms of Bipolar Disorder. Additionally, the elderly may tolerate VPA better due to less cognitive and renal effects.

Answer 6

highly protein bound with unbound drug crossing the blood brain barrier. Half-life is 10 to 16 hours. Metabolism is primarily by glucuronidation with some oxidative metabolism (producing an active metabolite) and minimal P450 metabolism on VPA. Valproic acid (Depakene) is combined with a second identical molecule and Na to form divalproex sodium (Depakote) which is available as an enteric coated tablet to minimize GI side effects. Depakote also exists in “ sprinkle” formulation (it is neither colorful nor tasty—a total letdown), a once- daily Extended Release Formulation (with up to 30% less bioavailability), and IV formulation. Depakene is available in tablet and liquid formulation. Dosing is generally BID or TID and trough levels are drawn 3 days after continuous dosing. Therapeutic levels are considered between 50-200 for the prevention of seizures, with many side effects starting after crossing 100.

Answer 7

nausea/vomiting, pancreatitis, elevated LFTs, liver failure, tremor, sedation, neutropenia, thrombocytopenia, hair loss, weight gain, polycystic ovarian syndrome, neural tube defect in pregnancy. Overall, the list of side effects is longer and worse with lithium than with VPA.

Answer 8

protein bound drugs displace VPA, making it more toxic/cross BBB more readily. This includes interaction with aspirin, carbamazepine, and diazepam. Lithium plus VPA has increased risk of tremor. Antipsychotics plus VPA have more combined sedation (the same is true for alcohol). Regarding VPA and oxidation in the liver, VPA will increase carbamazepine, diazepam, amitriptyline, and Phenobarbital. VPA decreases phenytoin and desipramine. VPA may augment anticoagulants and should be monitored closely. Fluoxetine may increase VPA levels. Most importantly, VPA decreases glucuronidation of lamotrigine leading to doubled levels and high risk for Stevens-Johnson syndrome.

Answer 9

structurally similar to imipramine, carbamazepine (CBZ) was intended initially as an antidepressant. In the late 1960s it was recognized as treatment for trigeminal neuralgia and temporal lobe epilepsy (complex partial seizures). Is considered second-line treatment for acute mania after lithium and VPA. It can also be used in refractory depression and to treat aggression. It should be avoided in pregnancy due to craniofacial abnormalities and spina bifida.

Answer 10

e average half-life is 26 hours and it is better absorbed with food. CBZ induces (helps) P450 enzyme 3A4. This means that any medications taken with CBZ that require 3A4 to break them down will have decreased dose. Example: warfarin is broken down by 3A4. If taken with CBZ, 3A4 action is increased and warfarin is broken down more than expected. This can lead to loss of warfarin effect (increased blood clotting—i.e., bad). Additionally, CBZ is also broken down by 3A4. With chronic administration of CBZ, the half-life diminishes to 12 hours due to induction of its own metabolism by 3A4 (auto induction). Thus after 3-5 weeks, 3A4 breakdown of CBZ increases, requiring increased dosing and can lead to unpredictable blood levels of CBZ during this time due to autoinduction. After initial processing in the liver, CBZ has an active epoxide metabolite that is the stronger form of the medication. This active metabolite is associated with better anticonvulsant properties and likely more side effects than related medication oxcarbazepine (see next section). Whereas lithium and VPA work to increase GABA and decrease glutamate, CBZ works more on inactivating Na channels to stop depolarization.

Answer 11

Due to irregular absorption, CBZ needs to be taken TID, even with food. An XR formulation exists that can be taken just once or twice per day. Generally dosing starts at 200 mg BID and increases by 200 mg every 2 to 3 days. The target dose is 1,200 mg per day and blood levels are often unreliable due to the epoxide metabolite not being the focus of drug monitoring (detects both parent and metabolite indiscriminately) and the risk of autoinduction.

Answer 12

: mild nausea, sedation, vertigo, and diplopia are the most common and are dose dependent with diminishing side effects over time as the drug diminishes with autoinduction. Weight gain is minimal. More seriously, it can cause aplastic anemia or agranulocytosis that is not dose dependent in 1/125,000. Benign leukopenia is seen in up to 2% of patients and does not correlate with more serious side effects. Monitor for fever, sore throat, rash, petechiae, bruising and easy bleeding. Additionally, CBZ can cause hepatitis with elevated LFTs. Up to 15% of patients on CBZ develop a benign maculopapular rash in the first 3 weeks of treatment. The concern is the risk of toxic epidermal necrolysis and Steven Johnson ’ s, which also may present with a rash. Stopping CBZ removes the rash and in patients with significant response to the medication may be re-trialed on CBZ as long as rash was the only presenting symptom (no malaise, oral lesions, flu symptoms). CBZ can create symptoms opposite of lithium with hyponatremia and water loading (similar to SIADH), but cannot correct abnormalities in lithium use. Before starting CBZ, CBC, Chem 13 including renal function, and HCG are needed

Answer 13

due to CYP3A4 induction, it reduces the concentrations of many drugs, including antipsychotics (haloperidol, clozapine, olanzapine, aripiprazole, quetiapine), TCAs (amitriptyline, clomipramine, desipramine, doxepin, imipramine), benzodiazepines (alprazolam, clonazepam), seizure meds/mood stabilizers (lamotrigine, VPA, phenytoin, ethosuximide) and others (warfarin, Tylenol, methadone, doxycycline, oral contraceptives). Medications that inhibit 3A4 cause CBZ toxicity, including fluoxetine, fluvoxamine, cimetidine, verapamil, diltiazem, gemfibrozil, and grapefruit juice. CBZ is diminished by phenytoin and ETOH (3A4 inducers). When combined with VPA, CBZ is displaced from plasma proteins, leading to increased risk of toxicity. Generally, on tests, when asked about CBZ, the correct answer is that it decreases the dose of whatever medication administered with.

Answer 14

approved for treatment of epilepsy, Novartis pled guilty in September 2010 for marketing oxcarbazepine for the treatment of trigeminal neuralgia and Bipolar Disorder without approval or sufficient data. Profile: unlike CBZ,

Answer 15

unlike CBZ, absorption is rapid and does not require food. The active metabolite is a monohydroxide with a half-life of 9 hours. In trials, dosing was started at 300 mg at night and increased to a total of 1,200 mg per day in BID dosing.

Answer 16

sedation, nausea, dizziness, vertigo are common. Does not have the serious side effects of CBZ. Hyponatremia can occur in 3% of patients and must be monitored closely initially as it may not present with symptoms and can lead to seizures and confusion.

Answer 17

minimal compared with CBZ. May induce 3A4 mildly, thus avoid use of oral contraceptives as primary form of birth control. Phenytoin and ETOH will decrease the dose of oxcarbazepine.

Answer 18

helpful in reducing depressive episodes in maintenance treatment of Bipolar Disorder, partial epilepsy and Lennox-Gastaut seizures. Other reports using lamotrigine for aggression in Rhett disorder, Alzheimer ’ s and in mentally retarded patients. There is no data to show that it can manage either acute bipolar depression or mania.

Answer 19

initially developed as a folate antagonist (elevated folate induces seizures), was noted to block Na voltage channels like CBZ/Trileptal. Additionally, it inhibits 5HT reuptake to increase 5HT concentrations. Half-life is 25 hours and has 98% bioavailability. Lamotrigine is mainly metabolized by glucuronidation in the liver. Due to a varied rate of absorption, BID dosing is recommended. No efficacy has been seen in doses above 200 mg for the treatment of bipolar disorder. Alone, it is dosed 25 mg a day for 2 weeks, then 50 mg a day for 2 weeks then 100mg a day by week 4. When given with CBZ (induces/decreases lamotrigine), the above dosing schedule is doubled (i.e. start with 50 mg per day). When coadministered with VPA (increases lamotrigine), the dosing schedule is changed to 25 mg given every other day for 2 weeks, then 25 mg per day for 2 weeks, then 50 mg by week four to increase by 25 mg per week. Lamotrigine exists in an orally dissolving tablet (ODT) and in chewable tablets.

Answer 20

overall is well-tolerated. Minimal sedation or weight gain. Mild dizziness and nausea are possible. Some data shows that taking lamotrigine after 5pm leads to disruption of stage 3 sleep (restorative sleep and where most parasomnias occur). The main concern is rash associated with Steven Johnson s syndrome. About 8% of patients on lamotrigine develop a benign maculopapular rash within the first 4 months of treatment. The risk of a serious rash is about 0.08%. Despite this low rate, the presence of any rash should lead to discontinuation of the medication. Treatment with concomitant VPA and treatment in patients under age 16 is associated with higher risk of serious rash.

Answer 21

s: as mentioned, VPA increases lamotrigine concentrations and should be monitored closely or avoided. CBZ, phenytoin, and Phenobarbital decrease lamotrigine by up to 50%. In the presence of oral contraceptives, lamotrigine itself may be decreased, but not the reverse.

Answer 22

discussion should begin here. Over 90% of prescribed Neurontin is off-label use. Seriously. Additionally, Pfizer was fined $430 MILLION in criminal fines related to illegal marketing of the medication for off-label use in 2004. After paying that, continued off-label use and marketing led to a Kaiser Permanente suit for an additional $141 MILLION in March, 2010. Thus, gabapentin has been marketed for Bipolar Disorder, migraines, fibromyalgia, sleep, anxiety, diabetic neuropathy, and HIV neuropathy. The FDA has only ever approved gabapentin for add-on therapy for the treatment of seizures. Just a side note about Pfizer, in September 2009 the United States Department of Justice forced Pfizer to plead guilty to the largest criminal penalty ever imposed in American history: $2.3 BILLION in civil and criminal charges for illegal marketing of four medications, including Geodon and Lyrica.

Answer 23

add on therapy for treatment of seizures.

Answer 24

unbound by proteins and is not appreciably metabolized. Eliminated renally. Increases GABA and 5HT. Dosing is usually started at 100 mg TID and gradually increased for a total of 2,700 mg per day. Exists as capsules 100, 300, and 400 mg as well as 600 and 800 mg tablets (useful in gastric bypass). Dosage is decreased in patients with impaired renal function. Bioavailability diminishes by 20% when given with antacids

Answer 25

somnolence, ataxia, diplopia, and dizziness. Side effects are dose dependent.

Answer 26

has 6x the GABA binding affinity of gabapentin, is the first medication ever approved by the FDA specifically for the treatment of fibromyalgia. Standard dosing is 50 mg BID or TID and comes in capsules or strawberry flavored syrup. Has the ability to potentiate benzodiazepines and opiates and is a Schedule V drug.

Answer 27

antiepileptic, migraines, smoking cessation (especially in alcoholics), tremor, bulimia and binge eating, some studies show decreased self-mutilatory behavior in borderline personality disorder, management of anxiety

Answer 28

is renally excreted 70% and needs to be decreased in dose in patients with renal issues. Half-life 24 hours. Increases cerebral GABA. Dosing begins at 25 mg at bedtime and gradually increases to BID dosing

Answer 29

paresthesia, especially numbness and tingling in fingertips and peripheral extremities. Sometimes improved by QHS dosing), weight loss, sedation, dizziness, word-finding difficulties. Generally, above 100 mg this is seen. Patients call it “ dopamax.” Lowers serum bicarbonate through carbonic anhydrase inhibition (causing cardiac arrhythmias and renal stones in 1.5%).

Answer 30

increases phenytoin and VPA levels. CBZ and phenytoin decrease topiramate levels. Avoid with other medications that are carbonic anhydrase inhibitors (acetazolamide/Diamoxglaucoma, altitude sickness, pseudotumor cerebri).

Answer 31

Structurally related to the typical antipsychotic chlorpromazine, imipramine was initially designed as a medication to manage schizophrenia. However, it was noted that the new medication in exacerbated mania (up to 25% of patients with pre-existing Bipolar Disorder will have mania or hypomania when on imipramine). After this was discovered, imipramine was used in the late 1950s as an antidepressant. Many of the TCAs are structurally related to imipramine, which is initially derived from the antihistamine methylene blue. The term “ tricyclic” and structures of these medications.

Answer 32

the three ringed TCAs are divided into tertiary and secondary amines. Tertiary amines have high affinity for blocking 5HT reuptake. Secondary amines have high affinity for blocking NE reuptake. Interestingly, tertiary amines are metabolized to secondary amines in the liver. Thus, a person taking the tertiary TCA amitriptyline is getting a medication that is strongly serotonergic yet still somewhat noradrenergic. In this way, the CAs serve as the first SNRIs.

Answer 33

MDD (but are more likely to induce mania than SSRIs), Panic Disorder with Agoraphobia (imipramine is best), Generalized Anxiety Disorder (especially imipramine and doxepin), OCD (clomipramine is FDA approved), and chronic pain and migraine (amitriptyline is used most for this). Imipramine can be used to treat childhood enuresis but due to reports of sudden death in children and adolescents, TCAs should be avoided in this population if possible.

Answer 34

: in addition to inhibiting reuptake of 5HT and NE, TCAs can antagonize muscarinic acetylcholine, histamine, and alpha 1 and 2 receptors. Additionally, Na and Ca channels can be blocked, leading to cardiac side effects. TCAs are more likely to cause anticholinergic side effects than SSRIs but are less likely to cause sexual side effects, weight gain, and sleep disturbance than SSRIs. • Clomipramine: most serotonergic • Amitriptyline: most anticholinergic and alpha • Desipramine: most noradrenergic, low anticholinergic • Nortriptyline: low anticholinergic • Doxepin: most antihistamine • Protriptyline: closest to nortriptyline but may be more noradrenergic

Answer 35

absorption in small intestine is rapid. Half-lives vary from 10-70 hours with most TCAs able to be given once-daily. Nortriptyline and doxepin exist in liquid solutions.

Answer 36

hepatic metabolism focuses primarily on demethylation and hydroxylation. The tertiary TCAs are demethylated by 2C19 and other enzymes, leading to the formation of secondary TCAs. Example: clomipramine → desmethylclomipramine, a secondary TCA. In the case of amitriptyline and imipramine, they are converted to the secondary TCAs nortriptyline and desipramine. Secondary amines are active compounds that are hydroxylated in the liver to active hydroxymetabolites. Due to the multiple metabolites floating around and the high variability from person to person (think: different enzyme numbers and functionality), most of the TCAs cannot be measured in serum reliably. The main TCAs that are associated with a reliable serum level that correlates to therapeutic response are desipramine, nortriptyline, and imipramine. For nortriptyline, plasma levels between 50-150 are more effective than levels below or above. This is called a curvilinear therapeutic window. In the presence of 2D6 inhibitors, TCAs can raise to toxic levels (fluoxetine, paroxetine, sertraline, cimetidine).

Answer 37

CNS: delirium due to anticholinergic and antihistamine effects, especially with amitriptyline. Increased risk of seizures, up to 2% with clomipramine • Anticholinergic: dry mouth, blurred vision, constipation, urinary retention. Symptoms may be reversed with bethanechol. Amitriptyline and clomipramine are most common. Avoid in narrowangle glaucoma (is fine in chronic open-angle glaucoma) • Antihistamine: doxepin is most potent (but still less than mirtazapine and olanzapine) • Cardiovascular: orthostatic hypotension due to alpha 1 blockade is present with many TCAs. Least with nortriptyline. As a class, the TCAs have type I antiarrhythmic qualities with QTc prolongation and should be avoided in cardiac patients • Hepatic: increased LFTs are associated with imipramine and desipramine. Generally associated with AST>>ALT. Acute hepatitis can be fatal and may be seen in 0.1% of patients • Overdose: death occurs as the result of cardiac arrhythmia. After acetaminophen, TCAs are the most lethal cause of OD in the US, with amitriptyline deaths exceeding total fatalities of all TCAs combined. Today, OD on SSRIs is 4.5x more common than TCAs. However, the rates of deaths of SSRIs in OD (1.5 deaths/1,000 OD) are much lower than TCAs (8.5 deaths/1,000 OD)

Answer 38

Similar to the TCAs, the tetracyclics bind to 5HT and NE transporters to prevent reuptake. Amoxapine is considered by some to be a tricyclic antidepressant as it structurally has 3 rings with a fourth ring as a side group.

Answer 39

derived from mid-potency antipsychotic, loxapine. Amoxapine increases 5HT, NE, and blocks DA. It is the only TCA/tetracyclic with both antidepressant and antipsychotic properties. Has an active metabolite. Half-life is 8 hours, but the active metabolite has a half-life of >30 hours. May have TD and may have greater risk of seizures than other TCAs.

Answer 40

greatly differs from the others in that it lacks 5HT reuptake inhibition and primarily acts to inhibit NE reuptake. Is a strong antihistamine, thus is sedating. Is less anticholinergic and alpha blocking than amitriptyline. Half-life is 30-60 hours.

Answer 41

the 1950s an antituberculosis drug, isoniazid (INH), was found to have antidepressant properties. Ultimately, INH showed quick resistance to active TB and is generally used in prevention and augmentation of treatment today. Additionally, INH has no MAO inhibition. Isoniazid was altered (simple addition of N-isopropyl group) to create iproniazid (Euphozid) and approved for the treatment of depression in 1958. This medication was an MAOI, and was the first antidepressant ever marketed, beating imipramine narrowly. Three years later in 1961 it was removed from the market due to hepatotoxicity. This medication paved the way for other MAOIs which were used steadily until the advent of the SSRIs. The second-line status of the MAOIs currently is related to safety and side effect profile, not efficacy. Currently, MAOIs available include phenelzine (Nardil), isocarboxazid (Marplan), tranylcypromine (Parnate), rasagiline (Azilect), moclobemide (Manerix) and selegiline (Eldepryl). In 2006, a transdermal delivery of selegiline for the treatment of parkinsonism was introduced.

Answer 42

these enzymes are found on the outer mitochondrial membranes, where they degrade monoamine neurotransmitters (NE, 5HT, DA, Epi, Tyramine). MAOI medications act in the CNS, the GI system, the liver, and the sympathetic nervous system. MAO-A breaks down NE, 5HT, and Epinephrine. DA and tyramine are broken down by MAO-A and MAO-B.

Answer 43

MDD, some data may show that phenelzine may better treat atypical depression (hypersomnia and hyperphagia) than TCAs, may treat depression in Bipolar Disorder better than TCAs with less hypomania/mania, anxiety, phobias, pain, migraines, depression associated with TBI. Tranylcypromine was included in the STAR*D trials as an effective option in treatment-resistant depression.

Answer 44

phenelzine, tranylcypromine, and isocarboxazid have half-lives ranging from 2-3 hours but have tissue half-lives with longer times. They irreversibly inactivate MAOIs, thus the effect can last up to 2 weeks, even with a single dose. Moclobemide is a reversible MAO-A inhibitor, and has less side effects and less dietary restrictions. It is not approved for use in the United States at this time. Selegiline, phenelzine, and tranylcypromine are structurally related to amphetamines, thus have stimulant effects in the brain.

Answer 45

orthostatic hypotension, insomnia, weight gain, paresthesia (possibly from pyridoxine deficiency), and induction of mania. When switching from an irreversible MAOI to another antidepressant, it is important to give a 14-day washout period due to loss of MAO.

Answer 46

first noted as headaches, seen more commonly in tranylcypromine and less in phenelzine. Tyramine, present in many foods, is usually broken down by MAO. In the presence of MAOIs, it is not broken down, leading to hypertensive crisis and other symptoms. Symptoms may include hypertension, sweating, chills, headache, nausea, pyrexia, dilated pupils, stiff neck, and restlessness. This can progress to alteration of consciousness, fever, cerebral hemorrhage, and death (0.02%). Treatment with Ca2+ channel blocker, nifedipine, is helpful. Foods to avoid include cheese (except cream cheese), fava beans, overripe fruit, sherry, sauerkraut, MSG, picked foods, red wine, and to use caffeine, coffee, chocolate, tea, and beer in moderation.

Answer 47

an irreversible MAO-B inhibitor used primarily to treat Parkinson s as an adjunct to L-Dopa treatment. Intestinal tyramine interactions with MAO-B are much less than MAO-A and as a result, selegiline requires less food restrictions. Side effects of nausea and lightheadedness are minimal. Due to being metabolized to L-methamphetamine, the medication will have a positive UDS. In addition to a regular tablet, it exists as an orally dissolving tab and a transdermal patch that delivers a steady 6 mg per 24 hours, marketed under the name EMSAM for the treatment of depression. The theory behind selegiline for depression is related to studies from the 1960s where the D-isomer of selegiline (D-deprenyl) showed strong antidepressant properties when high doses of selegiline were used. NE and DA increases were noted with the isomer. In recent trials using oral selegiline for the treatment of depression, required high doses led to a loss of selectivity for MAO-B, thus having affinity for MAO-B and intestinal MAO-A, leading to tyramine interactions. The transdermal patch was a strategy created to bypass the intestinal MAO-A responsible for tyramine reactions. Results for the treatment of depression with the patch are mixed, with some studies showing efficacy and some showing no benefit over placebo.

Answer 48

1970, Eli Lilly and Company began research on 3-Phenoxy-3-phenylpropylamine, a structure similar to diphenhydramine (known at the time to have some antidepressant properties). Over the next 2 years, many derivatives of this compound were creating, ultimately leading to the discovery of fluoxetine. The medication entered the market in 1986. Lilly researchers published a paper entitled “ Prozac, the first selective serotonin reuptake inhibitor and an antidepressant drug.” For the next 20 years, Eli Lilly strongly marketed Prozac into popular culture as the first SSRI. In actuality, the first SSRI was zimelidine (now banned for causing Guillain-Barre syndrome and other sometimes fatal side effects). Interestingly, fluvoxamine entered the market 2 years prior to fluoxetine but it was not approved for treatment of depression. Thus, “ Prozac, the first SSRI” continues in public knowledge despite the inaccuracy ( the first SSRI marketed in the USA” would be accurate).

Answer 49

MDD (all except fluvoxamine are approved by the FDA for MDD), depression in pregnancy and postpartum depression (over 70% of patients with MDD relapse into depression upon diminishing or discontinuing their SSRI during pregnancy. Studies following children exposed to fluoxetine in utero show no related decreases in IQ, language, or behavioral issues), depression in the elderly (avoid paroxetine due to anticholinergic), OCD (fluvoxamine, paroxetine, sertraline, and fluoxetine are FDA approved. Use higher doses than used in MDD), panic disorder (paroxetine, sertraline), PTSD, GAD, Bulimia Nervosa (fluoxetine, generally over 60 mg), Anorexia (less dropout from treatment and better treatment of comorbid disorders with fluoxetine), Premenstrual Dysphoric Disorder (Eli Lilly marketed fluoxetine as Sarafem in the early 1990s as the patent for Prozac expired. Literally pink and purple fluoxetine capsule with a new logo. In trials, sertraline and fluoxetine work equally well). In children, the FDA has approved fluoxetine for the treatment of depression and fluoxetine, fluvoxamine, and sertraline for the treatment of OCD.

Answer 50

2004, the FDA issued a black box warning for the use of SSRIs in patients under the age of 24. This was based upon meta-analyses that showed increased risk of suicidal thoughts and behaviors, in addition to aggression and hostility in children treated with SSRIs. While not issued in the treatment of the adults, the black box is well-known to many patients and is a subject of concern in the general public. All depressed patients should be closely monitored in the first 1-2 weeks of SSRI treatment.

Answer 51

the second chart below for the half-lives of the various SSRIs. Regarding CYP interaction, fluvoxamine has the most interaction with 1A2, 2C, and 3A inhibition (with minimal 2D6 inhibition). Fluoxetine and paroxetine are the strongest 2D6 inhibitors, with sertraline having moderate inhibition.

Answer 52

citalopram and escitalopram are the most selective inhibitor of 5HT reuptake, having little inhibition of DA, NE, histamine, or GABA. Fluoxetine weakly inhibits NE reuptake and binds to 5HT 2C. Sertraline weakly inhibits NE and DA reuptake. Paroxetine has significant anticholinergic activity at higher doses.

Answer 53

2D6 inhibitors will slow the metabolism of carbamazepine, diazepam, phenytoin, and antineoplastic agents. Sertraline may displace warfarin from proteins, leading to increased PTT. Fluvoxamine increases concentrations of multiple BZD, warfarin, clozapine, carbamazepine, methadone, propranolol, and diltiazem. It has little interaction with lorazepam.

Answer 54

Sexual side effects: the most common side effect with long-term use of the SSRIs, with incidence of 50-80%. Treatment includes decreasing the dose, adding bupropion (increases DA) or buspirone (antagonism of 5HT via autoreceptor), or use of sildenafil • GI: nausea, diarrhea, vomiting are most common with sertraline and fluvoxamine. Medicated through 5HT3. Paroxetine is associated with constipation (anticholinergic). Up to 30% of patients on SSRI will gain weight, especially with paroxetine • CNS: increased anxiety (fluoxetine), insomnia (fluoxetine) and sedation (varied with many of the SSRIs), emotional blunting (feelings of apathy, in ability to cry, “zombie” effect), seizures (0.2%), and EPS • Hematologic: can inhibit platelet binding, leading to bruising (Seen commonly with sertraline) • Serotonin syndrome: a potentially fatal condition involving diarrhea, restlessness, agitation, autonomic instability, hyperthermia, myoclonus, rigidity, delirium, and coma. On examinations, clinically distinguishing between NMS and Serotonin Syndrome generally comes down to myoclonus in Serotonin Syndrome. Treatment is removal of the offending agents, nitroglycerine, dantrolene, BZD, cooling, and possibly ventilation

Answer 55

due to the majority of the SSRIs existing in generic formulation (exception: escitalopram), the medications we commonly prescribe today do not have the same side effects and profiles of the original brand medications. A generic medication is required by the FDA to have 70% bioavailability of the original brand medication. Thus, when a patient swallows citalopram, the amount of drug in the serum has to be 70% of what would be present had they swallowed Celexa. That ’ s it. A generic medication does not have to be made with the same materials, is not required to have a similar side effect profile, and may not have the same efficacy due to the possibility of 30% less bioavailable. Imagine a patient stable on Wellbutrin XL 300 mg (max dose). A few years later the medication becomes generic and the patient ’ s insurance changes to the generic budeprion XL due to lower cost. The insurance company is not required to continue to provide the patient with Wellbutrin XL because the FDA has approved the generic budeprion XL as equivalent to the brand medication. As a result, the patient now notes that he feels more depressed (loss of 30% of his medication) despite max dose of the medication. He has terrible headaches and irritability that were never present on the original medication. He calls his psychiatrist and says that he wants to go back on the brand Wellbutrin XL. He is informed that his insurance company will not pay for the medication as it now has a generic formulation and that he can instead pay $140 a month out of pocket to get Wellbutrin XL. Generics suck. But it hard to argue with $4 a prescription.

Answer 56

have noted that some patients get tired on the medication and benefit from pm dosing. While considered activating, the generic may not be. Another note is that each brand of generics is different; the side effects of generic fluoxetine capsules made by one company differ from another company. Is likely the safest medication used in pregnancy with a significant amount of clinical data present. For breastfeeding mothers, sertraline may be a better choice than fluoxetine.

Answer 57

sexual side effects are severe. They appear to be dose dependent and may be equal to paroxetine. A number of patients get tired on it so I generally now start it at night. In addition to hyponatremia, SIADH has been seen a number of times with citalopram. Headaches similar to generic Wellbutrin are also seen with citalopram. Additionally, according to a report from the FDA (8/24/11) “ Citalopram causes dose-dependent QT interval prolongation. Citalopram should no longer be prescribed at doses greater than 40 mg per day.” This likely will impact prescription of this common medication.

Answer 58

commonly has bruising and hair loss. The original medication was often sedating, leading to pm dosing. The generic often has the opposite effect, with patients initially experiencing feelings of restlessness, anxiety, and hypervigilance (which are problematic considering sertraline is used for anxiety). Have seen a couple cases of bruxism which improves with buspirone. Seen Torsades and neutropenia x1 recently with sertraline. Sertraline is probably the best medication to use when breastfeeding as a minimal amount is expressed in breast milk.

Answer 59

avoided this medication for a long time due to fear of weight gain and sexual side effects. Now that the side effects of citalopram are more apparent, I am less hesitant to use paroxetine (a medication that may have better efficacy that citalopram). As associated with pulmonary hypertension in newborns when used during pregnancy.

Answer 60

when your patient complains of a SSRI side effect, believe them. Unless they endorse the side effect of My right index finger is numb every other Thursday,” go with it. Side effects often resolve 10-14 days after initiation of the medication. If they do not, consider managing the side effects or discontinuing the medication. Putting generic SSRIs at night seems to have a few less noted side effects.

Answer 61

tructurally similar to Trazodone, this is a selective serotonin reuptake inhibitor in addition to 5HT1A agonist (like buspirone). Thus, it is similar to combining citalopram+buspirone. This medication has less sexual side effects and weight gain than other SSRIs. Half-life is 25 hours and dosing starts at 10 mg to increase by 10 mg per week to a goal of 40 mg. Discontinuation symptoms may occur if stopping quickly. Is metabolized by CYP3A4. GI side effects are most common. There may be QTc prolongation a well in doses at or above 80 mg. This may be a “ me too” medication; more studies to follow.

Answer 62

MDD, GAD, Panic Disorder. Has been used for diminishing symptoms of menopause, treating chronic pain, and dual diagnosis of MDD and cocaine dependence.

Answer 63

inhibits reuptake of 5HT and NE without much interaction at other sites. Exists as immediate release IR (BID dosing) and extended release XR (once daily). Due to short half-life, a discontinuation syndrome may exist if abruptly stopped. Metabolized by 2D6 to active metabolite desvenlafaxine (now marketed as Pristiq). Patients with poor 2D6 activity may have higher side effect profile, leading to the isolation and marketing of the metabolite as treatment (or so they say). The IR is most associated with nausea and often is started in low doses of 37.5 mg twice daily (use in the am and at 1pm due to risk of insomnia if taken at bedtime). As dose increases, affinity for NE transporter increases. As a result, HTN and anxiety are more associated with higher doses of the medication. When taken as the XR, the maximum dose is 375 mg. Desvenlafaxine has a therapeutic dose of 50 mg (which happens to be the starting dose) with no significant data to support improved efficacy of 100 mg.

Answer 64

nausea and sexual dysfunction in up to 30% are serotonergic side effects. While appearing anticholinergic, side effects of headache, insomnia, dizziness, constipation, sweating, and nervousness are due to NE effects. HTN occurs with higher doses. Discontinuation syndrome appears as dizziness, insomnia, nausea, and diarrhea.

Answer 65

MDD and Neuropathic pain associated with diabetes (first drug FDA approved). For the treatment of stress incontinence, duloxetine increases the tone of the urethral sphincter and will be marketed as Yantreve (important to know if your patient is taking Yantreve aka duloxetine, especially before you start them on SSRI or SNRI).

Answer 66

similar to venlafaxine, but has equal affinity for 5HT and NE transporters at all doses. There is little data to show greater clinical efficacy in doses above 60 mg for the treatment of depression. BID dosing may reduce side effects seen with once-daily dosing. Starting dose is 20 or 30 mg.

Answer 67

similar to venlafaxine, including nausea, dizziness, constipation, insomnia, and sexual dysfunction. Less likely to cause HTN. May increase Hgb A1c in long term treatment. Potentially increases LFTs (especially in hepatically compromised patients). Discontinuation syndrome can occur.

Answer 68

Approved by the FDA and marketed in 1985 (a year before fluoxetine). The original recommended dose was 400-600 mg. This dosing was associated with a risk of seizures and resulted in the drug being pulled for 3 years before being reintroduced with a recommended max dosage of 450 mg. In 2007, in response to multiple patient reports about the generic Bupoprion XL having more side effects and being less efficacious than Wellbutrin XL, the FDA concluded that the discrepancy was due to variation.”

Answer 69

MDD and seasonal affective disorder, smoking cessation (under Zyban brand name, generally used in combination with nicotine substitutes), BMD (less likely to precipitate mania in BMD I than TCAs and in BMD II than most other antidepressants), ADHD, cocaine detoxification (reducing cravings), hypoactive sexual desire disorder due to SSRIs.

Answer 70

available in immediate release IR (BID or TID), sustained release SR (used BID), and extended release ER (once daily). The active ingredient is the same in each. The IR reaches peak concentration in 2 hours, SR in 3 hours and ER in 5 hours. The half-life is 12 hours. Mechanistically, bupropion inhibits the reuptake of DA and NE. Is metabolized to active metabolite hydroxybupropion by CYP2B6 (inhibited by fluoxetine). Hydroxybupropion itself inhibits 2D6. Bupropion has affinity for DA transporters while hydroxybupropion has more selective affinity for NE transporters. Bupropion may have a false positive UDS for amphetamines.

Answer 71

seizure risk is 2% with 600 mg and 0.1% with 300-450 mg (the SR and ER at same doses has risk of 0.05%, equivalent to the other antidepressants). Side effects most common include headache, insomnia, dry mouth, tremor, and nausea. Severe anxiety and panic disorder can be worsened by bupropion. Can worsen psychosis and delirium due to dopaminergic activity. Have seen severe psychosis with use of bupropion in pregnancy.

Answer 72

tetracyclic antidepressant that is both serotonergic and noradrenergic through a mechanism different from serotonin reuptake blockade or monoamine oxidase inhibition.

Answer 73

MDD (especially with insomnia or weight loss), reduction of side effects associated with chemotherapy, augmentation of antidepressant therapy.

Answer 74

half-life of 30 hours. Clearance is impaired in hepatic impaired patients by 30%, in renal impaired patients by 50%, and is impaired in the elderly (by 40% in males and 10% in females). Mechanistically, mirtazapine works to increase 5HT at the 1A receptor (the main site for the antidepressant actions of most antidepressants). It does this by blocking the 5HT2A, 5HT2C and 5HT3 receptors, resulting in all serotonin being directed to the 5HT1A receptor. As a result, there are less sexual and GI side effects than other antidepressants. Additionally, it increases NE and DA transmission (recall 5HT2C normally inhibits DA—think atypical antipsychotic mechanism of action). Strong histamine affinity causes sedation and weight gain. There is minimal anticholinergic effect. Starting dose ranges from 7.5 to 15 mg. Increasing dose above 30 mg leads to higher NE effects and less sedation. Metabolized by 2D6 and 3A4.

Answer 75

somnolence occurs in >50% (worsened by alcohol or other sedatives), increases appetite and cholesterol, reduction of ANC (monitor for fever, chills, sore throat), and agranulocytosis.

Answer 76

extended release capsules, 40-120 mg once daily, initiate at 20 mg.

Answer 77

Savella) is one of only 3 medications approved by the FDA for the treatment of fibromyalgia. As a racemic mixture of d and l-enantiomers, it inhibits 5HT and NE reuptake equally. It is considered less potent than other SNRIs and has less affinity for cortical sites (and possibly more peripheral affinity, thus management of pain) than do venlafaxine and duloxetine. The L-enantiomer, levomilnacipran, is also dual serotonin and norepinephrine reuptake inhibitor. However, it has much higher selectivity for reuptake blockade of NE than 5HT reuptake blockade. Unlike Savella, Fetzima is approved for the treatment of MDD in the United States. Additionally, Fetzima may inhibit a beta-site amyloid precursor protein cleaving enzyme (BACE-1). This enzyme is thought to be responsible for βamyloid plaque formation. This medication may ultimately be considered in the treatment of Alzheimer ’ s disease.

Answer 78

HTN, tachycardia, GI symptoms (N/V, constipation), hyperhidrosis, urinary hesitancy/retention, erectile dysfunction

Answer 79

GAD (not panic, OCD, or social phobia). May reduce aggression and hostility in anxiety better than BZD. Less effective in managing somatic symptoms of anxiety than BZD. Can be used to treat sexual side effects and bruxism caused by SSRIs (through inhibition of 5HT2 and via DA agonism).

Answer 80

half-life 2-11 hours so is dosed TID. Has an active metabolite that is 20% less potent but 30% more concentrated in the brain than the parent compound. Primary mechanism is 5HT1A agonist, helping with anxiety (think: 5HT2 is activating, 5HT1 is calming). Dosing begins at 5mg TID and maximum dose is 60 mg. Metabolized by 3A4. Grapefruit juice increases buspirone concentrations.

Answer 81

D oes not cause weight gain, sedation, or sexual side effects (no 5HT2 or H1). Main side effects are headache, nausea, and dizziness. Safe in overdose (no deaths have been reported) and the estimated lethal dose is >300x the recommended daily dose.

Answer 82

GAD, Panic, acute mania, agitation, short term management of insomnia, anticonvulsant, akathisia. They can be used for the short-term management of anxiety and panic (1-2 weeks) while a long-term agent is initializing (SSRI). Chronic use must be monitored closely and generally BZD with long half-life and gradual onset of action are less likely to be abused.

Answer 83

anxiolytic properties are due to modulation of GABA. All are lipid-soluble, allowing them to cross the blood brain barrier. The most addictive BZD are highly lipophilic with a short onset of action (patient notices the effects quickly). Tolerance with alprazolam, for example, can occur within 1-2 weeks. See chart on next page.

Answer 84

sedation, ataxia, dizziness, respiratory depression in COPD or sleep apnea, dependence to BZD (especially with rapid onset) and risk of withdrawal, which can be fatal if not managed. Most recent studies do not show fetal cleft/palate abnormalities or cardiac malformations. Use of BZD in the 3rd trimester can result in withdrawal symptoms, decreased APGARS and poor feeding in the newborn.

Answer 85

treatment of mild to moderate cognitive impairment in Alzheimer ’ s Dementia. They slow the progression of memory loss and diminish apathy, depression, hallucinations, and mood reactivity. They may also help to delay the need for nursing home placement. Donepezil and rivastigmine are also used in Parkinson ’ s and Lewy Body Dementia in addition to being used for cognitive effects related to traumatic brain injury. Use in vascular dementia may produce improvement but not in all cases.

Answer 86

Alzheimer ’ s is due to destruction and impaired production of acetylcholine. The cholinesterase inhibitors reversibly inhibit the enzymes that break down Ach, increasing synaptic concentrations of Ach especially in the hippocampus and cerebral cortex. Blocking the breakdown of Ach in the periphery leads to nausea, diarrhea, vomiting, and cardiac abnormalities including bradycardia. Side effects include nausea, diarrhea, vomiting, bradycardia, and syncope. Avoid with bethanechol and also avoid with other anticholinergic medications (like paroxetine).

Answer 87

has a half-life of 70 hours in the elderly and is taken once daily. Cirrhosis reduces the clearance by 20%. Donepezil works selectively in the CNS with less activity in the periphery on cholinesterases (less GI symptoms etc). Donepezil starts at 5 mg qhs with a maximum dose of 10 mg. Metabolized by 2D6 and 3A4. Highly protein bound but does not displace other medications. Benefit: least GI side effects and may be more effective than galantamine in treatment of cognitive disorders.

Answer 88

has a 1-hour half-life, but it remains bound to cholinesterases, leading to effective dose for 10 hours. Rivastigmine has more peripheral activity and inhibits both acetylcholinesterase and butyrylcholinesterase. As a result, it has more GI and cardiac effects. Rivastigmine starts at 1.5 mg BID and gradually increases to 3 mg BID gradually over the course of a month. The creation of a rivastigmine patch has led to more effective treatment with less peripheral effects. Unbound to proteins and has minimal drug-drug interactions as it is not metabolized in the liver. Benefit: patch good in patients with difficulty swallowing or with questionable compliance.

Answer 89

extracted from daffodils and has a half-life of 6 hours. Side effects are minimal and transient. It is dosed at 4 mg BID per day for 4 weeks and any subsequent dose increases should occur at 4-week intervals. Maximum dose is 16 mg BID. Metabolized by 2D6 and 3A4 like donepezil. Is an allosteric agonist at the nicotinic receptor, similar to the way that BZD work on GABA receptors, in addition to stopping the breakdown of Ach? Benefit: least expensive of the cognitive enhancers with minimal side effects.

Answer 90

Tardive Dyskinesia: discontinue the medication, some indication for Vitamin E • Akathisia: propranolol or BZD • NMS: dantrolene, bromocriptine, cooling measures • Sexual side effects: change SSRI, add bupropion, buspirone, sildenafil • Anticholinergic side effects: take with food (GI), sugarless gum and pilocarpine mouthwash (dry mouth), pilocarpine eye drops (blurred vision), bethanechol (urinary retention) • Orthostatic hypotension: increase fluid intake, decrease caffeine, increase sodium if approved by PMD, ted hose, consider changing HTN meds

Answer 91

BZD: emesis, lavage, charcoal, flumazenil • Bupropion: lavage, charcoal, prophylactic BZD to prevent seizures • Clozaril: charcoal and sorbitol • Antipsychotics: lavage, charcoal, norepinephrine for hypotension, monitor EKG • SSRI: lavage, charcoal, monitor EKG • Lithium: emesis, lavage, dialysis (no charcoal), 0.9% NaCl if Na depletion caused toxicity • MAOI: emesis, lavage, charcoal, pressors, BZD to prevent seizures, phentolamine for hyperthermia, avoid Demerol • TCAs: lavage, charcoal, telemetry, EKG, anti-arrhythmia medications, BZD to prevent seizures • Thyroid hormones: emesis, lavage, charcoal, cholestyramine, propranolol • Opiates: naltrexone, monitor for respiratory depression and maintain airway ETOH: banana bag for volume and nutrient depletion, BZD to prevent seizure, maintain airway

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