Pharm Flashcards
Name typical antipsychotics
High Potency: fluphenazine (Prolixin), haloperidol (Haldol), thiothixine (Navane), trifluoperazine (Stellazine)
Medium Potency: perfenazine (Trilafon), molindone (Moban), loxipine (Loxitane)
Low Potency: chlorpromazine (Thorazine), thioridazine (Mellaril)
Side effects typical antipsychotics (EPS)
Acute dystonia: treat with benztropine, diphenhydramine (benadryl)
Pseudoparkinsonism: benztropine, diphenhydramine, amantadine (dopamine agonist)
Akathisia: bb, benzodiazepine or clonidine
Tardive dyskinesia: vmat. Inhibitor (valbenazine).
NMSL fever, rigidity, autonomic instability, acute mental status change: bromocriptine, dantrolent
Non eps side effects typical antipsychotics
Alpha Blockade: orthostatic hypotension • Anticholinergic: dry mouth (treat with sugarless gum), constipation, sore throat, urinary retention (treat with bethanechol), blurred vision, confusion •
Antihistamine: weight gain and sedation • Endocrine: prolactin causes sexual side effects like erectile dysfunction, priapism, increased time to ejaculation, gynecomastia, impotence, and anorgasmia
• Hepatic: jaundice and elevated LFTs (less severe than with atypicals)
• Cardiac: arrhythmia and prolonged QTc • Hematologic: agranulocytosis (monitor for fever, sore throat) •
Neurologic: epilepsy due to lowered seizure threshold
• Dermatologic: skin discoloration and photosensitivity in chlorpromazine • Opthomologic: retinitis pigmentosa and blindness in thioridazine
Choosing between typical antipsychotics
Choosing Between Typicals • Cardiac patients: avoid low potency, especially thioridazine (Mellaril) • Elderly: avoid low potency due to anticholinergic confusion • Weight gain: molindone (Moban) and loxipine (Loxitane) have the least weight gain. High potency has less weight gain. Currently molindone is off the market due to lack of high volume clinical use • Sexual side effects: most common in thioridazine (Mellaril) • Sleep: chlorpromazine is a sedating typical and is a good choice for aiding sleep in a patient with mania or psychosis • Mood: loxipine (Loxitane) has mild 5HT antagonism, making it similar to atypical. Additionally, it is metabolized to the TCA amoxepine. It is useful when a patient cannot get quetiapine or aripiprazole due to cost. DA blockade is similar to quetiapine and the mood component is like aripiprazole. Additionally, Stahl notes the use of loxipine for the augmentation of schizophrenia management with an atypical antipsychotic • Compliance: Haloperidol has a depot formulation that lasts 3-4 weeks to ensure compliance. Fluphenazine (Prolixin) has a depot formulation that lasts 2 weeks. Always do an oral test dose before giving a depot injection due to risk of irreversible EPS once depot is given. Consider avoiding fluphenazine depot in med-naïve young muscular males due to EPS risk • Dysphagia: Haloperidol has a liquid formulation to aid in ease of administration and an IV formulation. Reminder that IV formulations are much higher potency due to lack of first pass in the liver. Thus, start with lower doses than would use in PO or even IM (2-5mg IV
History typical antipsychotics
Phenothiazines are compounds derived from the original parent drug, methylene blue. This chemical is used in histologic staining, analytic chemistry, and as an antimalarial medication (as early as 1891). During WW2 methylene blue ’ s use as an antimalarial due to lack of access in the Pacific tropics and side effects of turning urine green and sclera blue. The antihistamine properties of methylene blue were found to be helpful as anesthetic agents. In 1951, French surgeon Laborit asked a pharmaceutical company to create a specialized phenothiazine to reduce post-surgical psychosis. This medication was chlorpromazine. Shortly thereafter, the medication was used serendipitously in psychiatric patients to reduce psychosis. Through further research and development, a similar structure, imipramine was created. This medication was one of the first antidepressants.
Indications typical antipsychotics
Indications: schizophrenia (improves positive symptoms, may worsen negative symptoms), acute mania, MDD with psychosis, hemiballismus, hiccups, Tourette ’ s. High potency antipsychotics are better used in patients with psychosis due to tumor/organic causes. As they decrease seizure threshold, use with caution in ETOH detox. Low potency antipsychotics should be avoided in the elderly and medically ill due to multiple anticholinergic and cardiac side effects. Avoid use in 1st trimester (especially chlorpromazine); 2nd and 3rd trimester are safer. Contraindicated in cardiac patients, acute angle glaucoma, and patients with a history of TD.
Mechanism of action typical antipsychotics
Mesocortical(ventral tegmentum to prefrontal cortex): negative symptoms
mesolimbic (ventral tegmentum to limmbic region)(positive symptoms): diminishes psychosis
Tuberoinfundibular (accurate nucleus in hypothalamus to to median eminence): increases PRL (DA decreases PRL; DA blockade increases PRL) 50
• Nigrostriatal (substantia Niagra to pars comapcta in midbrain with dorsal striatum in forebrain): basal ganglia and caudate. Movement disorders including EPS, PD, tremor
Typical antipsychotics and drug interactions
typicals are metabolized by 2D6 and 3A4, thus are increased in the presence of Prozac, Paxil and Luvox. They are reduced by coadministration with Tegretol. Antacids decrease the absorption of typicals. Anticholinergic delirium is possible in the presence of anticholinergic medications, low potency typical and TCA coadministration. Typicals increase blood concentrations of valproic acid. Cigarettes decrease blood concentrations of typical. Thus, if a patient is stabilized on a specific dose of a typical and quits smoking there is risk for EPS and other side effects.
Atypical antipsychotics history
Due to the prevalence of EPS with typical antipsychotics, the atypicals were created. If excessive DA blockade leads to EPS, then less severe DA blockade would cause less EPS. The best way found to modulate the amount of DA blockade was through 5HT. Normally, serotonin binds to 5HT receptors on DA neurons and inhibits DA release. By blocking these 5HT receptors, DA release is not inhibited. The combination of DA receptor blockade plus 5HT blockade (less inhibition) leads to a net increase in free DA compared with straight DA blockade in the typicals. Thus, the atypicals have less EPS. Additionally, they better treat the negative symptoms of schizophrenia than the typicals do. However, the atypicals appear to have more metabolic side effects (weight gain, diabetes) than the typicals do due to effects on other receptors. Additionally, the atypicals may have more liver effects and leukopenia than the typicals do. The majority of the atypicals are also approved by the FDA for treating bipolar mania and monotherapy for bipolar disorder.
Risperdal
Risperidone (Risperdal): the first atypical to become generic, thus lower cost. In addition to mania and psychosis, it is approved for the treatment of aggression and self-injurious behavior in autistic children. It can be used in children with tic disorders (consider also using haloperidol) or impulsive/disruptive behaviors. Half-life is 20 hours; thus once-daily dosing is fine. Equivalent to haloperidol in D2 binding affinity with less incidence of EPS when kept below 6 mg per day. Minimal alpha and muscarinic affinity. Has an active metabolite that is formed by 2D6, thus inhibiting 2D6 (paroxetine, fluoxetine) leads to less efficacy of risperidone. Has most prolactin increase of all antipsychotics. Watch for pedal edema and increased LFTs. Weight gain is #3 after clozapine and olanzapine. Formulation includes pill, dissolving MTabs, and Risperdal Consta (depot preparation lasting 2 weeks, but need oral risperidone x3 weeks after start Consta. Useful in severe OCD, impulse control issues, and body dysmorphic symptoms.
Paliperidone (Invega):
the isolated active metabolite of risperidone (i.e., risperidone is converted to Paliperidone in the liver normally), which may be a better choice in hepatically impaired patients. While it is considered to have less side effects than risperidone, paliperidone has more QTc prolongation and requires lower dosing in renal impaired patients (as it is excreted unchanged through the kidneys). It exists as an immediate release and a delayed release medication (avoid in gastric bypass) and also occurs in a depot formulation (Sustenna). Sustenna requires no continued oral dosing once the depot is given. Injection into deltoid has nearly 30% higher plasma concentration that gluteal. Most likely is a “ me too” drug with no major benefit over risperidone, but depot formulation has best evidence for avoiding hospital readmission.
Olanzapine
half-life averages 31 hours, leading to once-daily dosing is fine. Metabolized by 1A2, thus fluvoxamine, cimetidine, and ciprofloxacin increase olanzapine concentrations (inhibitors of 1A2), while carbamazepine reduces olanzapine. Weight gain and metabolic side effects are common (#2 after clozapine). Can be very sedating and alcohol coadministration leads to an increased olanzapine absorption by 25%, worsening sedation. Became generic in late 2011. Studies show best oral adherence despite SEs. Formulation includes pill, dissolving Zydis tabs, IM, and depot Relprevv (injections q 2-4 weeks), however it requires monitoring due to Post-Injection Delirium/Sedation Syndrome.
Seroquel
half-life is 7 hours, thus BID or TID dosing is recommended. While it has less EPS than other atypicals, it is sedating and has weight gain. Is used off label for the management of anxiety, PTSD and sleep. Has orthostatic hypotension commonly. Has an XR formulation with equivalent bioavailability. Dilantin increases Quetiapine ’ s clearance 5-fold, thus consider higher dosing in patients on Dilantin. Weight gain appears to be somewhat dose dependent. If using it for sleep, once exceeding 200mg consider changing to another medication for sleep, like Trazodone, Vistaril or Doxepin. Additionally, because the weight gain is metabolic in origin, telling the patient that the medication will cause weight gain due to appetite increase alone is inaccurate. It is important to have the patient monitor their weight while on most of the atypicals.
Geodon/ziprasidone
half-life is 5-10 hours, thus BID dosing needed. Bioavailability doubles when taken with food, preferably a 500-calorie meal. Due to 5HT1A agonism and SSRI/SNRI properties, it has some benefit in treating or augmenting depression treatment. Has less weight gain and EPS than other atypicals. Common side effects include sedation and QTc prolongation (more than other atypicals). Ziprasidone has BID dosing and exists as a capsule (cannot be broken in half), liquid, and IM. While ziprasidone is not a highly potent atypical, it is useful in treating MDD with psychosis.
Clozapine
likely the most effective antipsychotic. Half-life of 12 hours. Considered to have higher affinity for limbic than striatal areas, compared with atypicals. Is metabolized primarily by 1A2 (increased in presence of fluvoxamine or ciprofloxacin). Side effects include severe sedation, weight gain, sialorrhea, agranulocytosis, QTc prolongation, and requires weekly blood draws for 6 months to monitor the ANC. Dosing is held if WBC <3000 or granulocytes <1500. Additionally, this medication is only dispensed at certain pharmacies and requires proof of labs to dispense. There is a national clozapine registry where all patients on the medication are followed and their labs reported. In order to start clozapine, the patient ’ s information must be given to the registry and pretreatment labs must be normal (lipids, CBC with ANC, Chem 13 and EKG). The risk of agranulocytosis is <1% in the first year of treatment with clozapine. The risk of TD is incredibly low and it is the best treatment for psychosis that has not responded to other agents. It occurs in pill and dissolving tablet formulations and is BID dosing. Dosing starts at 25mg BID and can increase by 25mg per day maximum. Sialorrhea may respond to clonidine. Like risperidone, is generic. Lithium can be used to raise the ANC in order to help with clozapine titration. A simple dosing of 600 mg at night of Li can help improve the ANC enough to start or continue clozapine.
Abilify
unlike the other atypicals, is a D2 partial agonist, competing with endogenous DA (both postsynaptic and presynaptic) and binds less robustly. This is considered to be modulation of the DA receptor rather than blockade. The net result is diminished DA activity in the limbic system (which is elevated in schizophrenia) and increased DA activity in the frontal and prefrontal areas (which is considered low in schizophrenia). In addition to mania and psychosis, it is indicated for augmentation of depression treatment. The half-life is about 75 hours; thus once-daily dosing is fine. Metabolized by 3A4 and 2D6. Is a strong 5HT2C agonist (unlike the other atypicals), which means less weight gain. It is also a strong 5HT-7 antagonist, improving mood. Side effects include akathisia, orthostatic hypotension (alpha blockade), nausea/GI effects, somnolence or insomnia.
Asenapine/saphris
like clozapine, has higher affinity for D3 and D4 receptors than D2 receptors. It has minimal anticholinergic side effects. Is associated with akathisia, dizziness, sedation, and weight gain (histamine affinity). Metabolized by 1A2 and is dosed BID in a sublingual formulation. The patient may not eat or drink for 10 minutes after dosing. Preliminary drug company data reports results from 1,500 patients but there is paucity of published data on actual efficacy (the main published study only evaluated 174 patients). Thus, asenapine has weight gain, sedation, must be dosed sublingually, and is very expensive. There is limited published data on the efficacy on this medication as compared with other atypicals.
Iloperidone (fanapt)
ot structurally related to any other atypicals. Has mixed D2 and 5HT2 antagonism with low affinity for histamine and muscarinic receptors. Metabolized by 2D6 and 3A4 and the half-life varies between 18-37 hours based on the strength of 2D6 enzymes (longer half-life in poor metabolizers). Avoid in hepatic impairment. Prolongs QT interval as much as ziprasidone. It is also associated with orthostatic hypotension (alpha blockade), dizziness, and somnolence. Iloperidone has minimal weight gain. Prolactin is increased in over 25% of patients. Due to risk of orthostatic hypotension, dosing must be gradual over 4 days in BID scheduling. Considering that this medication was first in trials in 1998 and took over 10 years to be released after moving between multiple drug companies, likely due to subpar efficacy results. The bottom line: this medication is similar to ziprasidone in QTc prolongation with less akathisia but more weight gain. It must be titrated slowly due to orthostatic hypotension and many studies do not show it to be any better than existing atypicals.
Latuda/lurasidone
strong D2/5HT2 antagonist with minimal histamine interaction (thus low weight gain). It does have sedation, which may be related to strong 5HT-7 antagonism (see below). Metabolized by 3A4. There are only four 6-week trials of this medication submitted to the FDA, thus the clinical data is limited. One study suggested that it upregulates BDNF in the prefrontal cortex, suggesting that the medication may be “ pro-cognitive.” Has once-daily dosing, but must be taken with food to be absorbed. Minimal weight gain, no QTc issues. EPS is equivalent to other atypicals. Further data on lurasidone efficacy will show if this medication is a “ me too” medication.
5ht-7
some of the new antipsychotics are boasting 5HT-7 antagonism. While not fully understood, the 5HT-7 receptor may be associated with depression. Medications that block 5HT-7 improve depression. Additionally, they may improve hippocampus-mediated actions, like memory. Many of the atypicals (risperidone, ziprasidone) are potent 5HT-7 antagonists.
Pimavanserin (nuplazid)
Indication: FDA approved in 2016 for psychosis within the context of Parkinson ’ s Disease. Unlike other antipsychotics, Nuplazid reduces hallucinations without worsening parkinsonism
Dosing: recommended 34 mg once daily with or without food, no titration needed. No dose adjustment of carbidopa/levodopa is required Profile: non-dopaminergic atypical antipsychotic, inverse agonist and antagonist activity at serotonin 5HT2A receptor. While traditionally we think of treatment of hallucinations by D2 blockade, in PD this mechanism substantially worsens the underlying movement disorder. Placebo-controlled trials support the use of clozapine (at a miniscule dose of 6.25-75 mg/day) to treat PD psychosis (PDP). A dose that low is not expected to do much DA blockade, and another mechanism has been proposed. Clozapine blocks 5HT2A receptors, reducing PDP. Wait, 5HT2A receptors? Consider that the mechanism for LSD induced hallucinations is through cortical 5HT pathways. Pimavanserin works as an antagonist and inverse agonist specifically at 5HT2A receptors. There is minimal binding at 5HT2C and no appreciable affinity for 5HT2B, dopaminergic (including D2), muscarinic, histaminergic, or adrenergic receptors.Pimavanserin is highly protein bound (~95%) in human plasma. Pimavanserin is predominantly metabolized by CYP3A4 and CYP3A5.
Side Effects: Nausea (7%), Constipation (4%), Peripheral edema (7%), confusional state (6%), possible QTc prolongation
Rexulti (brexpiprazole)
Indication: schizophrenia and adjunctive treatment for depression
Dosing: start at 0.5mg-1mg once daily and titrate. For schizophrenia: 2–4 mg once daily. For depression: 2 mg once daily. Can be taken with or without food.
Profile: related to aripiprazole, is also a D2 partial agonist, along the agonism spectrum. It is closer to the antagonist end than aripiprazole. Is also a partial agonist at serotonin 1A receptors (improve mood and cognition). Acts as a 5HT-2A receptor antagonist (see Nuplazid). Also potentiates nerve growth factor. Metabolized primarily by CYP450 2D6 and CYP450 3A4.
Side effects: weight gain and dose-dependent akathisia. Others include upper respiratory infection, nasopharyngitis, somnolence, tremor, fatigue, headache, hyperglycemia, theoretical risk of tardive dyskinesia, NMS (rare), seizures (rare)
Pregnancy: In animal studies, brexpiprazole did not demonstrate teratogenicity. There is a risk of abnormal muscle movements and withdrawal symptoms in newborns whose mothers took an antipsychotic during the third trimester. In the newborn, symptoms may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty feeding.
Vralyar (cariprazine)
Indication: schizophrenia and bipolar 1- manic/mixed episodes
Dosing: starting dose 1.5 mg, max 6 mg per day for both BMD and Schizophrenia. Has the longest halflife of the atypical antipsychotics, half-life of 2-4 days with an active metabolite that has a half-life of 1-3 weeks.
Profile: D2 partial agonist like aripiprazole and brexpripazole, unique high affinity for D3 receptors. D3 agonism is associated with wakefulness, thus partial agonism is associated with the treatment of mania. Additionally, effects at D3 may be precognitive and diminish negative symptoms of schizophrenia. Also has high affinity for the serotonin 1A (partial agonist) and moderate affinity for the serotonin 2A receptor (antagonist). Metabolized by CYP450 3A4.
Side effects: akathisia, EPS, may cause dose-dependent weight gain, GI symptoms (N/V), sedation
Mood stabilizer history
The basic mechanism of action of the mood stabilizers is to enhance the actions of GABA and reduce the actions of glutamate. In this way, both seizures and mood swings are controlled. Additionally, mood stabilizers can be used to aid in the treatment of anxiety for similar reasons. Lithium is the first known mood stabilizer, and is mechanistically different from the others in that it does not also treat seizures. Regarding historic serendipity, lithium was first used in the 1800s for the treatment of gout. It was known to help dissolve urate, a particle initially blamed for mania and psychosis. Around 1900 lithium was abandoned for the treatment of mania and was not rediscovered until 1949 by Australian psychiatrist Henry Cade. Due to understanding that disorders such as thyrotoxicosis could be detected by metabolites in urine, Cade examined manic patients ’ urine for detectable particles related to mania. His study focused on injecting guinea pigs with manic patient urine to see if behavioral disturbance occurred. Long story short, the guinea pigs he was injecting with manic patients ’ urine kept dying so he decided to add lithium to the urine to help break down urate. Ultimately, he discovered that lithium alone led to calming of mania. The FDA did not approve the use of lithium for the treatment of mania until 1970. Strangely, in the 1930s - 50s if you wanted to have access to lithium, it was most easily found as a common replacement for table salt in patients with heart disease OR in 7-UP. Seriously. Originally labeled as Bib-Label Lithiated Lemon-Lime Soda,” 7-UP containing lithium was marketed specifically as a hangover cure. “ Valproic Acid was first synthesized in 1882 from valerian as a solvent for organic compound that was believed to be inert metabolically. By the 1960s it was discovered that medications that had long been considered anticonvulsant had no ability to prevent seizures and that the valproic acid solvent had been the active treatment.
Lithium indications
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.
Lithium profile
: 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.
Lithium side effects
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.
Lithium drug interactions
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.
Valproate acid indications
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.
Valproate acid profile
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.
Valproate acid side effects
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.
Valproic acid drug drug interactions
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.
Carbamazepine (Tigretol) indications
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.
Carbamazepine profile
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.
Carbemazepine profile 2
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.
Carbemazpine side effects
: 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
Carbemazepine drug interactions
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.
Oxcarrbazepine (trileptal) indications
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,
Oxcarbazepine profile
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.
Oxcarbazepine side effects
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.
Oxcarbazepine drug drug interactions
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.
Lamotrigine (lamictal) indications
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.
Lamotrigine (lamictal) profile
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.
Lamotrigine side effects
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.
Lamotrigine drug-drug interactions
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.
Gabapentin (neurontin) legal
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.
Gabapentin. Indications
add on therapy for treatment of seizures.
Gabapentin profile
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
Gabapentin side effects
somnolence, ataxia, diplopia, and dizziness. Side effects are dose dependent.
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NDRI and mixed action antidepressants chart
Benzo chart
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