Neuro pharm

Life Span Considerations Sz med Pregnancy:

Avoid valporic acid unless it is absolutely necessary and then only if no other drug is effective. Use just one drug whenever possible. Valproate (Depakote) can cause severe physical malformations & markedly reduced cognitive function if in utero exposure. Use this drug as last resort in preg Canada prohibits Vigabatrin in preg Human fetal harm documented w/ carbamazepine, lamotrigine, phenytoin, phenobarbital, & topiramate & the remaining drugs- fetal harm has been documented in animal studies (probably lack of human studies) *Some recommend vit K administration 1 month before delivery & during delivery- if pt on phenytoin, phenobarbital, carbamazepine, & primidone (can decrease vit K synthesis)

AD Drugs for Neuropsychiatric Symptoms:

(e.g., agitation, aggression, delusions, hallucinations) occur in more than 80% of people with AD. Although multiple drug classes have been tried as treatment, very few are effective, and even then, the benefits are limited. These are Antipsychotics: Convincing evidence that neuropsychiatric symptoms can be reduced with two atypical antipsychotics: risperidone (Risperdal) and olanzapine (Zyprexa). However, benefits are modest, and these drugs slightly increase mortality, mainly from cardiovascular events and infection.

Identify the possible risk factors in the development of Alzheimer's disease.

--Being female --Head injury --Low educational level --Production of apolipoprotein E4 --High levels of homocysteine --Low levels of folic acid --Estrogen/progestin therapy --Nicotine in cigarette smoke --Sedentary lifestyle

SZ Basic Therapeutic Considerations treatment drug selection initial treatment patient education

--Ideally, treatment would eliminate sz entirely, but this isn't always possible. Many drugs will cause intolerable SE. We must balance the SE against need for complete sz control. --Drug selection is based on sz type, so proper diagnosis is crucial. (Valproic acid seems to be only drug effective for practically all forms of epilepsy). --Pharmacologic treatment for sz is highly individualized, and it's common for pts to try several drugs before finding an effective and tolerable regimen. --Initial treatment should begin with only one drug. If it doesn't work, it should be discontinued, and another tried. If second drug fails, options are to either try a 3rd drug alone or start combining drugs. --Patient education - no driving or other hazardous activities until sz control is certain. Encourage pt/family to keep a sz frequency chart.

Sz meds Valproic Acid (Depakene, Depakote, Depacon, Epival) AEs:

--Minimal sedation & cognitive impairment --GI effects are most common --Hepatotoxicity & pancreatitis- rare & serious Valproic Acid BBW: 1. Fatal hepatic failure has occurred- young children & pts w/ mitochondrial disease at increased risk 2. Fatal & rapidly progressing pancreatitis has occurred. Common s/s- n/v, anorexia, abd pain 3. Highly teratogenic.* neonates who survive - major congenital malformations & decreased mental capacity --Common but transient n/v, indigestion (less intense w/ enteric coated forms) --Minimize GI effects by giving w/ food & using enteric-coated products --Rare- Fatal liver failure. High risk pts: < age 2 receiving multidrug therapy (incidence is much higher) minimize by: do not use valproic acid in conjunction w/ other drugs if < age 2 do not use w/ preexisting liver dysfunction check liver function at baseline & periodically thereafter (monitoring tho can fail to give warning bc severe hepatic toxicity can develop rapidly w/o prior abnormal test) inform pts s/s of liver injury & instruct to inform HCP: reduced appetite, malaise, nausea, abd pain, jaundice use in lowest effective dose* Life-threatening pancreatitis. Some have been hemorrhagic. Can rapidly progress from 1st symptoms → death. Can develop anytime throughout therapy. inform pts of s/s & to instruct immediately see HCP if: abd pain, n/v, anorexia if dx with pancreatitis- d/c valproic acid & substitute w/ alternative * Highly teratogenic - esp in 1st Tri. risk of major congenital anomalies 4x higher than w/ other antiseizure drugs neural tube defects (like spina bifida) greatest concern also atrial septal defect (ASD), cleft palate, hypospadias, polydactyly, craniosynostosis exposure in utero can impair cognitive function* Valproic acid exposure in utero → significantly lower IQ scores than with other antiseizure agent exposures. & increases risk for autism* Rash, wt gain, hair loss, tremor, blood dyscrasias (leukopenia, thrombocytopenia, RBC aplasia)

SZ Basic Therapeutic Considerations monitoring plasma levels vs. clinical observation: to determine drug therapy and dosages how to withdrawal

--Monitoring plasma levels - especially helpful for tonic-clonic seizures, as these are dangerous sz and delay in therapy may worsen condition. Rapid control is desirable. However, these sz tend to occur infrequently, so relying only on clinical outcome alone to determine efficacy would be impractical. This is why we adjust dosage based on plasma levels. For absence sz which tend to occur very frequently, clinical observation is the best means for establishing effective dosage. --Withdrawing antiseizure drugs - some forms of epilepsy undergo spontaneous remission, so eventually discontinuing meds may be appropriate. There's no specific guideline for how to do this, but the general rule is they must be withdrawn slowly (6 weeks to several months). If pt is taking multiple drugs, they should be withdrawn sequentially, not simultaneously.

Seizure drugs Carbamazepine (Tegretol, Carbatrol, Epitol, Equetro) - AEs: Don't use in certain patients

--Take largest portion of the daily carbamazepine dose at bedtime to decrease CNS AEs --Minimize SEs by: initial low dosing then gradually increase (q1-3 wks) until seizure control --minimal on cognitive function in contrast to phenytoin & phenobarbital Neurologic effects - visual disturbances (nystagmus, blurred vision, diplopia), ataxia, vertigo, unsteadiness, h/a. Common in 1st few weeks, but tolerance develops w/ continued use Initiate tx w/ low doses & take largest dose of the day before bed to decrease AEs Carbamazepine-induced bone marrow suppression → leukopenia, anemia, thrombocytopenia but serious rxns are rare* thrombocytopenia & anemia (5%) respond to drug d/c leukopenia (10%) is transient & subsides even w/ continued use Do not withdraw drug unless WBC count < 3,000/ mm *Get baseline CBC & periodically after* Fatal aplastic anemia- extremely rare Pts w/ preexisting hematologic abnormalities should not use this drug * Inform pts manifestations of this: fever, sore throat, pallor, weakness, infection, easy bruising, petechiae - instruct pts to inform HCP of these* Teratogenic* - 2.6 fold increase in spina bifida drug should only be used if seizure benefits outweigh risks to fetus Can inhibit renal excretion of water by promoting ADH secretion → H2O retention → reduces osmolarity of blood & other body fluids → threat to HF pts* Hyponatremia* - dose dependent. Periodically monitor Na levels* esp in older adults who are at greater risk of hyponatremia w/ this drug Many dermatologic effects morbilliform rash (10%), photosensitivity rxns, SJS, TEN. Tx mild rxns w/ prednisone or an antihistamine W/ skin eruptions, important to be alert of s/s of DRESS rare condition; severe dermatologic rxns are accompanied by systemic sxs (e.g., fever, generalized lymphadenopathy) & multi-organ involvement major risk factor for SJS, TEN & DRESS: HLA-B*1502 (genetic variation seen in ppl of Asian descent- among ppl w/ variant- 5% get SJS or TEN w/ this drug) Pts of Asian descent should be tested for HLA-B*1502 variant before given carbamazepine *** may also increase risk of SJS & TEN w/ phenytoin too. Phenytoin should not be used as an alternative in pts w/ this mutation **

sz meds Phenobarbital AEs: toxicity drug withdrawal

--most common CNS effect: drowsiness --initial tx- sedation in all pts, but tolerance develops --paradoxical responses in kids & older pts → irritable & hyperactive --cognitive deficits may occur in kids --depression may occur in adults --agitation & confusion in elderly --Barbiturates contraindicated in pts w/ personal or fam hx of acute intermittent porphyria (barbs can increase risk for acute intermittent porphyria) --Respiratory depression risk. Do not give to pts w/ significant resp compromise --Like phenytoin, phenobarbital can interfere w/ the metabolism of vitamin D & K* Vit D metabolism disruption → ricketts & osteomalacia Instruct pts to eat foods high in vit D, K & calcium. May need to supplement some pts Toxicity moderately excessive doses → nystagmus & ataxia severe overdose → generalized CNS depression; death from resp depression Drug Withdrawal: gradually reduce dose. Abrupt withdrawal can precipitate SE. Warn pts against this danger & instruct not to d/c drug abruptly.

Pt Education - Antiseizure Drugs

--optimal dose takes time to find & med regimen may need tweaking over several appointments to promote adherence: educate pts it's important to take meds as prescribed. After a safe & effective dose has been established, small deviations in dosage can → toxicity or loss of seizure control --Inform of dangers of abrupt drug d/c. Never d/c drug without consulting prescriber. If pt is planning a trip, advise them to carry extra meds to ensure uninterrupted supply. --Explain need for refills to be obtained on time. --Maintain seizure frequency chart w/ date, time, & nature of all seizures & bring it to all appts --Important to keep appts of periodic drug monitoring (for some drugs) --avoid potential hazardous activities (driving operating dangerous machinery) until seizure control. Explain the laws concerning the risk. Carry some ID to aid in dx & tx (medical alert bracelet) bc seizure may recur after they're largely under control --warn pts about CNS depression as a drug side effect. --Advise to avoid hazardous activities w/ significant CNS dep. Warn pts against using alcohol or other CNS deps. --Women should take folic acid before & during preg to reduce neural tube defect risk --educate pts, families, caregivers about signs that precede suicidal behavior (increased anxiety, agitation, mania, hostility) & advise to report them immediately

AD Patient Education Cholinesterase inhibitors:

Explain that this drug is prescribed to improve thinking and function in patients with Alzheimer disease. It does not work on everyone. Explain that lightheadedness may occur and that this increases the risk for falls. If these symptoms occur, sit or lie down until it passes. It may help to move slowly when changing to a standing position because sudden movement may increase dizziness. Encourage patient and family to ensure adequate intake with supplemental meals and snacks to maintain optimal weight. Have the patient keep a list of new symptoms and problems so that these can be discussed at each patient encounter.

Life Span Considerations Sz med Children:

FDA approved antiseizure drugs approved for kids (except eslicarbazepine). approved, but inadequate studies have been done on kids < age 2 who are taking Valproate- higher risk for hepatotoxicity & can be fatal

There is a complete understanding of the role of CNS neurotransmitters. True or false

False: The study is difficult and a relationship between neurotransmission and the production of behavioral or psychological processes has not been established.

Parkinson's Disease general defn: pathophys what is its neurotransmission problem characteristic? when do symptoms appear usually? what are the symptoms? what can med therapy do?

A neurodegenerative disorder of the extrapyramidal system associated with the disruption of neurotransmission in the striatum. Pathophys: Severe degeneration of the dopaminergic neurons of the substantia nigra within the basal ganglia and the dopamine pathways; development of Lewy bodies (clumps of built-up protein) in the residual dopaminergic neurons. The characteristic dyskinesias and akinesia is created through imbalance between dopamaine (DA) which is TOO LOW and acetylcholine (Ach) which is TOO HIGH Symptoms that generally appear in middle age and progress. Symptoms: tremor at rest, rigidity, postural instability, bradykinesia, autonomic disturbances, depression, pychosis, and dementia. Medication therapy can maintain functional mobility for years and improves and prolongs the quality of life. NO CURE.

Drug class: Antiseizures: Drug: Topiramate- AE DI

AE Common- somnolence dizziness, ataxia, nervousness, diplopia, nausea, anorexia, weight loss Confusion, memory difficulties, altered thinking, reduced concentration, difficulty finding words, kidney stones, parethesias Metabolic acidosis d/t causing increased secretion of bicarb- risk factors are renal disease, severe respiratory disorders, diarrhea, keto diet --Measure serum bicarb baseline and periodically thereafter, instruct pt to report any hyperventilation or fatigue and anorexia Abrupt withdraw can cause rebound effects, tapper off med Hypohidrosis(reduced sweating)- increases risk for hyperthermia Angle closure- glaucoma- educate pt on symptoms and seek immediate help Women who are of childbearing age should use contraceptives or switch to a safer anti seizure med Increased risk of suicide- screen pts before therapy starts Drug interactions- Phenytoin and carbamazepine decreased topiramate levels. Topiramate can increase phenytoin levels. Combination with valproic acid increased risk for hyperammonemia

Dopamine Agonist- First line drugs for pts with mild to moderate symptoms of PD 2 groups

Advantages of use: These drugs are not dependent on enzymatic conversion to become active, they are not converted to potentially toxic metabolites and they do not compete with dietary proteins for uptake from the intestine or transport across the BBB When used long term they are less likely to have a response failure and less likely to cause disabling dyskinesias Adverse effects- hallucinations, daytime sleepiness, postural hypotension- reserved for younger pts who tolerate side effects better TWO GROUPS: 1. Derivatives of ergot- bromocriptine and cabergoline- less selective. More SE. 2. Nonergot derivatives- pramipexole, ropinirole, rotigotine, apomorphine- highly selective for dopamine receptors. These meds have fewer side effects and are preferred Take with food to avoid GI upset.

Explain side effects in patients with PD if anticholinergic or antiadrenergic.

Anticholinergic can increase dementia, antiadrenergic can cause hypotension.

Key prescribing considerations for Seizure drugs !!!!!!!!!!!!!!!!!!!!!! Lots

Baseline data- pregnancy test. Assess seizure frequency and type and conduct a depression screen Additional baseline data are needed for the following: Brivaracetam- CBC with diff, liver function, renal function Caramazepine- CBC with diff, liver function, renal function, screen for HLA-B*1502 allele variant for pts of Asian ancestry Eslicarbazepine- CBC with diff, liver function, serum sodium Ethosuximide- CBC with diff Felbamate- CBC with diff, liver function Gabapentin- Renal function Lacosamide- EKG, check for h/o drug abuse and assess potential for dependent Lamotrigine- CBC with diff Oxcarbazepine- CBC with diff, serum sodium Phenobarbital- CBC with diff, liver function, renal function, check for h/o drug abuse and potential for dependency Phenytoin- screen for HLA-B*1502 allele variant for pts of Asian descent (increased risk for SJS and TEN) Rufinamide- EKG Tiagabine- Liver function Valproic acid- Liver function Vigabatrin- HandH (if abnormal get cbc), visual acuity, dilated ophthalmologic exam Zonisamide- CBC with diff, liver function, renal function, metabolic panel, serum bicarbonate

Life Span Considerations Sz med Older adults:

Beers Criteria: carbamazepine, oxcarbazepine, phenobarbital possibly inappropriate for age 65+. Phenobarbital identified as high risk for pts age 56+. elderly at increased risk for AEs (falls bc of sedation, etc). Cautious prescribing of all antiseizure drugs. Lower initial doses are advised.

Sz meds Oxcarbazepine (Oxtellar, Trileptal, etc.) AE

CNS effects: drowsiness, dizziness, double vision, nystagmus, h/a, n/v, ataxia avoid driving & other activities, unless low degree of drowsiness Hyponatremia: clinically significant hyponatremia (<125) in 2.5%. S/S: nausea, drowsiness, h/a, confusion. monitor Na levels if oxcarbazepine + other Na depleting drug Dermatologic effects: like carbamazepine, this drug can cause serious skin rxns (SJS, TEN). 30% cross sensitivity among pts hypersensitivity to carbamazepine- Do not use either drug if sensitivity hx to either* Hematologic effects: Rare. Some suggest routine blood counts monitoring. Assess pts for s/s of blood dyscrasias (pallor, fatigue, weakness, exercise intolerance, fever, infection, easy bleeding/bruising, petechiae) & order CBC for confirmation Hypersensitivity effects: assoc w/ multiorgan hypersensitivity rxns Usual S/S: fever & rash assoc w/ at least one: lymphadenopathy, hematologic abnormalities, pruritus, hepatitis, nephritis, hepatorenal syndrome, oliguria, arthralgia, asthenia Long term use can → decreased bone mineral density → osteopenia & osteoporosis- increased risk for fractures

sz meds High risk pts for specific drugs-

Brivaracetam- Caution in pts with hepatic and renal impairment. Do not use in pts in end-stage renal failure Carbazepine- Do not use in pts with h/o bone marrow depression or preexisting hematologic abnormalities. Increased risk for SJS and TEN in pts with the variant HLA-B* 1502 allele Eslicarbazepine- Not recommended for pts with impaired renal function Felbamate- Do not use in pts with anemia and hepatic impairment Gabapentin- Caution and dosage adjustment recommended for pts with renal impairment. Increased risk for psychological and physical dependence is increased in pts with history of drug abuse Lacosamide- Not recommended for pts with cardiac conduction disorders or pts who are taking drugs that can prolong the PR interval. Risk for abuse and dependency may be increased in pts with a h/o abuse or dependency Oxcarbazepine- may worsen Osteopenia and osteoporosis Phenobarbital- Do not use in pts with a personal or family h/o porphyria and in pts with marked anemia, or liver impairment or pts with significant respiratory disease Phenytoin- IV is contraindicated for pts with bradycardia or AV block. PO can worsen these conditions Rufinamide- Do not use in pts with family h/o short QT syndrome Tiagabine- not recommended for pts with liver impairment Valproic acid- Do not use in pts with significant hepatic dysfunction, and in children less than 3 who are taking other antiseizure meds. Last resort in pregnancy Vigabatrin- caution in pts with anemia or vision loss Zonisamide- Do not use in pts with conditions that contribute to a tendency towards metabolic acidosis. Do not use in pts with sulfa allergies Educate pts to keep a seizure chart of the nature, time, and frequency

Sz meds Lamotrigine (Lamictal) MOA FDA approval uses

Broad spectrum antiseizure activity. MOA: Benefits from blocking Na channels & partly from blocking Ca channels. both → decrease release of glutamate (an excitatory neurotransmitter) FDA approved for: --adjunctive therapy of partial seizures in age 2+ --adjunctive therapy of generalized seizures assoc w/ Lennox-Gastaut syndrome age 2+ --adjunct therapy of primary generalized tonic-clonic seizures in age 2+ --monotherapy of partial seizures in age 16+ who are converting from another antiseizure drug --long term maintenance of bipolar disorder --Guidelines recommend use for absence seizures

AD Cholinesterase inhibitors: Adverse effects:

By elevating acetylcholine in the periphery, all cholinesterase inhibitors can cause typical cholinergic side effects. Gastrointestinal (GI) effects—nausea, vomiting, dyspepsia (indigestion), diarrhea—occur often. Dizziness and headache are also common. The elevation of acetylcholine at synapses in the lungs can cause bronchoconstriction. Accordingly, cholinesterase inhibitors should be used with caution in patients with asthma or chronic obstructive pulmonary disease (COPD). Cardiovascular effects (uncommon, serious concern): Increased activation of cholinergic receptors in the heart can cause symptomatic bradycardia, leading to fainting, falls, fall-related fractures, and pacemaker placement: drug withdrawal may be indicated, especially if cognitive benefits are lacking.

SZ MEDS Minimizing AE: AEs how to minimize them

CNS depression- sedation, drowsiness, lethargy most prominent during initial phase of treatment and they decline with continued drug use. Avoid driving until symptoms have passed. Use low initial dose and give largest portion at bedtime Withdrawal seizures- Abrupt discontinuation of antiseizure meds can lead to status epilepticus. Withdraw slowly (6 weeks to several months) Usage in pregnancy- take the lowest effective dose and try to use only one drug. Use valproic acid last- its highly teratogenic and decrease IQ of children exposed. Pregnant pts should take 0.04mg of folic acid daily if taking any kind of AED, start prior to pregnancy Suicidal thoughts and behaviors- screen for depression and suicidality before treatment. Involve loved ones

Sz drugs Carbamazepine Significant Drug & Food Interactions

Carbamazepine INDUCES hepatic-drug metabolizing enzymes & can increase the rate at which it & other drugs are inactivated Particular concern: warfarin & OCs levels are lowered (increase these drugs' when taken with carbamazepine) Phenytoin & phenobarbital INDUCE hepatic drug metabolism too so if these drugs are taken w/ carbamazepine → induction of hepatic drug metabolism will be greater than carb alone Phenytoin & phenobarbital can further accelerate carbamazepine metabolism → decreasing its effects and plasma levels. More metabolism = less drug available in plasma AVOID Grapefruit juice* can inhibit metabolism of many drugs like carb: grapefruit + carbamazepine → carb peak & trough levels can rise by 40%

Drugs for Parkinson's Disease Patient Centered Care:

Children- Juvenile PD (under 18) is extremely rare and therefore many drugs have not been tested. Only Amantadine, Benztropine, Bromocriptine have approval Do not use Selegiline in pts under 12 Pregnancy: Bromocriptine and Cabergoline are not associated with any AE but the manufacture recommends stopping these meds once pregnancy is determined Animal studies on the rest have shown potential fetal harm Ropinirole- animal studies have demonstrated teratogenic effects and pregnancy loss Breast feeding- Bromocriptine and Cabergoline- interfere with lactation Anticholinergics can suppress lactation Not recommended to breastfeed with these meds Older adults-Ave age of PD is 62 AE are more common and more severe in these patients BEERS criteria designate anticholinergics (benztropine and trihexyphenidyl) as potentially inappropriate for these pts

DRUGS FOR ALZHEIMER DISEASE (AD) ~~~~~~~~~~~~~~~~~~ Pharmacological treatment involves the use of what 2 classes and what FOUR drugs approved for tx? general MOA for each class?

Cholinesterase inhibitors: donepezil, galantamine, and rivastigmine --for mild, moderate and (donepezil would be) severe forms --MOA: increase availability of acetylcholine at cholinergic synapses. N-methyl-D-aspartate receptor antagonist: memantine --only for moderate and severe - can combine with cholinesterase inhibitor --MOA: --modulates the effects of glutamate (the major excitatory transmitter in the central nervous system) at NMDA receptors, which play a critical role in learning and memory. --blocks calcium influx when extracellular glutamate is low but permits calcium influx when extracellular glutamate is high

Seizure drugs Phenytoin (Dilantin) - Clinical indication? MOA? PK?

Clinical indication: most widely used antiseizure drug. Active against partial and tonic-clonic. (Carbamazepine better for young children). Was also used to treat dysrhythmias in the past, but has been replaced by better agents. Not used for absence sz. MOA - selective inhibition of sodium channels. Blockade limited to hyperactive, seizure-generating neurons, leaving healthy neurons unaffected. PK - phenytoin has unusual pharmacokinetics that must be accounted for in therapy. Due to saturation kinetics, small changes in dosage can produce disproportionately large changes in serum drug levels. Narrow therapeutic index!!!! Aim to keep levels between 10 and 20 ug/mL. Doses of phenytoin needed to produce therapeutic effect only slightly smaller than dose needed to saturate hepatic enzymes that metabolize it. So, if it's administered in doses only slightly greater than those needed for therapeutic effects, liver's capacity to metabolize the drug will be overwhelmed, and plasma levels of phenytoin will rise dramatically. Also d/t saturation kinetics, phenytoin's half-life varies considerably. Low doses have short half-life (8 hours); higher doses have longer half-life (up to 60 hours).

Sz meds Lamotrigine (Lamictal) Adverse effects-

Common: dizziness, diplopia, blurred vision, nausea, vomiting, and headache Blood disorders, hypersensitivity and immune system reactions, aseptic meningitis (headache, fever, stiff neck, nausea, vomiting, rash, sensitivity to light), risk for suicide is increased (screen pts before start of therapy) More serious reactions- TENS, SJS, and DRESS Increased incidents with concurrent use of valproic acid Black box warning ! ! ! - may cause serious skin reactions like SJS and TEN. Death can occur withdraw medication if these occur

Tolerance: Defn

Decreased response occurring during the course of prolonged drug use

Sz meds Oxcarbazepine (Oxtellar, Trileptal, etc.) derivative of which traditional sz med? MOA

Derivative of carbamazepine & shares same features MOA: blockade of voltage-sensitive sodium channels in neuronal membranes, an action that stabilizes hyperexcitable neurons & thereby suppresses seizure spread. Uses: monotherapy & adjunct therapy for partial seizure management approved for monotherapy in age 4+ & adjunctive therapy in age 2+

Drugs for Parkinson Disease Prototype drugs

Dopaminergic Drugs 1. Levodopa- increases dopamine synthesis: 2. Carbidopa- blocks levodopa destruction (The two above together make 1st line tx) 3. Pramipexole- DA receptor agonist 2nd line tx Entacapone- Inhibits MAO-B Amantadine- promotes DA release Centrally acting Anticholinergic Drugs Benztropine

Seizure drugs Phenytoin (Dilantin) - Drug Interactions

Drugs Phenytoin decreases: oral contraceptives, warfarin, and glucocorticoids. Drugs that increase Phenytoin levels: diazepam, isoniazid, cimetidine, and alcohol (when taken acutely), and Valproic acid. Remember, these ones are especially dangerous to combine since Phenytoin has such a narrow TI. CNS depressants (alcohol, barbiturates, etc.) will add to CNS depressant effect of phenytoin and should be avoided. Enteral tube feedings - tube feeds will decrease phenytoin absorption causing subtherapeutic levels. Hold feeds for 1 to 2 hours before and after drug administration.

AD-- Cholinesterase inhibitors: Drug interactions

Drugs that block cholinergic receptors can reduce therapeutic effects and should be avoided: anticholinergic agents first-generation antihistamines tricyclic antidepressants conventional antipsychotics

PD dopaminergic agents MOAs

Drugs that directly or indirectly active dopamine receptors Dopaminergic drugs have several MOA: Levodopa is converted to dopamine which activates dopamine receptors directly; inhibitors of monoamine oxidase-B (MOA-B) prevent dopamine breakdown; amantadine promotes dopamine release (and may also block dopamine reuptake); inhibitors of catechol-O-methyltransferase enhance the effects of levodopa by blocking its degradation

sz meds Phenobarbital general MOA PK

Effective & inexpensive. Can be given once daily Not as widely used now (AEs like lethargy, depression, learning impairment can be significant) & been replaced w/ newer equally effective & better tolerated drugs * belongs to barbiturate family, but can suppress seizures at doses that only produces only moderate disruption in CNS function Phenobarbital - anticonvulsant barbiturate (doesn't cause signif sedation) Schedule IV controlled substance. Can cause physical dependence, but not as likely w/ antiepileptic doses MOA: suppresses seizures by potentiating GABA effects. Drug binds to GABA receptors causing receptors to respond more intensely to GABA itself Uses: effective against partial seizures & generalized tonic-clonic seizures (not absence). PK: IV phenobarbital can be used for generalized convulsive SE, but other drugs are preferred. -can be used for sedation & to promote sleep Dosing: long ½ life: 4 days - permits once daily dose. 2-3 wks needed for plasma levels to reach plateau. loading doses often given to increase serum levels

AD: N-methyl-D-aspartate receptor antagonist: memantine Eval of Therapeutic effects Minimize adverse effects

Evaluating Therapeutic Effects: Evaluate for improvement of cognitive and functional status. Minimizing Adverse Effects: Dizziness can increase the risk for falls. Institute fall risks if hospitalized. Advise patients to take acetaminophen or a nonsteroidal anti-inflammatory for headaches. Patient Education: Memantine Explain that this drug is prescribed to improve thinking and function in patients with Alzheimer disease. It does not work on everyone. Explain that dizziness may occur and, if it does, sit or lie down until it passes. It may help to move slowly when changing to a standing position because sudden movement may increase dizziness. Have the patient notify you if they have changes in vision, develop a rash, or have chest pain or other new symptoms

AD: Cholinesterase inhibitors: Evaluating therapeutic effects minimizing AE

Evaluating Therapeutic Effects: Evaluate for improvement of cognitive and functional status. Minimizing Adverse Effects: Most adverse (anticholinergic) effects (e.g., nausea, diarrhea, insomnia) are dose related and can be decreased by starting with lower doses and increasing gradually. These symptoms usually abate in 2-3 weeks. Falls are more likely to occur because of bradycardia and other cardiac changes. Initiate fall precautions if hospitalized and teach patient and family how to prevent falls at home. To prevent weight loss, encourage nutritional supplements (e.g., Boost) and snacks between meals. Schedule an appointment with a registered dietician.

PD Drug: Levodopa- Drug and food interaction Drugs that decrease effects Drugs that increase effects

First gen antipsychotics (chlorpromazine, haloperidol)- decrease therapeutic effects of levodopa by blocking receptors for dopamine- avoid combination BUT two SGA can be used safely: clozapine+quetiapine MAOI's- levodopa can cause hypertensive crisis if given with a nonselective inhibitor or MAO. Mechanism- Levodopa elevates neuronal stores of dopamine and norepinephrine by promoting their synthesis. MOA inactivates dopamine and NE, inhibition of MAO allows elevated neuronal stores of these transmitters to grow even larger. Both dopamine and NE promote vasoconstriction, therefore the release of these agents in supranormal amounts can lead to massive vasoconstriction causing BP to rise Withdraw MAOI's two weeks before starting levodopa Vitamin B6 enhances enzyme that catalyzes levodopa to dopamine Food decreases absorption

Sz meds Lamotrigine (Lamictal) Drug interactions:

Half life of lamotrigine is impacted by drugs that induce or inhibit hepatic drug metabolizing enzymes Enzyme inducers- carbamazepine, phenytoin, phenobarb all decrease the half life (decrease lamictal) Enzyme inhibitors- Valproate, increase the half life (increase lamictal) Estrogens lower lamictal levels and lamictal lowers progestin levels- affects women of childbearing age who wants to be on birth control

sz meds Phenobarbital Significant Drug Interactions

INDUCES hepatic drug-metabolizing enzymes CYP 1A2, 2A6, 2C8, 2C9, 3A4, 2B6 so can accelerate metabolism of drugs that are substrates for these enzymes- causing loss of therapeutic effects. particular concern for OCs & Warfarin - increase these drugs' doses when used with phenobarbital Phenobarbital + other CNS depressants (alcohol, benzos, opioids). Severe resp dep & coma risk Valproic acid (antiseizure agent) has been used w/ phenobarbital. Valproic acid can increase phenobarbital levels by 40%. Must reduce phenobarb dose if using with valproic acid.

PD Overview of motor symptom management: Therapeutic goal-

Improve patients' ability to carry out activities of daily living. Drug selection and dosages are determined by the extent of PD interference with work, walking, dressing, eating, bathing, ect. Drugs benefit pt by improving bradykinesia, gait disturbances, and postural instability There is no treatment that reverses or prevents neuronal damage

how and why levodopa with carbidopa is effective in the management of PD? Fate of Levodopa in the presence and absence of Carbidopa:

In the absence of carbidopa, 98% of an administered dose of levodopa is metabolized in intestinal and peripheral tissues—either by decarboxylases or catechol-O-methyltransferase (COMT)—leaving only 2% for actions in the brain. Therefore to deliver 10 mg of levodopa to the brain, the dose of levodopa must be large (500 mg). By inhibiting intestinal and peripheral decarboxylases, carbidopa increases the percentage of levodopa available to the brain. Thus the dose needed to deliver 10 mg is greatly reduced (to 100 mg in this example). Since carbidopa cannot cross the blood-brain barrier, it does not suppress the conversion of levodopa to dopamine in the brain. Furthermore, since carbidopa reduces peripheral production of dopamine (from 140 mg to 50 mg in this example), peripheral toxicity (nausea, cardiovascular effects) is greatly reduced.

AD: N-methyl-D-aspartate receptor antagonist: memantine Drug interactions:

In theory, combining memantine with another NMDA antagonist, such as amantadine or ketamine, could have an undesirable additive; use w/caution. Sodium bicarbonate and other drugs that alkalinize the urine can greatly decrease the renal excretion of memantine. Accumulation of the drug to toxic levels might result.

Suicide Risk with Antiseizure Drugs - which 2 sz meds are at risk?

Information is conflicting. FDA warned all sz drugs carry this risk. Studies show only lamotrigine and topiramate are likely to increase suicidality. Generally, it may be more that epilepsy itself and not the treatment increases suicide risk.

Drug class: Antiseizures: Drug: Topiramate- MOA- 4 mechanisms Clinical indication - 3 Off label uses too

MOA- 4 mechanisms by which it is a broad spectrum antiseizure med. (1) potentiation of GABA-mediated inhibition (2) blockade of voltage-dependent sodium channels (3) blockade of calcium channel (4) blockade of receptors for glutamate Clinical indications- (1) adjunctive therapy for partial seizures, primary generalized tonic-clonic seizures and seizures related to Lennox- Gastaut of pts 2 and older. (2) monotherapy for partial seizures or generalized tonic-clonic seizures pts 10 and up. (3) prophylaxis of migraine in adults Off label for BPD, cluster headaches, neuropathic pain, infantile spasms, essential tremor, binge eating, bulimia nervosa, weight loss, alcohol and cocaine dependence

Drug class: antiseizure: Drug: Perampanel:

MOA- Blocks AMPA glutamate receptors on postsynaptic neurons Clinical indications- Adjunctive therapy for tonic clonic and partial seizures in pts 12 and up Adverse effects- Black box warning- serious psychiatric reactions- anger, aggression, HI Common- Dizziness, drowsiness, fatigue, headache, Nausea, vomiting, abdominal discomfort and weight gain Drug interactions- can decrease effectiveness of hormonal contraceptives, enhances CNS depressants (increases risk for resp drive suppression) Phenytoin, carbamazepine and oxcarbazepine decrease perampanel levels

Drug class: antiseizure: Drug: Vigabatrin

MOA- Prevents GABA inactivation causing an increase in GABA availability, enhancing GABA mediated inhibition of neuronal activity Clinical indications- (1) add on for complex partial seizures in adults who are refactory to other drugs. (2) monotherapy of infitial spasms in pts 6months to 2 years AE- Black box warning- irreversible damage to the retina leading to tunnel vision and permanent loss of peripheral vision- test vision at baseline than at 4 weeks, then every 3 months after This drug is only available through SHARE- requires registration by providers, pharmacists, adult pts, parents/guardians Common adults effects- headache, somnolence, fatigue, dizziness, convulsions, increased weight with edema, depression, suicidal thoughts and behavior Common child effects- somnolence, bronchitis, otitis media Drug interactions- Combination of Vigabatrin and hydroxychloroquine, glucocorticoids, tricyclic antidepressants increase risk of retinal damage. Vigabatrin reduces levels of phenytoin and increases levels of clonazepam

Drug class: antiseizure: Drug: Ezogabine:

MOA- activates voltage-gated potassium channels in the neuronal membrane, thereby facilitating potassium efflux, reducing repetitive firing and related seizure activity Clinical indications- adjunctive therapy of partial onset seizures. Schedule V Adverse effects- Black box- retinal abnormalities and potential vision loss, therefore this is not a first line agent Urinary retention- use in caution in pts with voiding difficulty Common- somnolence, dizziness, fatigue, confusion, vertigo, tremor, incoordination, double vision, memory impairment, reduced strength, hallucinations, psychosis, suicidal thoughts/behaviors, blue, gray blue, and brown skin discoloration, red orange color to urine Drug interactions- carbamazepine and phenytoin decrease plasma concentrations of this drug

Drug class: antiseizure: Drug: Rufinamide

MOA- appears to suppress seizure activity by prolonging the inactive state of neuronal sodium channels Clinical indications- add on therapy for seizures associated to Lenonx-Gastaut AE- Children- somnolence, vomiting headache. Adults- Dizziness, fatigue, nausea, somnolence Can reduce QT interval- do not use in pts with familial QT syndrome Can increase suicidal thought/behaviors Drug interactions- Carbamazepine, Phenobarb, phenytoin, primidone reduce levels of Rufinamide. Valproic acid increases rufinamide by 70%. Rudinamide reduces levels of contraceptives. Use in caution with Dig as it also shortens QT intervals

Drug class: antiseizure: Drug: Eslicarbazepine

MOA- blocks sodium channels Clinical indications- partial seizures either monotherapy or adjunct Adverse effects- dizziness, sedation, headache, diplopia, blood dyscrasias, hepatic impairment, SJS, TEN, hyponatremia Drug interactions- This drug is a CYP2C19 inhibitor and inducer. When used in combo with Phenytoin, phenytoin levels are increased by this drug and Eslicarbazepine levels are decreased Carbamazepine and phenobarbital decrease levels of this drug STATINS, hormonal contraceptives, warfarin levels are all lowered by this drug NOT FOR USE IN CHILDREN!

Drug class: antiseizure: Drug: Lacosamide:

MOA- slow inactivation of sodium channels, which stabilizes hyperexcitable neuronal membranes and subsequent inhibition of repetitive firing Clinical indications- add on therapy and monotherapy or partial onset seizures in 17 and older 2 advantages- few drug interactions and can be administered IV/PO Adverse effects- common- dizziness, headache, diplopia, nasopharyngitis Vomiting, fatigue, incoordination, blurred vision, tremor, somnolence, impaired memory, confusion, attention disruption, prolong PR interval, euphoria, suicidal thoughts Schedule V Use in caution with pts with cardiac history Drug interactions- Carbamazepine, fosphenytoin, phenytoin, and phenobarbital can decrease serum concentration of lacosamide. Use in caution with pts taking drugs that prolong PR interval (b blockers, CCB's)

Drug class: Antiseizure: Drug Zonisamide:

MOA- suppresses focal seizures, blocks neuronal sodium channels and calcium channels Clinical indications- adjunctive therapy of partial seizures in adults. Off label for BPD, migraine prophylaxis and Parkinson's Adverse effects- common: drowsiness, dizziness, anorexia, headache, nausea, metabolic acidosis Impaired speech, concentration, and other cognitive processes- avoid hazardous activity Can cause severe depression and suicide attempts Can cause SJS, TENS, fulminant hepatic necrosis, withdraw immediately if hypersensitivity occurs Nephrolithiasis (drink 6-8 glasses of water a day), impaired GFR- use in caution in kidney disease Metabolic acidosis- risk increased with renal disease, resp disease, diarrhea, and keto diet. Can delay growth in children and lead to kidney stones and fractures overtime Get baseline bicarb levels and follow periodically, report any hyperventilation Hypohidrosis- leads to hyperthermia. Monitor closely in warm weather Drug/food interactions- inducers of CYP34A (St johns wart, phenytoin, phenobarb, carbamazepine can accelerate metabolism of zonisamide reducing its half life. Inhibitors of CYP34A (grapefruit juice, azole antifungal agents- ketoconazole, and ritonavir, slow metabolism and prolong and intensify zonisamides effects

Drug class: antiseizure: Drug: Felbamate

MOA- unknown but it increases seizure threshold and suppresses seizure spread, does not interact with GABA receptors and does not enhance inhibitory actions of GABA Clinical indications- (1) adjunctive or monotherapy in adults with partial seizures (2) adjunctive therapy in children with Lennox-Gastaut Adverse effects- use is limited due to severe AE Black box warning- aplastic anemia and liver injury, can both be fatal Common- GI disturbances, insomnia, somnolence, dizziness, headache, diplopia Drug interactions- increases levels of phenytoin, valproic acid. Felbamate levels are increased by valproic acid and decreased by phenytoin and carbamazepine. Monitor drug levels to avoid toxicity

Drug Class: Antiseizures: Drug: Levetiracetam (Keppra) MOA Clinical indications Off label use AE DI?

MOA- unknown, but it is chemically and pharmacologically different than all other antiseizure meds. It does not bind to receptors for GABA or any other known neurotransmitter Clinical indications- Adjuncive therapy of (1) myoclonic seizures in pts 12 and older, (2) partial-onset seizures in pts 4 and older, (3) primary generalized tonic-clonic seizures in pts 6 and older Off label use- migraine, BPD, new onset pediatric epilepsy Adverse effects Common- drowsiness, asthenia (lack of strength, weakness) Agitation, anxiety, depression, psychosis, hallucinations, depersonalization Possible renal injury NO DRUG INTERACTIONS

Drug class: Antiseizure: Drug: Gabapentin (Neurontin) MOA Clinical indications Off label use dosage considerations-high doses mean what? AE DI

MOA- unknown, but it may enhance GABA release, thereby increasing GABA-medicated inhibition of neuronal firing Clinical indications use in epilepsy is adjunctive therapy for partial seizures (with or without secondary generalization) or monotherapy postherpetic neuralgia Off label use- diabetic neuropathy, prophylaxis for migraines, fibromyalgia, restless leg syndrome, alcohol withdrawal, chronic cough, hiccups Gabapentin ER and Gabapentin enacarbil are NOT for use in epilepsy Dosage considerations- the higher the dose the percentage that gets absorbed gets smaller due to saturation of the intestinal transport system Adverse reactions- somnolence, dizziness, ataxia, fatigue, nystagmus, peripheral vision. These diminish with continued use. Avoid driving and other hazardous activities until they are not impaired. Significant drug reactions- YAY! NONE apparently. well suited for combination with other antiseizure medications. Gabapentin does not induce or inhibit drug metabolizing enzymes and does not affect the metabolism of other drugs

Drug class: antiseizure: Drug: Brivaracetam

MOA- unknown, has a selective affinity for a synaptic vesicle protein located in the brain, this is the possible MOA Clinical indications- partial onset seizures in pts 4 and older. Injection restricted to pts 16 and older. Monotherapy or adjunctive therapy AE- CNS depression, suicidal risk, other mental health concerns, can also cause neutrophil count to decrease and cause serious hypersensitivity reactions Use in caution with patients who have hepatic or renal impairment, do not use in end stage renal failure Drug interactions- CYP2C19 inducers may reduce serum levels while CYP2C19 inhibitors may increase serum levels of the drug. Additive effect when given with other CNS depressants

PD Drug: Levodopa- MOA Adverse/Side effects & what to do about them Beneficial effects (with some PK)

MOA: "Dopamine replacement" class. Reduces symptoms by increasing dopamine synthesis in the striatum. Promote activation of dopamine receptors SE: Nausea/vomiting (common esp in beginning; administer in low doses with meals initially--avoid if possible since food, esp protein, delays absorption & reduces therapeutic effects-- or give larger doses of carbidopa) dyskinesia (either reduce dosage or give amantadine) orthostatic hypotension (increase salt/water) psychosis (give SGA like clozapine/quetiapine) darken sweat & urine activate malignant melanoma (full skin assessment) Beneficial effects- FIRST LINE. most effective drug --If the pt fails to respond we should question the diagnosis of Parkinson's --Full effects may take several months --Long term therapy leads to diminished therapeutic effects- by year 5 the ability to function may deteriorate- most likely is an effect of the disease progression and not tolerance to the med

Drug Class: antiseizure: Drug Tiagabine: MOA Clinical indications Off label uses AE DI

MOA: blocks reuptake of GABA which inhibits influence of GABA suppressing seizures Clinical indications- Adjunctive therapy of partial seizures 12 and older Off label- generalized anxiety, MS, neuropathic pain, PTSD, psychosis, spasticity Adverse effects- common- dizziness, somnolence, asthenia, nausea, nervousness, tremor Confusion, abnormal thinking, trouble concentrating Can cause seizures but only in those using it off label, therefore off label use is discouraged Drug interactions- levels can be decreased by phenytoin, phenobarb, and carbamazepine

Sz meds Primidone (Mysoline) *like phenobarbital MOA Use AE DI

MOA: nearly identical structure to phenobarbital, so similar pharmacology Effective against tonic-clonic, simple-partial, & complex seizures Employed in combo w/ another antiseizure drug (carbamazepine, phenytoin) never taken w/ phenytoin bc phenytoin is the active metabolite of primidone Therapeutic levels: 5-12 mg/mL; Toxic levels: >15mg/mL AEs: sedation, ataxia, dizziness common initially but diminish w/ continued use Like phenobarbital, primidone can → confusion in elderly & paradoxical excitement in children sense of acute intoxication can happen shortly after dosing Like phenobarbital, primidone absolutely contraindicated in pts w/ acute intermittent porphyria rare serious adverse rxns- acute psychosis, leukopenia, thrombocytopenia, SLE Significant Drug Interactions similar to phenobarbital can INDUCE hepatic drug-metabolizing enzymes → can reduce effects of OCs, warfarin & other drugs can intensify responses of other CNS depressants

Seizure drugs Fosphenytoin (Cerebyx)

MOA: prodrug that's converted to phenytoin when metabolized. Recommended as a sub for oral phenytoin when oral route is contraindicated Uses: same as phenytoin. Active against both tonic-clonic & partial seizures Unique dosing: Fosphenytoin is dosed in phenytoin equivalents (PE) Fosphenytoin 1mg PE = 1 mg phenytoin IV fosphenytoin formulation is compatible with w/ standard IV solutions (unlike phenytoin) IM: full dose may need to be divided into 2-4 separate injections AEs: same as phenytoin w/ 1 exception Temporary paresthesias & itching (esp in groin area) may occur during IV infusion; will resolve when infusion rate is decreased or w/in 10 mins after completion of infusion

Ethosuximide (Zarontin) MOA use AEs

MOA: suppresses neurons in the thalamus responsible for generating absence seizures inhibition of low-threshold Ca currents (T currents). Drug of choice for absence seizures (& it's only indication) eliminates in 60% of pts, & practical control achieved in 80-90% of newly dx pts Dosing: long ½ life. Allows for once a day dosing, but 2x/day is better tolerated Determine dose by monitoring clinical response rather than plasma levels bc absence seizures occur many times a day. Increase dose until seizures have been controlled or until AEs have become too great trough levels can be used to guide dosing AEs: generally devoid of significant AEs & interactions initial tx: drowsiness, dizziness lethargy - diminish w/ continued use n/v can be reduced taking drug w/ food rare: SLE, leukopenia, aplastic anemia, SJS

Drug class: antiseizure: Drug Pregabalin: MOA clinical indications AE Abuse drug interact

MOA: unknown, but as an analog of GABA, it does not bind with GABA receptors or with benzodiazepine receptors and does not work by mimicking or enhancing the inhibitory actions of GABA. It can bind with calcium channels on nerve terminals and thereby inhibit calcium influx which inhibits the release of several neurotransmitters (glucamate, NE, substance P). The reduced transmitter release may underlie seizure control and relief of neuropathic pain. Clinical indications: neuropathic pain associated with diabetic neuropathy, postherpetic neuralgia, adjunctive therapy of partial seizures, and fibromyalgia. Adverse effects- Common- dizziness, somnolence- persist for entire treatment Others: blurred vision (resolves with continued use), weight gain, difficulty thinking, headache, peripheral edema, dry mouth, hypersensitivity reactions (angioedema), rhabdomyolysis Abuse/physical dependance- Schedule V. Abrupt d/c can cause insomnia, nausea, headache, diarrhea. D/C slowly over 1 or more weeks Reproductive risks or men and women- in female animals- fetal growth delay, fetal death, structural abnormalities, impaired function of nervous and reproductive system In male animals- decreased sperm count/motility, decreased fertility, decreased fetal weight, fetal abnormalities even when female was untreated- instruct men to wear condoms Drug interactions- alcohol, opioids, benzos, and other CNS depressants may intensify pregabalins depressant effects- avoid combinations

PD Drug selection Mild vs Severe

Mild symptoms- treatment begins with an MAO-B inhibitor (to prevent dopamine breakdown) Severe symptoms- treated with levodopa combined with carbidopa, or a dopamine agonist Levodopa is more effective but has higher risk of disabling dyskinesias Therefore, if improving motor function is the primary objective levodopa should be used. If drug induced dyskinesias are a primary concern than dopamine agonist is preferred

PD Drug: Levodopa- Preparations 1. Levodopa/ carbidopa and levodopa/carbidopa/entacapone

Most effective therapy for PD MOA- carbidopa has no therapeutic effects on its own. It inhibits decarboxylation of levodopa in the intestines and peripheral tissues making more levodopa available in the CNS --Carbidopa in unable to cross BBB --When used with carbidopa only 90% of levodopa is lost compared to the 98% that is lost when used alone Carbidopa allows the dosage of levodopa to be decreased. It reduces the production of dopamine in the periphery thus reducing cardiovascular responses and nausea and vomiting. And it inhibits decarboxylase --Disadvantages of carbidopa- when combined with levodopa it can cause abnormal movements and psychiatric disturbances to occur sooner and more intensely than when levodopa is used alone

Seizure drugs Phenytoin (Dilantin) - What are the therapeutic levels? AE -& what to do about them?

Narrow therapeutic index!!!! Aim to keep levels between 10 and 20 ug/mL. AE: CNS - at therapeutic levels, causes mild sedation. With toxic doses, CNS effects more profound, and include nystagmus, oversedation, ataxia, diplopia, and cognitive impairment. Keep within TI to avoid toxic AE Gingival hyperplasia - characterized by swelling, tenderness, and bleeding gums. In severe cases, may need gingivectomy. Gingival hyperplasia seen in about 20% of pts taking phenytoin. Risk may be minimized with good oral hygiene. Folic acid supplementation also may or may not help. Dermatologic effects - some pts develop morbilliform (measles-like) rash. Rarely can progress to SJS or TEN (toxic epidermal necrolysis). Strong association with genetic mutation HLA-B*1502, which is seen almost exclusively in people of Asian descent. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) - potentially fatal, hypersensitivity reaction. Also associated with HLA-B*1502 genetic mutation. Characterized by skin eruptions, lymphadenopathy, fever, and multiorgan involvement. Drug must be discontinued. Pregnancy - teratogenic. Can cause cleft palate, heart malformations and fetal hydantoin syndrome (growth deficiency, motor/mental deficiency, microcephaly craniofacial distortion, positional deformities of limbs, hyperplasia of nails and fingers, and impaired neurodevelopment). Can also increase risk for bleeding tendencies in newborns. Cardiovascular - ***Black Box Warning*** when administered IV, cardiac dysrhythmias and hypotension may occur. Reduce risk by running no faster than 50 mg/min. Other - hirsutism, interference with vitamin D metabolism that may cause rickets and osteoporosis, GI upset.

Seizure drugs Carbamazepine (Tegretol, Carbatrol, Epitol, Equetro) - Uses MOA

Often preferred; #1 for partial seizures Cornerstone of epilepsy therapy Active against partial & tonic clonic seizures, but not absence seizures Uses: effective against tonic-clonic, simple partial, & complex partial seizures Often the preferred agent* ( less AEs than phenytoin & phenobarbital) Can give sx control in bipolar disorder & often effective in pts who are refractory to lithium Can reduce neuralgia assoc w/ trigeminal & glossopharyngeal nerves (used for specific neuralgias, but not effective as an analgesic for other kinds of pain) MOA: suppresses high-frequency neuronal discharge in & around seizure foci mechanism same as phenytoin- delayed recovery of NaCl channels from their inactivated state

Sz meds Oxcarbazepine (Oxtellar, Trileptal, etc.) Significant Drug interactions:

Phenytoin: Oxcarbazepine INHIBITS the enzymes that metabolize phenytoin. Oxycarbazepine can raise phenytoin levels* Phenytoin can decrease serum oxcarbazepine concentrations these 2 drugs → phenytoin toxicity & subtherapeutic oxycarb effects monitor both levels closely Perampanel, phenobarbital, & valproic acid: Perampanel can increase oxcarbazepine serum levels Valproic acid can decrease oxcarbazepine serum levels Phenobarbital can decrease oxcarbazepine's active metabolite if these taken together- monitor oxcarb's levels Eslicarbazepine: oxcarbazepine can increase eslicarbazepine serum levels. Not recommended to combine OCs: Oxcarbazepine INDUCES enzymes that metabolize both estrogens & progestins. Women who may become pregnant should employ alternate b/c methods Sodium-depleting drugs: Na depleting drugs can increase risk of hyponatremia. Use oxcarbazepine w/ caution in pts taking diuretics & other Na depleting drugs AVOID Alcohol- can intensify CNS depression caused by oxcarbazepine

Discuss how CNS medications produce therapeutic effects? Comment on the adaptation of the central nervous system to prolonged medication exposure.

Precise Mechanism Versus Plausible Hypotheses We do not fully understand the brain in either health or disease. Although we cannot state with certainty how CNS drugs act, we do have sufficient data to permit the formulation of plausible hypotheses. Adaptation of the CNS to Prolonged Medication Exposure Different effects possible when a drug is taken chronically versus the initial use of the drug. Increased therapeutic effects. Certain drugs used in psychiatry (such as antipsychotics or antidepressants) must be taken for several weeks before full therapeutic effects develop. Beneficial responses may be delayed because they result from adaptive changes and not from the direct effects of drugs on synaptic function. Full therapeutic effects are not seen until the CNS has had time to modify itself in response to prolonged drug exposure. Decreased side effects: When CNS drugs are taken chronically, the intensity of the side effects may decrease, but the therapeutic effects remain undiminished. Examples: --Morphine is taken to control pain: Nausea is a common side effect early on Treatment continues, nausea diminishes, and analgesic effects persist --Tolerance: Decreased response occurring during the course of prolonged drug use --Physical dependence: State in which abrupt discontinuation of drug use will precipitate a withdrawal syndrome

sz meds Identifying high risk patients-

Pts with depression and pregnancy. However, when seizures are a concern the benefits outweigh the risks

Define spasticity and spasm.

Spasticity: Refers to a group of movement disorders originating in the CNS characterized by heightened muscle tone, spasm, and loss of dexterity. Spasm: Involuntary contraction of a muscle or muscle group.

Physical dependence: Defn

State in which abrupt discontinuation of drug use will precipitate a withdrawal syndrome

How Antiseizure Drugs Work

Suppression of Sodium Influx - Phenytoin, Lamotrigine, Carbamazepine, Eslicarbazepine, Oxcarbazepine, Lacosamide, Rufinamide, Zonisamide, Topiramate. These drugs reversibly bind to sodium channels while they're in the inactivated state, prolonging channel inactivation. This decreases ability of neurons to fire at high frequency. Suppression of Calcium Influx - Ethosuximide. Promotion of Potassium Eflux - Ezogabine. Potassium causes neurons to repolarize. This drug is believed to act on potassium channels to slow repetitive neuronal firing. Antagonism of Glutamate - Perampanel, Felbamate, Topiramate. Glutamic acid is primary excitatory transmitter in CNS. Perampanel is an AMPA glutamate receptor antagonist. Other two block actions of glutamate at NMDA receptors and thereby suppress neuronal excitation. *Pregabalin, Levetiracetam, and Brivaracetam have unknown MOAs.

Summary of Key Prescribing Considerations: Cholinesterase inhibitors: Therapeutic goal baseline data monitoring identifying high-risk patients

Therapeutic Goal: Improved cognition and function for patients with AD by increasing availability of acetylcholine at cholinergic synapses. Baseline Data: Assess cognitive and functional neurological status. Assess for evidence of gastrointestinal problems. Check baseline weight and basic respiratory and cardiovascular status. Monitoring: At each visit, assess orientation, cognition, and functional status. Check weight and examine for changes in respiratory, cardiovascular, or gastrointestinal status compared to baseline. If significant adverse effects occur, consider the degree of drug benefit achieved when determining whether to continue therapy. Identifying High-Risk Patients: Cholinesterase inhibitors should be prescribed cautiously for patients with a history of respiratory or peptic ulcer disease. Exercise caution when prescribing for patients with bradycardia or first-degree heart block; benefits may not be worth the risks. Avoid prescribing to patients with higher degrees of heart block.

AD: N-methyl-D-aspartate receptor antagonist: memantine Summary of Key Prescribing Considerations

Therapeutic Goal: Slow cognitive and functional decline of patients with moderate to severe Alzheimer disease. Baseline Data: Cognitive and functional neurological status. Rule out corneal conditions and hepatic conditions. Monitoring: At each visit, assess cognition, and functional status. Canadian labeling recommends scheduling ophthalmic exams while taking this drug. Identifying High-Risk Patients: Use caution with prescribing to patients with a history of cardiovascular disease, hepatic or renal impairment, or ophthalmic disease.

Types of Sz Meds (Traditional, New) Generalized - may be convulsive or nonconvulsive. As a rule, produce immediate loss of consciousness. Absence Seizures MEDS - characterized by brief loss of consciousness (10 -30 seconds). Usually involve mild, symmetrical motor activity (such as eye blinking), but not always. Pt may experience hundreds of these per day. Usually seen in children and disappear in early teen years.

Traditional Ethosuximide, Valproic acid, New Lamotrigine

Types of Sz Meds (Traditional, New) Generalized - may be convulsive or nonconvulsive. As a rule, produce immediate loss of consciousness. Myoclonic MEDS - sudden muscle contraction that last for 1 second. May be limited to one limb or involve entire body.

Traditional Valproic acid New Lamotrigine, Levetiracetam, Topiramate

Types of Sz Meds (Traditional, New) Partial seizures MEDS 1. Simple Partial - manifest with discrete symptoms that are determined by the brain region involved. No loss of consciousness. Last 20 - 60 seconds. 2. Complex Partial - characterized by impaired consciousness and lack of responsiveness. Motionless with fixed gaze, followed by automatism (repetitive, purposeless movements, such as lip smacking or hand wringing). 45 - 90 seconds. 3. Secondarily generalized - sz begins as simple or complex partial and progresses to tonic-clonic with loss of consciousness. 1 - 2 minutes.

Traditional Carbamazepine, Phenytoin, Fosphenytoin, Phenobarbital, Primidone, Valproic Acid, New Brivaracetam, Ezogabine, Felbamate, Gabapentin, Lacosamide, Lamotrigine, Levetiracetam, Oxcarbazepine, Pregabalin, Tiagabine, Topiramate, Vigabatrin, Zonisamide

Types of Sz Meds (Traditional, New) Generalized - may be convulsive or nonconvulsive. As a rule, produce immediate loss of consciousness. Tonic-Clonic MEDS - both hemispheres involved. Manifest as major convulsions, characterized by a period of rigidity (tonic phase) followed by synchronous muscle jerks (clonic phase). Accompanied by marked impairment of consciousness followed by CNS depression (postictal state). Sz usually 90 seconds or less.

Traditional Carbamazepine, Phenytoin, Fosphenytoin, Phenobarbital, Primidone, Valproic acid New Lamotrigine, Levetiracetam, Topiramate

Sz meds Valproic Acid (Depakene, Depakote, Depacon, Epival) Indication/Uses 3 forms MOA

Used widely to treat all major seizure types.* & bipolar disorder & migraine h/a Uses: 1st line for all partial & generalized seizures * also used in bipolar disorder & migraines Available in 3 closely r/t chemical forms that have identical antiseizure effects: 1: valproic acid 2: valproate (the sodium salt of valproic acid) 3: divalproex sodium (valproic acid + its sodium salt) MOA: unknown. May augment the inhibitory influence of GABA or increase GABA concentration in the brain Therapeutic responses w/ plasma levels of 50-100mg/mL, but correlation b/t plasma levels & therapeutic effects not narrow

Sz meds Valproic Acid (Depakene, Depakote, Depacon, Epival) Significant drug interactions

Valproic acid reduces the rate phenobarbital is metabolized (phenobarb levels may rise by 40% → significant CNS depression*) Monitor phenobarbital levels if taking both drugs* & reduce phenobarb dose if level increases Valproic acid can displace phenytoin from binding sites on plasma proteins → increase in free phenytoin → phenytoin toxicity. Monitor phenytoin levels & clinical status Valproic acid + Topiramate → risk of hyperammonemia w/ or w/o encephalopathy. S/S: vomiting, lethargy, altered LOC & cognitive function Suspect hyperammonemia encephalopathy if these sx develop & measure blood levels of ammonia. Sx abate after d/c of either drug* AVOID 2 carbapenem antibx - meropenem & imipenem/cilastatin (2 carbapenem antibx)- can reduce valproic acid levels. breakthrough seizures have occurred. increasing valproic acid dosage may be insufficient to overcome this

AD: N-methyl-D-aspartate receptor antagonist: memantine AE

Well tolerated. Common SE are dizziness, headache, and confusion—and these occur in only 5% to 7% of those taking the drug. Other less common effects include diarrhea or constipation. In clinical trials, the incidence of all these effects was about the same as in patients taking placebo. Rarely, skin reactions, such as erythema multiforme and Stevens-Johnson syndrome Cardiovascular events, such as bradycardia, hypertension, and angina, have occurred. Dosage adjustment is required for patients with renal impairment having creatinine clearance of less than 30 mL/min. Canadian labeling also recommends avoiding memantine in patients with severe hepatic impairment as a precaution due to inadequate studies and in patients with corneal conditions as these have worsened during treatment.

The action of the cholinesterase inhibitors is thought to: a. Prevent the breakdown of acetylcholine by acetylcholinesterase (AChE), increasing the availability of acetylcholine at cholinergic synapses. b. Enhance the breakdown of acetylcholine by acetylcholinesterase (AChE) and increase the availability of acetylcholine at cholinergic synapses. c. Reduce transmission by central cholinergic neurons that have not yet been destroyed. d. Build new central cholinergic neurons.

a. Prevent the breakdown of acetylcholine by acetylcholinesterase (AChE), increasing the availability of acetylcholine at cholinergic synapses. The action of the cholinesterase inhibitors is the prevention of the breakdown of acetylcholine by acetylcholinesterase (AChE), increasing the availability of acetylcholine at cholinergic synapses thus improving transmission by central cholinergic neurons that have not yet been destroyed. (See Chapter 19.)

The advanced practice prescriber is cognizant that: a. The exact mechanism of action of most CNS agents for therapeutic results is unknown. b. There are only three neurotransmitters in the CNS system. c. The CNS system is well researched with sound information for disorder treatment. d. No evidence supports the use of norepinephrine or dopamine in treatment plans.

a. The exact mechanism of action of most CNS agents for therapeutic results is unknown. The advanced practice prescriber is cognizant that the exact mechanism of action for most CNS agents is unknown. There is evidence that supports the use of norepinephrine, dopamine, and enkephalins in treatment plans for a variety of disorders. With over 21 neurotransmitters in the CNS system and some evidence of actions that are not explained with the known neurotransmitters, more research is indicated. The CNS system is complex and current technology is not adequate to capture the complexities. (See Chapter 18.)

Identify the major risk factors in the development of Alzheimer's disease.

advancing age and family history.

Medications for muscle spasm include

analgesics, carisoprodol, chlorzoxazone, cyclobenzaprine, diazepam, metaxalone, methocarbamol, and orphenadrine. Adverse reactions involve depressing the CNS (fatigue, dizziness, hypotension), anticholinergic responses, and cardiac rhythm disturbances. These medications are contraindicated in patients using a variety of antidepressants, or those who cannot avoid alcohol.

Medications for spasticity include

baclofen, diazepam, dantrolene, and tizanidine. Adverse effects are CNS related (change in cognition, fatigue, dizziness), withdrawal with rapid discontinuation, nausea, vomiting, constipation, and urinary retention. These medications are contraindicated in patients with comorbid psychiatric conditions, urinary retention, those using other CNS depressants, or individual's incapable of avoiding alcohol.

NEWER ANTISEIZURE DRUGS 15 drugs; appear equally effective, although not compared directly w/ traditional drugs or each other more appealing properties

better tolerated, smaller fetal risks, less interactions (besides oxcarbazepine) oxcarbazepine- induces drug-metabolizing enzymes to a significant degree 7 of the newer drugs approved for monotherapy: eslicarbazepine, felbamate, lacosamide, lamotrigine, oxcarbazepine, topiramate, vigabatrin the rest only approved for adjunct therapy bc clinical trials tested them as adjunct to traditional antiseizure drugs not as monotherapy

Alzheimer disease (AD) (Alzheimer's) general defn/sx causes?

brain disorder marked by gradual and progressive mental deterioration (dementia), personality changes, and impairment of daily functioning CAUSES unknown but these factors contribute: Degeneration of neurons **Reduced cholinergic (acetylcholine) transmission β-Amyloid and Neuritic Plaques: hallmark signs of the disease! Neurofibrillary Tangles and Tau: prominent features of AD Apolipoprotein E4 (apoE4): Genetic component Endoplasmic Reticulum-Associated Binding Protein (ERAB) Homocysteine (Eat foods rich in folic acid and vitamins B6 and B12 or take dietary supplements that contain these compounds.)

Even as the advanced practice prescriber arranges further diagnostic testing for Alzheimer's disease, they are aware that current medications: a. Reverse the cognitive decline completely. b. Restore independent function in all patients. c. Can slow the cognitive decline but not reverse it. d. Have statistical significance and marked clinical improvement in symptoms.

c. Can slow the cognitive decline but not reverse it. The advanced practice prescribed is aware that the current medications for the treatment of Alzheimer's disease can slow the cognitive decline but not reverse it. The medications have statistical significance but limited clinical manifestations.

Contraception and Pregnancy Concerns 8 antiseizure drugs decrease effectiveness of OC -

carbamazepine, eslicarbazepine, lamotrigine, oxcarbazepine, phenytoin, phenobarbital, rufinamide, and topiramate. There is risk for congenital anomalies with antiseizure meds, however, it's important to remember that the risk to the fetus with uncontrolled sz is greater, and that >90% of women who take an antiseizure med while pregnant don't experience any problems. --Avoid Valproic acid unless absolutely necessary Use lowest effective dose --Take folic acid supplement to reduce risk of neural tube defects --Maternal and fetal bleeding risks are a concern - phenytoin, phenobarbital, carbamazepine, and primidone can decrease synthesis of vitamin K-dependent clotting factors. Some experts recommend administering vitamin K to the mother for one month before and during delivery, but others don't recommend.

Life Span Considerations Sz med Lactation:

carefully weigh risk vs benefit of BF over the risks of AEs in the infant. Valproic acid & phenytoin often selected preferentially bc highly protein bound (they don't enter breastmilk like lipid would). (Canadian labeling for Vigabatrin contraindicates BF)

PD Anticholinergic agents MOAs

drugs that block receptors for acetylcholine All anticholinergic agents share the same MOA: blockade of muscarinic receptors in the striatum to decrease acetylcholine activity

sz meds - general monitoring

evaluating frequency and type of seizures, degree of CNS change, and depression, suicidality, or behavioral change

Sz drugs Carbamazepine BBW

may cause serious skin rxns like SJS & TEN. Fatalities may occur. Risk for a rxn is strongly assoc w/ the HLA-B*1502 variant of the HLA-B gene found predominantly in ppl of Asian ancestry. Aplastic anemia & agranulocytosis have occurred. Rare (2-6 pts/1 million)

Add'l monitoring sz meds

needed for the following meds: * some of these are the same but for monitoring instead of baseline Brivaracetam- CBC with diff, liver function, renal function Caramazepine- CBC with diff, liver function, renal function, serum iron, assess for SandS of blood abnormalities (pallor, fatigue, easy bruising and petechial associated with thrombocytopenia, or symptoms of infections associated with leukopenia) Eslicarbazepine- CBC with diff for signs of blood abnormalities, liver function serum sodium for signs of hyponatremia. Assess for rash because this can progress to SJS or TEN Ethosuximide- Trough concentrations to guide dosage. Assess for rash and other skin reactions Felbamate- CBC with diff, liver function Gabapentin- Renal function Lacosamide- EKG after pt is on maintenance or if there are signs or symptoms suggestive of atrioventricular block or other cardiac rhythm disturbances Lamotrigine- CBC with diff, assess for rash which can progress to SJS and TEN. Ask about suicide and depression Oxcarbazepine- serum sodium, CBC with diff for evidence of blood abnormalities (pallor fatigue, weakness, exercise intolerance, fever, infection, easy bleeding or bruising, petechiae) Assess for rash may progress to SJS or TEN Phenobarbital- CBC with diff, liver function, renal function, serum drug levels at maintenance and when clinically indicated Phenytoin- obtain serum drug level and trough concentrations for dosage considerations. Assess for rash may progress to SJS or TEN. Asses for gingival hyperplasia Rufinamide- EKG if history or physical exam positive for palpitations or other indications of cardiac rhythm changes Tiagabine- Liver function Valproic acid- Liver function. Assess for S&S of pancreatitis Vigabatrin- CBC if signs of anemia develop. Dilated ophthalmologic exam every 3 months. Assess for fluid retention Zonisamide- CBC with diff, liver function, renal function, metabolic panel, serum bicarbonate

Seizure drugs Carbamazepine (Tegretol, Carbatrol, Epitol, Equetro) - Pharmacokinetics:

½ life decreases as therapy progresses (initial tx- ½ life is 40 hrs then decreases to 15 hrs w/ continued tx) Carbamazepine (like phenytoin & phenobarbital) induces hepatic drug-metabolizing enzymes ** By decreasing its own metabolism- carbamazepine causes its own ½ life to decline