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65 Cards in this Set
- Front
- Back
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________ seizures include febrile seizures, seizures precipitated by stroke, trauma, tumor, metabolic disturbances (e.g. --hypocalcemia, alkalosis), drug overdose, or structural changes to the brain.
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provoked
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__________ seizures are those for which no identifiable cause can be determined.
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unprovoked
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confined to 1 hemisphere and do not involve loss of consciousness. These can be manifested by focal motor symptoms (convulse jerking) or somatosensory symptoms (e.g. – parasthesias or tingling) that spread (or "march") to different parts of the limb or body depending upon their cortical representation. In other instances, special sensory symptoms (e.g. – light flashes or buzzing) indicate involvement of visual auditory, olfactory, of gustatory regions of the brain, or there may be autonomic symptoms or signs (e.g. – abnormal epigastric sensations, sweating, flushing)
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simple partial seizures
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begin in a localized area, spread to both hemispheres, and involve impairment of consciousness
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complex partial seizures
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These are generalized, non-convulsive seizure events that are expressed mainly by brief periods of unconsciousness.
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absence (petit mal) seizures
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GENERAL MECHANISMS OF ANTICONVULSANT DRUG ACTION
Either prevent the start of abnormal brain electrical activity (i.e., prevent seizures from starting; called suppression of the seizure focus, which is where the abnormal electrical activity starts), or … • . …prevent it from spreading to other parts of the brain • Do so by: o _________ activity of GABA (gamma-aminobutyric acid), which is an inhibitory neurotransmitter in parts of the brain) or ….. o inhibiting ____ influx into neurons (suppressing depolarization) o ????? |
enhancing
Na+ |
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• The drug(s) is selected according to ______(s) of seizures the patient has (generalized or partial; convulsive or not; etc.), not based on the _______ of the seizures (e.g., idiopathic vs. brain tumor, drug overdose, etc.)
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type
cause |
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• Most of the older anticonvulsants (e.g., phenytoin) induce the P450 system and can speed-up the metabolic elimination of many other drugs (other anticonvulsants or other classes of drugs), reducing blood levels and effectiveness of those other agents
• __________ is rather unique in that it is a P450 inhibitor (and so causes DDIs by that mechanism) |
Valproic acid
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The "older drugs" are less expensive than the newer agents and are considered appropriate selections for the initial treatment of seizures in older adults. In older adults, treatment with ____________ or __________ is not widely recommended because of significant side effects, including sedation and drug-induced cognitive impairment. Many clinicians consider _____________ the drug of choice for seizures only in infants
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phenobarbital or primidone
phenobarbital |
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___________ has been around for over 60 years, and its risk-to-benefit ratio is well developed. It is available in oral solid, oral liquid, extended-release oral solid, and parenteral dosage forms, allowing flexibility in dosing and use in emergent conditions. Has long been a first-line AED for primary generalized convulsive and partial seizures. Its use in therapy may be re-evaluated as more experience is gained with newer AEDs.
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Phenytoin (Dilantin, Phenytek)
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MOA
• Blocks Na+ channels and inhibits the generation of repetitive action potentials Pharmacokinetics • Highly protein-bound (lots of potential for DDIs from displacement by other drugs) – for example, aspirin can potentiate the effects of • Saturable hepatic metabolism -- at high levels (in high-therapeutic or toxic ranges), the liver enzymes are “swamped” and they can’t metabolize as much ; thus relatively small increases in dose can produce large increases in the plasma concentration • induces metabolism of many other drugs o Oral anti-coagulants (warfarin) o Oral contraceptives o Furosemide (Lasix) o Tricyclic anti-depressants • Inhibition of ________ metabolism o Carbamazepine o Chronic alcohol ingestion |
Phenytoin (Dilantin, Phenytek)
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Uses
• Generalized tonic-clonic seizures • Partial seizures, especially complex partial seizures • NOT effective for absence seizures; may aggravate absence seizures |
Phenytoin (Dilantin, Phenytek)
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Side Effects
• GI – nausea, vomiting are common • CNS o drowsiness, sedation, lethargy o ataxia, decreased coordination, nystagmus o cognitive difficulty (esp. w/ high blood levels) • Facial/cosmetic: hirsutism, skin coarsening, acne • Decreased thyroid hormone levels (monitor TSH) • Vitamin deficiencies: folic acid (“folate”) and vitamin K o Folate deficiency of importance if patient is pregnant – can cause neural tube (brain, spinal cord) defects in fetus; prophylactic use of folic acid is recommended for all women of child-bearing age o Important to supplement mom’s diet w/ folic acid o Vitamin K deficiency can cause bleeding problems in newborn o Vitamin K given to mom at least 1 month before delivery o Baby given Vitamin K injections at birth |
Phenytoin (Dilantin, Phenytek)
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side effect:
• Gingival hyperplasia: a unique side effect of the drug o The condition may become aggravated by superimposed gingivitis and periodontitis; there is evidence this drug may impair the secretion of collagenase by gingival fibroblasts permitting the accumulation of excessive gingival collagen. o Treatment: The inflammatory component may be reduced by good dental hygiene; the fibrous overgrowth requires surgical removal. Discontinuance of this therapy may result in gradual regression of the overgrowth within one year. |
Phenytoin (Dilantin, Phenytek)
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approved as an AED in 1974 and has been well studied. Oral immediate- and extended-release solid and liquid dosages are available. It should be considered a first-line therapy for patients with newly diagnosed partial seizures and for patients with primary generalized convulsive seizures who are not in an emergent situation.
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Carbamazepine (Tegretol, Cabatrol)
"older" |
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MOA
• Blocks Na+ channels and inhibits the generation of repetitive action potentials Pharmacokinetics • Not highly protein-bound • Metabolism is inhibited by many other drugs, most notably erythromycin & cimetidine Uses • Generalized tonic-clonic seizures • All types of partial seizures |
Carbamazepine (Tegretol, Cabatrol)
"older" |
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Side Effects
• Dizziness / Vertigo • Diplopia • Headache • Mild GI upset • Hyponatremia Idiosyncratic reactions: skin rashes; erythema; leukopenia; thrombocytopenia aplastic anemia (fatal) Pregnancy category D Oxcarbazepine (Trileptal) is a newer agent that is closely related and useful for the same seizure types. |
Carbamazepine (Tegretol, Cabatrol)
"older" |
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a long-acting barbiturate, which is a major CNS depressant; rapidly absorbed
• Exact MOA of is unknown • Indicated for simple partial seizures and generalized tonic-clonic seizures • Use of this or related barbiturates for management of epilepsy is probably the only medically justifiable long-term use of these drugs (i.e., they should NOT be used for anxiety relief, sedation, hypnosis; benzodiazepines (e.g – diazepam, alprazolam) are used for these purposes) –• Induces liver enzymes, thereby creating lots of interactions with many other drugs (e.g., warfarin, oral contraceptives, many others) • Side effects include sedation, dizziness, nausea, vomiting |
Phenobarbital & Primidone (Mysoline)
"older" |
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A pro-drug that is converted to phenobarbital by the body
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primidone
"older" |
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• Blocks Na+ channels and inhibits the generation of repetitive action potentials
• Indicated for absence seizures and partial complex seizures • Slow onset—> temptation to increase dose too soon before blood levels, effect, stabilize, eventually leading to excessive blood levels, more side effects or true toxicity • Inhibits hepatic metabolism of many other drugs, anticonvulsants and others • Protein-bound, displaced by aspirin |
Valproic Acid (Depakene, Depakote)
"older" |
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Side effects and adverse effects
o GI distress o Appetite stimulation (weight gain) o Alopecia o Decreased platelet count, platelet function – leads to increased bleeding risk o Hepatotoxicity -- contraindicated in patients with hepatic disease or significant hepatic dysfunction – patients on the drug should have LFTs done periodically in the event a liver problem develops • classified as pregnancy category D and hence is not recommended in pregnant females and nursing mothers |
Valproic Acid (Depakene, Depakote)
"older" |
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• Indicated for absence seizures
• A "first choice" drug over valproic acid because it is not as likely to cause hepatotoxicity • Most common SEs include gastric distress, nausea and vomiting |
Ethosuximide (Zarontin)
"older" |
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• Mainly used for absence seizures resistant to other AEDs
• Comes in tablets and wafers • Less effective compared to ethosuximide or valproic acid • Common SEs include drowsiness & depression • Withdrawal symptoms typical after abrupt discontinuation |
Clonazepam (Klonopin)
"older" |
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• Approved in the US in early 1990s
• Many patients switched to it, but after drug was approved it was found that “too many” patients were developing aplastic anemia or hepatic failure • Known to inhibit metabolism of many other anticonvulsants • Not a "first-line" treatment – use is for refractory partial seizures only |
Felbamate (Felbatol)
"newer" |
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• Indicated for partial seizures
• GABA agonist • Is NOT metabolized and does NOT induce or inhibit hepatic enzymes • NOT bound to plasma proteins • Only major DDI is with antacids – advised to take at least 2 hrs following antacid administration • Excreted by the kidneys unchanged • Most common side effects are somnolence, fatigue, dizziness, blurred vision and diplopia |
Gabapentin (Neurontin)
"newer" |
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• Can be used as monotherapy in adults with partial seizures or as adjunct in children or adults with partial seizures
• Same MOA as phenytoin: Blocks Na+ channels and inhibits the generation of repetitive action potentials • Most common adverse effect is a rash that can develop during the first 8 weeks of treatment; otherwise, same "depressive" side effects as other AEDs, but usually milder |
Lamotrigine (Lamictal)
"newer" |
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• GABA reuptake inhibitor
• Adjunct in partial seizures • Should be taken with food to minimize abdominal pain and nausea • Does not induce or inhibit hepatic enzymes |
Tiagabine (Gabitril)
"newer" |
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• MOA same as phenytoin:Blocks Na+ channels and inhibits the generation of repetitive action potentials
• Adjunct in partial seizures or generalized tonic-clonic seizures • Common SEs drowsiness, dizziness, headache, impaired concentration and memory lapses |
Topiramate (Topamax)
"newer" |
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• Indicated for partial seizures
• MOA unknown • Common SEs include dizziness, weakness and irritability |
Levetiracetam (Keppra)
"newer" |
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indicated for for diabetic peripheral neuopathy
• Also indicated for partial seizures • MOA unknown • Common SEs include dizziness, dry mouth, blurred vision and weight gain • Downside is that is scheduled (C-V) |
Pregabalin (Lyrica)
"newer" |
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• Indicated for partial seizures
• Common SEs include dizziness, irritability, nausea and confusion |
Zonisamide (Zonegran)
"newer" |
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continuous seizure lasting > 5 min, with no evidence that the seizure has stopped
• Some common causes (don’t memorize the numbers) o noncompliance with long-term antiepileptic drug therapy (about 20- 25% of cases) o idiopathic (about 15%) o anoxia or stroke (about 12-15% each) o ethanol/drug withdrawal syndrome (about 8-10%) Preferred approach • Initially IV diazepam (VALIUM; a benzodiazepine), in incremental dosages, for immediate effects, then (always and right after giving diazepam)…. • IV phenytoin (or fos-phenytoin) to follow-up, for longer coverage *** some clinicians prefer lorazepam (ATIVAN) instead of diazepam, which is somewhat longer-acting |
status epilepticus
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Preferred approach
• Initially IV diazepam (VALIUM; a benzodiazepine), in incremental dosages, for immediate effects, then (always and right after giving diazepam)…. • IV phenytoin (or fos-phenytoin) to follow-up, for longer coverage *** some clinicians prefer lorazepam (ATIVAN) instead of diazepam, which is somewhat longer-acting |
status epilepticus
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Problems with drugs given IV:
• Old “standby” of ________ (often used alone) enters brain quickly, but also leaves brain quickly such that seizure may recur (this is typically true of all benzodiazepines), also causes significant venous irritation when injected too quickly • __________ (as only drug) enters brain too slowly to stop seizures quickly enough, plus has physical properties that make it less than ideal o formulated in propylene glycol } irritating o very alkaline (pH about 12) } to veins o must be diluted before injection IV o is insoluble in glucose-containing fluids |
diazepam
phenytoin |
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• is a prodrug — phenytoin linked to a phosphate (“fos”) ester — that forms free (active) phenytoin with a half-life of about 10 minutes when the body naturally metabolizes the phosphate off, making free phenytoin, which has the actual anticonvulsant activity
• more soluble (and soluble in more common vehicles) than phenytoin • more “compatible” pH: about 9, vs about 12 for phenytoin • can be injected faster than regular phenytoin |
Fos-phenytoin (Cerebyx)
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it appears—from whatever cause—that children born to mothers taking anti-seizure drugs have an increased risk, perhaps twofold, of congenital malformations. Phenytoin has been implicated in a specific syndrome called fetal __________, although not all investigators are convinced of its existence and a similar syndrome has been attributed both to phenobarbital and to carbamazepine. ________, has also been implicated in a specific malformation, spina bifida. It is estimated that a pregnant woman taking valproic acid or sodium valproate has a 1-2% risk of having a child with spina bifida. Topiramate has shown some teratogenicity in animal testing
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hydantoin syndrome
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Some drugs are more easily withdrawn than others. In general, withdrawal of ___________ drugs is easier than withdrawal of drugs needed for partial or generalized tonic-clonic seizures. ____________ and benzodiazepines are the most difficult to discontinue; weeks or months may be required, with very gradual dosage decrements, to accomplish their complete removal, especially if the patient is not hospitalized.
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anti-absence
barbiturates |
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what are the two major therapeutic groups of skeletal muscle relaxants:
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neuromuscular blockers
spasmolytics/"centrally acting' muscle relaxants |
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These drugs are used during surgical procedures and in intensive care units to cause paralysis. They can be particularly useful in critically ill patients who have ventilatory failure from various causes (e.g. – severe bronchospasm, COPD), as they can eliminate chest wall resistance and ineffective spontaneous ventilation when patients are placed on mechanical ventilation.
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Neuromuscular Blockers
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They are typically administered IV and specifically interfere with transmission at the neuromuscular junction. They do not affect the CNS, but are generally used as adjuncts to general anesthesia
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Neuromuscular Blockers
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These are typically oral agents that are used to reduce painful muscle spasm and tightness (e.g. – in the back, associated with TMJ disorders, etc.). The term "___________" is a bit of a misnomer, as some of these drugs have no significant central effects (e.g. – dantrolene).
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Spasmolytics / "Centrally Acting" Muscle Relaxants
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There are two classes of neuromuscular blockers, based on how they act at the neuromuscular junction:
1)______________ agents — prototype: tubocurarine (“curare”); other examples include: Atracurium (Tracrium) Doxacurium (Nuromax) Pancuronium (Pavulon) Pipecuronium (Arduan) Rocuronium (Zemuron) Vecuronium (Norcuron) 2) ____________________ — prototype (and only drug in USA): succinylcholine (Anectine) |
nondepolarizing
depolarizing |
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General Properties of All N/M Blockers:
Paralyze skeletal muscle by interfering with normal muscle activation or reactivation (i.e., depolarization by ACh and/or subsequent repolarization) via the __________ receptors found on skeletal muscle Are used specifically (and commonly) to paralyze skeletal muscle Virtually all skeletal muscles in the body are paralyzed when therapeutic doses are given |
nicotinic
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General Properties of All N/M Blockers:
Do not affect sensory function/sensory nerves (e.g., sensation of ____) Do not affect CNS or alter level of consciousness (assuming patient’s ventilation & cardiovascular functions are supported at normal levels) Have no major direct autonomic effects Primary cause of death from overdose or improper use is ventilatory impairment/apnea (i.e., asphyxiation); primary treatment for (and prevention of) this is mechanical support of ventilation (plus CV function as needed) |
pain
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Mechanism of action
Competitively blocks nicotinic receptors, on skeletal muscle, that are normally activated by ACh released from somatic nerves. This prevents depolarization (activation) of skeletal muscle cells by Ach and leads to flaccid muscle paralysis. |
nondepolarizing agents
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nondepolarizing agents:
Mechanism of action Be clear that these drugs act on nicotinic receptors at the _________ junction. They do not act on nicotinic receptors that are found in autonomic ganglia. They do not act on _________ receptors (or any other kind of receptor, for that matter). |
neuromuscular junction
muscarinic |
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nondepolarizing agents:
Mechanism of action Effects are surmountable: can overcome effects (paralysis) and restore normal muscle function (before effects of the blocker wear off normally) by making more ACh available to activate nicotinic receptors clinically is accomplished by injecting _________ or a similar acetylcholinesterase inhibitor just before receiving acetylcholinesterase inhibitor, patient is pretreated with _________ (or another antimuscarinic) to prevent unwanted parasympathomimetic effects of the acetylcholinesterase inhibitor that will arise due to simultaneous activation of muscarinic receptors by ACh |
neostigmine
atropine |
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nondepolarizing agents:
Pharmacokinetics of tubocurarine Eliminated mainly by _____ excretion of unmetabolized drug Onset a few minutes, normal duration about ___ minutes with a single dose Action may be prolonged by repeated injection of the drug as needed Action may be (and often is) intentionally shortened by reversing drug’s effects by administering ___________ inhibitor Related nondepolarizing blockers differ from prototype: In terms of route(s) of elimination (which may affect selecting a particular agent for patients with renal or hepatic dysfunction) In onset and duration of action (can use a related curare-like drug if shorter or longer effects are wanted) |
renal
60 minutes acetylcholinesterase |
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Nondepolarizing Agents :
Pharmacokinetics of tubocurarine Actions may be prolonged, undesirably and unpredictably, by other drugs and conditions, including aminoglycoside ________(e.g., gentamicin) and ___________ agents (common ones, incl. most inhalation anesthetics |
antibodies
anesthetic |
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Indications
Whenever more than “brief” muscle paralysis is wanted: during certain diagnostic or surgical procedures (e.g., facilitates positioning of broken limbs, aids surgeon in opening and retracting incision to access body cavity such as abdomen) adjunct to mechanical ventilation (“ventilator control:” muscle paralysis prevents patient from “fighting the ventilator”) |
nondepolarizing agents
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Mechanism of action
Quickly, intensely activates nicotinic receptors on skeletal muscle (acts sort of like a “super ACh”) This depolarizes (activates) skeletal muscle cells and leads to initial fasciculations, potentially intense contraction Muscle cells remain depolarized, unable to repolarize normally in presence of drug, muscle is thereby paralyzed |
depolarizing agents
succinylcholine (Anectine) |
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Effects not surmountable: cannot overcome or reverse effects (paralysis) as is done with nondepolarizing agents (i.e., administering acetylcholinesterase inhibitor does not reverse drug’s effects and may actually prolong/intensify them)
Normal muscle function restored naturally and rapidly as effects of drug wear off due to metabolism by plasma cholinesterases |
depolarizing agents
succinylcholine (Anectine) |
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depolarizing agents:
Pharmacokinetics Rapidly eliminated by metabolism via plasma __________ Onset <<1 minute, duration normally only 3-5 minutes with a single dose Some patients have genetic deficiency in plasma ___________, will experience very prolonged muscle paralysis (and all its adverse consequences) because the drug won’t be metabolized as quickly as it should Action may be prolonged by continuous infusion or repeated injection of the drug as needed |
cholinesterases
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When “brief” or very rapid muscle paralysis is wanted
to facilitate intubation, for whatever reason, especially when this must be done quickly often used to initiate paralysis quickly (e.g., pre-operative intubation), with longer paralysis maintained by using longer-acting nondepolarizing blocker (or by infusing more succinylcholine |
depolarizing agents
succinylcholine (Anectine) |
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Important adverse reactions and other considerations
Initial muscle contractions upon administration may be intense & severe Drug contraindicated when there is skeletal or ocular trauma (risk of limb fractures, damage to eye when ocular muscles contract) Many patients complain of severe muscle pain upon recovery, regardless of when/how this drug is used, because of intense contractile effects of the drug |
depolarizing agents
succinylcholine (Anectine) |
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Important adverse reactions and other considerations
Malignant hyperthermia, a drug interaction between __________ and the commonly used inhaled general anesthetic agent, _________ Incidence “rare” — about 1 in 40,000 anesthesias when this drug combination is used Some evidence that patients are genetically predisposed to it Although reaction is rare, outcome is often fatal unless detected, properly treated, early enough May occur during combined drug administration (e.g., intraoperatively) or up to several hours after (postoperatively) |
succinylcholine
halothane (Fluothane) |
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rapidly developing and worsening (i.e. - malignant), intense muscle contractures (tightening/contraction of muscles without intervening relaxation)
rapidly developing, very high fever (intense muscle contraction generates lots of metabolic heat) death mainly from ventilatory failure (apnea) during intense muscle contractures complicated by cardiac arrhythmias from hyperkalemia (intense muscle contractions damage muscle cells, which then leak large amounts of K+ into the circulation) |
malignant hyperthermia
DDi: succinylcholine and halothane (Fluothane) |
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Malignant Hyperthermia -- Management:
anticipate potential for reaction, monitor closely body temperature must be reduced/normalized rapidly with physical means (not with antipyretic drugs, which may be ineffective at usual doses, toxic if high doses used in attempt to lower temperature) administer __________, a drug that may help restore normal skeletal muscle function also treat symptomatically, supportively (with focus on ventilatory, cardiovascular status, correcting fluid and electrolyte imbalances) improvements in patient’s condition may take days will require very close monitoring |
dantrolene (Dantrium)
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Most of the drugs in this category are promoted for the relief of acute muscle spasm caused by local tissue trauma or muscular strains. The MOA is not entirely known, but there is preliminary evidence that they may act at the level of the brainstem.
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Spasmolytics / "Centrally Acting" Muscle Relaxants
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Examples include:
Carisoprodol (Soma) Cyclobenzaprine (Flexeril) Metaxalone (Skelaxin) Methocarbamol (Robaxin) Orphenadrine (Norflex) |
Spasmolytics / "Centrally Acting" Muscle Relaxants
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One of the most common problems with these agents is the propensity to cause drowsiness and/or dizziness. For that reason, they have to be used with caution in the elderly and patients need to be educated on:
Avoiding alcohol and other CNS depressants The drug's ability to impair mental alertness and physical co-ordination, especially when operating machinery or driving a car Other possible side effects include dry mouth, headache & GI upset. |
Spasmolytics / "Centrally Acting" Muscle Relaxants
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Other drugs that have spasmolytic properties include:
In addition to the centrally acting drugs, ________ reduces skeletal muscle strength by interfering with excitation-contraction coupling in the skeletal muscle fibers. It is the agent that is the drug of choice for treating malignant hyperthermia. It can also be used for the treatment of spasticity that may occur with stroke, multiple sclerosis, cerebral palsy and spinal cord injury. |
Dantrolene (Dantrium)
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Other drugs that have spasmolytic properties include:
exerts its spasmolytic activity at GABA receptors in the brain and spinal cord. It is indicated for spasticity associated with MS and spinal cord injury. |
Baclofen (Lioresal)
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a central a2-agonist that has the ability to reduce muscle spasm.
A Spasmolytics / "Centrally Acting" Muscle Relaxants |
Tizanidine (Zanaflex)
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A Spasmolytics / "Centrally Acting" Muscle Relaxants
This is used mainly as a sedative (anxiolytic). It belongs to a class of drugs called the benzodiazepines, which facilitate the action of GABA in the CNS. Acts at all GABA synapses, but its action in reducing spasticity is at least partly mediated in the spinal cord because it is somewhat effective in patients with cord transection. It can be used in patients with muscle spasm of almost any origin, including local muscle trauma. However, it produces sedation in most patients at the doses required to significantly reduce muscle tone. Other benzodiazepines have been used as spasmolytics, but experience with them is much more limited |
Diazepam (Valium)
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