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101 Cards in this Set
- Front
- Back
Describe Parkinson's and it's characteristic symptoms.
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Most common form is idiopathic, characterized by slow, progressive degeneration of pigmented neurons in the substantia nigra pars compacta (SNpc).
Symptoms: resting tremor -disappears during sleep or purposeful movement. rigidity- incr muscle tone. bradykinesia- poverty of movement => akinesia. |
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What are the secondary Parkinson motor manifestations?
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-Stooped posture
-poor righting reflex -shuffling gait Also difficulty in speaking(microphonia), writing(micrographia) and swallowing. In advance stages, pts become immobile, frozen(akinetic). |
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What role does oxidative stress play in Parkinsons'?
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Oxidation of DA => H2O2 & oxyradicals. This may lead to damage of DAergic neurons via DNA damage, peroxidation of membrane lipids, & neuronal death. In pts w/ Parkinsons, there's a deficiency of Gltathione in the striatum and incr Fe in the SNpc. This makes brain susceptible to free radical accumulation and oxidative stress.
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Whats the DA Theory in Parkinson's?
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Imbalance b/w Dopaminergic(inhibitory) & cholinergic(excitatory) neurons within the striatum.
*depletion of DA in the striatum is proportional to the severity of DA cell loss in the Substantia nigra. |
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How does depletion of DA => Parkinson's?
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Loss of inhibitory DA input from the SN to the striatum shifts the balance in favor of Ach mediated excitation of:
1) inhibitory GABAergic interneurons 2)inhibitory GABAergic efferent projections. |
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What does MAO and COMT enzymes do?
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-MAO is an enzyme involved in the oxidative deamination of monoamines like DA,NE,Epi,5HT,Histamine.
-COMT: involved in the degragation of catecholamines(DA,NE,Epi). |
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How is drug therapy in Parkinsons directed?
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Goal of therapy is to return the system to a balanced state by:
1) increasing DA-ergic function w/ DA precursors, DA agonist, or inhibitors of enzymes which degrade catecholamines(MAO-B, COMT). 2) reduce dominance of cholinergic system w/ anticholinergic drugs. NOTE: drug therapy is symptomatic, not curative!!! |
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Name the drugs used to reduce cholinergic dominance?
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Benztropine- balance DA-Ach systems by reducing cholinergic dominance.
Diphenhydramine- central muscarinic blockade |
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Benztropine in Parkinsons?
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has modest anti-parkinsonian action useful in mild to moderate dz. Has beneficial effect on tremor & rigidity but little to no effect on bradykinesia. Use in combo w/ levodopa/carbidopa for severe parkinsonism.
Used to manage drug induced parkinsonism in schizo's being tx w/ neurolepics. |
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Diphenhydramine in Parkinson's?
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Therapeutic action via prominent anticholinergic properties.
Has common S/E of dry mouth, blurred vision, constipation & urinary retention, and Sedation, mental confusion. |
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When is Diphenhydramine contra-indicated?
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In pts with bowel or bladder dysfunction, memory disorder, & narrow angle glaucoma.
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What are the drugs which increase dopaminergic function?
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levodopa
levodopa + carbidopa bromocriptine pergolide pramipexole selegiline entacapone amantadine |
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Levodopa?
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L-Dopa, the precursor for DA synthesis via decarboxylation. Levodopa crosses the BBB, DA doesn't.
Large doses required to cross BBB. 95% of oral levodopa is rapidly decarboxylated. |
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Levodopa precautions?
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levodopa=>DA synthesis may cause oxidative stress and hasten degeneration of striatal neurons. For this reason, pts w/ mild dz may be started on other drugs like amantadine for starts.
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S/E's of levodopa?
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-anorexia
-n/v -cardiac arrythmias |
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Levodopa + carbidopa?
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Carbidopa is a DOPA decarboxylase inhibitor that doesn't cross the BBB, it's used to prevent conversion of levodopa => DA in the periphery.
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Benefits of using carbidopa?
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-dose of levodopa need can be decreased.
-n/v is eliminated -CV effects are diminished -effective doses can be reached more quickly. -antagonism of levodopa's efficacy by Vit B6 is avoided. |
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Psychic effects of levodopa?
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apathy and depression are replaced w/ increased vigor and mood. Improvement in mental function, self interest, and relationships w/ surroundings and family.
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Major S/E's of levodopa?
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-Cardiac arhythmias & transit tachycardia due to DA on b-adrenergic receptors. Can be prevented w/ carbidopa and beta-blockers.
-orthostatic hypotension: occurs in early therapy then decreases w/ time. -n/v: early in therapy and decr. w/ time. Due to action of DA on chemoreceptor trigger zone in area postrema of medulla. Minimized w/ carbidopa. -abnormal involuntary movements(dyskinesia): dose limiting S/E. -Mild rxn early in therapy: nervousness, insomnia, anxiety, agitation & nightmares -psychotic rxns(confusion, delirium) are dose limiting. suicidal tendencies and depression may occur. |
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Pharmacokinetics considerations?
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levodopa is short acting w/ half-life of 1.5 hrs. Best results are made early in tx. Tremors, rigidity, and bradykinesia are resolved nearly completely. Beneficial effects exceed lifetime of levodopa.
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What is "end of dose akinesia" (wearing off)?
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With time and continued degeneration, levodopa buffering capacity is lost.
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What is On/OFF phenomena?
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In later stage of dz, pts flucuate b/w being off having no beneficial effects and being on but w/ disabling dyskinesias.
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What is done to alleviate "end of dose akinesia and On/Off fluctuations?
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-smaller doses of levodopa taken more often.
-Use of sustained release formulations. -addition of DA agonist to regimen(dyskinesia is a S/E of agonist though). -addition of cholinergic antagonist to regimen. -addition of MAO-B inhibitors or COMT inhibitors to regimen. |
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Drug-Drug interactions w/ levodopa?
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-drugs which deplete brain monoamines(reserpine).
-drugs that interfere w/ DA synthesis(a-methyldopa) -dopamine receptor antagonist. -non-selective monoamine oxidase inhibitors. |
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Advantages of DA receptor agonist?
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-they don't require enzymatic conversion and they don't depend on the functional capacity of the nigrostriatal neurons.
-DA receptor agonist are more selective for D2(indirect) DA receptors. |
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Bromocriptine?
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DA agonist w/ D2 selectivity.
-Use as adjunctive therapy w/ levodopa/carbidopa in pts who are experiencing On/Off and "end of dose akinesia". |
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Other uses of bromocriptine?
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Tx of hyperprolactinemia in prolactin secreting tumors or as a S/E of antipsychotics.
Tx of Neuroleptic Malignant Syndrome(NMS). NMS is believed to result from an extremely rapid blockade of postsynaptic dopamine receptors. |
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Pergolide?
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DA agonist at both D1 and D2. More potent than bromocriptine. Useful in late stages of Parkinsons as adjunctive therapy w/ levodopa/carbidopa.
as with bromocriptine, duration of action of a single dose of pergolide is longer than that of levodopa. Derived from Ergot fungus. |
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Pramipexole?
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Non-ergot DA agonist specific for D2 subfamily with higher affinity for D3 subtype.
-Effective as monotherapy in early stages of dz. -Useful in later stages of dz as adjunctive therapy with levodopa/carbidopa. |
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S/E of DA agonists?
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orthostatic hypotension w/ low doses. More common w/ DA agonist than w/ levodopa.
n/v early in therapy. Psychotic rxn are more common and severe than that w/ levodopa. Dyskenesias. |
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Selegiline?
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MAO-B inhibitor. Slow the degradation of DA via irreversible inhibition of MAO-B. May have neuroprotective effect via anti-Oxidative stress.
Does not inhibit peripheral metabolism of NE or 5HT or interact with food containing tyramine like non-specific MAOI's do. Attenuates mild On/Off and "end of dose" akinesias. Thus useful as adjunctive therapy w/ levodopa. In advanced dz, levodopa induced dyskinesias may be exacerbated by Selegiline. |
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What is Selegiline metabolized to?
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Amphetamine. Leads to S/E of anxiety and insomnia.
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Entacapone?
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COMT inhibitor. elevates DA levels by inhibiting degradation and may provide neuroprotective effects.
Use as adjunctive therapy w/ levodopa/carbidopa. No liver toxicity w/ entacapone. |
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Amantadine?
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Antiviral. MOA is unclear but thought to release DA from nerve terminals.
use as monotherapy in mild dz and adjunctive therapy in fluctuating response to levodopa. Less effective than levodopa but w/ less S/E. |
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What is MPTP induced parkinsonism?
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MPTP is a byproduct in illicit drug prep know to cause parkinsonism. MPTP is converrted by MAOB to MPP+ which is extremely toxic to dopaminergic neurons leading to selective destruction in the substantia nigra.
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Tourettes Syndrome?
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Characterized by multiple, complex involuntary movements including respiratory and vocal tics. Probably a dysfunction involving both basal ganglia and limbic structures.
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Tx of Tourettes Syndrome?
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For BJE, drug of choice is haloperidol, a typical antipsychotic but the tardive dyskinesia is a serious concern.
Use Clonidine, a-adrenergic receptor agonist in pediatric pts to avoid tardive dyskinesia associated w/ haloperidol. |
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Epilepsy?
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heterogeneous symptom complex - chronic disorder characterized by recurrent seizures. Seizures are finite episodes of brain dysfunction.
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Where do seizures originate from?
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From hyperexcitable cells (the focus) from which discharges periodically spread to limited areas of the brain = partial seizures or to large areas = generalized seizures.
Seizures are believed to involve the cerebral cortex and limbic system and not other areas of the brain. |
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Describe Partial seizures?
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Focal seizures who's symptoms depend on area of brain effected.
Simple partial seizures - not accompanied by a change in consciousness. Complex partial seizures - accompanied by loss of consciousness Partial seizures w/ secondary generalization - focal seizures spread until it generalizes. |
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Describe Generalized Seizures?
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Tonic Clonic(grand mal) sudden loss of consciousness with tonic contraction of body muscles w/ rhythmic jerking then depression of CNS function for varying periods.
Absence(petit mal) - brief loss of awareness but w/o loss of consciousness. may have eye-blinking or lip-smacking. Seen in young children. Myoclonic - sudden jerks of limb, trunk or whole body. Seen in children to adolescence. Atonic seizures - sudden loss of postural tone Infantile spasms - not a seizure type. brief recurrent myoclonic jerks of body. Most pts are mentally retarded. |
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How is absence seizures treated?
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Ethosuximide
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How is infantile spasms treated?
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BZ like clonazepam. These seizures are refractory to usually antiseizure agents.
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How is generalized tonic clonic seizures and partial seizures treated?
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Carbamazepine
phenytoin ethotoin phenobarbital gabapentin |
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What drugs have a wide spectrum of antiseizure activity?
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valproate
lamotrigine zonisamide |
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What drugs are approved for treatment of status epilepticus?
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phenytoin
diazepam |
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What are the MOA of anti-seizure medication?
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-they depress excitability of epileptic focus and prevent spread of seizure
-They enhance the inhibitory GABA neurotransmission. |
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What are the mechanisms which excitatory neurotransmission is inhibited?
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-alteration of ion channel conductance => prolonged Na channel inactivation => reduced action potential frequency. OR reduce low threshold Ca++ currents(T currents).
-Blockade of excitatory glut receptors. |
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What are T currents implicated in?
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Absence seizures
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What are mechanisms which inhibitory GABA neurotransmission is enhanced?
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-act at allosteric binding sites to enhance GABA mediated Cl- conductanace.
-increase GABA levels via glutamic acid decarboxylase stimulation. -promote release of GABA -inhibit degradation of GABA |
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Pharmacokinetics of anti-seizure drugs?
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-Absorption is good (80-100%) w/ exceptions of phenytoin & carbamazepine.
-they are not highly bound to plasma proteins. -Cleared via hepatic mechanisms which contributes to induction of liver microsomal enzymes and many drug interactions -Plasma clearance is slow -many are converted to active metabolite by the liver. |
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What drug is eliminated by renal excretion?
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gabapentin
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What are two important drug interactions in the liver?
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-Acute interactions: drugs compete for hepatic microsomal enzymes => decrease metabolism of each other.(phenobarbital, diazepam decrease metabolism of phenytoin).
-Delayed interactions: drugs induce hepatic microsomal enzymes w/ chronic use => increase metabolism of drugs metabolized by the same enzymes(carbamazepine, phenobarbital may increase phenytoin metabolism) |
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Phenytoin?
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Prolongs state of Na channel inactivation. DOC for generalized tonic clonic seizures. Also effective in tx of partial seizures but not effective for absence seizures.
-Given IV for status epilepticus. -at therapeutic doses => liver enzymes are saturated. thus, small incr in dose = large incr in plasma concentration. |
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S/E's of Phenytoin?
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-Hair growth(hirsutism)
-gingival hyperplasia -osteomalacia(give vit-D) -megaloblastic anemia(give folate) **TERATOGENIC** FETAL HYDANTOIN SYNDROME. |
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Ethotoin?
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A hydratoin related to phenytoin. DOC generalized tonic clonic seizures and complex partial seizures.
-like phenytoin, blood dyscrasias S/E. -Use in children since it lacks hirsutism and gingival hyperplasia S/E's. |
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Valproate?
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WIDE SPECTRUM of anti-seizure activity. DOC for atonic & myoclonic seizures or for pts with multiple seizure types.
-effective for absence seizures. -hepatotoxicity: valproate metabolism produces toxic intermediates. |
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Carbamazepine?
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DOC for all partial seizures.
-very effective in tx of grand mal seizures but not in absence seizures. -DOC for tx of trigeminal neuralgia -10,11 epoxide metabolite of carbamazepine has anticonvulsant activity. |
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What are the serious S/E's of Carbamazepine?
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-Bone marrow depression
-aplastic anemia -agranulocytosis -hyponatremia -water retention(prob w/ elderly w/ CV dz) |
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Lamotrigine?
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WIDE SPECTRUM of antiseizure activity.
-Effective in tx of partial, generalized, and absence seizures(2nd DOC). -use for refractory partial seizures in combo w/ other anti-epileptics. |
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Zonisamide?
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WIDE SPECTRUM of activity. Effective in a wide variety of seizures, especially those refractory to other drugs.
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S/E's in Zonisamide tx?
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-Cognitive impairment and drowsiness
-Oligohydrosis(low sweat production) & hyperthermia in pediatric pts => heat stroke -nephrolithiasis: related to carbonic anhydrase inhibition |
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Drugs that reduce low threshold Ca++ currents (T currents).
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-Ethosuximide: DOC for absence seizures(T currents indicative of). S/E's Bone marrow depression and blood dyscrasias
-Zonisamide -Valproate |
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Phenobarbital?
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Enhances GABA-mediated increase in Cl- conductance => increase DURATION of channel opening.
-Effective in tx of generalized tonic clonic seizures and all partial seizures. -INEFFECTIVE in absence seizures. -maximal antiseizure action dose is below that of hypnotic effects. |
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Pharmacokinetics of Phenobarbital?
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Lipid solubility: Phenobarbital has a low lipid solubility. High lipid solubility => increase rate of distribution => termination of CNS effects.
Hepatic metabolism: transformation to water soluble metabolites for renal excretion. Liver dz and old age can affect rate of metabolism. Renal excretion: some is excreted unchanged w/ a pKa of 7.3 so making urine alkaline will increase its elimination rate. Useful in phenobarbital overdoses. |
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S/E's of longterm barbiturate use?
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-osteomalacia(Give Vit-D)
-megaloblastic anemia(give folate) -hemorrhage in newborns(give vit-K) -porphyria -Severe CNS depression when combined w/ other depressants(alcohol, antihistamines, BZ, antipsychotics, narcotics, sedative antidepressants). |
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BZ's: Clonazepam?
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effective in tx of absence seizures & myoclonic seizures
-widely used in tx of infantile spasms. |
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BZ's: Diazepam?
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DOC for management of status epilepticus.
-increases the frequency of the chloride channel opening!! |
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What else does Valproate do?
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It's a drug that increases GABA levels by stimulating the synthetic enzyme, glutamic acid decarboxylase.
Valproate also inhibits the degradation of GABA. |
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Gabapentin?
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A drug that promotes release of GABA via an unknown mechanism.
-adjunctive therapy for tx of partial seizures and generalized tonic clonic seizures. -also effective for postherpetic neuralgia. -excreted unchanged via kidneys. RENAL!!! -S/E's: dizziness, drowsiness |
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Anti-epileptic drugs which cause cognitive impairment?
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Phenytoin
phenobarbital carbamazepine zonisamide valproate BZ's |
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Anti-epileptic drugs which cause little to no cognitive impairment?
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gabapentin
lamotrigine |
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Teratogenicity in anti-epileptic drugs?
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Cat-D:
Phenytoin carbamazepine valproate Cat-C: gabapentin zonisamide |
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Drugs that do NOT decrease the effectiveness of oral contraceptives?
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Lamotrigine
gabapentin valproate |
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What are the MOA's of CNS stimulants?
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-indirect action releasing endogenous monoamines(NE,DA,5HT)
-prolonging action of monoamines at synapse by preventing their reuptake. -direct agonist action -inhibit degradation of intracellular second messengers produced as a result of receptor activation by an agonist. |
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Name sympathomimetic amines used as anorexiants?
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amphetamines
phentermine |
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Name anorexiants that are inhibitors of monoamine reuptake ?
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sibutramine
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Name drugs used to tx ADHD?
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methylphenidate
dextroamphetamine atomoxetine |
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Name drugs used to tx narcolepsy?
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amphetamine
methylphenidate modafinil |
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Name drugs used to tx neonatal apnea syndrome?
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theophylline
caffeine |
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Amphetamine?
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Sympathomimetic amine that produces mood elevation, increases wakefulness, alertness, concentration and physical performance.
-Schedule II controlled drug: high potential for abuse. -anorexic effect due to action in lateral hypothalamus combined w/ increased energy expenditure. |
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MOA of amphetamines?
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Indirect acting sympathomimetics. They act to release catecholamines from their stores and to prevent their reuptake.
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Amphetamine S/E's?
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-increased CV s/e due to catecholamine release => increased systolic and diastolic BP + tachycardia.
-Acute toxicity(I.V.): marked CNS stimulation, paranoid psychosis, CV effects above, hyperthermia, convulsions & coma. -Chronic Toxicity: tolerance develops and pt becomes psychological and physiological dependent. Amphetamine psychosis develops=> hallucinations, delusions of persecutions, feelings of omnipotence |
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Withdrawal effects from Amphetamines?
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Withdrawal syndrome => fatigue, prolonged sleep, apathy, PROFOUND LONG LASTING DEPRESSION(suicide?),
-Confusion, memory loss & delusional ideas may remain for months. |
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Phentermine?
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Amphetamine derivative. Lower abuse potential(schedule IV).
-Same MOA as amphetamine -FDA approve for short-term use in obesity tx. -was one of the drugs in "fen-phen". |
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Sibutramine?
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MOA: blocks reuptake of NE, 5HT, DA.
-No CNS depression, abuse potential, drug dependence or valvular pathology. -Metabolized to active form in liver. -Not an Amphetamine but still schedule IV. -Once daily dosing and FDA approved for long term use. -No tolerance to anorexiant effect!!! |
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ADHD treatment?
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PSYCHOMOTOR STIMULANTS:
-D-amphetamine *DOC* -methylphenidate *DOC* -amphetamine -action of these drugs seems paradoxical as they act to increase persistence, attentiveness and concentration but decrease excessive motor activity in ADHD children. -MOA: drugs release NE and DA from neurons and block the reuptake back into the neuron. |
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Methylphenidate in ADHD tx?
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Duration of action is 4-5 hrs, so children require a second dose at lunch to control behavior in school throughout the afternoon.
-Schedule II drug -generally less peripheral effects & more prominent CNS effects.(PSYCHOMOTOR VS. sympathomimetics) -The Sustained Release version hasn't proved to be better than regualar Methylphenidate. |
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Adderall?
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mixture of amphetamine and dextroamphetamine.
-Has longer duration of action(8-10hrs). |
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Concerta?
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Slow release methylphenidate
-Duration of action = 12hrs -outer coat has small dose of methylphenidate which rapidly achieves a therapeutic plasma concentration. remainder is released at a constant rate from inside tablet. |
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Daytrana?
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transdermal methylphenidate.
-patch placed on hip for 9 hrs. -low abuse potential. -Dosage is proportional to size of patch. |
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Metadate CD?
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Extended release methylphenidate.
-30% is immediate release beads and 70% is extended release beads. |
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Ritalin LA?
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extended release methylphenidate.
-Uses Spheroidal Oral Drug Absorption System (SODAS) technology. IR beads w/ half enteric coated ER beads. |
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Atomoxetine in ADHD tx?
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MOA: selective NE reuptake inhibitor.
-pts don't like this med. -Black box label for suicide -DO NOT GIVE WITH MAOI!!! -S/E's: headache, aggression, irritability, palpitations, insomnia, urinary retention. |
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What is Narcolepsy?
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recurrent, uncontrollable, sudden episodes of sleep under conditions not normally conducive to sleep.
-Accompanied by hallucinations, cataplexy(sudden loss of muscle tone), and sleep paralysis. -Treat cataplexy w/ TCA Imipramine & MAOI's |
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Treatment of Narcolepsy?
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Amphetamines has risk of abuse, tolerance development, and fact that they may disturb normal sleep rhythm.
-Methylphenidate is an alternative. |
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Modafinil in Narcolepsy?
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Amphetamine substitute approved for use in narcolepsy.
-S/E's headache, nausea, nervousness, anxiety, insomnia. -Schedule IV drug (Amphetamine is schedule II) |
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Neonatal Apnea treatment?
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Pathological apnea is apnea exceeding 20 seconds.
-attributed to neuronal immaturity of the brainstem. -treat w/ caffine, theophylline |
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Theophylline in apnea tx?
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DOC for neonatal apnea tx.
MOA: inhibition of phosphodiesterases => increasing intracellular cAMP. -Direct effects on intracellular Ca++ concentrations. -antagonism of adenosine receptors Therapeutic actions =>Stimulate contraction of diaphragmatic muscle, stimulates central respiratory drive centers, and increases ventilatory centers sensitivity to CO2. -Theophylline can eliminate apnea episodes of greater than 20 seconds and reduce the # of episodes as a whole. -Caffeine is now preferred by some MD's due to simpler and more predictable dosing regimens |
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Theophylline S/E's?
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Rapid iv infusino can result in severe toxicity or sudden death, drug should be injected slowly over 20-40 min period.
S/E's: headache, tachycardia, severe restlessness, nausea, emesis, abdominal pain. Theophylline plasma concentrations should be measured during therapy. |
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What does caffeine and/or theophylline use do?
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-relax smooth muscle(brochial muscle)
-Stimulate CNS -Stimulate cardiac muscle -Act on kidney as diuretic. |