Pharm - Therapies for Parkinson's Disease & Epilepsy
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- Parkinson's Disease
-
- degenerative neurological disorder (2nd most common - next to Alzheimers disease)
- slow progression
- onset: middle age
- S&S of Parkinson's Disease
-
- tremors
- rigidity
- postural instability
- dementia, depression, impaired memory (later)
- slowed movement (bradykinesia) --> akinesia (absence of movement)
- Pathophysiology of Parkinson's Disease
-
- loss of DOPAMINERGIC neurons in SUBSTANTIA NIGRA
- disorder of extrapyramidal system (neuronal network that helps regulate movement)
- disruption of neurotransmitter function (1st identified in STRIATUM)
- proper balance of striatum requires a balance between 2 neurotransmitters: DOPAMINE (inhibitory) & ACETYLCHOLINE (excitatory) --> body movement is controlled when balanced
- 70-80% of neurons are lost before clinically diagnosed - Extrapyramidal System
- neuronal network that helps regulate movement
- Bodily movement is controlled when there is balance between these 2 neurotransmitters of the striatum
-
1. Dopamine
2. Acetylcholamine (excitatory) - What neurotransmitter decreases GABA?
-
Dopamine (DA)
*if there is no Dopamine, GABA increases - Goals of PD therapy
-
- functional mobility & prolonged quality of life
- drug selection & dosage based on extent to which PD interferes with ADL
- drugs relieve symptoms (there is no cure) - 2 types of drugs for treating PD
-
1. Dopaminergic Agents (activate dopamine receptors)
2. Anticholinergic Agents (block Ach receptors) - Bromocriptine
-
- dopamine AGONIST
- stimulates dopamine receptors DIRECTLY
- used to diminish loss of effect of Levodopa - Selegiline or Rasagiline
-
- MAO-B inhibitor
- prevents breakdown of dopamine
- reduces "wearing off" effect
- SELECTIVE & IRREVERSIBLE inhibition of MAO-B
- used in newly diagnosed patients with mild symptoms
- adverse effect: insomnia
- give at breakfast/noon to prevent insomnia
- amphetamine metabolites derived - Amantidine
-
- promotes release of dopamine
- blocks reuptake of dopamine - Anticholinergics
- block MUSCARINIC receptors in the striatum
- 2 Loss Effects that accompanies Levodopa
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1. Gradual Loss ("wearing off")
- develops near end of dosing intervals
- drug levels decrease to sub-therapeutic levels with disease progression
2. Abrupt Loss ("on-off")
- occurs at any time (even while drug levels are high)
- "off" times (may last mins to hrs)
- episodes of "off" increase frequency & intensity - Ways to diminish loss of effect of Levodopa
-
1. SHORTEN dosing intervals
2. COMT inhibitor - to prolong Levodopa life (ex. ENTACAPONE) - most effective
3. DOPAMINE AGONIST - ex. BROMOCRIPTNE (which is direct acting)
4. SINEMET CR - Levodopa + Carbidopa
5. Avoid high protein meals (later)
6. MAO-B inhibitor - Rasagiline (2nd most effective) or Selegiline (inhibits breakdown of dopamine) - Why dopamine cannot be used for therapy of PD? (2 reasons)
-
- cannot cross BBB
- short half-life (not practical) - Adverse effects of Levodopa:
-
1. Psychosis
2. Neurotoxicity - metabolites from conversion process are toxic
3. Darkens sweat & urine
4. may activate malignant melanoma
5. N/V - stimulates CTZ
6. DYSKINESIAS - once therapeutic levels are achieved
7. CV effects of postural hypotension & dysrhymias - 5 ways to address adverse effects of Levodopa?
-
1. lower initial doses (decrease N/V, dyskinesias & psychosis)
2. increase salt and H20 (to decrease hypotension)
3. avoid protein rich meals (amino acids compete for absorption sites and transport across BBB)
4. Clozapine - decrease psychosis (2nd generation)
5. Avoid in people with skin lesions (may lead to melanoma) - What is the primary food interaction with Levodopa?
-
High protein rich meals
- decrease effects of Levodopa
- amino acids compete with levodopa for absorption sites and transport across BBB
- could trigger abrupt loss of effect (an "off" episode) - Drug holiday benefits
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- interruption of Levodopa treatment for approx. 10 days
- when adverse effects increase & therapeutic effects decrease
- restart on LOW doses
- dangerous (done with hospital supervision because it may immobilize patient)
- increases risk for DVT, decubitus ulcers & aspiration pneumonia - Levodopa
-
- dopamine replacement
- promotes dopamine synthesis
- route: only PO & take on empty stomach
- crosses BBB by active transport
- is taken up into few remaining dopamine terminals (in striatum) & converts to dopamine (active form) in brain & further stimulates other dopamine receptors
- utilizes decarboxylase (enzyme) & pyridoxine (vit B6)
- active dopamine enters synaptic space and binds to dopamine receptors on striatal GABAergic neurons which slows firing of GABA neurons
- full therapeutic effects takes several months (no immediate improvements) and benefits diminish over time
- after 5 years of Levodopa therapy, patients deteriorate to pre-treatment levels and disease gets worse - Carbidopa
-
- used to enhance the effects of Levodopa
- no therapeutic or adverse effects of its own
- cannot cross BBB
- inhibits decarboxylation (metabolism or degradation) of Levodopa in periphery which makes Levodopa more available in CNS - Clozapine
-
- decreases psychosis
- 2nd generation antipsychotic
- blocks dopamine (but lower affinity for dopamine receptors) and serotonin receptors (not in striatum)
*does not block dopamine receptors in striatum - Entacapone
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- prevents breakdown of Levodopa
- COMT inhibitor - Sinemet
- Levodopa + Carbidopa
- Epilepsy
-
a group of disorders characterized by excessive excitation of neurons within the CNS
(usually chronic condition) - Seizure
- general term applied to all types of epileptic events
- Convulsion
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abnormal motor phenomena (ex. jerking movements)
***NOTE: all convulsions can be seizures, but not all seizures are convulsions (ex. absence seizures) - What is the cause of seizures?
-
- seizures are initiated by synchronous high frequency discharges from a group of hyper-excitable neurons
- head trauma
- hypoxia at birth
- cancer (brain tumours)
- congenital defects - 2 main classes of seizures
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1. Partial (focal) - activity begins focally (centrally) in cerebral cortex & spreads minimally to cortical areas
2. Generalized - focal seizure activity is conducted widely throughout both hemispheres - 3 types of PARTIAL (focal) seizures
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1. Simple - discrete symptoms (depends on area of brain affected) - ex. twitching, numbness, hallucinations, salivation, incontinence, feelings of unreality
- lasts 20-60 seconds
- no loss of consciousness
2. Complex - impaired consciousness & lack of responsiveness (ex. motionless, fixed gaze, repetitive purposeless movements
- lasts 45-90 seconds
3. Secondarily Generalized - begins as simple/complex and evolves to tonic-clonic
- lasts 1-2 mins - 4 Types of GENERALIZED seizures
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1. Tonic Clonic (grand mal) - neuronal discharge spreads throughout entire cerebral cortex (ex. major convulsions, muscle rigidity, jerking, incontinence, loud cry, CNS depression (postical state)
2. Absence (petit mal) - brief loss of consciousness
- lasts 10-30 seconds)
- may or may not have motor activity
3. Myoclonic - sudden muscle contractions (1 limb or whole body)
- lasts 1 second
4. Febrile - 6 months to 5 years from increased fever
- does not increase one's risk for developing epilepsy later in life - Myoclonic
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sudden muscle contractions (1 limb or whole body)
- lasts 1 second - Tonic Clonic (grand mal)
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- neuronal discharge spreads throughout entire cerebral cortex
- ex. major convulsions, muscle rigidity, jerking, incontinence, loud cry, CNS depression (postical state) - Absence (petit mal)
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- brief loss of consciousness
- lasts 10-30 seconds)
- may or may not have motor activity - Febrile
-
- 6 months to 5 years from increased fever
- does not increase one's risk for developing epilepsy later in life - Status Epilepticus (SE)?
-
- generalized seizure
- seizure that lasts 30 mins or more
- may be various types
- must go to to ED
- IV Benzodiazepine - Valium (Diazepam)
- oxygen is limited to the brain - What is the goal of treatment for epilepsy?
-
- to reduce seizures (enable person to live a near normal life)
- epilepsy meds benefit 60-70% of patients - Options for treating epilepsy
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1. Surgery (Lobectomies)
2. Vagal nerve stimulation (uncertain)
3. Ketogenic diet (high fat and low carbs)
**keotacidosis decreases seizures in some - What meds should be taken for simple/complex partial and secondarily generalized (tonic-clonic - grand mal) seizures?
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1. Carbamzapine
2. Phenytoin
3. Valproic acid - What meds should be taken for absence seizure?
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1. Ethosuximide
2. Valproic acid - What meds should be taken for myoclonic seizures?
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1. Clonazepam
2. Valproic Acid - Nursing interventions for people taking anti-epileptics
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- record seizures
- avoid grapefruit juice
- complete blood count
- visually monitor for absence seizures
- greater caution if sexually active
- avoid operating heavy machinery or driving
- good dental hygiene - Sodium Channel Physiology
-
- neuronal action potentials are moved along by Na+ moving into Na+ channels (gated pores in CM)
- channel must be active for Na+ influx to occur
- channel becomes inactivated after Na+ entry to block further entry of Na+ (refractory period)
- normally, channel recharges quickly to become active again - What medication should be given for Status Elipticus (SE)?
- IV Diazepam (Valium) - Benzodiazapine
- What is a ketogenic diet?
-
- high fat
- low carb
**ketoacidosis decreases seizures in some - MOA of Carbamazepine (Tegretol) & Phenytoin (Dilantin)
- - suppression of Na+ influx
- Phenytoin (Dilantin)
-
- VERY NARROW THERAPEUTIC RANGE
- overwhelms liver
- contraindicated: Liver Disease - Adverse effects of Phenytoin (Dilantin)
-
- Sedation
- Nystagmus (rapid eye movement)
- Diplopia (double vision)
- Ataxia (inability to walk properly)
- Gingival hyperplasia (gum tissue overgrowth)
- Skin rash - Which drugs decrease effects of Phenytoin (Dilantin)?
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Warfarin
Glucocorticoids
Oral Contraceptives - Which drugs increase plasma levels of Phenytoin (Dilantin)?
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Diazepam
Alcohol
Cimetidine
*may cause toxicity - Which drugs decrease plasma levels of Phenytoin (Dilantin) to sub-therapeutic levels?
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Carbamazepine
Phenobarb - Which drugs increase the CNS depressant effects of Phenytoin (Dilantin)?
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Alcohol
Barbiturates
CNS depressants - Carbamazepine (Tegretol)
-
- MAINSTAY of epilepsy treatment
- delays recovery of Na+ channels from inactivated state
- HALF-LIFE decreases as therapy progresses (40-->15 hours)
- FEWER side effects than Phenytoin (Dilantin)
- mood stabilizing effects: Bipolar disorder - Adverse effects of Carbamazepine (Tegretol)
-
- Leukopenia, anemia, thrombocytopenia
- vertigo
- nystagmus (rapid eye movement)
- diplopia (double vision)
- birth defects
- Drug interactions of Cabamazepine (Tegretol)
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- Oral contraceptives & grapefruit juice (decrease effects)
- Dilantin (Phenytoin) & Phenobarb (decrease plasma levels to sub-therapeutic levels by increasing metabolism of drug)