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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
- 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)
- 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
- used in newly diagnosed patients with mild symptoms
- adverse effect: insomnia
- give at breakfast/noon to prevent insomnia
- amphetamine metabolites derived

- promotes release of dopamine
- blocks reuptake of dopamine
block MUSCARINIC receptors in the striatum
2 Loss Effects that accompanies Levodopa
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
- 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

- 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

- 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

- 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

- prevents breakdown of Levodopa
- COMT inhibitor
Levodopa + Carbidopa
a group of disorders characterized by excessive excitation of neurons within the CNS
(usually chronic condition)
general term applied to all types of epileptic events
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
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
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
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

sudden muscle contractions (1 limb or whole body)
- lasts 1 second
Tonic Clonic (grand mal)
- neuronal discharge spreads throughout entire cerebral cortex
- ex. major convulsions, muscle rigidity, jerking, incontinence, loud cry, CNS depression (postical state)
Absence (petit mal)
- brief loss of consciousness
- lasts 10-30 seconds)
- may or may not have motor activity

- 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
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?
1. Carbamzapine
2. Phenytoin
3. Valproic acid

What meds should be taken for absence seizure?
1. Ethosuximide
2. Valproic acid
What meds should be taken for myoclonic seizures?
1. Clonazepam
2. Valproic Acid
Nursing interventions for people taking anti-epileptics
- 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)
- 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)?
Oral Contraceptives

Which drugs increase plasma levels of Phenytoin (Dilantin)?

*may cause toxicity

Which drugs decrease plasma levels of Phenytoin (Dilantin) to sub-therapeutic levels?
Which drugs increase the CNS depressant effects of Phenytoin (Dilantin)?
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)
- Oral contraceptives & grapefruit juice (decrease effects)
- Dilantin (Phenytoin) & Phenobarb (decrease plasma levels to sub-therapeutic levels by increasing metabolism of drug)

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