Pharm Ch 48 & 53 Neuromuscular Medications

Parkinson’s Disease

• chronic, progressive, degenerative disorder of the CNS characterized by

  • ____Resting______ tremor

  • Bradykinesia (slowness of movement)

  • Rigidity

  • Postural instability

PD Pathophysiology

• Imbalance between Dopamine and Actylcholine results from degeneration of the neurons that supply dopamine 

• Parkinson → degeneration of neurons that supply dopamine in the central nervous system → reduction of Dopamine production → excessive presence of the Acetylcholine → excessive stimulation of the GABA (one of the primary neuro inhibitory neurotransmitter)

Dopamine

• Send information to brain to control body movement and coordination 

PD Symptoms

• Initial: resting tremor that begins in fingers and thumb of one hand

  • Pill-rolling movements

• Bradykinesia (slow movement)

• Inability to move (akinesia)

• Rigid limbs

• Shuffling gait, stooped posture

• Mask-like facial expression

• Soft-speaking voice

PD Less common symptoms

• Autonomic disturbances (altered BP levels & GI functions)

• Depression

• Personality changes

• Loss of appetite

• Sleep disturbances

• Speech impairment

• Sexual difficulty

Primary Goal is of PD…

•  restore the balance between _____dopamine______ and ______acetylcholine_________.

• To improve patient’s ability to carry out activities of daily life

• There is no cure to Parkinson disease

Drugs used to treat Parkinson disease

• increase dopamine levels, 

• stimulate dopamine receptors, 

• extend the action of dopamine in the brain, or 

• prevent the activation of cholinergic receptors (responsible for the acetylcholine level)

Two major categories of PD drugs

• Dopamine receptor agonist/Dopaminergic agents

• Anticholinergic agents

Dopamine receptor agonist/Dopaminergic agents

• The most commonly used drugs for PD.

• → increase the amount of dopamine in the brain via various mechanisms 

Example of Anticholinergic agents

Benztropine (Cogentin)

Benztropine (Cogentin) MOA

• prevent/decrease activation of cholinergic receptors

  •  = less amount acetylcholine available in the body or make those receptors less active

Benztropine (Cogentin) is more effective for

• Secondary drug of choice for PD & mgt symptoms (tremors) of Extrapyramidal symptoms.

  • Extrapyramidal = pyramidal (corticospinal) tract that help control movement, coordination, and posture

• tremor and rigidity.

Benztropine (Cogentin) AE

• CNS (sedation, confusion) &  dry mouth, urinary retention, constipation, aggravate glaucoma

• Have to be very careful in geriatric population because CNS effects can increase risk for falls 

Dopaminergics MOA

• Increase the amount of dopamine in the brain via various mechanisms

• Increase activity of dopamine to help improve the nerve impulse control and decrease symptom of PD

Prototype drug for Dopaminergics is…

• Levodopa-carbidopa (Sinemet, Parcopa).

  • Combination drug

Dopaminergics Contraindications to use with

• Hypersensitivity to medication

• Narrow/close-angle glaucoma 

• Depression

• May activate malignant melanoma/unknown or undiagnosed skin lesion

• Hypertensive crisis, peptic ulcer disease

• Severe cardiovascular, pulmonary, renal, hepatic, or endocrine disorders.

Dopaminergics Preg Cat

• C

  • Have to look at risk vs benefit before patient can use

Levodopa-Carbidopa Pharmacotherapeutics

Combination drug for Parkinson’s disease.

Levodopa-Carbidopa Administered

oral

Levodopa-Carbidopa Metabolized

peripherally

Levodopa-Carbidopa Onset

1 to 2 months.

Levodopa-Carbidopa Half life

1 to 2 hours.

Levodopa-Carbidopa Pharmacodynamics

• Diffuses levodopa into the central nervous system (CNS), where it is converted to dopamine

• Carbidopa - prevent the conversion of levodopa to dopamine in the periphery.

Levodopa (L-dopa) in Parkinson’s Disease Purpose

Levodopa is the main drug used to manage Parkinson’s disease (PD).

Levodopa Mechanism

• Levodopa is a precursor of dopamine.

• It can cross the blood–brain barrier (BBB), unlike dopamine itself.

• Once inside the CNS, levodopa is converted into dopamine, replenishing low dopamine levels in PD.

Levodopa Problem in periphery:

• In the bloodstream, decarboxylase enzymes convert levodopa → dopamine before it reaches the brain.

• This causes most of the levodopa to be inactivated in the periphery, leaving too little available for the CNS.

Solution to Levodopa Problem in periphery:

• Carbidopa inhibits peripheral decarboxylase.

• Prevents premature conversion of levodopa → dopamine in the periphery.

• Allows more intact levodopa to reach the brain.

Combination therapy:

• Levodopa + Carbidopa (e.g., Sinemet) is standard treatment.

• Provides higher CNS dopamine levels with lower doses of levodopa.

• Take several months for full therapeutic effects.

• Highly effective, but benefits diminish over time.

  • After 2-5 yrs of continuous therapy → lose the overall effectiveness in controlling symptoms of PD.

Levodopa-Carbidopa AE

• Nausea, vomiting, anorexia, darken sweat & urine, incr. involuntary movements/dyskinesias, cardio-vascular effects (induce orthostatic hypotension), blurred vision, activate malignant melanoma, bruxism (teeth grinding and jaw clenching) , and ballismus (jerking, movement). 

• Psychosis – hallucination & paranoia

Levodopa-Carbidopa Culture and inherited traits

• The drug is less effective in those of Chinese, Filipino, or Thai descent.

Levodopa-Carbidopa Drug Interactions:

• Decreases the effects of first-generation antipsychotics (Haloperidol; Chlorpromazine); hydantoins (treat epilepsy); TCAs (tricyclic antidepressants). 

• MAOIs → hypertensive crisis 

  • → avoid interactions at least 2 weeks.

• Anticholinergics increase the effects of the med.

Levodopa-Carbidopa Food Interactions:

• Protein & vitamins containing pyridoxine/vit.B6

• Food delays absorption.

• Competing for the absorption rate in the small intestine

• If patient has bad GI symptom, take with small amount of food

Levodopa-Carbidopa Maximizing therapeutic effects

• Take on an empty stomach.

• Monitor diet for high protein and pyridoxine (Vitamin B6).

Levodopa-Carbidopa Minimizing adverse effects

• Administer carbidopa-levodopa at evenly spaced intervals.

  • so that the body can maintain the therapeutic level constantly

Levodopa-Carbidopa Nursing mgt:

• Palliative care is not a cure.

• Monitor for improvement in mobility & ability to perform ADLs.

• Do not crush the sustained-release preparation.

• Do not take multivitamin preparations containing pyridoxine.

• Understand that there are adverse effects of medication such as drowsiness, dizziness, and orthostatic hypotension.

• Change positions slowly to prevent drop in blood pressure.

• Avoid alcohol.

• Take the medication with food to prevent nausea and vomiting.

• Do not take the medication with a high-protein meal.

• Report fainting, light-headedness, irregular heart rate, uncontrolled facial movements, urinary retention, nausea, and vomiting to the prescriber.

• Notify the prescriber of any increase in symptoms such as static gait, altered mobility, and “pill-rolling.”

Dopamine agonists:

stimulate dopamine receptors directly

MAO-B Inhibitors:

• inhibits dopamine breakdown

• MAO-B enzyme is responsible for breaking down the dopamine level in the central nervous system

Oral antiviral Example

Amantadine (Symmetrel)

Amantadine (Symmetrel): MOA

• promotes dopamine release

• alleviate the drug-induced dyskinesias (from levadopa) 

Amantadine (Symmetrel): AE

→ insomnia, daytime fatigue; swollen feet; urinary retention; depression; hallucination.

• should take early in morning

COMT inhibitors:

• enhance effects of levodopa by blocking its degradation 

  • Enzyme in the periphery that would convert the levodopa into dopamine at a lesser extent as compared to the decarboxylase

  • inhibit the COMT enzyme from converting levodopa into dopamine

Dopamine Receptor Agonists Example 1

Pramipexole (Mirapex)

Dopamine Receptor Agonists Example 2

Ropinirole (Requip)

Dopamine Receptor Agonists MOA

• directly activates dopamine receptors by blinding to DA receptors and mimicking action of DA

• Used alone in early PD and with levodopa in advancing PD 

• Maximal benefits may take several weeks.

Dopamine Receptor Agonists AE Monotherapy

• nausea, dizziness, daytime somnolence, insomnia, constipation, weakness, and hallucinations.

Dopamine Receptor Agonists AE Combined (combined with levodopa)

• orthostatic hypotension and dyskinesias and increase in hallucinations.

  • Mostly come from levodopa

• Rare instances of pathologic gambling and other compulsive self-rewarding behaviors.

Pramipexole (Mirapex) Interactions

• Cimetidine (Gi medication) increases the med level

• Metoclopramide (Gi medication) decreases the effects.

Pramipexole (Mirapex) Interventions

• Avoid using with other CNS depressants (alcohol, antidepressants, etc)

• Safety measures

• When d/c (discontinue), need to taper down dosage slowly > 1wk

Catechol-O-methyltransferase (COMT) Inhibitors

• blocking the enzyme COMT, which breaks down levodopa and dopamine

• → incr. levodopa availability.

• No direct therapeutic effects of their own

• Only used in combination w/ levodopa-carbidopa.

COMT inhibitors Example 1

Tolcapone

Tolcapone AE

liver failure, induce CNS effects (confusion, hallucinations, psychosis, dizzyness)

COMT inhibitors Example 2

Entacapone

Entacapone AE

• (safer and more effective) → vomiting, yellow-orange urine.

• also have CNS effects

Stalevo

combination of carbidopa, levodopa and entacapone

Patient Teaching Guidelines for Tolcapone

• Do not stop the medication abruptly; taper it over 2 weeks.

• Take the medication in conjunction with levodopa–carbidopa.

• Use barrier contraceptives while using this medication.

• Do not breast-feed while taking the medication.

• Use caution when operating machinery due to central nervous system (CNS) depression.

• Use hard candy to decrease dry mouth.

• Have liver function tests as scheduled.

• Avoid concurrent use of alcohol or other CNS depressants.

MAO-B Inhibitors Prototype

Selegiline (Eldepryl, Zelapar)

Selegiline (Eldepryl, Zelapar) MOA

• inhibit the breakdown of Dopamine

• Second/third-line drugs for treatment of PD

• Combination with levodopa – reduce the wearing-off effect. 

Selegiline (Eldepryl, Zelapar) AE

• insomnia

  • Take early in day

Selegiline (Eldepryl, Zelapar) Interactions

• Meperidine & other opioids → high fever & rigidity

• Hypertensive crisis (w tyramine containing products or herbals-St.John’s wort, ginseng).

• Hypotension-when taken w antihypertension, diuretics & general anesthetics.

PD Nursing Implications

• The drug therapy is palliative not to cure the disease.

• Coordinate counseling and physical & occupational therapy to optimize therapeutic outcome.

PD Nursing diagnoses

• Impaired Physical Mobility; or Risk for Injury, knowledge deficits 

PD Patient/Family Education

• would take several weeks to several months for a patient to notice to feel the benefit

PD On going assessment 

• Would take several weeks to several months for a patient to notice to feel the benefit

• Be sure that patients take their medication as prescribed, 

• Change position slowly, monitoring blood pressure.

• Notify provider if they notice any uncontrollable movement, indicate patient not experiencing the therapeutic effect of the medication anymore

• Notify the doctor if they experience any kind of cardiovascular symptom

• Educate patients avoid or minimize any high-protein diet

Epilepsy

• a brain disorder, characterized by recurrent seizures

  • From excessive excitability of neurons 

Seizures

• are loss of consciousness with generalized muscle twitching or mild alterations in consciousness with repetitive blinking.

• → Treated with antiepileptic drugs (AEDs).

Seizures Physiology

• Action potentials within neurons are initiated by an influx of sodium into the cell.

• Influx of calcium through specialized voltage-dependent channels also plays a role in creating an action potential.

• When the cell fires → release of neurotransmitters into the synaptic cleft.

• The neurotransmitter glutamate produces excitation (excitatory postsynaptic potentials / stimulation of the next neuron)

Glutamate

• neurotransmitter

• produces excitation (excitatory postsynaptic potentials / stimulation of the next neuron)

GABA

• GABA – acts as a inhibitory counterpart_____ to glutamate, preventing over-excitation / excessive neuronal firing

A Focus Pathophysiology

• when a group of neurons exhibits coordinated, hi-frequency discharge → caused by head trauma, tumor growth, hypoxia, and inherited birth defects.

Seizures Pathophysiology

• when the activity from a focus spreads to other areas of the brain → hyperactivity.

• Seizures may result from either high levels of glutamate or low levels of GABA.

Partial seizures Pathophysiology

• when focus activity is limited to an area of the brain.

Generalized seizures Pathophysiology

• when the focus activity is within both hemispheres.

Partial (focal) seizures: Simple partial

• Symptoms depend on the part of the brain affected; 

  • motor symptoms (twitching thumb); sensory sx (local numbness); 

  • autonomic (nausea, urinary incnt); 

  • NO LOSS of consciousness; these last 20-60sec.

Partial (focal) seizures: Complex partial

• w impaired consciousness & lack of responsiveness.  

  • At the onset the pt becomes motionless and stares w a fixed gaze w lip smacking; 

  • these last 45 -90sec.

Partial (focal) seizures: Secondary generalized

• begin as simple or complex sz, and then evolve into generalized tonic-clonic sz w Loss of Consciousness; 

  • these sz last 1-2mins

Generalized seizures: Tonic-clonic (grand mal)

• loss of consciousness; jaw clenching; muscle contraction alternating w muscle relaxation; & period of cyanosis.

Generalized seizures: Absence (petit mal)

• loss of consciousness briefly w eye blinking and staring into space.

Generalized seizures: Atonic

• sudden loss of muscle tone.

Generalized seizures: Myoclonic

• sudden contraction that may be limited to one limb or involve entire body.

Generalized seizures: Status epilepticus (SE)

lasts >30mins.

Generalized seizures: Febrile

common in 6m-5yr w  hi fever develop generalized tonic-clonic convulsion of short duration.

Antiepileptic Drugs works in 3 main ways…

• Decreasing the rate at which sodium flows into the cell.

• Inhibiting calcium_ flow rate into the cell through specific channels.

• Increasing the effect of the neuroinhibitory gamma-aminobutyric acid (GABA)

Antiepileptic Drugs that Decrease Sodium Influx: Drug class

Hydantoins

Antiepileptic Drugs that Decrease Sodium Influx: MOA

Control seizures by decreasing sodium influx into the cells

Antiepileptic Drugs that Decrease Sodium Influx: Prototype drug

phenytoin (Dilantin)

• Do not change Brand name without consulting with the physician!!

phenytoin (Dilantin) MOA

Decrease Sodium Influx

phenytoin (Dilantin) Indications

For partial and generalizes sz.

phenytoin (Dilantin) Therapeutic range:

10 – 20 mcg/mL

Phenytoin (Dilantin) Contraindications and precautions

• Bradycardia and heart block.

• Preg. Cat. D & lactation

Phenytoin (Dilantin) AE

• Drowsiness, slurred speech, dizziness, mental confusion, tremor, gingival hyperplasia, cardiovascular effects (w fast IV), risk of suicidality.

Phenytoin (Dilantin) Toxicity

• (> 20mcg/mL):

  • Nystagmus, ataxia, sedation, blurred vision/diplopia, cognitive impairment, bone marrow suppression, N/V.

Phenytoin (Dilantin) Nursing consideration

• Never mix with other IV med or dextrose 

• Take the med with at least a glass of water or with meals 

• Sweat and urine may turn red-brown or pink 

• Good oral hygiene 

• ETOH can increase serum levels 

Phenytoin (Dilantin) Drug interactions

• decr. the effects of Oral Contraceptives (OCs), Warfarin, and Glucocorticoids.

• Amiodarone, Chloramphenicol, Omeprazole, Ticlopidine, & Alcohol (chronic use) → can incr. plasma levels of the drug / increase toxicity level

• Enteral feedings → can decr. levels of the drug. 

Phenytoin-Nursing Considerations

• Meds must be taken regularly

  • Taking the med at same time everyday help maintain therapeutic blood levels of the drug.

• Avoid stopping the meds abruptly.

  • To reduce risk of developing status epilepticus ( can cause permanent damage to body or death) 

• If IV, infuse at no faster than 50mg/min.

  • Too fast can cause CV (cardiovascular) collapse 

• Only compatible w/ NS.

  • Don’t mix with any other medication or fluids 

• Precautions when administer med via feeding tube.

  • More medication will be bound to feeding (because it has lots of protein), so patient will be under therapeutic

  • turn TF off 1 hour before adm, and leave off for 1 before restarting TF

  • Flush before and after giving med

  • If the med is in SUSPENSION form → shake the suspension well before measuring the dosage.

• May take w food for GI distress.

• Monitor for drug/drug interactions.

• Monitor renal and hepatic functions.

• Evaluate therapeutic responses.

  • How many seizures have occurred in a month, etc

• Safety measures.

  • In prolonged malnourishment -- the drug free levels incr from PROTEIN DEFICIT.

Carbamazepine (Tegretol)

Suppresses the inflow of sodium into the cell

Carbamazepine (Tegretol) Therapeutic range

4 – 12 mcg/mL

Carbamazepine (Tegretol) Uses

• Most effective against partial seizures with complex symptoms.

• Also used to manage bipolar; trigeminal neuralgia; diabetic neuropathy.

Carbamazepine (Tegretol) AE

• Neuro effects: nystagmus, ataxia, HA (headache)

• Dizziness, drowsiness, unsteadiness, N/V/D. fluid retention (><HF, renal failure).

• Hematologic effects: anemia, thrombocytopenia, agranulocytosis.

  • → need baseline CBC and periodically.

• Increase LFT (liver function test) to detect hepatic failure 

Carbamazepine (Tegretol) Contraindications/Precautions

• Pregnancy category D

• Asian descent (w HLA-B 1502 gene)  → increase risk for Steven Johnson syndrome; toxic epidermal necrolysis.

• Is preferred over phenytoin

• Assess hepatic function to check for hepatic adverse effects, including hepatic failure.

• Neurologic effects can be minimized w initial low doses and taken toward bedtime

Carbamazepine (Tegretol) Interactions

• Grapefruit incr. peak & trough levels.

• Erythromycin, cimetidine, isoniazid, & verapamil incr. the drug level (toxicity level)

• Phenobarbital, theophylline, & phenytoin reduce the effects of the med.

• Carba can cause false neg preg test and decreases the effects of OCP.