Neuro Pharm Flashcards
Why is skeletal muscle pharmacology important for PT
our treatments rely on control of muscle spasms and spasticity
what does spasticity involve
- exaggerated muscle stretch reflex that is velocity dependent
- involves diminished supra-spinal inhibition or control secondary to lesion of SC or brain
What is spasm
- increased and involuntary muscle tension seen after musculoskeletal injury
- Involves afferent, nociceptive input from peripheral pain receptors, causing excitation of outflow to muscles
Seth wants you to know GABA pathway
its on slide 5
mechanism of muscle spasm
a pain reflex results in increased muscle activity (tone)
targets of frugs for muscle spasm
- alpha motor neuron or supra-spinal neurons that activate alpha motor neurons
Two sub-classes of anti-spasm medications
- benzodiazepines
- polysynaptic inhibitors
Benzodiazapines
Diazapam (Valium) and a few others
All stimulate GABA-ergic synapses on SC alpha-motor neurons
Indications: musculoskeletal injuries such as LB
Polysynaptic Inhibitors
Cyclobenzaprine (Flexeril) & methocarbamol (Robaxin) or in preparation with analgesic: Norgesic (orphenadrine combined aspirin)
Function as general CNS relaxants, but have no specific effects on alpha-motor neurons
Often used as adjunctive Rx with rest and PT
Side effects of anti-spasm agents
- primary side effects: drowsiness, sedation, and dizziness
- Tolerance (long term)
- Addiction: not recommended for long term use
Very important side effect of valium and muscle relaxants
- anterograde memory loss
- esp valium
- don’t count on pt remembering instructions
what is epilepsy
neurological condition in which the brain experiences seizures or episodes of intense
involuntary and synchronized neuronal activity
What are seizures?
Spontaneous burst of neuronal activity caused
by a group of neurons (or focus) that are
“hyperexcitable” or “irritable”
Status Epilepticus
- a state of “continual seizure activity” brought on by withdrawal of antiepileptic drugs, ETOH or drug withdrawal, CVA or severe intracranial infection
- Seizures activity > 5 minutes or seizures occurring so close together the patient does have time to recover from the previous one
Are seizures usually “self-limiting?”
Yes - except in Status Epilepticus
the high level of neuronal activity can’t be sustained and neurons become refractory
most seizures do not last longer than 2 minutes. The longer a seizure lasts, the less likely it will stop on its own without medication. Very long seizures (i.e., status epilepticus) are dangerous and increase the chance of permanent brain damage or deat
Harmful Seizures:
uncontrolled seizures may damage healthy and already injured neurons
potential for fall or accident
cardiac arrhythmia or cardiac arrest
* sidelying is the safest position
What do drugs for seizure disorder focus on?
- suppressing the excitability of cortical neurons that trigger the seizure by promoting inhibitory effects of GABA or decreasing Na+ ion permeability – both result in decreased depolarization
GABA
gamma-aminobutyric acid (GABA): inhibitory NT found throughout the brain
most drugs that suppress seizures work by enhancing the action of GABA
Side Effects of Antiepileptics (& sedative-hypnotics/anxiolytics)
Drowsiness/sedation is the primary side effect
Ataxia & dizziness
Antero-grade memory loss (especially w/ valium)
Memory loss period related to half life of drug
Cognitive effects with Topiramate
Barbituates:
- Pentobarbital (Solfoton). This class of drugs are given for nearly all seizures, but work best for “grand mal” type
All increase inhibitory effect of GABA, may block excitatory effect of glutamate
Side Effects of Barbituates
- sedation, ataxia, nystagmus, folate &
Vit-K deficiency
May paradoxically increase seizures and hyperactivity in children
Benzodiazepines
- Diazepam (Valium) works best for “status epilepticus”, Clonazepam (Klonopin) works best for absence or petit mal
Side Effects of Benzos
sedation, ataxia, behavioral changes
Carboxylic Acids
- Valporic acid (Depakene) used to Rx partial seizures in adults & children
- Increase GABA effects
Side Effects of Carboxylic Acids
hair loss, wt gain /loss, bleeding & GI problems
Hydantoins
- Phenytoin (Dilantin): often first drug
used for focal onset & tonic-clonic seizures. - Phenacemide (Phenurone) Rx seizures that
don’t respond to other medications. Both
decrease excitability by impairing Na+ entry
Side Effects of Hydantoins
cerebellar signs (nystagmus, ataxia, dysarthria, mild sedation, peripheral neuropathy and diminished reflexes
Tricyclic
Carbamazepine (Tegretol): Impairs Na+ entry – good for focal seizures
Tricyclic Side Effects
GI distress, dizziness, ataxia, visual disturbance – not as much sedation
New 2nd Generation Anti-Epileptics Characteristics
Slight advantage due to fewer side effects
Not as effective with mono use - Used as adjunct to other anti-epileptics to decrease dose
2nd Generation Anti-Epileptic Drugs
Topiramate (Topomax): blocks Glutamate
neurotransmission and decrease Na+ movement Gabapentin (Neurontin): increases inhibitory
effect of GABA
Same side effects as other common anti-
epileptics, but slightly milde
Rehabilitation and Epilepsy Pharmacology
Aware of potential risk of a seizure
Seizure control versus sedation relationship in
the patient
Ataxia as side effect versus result of illness
Exacerbation of seizures by physical stimuli
Ataxia as a side effect versus result of illness:
patients with TBI or CVA may require balance or coordination exercises, but performance may be limited by the medication or they may need even more Rx secondary to the medication
What is Parkinson’s disease characterized by:
resting tremor (4-5/sec)
bradykinesia (slow movement)
akinesia (impaired ability to initiate movement)
rigidity
postural instability (maintain low posture)
microphonia (decreased voice volume)
mask like, expressionless face
When does Parkinson’s disease begin
Begins in 5th or 6th decade (1% of pop > 60)
progressive over 20-30 years, leading to complete incapacitation
3 Types of Drugs used to treat PD
- Dopamine Precursor
- Anticholinergic
- Dopamine Agonist or Stimulators
Dopamine Precursors
Levadopa (L-dopa): primary drug to treat PD –> dopamine precursor that crosses BBB
Sinemet (1:4 or 1:10 levadopa : carbadopa)
Carbadopa (DC-inhibitor)
Anticholinergic Drugs to treat PD
Benzotropine
Dopamine Agonist or Stimulators to treat PD
Bromocriptine
Selegiline MAO inhibitors
Levodopa Characteristics
- 1-3% crosses BBB & converted to dopmaine (by dopa carboxylase), so large quantities must be
given - dramatic improvement in symptoms in most cases, but not all patients respond or can tolerate it
What should Levodopa be given with?
- peripheral decarboxylase inhibitor
(carbadopa) (Sinemet) - Allows more to get to brain.
Side Effects of Levodopa
- GI Problems: N & V (milder when given with carbadopa)
- Cardiac Arrhythmia (caution with exercising)
- Orthostatic Hypotension (quite severe at beginning)
- Dyskinesia: 80% –> begins 3-7 months after beginning
- Behavioral Changes: depression, anxiety, confusion, hallucinations, esp in older adults (worse with carbidopa)
- Diminished Response: 2-3 years after beginning
Fluctuations in response to levodopa
End-of -dose akenesia: wears off prior to next
dose
On-off phenomena: abrupt change in
responsiveness
Drug holiday for Levodopa
restores effectiveness, but depends on pt and
may not last
Risk of death w/ sudden withdrawal of
levadopa - thus not used commonly
Anticholinergics for PD
- Treats rigidity and tremor
- Benzotropine
Benzotropine Side Effects
N &V, blurred vision, confusion, dry mouth,
hallucinations, sedation, cardiac irregularities
Dopamine Agonists or Dopamimetics to treat PD
- Bromocriptine: used with Levodopa or when Levodopa becomes ineffective
- Selegiline: Inhibits MAOb and dopamine breakdown
How do Dopamine agonists affect side effects?
- may provide same benefits in terms of alleviating symptoms, but with fewer side effects compared to L-Dopa or Sinemet
Many of the D-agonists are longer acting
than L-Dopa and can be given 2 times/day rather than 3 or 4 times/day.
Future research on D-R subtypes may allow
for even better control of symptoms without side effects.
Controversy about when to begin levodopa
should it be saved until symptoms are severe since it looses effectiveness?
should it be started w/ symptoms since decline in
drug effectiveness is actually due to disease
progression?
Tissue Transplantation in patients with PD
- surgically implant dopaminergic cells into substantia nigra
source of cells: human fetus mesenchymal tissue difficulty in procedure (keep cells alive, implant them w/o further damage to brain, keep them from
differentiating)
PT with PD Pharmacology
- Coordinate with peak (Levodopa and Sinemet peak in 1 hr)
- Need PT during drug holiday to prevent decline in function
- Be aware of side effects: monitor BP and behavioral changes
What has optimal beneficial effect for patients with PD
PT combine with drug therapy
Side effects of Alzheimer’s disease Pharmacology
- Indirect Cholinergic Stimulants
Similar to the old drug neostigmine and other
cholinesterase inhibitors – only work early in
disease process
Caution in patients with bradycardia, hypotension, and asthma
Side effects: commonly produces N&V and
diarrhea, liver dysfunction, muscle cramps,
anorexia, headache & insomnia
Things about Neuropharmacology and PT
- Neuropsychiatric symptoms and the drugs used to control them can and often impact therapy outcomes.
- Use of the biopsychosocial model can aid in developing a complete approach to patient care - Biological / chemical aspect of mental illness, Psychological/ behavioral aspect, Social/ real world aspect
- Psychotropic drugs are “partially” effective, numerous, and treat specific symptoms rather than syndromes
How many patient who suffer a “major” illness experience some level of depression in the months following?
up to 90%
For which patent population may the degree of depression be even more severe?
CVA, amputation, heart attack, SCI
Theories of Depression Pathophysiology
- Lack of amine neurotransmitters – norepinephrine and serotonin – leads to increased sensitivity of amine serotonin, dopamine & norepinephrine) receptors
- Impaired formation of new neurons – deficiency in trophic support for neurons (BDNF) stress and pain decrease BDNF
- Hormonal abnormalities – increased HPA axis – increased CRH & ACTH levels
3 types of anti-depressant drugs
- Tricyclics Antidepressants
- Monoamine Oxidase Inhibitors
- 2nd Generation Antidepressants (SSRIs and SNRIs)
How do Tricyclics Antidepressants work?
block re-uptake of amine NT into presynaptic membrane
How do Monoamine Oxidase Inhibitors work?
-block enzymatic breakdown of amines
-Not used today secondary to adverse side effects
How do 2nd Generation Antidepressants work?
-block amine NT (serotonin and/or norepinephrine) re-uptake or increase serotonin levels
-more rapid onset
-fewer side effects
How long do antidepressants take for full effect?
- 2 weeks or longer
- Fluoxetine (Prozac): 5 days - 5 weeks
- Sertraline (Zoloft): 2-4 Weeks
Serotonin Syndrome
Toxic reaction to excessive build up of serotonin
May occur when two SSRIs are taken together
Agitation, HTN, diarrhea, tachycardia, LOC, hyperthermia, hallucinations, ataxia, N&V & hyper-reflexia.
Potentially fatal
Side Effects of Antidepressants
Sedation
Central & peripheral anti-cholinergic activity (dry
mouth, constipation, confusion & delirium)
Arrhythmia
Orthostatic hypotension
Restlessness, sleep disturbance, irritability, agitation
HTN (hypertensive crisis)
Do 2nd Generation Antidepressants have any advantage over the other types of meds?
- nope just fewer side effects
- may exacerbate depression/suicidal ideation
Off Level Uses of Antidepressants
- Pain
- OCD
- ADHD
- Anxiety Disorder
How can antidepressants help pain?
- Depression linked to “helplessness” due to intractable pain or physical limitations
Even when no symptoms of depression are present, patients with chronic pain report improvement with anti-depressant therapy
improved sleep patterns or alter the
patient’s perception of pain
What do anxiety disorders include?
panic and social anxiety disorders, generalized anxiety, OCD and post-traumatic stress disorder
50% of hospitalized patients are prescribed what?
Anxiolytic Agents (anti-anxiety)
What are well recognized complications of TBI
Anxiety and OCD
OCD is related to many different conditions:
over-eating, panic disorders, repetitive hand-
washing compulsions, etc
Sedative-Hypnotic Drugs
- Used to Rx anxiety: induce relaxation (sedation),
sleep (hypnosis) & anesthesia - Most sedative-hypnotics have anesthesia effects
at high doses: act as “CNS-depressants”
Why are many patients prescribed sedative-hypnotic drugs in rehab?
Due to apprehension caused by either the injury itself or rehabilitation/hospitalization (esp for TBI)
Barbituates Facts
narrow therapeutic
highly addictive
tolerance (liver enzymes)
lipid soluble (fat storage, hang-over & retro amnesia)
acts on GABA- benzodiazapine-Cl-receptor, also inhibit pre-synaptic NT release
Benzodiazepines Facts
- Broader Therapeutic Window
- Addictive
- Moderate Tolerance
- Lipid soluble (fat storage, hang-over and retro-amnesia)
- GABA-Benzodiazapine-Cl-channel
What is the prototype of Benzodiazepines
- Valium
- Sedative properties at low dose, preferentially affect limbic system
Limitations of Benzodiazepines
“Relatively safe” compared to barbiturates –> preferentially bind GABA-Cl- channels in limbic
system, rather than in reticular activating system, so less hypnosis
Due to lipid solubility, hangover and
retrograde amnesia are still a problem
Caution when giving these drugs to patients who are depressed secondary to potential
for suicide
Other anti-anxiety Medications
- Sedative Hypnotics: Azapriones (Busprone or BuSpar)- serotonin agonist –> Useful for anxiety associated with OCD, post-traumatic stress, panic disorders
- Beta-Adrenergic Blockers (Propranolol etc…) –> Help control physical signs of anxiety and “anticipatory” anxiety
- Anti-depressants (SSRIs) –> useful for OCD and panic disorder
Anti-Anxiety Meds and Rehab
All tend to cause sedation, lethargy and somnolence –> need to be titrated to minimize does to achieve anxiolytic effect.
Drug interactions are common when more than one anxiolytic agent is used or with any CNS depressants.
Hangover and retrograde amnesia are problematic
Addiction and abuse
Rebound anxiety when discontinued
Scheduling: 2-4 hour peak action, so schedule
therapy accordingly
What is Psychosis:
Group of severe mental illnesses characterized by
marked thought disturbance & impaired
perception of reality
Schizophrenia: affects 1 % of population
Paranoid disorders
Psychotic depression
Often associated with TBI and less often CVA- 48% of patients with TBI in acute care setting received neuroleptics
What is pharmacology associated with?
- Excessive dopamine activity
- Based on findings that D-R blockers have beneficial effect
- Most anti-psychotics are dopamine receptor blockers
- Atypical anti-psychotics block both dopamine and serotonin
Dopamine facts
~ Fluidity of movement (in BG, cerebellum)
~ Fluidity of thought
~ Satisfaction
~ Repetition drive
Traditional Anti-Psychotic Drugs
Dopamine receptor antagonists:
Haloperidol (Haldol)- high potency D-R blocker
Chloropromazine (Thorazine)- lower potency
Both are associated with “extra-pyramidal side effects” –> Dystonic reactions, akathisia, tardive dyskinesia
Second Generation or Non-Traditional Anti-psychotic Drugs
distinguished by side effect profile, not
mechanism
Clozapine (Clozaril)
Risperidone (Risperdal)
Fewer side effects and help with affect and “resistance
Dopamine Excess vs. Dopamine Deficiency
Excess: psychosis, schizophrenia
Deficiency: PD and pseudo PD
What is the most common neuroleptic prescribed for patients with TBI
Haloperidol - member of Butyrophenone family
Pharmacokinetics of Anti-psychotics
For an acute psychotic episode, high dose is
given orally 4 x /day, or intramuscularly
Cut back to a maintenance dose
Some tolerance develops
Side effects usually begin after 12 months and
become progressively worse w/ use
Antipsychotics may be given to help w/ GI side
effects of Parkinsons medication
Extrapyramidal Symptoms of Anti-psychotics
motor side effects resulting from alterations in dopamine imbalance in basal ganglia
tardive dyskinesia: involuntary and fragmented movements (15 - 20%)
in some patients symptoms stop when drug is
stopped, but in some patients, irreversible
“disuse” super-sensitivity of dopamine R’s in BG
mouth, tongue & jaw movements
choreoathetiod movements of limbs
dystonia of trunk & neck
Pseudoparkinsonism
Akathisia: motor restlessness
Dyskinesia and dystonia: bizarre movements of limbs or neck
Neuroleptic malignant syndrome
Pseudoparkinsonism from Anti-Psychotics
PD caused by lack of dopamine transmission in substantia nigra motor synapses
Antipsychotics deplete dopamine or interfere with dopamine neurotransmission
resting tremor, bradykinesia and rigidity (especially in elderly), but usually reversibly
What is Neuroleptic Malignant Syndrome
catatonia, stupor, rigidity, tremor occurring with high doses
- Mortality: 25%
- Affects males <40
Time of Onset of Extra-Pyramidal Side Effects:
Days 1-3: Acute Dystonic Reactions
Day 3: Akathisia
Day 5: Pseudo-Parkinsonism
Day 90: Tardive Dyskinesia
Tardive Dyskinesia due to anti-psychotics
- Protrusion of Tongue
- Puffing of Cheeks
- Chewing Movements
- Involuntary Movements of Extremities
- Involuntary Movement of Trunk
Non-Motor Side Effects of Anti-Psychotics
Sedation: all have sedative properties
Anticholinergic affects (dry mouth, constipation, urinary retention, blurred vision)
Orthostatic hypotension (with initiation of Rx)
Light sensitivity
Withdrawal symptoms (GI distress, N&V)
Special Concerns for Anti-Psychotics and Rehab Patients
These drugs can help improve the patient’s
performance in therapy as well as outcome
secondary to improve cooperation, attention,
compliance, etc.
Need to be aware of serious side effects: Orthostatic hypotension, extra pyramidal motor side effects, neuroleptic Malignant Syndrome
Two Categories of Neuro-Stimulants
Amphetamines
Parasympathomimetics (cholinergic stimulants)
What are Neuro-Stimulants used for?
Patients with attention deficit disorder
Slowed cognitive function
Delirium
Dementia
Amphetamines: Methylphenidate (Ritalin)
- Indirect Acting sympathomimetic (amphetamine)
- Blocks re-uptake of norepinephrine at alpha and be a adrenergic synapses and increases dopamine activity
- Affects RAS & cortex in CNS
- Mild CNS stimulant
- Potential for abuse
- Many CNS side effects: most notably nervousness, insomnia, changes in BP and HR
- More commonly prescribed for children, but increasingly used in adults
Effects of Amphetamines
- Increased use-dependent neuroplasticity following a TBI in humans with d-amphetamine
- Potential benefit for both patients with TBI and CVA
- Present problem when BP control is an issue
How do drugs for MS work?
stimulate the immune system to slow the degeneration of the neurons (Interferons/anti-virals)
Common adverse effects of drugs for MS
flu-like symptoms, nausea, fatigue, weight loss, hematological toxicities, elevated transaminases, and psychiatric problems (e.g., depression, suicidal ideation)
