Pharm: Neurodegenerative, movement disorders, and anti-epileptic Drugs Flashcards
What are the characteristics of Idiopathic Parkinson’s Disease?
- Muscle rigidity
- Tremor (at rest)
- Bradykinesia
- Postural instability
- Shuffling gait
What is the pathophysiology of Idiopathic Parkinson’s Disease?
- death of DA neurons in substantia nigra pars compacta
- Decreased DA in striatum
- (-) direct pathway (which stimulates movement)
- (+) indirect pathway (which inhibits movement)
Levodopa/ Carbidopa (Sinemet)
- IND
Idiopathic Parkinson’s Disease
Levadopa
- MOA
- IND
- SE
- MOA
- Synthesized to DA by LAAD
- need pyridoxine (B6)
- Increase DA in brain
- Synthesized to DA by LAAD
- IND
- IPD
- SE
- Vomiting (DA at area postrema)
- Dyskinesias
- choreathetosis of face, distal extremities
- Psychosis
- Treat with clozapine
- Cardiac dysrhythmias
- metabolism in periphery causes increased catecholamines
- Loss of effect after about 5 years
Carbidopa
- MOA
- IND
- MOA
- inhibits peripheral metabolism of levodopa by inhibiting DOPA decarboxylase
- Decreased side effects in periphery
- increased half life of L-DOPA
- IND
- IPD with L-DOPA treatment
What competes for the same transporter as Levadopa in the GI and can inhibit uptake of the drug?
Amino acids
(absorption by saturable amino acid transporter
Levodopa metabolism
What drug is indicated for psychosis resulting from Levodopa treatment of IPD?
Clozapine
COMT inhibitors (Stalevo)
- MOA
- IND
- SE
- Tolcapone, entacapone
- MOA
- inhibits COMT in the periphery
- increases levodopa in brain
- IND
- IPD when patients start to experience “off” periods to levodopa/ carbidopa
- SE
- Same as levodopa due to increased lvls
- diskinesia
- vomiting
- psychosis
- Same as levodopa due to increased lvls
Non-ergot derivatives, DA agonists
- MOA
- IND
- SE
- MOA
- D2 receptor agonists
- increases the “on” time with levodopa
- inhibits indirect pathway
- D2 receptor agonists
- IND
- IPD (used w/ or w/o levadopa)
- Restless leg syndrome
- SE
- Daytime somnolence
- Sleep attacks
- Hallucinations
- Dyskinesia when used w/ levadopa
- Orthostatic hypotension
Ergot derivatives, DA agonists
- MOA
- IND
- SE
- MOA
- D2 receptor agonist
- IND
- not used in US due to association with valvular heart disease
- SE
- valvular heart disease
- Pulm Fibrosis
- Raynaud-like phenomena
- Orthostatic hypotension
Selegiline
- MOA
- IND
- SE
- MOA
- selective MAO-B inhibitor
- Increased lvls of DA in neuron
- IND
- Parkinsons
- SE
- exacerbate Levodopa SEs
- Insomnia (stimulant metabolite)
- Seizure at high dose
- CON: epilepsy
Benztropine
- MOA
- IND
- SE
- MOA
- M1 receptor antagonist in corpus striatum
- stimulates GABA-ergic outflow
- IND
- Tremor, some rigidity in parkinson’s
- SE
- Antimuscarinic SEs (think atropine)
- Closed Angle Glaucoma
- Neuroleptic Malignant Syndrome
- CNS: sedation, hallucinations
Amantadine
- MOA
- IND
- SE
- MOA
- Stimulates release of DA from neurons of the nigra striatum
- IND
- Diskinesia in late Parkinson’s
- SE
- Anticholinergic
- Livedo reticularis: skin discoloration
What drugs are used for early wearing off of levodopa effect in Parkinson’s?
- Adjust levodopa (change dose, timing)
- Add dopamine agonist
- Add COMT inhibitor, MAO B inhibitor
What is used to treat dyskinesia of Parkinson’s?
- Reduce levodopa dose
- add or increase dopamine agonist
- add amantadine
What is used to treat tremor in Parkinson’s?
Benztropine (M1-receptor antagonist)
What is used to treat freezing in Parkinson’s?
- apomorphine (non-ergot DA agonist)
- orally disintegrating L-dopa
What are the characteristics of dystonias?
- sustained muscle contractions
- twisting and repetitive movements
- abnormal postures
What are the characteristics of spasticity?
Stiff or rigid muscles with exaggerated, deep tendon reflexes
UMN disorder
What drug is used to treat spasticity associated with MS?
Baclofen
Baclofen
- MOA
- IND
- SE
- MOA
- GABA-B receptor agonist
- inhibits reflex at spinal level
- IND
- spasticity associated with MS
- SE
- Sedation
- Withdrawal: seizures and acute psychosis
- CON: spasm from rheumatic disease
Dantrolene
- MOA
- IND
- SE
- MOA
- inhibits Ca2+ release from the sarcoplasmic reticulum in muscle
- decouples excitation - contraction
- muscles relax
- IND
- Spasticity
- Neuroleptic Malignant Syndrome
- Malignant Hyperthermia
- SE
- CNS effects: speech and visual disturbance
- Hepatitis (Hepatotox)
Botulinum Toxin (Botox)
- MOA
- IND
- SE
- MOA
- Toxin
- inhibits vesicle binding to presynaptic membrane
- IND
- Focal dystonia
- Upper limb spasticity
- VII nerve disorders
- SE
- asthenia (weakness)
- Dysphagia and breathing difficulties (treatment of cervical dystonia)
Tizanidine
- MOA
- IND
- SE
- MOA
- centrally-acting alpha-2 adrenergic agonist
- increases presynaptic inhibition of motor neurons
- Less muscle weakness than baclofen and benzodiazepines
- IND
- spasticity
- fibromyalgia
- migraine
- anticonvulsant
- SE
- Hepatotox (hepatitis)
What is the advantage of using Tizanidine to treat spasticity instead of Baclofen?
Less muscle weakness
What are the characteristics of Huntington’s disease?
- Motor Signs
- Chorea
- dysarthria/ dysphagia
- bradykinesia
- Mental:
- personality changes
- Depression
- Dementia
- Psychosis
- Chemical cause:
- Degeneration of GABAergic neurons in the striatum
What drug is used to treat chorea, like that found in Huntington’s disease?
Tetrabenazine
Tetrabenazine
- MOA
- IND
- SE
- MOA
- Inhibits VMAT2 (uptake of monoamines into vesicles)
- Depletes monoamine stores
- IND
- Chorea
- SE
- Sedation
- Insomnia
- Akathisia (restlessness)
- Depression
What are the characteristics of Alzheimer’s Disease? Pathology?
- Signs:
- Loss of memory
- Impaired thinking
- Inability to perform daily tasks
- Path:
- Loss of cholinergic neurons
Donepezil
- MOA
- IND
- SE
- MOA
- AChE inhibitor
- increases ACh at the synapse
- IND
- Alzheimer’s
- improves quality of life but does not slow progression
- SE: Cholinergic effects:
- GI: vomiting, dyspepsia
- CV: syncopy, headache
- Resp: bronchoconstriction
- CNS: tremor, restlessness
Rivastigmine
- MOA
- IND
- SE
- MOA
- AChE inhibitor
- increases ACh at the synapse
- IND
- Alzheimer’s
- improves quality of life but does not slow progression
- SE: Cholinergic effects:
- GI: vomiting, dyspepsia
- CV: syncopy, headache
- Resp: bronchoconstriction
- CNS: tremor, restlessness
Galantamine
- MOA
- IND
- SE
- MOA
- AChE inhibitor
- increases ACh at the synapse
- IND
- Alzheimer’s
- improves quality of life but does not slow progression
- SE: Cholinergic effects:
- GI: vomiting, dyspepsia
- CV: syncopy, headache
- Resp: bronchoconstriction
- CNS: tremor, restlessness
Memantine
- MOA
- IND
- SE
- MOA
- NMDA receptor antagonist
- IND
- moderate to advanced Alzheimer’s
- SE
- headache
- confusion
- constipation
Riluzole
- MOA
- IND
- SE
- MOA
- Decreases glutamate release
- Inhibits Na and Ca channels
- IND
- ALS (lengthens survival)
- SE
- Allergic reaction
- Liver problems
- increased aminotransferases
What drugs are used to treat restless leg syndrome?
- Non-ergot DA agonists
- Praipexole
- Ropinirole
- Gabapentin enacarbil
Gabapentin Enacarbil
- IND
- SE
- IND
- Restless leg syndrome
- SE
- Somnolence
- Sedation
IFN-ß
- MOA
- IND
- SE
- MOA
- anti-inflammatory
- increased integrity of BBB
- IND
- MS
- SE
- Flu-like symptoms
- Hepatotoxicity
- Myelosuppression
- Seizure
- increased Depression and Suicide
Glatiramer Acetate
- MOA
- IND
- SE
- MOA
- looks like myelin basic protein (decoy?)
- Shifts pro-inflammatory T cells to anti-inflamm.
- IND
- MS (first attack or recurrent)
- SE
- Injection site lipoatrophy and necrosis
- Rash
- Chest pain
- CON: mannitol hypersensitivity
Natalizumab
- MOA
- IND
- SE
- MOA
- Ab against alpha-4-integrin (cell adhesion)
- decreased inflammatory cell passage thru BBB
- IND
- MS (2nd line, monotherapy)
- SE
- Severe Liver injury
- Increased risk meningitis/ encephalitis from HSV/ VZV
- Progressive Multifocal Leukoencephalopathy (PML)
Fingolimod
- MOA
- IND
- SE
- MOA
- sphingosine-1-P receptor modulator
- sequesters lymphocytes in nodes
- can’t travel to CNS
- IND
- Relapsing MS
- SE
- Bradycardia/ AV block
- Fatal infection
- CON: vaccines
- Skin cancer
- Macular edema
- CON: diabetes
- Teratogen
- Liver Tox
Teriflunomide
- MOA
- IND
- SE
- MOA
- decreased activated lymphocytes in CNS
- IND
- Relapsing MS
- SE
- Immunosuppressant
- Decreased WBCs and platelets
- Acute renal failure
- Liver Tox
- Hypercalcemia
- Peripheral neuropathy
- Teratogen
- Immunosuppressant
Dimethyl fumarate
- MOA
- IND
- SE
- MOA
- Unknown
- IND
- Relapsing MS
- First line
- SE
- Decreased lymphocyte counts
- GI symptoms
Mitoxantrone
- MOA
- IND
- SE
- MOA
- Immunosuppressant
- (-) growth
- IND
- Progressive Relapsing MS
- SE
- tissue necrosis if extravasation occurs
- GIVE IV!!
- Cardiotox
- AML
- Neutropenia
- Teratogen
- tissue necrosis if extravasation occurs
What drugs are used as first-line agents to treat Relapsing MS?
- IFNβs
- Glatiramer acetate
- Monoclonal antibody
Patient reports seizures with unvoluntary, repetitive movements. Consciousness is preserved. What type of seizure is this?
Simple partial seizure
Can also occur with paresthesias (sensory cortex) or flashing lights (visual cortex)
Patient reports seizures preceeded by a bad odor. during the seizure there is an alterned consciousness and involuntary hand wringing. Afterward there is no memory of what has occured. What type of seizure is this?
Complex partial seizure
Patient reports seizures preceded by a bad odor. The seizure starts with involuntary, repetative movements followed by loss of consciousness and sustained contractions followed by rhythmic movements of all limbs. What type of seizure is this?
Partial seizure with secondary generalization
Patient’s spouse reports moments of blank stares after which the patient continues with their activity as if nothing has happened. The patient does not notice anything that signals one of these episodes will happen. Why type of seizure is this?
Absence seizure
Patient has sudden falls due to brief muscle spasms. There is no indication that something is about to happen. Patient also has liver failure. What type of seizure is this?
Myoclonic seizure
Associated with systemic disease
Patient reports seizures with loss of consciousness and jerking movements that last about 2 minutes. What type of seizure is it?
Tonic-clonic
What is the MOA of Carbamazepine?
- Stabilizes voltage-gated Na channels in the inactivated conformation
- decreased AP propagation (inhibits spread)
- Increased seizure threshold
What are the indications for Carbamazepine?
- Focal Seizures w/ or w/o secondary generalization
- Generalized tonic-clonic seizures
- Status Epilepticus
What are the side effects of Carbamazepine?
- Hyponatremia
- Visual (nystagmus, blurred vision, diplopia)
- Ataxia
- Myelosuppression
- Stevens Johnson Rash
- common in Asians with HLA-B*1502
- Teratogen
- Increased suicide risk
What is the benefit of using Oxcarbazepine over Carbamazepine?
- Fewer side effects
- No myelosuppression
- Fewer drug interactions
- no autoinduction
- only with oral contraceptives
With what seizure types can Oxcarbazepine not be used?
- Absence
- Myoclonic
Used in:
- Partial
- Tonic-clonic
What are the indications for Eslicarbazepine?
Focal-onset (Partial) Seizures
What is the MOA of Phenytoin?
- decrease flow of Na into cell
- increase refractory period
- Decrease Ca ion flow into cell
- Needed for vesicle - membrane fusion
- decreased synaptic transmission
- Overall
- decreased AP
- Decreased size and spread of seizure
What are the therapeutic uses of Phenytoin?
- Partial seizures
- Generalized tonic-clonic seizures
- Status epilepticus
- Lennox-Gastaut syndrome
What are the side effects of Phenytoin?
-
Cerebellar/ Vestibular signs
- loss of horizontal gaze nystagmus and smooth pursuit eye mvmts
- Gingival hyperplasia
- Drug-induced Lupus
-
Teratogen
- interferes with folate metabolism
- leads to megaloblastic anemia
- Osteomalacia
What drug is preferred for treating seizures (not myoclonic) in children, elderly, and pregnant women? Why?
Lamotrigine
- Low SE profile
- Low CNS tox
- NOT teratogen
What is the MOA of Lamotrigine?
- Block fast voltage- gated Na channels
- Block T-type Ca channels
- Decrease glutamate release
What are the therapeutic uses of Lamotrigene?
- Partial seizures
- Generalized seizures except myotonic
- Epilepsy
- Lennox-Gastaut Syndrome
Children and elderly
Pregnant women
What are the side effects of Lamotrigene?
- Stevens Johnson Syndrome
- Aseptic meningitis
Low CNS tox
NOT teratogen
Ethosuximide
- MOA
- IND
- SE
- MOA
- blocks low- threshold T-type Ca channels
- IND
- Absence seizures
- SE
- Lupus-like syndrome
- sleep disturbance
Clonazepam
- MOA
- IND
- SE
- MOA
- Benzodiazepine
- enhance GABA binding to GABA-A
- IND
- Absence
- Myoclonic
- Atonic seizures
- SE
- Sedation!
- Respiratory depression
What are the therapeutic uses of Diazepam and Lorazepam?
Prolonged generalized seizures
Tonic-clonic status epilepticus
(BZDs)
Phenobarbital
- MOA
- IND
- SE
- MOA
- Binds GABA-A channel and increases time of chloride channnel opening
- Limits seizure spread
- Elevates threshold
- IND
- Simple partial seizures
- Generalized tonic-clonic
- CON: absence seizure
- SE
- Sedation
- Depressed cognition
- Lupus syndrome
Tiagabine
- MOA
- IND
- SE
- MOA
- inhibits GABA reuptake
- (potentiates effect of GABA at post-synaptic neuron)
- IND
- Refractory partial seizure
- SE
- Sedation
- Tremor
- New-onset seizures and status epilepticus
Vigabatrin
- MOA
- IND
- SE
- MOA
- inhibits GABA- transaminase ((-) breakdown)
- IND
- Infantile spasms
- (Refractory seizures)
- SE
- Visual field constriction
- Blindness
Felbamate
- MOA
- IND
- SE
- MOA
- Inhibits glutamate NMDA receptors
- Potentiates GABA
- IND
- refractory partial seizure
- Secondary generalized
- SE
- Hepatitis
- Aplastic anemia
Perampanel
- MOA
- IND
- SE
- MOA
- Glutamate NMDA receptor antagonist
- IND
- Focal-onset seizures
- SE
- Severe psychiatric adverse reactions (homicidal ideation)
What is the MOA of Valproate?
- Blocks T-type Ca channels
- Slows Na channel recovery
- incresed GABA
- Stimulates synthesis
- inhibits metabolism
Overall:
- Blocks sustained, repetitive firing
- Blocks seizure spread
What are the therapeutic uses of Valproate?
- Drug of choice: idiopathic generalized seizures
- 2nd choice: infantile spasms
- Bipolar
- Migraine
What are the side effects of Valproate?
- Hepatitis that can be fatal
- Pancreatitis
- Hyperammonemia
- can cause brain damage
- Teratogen
- Neural tube defects
** Has zero-order kinetics!!**
What is the MOA of Topiramate?
- Blocks voltage gated Na channels
- Agonist at GABA-A receptors
- Inhibits glutamate activity
What are the therapeutic uses of Topiramate?
- Newly-diagnosed partial and mixed seizures
- Refractory generalized tonic-clonic and partial seizures
- Lennox-Gastaut
- Migraine
What are the side effects of Topiramate?
- Cognitive deficits
- Parasthesias
- Metabolic acidosis
- Kidney stones
- Hyperthermia
- Closed-angle Glaucoma
- Teratogen
What drugs are good for patients on complex drug regimens or with hepatic disease for the treatment of partial seizures?
Gabapentin / Pregabalin
Levetiracetam
Gabapentin
- MOA
- IND
- SE
- MOA
- inhibits high-voltage activated (HVA) Ca channels
- (-) neurotransmitter release
- inhibits high-voltage activated (HVA) Ca channels
- IND
- Refractory partial seizures
- Neuropathic pain
- SE
- Sedation
- Uncontrolled eye movements
Pregabalin
- MOA
- IND
- SE
- MOA
- inhibits high-voltage activated (HVA) Ca channels
- (-) neurotransmitter release
- inhibits high-voltage activated (HVA) Ca channels
- IND
- Refractory partial seizures
- Neuropathic pain
- SE
- New onset myoclonus
- Sedation
- Ataxia
- Tremor
Levetiracetam
- MOA
- IND
- SE
- MOA
- binds synaptic vesicle protein
- alters vesicle fusion
- binds synaptic vesicle protein
- IND
- Partial seizures
- Tonic-clonic
- SE
- Sedation
- Pins and needles sensation in extremities
- Behavioral change
- Teratogen
Few drug interactions
Not metabolized by liver
Ezogabine
- MOA
- IND
- SE
- MOA
- Enhanced K+ transmembrane current
- Stabilizes membrane
- IND
- Adult partial-onset seizure
- SE
- Retinal change
- Vision loss
- long Q-T (arrhythmia)
- Psych symptoms
Carbonic Anhydrase Inhibitors in Seizure Treatment
- MOA
- IND
- MOA
- increase intracellular H+, decrease pH
- K+ pushed out of cell to balance
- hyperpolarization
- increased seizure threshold
- IND
- catamenial pattern seizure (around menstration)
What is the risk of seizure to a fetus? The risk of AEDs?
Seizure:
- threshold lowered during pregnancy
- increased risk stillbirth
AED:
- Neural tube defects
- Hemorrhagic disease
**Supplement with Folate!
What is the drug of choice for Status Epilepticus? Second line choice?
Drug of choice:
- Benzodiazepines (followed by phenytoin for long duration action)
- Diazepam
- Lorazepam
Second line:
- Phenobarbital
What side effects are commonly associated with AEDs?
Sedation
hyponatremia
ataxia
tremor
Diplopia/ blurred vision
Mental slowing
Steven-Johnson syndrome
What AEDs cause renal stones?
- topiramate
- zonisamide
Which AEDs cause aplastic anemia?
- felbamate
- zonisamide
- valproate
- carbamazepine
Which AED causes agranulocytosis?
carabamazepine
Which AEDs cause hepatic failure?
- valproate
- felbamate
- lamotrigine
- phenobarbital
Which AED causes anhydrosis and heat stroke?
topiramate
Which AED causes closed-angle glaucoma?
topiramate
Which AED causes aseptic meningitis?
Lamotrigine
Which AED causes polycystic ovarian syndrome in young women?
Valproate
Which AED causes cerebellar syndrome?
Phenytoin
