ICL 5.0: Pharmacology of Neurodegenerative Disease Flashcards
what is the direct pathway involving the basal ganglia?
DIRECT PATHWAY:
cortex –> striatum –> globus pallidus internus and substantia nigra –> thalamus –> cortex
so the cortex releases glutamate which activates the striatum –> then the putamen synapses in the globus pallidus internus and releases inhibitory GABA
the globus pallidus neurons usually go to the thalamus and release GABA to inhibit the thalamus but since the globus pallidus is being inhibited by the putamen, the thalamic neurons are now active! the thalamus then goes and activates the motor cortex so that it can go and initiate movement
the direct pathway initiates movement!
what is the indirect pathway involving the basal ganglion?
INDIRECT PATHWAY:
cortex –> striatum/putamen –> globus pallidus externus –> subthalamic nucleus –> globus pallidus internal –> thalamus –> cortex
so the cortex is stimulating the putamen by releasing glutamate and then the neurons from the putamen synapse in the globus pallidus externus and release GABA to inhibit the GPE –> the GPE then normally inhibits the subthalamus but since the GPE is inhibited, the subthalamus is activated and it goes and releases glutamate to activate the globus pallidus internus
the globus pallidus internus is inhibitory so it will go and release GABA and inhibit the thalamus so the thalamus no longer stimulates the cortex to produce movement
so the indirect pathway stops movement!
striatum = caudate nucleus + putamen
how does the substantia nigra effect the direct and indirect pathways normally?
the direct pathway is used to initiate movement while the indirect pathway is used to inhibit movement so together they work together to allow for proper movement!
the substantia nigra has dopaminergic neurons that synapse in the putamen either on the D1 receptors of the direct pathway neurons or on the D2 receptors of the indirect pathway neurons –> D1 receptors activate a stimulatory pathway while D2 receptors activate an inhibitory pathway
so dopamine binding to D1 receptors provides more intense action potentials in the direct pathway and allows for even more movement! but if dopamine binds to the D2 receptors in the indirect pathway and inhibits them, you stimulate the primary motor cortex! so dopamine is trying to enhance motor movement overall!
when you want to flex your biceps, you have to activate the biceps and inhibit the triceps –> in Parkinson’s, if there’s alternating contraction and relaxation that’s how you get tremors! also if there’s constant contraction through the direct pathway, that’s what gives you the rigidity!!
how do cholinergic neurons play a role in the effect of dopamine on the direct and indirect pathway?
dopamine normally activates the direct pathway and inhibits the indirect pathway in the putamen of the basal ganglia
the cholinergic neurons in the putamen do the exact opposite effect of dopamine –> so cholinergic neurons stimulate the indirect pathway and inhibit the direct pathway in the putamen
what happens to the neuroanatomy of the basal ganglia involved in motor function in a Parkinson’s patient?
there is degeneration of the dopaminergic neurons in the pars compacta of the substantia nigra, leading to overactivity in the indirect pathway = lots of inhibition of movement!
without dopamine being released on the D1 receptors of the direct pathway and the D2 receptors of the indirect pathway, the direct pathway won’t be activated as much and indirect pathway won’t be inhibited as much which leads to overactivity of the indirect pathway! this is why Parkinson’s patients have such a hard time contracting their muscles = akinesia/bradykinesia!!! this is why they have a shuffling gait because they can’t get their muscles to go but it’s also why sometimes they have the march a petit where their walker ends up really ahead of them because they also can’t stop the movement once they get going because that also requires muscles!
loss of the inhibitory effect of dopamine results in more production of Ach which triggers a chain of abnormal signaling leading to impaired mobility
there is also aggregation of Lewy bodies in the substantia nigra which leads to neuron death of dopaneurgic neurons
what is Parkinson’s disease?
a progressive neurodegenerative disease where there is loss of dopamine neurons in the substantia nigra and the presence of Lewy bodies (eosinophilic cytoplasmic inclusions) in the surviving dopamine neurons
aggregates of the Lewy bodies in the dopaneurgic neurons is what’s killing them
what is the clinical presentation of Parkinson’s disease?
- resting tremor –> pill-rolling tremor
- bradykinesia (slowness)
- rigidity –> cog-wheel rigidity in upper limbs and lead rigidity in lower limbs
- postural instability = impaired balance and hunched back; appears late in the course of the disease
- long term disability includes: worsening motor fluctuations and dyskinesias, dementia
- masked face = doesn’t show emotions
TRAP = tremors, rigidity, akinesia, postural instability
why do Parkinson’s patients have tremors and rigidity?
the cholinergic neurons love to oppose dopamine so they love to inhibit the direct pathway and excite the indirect pathway in the putamen
normally ACh and dopamine are in balance but in Parkinson’s there is a decreased amount of dopamine which increases the effect of the cholinergic neurons – this fluctuation between ACh and dopamine is what causes both tremors and rigidity!
how do you treat Parkinson’s?
you can’t actually treat it….
once the neurons in the substantia nigra die, they can’t be regenerated so you just have to treat the symptoms
what are the 3 primary compounds used to treat Parkinson’s?
- increase dopamine synthesis
- decrease dopamine catabolism
- stimulate dopamine receptors (agonists)
what are the 3 secondary compounds used to treat Parkinson’s?
- antagonize muscarinic cholinergic receptors
- enhance dopamine release
- N-methyl-D-aspartate (NMDA) gluta mate receptors
how is dopamine synthesized?
tyrosine –> L-dihydroxy phenylalanine via tyrosine hydroxylase (TH)
then L-dopa –> dopamine via dopa decarboxylase
what is the MOA of levodopa/carbidopa?
levodopa + carbidopa = Sinemet®
this is used to treat Parkinson’s!
levodopa is the immediate metabolic precursor of dopamine which crosses the blood-brain barrier
however, the problem is that it can be decarboxylated into dopamine!! before it even gets to the brain! so that’s why levodopa is combined with carbidopa because carbidopa is a peripheral dopa-decarboxylase inhibitor so it keeps levodopa in the levodopa form until it gets to the brain where it can be decarboxylated into dopamine
if you give levodopa by itself, only 1-3% wlll get to the brain whereas when it’s combined with carbidopa 10% will get to the brain
should you take levodopa with or without food?
Levodopa should be taken on an empty stomach
ingestion of meals containing high protein content interferes with the transport of levodopa
what are the adverse effects of levodopa if it’s given alone with carbidopa?
- GI distress = anorexia, nausea, vomitting
- cardiac arrhythmias
- hallucinations
- dyskinesias
- motor fluctuations
when you give levodopa with carbidopa you reduce its metabolism in the peripheral tissues and GI tract which decreases the side effects
what drug interactions does levodopa have?
pyridoxine (vitamine B6) enhances the extracerebral metabolism of levodopa
so patients are told to avoid vitamin B6 since it promotes the metabolism of levodopa in the periphery
what is the MOA of entacapone?
aka Comtan®
entacapone is a peripherally acting inhibitor of catechol-O-methyltransferase (COMT)
when peripheral dopamine decarboxylase activity is inhibited by carbidopa a significant concentration of 3-O-methyldopa is formed via COMT –> 3-O-methyldopa competes with levodopa for active transport into the CNS
inhibition of COMT by entacapone leads to decrease concentration of 3-O-methyldopa which increases the central uptake of levodopa = more dopamine in the brain
entacapone prolongs the action of levodopa by diminishing its metabolism
used to treat Parkinson’s
what is the MOA of tolcapone?
it’s a central AND peripheral inhibitor of COMT
when peripheral dopamine decarboxylase activity is inhibited by carbidopa a significant concentration of 3-O-methyldopa is formed via COMT –> 3-O-methyldopa competes with levodopa for active transport into the CN
inhibition of COMT by tolcapone leads to decrease concentration of 3-O-methyldopa which increases the central uptake of levodopa = more dopamine in the brain
used to treat Parkinson’s
what are the adverse effects of tolcapone and entacapone?
COMT inhibitors increase levodopa availability and consequently cause:
- dyskinesias
- nausea
- confusion
- abdominal pain
- sleep disturbances
- orange discoloration of the urine
**tolcapone is related to hepatotoxicity so it’s not prescribed often
what is Stalevo?
a commercial preparation composed of Entacapone/Levodopa/Carbidopa
used to treat Parkinson’s
what is the MOA of selegiline?
aka Deprenyl®
selegiline is a selective inhibitor of monoamine oxidase B (MAO-B) which metabolizes dopamine in the CNS
so selegiline enhances and prolongs the antiparkinsonism effect of levodopa (so it’s given as a booster of Sinemet)
what do you have to be cautious of when dosing selegiline?
- at higher doses, selegiline can also inhibit MOA-A too though which isn’t good because you could cause serotonin syndrome due to a build up of serotonin so you have to have a balanced dose
serotonin syndrome triad = confusion, fever and myoclonus (involuntary muscle jerk)
- “cheese effect”
hypertensive crisis – certain foods like cheese, wine and meat are high in tyramine and MAO inhibitors like selegiline block the breakdown of tyramine and high levels of tyramine cause hypertension
what are some of the adverse effects of selegiline?
- insomnia and excessive daytime sleepiness
- mood changes
- dyskinesias
- GI distress
- hypotension
what is the MOA of rasagiline?
aka Azilect®
it’s a selective inhibit of MAO-B which metabolizes dopamine
it’s used as a neuroprotective agent and for early symptomatic treatment
what do you have to be careful with when administering rasagiline?
it’s an MAO-B inhibitor that is more potent than selegiline so you can have a lot more side effects like insomnia and dyskinesia!!
also, the combined administration of levodopa and an inhibitor of both MAO-B and MAO-A must be avoided because it may lead to hypertensive crises due to increase of peripheral norepinephrine
which drugs used to treat Parkinson’s increase dopamine synthesis?
- levodopa/carbidopa =
Sinemet® - entacapone
- tolcapone
- silegiline = Deprenyl®
- rasagiline = Azilect®
what are the general characteristics of drugs that are dopamine receptor agonists?
these are drugs that mimic the action of dopamine
they have an important role as first-line therapy for Parkinson’s disease
what is the benefit of dopamine receptor agonists over levodopa?
their use is associated with lower incidence of the response fluctuations and dyskinesias that occur with long-term levodopa therapy
however, dopamine agonists may be also given to patients with parkinsonism who are taking levodopa
what are the 2 types of dopamine agonists that have antiparkinsonism activity? which drugs are in each class?
- older dopamine agonists are ergot derivatives
ex. bromocriptine and pergolide - newer dopamine agonists are non-ergot derivatives
ex. pramipexole and ropinirole
what is the MOA of bromocriptine?
Parlodel® is an ergot derivative = old dopamine agonist
it’s a partial D2 agonist –> dopamine binding to the D2 receptors of the indirect pathway inhibits it so you stimulate the primary motor cortex = more action
used to treat Parkinson’s
what is the MOA of pergolide?
Permax® is an ergot derivative = old dopamine agonist
it’s a partial agonist for both D1 and D2 receptors
dopamine binding to D1 receptors of the direct pathway excites it and dopamine binding to the D2 receptors of the indirect pathway inhibits it so it’s an overall excitatory effect that increases motor movement!
used to treat Parkinson’s
what are the side effects of the drugs are that ergot derivatives?
ergot derivatives = old dopamine agonists = bromocriptine and pergolide
- GI distress
- cardiovascular effects = postural hypotension, cardiac arrhythmias
- dyskinesias
- hallucinations and delusions from overstimulation of the D2 receptors which are involved in your cognitive function
hallucinations are more common with bromocriptine and pergolide than with levodopa
what is the MOA of pramipexole?
Mirapex® is a non-ergot derivative = new dopamine agonist
it’s an agonist for the D3 family of receptors
***possible role in neuroprotection due to its ability to scavenge hydrogen peroxidase and enhancement of neurotrophic activity
used to treat Parkinson’s
what is the MOA of ropinirole?
Requip® is a non-ergot derivative = new dopamine agonist
it’s a D2 receptor agonist
used to treat Parkinson’s
what are the adverse effects of the drugs that are non-ergot derivatives?
non-ergot derivatives = new dopamine agonists = pramipexole and ropinirole
- GI distress
- postural hypotension
- dyskinesias
- hallucinations
which drugs are considered to be the first-line drugs in the initial management of Parkinson’s?
Pramipexole and Ropinirole
these are non-ergot derivatives = newer dopamine agonists
what is the MOA of anticholinergic drugs?
anticholinergic drugs decrease the excitatory actions of cholinergic neurons in the striatum (putamen)
some anticholinergic drugs may improve: the tremor and rigidity of parkinsonism but have little effect on bradykinesia
which drugs are anticholinergic drugs?
- benztropine (Cogentin®)
- trihexyphenidyl (Artane®)
these are great for treating Parkinson’s tremors especially in the beginning when the tremor is the only symptom!
what are the side effects of anticholinergic drugs?
- dry mouth
- visual problems (so they’re contraindicated in patients with glaucoma)
- delusions
- confusion
what is the MOA of amantadine?
Symmetrel®
unknown but it may potentiate dopaminergic function by increasing the synthesis or release of dopamine or inhibition of dopamine reuptake
also muscarinic blocking actions
what are the benefits of amantadine?
- may improve bradykinesia, rigidity, and remote but usually only for a few weeks
- antiviral!
what are the adverse effects of amantadine?
- restlessness
- irritability
- insomnia
- dermatologic reaction
- GI distress
what is the MOA of apomorphine?
Apokyn® is a non-narcotic derivative
that activates both D1-like and D2-like receptors
apomorphine is effective for the temporary relief of off-periods of akinesia in patients on dopaminergic therapy –> apomorphine is given SC and taken up in the blood to the brain within 10 minutes of injection and persists for up to 2 hours
what are the adverse effects of apomorphine?
- cardiovascular = chest pain, pressure, angina
- drowsiness
- hallucinations
- dizziness or orthostatic hypotension
- gastrointestinal distress = nausea, vomitting
- dyskinesias
what is Huntington’s disease?
a neurodegenerative disease where there is a loss of striatal neurons (GABAergic neurons) due to the accumulation or aggregation of Huntington protein in cell bodies – cholinergic neurons are also effected
we all have Hungtinton protein but when there’s a CAG repeat mutation, the protein will be misfiled and aggregate and kill the neurons
what happens to the neuroanatomy of the nuclei in solved in motor function in a Huntington’s patient?
there is degeneration of striatal neurons (GABAergic neurons)
without the GABAergic neurons from the putamen going and inhibiting the globus pallidus externus via the indirect pathway, there is overactive direct pathway activity = chorea!
striatum = caudate nucleus + putamen
what are the gross changes you see in the brain of a Huntington’s patient?
- enlargement of the lateral ventricles
- reduction of stratal volume
striatum = caudate nucleus + putamen
what causes Hungtington’s?
expansion of a CAG repeat within exon 1 of the huntingtin gene on chromosome 4
normally there’s 10-28 CAG repeats but in Huntington’s there’s 36-120 repeats
what are the 2 forms of Huntington?
- adult-onset Huntington’s disease where patients usually develop symptoms in their mid 30s and 40s –> most common
- early-onset form of Huntington’s disease accounts for a small number of cases and begins in childhood or adolescence
what is the clinical presentation of Huntington’s?
- Irregular movement
- unpredictable and involuntary muscle jerks in different parts of the body
- impair of voluntary activity
- neurotransmitter imbalance: GABA functions ↓ and dopaminergic functions ↑
what are the two types of drugs that can be used to treat Huntington’s?
- dopamine depletion drugs
reserpine and xenazine
reserpine inhibits VMAT which normally packages dopamine into vesicles so that it can be released; if dopamine isn’t packaged then it can’t be released!
- antipsychotics
butryophenones, phenothiazines, and resperidone are dopamine receptor antagonists
what is a tremor?
a rhythmic and oscillatory movement of a body part with a relatively constant frequency and variable amplitude
it is caused by either alternating or synchronous contractions of antagonistic muscles
which drugs can be used to treat a tremor?
- propranolol = nonselective beta blocker
- primidone = blocks voltage gated sodium channels
- chlordiazepoxide = acts on benzodiazepine allosteric sites of GABA(A)
- gabapentin = similar structure to GABA; anti-epileptic drug
- alprazolam (xanax), clonazepam, diazepam = GABA(A) agonist
what is dystonia?
a neurological movement disorder that causes muscles in the body to contract or spasm involuntarily
it can be idiopathic, hereditary or secondary to numerous other conditions; dystonia can be focal, multifocal or generalized
pharmacological basis of this disorder is unknown
which drugs can be used to treat dystonia?
- trihexylphenidyl = muscarinic antagonists
- benzodiazepines (Klonapin) or diazepam (Valium)
- baclofen = GABA(B) agonist
- carbamazepine = blocks voltage gated Na+ channels
- botulinum toxin
what are the side effects of baclofen?
it’s a GABA(B) agonist used to treat dystonia
sedation is a dose-limiting adverse effect
also rapid discontinuation can elicit seizures and acute psychosis
what is the MOA of botulinum toxin and what is it used to treat?
botulinum toxin injections are effective for focal dystonia, cerebral palsy and other spastic disorders
it inhibits acetylcholine release from nerve terminals –> botox binds presynaptically to high-affinity recognition sites on the cholinergic nerve terminals and decreasing the release of acetylcholine, causing a neuromuscular blocking effect
injections are repeated approximately every 3 months for focal dystonia
The physician who is prescribing levodopa will (or should) know that the drug:
A. causes less severe behavioral side effects if given with carbidopa
B. fluctuates in its effectiveness with increasing frequency as treatment continues
C. prevents extrapyramidal adverse effects of antipsychotic drugs
D. protects against cancer in patients with melanoma
E. toxicity includes pulmonary infiltrates
B. fluctuates in its effectiveness with increasing frequency as treatment continues –> it has an on-off effect because eventually the CNS stops making its own L-dopa and the body becomes dependent on Sinemet so patient’s can’t take it for more than a few years without developing serious side effects
A: levodopa causes less peripheral toxicity but more behavioral side effects when used with carbidopa
C: the drug is not effective in antagonizing the akinesia, rigidity, and tremor caused by treatment with antipsychotic drugs
D: levodopa is a precursor of melanin and may activate malignant melanoma
E. use of levodopa is not associated with pulmonary dysfunction
which statement about bromocriptine is accurate?
A. it should not be administered to patients taking antimuscarinic drugs
B. its effectiveness in Parkinson’s disease requires its metabolic conversion to an active metabolite
C. the drug is contraindicated in patients with a history of psychosis
D. the drug should not be administered to patients who have already been treated with levodopa
E. mental disturbances occur more commonly with levodopa than with bromocriptine
C. the drug is contraindicated in patients with a history of psychosis –> confusion, delusions, and hallucinations occur more frequently with bromocriptine than with levodopa
A: use of dopaminergic agents in combination with muscarinic drugs is common in the treatment of parkinsonism
B: if combined with levodopa, bromocriptine should be used in reduced doses to avoid intolerable adverse effects
