ICL 5.0: Pharmacology of Neurodegenerative Disease

Question 1

what is the direct pathway involving the basal ganglia?

Answer 1

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!

Question 2

what is the indirect pathway involving the basal ganglion?

Answer 2

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

Question 3

how does the substantia nigra effect the direct and indirect pathways normally?

Answer 3

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!!

Question 4

how do cholinergic neurons play a role in the effect of dopamine on the direct and indirect pathway?

Answer 4

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

Question 5

what happens to the neuroanatomy of the basal ganglia involved in motor function in a Parkinson’s patient?

Answer 5

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

Question 6

what is Parkinson’s disease?

Answer 6

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

Question 7

what is the clinical presentation of Parkinson’s disease?

Answer 7

1. resting tremor –> pill-rolling tremor
2. bradykinesia (slowness)
3. rigidity –> cog-wheel rigidity in upper limbs and lead rigidity in lower limbs
4. postural instability = impaired balance and hunched back; appears late in the course of the disease
5. long term disability includes: worsening motor fluctuations and dyskinesias, dementia
6. masked face = doesn’t show emotions

TRAP = tremors, rigidity, akinesia, postural instability

Question 8

why do Parkinson’s patients have tremors and rigidity?

Answer 8

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!

Question 9

how do you treat Parkinson’s?

Answer 9

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

Question 10

what are the 3 primary compounds used to treat Parkinson’s?

Answer 10

1. increase dopamine synthesis
2. decrease dopamine catabolism
3. stimulate dopamine receptors (agonists)

Question 11

what are the 3 secondary compounds used to treat Parkinson’s?

Answer 11

1. antagonize muscarinic cholinergic receptors
2. enhance dopamine release
3. N-methyl-D-aspartate (NMDA) gluta mate receptors

Question 12

how is dopamine synthesized?

Answer 12

tyrosine –> L-dihydroxy phenylalanine via tyrosine hydroxylase (TH)

then L-dopa –> dopamine via dopa decarboxylase

Question 13

what is the MOA of levodopa/carbidopa?

Answer 13

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

Question 14

should you take levodopa with or without food?

Answer 14

Levodopa should be taken on an empty stomach

ingestion of meals containing high protein content interferes with the transport of levodopa

Question 15

what are the adverse effects of levodopa if it’s given alone with carbidopa?

Answer 15

1. GI distress = anorexia, nausea, vomitting
2. cardiac arrhythmias
3. hallucinations
4. dyskinesias
5. motor fluctuations

when you give levodopa with carbidopa you reduce its metabolism in the peripheral tissues and GI tract which decreases the side effects

Question 16

what drug interactions does levodopa have?

Answer 16

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

Question 17

what is the MOA of entacapone?

Answer 17

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

Question 18

what is the MOA of tolcapone?

Answer 18

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

Question 19

what are the adverse effects of tolcapone and entacapone?

Answer 19

COMT inhibitors increase levodopa availability and consequently cause:

1. dyskinesias
2. nausea
3. confusion
4. abdominal pain
5. sleep disturbances
6. orange discoloration of the urine

**tolcapone is related to hepatotoxicity so it’s not prescribed often

Question 20

what is Stalevo?

Answer 20

a commercial preparation composed of Entacapone/Levodopa/Carbidopa

used to treat Parkinson’s

Question 21

what is the MOA of selegiline?

Answer 21

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)

Question 22

what do you have to be cautious of when dosing selegiline?

Answer 22

1. 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)

2. “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

Question 23

what are some of the adverse effects of selegiline?

Answer 23

1. insomnia and excessive daytime sleepiness
2. mood changes
3. dyskinesias
4. GI distress
5. hypotension

Question 24

what is the MOA of rasagiline?

Answer 24

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

Question 25

what do you have to be careful with when administering rasagiline?

Answer 25

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

Question 26

which drugs used to treat Parkinson's increase dopamine synthesis?

Answer 26

1. levodopa/carbidopa = Sinemet® 2. entacapone 3. tolcapone 4. silegiline = Deprenyl® 5. rasagiline = Azilect®

Question 27

what are the general characteristics of drugs that are dopamine receptor agonists?

Answer 27

these are drugs that mimic the action of dopamine they have an important role as first-line therapy for Parkinson’s disease

Question 28

what is the benefit of dopamine receptor agonists over levodopa?

Answer 28

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

Question 29

what are the 2 types of dopamine agonists that have antiparkinsonism activity? which drugs are in each class?

Answer 29

1. older dopamine agonists are ergot derivatives ex. bromocriptine and pergolide 2. newer dopamine agonists are non-ergot derivatives ex. pramipexole and ropinirole

Question 30

what is the MOA of bromocriptine?

Answer 30

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

Question 31

what is the MOA of pergolide?

Answer 31

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

Question 32

what are the side effects of the drugs are that ergot derivatives?

Answer 32

ergot derivatives = old dopamine agonists = bromocriptine and pergolide 1. GI distress 2. cardiovascular effects = postural hypotension, cardiac arrhythmias 3. dyskinesias 4. 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

Question 33

what is the MOA of pramipexole?

Answer 33

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

Question 34

what is the MOA of ropinirole?

Answer 34

Requip® is a non-ergot derivative = new dopamine agonist it's a D2 receptor agonist used to treat Parkinson's

Question 35

what are the adverse effects of the drugs that are non-ergot derivatives?

Answer 35

non-ergot derivatives = new dopamine agonists = pramipexole and ropinirole 1. GI distress 2. postural hypotension 3. dyskinesias 4. hallucinations

Question 36

which drugs are considered to be the first-line drugs in the initial management of Parkinson's?

Answer 36

Pramipexole and Ropinirole these are non-ergot derivatives = newer dopamine agonists

Question 37

what is the MOA of anticholinergic drugs?

Answer 37

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

Question 38

which drugs are anticholinergic drugs?

Answer 38

1. benztropine (Cogentin®) 2. trihexyphenidyl (Artane®) these are great for treating Parkinson's tremors especially in the beginning when the tremor is the only symptom!

Question 39

what are the side effects of anticholinergic drugs?

Answer 39

1. dry mouth 2. visual problems (so they're contraindicated in patients with glaucoma) 3. delusions 4. confusion

Question 40

what is the MOA of amantadine?

Answer 40

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

Question 41

what are the benefits of amantadine?

Answer 41

1. may improve bradykinesia, rigidity, and remote but usually only for a few weeks 2. antiviral!

Question 42

what are the adverse effects of amantadine?

Answer 42

1. restlessness 2. irritability 3. insomnia 4. dermatologic reaction 5. GI distress

Question 43

what is the MOA of apomorphine?

Answer 43

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

Question 44

what are the adverse effects of apomorphine?

Answer 44

1. cardiovascular = chest pain, pressure, angina 2. drowsiness 3. hallucinations 4. dizziness or orthostatic hypotension 5. gastrointestinal distress = nausea, vomitting 6. dyskinesias

Question 45

what is Huntington's disease?

Answer 45

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

Question 46

what happens to the neuroanatomy of the nuclei in solved in motor function in a Huntington's patient?

Answer 46

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

Question 47

what are the gross changes you see in the brain of a Huntington's patient?

Answer 47

1. enlargement of the lateral ventricles 2. reduction of stratal volume striatum = caudate nucleus + putamen

Question 48

what causes Hungtington's?

Answer 48

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

Question 49

what are the 2 forms of Huntington?

Answer 49

1. adult-onset Huntington's disease where patients usually develop symptoms in their mid 30s and 40s --> most common 2. early-onset form of Huntington's disease accounts for a small number of cases and begins in childhood or adolescence

Question 50

what is the clinical presentation of Huntington's?

Answer 50

1. Irregular movement 2. unpredictable and involuntary muscle jerks in different parts of the body 3. impair of voluntary activity 4. neurotransmitter imbalance: GABA functions ↓ and dopaminergic functions ↑

Question 51

what are the two types of drugs that can be used to treat Huntington's?

Answer 51

1. 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! 2. antipsychotics butryophenones, phenothiazines, and resperidone are dopamine receptor antagonists

Question 52

what is a tremor?

Answer 52

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

Question 53

which drugs can be used to treat a tremor?

Answer 53

1. propranolol = nonselective beta blocker 2. primidone = blocks voltage gated sodium channels 3. chlordiazepoxide = acts on benzodiazepine allosteric sites of GABA(A) 4. gabapentin = similar structure to GABA; anti-epileptic drug 5. alprazolam (xanax), clonazepam, diazepam = GABA(A) agonist

Question 54

what is dystonia?

Answer 54

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

Question 55

which drugs can be used to treat dystonia?

Answer 55

1. trihexylphenidyl = muscarinic antagonists 2. benzodiazepines (Klonapin) or diazepam (Valium) 3. baclofen = GABA(B) agonist 4. carbamazepine = blocks voltage gated Na+ channels 5. botulinum toxin

Question 56

what are the side effects of baclofen?

Answer 56

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

Question 57

what is the MOA of botulinum toxin and what is it used to treat?

Answer 57

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

Question 58

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

Answer 58

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

Question 59

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

Answer 59

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