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Pharmacology MidTerm > Parkinsons Disease > Flashcards

Parkinsons Disease Flashcards

1
Q

What are the major differences of the CNS that distinguish it from the peripheral ANS?

A
  • CNS’ circuitry is more complex.
  • The CNS contains inhibitory neurons exclusively.
  • The CNS has much more types of neurotransmitters.
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2
Q

Which type of channels are the receptors at most synapses in the CNS coupled to?

A

Most of the receptors in the CNS are coupled to ion channels, enabling transient and rapid action.

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3
Q

What are the two types of action potentials in the CNS?

A
  1. EPSP.
  2. IPSP.
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4
Q

What are the two types of neurotransmitters in the CNS?

A
  1. Excitatory neurotransmitters (cause depolarization).
  2. Inhibitory neurotransmitters (cause hyperpolarization).
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5
Q

Describe how the postsynaptic membrane is depolarized in the CNS.

A
  1. Excitatory neurotransmitter binds to its receptor, which is coupled to an ion channel.
  2. Ion channel opens, and Na+ ions flux in, resulting in the depolarization of the postsynaptic membrane, exciting it.
    This process is called EPSP.
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6
Q

Describe how the postsynaptic membrane is hyperpolarized in the CNS.

A
  1. Inhibitory neurotransmitter binds to its receptor, which is coupled to an ion channel.
  2. Ion channel opens, and Cl- ions flux in, K+ ions flux out, resulting in the hyperpolarization of the postsynaptic membrane, inhibiting it.
    This process is called IPSP.
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7
Q

What are the two major excitatory neurotransmitters of the CNS?

A
  • Glutamate.
  • Acetylcholine.
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8
Q

What are the two major inhibitory neurotransmitters of the CNS?

A
  • Glycine.
  • GABA.
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9
Q

Do excitatory and inhibitory neurotransmitters bind to the same receptor?

A

No, each neurotransmitter binds to its own specific receptor.

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10
Q

Define neurodegenerative diseases.

A

Diseases characterized by the loss of structure and function of neurons, including their death.

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11
Q

How do most CNS drugs work?

A

By altering some step in the neurotransmission process.

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12
Q

What are the three most common neurodegenerative diseases?

A
  1. Parkinson’s disease.
  2. Alzheimer’s disease (most prevalent).
  3. Multiple sclerosis.
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13
Q

Define Parkinsons disease.

A

A progressive neurological disorder of muscle movement.

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14
Q

Which age group is most likely to develop Parkinson disease?

A

Most cases involve people over the age of 65.

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15
Q

What are the cardinal symptoms of Parkinson disease?

A
  1. Tremors.
  2. Muscular rigidity.
  3. Bradykinesia.
  4. Postural and gait abnormalities.
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16
Q

What causes Parkinson disease?

A

The actual cause of Parkinson disease is unknown, but it is correlated with the destruction of the dopaminergic neurons in the substantia nigra.

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17
Q

What does the basal ganglia consist of?

A

The corpus striatum and the substantia nigra.

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18
Q

Which type of neurons degenerate in Parkinson disease patients?

A

Dopaminergic neurons in the substantia nigra.

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19
Q

Which site of the brain experiences a reduction of dopamine action that result in the symptoms of Parkinson disease?

A

The corpus striatum.

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20
Q

Which type of neurons predominate the corpus striatum?

A

Cholinergic neurons.

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21
Q

How is the neostriatum connected to the substantia nigra?

A

By neurons that secrete GABA at their termini in the substantia nigra.

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22
Q

What is secondary parkinsonism?

A

Parkinsonian symptoms induced by factors other than actual neuronal degeneration, e.g., drugs.

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23
Q

Which drugs cause secondary parkinsonism? Why?

A
  • Phenothiazines (e.g., prochlorperazine).
  • Haloperidol.
    These drugs block dopamine receptors in the brain.
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24
Q

What is the strategy of treatment of Parkinson disease?

A
  1. Restoring dopamine in the basal ganglia:
    - Dopamine replacement therapy: levodopa.
    - Dopamine agonists: pergolide, apomorphine, etc.
  2. Antagonizing excitatory cholinergic neurons (antimuscarinic agents).

The ultimate goal is to reestablish the correct dopamine/acetylcholine balance.

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25
Q

Do anti-Parkinson disease drugs cure?

A

No. They only offer temporary relief from the symptoms of the disorder, but they do not arrest or reverse the neuronal degeneration caused by the disease.

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26
Q

What is Levodopa?

A

A metabolic precursor of dopamine (i.e., pro-drug) that, unlike dopamine itself, can cross the blood-brain barrier and so it is used as dopamine replacement therapy for patients with Parkinson disease.

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27
Q

How does levodopa work?

A

Levodopa restores dopaminergic neurotransmission in the corpus striatum by enhancing the synthesis of dopamine in the surviving neurons of the substantia nigra, making it useful in treating early stages of Parkinson disease.

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28
Q

Does levodopa cure Parkinson disease?

A

No, the relief provided by levodopa is only symptomatic and lasts only while the drug is present in the body.

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29
Q

Why shouldn’t we administer levodopa alone without carbidopa?

A

When we administer levodopa on its own, about 97% of it gets metabolized into dopamine peripherally, making the amount that actually reaches the brain insufficient to exert a therapeutic effect.

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30
Q

Why don’t we use dopamine itself to manage Parkinson disease directly?

A

Because dopamine itself doesn’t cross the blood-brain barrier. Levodopa, dopamine’s precursor, is actively transported into the CNS and is converted into dopamine in the brain.

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31
Q

What is Carbidopa?

A

A peripheral dopa decarboxylase inhibitor.

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32
Q

What is dopa decarboxylase?

A

An enzyme that converts levodopa into dopamine that exists peripherally and centrally.

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33
Q

How does carbidopa work?

A

Carbidopa decreases the metabolism of levodopa in the GIT and peripheral tissues by inhibiting dopa decarboxylase, increasing the availability of central levodopa.

34
Q

Does carbidopa inhibit central dopa decarboxylase?

A

No, carbidopa does not cross the blood-brain barrier, as it has no amino acid side chain.

35
Q

Which drug is similar to carbidopa?

A

Benserazide.

36
Q

Why is carbidopa co-administrated with levodopa?

A
  1. Increases CNS levodopa availability.
  2. Lowers levodopa dose needed by 4-5 times, reducing side effects caused by peripherally formed dopamine.
37
Q

What are the therapeutic uses of carbidopa+levodopa?

A

Levodopa in combination with carbidopa is a potent and efficacious drug regimen currently available to treat Parkinson disease. It reduces the severity of the disease for the first few years of treatment. However, patients then typically experience a decline in response over time due to dopaminergic neuron loss.

38
Q

Describe the pharmacokinetics of levodopa and their consequences in great detail.

A

Levodopa has a short half-life (1 to 2 hours), which unfortunately causes fluctuations in the plasma concentration that produces fluctuations in the motor response that manifest as sudden lose of normal mobility, tremors, and cramps.
The brief improvement followed by the sudden recurrence of the symptoms is called “on-off” phenomenon.

39
Q

How can we overcome the “on-off” phenomenon?

A

It can be overcome by gradual increasing of the dose or by combination with other drugs, such as:
- MAO-B inhibitors.
- Dopamine agonists.
- COMT inhibitors.
- Antimuscarinic agents.
- Amantadine.

40
Q

Why should levodopa be taken on an empty stomach?

A
  1. Levodopa is absorbed rapidly from the small intestine when it is empty of food.
  2. Neutral amino acids (e.g., leucine and isoleucine) compete with levodopa for absorption in the gut and for transport across the blood-brain barrier.
41
Q

What are the peripheral side effects of levodopa?

A
  1. Anorexia, nausea, vomiting (DA effect on the GIT).
  2. Tachycardia, hypotension, and ventricular extrasystoles (DA effect on the heart).
  3. Mydriasis (adrenergic receptor on the eyes).
  4. Brownish saliva and urine (melanin pigment produced from catecholamine oxidation).
42
Q

What are the central side effects of levodopa?

A
  1. Visual and auditory hallucinations.
  2. Dyskinesias (caused by DA overactivity at receptors).
  3. Mood changes (i.e., depression, psychosis, and anxiety).
43
Q

What are the drug-drug interactions with levodopa?

A
  1. Pyridoxine (B6) increases the peripheral breakdown of levodopa and diminishes its effectiveness.
  2. MAO-A inhibitors may produce hypertensive crisis caused by enhanced catecholamine production.
  3. Antipsychotic drugs, as they potently block dopamine receptors and produce a parkinsonian syndrome themselves.
44
Q

How are levodopa-induced psychiatric symptoms managed?

A

By using low doses of certain atypical antipsychotics.

45
Q

What are the two most common MAO-B inhibitors?

A

Selegiline.
Rasagiline.

46
Q

What is MAO-B?

A

Monoamine oxidase enzyme type B metabolites dopamine.

47
Q

How do MAO-B inhibitors work?

A

They selectively inhibit MAO type B (which metabolites dopamine), thereby decreasing the metabolism of dopamine in the brain, increasing dopamine levels in the brain.

Therefore, MAO-B inhibitors enhance the actions of levodopa when these drugs are administered together.

48
Q

How do MAO-B inhibitors enhance the actions of levodopa when these drugs are administered together?

A

MAO-B inhibitors prevent the metabolism of dopamine by MAO type-B enzyme, therefore decreasing the metabolism of dopamine that is associated with the levodopa-induced “on-off” phenomenon.

49
Q

Do MAO-B inhibitors help if they are taken alone?

A

No. They are meant to be taken alongside drugs like levodopa(+carbidopa) as they are ineffective on their own, as the endogenously available dopamine is not enough for MAO-B inhibitors to work.

50
Q

What is selegiline?

A

An irreversible and selective MAO type-B inhibitor.

51
Q

What is rasagiline?

A

An irreversible and selective MAO type-B inhibitor. It has 5 times the potency of selegiline.

52
Q

Describe the metabolism of selegiline.

A

Selegiline, unlike rasagiline, is metabolized to methamphetamine and amphetamine, producing insomnia and a caffeine-like buzz.

53
Q

How is the metabolism of rasagiline different from the metabolism of siligiline?

A

Rasagiline, unlike selegiline, is NOT metabolized to methamphetamine and amphetamine.

54
Q

Why should we take selegiline in the morning, at breakfast, or at lunch time?

A

Because its metabolites (methamphetamine and amphetamine) are stimulating.

55
Q

Why do both selegiline and rasagiline at recommended doses have a little potential for causing hypertensive crises?

A

Extreme caution should be practiced for when these drugs are used for Parkinsonian patients who also suffer from hypertension problems, as these drugs lose their selectivity at high doses and will inhibit MAO type-A alongside MAO type-B, causing a hypertensive crisis.

(Note: MAO type-A metabolites epinephrine and norepinephrine.)

56
Q

What are the two most common COMT inhibitors?

A

Tolacapone.
Entacapone.

57
Q

What is COMT?

A

Catechol-O-methyltransferase is an enzyme that converts levodopa into 3-O-methyldopa. In normal circumstances, this pathway is minor. However, when peripheral dopamine decarboxylase activity is inhibited by carbidopa, a significant concentration of 3-O-methyldopa is formed that competes with levodopa for active transport into the CNS.

(Note: COMT exists centrally and peripherally.)

58
Q

Why should we avoid the formation of high concentrations of 3-O-methyldopa when we treat Parkinsonian patients?

A

Because 3-O-methyldopa competes with levodopa for active transport into the CNS.

Methyldopamine is very weak and has negligible effect on dopamine receptors.

59
Q

What is entacapone?

A

A nitrocatechol derivative that selectively and reversibly inhibits COMT.

60
Q

What is tolacapone?

A

A nitrocatechol derivative that selectively and reversibly inhibits COMT.

61
Q

What are the pharmacokinetics of tolcapone?

A

Tolcapone has a relatively longer duration of action than entacapone and is also slightly more potent, probably due to its affinity for the COMT enzyme compared to entacapone.

62
Q

What are the pharmacokinetics of entacapone?

A

Its duration of action and potency is lower than tolcapone.

63
Q

What are the adverse effects associated with tolcapone?

A

Tolcapone causes side effects similar to the ones experienced with levodopa-carbidopa:
- Diarrhea.
- Postural hypotension.
- Nausea.
- Anorexia.
- Dyskinesias.
- Hallucinations.
- Sleep disorders.

However, tolcapone is known for its high hepatotoxicity, as fulminating hepatic necrosis is associated with tolcapone use. Dosage should be adjusted for patients with liver diseases.

64
Q

What are the adverse effects associated with tolcapone?

A

Entacapone causes side effects similar to the ones experienced with levodopa-carbidopa:
- Diarrhea.
- Postural hypotension.
- Nausea.
- Anorexia.
- Dyskinesias.
- Hallucinations.
- Sleep disorders.

Unlike tolcapone, which is known for its high hepatotoxicity, as fulminating hepatic necrosis is associated with tolcapone use, entacapone is NOT hepatotoxic and has largely replaced tolacapone.

65
Q

What are the two classes of dopamine-receptor agonists?

A
  1. Ergot-derivatives (older), such as: bromocriptine and pergolide, which are rarely used to treat parkinsonism as they are more toxic.
  2. Non-ergot derivatives (newer), such as: ropinirole, pramipexole, rotigotine, and apomorphine, which are considered as less toxic.
66
Q

How different are dopamine agonists from levodopa?

A

Dopamine agonists bind to dopamine receptors directly and restore dopaminergic neurotransmission.

These drugs, unlike levodopa, do not require enzymatic conversion into dopamine (like levodopa does), and do not undergo decarboxylation, so the issues associated with levodopa, such as its peripheral metabolism, the competition between levodopa and 3-o-methyldopa and other pathways that levodopa undergoes are not present with dopamine agonists. So, their usage is advantageous in this regard.

Also, their onset of action is more rapid, and their selectivity for specific dopamine receptors is high, which is also advantageous.

67
Q

Generally, when are dopamine agonists most useful?

A

In late stages of Parkinson disease, as levodopa’s therapeutic effect diminishes as less dopaminergic neurons are available to convert it into dopamine.

68
Q

How effective is bromocriptine? What are the most dangerous side effects associated with bromocriptine?

A

Its actions are similar to those of levodopa. However, hallucination, confusion, delirium, nausea, and orthostatic hypotension are much more common than levodopa, whereas dyskinesias are less prominent.

More dangerously, bromocriptine is known to cause pulmonary fibrosis, retroperitoneal fibrosis, and vasoconstriction and vasospasm.

Due to its high side effects, dopamine agonists are not used frequently.

69
Q

Why are newer generation non-ergot dopamine agonists used more often?

A

They have a long duration of action and have lower fluctuation, so combination of levodopa with dopamine agonists greatly reduces the fluctuation associated with levodopa use, therefore the incidence of the “on-off” phenomena associated with levodopa use is lower.

70
Q

Mention the two dopamine agonists that alleviate motor deficits in both levodopa-naive patients and patients with advanced Parkinson disease who are taking levodopa?

A

Apomorphine.
Rotigotine.

71
Q

Who are ropinirole and pramipexole most useful for?

A

They are effective in patients with advanced Parkinson’s disease complicated by motor fluctuations and dyskinesia.

They may:
- Delay the need to use levodopa therapy in early Parkinson disease.
- Decrease the dose of levodopa in advanced Parkinson disease.

72
Q

What are the side effects associated with non-ergot dopamine agonists?

A

Serious cardiac problems (i.e., cardiac arrythmias).
Peptic ulcers (avoid using for patients with active ulcers).

73
Q

Which anti-Parkinson drug is used as an injection to acutely manage the “off” hypomotility phenomena associated with levodopa use?

A

Apomorphine.
It is used in severe and advanced stages of the disease to supplement the oral medication.

74
Q

What is amantadine?

A

An antiviral drug used in the treatment of influenza that was found to also help manage Parkinsonian symptoms.

75
Q

How does amantadine relieve parkinsonian symptoms?

A
  1. By increasing the release of dopamine.
  2. By blocking cholinergic receptors.
  3. By inhibiting NMDA-type of glutamate receptors (neuroprotective).
76
Q

Compare amantadine to levodopa.

A

Amantadine is less efficient than levodopa but has fewer side effects. However, it can cause mottled skin.

77
Q

What are the most common antimuscarinic agents?

A

Benztropine.
Trihexyphenidyl.
Procyclidine.
Biperiden.

78
Q

How do antimuscarinic drugs work for managing parkinsonian symptoms?

A

They inhibit acetylcholine neurotransmission, thereby reducing motor effects associated with Parkinsons disease.

79
Q

What are the side effects of antimuscarinic effects?

A

Mood changes (dementia).
Xerostomia.
Visual problems.

80
Q

For which patients are antimuscarinic patients contraindicated for?

A

Glaucoma patients.
Prostatic hyperplasia patients.
Pyloric stenosis patients.

Pharmacology MidTerm (8 decks)

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