Neurodegenerative

Question 1

How DO THE CNS DRUGS WORK

Answer 1

act presynaptically by influencing the
production, storage, release, or termination of action of
neurotransmitters. Other agents may activate or block postsynaptic
receptors.

Question 2

How does the excitatory pathway work

Answer 2

Simulation —— depolarization of post synaptic membrane ——–EPSP——all or non Action potential

Question 3

How does the inhibitory pathway work

Answer 3

Stimulation ——- hyperpolarization—— influx of cl—— IPSP—- pushing it away from the threshold—— no more action potentials

Question 4

• Most neurons in the CNS receive both EPSP and IPSP input.
• Thus, several different types of neurotransmitters may act on the
same neuron, but each binds to its own specific receptor.
• The overall resultant action is due to the summation of the
individual actions of the various neurotransmitters on the neuron.

Question 5

Give examples on neurodegenerative disorders

Answer 5

• Parkinson disease,
• Alzheimer disease,
• Multiple sclerosis (MS), and
• Amyotrophic lateral sclerosis (ALS).

Question 6

What are the characteristics of neurodegenerative disorders

Answer 6

progressive
loss of selected neurons in discrete brain areas, resulting in
characteristic disorders of movement, cognition, or both.

For example, Alzheimer’s disease is characterized by the loss of
cholinergic neurons in the nucleus basalis of Maynert, whereas
Parkinson’s disease is associated with a loss of dopaminergic
neurons in the substantia nigra.

Question 7

What is Parkinson and what are the symptoms

Answer 7

• Also called paralysis agitata (الرعاشي الشلل(.

• A progressive neurological disorder of muscle movements.

• Symptoms: tremors, muscle rigidity, bradykinesiaالحركة بطء ,
akinesia, postural & gait abnormalities, shuffling gait, falls
(because the upper part of the body may move faster than the
feet), mask-face, microphonia صوت

• RAFT: rigidity of the skeletal muscles, akinesia (or
bradykinesia), flat facies, and tremor at rest.

• Many cases are overlooked by relatives who consider it normal
aging.

• Could be naturally occurring or drug-induced parkinsonism.

• Symptoms fluctuate between increased and decreased severity
(on-off phenomenon).

Question 8

What is PATHOPHYSIOLOGY OF PARKINSON

Answer 8

The substantia nigra is the source of
dopaminergic neurons that terminate in the
neostriatum.
In Parkinson disease, destruction of cells
in the substantia nigra results in the
degeneration of the nerve terminals
responsible for secreting dopamine in the
neostriatum.
This triggers a chain of abnormal
signaling, resulting in loss of the control of
muscle movements.

Less cells—–less dopa—-loss of inhibition of ach production ——– more ach——– impaired mobility

Question 9

How do we treat Parkinson

Answer 9

Therapy aims at ↑ dopaminergic &/or ↓ cholinergic
neurotransmission thus reestablishing the correct
dopamine/acetylcholine balance.

• Genetic factors do not play a dominant role in the etiology of
  Parkinson’s disease, although they may exert some influence on
  an individual’s susceptibility to the disease.

Question 10

What drugs do we use for Parkinson

Answer 10

1- levodopa and carbidopa
2-selegiline and rasagiline
3- comt inhibitors
4- dopamine agonists
5-amantadine
6-antimuscarinic agents

Alleviate some symptoms but do not stop or reverse neuronal
degeneration

Question 11

What is LevoDopa

Answer 11

is actively transported through BBB, enters into
dopaminergic neurons remaining in substantia nigra, where it is
converted to dopamine (by DOPA decarboxylase) & is then stored
& released by these neurons replenishes dopamine deficiency.
 Levodopa ↓ motor symptoms of parkinsonism.
-With decreasing no. of dopaminergic neurons, levodopa loses
efficacy.
Decline in response during the 3
rd to 5
th year.
-Levodopa decarboxylated in GIT & peripheral tissues causes s/e.

Question 12

What is carbidopa

Answer 12

a dopa decarboxylase inhibitor that does not cross
the BBB.
↑ conc of dopamine in the CNS
↓ the required dose of levodopa by four- to five-fold
↓ peripheral side effects.
• Levodopa in combination with carbidopa is an efficacious
drug regimen for the treatment of Parkinson’s disease.

• Without carbidopa, much of the drug is decarboxylated to
dopamine in the periphery, resulting in nausea, vomiting,
cardiac arrhythmias, and hypotension.

Question 13

What’s the dynamics, side effects and interactions of levodopa/carbidopa

Answer 13

Absorption and metabolism:
Short t1/2fluctuation in conc. on-off phenomenon.
Food ↓ absorption, esp. if rich in protein, which interfere with
absorption & transport of levodopa into the CNS.
 Take levodopa 45 minutes before a meal.
Adverse effects:
a. Peripheral effects:
- Anorexia, nausea, and vomiting. Tachycardia, ventricular
extrasystoles result from dopaminergic action on the heart.
Hypotension may also develop.
- Saliva and urine become brownish in color because of the
melanin pigment produced from catecholamine oxidation.
b. CNS effects: visual & auditory hallucinations, dyskinesia,
mood changes, depression, psychosis, and anxiety.

Interactions with
• The vitamin pyridoxine (B6
) increases the
peripheral breakdown of levodopa and
diminishes its effectiveness.
• Concomitant administration of levodopa and
non-selective MAOIs, such as phenelzine, can
produce a hypertensive crisis caused by
enhanced catecholamine production. Therefore,
concomitant administration of these agents is
contraindicated.
• Levodopa can exacerbate glaucoma.
• Levodopa can cause arrhythmias in cardiac
patients.
• Antipsychotic drugs are contraindicated in
parkinsonian patients (relative C/I

Question 14

What are Selegiline and Rasagiline and their side effects

Answer 14

elegiline is also called deprenyl.
A selective inhibitor of MAO type B (metabolizes dopamine) at
low to moderate doses.
•  lowers the required dose of levodopa and and may reduce
mild on-off or wearing-off phenomena.
Does not inhibit MAO Type A (metabolizes norepinephrine and
serotonin) unless given above recommended doses, where it
loses its selectivity.
A/E:
- Hypertension at high doses.
- Selegiline is metabolized to methamphetamine and
amphetamine, whose stimulating properties may produce
insomnia if the drug is administered later than mid-afternoon.

Rasagiline, an irreversible and selective inhibitor
of brain MAO type B, has five times the potency of
selegiline and is NOT metabolized to an
amphetamine-like substance.

Question 15

What are Catechol-O-methyltransferase inhibitors (comt inhibitors)

Answer 15

Entacapone & Tolcapone selectively and reversibly inhibit COMT

-when peripheral dopa decarboxylase activity is inhibited by carbidopa ——– comt start to compete with LevoDopa

• inhibiting comt leads to less comt concentrations in plasma—– more uptake of LevoDopa

Reduce the symptoms of “wearing-off” phenomena seen in patients on
levodopa–carbidopa.

Question 16

What are the kinetics of comt inhibitors and side effects

Answer 16

Oral absorption occurs readily and is not influenced
by food. They are extensively bound to plasma albumin, Both drugs are
extensively metabolized and eliminated in feces and urine. The dosage
may need to be adjusted in patients with moderate or severe cirrhosis.
- A/E: similar to levodopa-carbidopa
- Tolcapone caused fulminating hepatic necrosis replaced by
entacapone

Question 17

What are the different classes of dopamine agonists

Answer 17

a) Bromocriptine (an ergot derivative)

b) Ropinirole, pramipexole, rotigotine and the newer agent, apomorphine
(nonergot drugs).

• These agents have a longer duration of action than that of levodopa and are
effective in patients exhibiting fluctuations in response to levodopa.
- Initial therapy with the newer drugs is associated particularly with less risk
of developing dyskinesias and motor fluctuations when compared to
patients started with levodopa therapy.
• However, these drugs are ineffective in patients who have
• not responded to levodopa.
- Rotigotine is available as transdermal delivery systems.
 provides even pharmacokinetics over 24 hours..
- Apomorphine is an injectable dopamine agonist that is used in severe and
advanced stages of the disease.

Question 18

What is bromocriptine

Answer 18

The actions of bromocriptine are similar to those of levodopa,
except that hallucinations, confusion, delirium, nausea, and
orthostatic hypotension are more common, whereas dyskinesia
is less prominent.
- May worsen myocardial infarction, peripheral vascular disease,
and peptic ulcer (used with caution).
- Because bromocriptine is an ergot derivative, it has the potential
to cause pulmonary fibrosis.

Question 19

What are Pramipexole, ropinirole, rotigotine, & apomorphine:

Answer 19

• Apomorphine is used for acute management of the hypomobility “off”
phenomenon in advanced Parkinson’s disease.
• Delay the need to employ levodopa therapy in early Parkinson’s disease and
may decrease the dose of levodopa in advanced Parkinson’s disease.
- Do not exacerbate peripheral vasospasm and do not cause fibrosis.
- Dyskinesias are less frequent than with levodopa.
• Pramipexole is mainly excreted unchanged in the urine, and dosage
adjustments are needed in renal dysfunction.
A/E: Nausea, hallucinations, confusion, insomnia, dizziness, constipation, and
orthostatic hypotension.
Interactions:
- Cimetidine inhibits renal tubular secretion of pramipexole
 ↑ the half-life of pramipexole by 40 percent.
• The fluoroquinolone antibiotics and other inhibitors of CYP1A2 isoenzyme
may inhibit the metabolism of ropinirole, requiring an adjustment in
ropinirole dosage.

Question 20

What’s amantadine

Answer 20

• An antiviral that has several effects on a number of
neurotransmitters implicated in parkinsonism, including:
- increasing release of dopamine from surviving neurons
- blocking cholinergic receptors
- inhibiting the N-methyl-D-aspartate (NMDA) glutamate receptors.
It is indicated mainly for rigidity & bradykinesia of PD, but its effect
on tremor is weak.
• Side effects: agitation, restlessness, confusion & hallucinations,
and at high doses, it may induce acute toxic psychosis.
• Orthostatic hypotension, urinary retention, peripheral edema, and
dry mouth also may occur.
- Amantadine is less efficacious than levodopa.
• Tolerance to amantadine develops rapidly

Question 21

What antimuscarinic agents do we use for Parkinson

Answer 21

Benztropine, trihexyphenidyl, procyclidine, & biperiden.
-They decrease the excessive cholinergic activity
-Much less effective than levodopa
play only an adjuvant role in antiparkinsonism therapy.
• Blockage of cholinergic transmission produces effects similar to
augmentation of dopaminergic transmission, since it helps to
correct the imbalance in the dopamine/acetylcholine ratio.
-Indicated mainly for tremor & rigidity of PD but less effective for
bradykinesia.
-A/E: similar to those caused by high doses of atropine:
• Xerostomia, constipation, visual problems, confusion, &
hallucination.
- Contraindicated in patients with glaucoma or prostatic hyperplasia.

Question 22

What’s secondary Parkinsonism

Answer 22

Drug induced

• Antipsychotic drugs such as the phenothiazines and
haloperidol, whose major pharmacologic action is
blockade of dopamine receptors in the brain, may
produce parkinsonian symptoms.
• These drugs should be used with caution in patients with
Parkinson’s disease.