Neurodegenerative diseases Flashcards
What are the most common Neurodegenerative disease and what are the courses?
Parkinson disease
Alzheimer disease
MS
ALS
These diseases arise due to the reduction of neurons in the brain. This leads to development of characteristics such as movement disorder, cognition
What is the mechanism of Parkinson.
This is due to a reduction(degeneration) of dopamine neurons found in the substantia nigra. The substantia niga is part of the basal ganglia and it controls movement
. Dopamine is found in 4 pathways and the Neostriatum is responsible for sending GABA neurons to the Substantia nigra and it is also responsible for movement this is where the anti-parkinson medications specifically work
*Substantia nigra= role is to send dopamine neurons to the neostriatum
Mechanism pathway od dopamine
Tyrosine hydroxylase converts Tyrosine=Ldopa
Dopa decarboxylase is converted from L Dopa to Dopamine
Why do we need to provide large dose of Levodopa
Large doses of levodopa are required, because much of the drug is decarboxylated to dopamine in the periphery, resulting in side effects that include nausea, vomiting, cardiac arrhythmias, and hypotension.
additionally within the first hour or two the dopamine can be broken down by different enzymes in the brain. This can appear that the drug is not working
Why do we provide Levodopa and Carbidopa together
Okay, so another thing to keep in mind is that DOPA decarboxylase exists outside the CNS as well, such as the GI which can increase dopamine levels in the rest of the body. This can cause unwanted side effects like nausea, vomiting, anorexia, and orthostatic hypotension.
These problems can be lessened by taking lower doses more frequently throughout the day.
A more problematic side effect is that dopamine is enzymatically metabolized into other catecholamines, like epinephrine, which can cause tachycardia or even arrhythmias.
This is why levodopa is administered with carbidopa, a DOPA decarboxylase inhibitor that doesn’t cross the blood-brain barrier, so it prevents the conversion of Levodopa into dopamine outside the CNS, such as the GI.
What are Levodopa and Carbidopa used for
To decrease rigidity, tremors and other symptoms associated with parkinson.
What are the side effects of Levodopa and Carbidopa
Anorexia, nausea and vomiting
Tachycardia and Hypotension
Mydriasis due do adrenergic action. Saliva and Urine are brown in colour
visual and auditory hallucinations and abnormal involuntary movements (dyskinesias) may occur..
mood changes, depression, psychosis, and anxiety.
However, taking too much vitamin B-6 from supplements can cause: A lack of muscle control or coordination of voluntary movements (ataxia) Painful, disfiguring skin lesions. Heartburn and nausea.
Antipsychotics contraindicated
cardiac pt be carful along with pt who have Glaucoma as this can increase the intraocular pressure
What is the mechanism of Ropinirole (dopamine receptor agonist)
Now, a different strategy is to use dopamine-receptor agonists, which are molecules that are not dopamine, but can bind to the dopamine receptors and stimulate them. These include bromocriptine, pramipexole, and ropinirole.
These medications have a short half-life and are used alone or together with levodopa when the patient no longer responds to levodopa alone, or when it starts causing motor complications.
Bromocriptine causes a number of side effects, like nausea, vomiting, somnolence, and pulmonary fibrosis.
So pramipexole and ropinirole are preferred over bromocriptine because they cause fewer side effects, but they can still cause somnolence, which in rare cases can be so unpredictable that they lead to car crashes.
Pramipexole and ropinirole can also cause hallucinations and confusion.
Side effect= dizziness when you get up from sitting or lying down.
feeling tired and weak.
stomach pain.
heartburn.
feeling sick or being sick.
feeling anxious or nervous.
uncontrollable twitching or twisting movements – this is more likely if you’ve been taking ropinirole for a long time or at a high dose.
Alternatibe antiparkinson drug mechanism
COMT inhibitor
The first group of medications that do this inhibit an enzyme within the dopaminergic neurons called catechol-o-methyltransferase, or COMT, which degrades dopamine to 3-methoxytyramine and levodopa to 3-O-methyldopa.
COMT inhibitors like entacapone and tolcapone prevent the peripheral enzyme from degrading levodopa, and therefore allows more levodopa to get into the brain.
But only tolcapone can cross the blood brain barrier to enter the central nervous system, where it can prevent COMT from degrading dopamine.
COMT inhibitors are used together with levodopa
MAO-B mechanism
The next group of medications are the MAO-B inhibitors, which block the enzyme monoamine oxidase B, or MAO-B.
This enzyme breaks down dopamine to 3, 4-dihydroxyphenylacetic acid, or DOPAC, in the central nervous system, but it can also break down other neurotransmitters like serotonin and norepinephrine. Because of this, they can also be used as antidepressants. The main medications in this group include selegiline and rasagiline
This drug is used in combination with L-dopa and carbidopa
Amantadine drug mechanism
The last medication is amantadine, which is also an antiviral medication that’s thought to increase dopamine release and decrease its reuptake, but the mechanism is still not completely understood.
It isn’t very potent, and it’s used as initial treatment of mild Parkinson’s disease, or together with levodopa to reduce motor complications.
Side effects like lethargy, GI distress, and strange dreams are uncommon and usually mild when they’re present.
Anticholinergic drug mechanism
Drugs like Trihexyphenidyl are anti muscarinic drugs used to treat parkinson symptoms such as stiffness, tremors, spasms, poor muscle control and also control moods. side effect: dizziness or blurred vision. dry mouth. upset stomach. vomiting. constipation. headache. difficulty urinating.
Epilepsy drugs for seizure. Benzodiazepines
Such as Diazepam and Clonazepam used for partial and generalised treatment for seizures. It is useful as it binds to GABA receptors this inhibits the excitations of neuron transmission.
Epilepsy drugs for seizure Carbamazepine
These drugs work by blocking the sodium channels thus inhibiting propagations of abnormal impulses in the brain and for the message to be continued to be pass on. As Na+ ion channel is excitatory.
Carbamazepine is effective for treatment of partial seizures and, secondarily, generalized tonic-clonic seizures. It is also used to treat trigeminal neuralgia and bipolar disorder.
Carbamazepine should not be prescribed for patients with absence seizures because it may cause an increase in seizures.
Side effect-
Hyponatremia, drowsiness, fatigue, dizziness, and blurred vision. Drug use has also been associated with Stevens-Johnson syndrome. Blood dyscrasias: neutropenia, leukopenia, thrombocytopenia, pancytopenia, and anemias.
Epilepsy drugs for seizure Ethosuximide
Ethosuximide [eth-oh-SUX-i-mide] reduces propagation of abnormal electrical activity in the brain, most likely by inhibiting T-type calcium channels. It is effective in treating only primary generalized absence sei- zures (see Figure 15.5). Use of ethosuximide is limited because of this very narrow spectrum of activity.
Side effect
Drowsiness, hyperactivity, nausea, sedation, GI upset, weight gain, lethargy, SLE, and rash. Blood dyscrasias can occur; periodic CBCs should be done. Abrupt discontinuance of drug may causes seizures.
