Brief Summary
Alright, so this video is all about Parkinson's medications, going over the pathophysiology, anatomy, and pathways involved in Parkinson's disease before diving into the mechanism of action and specific drugs. Key takeaways include:
- Understanding the basal ganglia anatomy and the direct vs. indirect pathways.
- Recognizing the pathophysiology of Parkinson's, particularly the decrease in dopamine.
- Knowing the different drug classes and their mechanisms to increase dopamine or decrease acetylcholine.
Parkinson’s Disease Medications Introduction
The video is about Parkinson's medications. Before discussing the names, mechanisms, and adverse effects of these medications, it's important to understand the basic pathophysiology, anatomy, and pathways involved in Parkinson's disease.
Basal Ganglia Anatomy
The basal ganglia includes the caudate nucleus, lentiform nucleus (putamen, globus pallidus externus, and internus), thalamus, subthalamus, and substantia nigra. The caudate and putamen together are called the striatum, which is where dopaminergic neurons connect. In Parkinson's disease, destruction of neurons in the substantia nigra alters dopamine input to the striatum, impacting the nigrostriatal pathway.
Direct vs. Indirect Pathway
The direct pathway helps initiate desired motor movements, while the indirect pathway prevents unwanted motor movements. Cortical neurons release glutamate onto striatal neurons. In the direct pathway, these neurons extend to the globus pallidus internus, releasing GABA. The substantia nigra releases dopamine onto D1 receptors, stimulating the direct pathway and increasing motor movement. In the indirect pathway, neurons go to the globus pallidus externus, then to the subthalamic nucleus, and back to the globus pallidus internus. The substantia nigra releases dopamine onto D2 receptors, inhibiting this pathway.
Pathophysiology of Parkinson’s Disease
In Parkinson's disease, there is destruction of the substantia nigra, leading to decreased dopamine in the striatum. This imbalance between dopamine and acetylcholine results in decreased movement, tremors, rigidity, and postural instability. The goal of Parkinson's medications is to increase dopamine in the striatum and decrease acetylcholine to restore balance.
Drug Classes for Parkinson’s Disease
To increase dopamine, medications include L-Dopa, dopamine agonists, COMT inhibitors, MAO-B inhibitors, and amantadine. To decrease acetylcholine, anticholinergics are used.
Mechanism of Action
Tyrosine is converted to L-Dopa by tyrosine hydroxylase, then to dopamine by dopa decarboxylase. Dopamine is stored in vesicles and released into the synapse. After exerting its effect, dopamine is either re-uptaken or broken down by MAO-B or COMT. L-Dopa can cross the blood-brain barrier and be converted to dopamine in the brain. Dopamine agonists bind directly to dopamine receptors. COMT and MAO-B inhibitors prevent the breakdown of dopamine. Amantadine increases dopamine synthesis and release while inhibiting reuptake. Anticholinergics block muscarinic receptors, reducing the effect of acetylcholine.
L-Dopa + Carbidopa
L-Dopa is a first-line drug, especially for patients over 65. It is often given with carbidopa, which inhibits dopa decarboxylase, preventing the conversion of L-Dopa to dopamine in the periphery. This ensures more L-Dopa crosses the blood-brain barrier and reduces adverse effects. Adverse effects of elevated dopamine include tachycardia, orthostatic hypotension, anxiety, delirium, hallucinations, psychosis, impulse control issues, nausea, and vomiting. High doses of dopamine can also cause dyskinesia. The on-off phenomenon occurs as the disease progresses, and there are fewer neurons to utilize L-Dopa.
Dopamine Agonists
Dopamine agonists directly stimulate dopamine receptors. Ergot derivatives (like bromocriptine) are less commonly used due to side effects. Non-ergot derivatives (pramipexole and ropinirole) can be considered first-line agents in patients under 65. They can cause behavioral changes (due to effects on the mesolimbic pathway) and emesis. Ergot derivatives can also cause fibrosis and vasospasm.
COMT-Inhibitors
COMT inhibitors prevent the breakdown of dopamine. Tolcapone inhibits both central and peripheral COMT but is hepatotoxic. Entacapone inhibits peripheral COMT, increasing L-Dopa uptake. They are adjuncts to L-Dopa and carbidopa, often used in the on-off phenomenon. Adverse effects include hepatotoxicity (tolcapone), nausea, vomiting, and behavioral changes.
MAO-B-Inhibitors
MAO-B inhibitors prevent the breakdown of dopamine by inhibiting monoamine oxidase B enzymes. Selegiline and rasagiline are MAO-B inhibitors, often used as adjuncts to levodopa and carbidopa. At high doses, they can inhibit monoamine oxidase A, leading to hypertensive crisis (especially if taken with tyramine) or serotonin syndrome.
Amantadine
Amantadine stimulates dopamine synthesis and release and inhibits dopamine reuptake. It may be neuroprotective and is used as an adjunct to levodopa and carbidopa, particularly in akinetic crisis. Adverse effects are mild but can include nausea, vomiting, behavioral changes, ataxia, livedo reticularis, and peripheral edema.
Anticholinergics
Anticholinergics block muscarinic receptors, reducing the effect of acetylcholine. Benztropine and trihexyphenidyl are used to inhibit tremors and rigidity. Adverse effects include delirium, pupil dilation, dry eyes and mouth, tachycardia, hypertension, hypothermia, constipation, and urine retention.
PD Medications - Practice Problems
A 75-year-old man with moderate Parkinson's disease no longer responds to anticholinergic treatment. A good treatment plan would be levodopa and carbidopa with entacapone. Peripheral adverse effects of levodopa include nausea, hypotension, and cardiac arrhythmias, which can be diminished by including carbidopa in the therapy. Bromocriptine is an anti-Parkinsonian drug that may cause vasospasm.
