85-year-old (male) with Parkinson's disease

00:02 An 85 year old male is brought to the physician by his wife for reappearance of his Parkinson’s symptoms for the last few months.

00:08 He has been treated with various drugs over the last 20 years.

00:12 The patient’s wife says that his symptoms are worse as he nears the time for the next dose of medication.

00:18 The patient’s movements have been slower and it’s difficult to initiate voluntary movements.

00:23 He was diagnosed with hypertension 10 years ago and has been compliant with his medications.

00:28 His current medications are carbidopa/levodopa, rasalagine, aspirin and captopril.

00:34 Vitals are a pulse 70, respirations 15, blood pressure 130/76 and temperature of 36.7 degrees celsius.

00:45 Examination reveals the expected, ‘pill-rolling’ resting tremor which is alleviated by movement.

00:51 Increased tone of arm muscles and resistance to passive movements at joints is noted.

00:57 When asked to walk across the room, he has difficulty taking the first step and has a stooped posture and takes short, rapid steps.

01:04 Laboratory examination reveal: serum glucose fasting of 97 (mg/dL), sodium 141 (mEq/L), potassium 4.0 (mEq/L), Chloride 100 (mEq/L), Cholesterol, total 190 (mg/dL), HDL (mg/dL), LDL 70 (mg/dL), and Triglycerides 184 (mg/dL).

01:20 He is started on a drug that increases the efficacy of his current anti-Parkinson’s medications.

01:25 Which of the following is most likely added to his current medication regimen? Answer choice (A) - Benztropine Answer choice (B) - Selegiline Answer choice (C) - Atorvastatin Answer choice (D) - Entacapone Answer choice (E) - Bromocriptine Now take a moment to come to an answer yourself before we go through it together.

01:49 Now let's jump right in.

01:51 Now let's first tackle the question characteristics.

01:54 Now this is a question that concerns both pathology and pharmacology.

01:58 We have to be aware that this is Parkinson's disease but we must be able to understand the underlying pharmacology of the medications listed in the answer choices.

02:07 Now this is a 2-step question.

02:08 We have to first determine what each of these medications does but then be able to as a second step determine which of the following medications will actually help increase the efficacy of his current Parkinsons medication regimen.

02:23 And the stem is absolutely required in this case because we need to know the patient's history, his clinical progression and what medications he's on and we need to look at the laboratory values.

02:33 So let's walk through this question together.

02:36 Step 1 - we have to determine the likely diagnosis.

02:39 Well it's clear this patient has Parkinsons disease but the key here in the diagnosis, is that the patient is showing "end-of-dose" deterioration or it's also called 'wearing-off' where Parkinsonian symptoms seem to worsen a few hours before the next dose of carbidopa/levodopa is required.

02:57 Now, end-of dose deterioration is seen after long term use of carbidopa/levodopa in advanced parkinsons disease.

03:05 and that's very important to know to appreciate the diagnosis in a clinical setting.

03:09 Now looking at the patient's vitals and labs, his blood pressure is unremarkable and his blood labs are grossly unremarkable except that he has a slightly raised triglyeride level.

03:20 Now step 2 - let's determine which drug would increase the efficacy of his current carbidopa/levodopa medication.

03:28 Now inhibitors of the catechol-O-methyltransferase or COMT inhibitors increase the efficacy of carbidopa/levodopa by inhibiting the breakdown of catecholamine neurotransmitters.

03:43 now let's refer to our image to better understand this pathway.

03:48 Now we can see on the image that we have a split between the peripheral and central nervous system.

03:53 Now let's look at the left side first, we have the peripheral system.

03:56 Now there in the middle we see L-Dopa.

03:59 Now L-Dopa can be broken down in two different ways to give you either dopamine or another substance.

04:05 Now what we want is peripherally for L-Dopa to remain unchanged so that it can cross the blood-brain barrier and go in to the central nervous system.

04:15 And then we convert it to dopamine where it can affect the basal ganglia and help us with our movement disorder in parkinsons disease.

04:23 we dont want to lose our L-Dopa peripherally thus we want to give medications to prevent the L-dopa breakdown peripherally.

04:30 Now levodopa is the medication we're looking at there in the middle.

04:34 Now if you've noticed, Sinemet or carbidopa/levodopa always go together.

04:38 And that's because carbidopa prevents the peripheral breakdown of L-dopa into dopamine.

04:44 now the medication in this case we're recommending as a possibility are what are called COMT inhibitors.

04:49 now if you see there, COMT also helps break, inhibit the breakdown of the COMT inhibitor so that you don't break down your L-Dopa.

04:58 So Tolcapone , Entacapone will prevent the COMT inhibitor from breaking it down.

05:03 So thus with both carbidopa on board, and a -capone, we can prevent peripheral breakdown of L-Dopa and have them cross the blood brain barier into a higher concentration dose into the central system.

05:15 Then centrally, we can see that again, the COMT will help us.

05:18 It will help prevent even central breakdown of dopamine and increase the central dose of the -capone.

05:24 So there's Tolcapone again helping us out.

05:27 And here is another point, you can just see that if you use low dose Selegeline or if you use Rasalagine, you can also then prevent, these are both MAO inhibitors, you can also inhibit the central breakdown of dopamine and increase dopamine levels centrally again you have to give more at the basal ganglia to help the Parkinsons.

05:44 So thus we can see how the -capones or the COMT inhibitors and also even here the MNLB inhibitors can actually help us in increasing dopamine peripherally and centrally respectively.

05:57 Now, so what we've shown here is that inhibitors of catechol-O-methyltransferase will actually increase the efficacy of carbidopa/levodopa because we'll have more levodopa in the total form peripherally which can then go centrally, and even centrally will stay more as dopamine as opposed to being broken down.

06:17 Now of the answer choices, Entacapone is a selective and reversible COMT inhibitor.

06:23 Now if we look in the patient's medication list, the patient's already on Rasalagine which is a MAO-B inhibitor which as we can see on the image also helps keep dopamine levels elevated centrally.

06:35 Thus, the answer to this question is answer choice (D)- Entacapone as it will keep levels of dopamine higher by preventing peripheral breakdown of L-dopa.

06:46 Now let's go through some high-yield facts of Parkinsons disease.

06:49 Now levodopa remains the most effective symptomatic treatment for Parkinsons disease.

06:55 levodopa is always given with a peripheral decarboxylase inhibitor carbidopa most consistently or benserazide to reduce its conversion to dopamine allowing lower doses of levodopa to be given to reduce side effects.

07:09 With advancing disease, there is progression of loss of neurons with a duration of effect, each levodopa dose will shorten and the return of symptoms some hours before the next dose and this is called 'end-of-dose deterioration' or 'wearing off'.

07:23 Now, end of dose deterioration can be improved at least initially by increasing the frequency of levodopa doses or by adding a COMT inhibitor such as Entacapone which reduces the breakdown of catecholamine neurotransmitters both peripherally and centrally.