In this lecture we’re gonna cover the pharmacology
of drugs for Parkinson’s disease. So let’s get right into it. Parkinson’s disease is a neurological disorder
that results in a progressive loss of coordination and movement. Now, the neurons responsible for coordinating
movement are located in a part of the brain called the striatum, which receives information
from two major sources — the neocortex and a region known as the substantia nigra. The cortex relays sensory information as well
as plans for future action, while the substantia nigra sends dopamine that helps to coordinate
all of the inputs. Now, Parkinson’s disease develops when the
neurons connecting the substantia nigra to the striatum progressively degenerate. Since dopaminergic neurons that originate
in the substantia nigra normally exert inhibitory effects on GABA neurons located in the striatum,
too little dopamine results in more GABA causing increased inhibition of the thalamus, as well
as reduced excitatory input to the motor cortex. In addition to that, these same dopaminergic
neurons also exert inhibitory effects on the excitatory cholinergic neurons in the striatum. And again, without sufficient levels of dopamine
the production of acetylcholine is increased, which triggers a chain of abnormal signaling
leading to impaired mobility. Ultimately this imbalance between inhibitory
and excitatory activities leads to the manifestation of typical clinical symptoms that include
resting tremor, rigidity, postural instability, and slowed movement. The pharmacological therapy for Parkinson’s
disease is aimed at replenishing dopamine levels, mimicking dopamine’s action, or
antagonizing the excitatory effects of cholinergic neurons. Now, in order to get a better understanding
of the pharmacology of antiparkinson agents, first we need to take a closer look at the
dopamine producing neuron. So, here, inside this dopaminergic neuron,
dopamine is synthesized in a two-step process starting with the amino acid tyrosine. First, with the help of enzyme tyrosine hydroxylase
(TH), tyrosine gets converted to L-dopa, also known as levodopa. In the second step, the L-dopa formed by tyrosine
hydroxylation is quickly decarboxylated by another enzyme called aromatic L-amino acid
decarboxylase (AADC), to the neurotransmitter dopamine. Dopamine is then loaded into synaptic vesicles
and released by physiological stimuli into the extracellular space where it can bind
to dopamine receptors that are expressed on the postsynaptic neuron. Finally, excess dopamine in the synapse is
reuptaken back into the neuron, or into glial cells where it gets metabolized by Monoamine
Oxidase (abbreviated MAO) and Catechol-O-methyltransferase (abbreviated COMT). It’s important to note that while the MAO
enzyme exists in two forms, known as type A and type B, the type that is predominantly
found in the glial cells is the MAO type B. Now, let’s move on to discussing drugs used
in treatment of Parkinson’s disease starting with one of the most commonly used drugs that
is Levodopa. But first things first, you may wonder, well
why would you use the precursor of Dopamine instead of Dopamine itself. And the answer is, it’s because of the blood-brain
barrier. Blood-brain barrier is a tightly packed layer
of endothelial cells that restricts free access of molecules between the blood and the brain. Dopamine happens to be one of those molecules
that cannot freely pass through this barrier, however, Levodopa can, with a little bit of
help. One of the biggest problems Levodopa faces
on it’s own is peripheral metabolism. There are two major enzymes in periphery,
which cause breakdown of levodopa before it can reach the brain, that is; peripheral dopa-
decarboxylase (DDC), which converts levodopa to dopamine, and catechol- O- methyltransferase
(COMT), which converts levodopa to 3-O-methyldopa (3-OMD). Because of this, Levodopa must be administered
with another agent called Carbidopa, which inhibits dopamine decarboxylase and thus reduces
metabolism of Levodopa in the periphery. Another agent that is used in combination
with Levodopa and Carbidopa is Entacapone, which inhibits peripheral COMT and thus just
like Carbidopa, it prolongs the time that Levodopa is available to the brain. Now, Levodopa is carried across blood-brain
barrier by amino acid transporter. Once inside the brain, Levodopa is efficiently
converted to dopamine thus supplementing depleted dopamine levels in the midbrain. However, lets not forget that dopamine is
also susceptible to breakdown by COMT as well as MAO-B, which convert dopamine to 3-methoxytyramine
(3-MT) and 3,4dihydroxyphenylacetic acid (DOPAC) respectively. So, here another useful drugs come into play,
namely Selegiline and Rasagiline, which selectively inhibit MAO-B, and Tolcapone, which inhibits
COMT. As a side note here, in comparison to Entacapone,
Tolcapone can better penetrate the blood–brain barrier, and thus can act both in the central
nervous system and in the periphery. So, again, as you can see, by decreasing the
metabolism of dopamine, these drugs help to increase dopamine levels in the brain. Unfortunately, because Parkinson’s is a
progressive disease, with time, the number of dopamine producing neurons decreases, and
fewer cells are capable of making dopamine. Taking that into consideration, some drugs
have been developed to mimic dopamine and directly stimulate dopamine receptors in the
brain. Drugs that belong to this class include; Bromocriptine,
Ropinirole, Pramipexole, Rotigotine, and Apomorphine. Now, as I mentioned at the beginning of this
lecture, in Parkinson’s disease, dopamine depletion leads to increased acetylcholine
release, which then activates muscarinic receptors located on the neurons responsible for smooth
motor control. The overstimulation of these neurons by acetylcholine
then causes tremors and rigidity. This is where Antimuscarinic agents come into
play by blocking the muscarinic acetylcholine receptors and cholinergic nerve activity. As a result, these anticholinergic agents
restore the balance between acetylcholine and dopamine, which may improve the symptoms
of Parkinson’s disease. Drugs that belong to this class include; Benztropine,
Biperiden, Procyclidine, and Trihexyphenidyl. Now, before we move on, I wanted to briefly
mention here one more drug used in the treatment of Parkinson’s disease, that is Amantadine. Amantadine doesn’t exactly fit into any
of the classes that we discussed so far. Its mechanism of action is poorly understood,
however, some of the speculated ones are that it prevents dopamine reuptake, facilitates
presynaptic dopamine release, and blocks glutamate NMDA receptors. Now, when it comes to side effects, Levodopa
in combination with Carbidopa may cause nausea, loss of appetite, hypotension, mental disturbances,
and discoloration of urine, sweat or saliva. Selegiline and Rasagiline may cause nausea,
insomnia, dyskinesia, and visual hallucinations. Entacapone and Tolcapone may cause discoloration
of urine, sweat or saliva, and diarrhea, which can get severe particularly with the use of
Tolcapone. In addition to that Tolcapone has been associated
with liver toxicity. All dopamine agonists may cause nausea, orthostatic
hypotension, mental disturbances, and daytime sleepiness. In addition to that, Bromocriptine has been
associated with pulmonary and cardiac fibrosis. Lastly, drugs that block muscarinic receptors
generally produce anticholinergic side effects such as constipation, urinary retention, dry
mouth, and blurred vision. And with that, I wanted to thank you for watching,
I hope you found this video useful, and as always, stay tuned for more.

74 Replies to “Pharmacology – DRUGS FOR PARKINSON’S DISEASE (MADE EASY)”

  1. I always keep waiting for your videos and the moment you upload one and I receive the notification, I know my day is good. Thanks for the quality content, man.

  2. Imagine being able to replace lost neurons, instead of just slowing down the inevitable degeneration of these dopaminergic neurons. I attended a research symposium today where they were debating on the future implementation of 'preimprinted' neurons, from a petridish, grown out of pluripotent stem cells. Although early steps, I think this will become the future 🙂

  3. Within 9:30 minutes you gave me more knowledge than two hours class in my college ….you r the best 👍

  4. Parkinson's disease

    Diagnosed 2012
    My regimen:
    The positives: no bradykinesia, I cut my food with a knife, no button difficulties, brush my teeth now w/o needing elect brush, more strength. Getting in and out of bed, turning over is easier. No more constipation. Parkinson's progression stopped. Suppressed all motor and non-motor symptoms…
    Entering my 7th year post diagnosis and have not fallen, not once, to the surprise of my neuro. Was seeing neuro every 6th month, last visit he set app one year. He said if needed we could do some changes earlier. He said my condition can change in as little time as one week.
    New schedule, now I follow this regimen:
    3 x day C/L 50-200 ER : 8 am, 2 pm, 8 pm. Because it is ER, I take with or w/o food.
    2 x day (8 am 2g, and 2 pm 2g) Vitacost vitamin B1 (as thiamine HCL) 500mg, easy swallow capsules

    B1 Thiamine therapy reference / stop progression, suppress motor and non-motor symptoms:
    (Thiamine HCL is oral substitute to injecting B1) 2 x day (morning 2g and at lunch 2g)
    Doctor Costantini strategy that I find helpful "thiamine hcl stops the progression forever…".

    join my facebook group:
    "parkinson's thiamine hcl"  …
    Parkinson's Relief, Questions and Answers

    facebook group: 
    "parkinson's thiamine hcl"
    1. Read page, About, open links.,
    2. On Files page, open B1 FAQ document.
    3. On Files page, download First Appointment document , answer and submit.
    4. In Files, Dose Adjustment
    5. In Files, (2) From and by Dr. Costantini
    6. read Announcements

  5. Whoever doing these videos…, Dude. It's awesome.
    But please change the pitch and make yur voice a bit enthusiastic.
    Thank you 😊

  6. Hi
    Your video is very very helpful
    I wish you make video about
    Principles of antimicrobial therapy
    Protein synthesis inhibitors
    Cell wall inhibitors
    Antifungal drugs
    Antivirals drugs
    Anticancer drugs
    Please i need it
    Final exam about these above

  7. Your videos are just awsome!!
    It would be nice if you could include drug interactions and contraindications of drugs

  8. Thank you! These videos are very helpful. Do you have a recommendation for a pharmacology textbook that would be a good reference to have?

  9. Dear sir, please do a video on cardio drugs …BB, CCB, ACE, ARB, nitrates etc pleaseeeeeeee…you've been a life savior @speedpharmacology

  10. Where are the sources though? The videos are great but the lack of sources drives me towards other channels that provide cited research.

  11. Am confused I studied that. Selegiline blocks conversion of dopamine into 3-mt by inhibiting MAO-B, While tolcapone blocks conversion of dopamine to DOPAC by inhibiting central COMT.
    Does This means that MAO-B which is predominant, converts dopamine to 3-MT and COMT Converts dopamine into DOPAC.

  12. Sir please upload video on topical dosage form i.e, difference between cream ,gel , ointment ,etc, please

  13. Can you do a video on non parkison tremors like essential tremors and how medicines like inderal and primidone work for these tremors.

  14. You are best aur more than best please make more videos on pharmacology , now because of I love pharmacology thanks 🙂🙂

  15. Sir please aap jitne bhi lesson's hai kd tripathi book main pharmacology ke sab pe video bana do dhire dhire , hamara bhala hoga please fir hamain vo itni badi book padke sir nahi khapana hoga

  16. One tip, i think that if u write down the key words of for explanation on the screen you would improve clarity n fixation. Keep up the great work

  17. Please tell me about the Botox injections and it's roll in the treatment of writings cramps assencial tremors and P.D.

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