NTA Level 5 • Semester 1 • PST05104

Pharmacodynamics of Drugs Used in Parkinson's Disease

Pharmacology and Therapeutics • Source Session/Topic 31

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Session 31: Pharmacodynamics of Drugs Used in Parkinson's Disease

Total Session Time: 120 minutes

Prerequisites

None

Learning Tasks

By the end of this session students are expected to be able to:

Describe mechanism of action of Drugs Used in Parkinson's Disease

Describe drug interactions associated with Drugs Used in Parkinson's Disease

Describe side effects of Drugs Used in Parkinson's Disease

Describe contraindications of Drugs Used in Parkinson's Disease

Resources Needed:

Flip charts, marker pens, and masking tape

Black/white board and chalk/whiteboard markers

Computer and LCD projector

SESSION OVERVIEW

Step

Time

Activity/

Content

Step

Time

Activity/

Content

Step

Time

Method

Content

Method

05 minutes

Presentation

Introduction, Learning Tasks

45 minutes

Presentation/

Mechanism of Action of Drugs Used in

45 minutes

Buzzing

Parkinson's Disease

Buzzing

Parkinson's Disease

20 minutes

Presentation/

Drug Interactions Associated With Drugs

20 minutes

brainstorming

Used in Parkinson's Disease

brainstorming

Used in Parkinson's Disease

20 minutes

Presentation

Adverse Effects of Drugs Used in Parkinson's

20 minutes

Presentation

Disease

20 minutes

Presentation/

Contraindications of Drugs Used in

20 minutes

Brainstorming

Parkinson's Disease

Brainstorming

Parkinson's Disease

PST 05104 Pharmacology & Therapeutics

242

NTA Level 5 Semester 1 Facilitator Guide

05 minutes

Presentation

Key Points

05 minutes

Presentation

Evaluation

PST 05104 Pharmacology & Therapeutics 243 NTA Level 5 Semester 1 Facilitator Guide

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning objectives and clarify

ASK students if they have any questions before continuing.

STEP 2: Mechanism of Action of Drugs Used in Parkinson's Disease (45 minutes)

Activity: Buzzing (5 minutes)

ASK students to pair up and buzz on the following question for 2 minutes

How do drugs Used in Parkinson's Disease produce their pharmacological effects?

ALLOW few pairs to respond and let other pairs add on points not mentioned

WRITE their response on the flip chart/board

CLARIFY and SUMMARIZE by using the content below

Parkinsonism is a progressive neurologic disorder of muscle movement, characterized by tremors, muscular rigidity, bradykinesia (slowness in initiating and carrying out voluntary movements), and postural and gait abnormalities.

The cause of Parkinson's disease is unknown for most patients.

The disease is correlated with a reduction in the activity of inhibitory dopaminergic neurons in the substantia nigra and corpus striatum parts-of the brain's basal ganglia system that are responsible for motor control.

Mechanisms of drugs used for treatment of Parkinsonism are:

Dopamine Precussors;

Levodopa

o Levodopa is a metabolic precursor of dopamine.

o Cross blood brain barrier as it is readily taken up by the amino transport systems.

o It restores dopamine levels in the extrapyramidal centers (substantia nigra) that atrophy in parkinsonism.

o Required in high doses because the drug is decarboxylated to dopamine in the periphery by L-aromatic amino acid decarboxylase enzyme.

o Since Parkinsonism results from insufficient dopamine in specific regions of the brain, attempts have been made to replenish the dopamine deficiency. Dopamine itself

PST 05104 Pharmacology & Therapeutics 244 NTA Level 5 Semester 1 Facilitator Guide

does not cross the blood-brain barrier, but its immediate precursor levodopa is readily transported into the CNS and is converted to dopamine in the brain

Actions: Levodopa decreases rigidity, tremors and other symptoms of parkinsonism.

Carbidopa

The effects of levodopa on the CNS can be greatly enhanced by coadministering carbidopa, a dopamine decarboxylase inhibitor that does not cross the blood-brain

barrier.

Carbidopa diminishes the metabolism of levodopa in the GI tract and peripheral

tissues; thus, it increases the availability of levodopa to the CNS.

The addition of carbidopa lowers the dose of levodopa needed by 4- to 5- fold and, consequently, decreases the severity of the side effects of peripherally formed dopamine.

Catechol-O-Methyl Transferase (COMT) Inhibitors:

Entacapone and tolcapone

COMT inhibitors increase the amount of dopamine available to the CNS. COMT is one of the two major enzymes involved in the metabolism of catecholamines (epinephrine, norepinephrine, and dopamine).

Thus one of the ways COMT inhibitors increase dopamine is by inhibiting its breakdown.

Monoamine oxidase B inhibitors (MAO B) Inhibitors:

Selegiline and Rasagiline

Selectively inhibit MAO-B which metabolizes dopamine more efficiently than NE and 5-HT. The net effect is an increase in brain dopamine levels. These drugs can be

used in conjunction with L-dopa.

Because selegiline and rasagiline selectively inhibit MAO-B, they are much less likely to produce a hypertensive reaction with cheese or other sources of tyramine than non-selective MAOIs, such as phenelzine.

Dopamine Agonists:

Bromocriptine

The absorption and extent of first-pass metabolism of bromocriptine is highly variable, leading to wide fluctuations in plasma concentrations and variability in dose

response.

Dopamine agonists bind to dopamine receptors to produce actions similar to dopamine.

The dopamine agonists used in Parkinson‘s disease have longer durations of action than L-dopa. Cabergoline, an agent not used for Parkinson‘s disease, has an

exceptionally long elimination half-life (approximately 100 hours).

Other dopamine agonist include cabergoline, pergolide, pramipexole, ropinirole

PST 05104 Pharmacology & Therapeutics 245 NTA Level 5 Semester 1 Facilitator Guide

Drugs that increase dopamine release:

Amantadine

A tricyclic amine used in prophylaxis of Influenza A virus. o Increase the release of dopamine from surviving neurons o It may also reduce dopamine reuptake

o Have anticholinergic effects too

o Use with L-dopa in patients who can‘t tolorate L-dopa or who don‘t respond to L-dopa therapy well.

Antimuscarinics:

Trihexyphenidyl, benzatropine, orphenadrine, procyclidine

Non-selective muscarinic receptor antagonism is believed to restore, in part, the balance between dopaminergic/cholinergic pathways in the striatum.

Muscarinic antagonists are effective in the treatment of parkinsonian tremor and – to a lesser extent – rigidity, but produce only a slight improvement in bradykinesia.

STEP 3: Drug Interactions Associated with Drugs Used in Parkinson's Disease (20 minutes)

Activity: Brainstorming (5 minutes)

Ask students to brainstorm on the following question:

What are drug interactions associated with Drugs used in Parkinson's disease?

ALLOW few students to respond

WRITE their responses on the flip chart/ board

CLARIFY and SUMMARISE by using the content below

Dopamine precursors:

Levodopa

o The vitamin pyridoxine (B6) increases the peripheral breakdown of levodopa and diminishes its effectiveness.

o Concomitant administration of levodopa and monoamine oxidase (MAO) inhibitors, such as phenelzine can produce a hypertensive crisis caused by enhanced catecholamine production; therefore, caution is required when they are used simultaneously.

o In many psychotic patients, levodopa exacerbates symptoms, possibly through the buildup of central amines (an increase in dopamine levels).

o In patients with glaucoma, the drug can cause an increase in intraocular pressure.

PST 05104 Pharmacology & Therapeutics 246 NTA Level 5 Semester 1 Facilitator Guide

Cardiac patients should be carefully monitored because of the possible development of cardiac arrhythmias.

Monoamine oxidase B inhibitors (MAO B) Inhibitors:

Selegiline and Rasagiline

At very high doses (six times the therapeutic dose), MAO-B selectivity is lost and

pressor responses to tyramine are potentiated. Hypertensive reactions to tyramine-containing products (e.g. cheese or yeast extract) have been described, but are rare.

o Amantadine and centrally active antimuscarinic agents potentiate the anti-parkinsonian effects of selegiline.

STEP 4: Adverse Effects of Drugs Used in Parkinson's Disease (20 minutes)

Dopamine precursors:

Levodopa

o Large doses of levodopa are required because much of the drug is decarboxylated to dopamine in the periphery resulting in peripheral side effects (nausea, vomiting, cardiac arrhythmias, and hypotension).

Catechol-O-Methyl Transferase (COMT) Inhibitors:

Entacapone and tolcapone

o Dopamine-related effects include dyskinesia (peak dose), vivid dreams, hallucinations, nausea, and hypotension.

Abdominal pain may occur. o Diarrhea may occur.

o Discoloration of urine is caused by the chemical structure of the drug and occurs only in alkaline urine.

o The side effect is harmless, but patients should be warned of the dark yellow or reddish brown tinge.

o Hepatotoxicity: observed only with tolcapone so far

Dopamine Agonists:

Bromocriptine and others

Ropinirole and pramipexole: Sudden sleep onset occurs without warning and poses a potential risk for activities requiring attention, such as driving. This may be a class effect but has been confirmed with ropinirole and pramipexole.

PST 05104 Pharmacology & Therapeutics 247 NTA Level 5 Semester 1 Facilitator Guide

STEP 5: Contraindications of Drugs Used in Parkinson's Disease (20 minutes)

Activity: Brainstorming (5 minutes)

Ask students to brainstorm on the following question:

What are the contraindications of Drugs used in Parkinson's disease? ALLOW few students to respond?

WRITE their responses on the flip chart/ board

CLARIFY and SUMMARISE by using the content below

Catechol-O-Methyl Transferase (COMT) Inhibitors:

Entacapone and tolcapone

Concomitant use with nonselective MAOIs: This includes the use of an MAO-A and an MAO-B inhibitor in combination.

o The MAO pathway becomes the key metabolic route for epinephrine and norepinephrine in the presence of COMT blockade.

There should be at least a 2-week washout before initiation of treatment with a COMT inhibitor.

Caution should also be exercised in patients on MAO-B selective inhibitors, as these become nonselective at higher doses.

History of neuroleptic malignant syndrome and/or non-traumatic rhabdomyolysis is a contraindication.

Liver impairment is a contraindication because of hepatotoxicity seen with tolcapone. o Pheochromocytoma is a contraindication because of increased risk of hypertensive

crisis.

Dopamine Agonists:

Bromocriptine and others

Pramipexole, Ropinirole: Caution should be exercised when driving or engaging in other activities that require alertness, because of the potential for sudden onset of sleep (see Side Effects).

PST 05104 Pharmacology & Therapeutics 248 NTA Level 5 Semester 1 Facilitator Guide

STEP 6: Key Points (5 minutes)

Drugs for parkinsonism aim at ensuring proper action of dopamine in the CNS

Drugs for parkinsonism are associated with adverse events

Non pharmacological approaches are also important in parkinsonism

STEP 7: Evaluation (5 minutes)

What is the mechanism of action of levodopa?

What are contraindications of Entacapone?

What are adverse effects of bromocriptine?

PST 05104 Pharmacology & Therapeutics 249 NTA Level 5 Semester 1 Facilitator Guide

References

Katzung, B. G. (2018). Basic and clinical pharmacology. New York: Mcgraw Hill Education.

Santos, R. R., Rang, H. P., Dale, M. M., Ritter, J. M., & Flower, R. J. (2007). Rang & Dale Farmacologia. Rio de Janeiro: Elsevier.

Tripathi, K. (2018). Essentials of Medical Pharmacology. Place of publication not identified:

Jaypee Brothers Medical P.

Ministry of Health and Social Welfare. (2013). Standard Treatment Guidelines & National Essential Medicines List Tanzania Mainland (4th ed.). Dar es salaam, Tanzania government printers.

Robert L. Talbert, Gary C. Yee, Gary R. Matzke, Barbara G. Wells, L. Michael. (2014). Pharmacotherapy: A Pathophysiologic Approach (9th ed.). New York, McGraw-Hill Education.

Sally S.R, Jeanne C.S. (2000). Introductory Clinical Pharmacology (6th ed) New York, Lippincott Williams and Wilkins.

School of Pharmaceutical sciences. (2011).Tanzania Pharmaceutical Handbook (2nd ed.).

Dar es Salaam, ARDHI University press.

The Royal Pharmaceutical Society of Great Britain. (2007). Martindale, the Extra Pharmacopoeia (5TH ed). London, pharmaceutical press.

The Royal Pharmaceutical Society of Great Britain. 2009. British National Formulary (59th ed). London, BMJ Group and RPS Publishing.

PST 05104 Pharmacology & Therapeutics 250 NTA Level 5 Semester 1 Facilitator Guide

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