Question

Mr. DM, a 79-year-old man who lives alone, is brought into A&E suffering from dehydration, which appears to be the result of prolonged (>24 hours) nausea and vomiting. He is shaking, confused, incoherent and unable to provide a lucid history. His basic laboratory values are: Na+ 152 mmol/L (137–145 mmol/L) K+ 3.1 mmol/L (3.6–5.0 mmol/L) Bicarbonate 29 mmol/L (22–30 mmol/L) Urea 7.3 mmol/L (2.5–7.5 mmol/L) Creatinine 115 micromol/L (62–133 micromol/L) White blood count 8.4 × 109 /L (4–11 × 109 /L) He has an intravenous cannula inserted and rehydration commenced with sodium chloride 0.9% w/v infusion. Mr. DM continues to retch and vomit. He is administered 10 mg metoclopramide by I.V. injection and promptly suffers an oculogyric crisis. This is reversed by the administration of I.V. Procyclidine. Twelve hours later Mr. DM is conscious and lucid but now has a pronounced tremor, characteristic of Parkinson’s disease. He reports he was initially diagnosed about a year ago by his GP. His GP has been prescribing Sinemet-110 (Co-careldopa) tablets, (the initial dose was titrated) but Mr. DM did not take any as the tremor did not really bother him until earlier this week. He decided to start taking the Sinemet but as the tremor was troublesome he started at the dose of 1 tablet T.D.S.

QUESTIONS:

1. Briefly outline the epidemiology, pathophysiology and clinical features of Parkinson’s disease.

2. Outline the pharmacological basis of the nausea and vomiting caused by the Sinemet.

3. Outline the pharmacological basis of the adverse effect, oculogyric crisis, Mr. DM suffered. '

4. Briefly discuss the alternative options that could have been considered for managing Mr. DM’s nausea and vomiting, with relative advantages and disadvantages.

5. Briefly outline the rationale for reducing the dosage interval rather than increasing the dosage.

6. The on/off syndrome and end-of-dose deterioration are both features of treated Parkinson’s disease. What are they, and are there any risk factors?

7. In addition to levodopa therapy, what other options are available to treat Parkinson’s disease and what is their place in therapy?

Answer 1

Q)1) Epidemiology, Pathophysiology and Clinical features of Parkinson's Disease?

A) Epidemiology: Over 1 million people in the United States have been diagnosed with PD. Usually the onset of diagnosis is after 50years of age. Approximately 1% of population over 50yrs of age has the disorder.

Pathophysiology : It is a chronic, progressive, neurodegenerative disorder of insidious onset, characterised by the presence of motor disturbances like bradykinesia ( slow Ness of movements), rest tremor,rigidity and postural disturbances.

It has been identified by the levels of dopamine responsible for communication between substantia nigra and corpus stritation to control and coordinate muscle movements, are lower in the brain of an individual with PD than in the normal brain,

These low levels of dopamine are due to degeneration of dopamine secreting nerve cells in a region of brain called Substantia nigra.

Clinical features : Symptoms of PD differ from patient to patient and they are usually defined as motor and non motor symptoms.

Motor symptoms: Bradykinesia : slowness of movement,

Tremors, rigidity, Impaired posture and balance or postural instability,

Additional symptoms are clues :

Unilateral onset,

Persistent asymmetry affecting side of onset most,

Rest tremors present,

Progressive disorder,

Excellent response to levodopa,

Severe levodopa infused dyskinesia,

Levodopa response for 5 years or more.

Non motor symptoms: Depression, anxiety, hallucinations, dementia,sleep disturbances, constipation,fall of blood pressure while standing,pain,and impulse control disorders.

Q)2) Pharmacological basis of the Nausea and vomiting caused by the Sinemet?

A) Sinemet is a combination of Carbidopa and Levodopa, reduses the nausea and vomiting due to decarboxylation of levodopa,

However Sinemet does not decrease the adverse reactions due to Central effects of levodopa.

Q)3) Pharmacological basis of Occulogyric crisis

ans) It is a acute dystonia which is a extra pyramidal symptoms mainly caused by drugs like metoclopramide, it happens due to blockade of post synaptic dopamine receptors in corpus staritum.

Q)4)ans) The other options of anti emetic drugs are antidopaminergic which are:

1. PROCHLORPERAZINE,

2. DOMPERIDONE,

3. METOCLOPRAMIDE.

4. Cyclizine

PROCHLORPERAZINE: effective in vestibular vomiting, side effects are extrapyramidal symptoms, cautiously in pts with PD, 20 mg PO initially,folowed by 10mg after two hours. Available sublingual, suppository and injectable form.

Cyclizine: effective where in contraindicated above , it can cause drowsiness, who are not tolerate stat 50mg IM.

DOMPERIDONE and Metoclopramide : dopamine receptor antagonists also function as prokinetic agents,

Metoclopramide contraindicated in git Obstruction and perforation,

Ondansetron: if all above fail, this serotonin 5-HT3 receptor antagonist given as 4mg dose IM or IV.

Q)5)ans) For the Continuous therapy with levodopa the patient's may experience certain motor fluctuations after 5 yrs of treatment, to prevent this low dose is prescribed rather than increased dose,

Q)6) ans) patients can develop neuroleptic malignant syndrome after sudden withdrawal of levodopa or dopamine agonists,

- serotonin syndrome can occur when monoamine oxidase inhibitors are combined with TCAs or SSRIs.

Q)7)ans) The primary aim of the treatment in PD is to restore the optimal levels of the neurotransmitters, dopamine and acetylcholine. Medications such as levodopa are generally used , ie the disease worsens, surgical interventions such as Brain stimulation implants may be required.

Medical treatment : Levodopa, Mono amino oxidase inhibitors, dopamine agonists, amantadine, catechol o methyl transferase, anticholinergic drugs.

Surgical treatment: Ablative surgery, Deep brain stimulation, cell transplant surgery

Others: physiotherapy, regular exercise,yoga, meditation,diet therapy, accupuncture,art,music,dance,and drama therapy.