Parkinson’s disease

Parkinson’s disease

Parkinson’s disease is the second commonest neurodegenerative disease. It is a specific neurodegenerative disease that is seen mostly in the elderly population; movement disorder characterized by motor and non-motor symptoms. It is caused by intracellular accumulation of Lewy bodies and subsequent neuronal loss, mainly within the substantia nigra pars compacta. The midbrain nucleus usually provides dopaminergic input to the neostriatum. These are the sites of domain synthesis and transmission. Neurodegenerative results in a deficiency of dopamine which causes an inability to control muscle tone. There is an imbalance between the dopaminergic and cholinergic systems.

How is Parkinson disease diagnosis?

Let’s talk about how Parkinson’s disease is diagnosed:-

  •  No specific laboratory test to diagnose Parkinson’s disease, 
  • Physical signs and distinguishing idiopathic PD used to identify the disease,
  • MRI may be used but it is not important in typical PD Cases (Radioactive dopamine scan) Dopamine transporter (DAT) imaging using SPECT or PET makes use of a radiolabeled ligand binding to dopaminergic terminals which are used to identify the amount of nigrostriatal cell loss. But this test doesn’t have the ability to differentiate Parkinson’s disease and other akinetic-rigid syndromes.

Pathophysiology for parkinson’s disease

The pathophysiology of Parkinson’s disease, it is mainly dependent on dopamine, arises from an imbalance between two striatal–thalamic–cerebral cortical circuits. It is useful that under normal circumstances the globus pallidus INternus inhibits thalamic communication with the frontal cortex. It causes the inability of voluntary movements. Since dopaminergic input to the striatum itself suppresses GPi, loss of dopaminergic input allows the GPi to be overactive, Hence it leads to inhibition of the motor cortex, so appear Cardinal signs. A low concentration of dopamine also encourages an indirect pathway between the striatum, subthalamic nucleus, and GPi. It has the net effect of increasing GPi braking of movement. (The Main cause is an imbalance of dopamine level.)

Is Parkinson’s disease curable?

PD can’t be cured, But it is manageable. There are lots of medicines to improve PD symptoms. some brain surgery also suggested improving symptoms

Is Parkinson’s disease genetic?

There is no absolute finding to date that states that Parkinson’s is hereditary/ genetic, although Genetic factors exert some relation with PD;  in a few families, Parkinson’s disease has been common for several generations. This might be due to certain components of Parkinson (PD) which are known to be genetic. Besides, abnormalities in 3 genes: Glucocerebrosidase (GBA), PARK2 (parkin), and LRRK2 (leucine-rich repeat kinase2) have been linked to the higher risk of developing Parkinson’s disease.

Is Parkinson’s disease fatal?

  • Death frequently results from complications of immobility, including aspiration pneumonia or pulmonary embolism.
  • The life expectancy of adequately treated patients has increased substantially, but overall mortality remains higher than that of the general population.

Parkinson’s disease prognosis 

Effective pharmacological drug treatment can alter the prognosis of parkinson disease; in most cases good functional morbidity can be maintained for many years.

What can mimic Parkinson’s disease?

  • The latter includes extensive small-vessel cerebral ischemia due to hypertension
  • Neuroleptic drugs
  • Other neurodegenerative diseases (multiple-systems atrophy or Huntington’s)
  • If this condition mimics Parkinson’s disease generally responds less to dopaminergic therapies.

How is Parkinson’s disease treated?

Initially prescriber should monitor individual patients,including symptoms, comorbidities and preferences. Prescriber should give some knowledge (benefit and harm) about different drugs available to patients.

Treatment for idiopathic parkinson disease is often initiated with a dopamine receptor agonist. Ergot derived ones are rarely used because of pleural, retroperitoneal and pericardial fibrosis.

Supplementary use of amantadine, bromocriptine, or the monoamine oxidase inhibitor, selegiline can be of value either to enhance the effect of levodopa or to reduce the end of dose fluctuation and on-off effects. Anticholinergic medicines are usually sufficient in drug-induced parkinsonism.

1. Pharmacological treatment for parkinson disease.

There are no current treatments to prevent PD progression. But there are two mechanisms to manage PD. The goal is to balance the acetylcholine level and dopamine level.

Parkinson's disease
Parkinson disease causes
  1. Enhancement of dopaminergic activity
  • Replenish neuronal Dopamine by supplying Dopamine precursor (levodopa)
  • Decreasing endogenous clearance and inhibit the dopamine breakdown enzyme such as monoamine oxidase (MAO) E.g selegiline, rasagiline or catechol-O-methyltransferase (COMPT) E.g: entacapone, tolcapone).
  • Dopamine agonists (ropinirole, pramipexole, Pergoline,cabergoline,bromocriptine ,rotigotine, apomorphine).
  • Release dopamine from stores and inhibit reuptake (amantadine).
  • Avoiding dopamine antagonists, example:- antipsychotics (chlorpromazine, haloperidol, and antiemetics – (prochlorperazine, metoclopramide).
  1. Reduction of cholinergic activity

Antimuscarinic drugs as example trihexyphenidyl, benztropine and orphenadrine

Most effective against tremor and rigidity.

Less effective in the treatment of bradykinesia.

2. Non pharmacological treatment for parkinson disease

  • Physiotherapy to improve motor function
  • Speech and language therapy
  • Occupational therapy
  • Dietitian advice is very important
  • Deep brain stimulation (Stereotactic insertion of electrodes into the brain)

There are few target places of the brain:- subthalamic nucleus – ( to reduce dyskinesia), globus pallidus – (to improve dyskinesia but levodopa required) and  the thalamus – (to treat tremor).This treatment method is helpful to reduce dopaminergic drugs.

What are the drugs for Parkinson’s disease?

medicine taking on time

There are different sizes, shapes and strengths of tablets. Number of pill counts depends on the strength of your drug. Your doctor will decide your disease management and drug regimen. if you have any problem ( allergy, any unusual feeling) ask from a doctor or other healthcare provider like a pharmacist. Do not use drugs (dose change,drug change or substitute) according to your choice, without doctors support.This article for information purpose only.

levodopa

Dopamine can not cross BBB (Blood Brain Barrier). Levodopa is the natural precursor of dopamine. it is readily absorbed from the small intestine. levodopa has the ability to cross BBB via active transport. But there is a problem with levodopa. Levodopa metabolism occurs in the peripheral tissue. We can give high doses of levodopa but there are many side effects (nausea, vomiting, cardiac arrhythmias, and hypotension) profile  with high dose. Thus levodopa combined with a peripheral decarboxylase inhibitor. decarboxylase inhibitor (carbidopa) increases availability of levodopa inside the central nerve system. Carbidopa does not cross BBB barrar. thus levodopa readily converted into dopamine.

Action of Levodopa

  • Decrease PD symptoms (rigidity, tremors, and other symptoms of DP)
  • Levodopa, a carbidopa combination is a potent and efficacious drug regimen nowadays.

Problem with levodopa

  • Levodopa is most effective in the 1st 2-5 years of treatment. After 5 years of therapy, patients have dose-related dyskinesia, inadequate response, or toxicity.
  • High protein-containing foods affect the transport of levodopa into the Central nervous system. So you should avoid high protein food.
  • neutral amino acids (for example, leucine, and isoleucine) interfere with the absorption of levodopa from the gut and for transport across the blood-brain barrier. thus levodopa should be taken on an empty stomach, typically 45 minutes before a meal.

Pharmacokinetics of levodopa

  • Absorption from the small intestine
  • Half-life is very short (1-2hr)
  • Metabolism occurs in peripheral tissue (levodopa to dopamine)
  • Levodopa started low dose then it titrated according to patient improvement.

Adverse effect of levodopa

  1. Anorexia, nausea and vomiting (Deuto dopamine receptor stimulation) uporn inial administration
  2. Cardiovascular effect, including tachycardia, arrhythmia, and orthostatic hypotension
  3. Mental disturbances, including vivid dream, delusion, and hallucination.
  4. Hyperkinesia.
  5. Sudden discontinuation can result in fever, rigidity, and confusion. The drug should be withdrawn gradually over 4 days.

Caution of levodopa

Severe pulmonary/cardiovascular system disease,psychiatric illness, endocrine disorder, history of convolution, peptic ulcer disease, glaucoma.

What are Contraindications of levodopa

In patients with unknown hypersensitivity to the medicine, narrow-angle glaucoma, skin lesion suspected to be melanoma, as it may activate a malignant melanoma.

Levodopa prescribing in special situations:

  • Pregnancy use with caution
  • Breastfeeding avoid as it may suppress lactation
  • Renal impairment: use with caution
  • Hepatic impairment: use with caution

Interaction with levodopa

  • There are many drugs that interact with levodopa, in here all are not mentioned.
  • The enhanced hypotensive effect when given with antihypertensives, nitrates, and diuretics; risk of hypertensive crisis when given with MAOI; effects antagonized by antipsychotics, benzodiazepine, methyldopa.
  • Vit B6 reduces the beneficial effect of levodopa by enhancing its extracerebral metabolism.

What are the Patient advices who has taken levodopa

  • Take medicine at the same time every day.
  • Do not stop drugs abruptly.
  • Always obey the doctor’s instructions.
  • If you feel drowsy, do not drive a vehicle (take rest)
  • Levodopa may cause dizziness on standing up quickly from seated/lying down position.

Carbidopa

  • Carbidopa is an inhibitor of dopa decarboxylase.
  • It acts to reduce the peripheral conversion of levodopa to dopamine. As a result, when carbidopa and levodopa are given concomitantly : 

(a). It can decrease the dosage of levodopa

(b).t can reduce the toxic side effect of levodopa.

Dopamine agonist drugs for pharkinson disease.

  • Dopamine agonist drugs stimulate D1 and D2 receptors. The D2 receptor is the principal target of PD. dopamine agonist have no advantage over levodopa
  • Dopamine agonists show the same adverse effects like levodopa (nausea,
  • psychiatric symptoms, postural hypotension, daytime somnolence,
  • impulse control disorders, e.g. gambling, hypersexuality).
  • Dopamine agonists have long action when compared with levodopa. Initially starting with dopamine agonist treatment less risk to develop dyskinesias and motor functions

1.Ergot derivatives (e.g: bromocriptine, cabergoline ) for pakinsan

Bromocriptine

  • Bromocriptine is the derivative of ergot.
  • It is a D2 receptor agonist, but also a weak alpha-blocker
  • Commonly used with levodopa.
  • Should be started at a very low dose, increasing at weekly intervals and according to clinical response.
  • Half-life is 5 hr

What are the indications of bromocriptine?

Rarely used in parkinson disease(fibrotic reactions limit their use), prevention/suppression of lactation, hyperprolactinemia,bromocriptine also indicated in acromegaly especially for recurrence after surgery,subfertility

What are the Interactions of bromocriptine?

Drug concentration increased by erythromycin, effect antagonise by antipsychotic, domperidone,metoclopramide and methyldopa

2.non ergot derivatives for parkinson (e.g: ropinirole pramipexole, rotigotine)

Non ergot derivatives  are nowaday preferred as first-line therapy in newly diagnosed parkinson disease  (under 70yars)

Ropinirole 

  • Ropinirole relatively selective D2 receptor agonist.
  • It is more effective against tremors, in addition, it is used for restless legs syndrome.
  • Should be started at a very low dose
  • Do not use it, if you are in pregnancy or breastfeeding period and severe hepatic impairment.

What are the pharmacokinetic of ropinirole

Rropinirol Well absorbed through the gut and extensively distributed from plasma compartment; bioavailability is approximately 50%; inactivated by metabolism in the liver. there are no active metabolites of ropinirole.

What are the drug interaction of ropinirole

Concentration increases by ciprofloxacin, oestrogens, effects antagonized by antipsychotics, methyldopa, metoclopramide.

Apomorphine

  • it is a derivative of morphine.
  • Apomorphine has a full agonist effect on D1 and D2 Receptors.
  • As well as it has a non-ergot-like effect. 
  • it can be used to treat severe motor fluctuations (i.e.on–off cycles).
  • To treat severe dyskinesias,
  • Overdose causes respiratory depression,

What are the side effects of apomorphine?

  • confusion,
  • psychosis
  • Dysphoria,
  • Induce penile erection (without causing sexual excitement)
  • Raynaud’s phenomenon
  • yawning.
  • Monoamine oxidase inhibitors (MAOI) 
  • Monoamine oxidase enzymes have the ability to modulate the intraneuronal content of neurotransmitters. There are two major forms of Monoamine oxidase inhibitors ,which are MAOA and MAOB.
  • Those show  substrate specificificity.
  • Monoamine oxidase B inhibitors are used for PD.

Selegiline for parkinson’s disease

  • Irreversibly inhibit MAO type B and reduces catabolism of dopamine in the brain. It does not inhibit dopamine catabolism in periphery.
  • The standard dose of selegiline is 5 mg with breakfast and 5mg with lunch.. Selegiline may cause insomnia when taken later during the day

What are the interactions of selegiline?

Central nerve system toxicity increase with pethidine, SSRI, Venlafaxine; hypertension worsened with SSRI, sympathomimetics; selegiline concentration increase with oestrogen,progestogens; effect antagonized by methyldopa; as it does not inhibit MAO type A at low doses does not interact with tyramine containing food. At high doses it can inhibit MAO type A and give rise to reactions.

What are Common side of selegiline 

pain . confusion . constipation . depression . diarrhoea . dizziness . dry mouth . fall . fatigue . hallucination . headache . hyperhidrosis . hypertension . hypotension . movement disorders . muscle cramps . nasal congestion . nausea . oral disorders . sleep disorders . throat pain . tremor . vertigo Angina . arrhythmias . duodenal ulceration

What are the Patient advices who has taken selegiline

  • if you feel uncomfortable, Do not drive vehicles (skill task) after taking of selegiline 
  • Better to avoid alcohol.

Catechol O methyltransferase Inhibitors for parkinson’s disease treatment.

  • Inhibition of dopa decarboxylase is associated with compensatory activation of other pathways of levodopa metabolism,
  • Especially catechol o methyltransferase (COMT),
  • COMPT increases plasma levels of 3 o methyldopa (3-OMD)
  • Elevated levels of 3-OMD have been associated with poor therapeutic response to levodopa.
  • Selective COMT inhibitors such as tolcapone and entacapone also prolong the action of levodopa by diminishing its peripheral metabolism.
  • Levodopa clearance is decreased, and relative bioavailability of levodopa is thus increased.
  • These agents may be helpful in patients receiving levodopa who have developed response fluctuations leading to smoother response, more prolonged on time.
  • Tolcapone has both central and peripheral effects, whereas the effect of entacapone is peripheral.
  • Adverse effects of the COMT inhibitors relate in part to increased levodopa exposure and include dyskinesia, nausea and confusion.

Antimuscarinic (anticholinergic) drugs for parkinson disease

  • Anticholinergic drug’s function is blocking acetylcholine receptors in the CNS.block muscarinic of acetylcholine in the CNS. The effects due to relative increase of cholinergic activity are blocked by this medicine.Synthetic derivatives are now used orally.These agent less efficacious than levodopa.
  • Example:-  benzhexol (trihexyphenidyl), orphenadrine, benztropine, procyclidine,
  • Biperiden.
  • Antimuscaranic have ability to improve tremor, rigidity, sialorrhoea, muscular stiffness and leg
  • Cramps
  • The main use of these drugs is in the treatment of drug‐induced parkinsonism (medicine induced extra pyramidal symptoms).
  • Antimuscarinic dose not effective (little efficacy) treatment for bradykinesia.

What are adverse effect of the animascaranic (anticholinergic) drug

  • dry mouth, blurred vision, constipation, urine retention, acute glaucoma, hallucinations,
  • memory defects and acute confusional states (in elderly patients).

Amantadine

  • Amantadine is an antiviral drug which ,given for influenza to aparkinsonian patient ,was noted to be beneficial.
  • Antiviral and antiparkinsonian effects of amantadine are related.
  • Antiparkinsonian effect is due to increased synthesis and release of dopamine, and diminish neuronal reuptake too.
  • Amantadine also has a slight antimuscarinic effect.
  • If you are pregnant or breastfeeding, avoid antimuscarinic agents (amantadine ).

What are the  adverse effect of amantadine

  • Anxiety
  • concentration impaired
  • confusion
  • constipation
  • Depression
  • dizziness
  • dry mouth 
  • hallucination
  • Hyperhidrosis
  • lethargy
  • mood altered
  • movement disorders
  • postural hypotension
  • vision disorders

What are Parkinson’s disease stages?

  1. Flexion of affected arm-tremor / learning toward the unaffected side
  2. Slow shuffling gait.
  3. Increased difficulty walking-looks for support to prevent falls
  4. Further progression of weakness- assistance with ambulation
  5. Profound disability-may be confined to a wheelchair

What are Cardinal signs of Parkinson’s disease?

  1. Rest Tremor — pill-rolling (hands, arms, legs, jaw, and face)
  2. Rigidity (Stiffness on passive limb movement)
  3. Bradykinesia (Slowness and poverty of movement)
  4. postural instability (leading to disturbances of gait and to falling)

Non-motor symptoms of parkinson disease:

  • Loss of sense of smell
  • Constipation
  • Rapid eye movement
  • Sleep behavior disorder
  • Mood disorders
  • Excessive saliva
  • Difficulty speaking and swallowing, softly, monotone, slur, or hesitate before talking
  • Slowed thinking
  • Depression/anxiety
  • restless legs syndrome.
  • Ache and pain
  • Writing pattern change (small, spiderly, traveling off at ends of words)

What are the Risk factors for Parkinson’s disease (Aetiology of PD)

Parkinson’s disease’s cause is unknown in most cases. There is no specific risk factor. But according to research Multiple risk factors involved in Parkinson’s disease. Age. Young adults rarely experience Parkinson’s disease. Risk increases with age. Most cases found around age 60 or older. Heredity. There is some chance to get PD disease if you have a patient with PD in the family. But it is not much. Sex. Parkinson’s disease is prominent among men. It is 1.5 times more than women. Environmental factors rural living and drinking well water herbicides and pesticides may slightly increase your risk of PD (OXIDATIVE STRESS). Smoking non-smokers have a higher risk of PD than smokers (the reason cannot explain theoretically)

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