Lesson 14- AntiParkinsonian drugs PDF

Lesson 14 Antiparkinsonian drugs 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25 SUMMARY 1. Parkinson. Symptoms. Introduction 2. Drug treatment – levodopa – dopamine agonists – MAO-B inhibitors – other drugs used in parkinson’s disease 3. Summ...

Lesson 14 Antiparkinsonian drugs 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25 SUMMARY 1. Parkinson. Symptoms. Introduction 2. Drug treatment – levodopa – dopamine agonists – MAO-B inhibitors – other drugs used in parkinson’s disease 3. Summary Annex 2  1. PARKINSON‘S DESEASE Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily affecting movement. Symptoms: – Non-motor symptoms:may appear before motor symptoms and often predominate in the later stages of the disease. – suppression of voluntary movements (bradykinesia) – tremor at rest usually starting in the hands (‘pill-rolling’ tremor), tends to diminish during voluntary activity – cognitive impairment (variable) – characteristic (shop window disease)* hard to start walking, and once in progress they cannot quickly stop or change direction. – associated with dementia, depression and autonomic dysfunction. * "Shop window disease" is a term often used to describe intermittent claudication, a condition characterized by pain or cramping in the legs when walking or exercising, which typically resolves with rest 3  1. PARKINSON‘S DISEASE Etiology: Parkinson’s disease often occurs with no obvious underlying cause. – After cerebral ischaemia, viral encephalitis or other types of pathological damage. – There are rare cases of early onset familial PD, and several genetic mutations have been identified. 4  1. PARKINSON‘S DISEASE Pathophysiology: Parkinson's disease is characterized by the formation of Lewy bodies, intracellular aggregates primarily composed of α-synuclein, and the degeneration of dopaminergic neurons in the substantia nigra, leading to a deficiency in dopamine, a neurotransmitter crucial for motor control. Diagnosis Diagnosis is primarily clinical, based on history and neurological examination. There are no definitive laboratory tests, but imaging studies like dopamine transporter (DAT) scans can support diagnosis. 5  1. PARKINSON‘S DESEASE Symptoms appear when striatal dopamine content has decreased to 20-40% of normal. Dopamine deficiency give rise to bradykinesia Rigidity and tremor involve more complex neurochemical alterations of other transmitters (Ach, NA, 5-HT, GABA and Dopamine). What mechanism we can use to treat Parkinson’s disease? 1. Increasing the concentration of DA in the synaptic cleft (using precursors of DA) 2. Using agonist of DA receptors 3. Inhibiting the metabolism of DA 4. Inhibiting the cholinergic transmission 7 SUMMARY 1. Parkinson. symptoms. introduction 2. Drug treatment: – levodopa – dopamine agonists – mao-b inhibitors – other drugs used in parkinson’s disease 3. Summary Annex 8 2. DRUG TREATMENT LEVODOPA Levodopa is the first-line treatment. Levodopa is the metabolic precursor of dopamine. Mechanism of action: Levodopa is rapidly decarboxylated, by the enzyme DOPA- DECARBOXYLASE, and converted to dopamine in extracerebral tissues. Only a small amount of intact levodopa reaches the CNS and is converted to dopamine in the brain. (administered with a Dopa-decarboxilase inhibitor – Carbidopa or Benzeraside) Pharmacokinetics: – It is well absorbed from the small intestine, – The plasma half-life is short (about 2 h). Oral and subcutaneous slow release preparations have been developed. 10 2. DRUG TREATMENT LEVODOPA Combination of : LEVODOPA + DOPA- DECARBOXYLASE INHIBITOR + COMT INHIBITOR (e.g. Entacapone or Tolcapone) to inhibit its degradation, is used in patients troubled by ‘end of dose’ motor fluctuations. 11 2. DRUG TREATMENT LEVODOPA Therapeutic effectiveness About 80% of patients: initial improvement with levodopa, particularly of rigidity and bradykinesia, 20% are restored virtually to normal motor function. As time progresses, the effectiveness of levodopa gradually declines: Levodopa increases the life expectancy of PD patients, probably as a result of improved motor function 12 2. DRUG TREATMENT LEVODOPA ADRs: Involuntary movements (dyskinesia):because Levodopa is short acting: the fluctuating plasma concentrations affect the face and limbs *longer acting dopamine agonists are less problematic Nausea and anorexia. Postural hypotension Psychological effects – schizophrenia-like syndrome with hallucinations. – 20% of patients: it causes confusion, disorientation, insomnia or nightmares. 13 2. DRUG TREATMENT The more advanced the Parkinson's disease, the shorter the clinical effect. 14 2. DRUG TREATMENT LEVODOPA Rapid Levodopa fluctuations in clinical state The "off effect" is a sudden worsening of motor symptoms in Parkinson's patients, where they may feel like they're stuck or unable to move, even while walking. This can be very distressing and interfere with daily activities – Solution: use of sustained-release preparations, or co- administration of COMT inhibitors such as Entacapone. 15 2. DRUG TREATMENT DOPAMINE AGONISTS Pramipexole, Ropinirole, Rotigotine, Apomorphine Pramipexole and Ropinirole are D1,2 selective and better tolerated, and do not show fluctuations cause somnolence and sometimes hallucinations to compulsive behaviours short plasma half-life (6–8 h). three-times daily dosage slow-release once-daily formulations are now available Rotigotine: newer agent, delivered as a transdermal patch. Apomorphine (injection), to control the ‘off effect’ with levodopa must be combined with an oral antiemetic drug last choice if other drugs fail. 16 2. DRUG TREATMENT MAO-B INHIBITORS Selegiline, Rasagiline Selegiline – Selective and Irreversible – used as an adjunct to levodopa. – ADRs:excitement, anxiety and insomnia Rasagiline – Selective and Irreversible – Retard the progression of the disease Safinamide:undergoing clinical trials 17 2. DRUG TREATMENT OTHER DRUGS Amantadine – Mechanism unknown:is believed to release dopamine, inhibition of amine uptake or a direct action on dopamine receptors. More recently block of NMDA receptors (may be a novel target) – less effective than levodopa but it is effective in reducing the dyskinesias Acetylcholine antagonists (Benztropine) – Muscarinic antagonists compensate for a lack of Dopamine. – rarely used, except to treat parkinsonian symptoms in patients receiving antipsychotic drugs. – ADRs: dry mouth, constipation, impaired vision, urinary retention… 18 SUMMARY 1. Parkinson. Symptoms. Introduction 2. Drug treatment – levodopa – dopamine agonists – MAO-B inhibitors – other drugs used in parkinson’s disease 3. Summary Annex 19  3. SUMMARY For motor complications of dopaminergic therapies such as motor fluctuations and dyskinesias: adjuvant dopamine agonists adjuvant MAO-B inhibitors such as rasagiline or selegiline adjuvant entacapone intermittent apomorphine injections – delayed-release levodopa may be used to reduce motor complications in patients with later-stage Parkinson’s disease (but should not be drug of first choice) – amantadine may be used to decrease dyskinesias 20 SUMMARY 1. Parkinson. Symptoms. Introduction 2. Drug treatment – levodopa – dopamine agonists – MAO-B inhibitors – other drugs used in parkinson’s disease 3. Summary Annex 21  ANNEX Disimpairment parkinson treatment. For depression, management should be tailored to individual Low frequency repetitive transcranial magnetic stimulation (rTMS) improves motor system function in patients with Parkinson disease deep brain stimulation physical therapy modest benefit exercise modest benefit home-based balance and strengthening exercise Program less severe Parkinson disease (reduce risk of falls), but not in patients with high disease severity tai chi is more effective than stretching or resistance training for reducing falls in patients with Parkinson disease 22 Annex: Disimpairment parkinson treatment. Diet: – patients with Parkinson are at increased risk for poor nutrition, weight loss and loss of muscle mass – assess patients for physical and psychosocial factors that may interfere with nutrition, such as chewing and swallowing problems poor dentition impaired ability to prepare meals use of nontraditional diets – encourage balanced diet that includes adequate amounts of fiber and fluid to prevent constipation calcium to maintain bone structure – timing of meals with levodopa ideally take levodopa on empty stomach 1 hour before or after meals to facilitate absorption (dietary amino acids can compete with levodopa for absorption) – consider multivitamin supplement, with or without calcium if unable to maintain balanced diet – consider referral to dietitian for evaluation and dietary recommendations 36