ANTI PARKINSONIAN DRUGS

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ANTI PARKINSONIAN DRUGS :

ANTI PARKINSONIAN DRUGS Dr.S.P.Dhanya Assistant Professor Govt TDMC Alappuzha

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History of Parkinson´s disease (PD) First described ---- 1817 ---James Parkinson , “ An Essay on the Shaking Palsy.” Charcot ---- described the syndrome later

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Epidemiology of PD most common movement disorder over the age of 65 years affecting 1-2 % The second most common neurodegenerative disorder after Alzheimer´s disease (AD).

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Tremor Rigidity Akinesia Postural prob

Causes:

Causes Idiopathic Parkinson’s Disease-Paralysis agitans Drugs (Dopamine Receptor Antagonists) Antipsychotics, Metoclopramide Neurotoxins-MPTP-oxidative stress Rotenone, Domoic acid Genetic-mutation of parkin and α synuclein

Causes……………:

Causes…………… Stroke Viral infection Trauma Wilson’s disease Space occupying lesion

Pathophysiology:

Pathophysiology Pathological hall mark of PD is loss of dopaminergic neurones of substantia nigra pars compacta LEWY

Normal:

Normal

Parkinson’s disease:

Parkinson’s disease

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Direct Pathway- Excitatory- D1 Receptors Indirect Pathway- Inhibitory – D2 Receptors Health – Direct pathway predominates PD - Indirect pathway predominates CHOLINERGIC OVER ACTIVITY

Drugs affecting brain dopaminergic system :

Drugs affecting brain dopaminergic system 1- Dopamine precursor – Levodopa 2-Peripheral Decarboxylase Inhibitors Carbidopa , Benserazide 3- Dopaminergic Agonists- Bromocriptine , Pergolide Ropinirole,Pramipexole 4- MAO-B inhibitors- Selegiline,Rasagiline 5- COMT inhibitors – Entacapone , Tolcapone 6 – Dopamine Facilitator - Amantadine

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Levodopa Bromocriptine Pergolide Pramipexole Ropinirole Selegiline Rasagiline Amantadine

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Levodopa

Drugs affecting brain cholinergic system :

Drugs affecting brain cholinergic system 1 – Central anticholinergic Trihexiphenidyl,Benztropine,Biperiden Procyclidine 2 – Antihistamines Orphenadrine , Promethazine

Levodopa:

Levodopa Universal antiparkinsonian drug Metabolic precursor of Dopamine Therapeutic effect ---- decarboxylation in brain 95% of oral dose is decarboxylated in periphery only 1 -2 % crosses BBB Always given along with peripheral decarboxylase inhibitor Half life – 1-3 hrs

Actions of Levodopa :

Actions of Levodopa CNS Hypokinesia and rigidity resolve first CVS Tachycardia , postural hypotension CTZ Nausea ,vomiting – tolerance later ENDOCRINE Inhibit Prolactin

Kinetics :

Kinetics Absorbed from small bowel – amino acid transporter Meal delays absorption 1 hr before and 1hr after food High first pass metabolism in liver, git

Side effects :

Side effects At the initiation of therapy 1 – Nausea and vomiting 2 – Postural hypotension 3 –Cardiac arrhythmias 4 – Exacerbation of angina 5 – Alteration of taste sensation

After prolonged therapy :

After prolonged therapy 1 – Abnormal movements 2 – Behavioral effects 3 – Fluctuation in response OFF/ON phenomenon Wearing of reactions – end of dose

Interactions :

Interactions 1 – pyridoxine 2 – Phenothiazines , Butorphenones X Metoclopramide Domperidone 3 – MAO inhibitors 4 -- Atropine

Peripheral decarboxylase inhibitors :

Peripheral decarboxylase inhibitors Carbidopa , Benserazide Do not cross BBB Half life of L- Dopa increased Systemic side effects less Pyridoxine reversal does not occur ON/OFF phenomenon is minimized Degree of improvement higher Smooth control of symptoms Less diurnal fluctuations LEVODOPA + CARBIDPOA

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X 15% 10%

Dopamine receptor agonists :

Dopamine receptor agonists ERGOT Bromocriptine Pergolide NON ERGOT Ropinirole Pramipexole

Dopamine receptor agonists :

Dopamine receptor agonists No enzymatic conversion needed Don’t require functional integrity of neurons Longer duration of action Less dyskinesia Less ON/OFF More selective

BROMOCRIPTINE :

BROMOCRIPTINE Synthetic ergot derivative D2 agonist Levodopa like action ↓GH and ↓ Prolactin Nausea &Vomiting-CTZ Hypotension – α blockade PK------1 st pass metabolism -----------t ½ -3-6 hours

USES:

USES Parkinsonism Hyperprolactinemia Gynecomastia , impotence & sterility in men Acromegaly Suppress lactation Hepatic coma

Side effects:

Side effects Early Nausea, Postural hypotension,Vomiting,Constipation,nasal block Late Hallucination, psychosis,pulmonary infiltrates, retroperitoneal fibrosis,digital vasospasm,erythromelalgia

PERGOLIDE :

PERGOLIDE D1 and D2 agonist Increase ON time Less dose of L- dopa Withdrawn--- Valvular heart disease

PRAMIPEXOLE:

PRAMIPEXOLE D3 agonist Antioxidant property Early and advanced disease Less GI side effects Episodes of day time sleep-sleep attacks

ROPINIROLE :

ROPINIROLE D2 agonist Metabolised in liver by CYP1A2 Used in Restless leg syndrome Day time sleep

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MAO MAO MAO I

MAO inhibitors :

MAO inhibitors Selegiline Irreversible MAO-B inhibitor Minimal effect when used as monotherapy Increases ON time Reduce wearing off reaction ANTI OXIDATIVE EFFECT

MAO Inhibitors:

MAO Inhibitors Insomnia when taken later in the day 5mg with break fast and 5mg with lunch S/E – Confusion , insomnia, hallucination Serotonin syndrome RASAGILINE

COMT INHIBITORS :

COMT INHIBITORS Tolcapone , Entacapone Inhibit levodopa metabolism ↑ BA of levodopa Extends the t ½ of levodopa No role as monotherapy Indicated for patients with PD who have end-of-dose wearing off

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S/E Dyskinesia , nausea, confusion diarrhoea , abdominal pain, orange coloured urine Tolcapone ------ hepatotoxicity

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Amantadine

Dopamine facilitator AMANTADINE :

Dopamine facilitator AMANTADINE Anti viral agent - Influenza A Influence pre synaptic synthesis,Release or Reuptake of dopamine Anticholinergic activity Modulate NMDA glutamate receptor

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Amantadine used as initial therapy in mild PD S/E - Livedo reticularis , ankle edema Toxic psychosis , convulsion Heart failure ,postural hypotension Contraindicated in seizure , CHF

Central anticholinergics :

Central anticholinergics Only drugs effective in DRUG INDUCED PARKINSINISM Trihexyphenidyl , Benztropine Tremor is relieved first Efficacy lower than L-dopa Cheaper Contraindicated in narrow angle glaucoma, prostatic hyperplasia

ANTIHISTAMINE:

ANTIHISTAMINE Better tolerated by older patients S/E Dryness of mouth , suppurative parotitis

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