Parkinson

Parkinson

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  Parkinsonism It is anextra-pyramidal motor disorder characterized by rigidity, tremor and hypokinesia with secondary manifestations like defective posture and gait, mask-like face and sialorrhoea; dementia may accompany. If untreated the symptoms progress over several years to end-stage disease in which the patient is rigid, unable to move, unable to breathe properly; succumbs mostly to chest infections / embolism •First described by James Parkinson in 1817 •Majority of the cases are idiopathic, some are arteriosclerotic while post encephalitic are now rare •Wilson's disease (hepatolenticular degeneration) due to chronic copper poisoning, is a rare cause Reason behind the parkinsonism Antiparkinsonian Drugs •The most consistent lesion in PD is degeneration of neurones in the substantia nigra pars compacta (SN-PC) and the nigrostriatal (dopaminergic) tract . •This results in deficiency of dopamine (DA) in the striatum which controls muscle tone and coordinates movements. •An imbalance between dopaminergic (inhibitory) and cholinergic (excitatory) system in the striatum occurs giving rise to the motor defect. •Though the cholinergic system is not primarily affected, its suppression (by anticholinergics) tends to restore balance
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  •Oxidation of DAby MAO-B and aldehyde dehydrogenasegenerates hydroxyl free radicals (. OH) in the presence of ferrous ions ((basal ganglia are rich in iron) •Normally these free radicals are quenched by glutathione and other protective mechanisms •Age related and otherwise acquired defect in protective mechanism allows the free radicals to damage lipid membrane and DNA resulting in neuronal degeneration • genetic predisposition may contribute to the high vulnerability of nigrostatal neurones •Ageing induces defects in mitochondrial electron transport system •A svnthetic toxin N-methyl-4-phenyl tetrahydropyridine (MPTP) which occurred as a contaminant of some illicit drugs produces nigrostriatal degeneration and manifestation similar to PD by impairing energy metabolism in dopaminergic neurones •Drug-induced temporary parkinsonism due to neuroleptics, metoclopramide (dopamine blockers
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  DA is presentin the brain along with other monoamines DOPA is the precursor of dopamine (DA) CLASSIFICATION I. Drugs affecting brain dopaminergic system (a) Dopamine precursor : Levodopa (L-dopa) (b) Peripheral decarboxylase inhibitors :Carbidopa, Benserazide. (c) Dopaminergic agonists: Bromocriptine, Ropinirole, Pramipexole (d) MAO-B inhibitor: Selegiline (e) COMT inhibitors: Entacapone, Tolcapone (f) Dopamine facilitator: Amantadine. ll. Drugs affecting brain cholinergic system (a) Central anticholinergics: Trihexyphenidyl (Benzhexol), Procyclidine, Biperiden (b)Antihistaminics : Orphenadrine, Promethazine.
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  LEVODOPA Levodopa has aspecific salutary effect in PD: 1.It is inactive by itself, but is the immediate precursor of the transmitter DA More than 95% of an oral dose is decarboxylated in the peripheral tissues (mainly gut and liver). 2. DA thus formed acts on heart, blood vessels, other peripheral organs and on CTZ (though located in the brain, i.e. floor of IV ventricle, it is not bound by blood-brain barrier). 3. About 1-2% of administered levodopa crosses to the brain, is taken up by the surviving dopaminergic neurones converted to DA which is stored and released as a transmitter. 4. Brains of parkinsonian patients treated with levodopa till death had DA levels higher than those not so treated. Further, those patients who had responded well had higher DA levels than those who had responded poorly. Pharmacological actions A. CNS- 1. Levodopa hardly produces any effect in normal individuals or in patients with other neurological diseases 2. Marked symptomatic improvement occurs in parkinsonian patients. 3. Hypokinesia and rigidity resolve first, later tremor as well. 4. Secondary symptoms of posture, gait, handwriting, speech, facial expression, mood, self care and interest in life are gradually normalized. 5. 'general alerting response’- effect of levodopa on behaviour 6. progresses to excitement , frank psychosis may occur. disproportionate increase in sexual activity. 7. Levodopa has been used to - nonspecific 'awakening' effect in hepatic coma.
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  B. CVSB. CVS 1.The peripherally formed DA can cause tachycardia by acting on β adrenergic receptors 2. Though DA can stimulate vascular adrenergic receptors as well, rise in BP is not seen. 3. DA and NA formed in the brain decrease sympathetic outflow 4. DA formed in autonomic ganglia can impede ganglionic transmission. C.C. CTZCTZ 1. Dopaminergic receptors are present in this area and DA acts as a excitatory neurotransmitter. 2. The DA formed peripherally gains access to the CTZ without hindrance- elicits nausea and vomiting. D.D. EndocrineEndocrine 1. DA acts on pituitary mammotropes to inhibit prolactin release and on somatotropes to increase GH release 2. Though prolactin levels in blood fall during levodopa therapy, increased GH levels are not noted in parkinsonian patients 3. Probably the mechanisrns regulating GH secretion are altered in these patients PHARMACOKINETICPHARMACOKINETIC 1.Levodopa is rapidly absorbed from the small intestines by utilizing the active transport 2. Bioavailability of levodopa is affected by:
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  3. Gastric emptying:if slow, levodopa is exposed to degrading enzymes present in gut wall and liver for a longer time-less is available to penetrate blood-brain barrier. 4. Amino acids present in food compete for the same carrier for absorption: blood levels are lower when taken with meals. 5. Levodopa undergoes high first pass metabolism in G.I. mucosa and liver
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  6. About 1%of administered levodopa that enters brain, aided by amino acid carrier mediated active transport across brain capillaries 7. The plasma t1/2 of levodopa is 1-2 hours. 8. Pyridoxal is a cofactor for the enzyme dopa-decarboxylase 9.The metabolites are excreted in urine mostly after conjugation. ADVERSE EFFECTS Side effects of levodopa therapy are frequent and often troublesome. Most are dose-related and limit the dose that can be administered. but are usually reversible. At the initiation of therapy 1. Nausea and vomiting- It occurs in almost every patient. Tolerance gradually develops and then the dose can be progressively increased.(peripheral d2 receptor…>ctz) 2. Postural hypotension- It occurs in about 1/3 of patients, but is mostly asymptomatic; some patients experience dizziness, few have fainting (alpha receptor) 3.Cardiac arrhythmia - due to β adrenergic action of peripherally formed DA; 4. Exacerbation of angina - more in patients with pre existing heart disease. 5. Alteration in taste sensation After prolonged therapy Abnormal movements, Behavioral effects, Fluctuation in motor performance
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  Cautious use isneeded in elderly; patients with ischaemic heart disease, cerebrovascular, psychiatric, hepatic and renal disease, peptic ulcer and gout Drug Interactions 1. levodopa + Pyridoxine- Abolishes therapeutic effect by enhancing peripheral Decarboxylation of levodopa. Less is available to cross the blood brain. (metabolism) 2. levodopa +Phenothiazines/ butyrophenones/ metoclopramide - reverse therapeutic effect of levodopa by blocking DA receptor (pharmacodynamic) 3. levodopa+ Domperidon- blocks levodopa induced nausea and vomiting without abolishing its antiparkinsonian effect, because domperidone does not cross blood brain barrier (domperidone inhibit pripheral d2 receptor) 4. levodopa + Reserpine- abolishes levodopa action by preventing entry of DA into synaptic vesicles 5. Levodopa + Nonselective MAO inhibitors- prevent degradation of peripherally synthesized DA and NA- hypertensive crisis can occur 6. Levodopa + Antihypertensives- postural hypotension is accentuated, reduce their dose if levodopa is started.
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  7. Levodopa +Atropine, and other anticholinergic drug- have additive antiparkinsonian action with low doses of levodopa but retard its absorption, more time is available for peripheral degradation- efficacy of levodopa is reduced PERIPHERAL DECARBOXYLASE INHIBITORS Carbidopa and benzserazide extracerebral DOPA decarboxylase inhibitor 1. Do not penetrate blood brain barrier and do not inhibit conversion of levedopa to DA in the brain 2. along with levodopa, they increase its t1/2 in the periphery and make more of it Available to cross blood brain barrier Benefits of the combination are 1. The plasma t1/2 of levodopa is prolonged and dose is reduced to 1/4th 2. Systemic concentration of DA is reduced-nausea and vomiting are not Prominent – therapeutic doses of levodopa can be attained quickly 3. Cardiac complications are minimized 4. Pyridoxine reversal of levodopa effect does not occur 5. 'On-off‘ effect is minimized since cerebral DA levels are more sustained 6. Degree of improvement may be higher Combination of levodopa with carbidopa has been given the name 'Co-careldopa’
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  DOPAMINERGIC AGONISTS 1. TheDA agonists can act on striatal DA receptors 2. who have largely lost the capacity to synthesize, store and release DA from levodopa 3. they are longer acting Bromocriptine 1. It is an ergot derivative which acts as potent agonist on D2, but as partial agonist or antagonist on D1receptors. 2. Improvement in parkinsonian symptoms occurs within 11/2 - 1 hr of an oral dose of bromocriptine and lasts for 6-10 hours. 3. often produce intolerable side effects- vomiting, hallucinations, hypotension, nasal stuffiness, conjunctival injection. 4. Marked fall in BP with the 'first dose' has occurred in some patients, especially those on antihypertensive medication 5. In parkinsonism, bromocriptine is used only in late cases as a supplement to levodopa 6. starting with low doses (1.25 mg once at night) and gradually increasing as needed upto 5-10 mg thrice daily. 7. serves to improve control and smoothen 'end of dose' and 'on-off' fluctuations..
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  8. Dyskinesias areless prominent with bromocriptine compared to levodopa Ropinirole and Pramipexole 1. These are two recently developed nonergoline, selectiveD2 /D3receptor agonists with negligible affinity for D1and non-dopaminergic receptors. 2. Pramipexole has relatively greater affinity for D3 receptors. 3. Better tolerated than levodopa with fewer gasrointestinal symptoms. 4. Ropinirole and pramipexole are now frequently used as monotherapy for early PD 5. Use of these DA agonists may be associated with slower rate of neuronal degeneration 6. newer DA agonists are effective alterative to levodopa and afford longer symptom-free life to PD patients. 7. Ropinirole is rapidly absorbed orally, 40% plasma protein bound, extensively metabolized, mainly by hepatic CYP1A2, to inactive metabolites. 8. Elimination rate- t1/2 - 6 hrs.
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  9. longer actingthan levodopa, useful in the management of motor fluctuations and reducing frequency of on-off effect. 10. Side-effects are nausea, dizziness, hallucinations, and postural hypotension. 11. Episodes of day time sleep have been noted with ropinirole as well as pramipexole. 12. The higher incidence of hallucinations and sleepiness may disfavour their use in the elderly. 13. Ropinirole has recently been approved for use in ‘restless leg syndrome'. Ropinirole: Starting dose is 0.25 mg TDS, titrated to a maximum of 4-8 mg TDS. Early cases generally require 1-2 mg TDS ROPITOR 0.25, 0 5, 1.0, 2.0 mg tabs ROPITO & ROPARK, ROPEWAY 0.25, 0.5, 1.0, 20 mg tabs .
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  MAO-B INHIBITOR Selegiline (Deprenyl) 1.It is a selective and irreversible MAO-B inhibitor. 2. Two isoenzyme forms of MAO, termed MAO-A and MAO-B are recognized 3. both are present in periphera adrenergic structures and intestinal mucosal while the latter predominates in the brain and blood platelets 4. Selegiline alone has mild antiparkinsonian action 5. Administered with levodopa, it prolongs levodopa action, attenuation motor fluctuations and decrease wearing off effect. 6. Adverse effects i) Postural hypotension, confusion, accentuation of levodopa induced involuntary movements and psychosis. ii) Contraindicated in patients with convulsive disorder iii) Selegeline interacts with pethidine causing, excitement, rigidity, hyperthermia, respiratory depression iv) It may also interact with tricyclic antidepressants and selective serotonin reuptake inhibitors. ELDEPRYL 5, 10 mg tab; SELERIN, Dose; 5 mg with breakfast and with lunch
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  COMT INHIBITORS 1. Twoselective, potent and reversible COMT inhibitors Entacapone and Tolcapone have been introduced as adjuvants to levodopa-carbidopa for advanced PD. 2. When peripheral decarboxylation of levodopa is blocked by carbidopa / benserazide, it is mainly metabolized by COMT to 3-O-methyldopa 3. Blockade of this pathway by entacapone / tolcapone prolongs the t1/2 of levodopa and allows a larger fraction of administered dose to cross to brain. 4. Since COMT plays a role in the degradation of DA in brain as well, COMT inhibitors could preserve DA formed in the striatum and supplement the peripheral effect. 5. However, entacapone acts only in the periphery (probably because of short duration of action -2 hr) 6. Both entacapone and tolcapone enhance and prolong the therapeutic effect of levodopa- carbidopa in advanced and fluctuating PD 7. They may be used to smoothen 'wearing off', increase 'on' time, decrease 'off' time, improve activities of daily living and allow levodopa dose to be reduced. They are not indicated in early PD cases 8. Tolcapone: 100-200 mg BD or TDS 9. Worsening of levodopa adverse effects such as nausea, vomiting, dyskinesia, postural hypotension, hallucinations, etc. occurs often when a COMT inhibitor is added. However, this can be minimized by adjustment of levodopa dose 10. Other prominent side effect is diarrhoea in 10-18% patients (less with entacapone and yellow orange discoloration of urine
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  11. Because ofreports of acute fatal hepatitis and rhabdomyolysis, tolcapone has been suspended in Europe and Canada, while in USA its use is allowed only in those not responding to entacapone. 12. Entacapone is not hepatotoxic. DOPAMINE FACILITATOR Amantadine : 1. Developed as an antiviral drug for prophylaxis of influenza A2, it was found serendipitously to benefit parkinsonism. 2. It acts rapidly but has lower efficacy than levodopa. though higher than anticholinergics 3. However, tolerance develops over months and the efficacy is lost 4. Amantadine appears to act by promoting presynaptic synthesis and release of DA in brain. 5. Action on NMDA type of glutamate receptors, through which the striatal dopaminergic system exerts its influence is now considered to be more important. 6. Amantadine can be used in milder cases, or in short courses to supplement levodopa for advanced cases. In the latter situation, it servesto suppress motor fluctuations and abnormal movements. 7. Fixed dose of 100 mg BD is used (not titrated according to response). Effect of a single dose lasts 8-12 hours
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  Side effects :These are generally not serious: a) insomnia, b) dizziness, c) confusion, d) nightmares, anticholinergic effects and rarely hallucinations. A characteristic side effect due to local release of CAs resulting in vasoconstriction is livedo reticularis and edema of ankles Side effects are accentuated when it is combined with anticholinergics. CENTRAL ANTICHOLINERGICS 1. These are drugs having a higher central : peripheral anticholinergic action ratio than atropine, but the pharmacological profile is similar to it. 2. Certain H1, antihistaminics have significant central anticholinergic property. 3. All anticholinergics produce 70-25% improvement in clinical features, lasting 4-8 hours after a single dose. 4. The overall efficacy is much lower than levodopa. However, they are cheap and produce less side effects than levodopa. 5 Anticholinergics are the only drugs effective in drug (phenothiazine) induced parkinsonism. livedo reticularis- A common cutaneous finding consisting of a mottled reticulated vascular pattern that appears like a lace-like purplish discoloration of the lower extremities