Anti Park In Son Ian Drugs

Drugs Used in Neurodegenerative Disorders (Anti-parkinsonian & Anit-alzheimer Drugs)

Parkinson's disease (PD) PD: an extrapyramidal motor disorder characterized by : – Muscular rigidity. – Resting tremor: pill-rolling movements. – Hypokinesia (bradykinesia) – Disturbances of gait, mask like face, sialorrhea and dementia. AntiPD drugs 1. Drugs affecting brain dopaminergic system I. Drugs that replace dopa (dopamine precursor)- e.g., levodopa (L-dopa) II. Peripheral decarboxylase inhibitors- carbidopa. III. Drugs which prevent breakdown of dopamine: o MAO-B inhibitors: selegiline, rasagiline o COMT inhibitors: entacapone, tolcapone. IV. Drugs that mimic the action of dopamine (dopaminergic agonists): Bromocriptine, pergolide, lisuride, ropirinole, pramipoxole, apomorphine. V. Drugs that facilitate dopaminergic transmission: amantadine 2.

Drugs affecting brain cholinergic system I. Central anticholinergics- benztropine. II. Antihistaminics- diphenhydramine, promethazine.

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Drugs affecting brain dopaminergic system Ldopa (prodrug) Usually given with a dopa decarboxylase inhibitor (DDCI- carbidopa). DDC L-Dopa à dopamine (acts on D2 rec. mainly, D1 also) > 95% of L-dopa is decarboxylated in liver and other tissues to dopamine. Only 1-2% L-dopa crosses brain by active process, reaches presynaptic nerve terminals of dopaminergic neurons in striatum is converted to active compound dopamine.

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Normal person- no effect is seen. In patient with PD- improvement occurs in hypokinesia, rigidity & tremors . Then secondary symptoms (posture, gait, handwriting, speech, facial expression, mood, self care and interest in life)- gradually improve. Behavior: a general alerting response - may progress to excitement -frank psychosis, inappropriate increase in sexual activity.

CVS • Tachycardia, positive inotropic action. • Postural hypotension due to D or NE decreasing sympathetic outflow- tolerance develops. • With large doses- rise in BP due to stimulation of α adrenergic receptors (NE). • Renal vasodilatation. CTZ Stimulation - nausea, and vomiting. Tolerance develops. Endocrine

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Drugs Used in Neurodegenerative Disorders (Anti-parkinsonian & Anit-alzheimer Drugs)

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Inhibits prolactin release. ADME • Absorbed by active transport in small intestine. Bioavailability affected by: amino acids present in food, gastric emptying, pH. • Undergoes high first pass metabolism in GI mucosa and liver. • 95% of L dopa converted to dopamine in peripheral tissues by dopa decarboxylase and less than 1% enters the brain. • When L-dopa is administered with carbidopa, 10% reaches brain. Metabolism: Decarboxylase MAO COMT L-dopa à Dopamine à DOPAC à HVA • • •

T ½ 1-3 hours. Metabolites exc.in urine after conjugation. Urine may be red colored and turn brown.

Adverse effects of L dopa Most are dose related. A. Acute effects (at beginning of therapy)- minimized by starting with a small dose. i. GI toxicity- nausea and vomiting, anorexia- tolerance develops. Domperidone & carbidopa prevent this. ii. CV toxicity: postural hypotension, palpitation, tachycardia, inc. AV conduction & arrhythmias, and exacerbation of angina. iii. CNS toxicity: psychological effects: schizophrenia- use atypical antipsychotics (clozapine or olanzapine) for psychosis- does not worsen PD. Behavioral effects: mild anxiety, confusion, disorientation, insomnia, nightmares, euphoria. iv. Miscellaneous – Alteration in taste and smell sensation. – Mydriasis and acute attack of glaucoma – Blood dyscrasias, +ve coomb's test, aggravation of gout, hemolysis, hot flushes, brownish discoloration of saliva, urine and vaginal secretion, increase in SGOP and PT, increase in BUN, priapism. B. On chronic use (after prolonged therapy- 2-5 years) i. Abnormal movements (dyskinesia): dose limiting side effect, no tolerance develops. Seen more with use of carbidopa. Treatment- reduction in dose and drug free holidays ii. On /off phenomenon or fluctuation in response On - dyskinesia due to excess of dopamine. Off - rigidity and akinesia (end of dose). This is due to degeneration of neurons- loss of buffering capacity. D is synthesized on a moment to moment basis. Treatment : – Dose fractionation and more frequent adm. – Use of slow release L-dopa – Addition of dopamine agonist. Cautions/contraindications

Drugs Used in Neurodegenerative Disorders (Anti-parkinsonian & Anit-alzheimer Drugs)

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IHD, peripheral vascular disease, recent MI, cerebrovascular accident, psychosis, hepatic, and renal disease; peptic ulcer; glaucoma, malignant melanoma (dopamine is precursor of melanin). How to enhance central effects of L-dopa and minimize peripheral effects. • Use or carbidopa/ benserazide to inhibit DDC in periphery. • Use of selegiline/ rasagiline- a MAO-B inhibitor- inhibits metabolism of dopamine in CNS. • Use of entacapone/tolcapone - a COMT inhibitors- inhibits dopamine degradation in CNS. • Use of domperidone – a peripheral dopamine receptor blocker. II. Peripheral decarboxylase inhibitors Carbidopa and benserazide are extracerebral dopa-decarboxylase inhibitors. Benefits obtained with DDCI : • T ½ of L dopa is prolonged and its dose is reduced to 1/4th to 1/8th . • Dec. in nausea and vomiting. • Dec. cardiac complications. • Less On-Off effect- cerebral D levels more sustained. • Higher degree of improvement. Currently L-dopa is practically always used with a decarboxylase inhibitor, except in patients who develop marked involuntary movements with the combination. Preparations: Standard release: senemet: contains carbidopa and L-dopa in a ratio of 1:10 or 1:4; taken 30-60 minutes before food. Sustained release preparation. III. Selective MAO-B inhibitors: selegiline, rasagiline a. Selegiline Actions: i. Prevention of breakdown of dopamine: given with L-dopa or L-dopa + carbidopa- prevents breakdown of dopamine, inc. conc. & storage of dopamine in striatum. No cheese reaction in usual dose but doses >10 mg/d may inhibit MAOA - avoid this dose. ii. Mechanism of neuroprotective action: MAOB inhibitors prevent the neuronal damage by following mechanism: MAOB • Exogenous neurotoxin MPTP à MPP + (methyl phenyl pyridinium ion)àtoxic to neurons. • Free radicals like 6-OHD superoxide, hydroxyl radicals formed by oxidation of dopamine by MAO-B in nigrostriatal tract are not removed and these produce neuronal damage. Desmethylselegiline exerts antiapoptotic effect. Adverse effects: • Postural hypotension • Nausea, confusion, accentuation of L-dopa induced involuntary movements and psychosis.

Drugs Used in Neurodegenerative Disorders (Anti-parkinsonian & Anit-alzheimer Drugs) • • •

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Selegiline is metabolized to amphetamine, which may cause anxiety, insomnia should not be given late in the evening. Should not be given to patient receiving meperidine, SSRI. Recently it has been seen that mortality is higher on triple therapy (L-dopa + carbidopa + selegiline) than with L-dopa alone. So don’t use triple therapy in new cases.

Rasagiline: More potent than selegiline. Uses: • Alone in early cases; retards progression of disease- exerts neuroprotective effect, its metabolite desmethylselegiline is involved in antiapoptotic mechanism. • More commonly used with L-dopa, reduces its dose. b. • • • •

COMT inhibitors Inhibition of DDC is associated with increased metabolism by other pathwaysCOMT- leading to increased plasma levels of 3-O-methyldopa (3OMD) which competes with L-dopa for active transport in the brain. COMT inhibitors prolong L dopa action by inhibiting its peripheral metabolism, increases availability of L dopa, which provides more prolonged on time. Decrease the dose of Ldopa. Smoothen out L-dopa effect.

Tolcapone and Entacapone: Entacapone, though less potent and has only peripheral effects, is preferred because it is not hepatotoxic. Adverse effects: With both (L-dopa excess): • Dyskinesisa, nausea and confusion. • Diarrhoea, abdominal pain, orthostatic hypotension, sleep disturbances, an orange discoloration of urine. With tolcapone, acute hepatic failure may occur- monitor LFT. IV. Drugs that mimic the action of dopamine (dopamine agonists): advantages over L-dopa: • More effective than L-dopa in late PD; have longer duration of action. • Act on striatal D receptors, good for patients who have lost the capacity to synthesize, store and release D from levodopa. • Don’t require enzymatic conversion to active metabolite. • Don’t form potential toxic metabolite. • No competition with other substances for active transport. • There is lower incidence of response fluctuation. • Preferred as first line drug for PD in younger patients with mild disease and no cognitive deficit. However, in most patients L-dopa has to be started in 1-5 years. • One may respond to one compound and other to other. a. • • •

Bromocriptine (BC) Potent agonist of D2 receptors. Is an ergot derivative. Inhibits prolactin release from anterior pituitary.

Drugs Used in Neurodegenerative Disorders (Anti-parkinsonian & Anit-alzheimer Drugs) • • •

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If used alone, doses are high and produce side effects like vomiting, hallucinations, hypotension, nasal stuffiness, conjunctival congestion. Duration of action 6-10 hours. Uses PD: – As a first line drug in the treatment of PD. – As a supplement to Ldopa in late cases, having peak dose dyskinesias or on-off phenomenon – In patients refractory to L-dopa In hyperprolactinemic conditions like galactorrhea- to suppress lactation. Gynecomastia in males and infertility in females. Acromegaly. Pergolide: D1 and D2 agonist, more effective than BC, decreases the dose of L-dopa.

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Ropinirole (D2) and Pramipexol (D3): Newer dopamine agonists. Ropinirole: metabolised in liver. Pramipexole: also exerts a neuroprotective effect by scavenging H2O2. Excreted through kidney.

Uses of dopamine agonists: • Monotherapy in mild cases of PD. Advantages over L dopa: long acting, less chances of on/off effects and dyskinesias, no oxidative stress and damage to neurons, are also better tolerated and therapeutic dose can be achieved soon. • With L-dopa to smoothen its effects in severe cases. d. • • •

Apomorphine: Short acting dopamine agonist, given SC. Acts rapidly in 5-10 minutes. Used as a rescue medication in akinetic emergencies. Always use domperidone (antiemetic) with it.

Adverse effects of dopamine agonists Adverse effects: • GIT- anorexia, nausea, vomiting (give with meals), constipation, dyspepsia, reflux esophagitis, bleeding from peptic ulcer. • CVS- postural hypotension at the beginning, painful digital spasm (Bc, pergolide), cardiac arrhythmias. Peripheral edema. • CNS – Seizures, psychosis, confusion, hallucinations, delusions and other psychiatric illnesses. – Dyskinesias- reduce dose Miscellaneous: i. With BC, pergolide, lisuride (ergot derivatives) :  Headache, nasal congestion, conjunctival congestion.  Erythromelalgia (red, tender, painful, swollen feet and occasionally hands, arthralgia) and digital vasospasm (painless).  Pleural, peritoneal fibosis.

Drugs Used in Neurodegenerative Disorders (Anti-parkinsonian & Anit-alzheimer Drugs) ii.

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With pramipexole, ropinirole: sudden attacks of sleep during daytime activities.

Contraindications Psychosis, recent MI, peripheral vascular disease (BC, pergolide), peptic ulceration. V. Drugs that facilitate dopaminergic transmission: Amantadine • An antiviral drug for influenza A2, accidentally found to have antiparkinsonian activity. • Causes release of dopamine, acts on dopamine receptors, and prevents its reuptake into neuron. • Has antiglutamate action - NMDA antagonist • Also causes release of catecholamines from peripheral stores Adverse effects: • Similar to L-dopa but are less severe. • A characteristic side effect - due to release of catecholamines results in vasoconstriction, livedo reticularis and edema of ankles- responds to diuretics. Uses • It may be used in milder cases or in short courses to supplement submaximal doses of L-dopa. It is less potent than Ldopa and its benefits are short lived. • As adjunct to L-dopa in patients with on/off phenomenon. Contraindications: H/O seizures or heart failure. 2. .i. ii. • • •

Centrally acting anticholinergics Atropine like drugs- have a higher central: peripheral anticholinergic ratio than atropine. Some H1 antihistaminics, like diphenhydramine - significant central anticholinergic property These reduce tremors more than rigidity or hypokinesia. Decrease salivation by their peripheral action. Overall efficacy is much lower than L-dopa.

Adverse effects: • Similar to atropine – peripheral side effects :dry mouth, acute suppurative parotitis, constipation, impaired vision, urinary retention, palpitation, etc - may be trouble some. • Impairment of memory, sedation and confusional states in elderly. Uses: • Drug induced parkinsonism (phenothiazines, butyrophenones, reserpine, metoclopramide, cholinergic drugs, etc.). • In patients where dopaminergic drugs are contraindicated e.g., schizophrenia and cardiac arrhythmia. • May be used alone in mild cases or may be used with L-dopa to reduce its dose.

Drugs Used in Neurodegenerative Disorders (Anti-parkinsonian & Anit-alzheimer Drugs) •

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The antihistaminics are less effective but better tolerated by older patients, their sedative effect also helps.

Alzheimer’s disease (AD) Neurochemistry • Selective loss of cholinergic neurons, reduced activities of choline acetyl transferase and cholinesterase - seen in the basal forebrain cortex and hippocampus. • Reduction in nicotinic receptors but not muscarinic receptors in cortex • Other neurotransmitters involved: glutamate, 5-HT and neuropeptides. Therapy A. To augment cholinergic function of the brain: Centrally acting AniChEs: i. Tacrine Rapidly absorbed; has extensive first pass metabolism in the liver -2-3 % bioavailable; T ½ - 2-3 H. Side effects: – Cholinergic side effects (abdominal cramps, nausea, vomiting, and diarrhea) – Hepatotoxicity- regular biweekly monitoring of LFT is a must- it has become drug of 2nd choice. ii.

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Donepezil- first line drug; highly selective centrally active antiChE, with minimal peripheral effects. 100% bioavailable. T ½ long (70h) hencegiven once a day Adverse reactions: nausea, vomiting, diarrhea and insomnia. Not hepatotoxic Drug of choice at present. Other antiChE: galantamine (also stimulates nicotinic receptors), rivastigmine- like donepezil- no hepatotoxicity.

B. NMDA receptor antagonist: memantine- for severe cases added to AChEIs, delays deterioration. Adverse reactions: Dizziness, headache, confusion, constipation, skin rashes