Anti-Parkinsonian Drugs PDF

Chapter 31 Antiparkinsonian Drugs These are drugs that have a therapeutic effect in the environment, small quantities of which accelerate age in parkinsonism. related or otherwise predisposed neuronal degeneration of...

Chapter 31 Antiparkinsonian Drugs These are drugs that have a therapeutic effect in the environment, small quantities of which accelerate age in parkinsonism. related or otherwise predisposed neuronal degeneration of parkinsonism, but there is no proof. Parkinsonism It is an extrapyramidal motor Excess of the excitatory transmitter glutamate can cause ‘excitotoxic’ neuronal death by inducing Ca2+ overload through disorder characterized by rigidity, tremor and NMDA receptors. hypokinesia with secondary manifestations like Drug-induced temporary parkinsonism due to neuro- defective posture and gait, mask-like face and leptics, metoclopramide (dopaminergic blockers) is now fairly sialorrhoea; dementia may accompany. If untrea- common, while that due to reserpine (DA depleter) is historical. ted the symptoms progress over several years Belladonna alkaloids had been empirically used to end-stage disease in which the patient is rigid, in PD. A breakthrough was made in 1967 when unable to move, unable to breathe properly; levodopa was found to produce dramatic succumbs mostly to chest infections/embolism. improvement. Its use was based on sound scien- Parkinson’s disease (PD) is a progressive degenerative tific investigations made in the preceding 10 disorder, mostly affecting older people, first described by years that: James Parkinson in 1817. Majority of the cases are idiopathic, DA is present in the brain; some are arteriosclerotic while postencephalitic are now rare. Wilson’s disease (hepatolenticular degeneration) due to it (along with other monoamines) is depleted chronic copper poisoning, is a rare cause. by reserpine; The most consistent lesion in PD is degeneration of reserpine induced motor defect is reversed neurones in the substantia nigra pars compacta (SN-PC) and by DOPA (the precursor of DA); the nigrostriatal (dopaminergic) tract. This results in deficiency of dopamine (DA) in the striatum which controls muscle tone striatum of patients dying of PD was deficient and coordinates movements. An imbalance between in DA. dopaminergic (inhibitory) and cholinergic (excitatory) system Thus, parkinsonism was characterized as a DA in the striatum occurs giving rise to the motor defect. Though the cholinergic system is not primarily affected, its sup- deficiency state and levodopa was used to make pression (by anticholinergics) tends to restore balance. good this deficiency, because DA itself does not The cause of selective degeneration of nigrostriatal cross the blood-brain barrier. In the subsequent neurones is not precisely known, but appears to be years, a number of levodopa potentiators and DA multifactorial. Oxidation of DA by MAO-B and aldehyde dehydrogenase generates hydroxyl free radicals ( OH) in the agonists have been developed as adjuvants/ presence of ferrous iron (basal ganglia are rich in iron). alternatives. Normally these free radicals are quenched by glutathione and other protective mechanisms. Age-related and/or otherwise CLASSIFICATION acquired defect in protective mechanism allows the free radicals to damage lipid membranes and DNA resulting in I. Drugs affecting brain dopaminergic neuronal degeneration. Genetic predisposition may contribute system to the high vulnerability of substantia nigra neurones. (a) Dopamine precursor : Levodopa (l-dopa) Ageing induces defects in mitochondrial electron transport chain. Environmental toxins and/or genetic factors (b) Peripheral decarboxylase inhibitors : may accentuate these defects in specific areas. A synthetic Carbidopa, Benserazide. toxin N-methyl-4-phenyl tetrahydropyridine (MPTP), which (c) Dopaminergic agonists: Bromocriptine, occurred as a contaminant of some illicit drugs, produces Ropinirole, Pramipexole nigrostriatal degeneration and manifestations similar to PD by impairing energy metabolism in dopaminergic neurones. (d) MAO-B inhibitor: Selegiline, Rasagiline It has been proposed that MPTP-like chemicals may be present (e) COMT inhibitors: Entacapone, Tolcapone 426 DRUGS ACTING ON CENTRAL NERVOUS SYSTEM (f) Glutamate (NMDA receptor) antagonist some patients this progresses to excitement— (Dopamine facilitator): Amantadine. frank psychosis may occur. Embarrassingly II. Drugs affecting brain cholinergic disproportionate increase in sexual activity has system also been noted. Dementia, if present, does not (a) Central anticholinergics: Trihexyphe- improve; rather it predisposes to emergence of nidyl (Benzhexol), Procyclidine, psychiatric symptoms. Biperiden. Levodopa has been used to produce a non- (b) Antihistaminics : Orphenadrine, specific ‘awakening’ effect in hepatic coma. Promethazine. Two subtypes of DA receptors (D1, D2) were originally described. Three more (D3, D4, D5) have now been identified SECTION 7 and cloned. All are G protein coupled receptors and are LEVODOPA grouped into two families: Levodopa has a specific salutary effect in PD: D1 like (D1, D5) Are excitatory: act by increasing cAMP formation and PIP2 hydrolysis thereby mobilizing intracellular efficacy exceeding that of any other drug used Ca2+ and activating protein kinase C through IP3 and DAG. alone. It is inactive by itself, but is the immediate D2 like (D2, D3, D4) Are inhibitory: act by inhibiting precursor of the transmitter DA. More than 95% adenylyl cyclase/opening K+ channels/depressing voltage of an oral dose is decarboxylated in the sensitive Ca2+ channels. peripheral tissues (mainly gut and liver). DA thus The various subtypes of DA receptors are differentially expressed in different areas of the brain, and appear to play formed is further metabolized, and the remaining distinct roles. Both D1 and D2 receptors are present in the acts on heart, blood vessels, other peripheral striatum and are involved in the therapeutic response to organs and on CTZ (though located in the brain, levodopa. They respectively regulate the activity of two i.e. floor of IV ventricle, it is not bound by blood- pathways having opposite effects on the thalamic input to the motor cortex (Fig. 31.1). Thus, stimulation of excitatory D1 as brain barrier). About 1–2% of administered well as inhibitory D2 receptors in the striatum achieves the levodopa crosses to the brain, is taken up by same net effect of smoothening movements and reducing muscle the surviving dopaminergic neurones, converted tone. to DA which is stored and released as a trans- Dopamine receptor in SN-PC and in pituitary is also of D2 type. The D3 receptors predominate in nucleus accumbans mitter. Brains of parkinsonian patients treated and hypothalamus, but are sparse in caudate and putamen, with levodopa till death had higher DA levels while D4 and D5 are mostly distributed in neocortex, midbrain, than those not so treated. Further, those patients medulla and hippocampus. who had responded well had higher DA levels 2. CVS The peripherally formed DA can than those who had responded poorly. cause tachycardia by acting on β adrenergic receptors. Though DA can stimulate vascular ACTIONS adrenergic receptors as well, rise in BP is not 1. CNS Levodopa hardly produces any effect seen. Instead, postural hypotension is quite in normal individuals or in patients with other common. This may be a central action. Excess neurological diseases. Marked symptomatic DA and NA formed in the brain decrease sym- improvement occurs in parkinsonian patients. pathetic outflow; also DA formed in autonomic Hypokinesia and rigidity resolve first, later ganglia can impede ganglionic transmission. tremor as well. Secondary symptoms of posture, Gradual tolerance develops to both cardiac stimulant and hypotensive actions. gait, handwriting, speech, facial expression, mood, self care and interest in life are gradually 3. CTZ Dopaminergic receptors are present in normalized. Therapeutic benefit is nearly this area and DA acts as an excitatory transmitter. complete in early disease, but declines as the The DA formed peripherally gains access to the disease advances. CTZ without hindrance—elicits nausea and The effect of levodopa on behaviour has been vomiting. Tolerance develops gradually to this described as a ‘general alerting response’. In action.  ANTIPARKINSONIAN DRUGS 427 CHAPTER 31 Fig. 31.1: Simplified scheme of side loop circuits in the basal ganglia that provide modulatory input to the motor cortex. The striatal GABAergic neurones receive side-loop excitatory glutamatergic (Glu) input from the motor cortex and modulatory dopaminergic (DA) projections from the substantia nigra pars compacta (SN-PC). There are also balancing cholinergic (ACh) interneurones. The striatal neurones express both excitatory D1 and inhibitory D2 receptors. The output from the striatum to substantia nigra pars reticulata (SN-PR) and internal globus pallidus (GP-I) follows a direct and an indirect pathway. The direct pathway modulated by DI receptors releases inhibitory transmitter GABA, while the dominant indirect pathway modulated by D2 receptors has two inhibitory (GABAergic) relays and an excitatory (glutamatergic) terminal. Due to this arrangement, dopaminergic action in the striatum exerts inhibitory influence on SN- PR and GP-I via both the pathways. The output neurones from SN-PR and GP-I feedback on the motor cortex through the thalamus using an inhibitory GABAergic link and an excitatory glutamatergic terminal. The basal ganglia modulatory loop serves to smoothen output to the spinal motor neurone and reduce basal tone. The degenerative lesion (in SN-PC) of Parkinson’s disease (PD) decreases dopaminergic input to the striatum, producing an imbalance between DA and ACh, resulting in hypokinesia, rigidity and tremor. 4. Endocrine DA acts on pituitary mammo- PHARMACOKINETICS tropes to inhibit prolactin release and on soma- Levodopa is rapidly absorbed from the small totropes to increase GH release. Though pro- intestines by utilizing the active transport process lactin levels in blood fall during levodopa therapy, meant for aromatic amino acids. Bioavailability increased GH levels are not noted in parkinso- of levodopa is affected by: nian patients. Probably the mechanisms regula- (i) Gastric emptying: if slow, levodopa is ting GH secretion are altered in these patients. exposed to degrading enzymes present in gut wall 428 DRUGS ACTING ON CENTRAL NERVOUS SYSTEM SECTION 7 Fig. 31.2: Metabolic pathways of levodopa in the periphery and the brain. 3-OMD—3-O-methyldopa; COMT—Catechol-O-methyl transferase; MAO—monoamine oxidase; 3-MT— 3-methoxytyramine; DOPAC—3,4 dihydroxy phenylacetic acid; HVA—Homovanillic acid (3-methoxy- 4-hydroxy phenylacetic acid), DDC—Dopa decarboxylase and liver for a longer time—less is available At the initiation of therapy These side to penetrate blood-brain barrier. effects can be minimized by starting with a low (ii) Amino acids present in food compete for dose. the same carrier for absorption: blood levels are 1. Nausea and vomiting It occurs in almost lower when taken with meals. every patient. Tolerance gradually develops and Levodopa undergoes high first pass meta- then the dose can be progressively increased. bolism in g.i. mucosa and liver. The peripheral 2. Postural hypotension It occurs in about and central pathway of metabolism of levodopa 1/3 of patients, but is mostly asymptomatic; some is depicted in Fig. 31.2. patients experience dizziness, few have fainting About 1% of administered levodopa that enters attacks. It is more common in patients receiving brain, aided by amino acid carrier mediated active antihypertensives. Tolerance develops with transport across brain capillaries, also undergoes continued treatment and BP normalizes. the same transformation. The plasma t½ of to β adrenergic action levodopa is 1–2 hours. Pyridoxal is a cofactor for the enzyme dopa-decarboxylase. The 3. Cardiac arrhythmias  Due of peripherally formed DA; metabolites are excreted in urine mostly after 4. Exacerbation  more in patients with pre- conjugation. of angina  existing heart disease. 5. Alteration in taste sensation ADVERSE EFFECTS Side effects of levodopa therapy are frequent After prolonged therapy and often troublesome. Most are dose-related 1. Abnormal movements (dyskinesias) Facial and limit the dose that can be administered, but tics, grimacing, tongue thrusting, choreoathetoid are usually reversible. Some are prominent in movements of limbs start appearing after a the beginning of therapy while others appear late. few months of use of levodopa at optimum  ANTIPARKINSONIAN DRUGS 429 therapeutic dose. These dyskinesias worsen with 2. Phenothiazines, butyrophenones, metoclo- time and practically all patients get involved after pramide reverse the therapeutic effect of few years. Their intensity corresponds with levodopa by blocking DA receptors. The levodopa levels. No tolerance develops to antidopaminergic domperidone blocks levodopa this adverse effect, but dose reduction decreases induced nausea and vomiting without abolishing severity. Abnormal movements may become as its antiparkinsonian effect, because domperidone disabling as the original disease itself, and are does not cross blood-brain barrier, but reaches the most important dose-limiting side effects. CTZ. Reserpine abolishes levodopa action by 2. Behavioural effects Range from mild preventing entry of DA into synaptic vesicles. 3. Nonselective MAO inhibitors: prevent degra- CHAPTER 31 anxiety, nightmares, etc. to severe depression, mania, hallucinations, mental confusion or frank dation of DA and NA that is synthesized in psychosis. Excessive DA action in the limbic excess from the administered levodopa at system is probably responsible (antidopaminergic peripheral sites. This may cause hypertensive drugs are antipsychotic). Levodopa is contra- crisis. indicated in patients with psychotic illness. 4. Antihypertensive drugs: postural hypotension caused by levodopa is accentuated in patients 3. Fluctuation in motor performance After receiving antihypertensive drugs; reduce their 2–5 years of therapy, the level of control of dose if levodopa is started. parkinsonian symptomatology starts showing 5. Atropine, and antiparkinsonian anticho- fluctuation. ‘End of dose’ deterioration (wearing linergic drugs have additive therapeutic action off) which is initially gradual, develops into rapid with low doses of levodopa, but retard its ‘switches’ or ‘on-off’ effect. With time ‘all or absorption—more time is available for peripheral none’ response develops, i.e. the patient is degradation—efficacy of levodopa may be alternately well and disabled. Abnormal reduced. movements may jeopardise even the ‘on’ phase. This is probably a reflection of progression of the disorder. With progressive degeneration of PERIPHERAL DECARBOXYLASE DA neurones the ability to regulate storage and INHIBITORS release of DA may be largely lost: DA is then Carbidopa and benserazide are extracerebral synthesized in the striatum on a moment-to- dopa decarboxylase inhibitors; they do not moment basis resulting in rapid and unpredic- penetrate blood-brain barrier and do not inhibit table fluctuations in motor control. Dose conversion of levodopa to DA in the brain. fractionation and more frequent administration Administered along with levodopa, they increase tends to diminish these fluctuations for a time. its t½ in the periphery and make more of it Cautious use of levodopa is needed in the available to cross blood-brain barrier and reach elderly; patients with ischaemic heart disease; its site of action. cerebrovascular, psychiatric, hepatic and renal Benefits of the combination are— disease; peptic ulcer; glaucoma and gout. 1. The plasma t½ of levodopa is prolonged and Dose: Start with 0.25 g BD after meals, gradually increase till adequate response is obtained. Usual dose is 2–3 g/day. its dose is reduced to approximately 1/4th. LEVOPA, BIDOPAL 0.5 g tab. 2. Systemic concentration of DA is reduced, nausea and vomiting are not prominent— Interactions therapeutic doses of levodopa can be attained 1. Pyridoxine: Abolishes the therapeutic effect quickly. of levodopa (not combined with carbidopa) by 3. Cardiac complications are minimized. enhancing its peripheral decarboxylation so that 4. Pyridoxine reversal of levodopa effect does less of it remains available to cross to the brain. not occur. 430 DRUGS ACTING ON CENTRAL NERVOUS SYSTEM 5. ‘On-off’ effect is minimized since cerebral but as partial agonist or antagonist on D1 DA levels are more sustained. receptors. Improvement in parkinsonian symp- 6. Degree of improvement may be higher; some toms occurs within ½–1 hr of an oral dose of patients, not responding adequately to bromocriptine and lasts for 6–10 hours. If used levodopa alone, also improve. alone, doses needed in parkinsonism are high, expensive and often produce intolerable side Problems not resolved or accentuated are— effects, especially vomiting, hallucinations, 1. Involuntary movements  may even be more hypotension, nasal stuffiness, conjunctival 2. Behavioural abnormalities pronounced and injection. Marked fall in BP with the ‘first dose’ appear earlier. 3. Excessive day time sleepiness in some has occurred in some patients, especially those SECTION 7 patients. on antihypertensive medication. 4. Postural hypotension. Bromocriptine has been largely replaced by the newer DA agonists ropinirole and prami- Currently, levodopa is practically always used pexole. However, it can be used in late cases along with a decarboxylase inhibitor, except in as a supplement to levodopa to improve control patients who develop marked involuntary and smoothen ‘on off’ fluctuations. movements with the combination. Dose: Initially 1.25 mg once at night, increase as needed upto Combination of levodopa with carbidopa has 5 mg TDS. PROCTINAL, SICRIPTIN, PARLODEL, 1.25, 2.5 mg tabs, been given the name ‘Co-careldopa’. ENCRIPT 2.5, 5 mg tabs. Preparations and dose Ropinirole and Pramipexole These are two Carbidopa Levodopa nonergoline, selective D2/D3 receptor agonists (per tab/cap) with negligible affinity for D1 and nondopa- TIDOMET-LS, SYNDOPA-110, 10 mg + 100 mg minergic receptors. Pramipexole has relatively SINEMET, DUODOPA-110 10 mg + 100 mg TIDOMET PLUS, SYNDOPA PLUS 25 mg + 100 mg greater affinity for D3 receptors. The therapeutic TIDOMET FORTE, SYNDOPA-275 25 mg + 250 mg effect as supplementary drugs to levodopa in BENSPAR, MADOPAR: Benserazide 25 mg + levodopa advanced cases of PD as well as side effect profile 100 mg cap. is similar to bromocriptine, but they are better Usual daily maintenance dose of levodopa is 0.4–0.8 g along tolerated with fewer g.i. symptoms. Consequently with 75–100 mg carbidopa or 100–200 mg benserazide, given dose titration for maximum improvement can in 3–4 divided doses. Therapy is started at a low dose and be achieved in 1–2 weeks, while the same may suitable preparations are chosen according to the needs of individual patients, increasing the dose as required. take several months with bromocriptine. Ropinirole and pramipexole are now DOPAMINERGIC AGONISTS frequently used as monotherapy for early PD as well. Trials have found them to afford symp- The DA agonists can act on striatal DA receptors tom relief comparable to levodopa. Fewer cases even in advanced patients who have largely lost treated with ropinirole needed supplemental the capacity to synthesize, store and release DA levodopa than those treated with bromocriptine. from levodopa. Moreover, they are longer acting, The Parkinson Study Group and other multi- can exert subtype selective activation of DA centric trials have noted lower incidence of dys- receptors involved in parkinsonism and not share kinesias and motor fluctuations among patients the concern expressed about levodopa of treated with these drugs than those treated with contributing to dopaminergic neuronal damage levodopa. There is some indirect evidence that by oxidative metabolism. use of ropinirole/pramipexole in place of Bromocriptine (see Ch. 17) It is an ergot levodopa-carbidopa may be associated with derivative which acts as potent agonist on D2, slower rate of neuronal degeneration. Such  ANTIPARKINSONIAN DRUGS 431 encouraging findings indicate that the newer DA MAO-B INHIBITOR agonists are effective alternatives to levodopa Selegiline (Deprenyl) It is a selective and and may afford longer symptom-free life to PD irreversible MAO-B inhibitor. Two isoenzyme patients. forms of MAO, termed MAO-A and MAO-B are Ropinirole is rapidly absorbed orally, 40% recognized; both are present in peripheral plasma protein bound, extensively metabolized, adrenergic structures and intestinal mucosa, mainly by hepatic CYP1A2, to inactive meta- while the latter predominates in the brain and bolites, and eliminated with a terminal t½ of blood platelets. Unlike nonselective MAO 6 hrs. It is thus longer acting than levodopa, inhibitors, selegiline in low doses (10 mg/day) useful in the management of motor fluctuations CHAPTER 31 does not interfere with peripheral metabolism and reducing frequency of on-off effect. of dietary amines; Accumulation of CAs and Side-effects are nausea, dizziness, halluci- hypertensive reaction does not develop, while nations, and postural hypotension. Episodes of intracerebral degradation of DA is retarded (Fig. day time sleep have been noted with ropinirole 31.2). This is responsible for the therapeutic as well as pramipexole. The higher incidence effect in parkinsonism. Higher doses can produce of hallucinations and sleepiness may disfavour hypertensive interactions with levodopa and their use in the elderly. Patients should be indirectly acting sympathomimetic amines. advised not to drive if they suffer this side effect. Selegiline alone has mild antiparkinsonian Ropinirole is FDA approved for use in action in early cases. Administered with levo- ‘restless leg syndrome’. dopa, it prolongs levodopa action, attenuates Ropinirole: Starting dose is 0.25 mg TDS, titrated to a motor fluctuations and decreases ‘wearing off’ maximum of 4–8 mg TDS. Early cases generally require effect. As an adjuvant to levodopa, it is beneficial 1–2 mg TDS. in 50–70% patients and permits 20–30% ROPITOR, ROPARK, ROPEWAY 0.25, 0.5, 1.0, 2.0 mg tabs. Also 1,2,4 and 8 mg ER tabs are approved. reduction in levodopa dose. However, advanced cases with ‘on-off’ effect are not improved and Pramipexole: It is twice as potent as ropinirole, but comparable in efficacy and tolerability. Starting dose 0.125 the peak dose levodopa side effects such as mg TDS, titrate to 0.5–1.5 mg TDS. dyskinesias, mental confusion or hallucinations PRAMIPEX 0.5 mg tab; PARPEX 0.5, 1.0, 1.5 mg tabs, may be worsened. Moreover, clinical benefits PRAMIROL 0.125, 0.25, 0.5, 1.0, 1.5 mg tabs. derived from selegiline are short lived (6–26 Restless legs syndrome (RLS): It is a peculiar sensory- months). motor disorder affecting the legs during periods of relaxation, Based on the hypothesis that oxidation of especially sleep. The affected subject feels an irresistable urge DA and/or environmental toxins (MPTP-like) in to constantly move the legs, usually associated with tingling, itching, discomfort, aching or cramps. The symptoms abate the striatum by MAO to free radicals was causa- by walking and do not appear during activity. The disorder tive in parkinsonism, it was proposed that early may be mild and go unnoticed. In some cases, symptoms therapy with selegiline might delay progression are severe and disrupt sleep, resulting in day-time sleepiness. of the disorder. However, no difference in the The disorder may be primary (idiopathic) or secondary to iron deficiency anaemia, folate or other vitamin deficiencies, course of the disease has been detected on varicose veins, peripheral neuropathy (diabetic/uraemic, follow up of selegiline treated patients in large etc.), or be associated with pregnancy. A genetic basis and multicentric studies. Nevertheless, there is some mild dopaminergic hypofunction in the brain have been recent data supporting a neuroprotective effect implicated. of rasagiline, another MAO-B inhibitor, in The nonergot dopaminergic agonists are the most effective drugs. Relatively low doses: ropinirole (0.25–1.0 mg) or parkinsonism. pramipexole (0.125–0.5 mg) taken 2–3 hours before bed-time each day afford dramatic relief in many cases. Other drugs used Adverse effects Postural hypotension, nausea, are benzodiazepines, gabapentin or pregabalin, but these are confusion, accentuation of levodopa induced mostly reserved for nonresponsive cases. involuntary movements and psychosis. Selegiline 432 DRUGS ACTING ON CENTRAL NERVOUS SYSTEM is partly metabolized by liver into amphetamine may be used to smoothen ‘wearing off’, increase which sometimes causes insomnia and agitation. ‘on’ time, decrease ‘off’ time, improve activities Selegiline is contraindicated in patients with of daily living and allow levodopa dose to be convulsive disorders. reduced. They are not indicated in early PD cases. Selegiline interacts with pethidine possibly by Entacapone: 200 mg with each dose of levodopa-carbidopa, favouring its metabolism to norpethidine which max. 1600 mg/day. ADCAPON 100 mg tab, COMTAN 200 mg tab. causes excitement, rigidity, hyperthermia, Tolcapone: 100–200 mg BD or TDS. respiratory depression. It may also interact with Worsening of levodopa adverse effects such tricyclic antidepressants and selective serotonin as nausea, vomiting, dyskinesia, postural hypo- reuptake inhibitors. tension, hallucinations, etc. occurs often when SECTION 7 ELDEPRYL 5, 10 mg tab; SELERIN, SELGIN 5 mg tab; a COMT inhibitor is added. However, this can Dose: 5 mg with breakfast and with lunch, either alone (in early cases) or with levodopa/carbidopa. Reduce by 1/4th levodopa be minimised by adjustment of levodopa dose. dose after 2–3 days of adding selegiline. Other prominent side effect is diarrhoea in 10– 18% patients (less with entacapone) and yellow- Rasagiline Another newer selective MAO-B orange discolouration of urine. inhibitor with selegiline-like therapeutic effect Because of reports of acute fatal hepatitis and in parkinsonism. However, it is 5 times more rhabdomyolysis, tolcapone has been suspended in Europe potent, longer acting and not metabolized to and Canada, while in USA its use is allowed only in those amphetamine. It is therefore given once a day not responding to entacapone. Entacapone is not hepatotoxic. in the morning, and does not produce excitatory side effects. GLUTAMATE (NMDA receptor) Dose: 1 mg OD in the morning. ANTAGONIST (Dopamine facilitator) RELGIN, RASALECT 0.5, 1.0 mg tabs, RASIPAR 1 mg tab. Amantadine Developed as an antiviral drug COMT INHIBITORS for prophylaxis of influenza A2, it was found serendipitiously to benefit parkinsonism. It acts Two selective, potent and reversible COMT rapidly but has lower efficacy than levodopa, inhibitors Entacapone and Tolcapone have been which is equivalent to or higher than anti- introduced as adjuvants to levodopa-carbidopa cholinergics. About 2/3rd patients derive some for advanced PD. When peripheral decarbox- benefit. However, tolerance develops over ylation of levodopa is blocked by carbidopa/ months and the efficacy is gradually lost. benserazide, it is mainly metabolized by COMT Amantadine promotes presynaptic synthesis and to 3-O-methyldopa (see Fig. 31.2). Blockade of release of DA in the brain and has anticholinergic this pathway by entacapone/tolcapone prolongs property. These were believed to explain all its the t½ of levodopa and allows a larger fraction beneficial effect in parkinsonism. However, an of administered dose to cross to brain. Since antagonistic action on NMDA type of glutamate COMT plays a role in the degradation of DA receptors, through which the striatal dopaminer- in brain as well, COMT inhibitors could preserve gic system exerts its influence is now considered DA formed in the striatum and supplement the to be more important. peripheral effect (Fig. 31.2). However, entaca- Amantadine can be used in milder cases, or pone acts only in the periphery (probably in short courses to supplement levodopa for because of short duration of action ~2 hr). For advanced cases. In the latter situation, it serves tolcapone also, the central action is less to suppress motor fluctuations and abnormal important. movements. Fixed dose of 100 mg BD is used Both entacapone and tolcapone enhance and (not titrated according to response). The effect prolong the therapeutic effect of levodopa- of a single dose lasts 8–12 hours; carbidopa in advanced and fluctuating PD. They AMANTREL, COMANTREL 100 mg tab.  ANTIPARKINSONIAN DRUGS 433 Side effects These are generally not serious: divided portions per day and gradually increase insomnia, restlessness, confusion, nightmares, till side effects are tolerated. anticholinergic effects and rarely hallucinations. 1. Trihexyphenidyl (benzhexol): 2–10 mg/day; PACITANE, A characteristic side effect due to local release PARBENZ 2 mg tab. 2. Procyclidine: 5–20 mg/day; KEMADRIN 2.5, 5 mg tab. of CAs resulting in postcapillary vasoconstric- 3. Biperiden: 2–10 mg/day oral, i.m. or i.v.: DYSKINON 2 mg tion is livedo reticularis (bluish discolouration) tab., 5 mg/ml inj. and edema of ankles. 4. Orphenadrine: 100–300 mg/day; DISIPAL, ORPHIPAL 50 Side effects are accentuated when it is combined mg tab. 5. Promethazine: 25–75 mg/day; PHENERGAN 10, 25 mg tab. with anticholinergics. CHAPTER 31 Some general points CENTRAL ANTICHOLINERGICS 1. None of the above drugs alter the basic patho- These are drugs having a higher central : peri- logy of PD—the disease continues to progress. pheral anticholinergic action ratio than atropine, Drugs only provide symptomatic relief and give but the pharmacological profile is similar to it. most patients an additional 3–6 years of happier In addition, certain H1 antihistaminics have and productive life. significant central anticholinergic property. Considering that oxidative metabolism of DA There is little to choose clinically among these generates free radicals which may rather hasten drugs, though individual preferences vary. degeneration of nigrostriatal neurones, it has They act by reducing the unbalanced choli- been argued that levodopa therapy might acce- nergic activity in the striatum of parkinsonian lerate progression of PD. There is no proof yet patients. All anticholinergics produce 10–25% for such a happening, and controlled prospective improvement in parkinsonian symptoms lasting studies have not detected any difference in the 4–8 hours after a single dose. Generally, tremor progression of disease due to levodopa therapy. is benefited more than rigidity; hypokinesia is However, appearance of dyskinesias is related affected the least. Sialorrhoea is controlled by to dose and duration of levodopa therapy. Thus, their peripheral action. The overall efficacy is it may be prudent to delay use of levodopa and much lower than levodopa. However, they are begin with anticholinergics/amantadine/selegiline cheap and produce less side effects than or newer direct DA agonists in early/mild/ levodopa. They may be used alone in mild cases younger patients. or when levodopa is contraindicated. In others, 2. Initially, when disease is mild, only anticholi- they can be combined with levodopa in an attempt nergics or selegiline may be sufficient. However, to lower levodopa dose. anticholinergics are often not tolerated by elderly Anticholinergics are the only drugs effective patients, especially males. Monotherapy with in drug (phenothiazine) induced parkinsonism. newer DA agonists ropinirole or pramipexole The side effect profile is similar to atropine. is being increasingly employed for early cases, Impairment of memory, organic confusional especially in younger patients, because of fewer states and blurred vision are more common in motor complications. However, psychotic the elderly. Urinary retention is possible in symptoms and sudden onset sleep has to be elderly males. The antihistaminics are less watched for. Selegiline may also be combined efficacious than anticholinergics, but are better with levodopa during the deterioration phase of tolerated by older patients. Their sedative action therapy to overcome ‘wearing off’ effect. also helps. Orphenadrine has mild euphoriant 3. Combination of levodopa with a decarboxy- action. lase inhibitor is the standard therapy, and has Trihexyphenidyl It is the most commonly replaced levodopa alone. Slow and careful used drug. Start with the lowest dose in 2–3 initiation over 2–3 months, increasing the dose 434 DRUGS ACTING ON CENTRAL NERVOUS SYSTEM as tolerance to early side effects develops and 6. Levodopa alone is now used only in those then maintenance at this level with frequent patients who develop intolerable dyskinesias with evaluation gives the best results. Full benefit lasts a levodopa-decarboxylase inhibitor combination. for about 2–3 years, then starts declining. 7. Amantadine may be used with levodopa for 4. Subsequently the duration of benefit from a brief periods during exacerbations. levodopa dose progressively shortens—end of dose ‘wearing off’ effect is seen. Dyskinesias 8. The direct DA agonists, especially ropinirole/ appear, mostly coinciding with the peak of levodopa pramipexole, are commonly used to supplement action after each dose. Relief of parkinsonian levodopa in late cases to smoothen ‘on off’ symptoms gets linked to the production of dyski- phenomenon, to reduce levodopa dose and SECTION 7 nesias. Still later (4–8 years) the ‘on-off’ phenomena possibly limit dyskinesias. and marked dyskinesias may become so prominent that the patient is as incapacitated with the drug 9. In advanced cases, the COMT inhibitor as without it. However, withdrawal of levodopa entacapone may be added to levodopa-carbidopa or dopamine agonists, particularly when higher to prolong its action and subdue ‘on off’ doses have been employed, may precipitate marked fluctuation. It can be given to patients receiving rigidity hampering even respiratory excursions, selegiline or DA agonists as well. hyperthermia, mental deterioration and a state 10. ‘Drug holiday’ (withdrawal of levodopa for resembling the ‘neuroleptic malignant syndrome’. 4–21 days) to reestablish striatal sensitivity to 5. Combination of levodopa with decarboxylase DA by increasing dopaminergic receptor inhibitor increases efficacy and reduces early population is no longer practiced. but not late complications. PROBLEM DIRECTED STUDY 31.1 A 70-year-old man has been under treatment for Parkinson’s disease for the last 5 years. He is currently receiving Tab. levodopa 100 mg + carbidopa 25 mg two tablets in the morning, afternoon and night. He now suffers stiffness, shaking and difficulty in getting up from bed in the morning. These symptoms decrease about ½ hour after taking the medicine, but again start worsening by noon. He notices one-sided twitching of facial muscles which is more frequent 1–2 hour after each dose of levodopa-carbidopa. (a) Should his levodopa-carbidopa medication be stopped/replaced by another drug or the dose be increased further? Alternatively, can another drug be added to his ongoing medication? If so, should levodopa-carbidopa dose be changed or left unaltered? (see Appendix-1 for solution)