Antiparkinson drugs

lecture notes

1. ANTIPARKINSON D RUGS By: Mrs. Dhanashri R Mali Assistant Professor, GES’s Sir Dr. M. S. Gosavi College of Pharmaceutical Education and Research, Nashik

2. PARKINSON DISEASE PD is a progressive neurodegenerative illness characterized by tremor, muscular rigidity, bradykinesia and postural imbalance. It is an extrapyramidal motor disorder. about 1% in the general population older than 60 years of age

3. Parkinson’s disease or Paralysis agitans was first described as early as 1817 by James Parkinson, London doctor, as consisting essentially of ‘Involuntary tremulous motion with decreased muscular power in parts not in action and even when supported, with a propensity to bend the trunk forwards and to pass from a walking to a running pace, the senses and intellect being uninjured’.

4. Dopamine pathway The neurotransmission of DA can be divided into several major pathways: The nigrostriatal , mesocortical , mesolimbic , and tuberohypophyseal The nigrostriatal pathway accounts for 75% of the DA in the brain, consisting of cell bodies in the substantia nigra whose axons terminate in the striatum involved in the production of movement, and is directly affected in PD.

5. Pathophysiology Dysregulation of the motor cortex via the nigrostriatal pathway. The dysregulation is caused by the depletion of DA-producing neurons within the pars compacta region of the substantia nigra that project to the striatum. This is often accompanied by Lewy bodies , which are abnormal aggregates of protein that develop inside nerve cells. Direct Pathway: stimulation of D1 receptors within the striatum excitatory outflow from the thalamus to the motor cortex Indirect Pathway : stimulation of the D2 receptors within the striatum excitatory outflow from the thalamus to the motor cortex In PD: Loss of dopaminergic input to the striatum activity in the direct pathway and activity in the indirect pathway the

6. Dysregulation of mesolimbic and mesocortical dopaminergic pathways directly contributes to the depression states common with PD. symptoms of PD are not seen until about 80% of the dopaminergic neurons in the striatum have been destroyed. Thus, significant disease progression must occur before there is an observable reduction of motor movement and control.

7. The pathophysiologic basis of this idiopathic(reason unknown) disorder may relate to exposure of some unrecognized neurotoxin or any generation of free radicals.

8. ETIOLOGY 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.

9. Without dopamine, inhibitory influences are lost and excitatory mechanism Neurons of basal ganglia are over stimulated Muscle tone, tremors & rigidity

10. Pharmacological attempts to restore dopaminergic activity with levadopa and dopamine agonist that have been successful. An alternative or complementary approach has been to restore the normal balance of cholinergic and dopaminergic influences on basal ganglia with antimuscarinic drugs

11. Treatment of PD Nevertheless, current PD pharmacotherapy is centered on replacement of dopaminergic activity within the striatum. Whether this is to enhance DA release from remaining neurons, increase DA synthesis, provide exogenous DA agonists, or reduce DA metabolism, none of these approaches or combinations therein have shown to provide successful long-term treatment of symptoms. Restore the normal balance of cholinergic and dopaminergic system

12. CLASSIFICATION I. Drugs affecting brain dopamine i . Drugs that increase brain levels of dopamine a. Levodopa ii. Drugs that decrease dopamine metabolism a. Carbidopa b. Benserazide c. Droxidopa

13. iii. Dopamine releasers a. Amantadine HCl iv. Dopamine receptor stimulation: Dopaminergic agonists v. Dopamine conservation, MAO-B Inhibitor a. Selegiline HCl

14. II. Anticholinergic agents i . Piperidine analogues ii. Pyrrolidine analogues a. Procyclidine HCl

15. iii. Phenothiazine anaologues a. Ethopropazine HCl Antihistamines with central anticholinergic activity b. Diphenhydramine

16. III. Miscellaneous drugs • Antidepressants: Amitriptyline , trazadone • α- tocopherol ( vitamine E) • Glutamate release inhibitor: Lamotrigine • Glutamate receptor antagonist: Remacemide • Glial -derived neurotrophic factor: GDNF • Benztropine • Orphenadrine citrate • Chlorphenoxamine HCl

17. I. Drugs affecting brain dopamine a. Levodopa With the introduction of high-dose levodopa , first significant breakthrough in the treatment of PD came out. The rationale for the use of levodopa was established in the early 1960s. It shows decreased striatal levels of DA and reduced urinary excretion of DA. levodopa has shown to be remarkably effective for treating the symptoms of PD. only a small percentage (1%–2%) of levodopa is delivered into the CNS. Because of enzymatic action of MAO-A in GIT and AADC in the periphery.

18. ( S)-2-amino-3-(3,4-dihydroxyphenyl) propanoic It is rapidly absorbed from the small intestine by an active transport system for aromatic amino acids. widely distributed to most body tissues, but less to the CNS, Plasm Protein Binding: minor extent (10%–30%). Extensively decarboxylated by first-pass metabolism in the liver. Antacids may enhance the GI absorption of levodopa .

19. Uses: It is essentially a prodrug ; that is itself inactive, but after penetrating, the BBB is metabolized to DA. Indicated for the treatment of idiopathic, postencephalitic and symptomatic parkinsonism. It is also used to treat the parkinsonism-like neurological syndrome of manganese intoxication, in which there is also a deficiency of dopamine in the basal ganglia. Levodopa is a precursor of melanin and may activate latent malignant melanoma. The effects of levodopa on bradykinesia and rigidity are more rapid and complete than the effects on tremor.

20. Levodapa and carbidopa Coadministration of levodopa with the AADC inhibitor, carbidopa , prevents decarboxylation of levodopa outside ofthe CNS. The combination of levodopa and carbidopa results in a substantial increase in DA delivery to the CNS with a decrease in peripheral side effects.

21. Carbidopa ( S)-3-(3,4-dihydroxyphenyl)- 2-hydrazinyl-2-methylpropanoic acid Absorbed slower than levodopa Plasma protein bounding: 36 Metabolized to two main metabolites α -methyl-3-methoxy-4-hydroxyphenylpropionic acid α -methyl-3,4-dihydroxyphenylpropionic acid. These metabolites eliminated in the urine unchanged or as glucuronide conjugates. Unchanged carbidopa : 30% of the total urinary excretion. No drug interactions have been described.

22. Uses: Has no direct therapeutic actions on its own, but rather is used only to protect levodopa and L-5-hydroxytryptophan. Both of which are decarboxylated by aromatic amino acid decarboxylase . When it is given concomitantly with levodopa , only about 25% as much levodopa is needed. The onset of response is more rapid.

23. MAO-B Inhibitors MAO inhibitors are utilized: Prolong the plasma half-life of levodopa block the striatal metabolism of DA. Use of nonselective MAO inhibitors led to serious adverse effects caused by peripheral inhibition of monoamines. Use of selective MAO-B inhibitors decreases the risk of a hypertensive crisis.

24. Selegiline ( R)-N-methyl-N-(1-phenylpropan-2-yl)prop-2-yn-1- amine is an irreversible MAO-B inhibitor. does not produce the so-called cheese effect ( MAO-A Inhibitor). Potentiates the effects of levodopa by blocking its metabolism by MAO. When administered with levodopa , reduction in the daily dosage and appears to improve the wearing-off effect of levodopa .

25. Readily absorbed from the GI tract. Well distributed in the body and it penetrates the CNS (has a high apparent volume of distribution), Short half-life, and a very high oral clearance, Indicating an extensive metabolism not only in the liver but also through extrahepatic biotransformation . Extensively first-pass metabolized to yield N- desmethylselegiline , l-methamphetamine, and l-amphetamine. These metabolites have been implicated in some of the psychomotor and cardiovascular adverse effects of selegiline

26. Transdermal delivery: first-pass metabolism and provides higher and more prolonged plasma levels of unchanged selegiline Selegiline transdermal system (EMSAM ) : approved for the treatment of depression. When administered with fluoxetine may produce a “serotonin” syndrome (CNS irritability, increased muscle tone, altered consciousness), and with meperidine could result in agitation, seizures, diaphoresis, and fever, which may progress to coma, apnea, and death . Drug reactions may occur several weeks following withdrawal of selegiline . The use of selegiline as monotherapy is limited to younger patients with early disease and without disabling symptoms .

27. Rasagiline ( R)-N-( prop- 2-ynyl )-2,3-dihydro-1 H-inden-1-amine methanesulfonate Belongs to the propargylamine family Selective irreversible inhibitor of MAO-B Rasagiline = 5 times more potent than selegiline . The R-isomer is the active enantiomer . Does not produce the characteristic cheese effect . The neuroprotective effect of rasagiline is inferred by the propargyl group. This effect is observed at drug concentrations well below those necessary to cause MAO-B inhibition.

28. Several mechanisms have been proposed for the neuroprotective effect of rasagiline including (a) a decrease in proapoptotic proteins ( Bax and Bad), (b) an increase in antiapoptotic proteins (Bcl-2 and Bcl-xL ), and (c) stabilization of mitochondrial membrane potential, thus preventing subsequent release of proapoptotic proteins Rasagiline is rapidly absorbed Plasma protein binding : 88% to 94%, with specific binding to serum albumin being 61% to 63%. Undergoes complete biotransformation before excretion, mainly via N- dealkylation and hydroxylation. Rasagiline and its metabolites undergo glucuronide conjugation with subsequent urinary excretion. Inhibitors of the CYP1A2 may increase plasma concentrations of rasagiline up to twofold. Its DOA is independent of the drug’s half-life and is instead determined by the regeneration rate of MAO-B (Irreversible). This characteristic is potentially beneficial in PD, where rasagiline’s prolonged effect may be able to limit the fluctuating responses that are characteristic of long-term drug treatment with levodopa

29. Dopamine Agonists The addition of DA agonists to levodopa therapy has gained widespread popularity in the treatment of PD . DA agonists not only produce less dyskinesia , but also have been hypothesized to slow the progressive degeneration of DA neurons. DA agonists are classified into : Ergot Derivatives : Pergolide , Cabergoline , and Bromocriptine Nonergot Derivatives: Apomorphine , Pramipexole , Ropinirole , and Rotigotine .

30. ERGOT DERIVATIVES Pergolide binds with high affinity as an agonist at D2-type and 5-HT2B receptors. The compound also binds at D1 receptors but with approximately 300-fold less affinity than at D2 receptors . Pergolide is believed to induce valvular heart disease by acting on 5-HT2B receptors. Because of the potential for cardiac valve damage, pergolide has been recently withdrawn from the market. Cabergoline exhibits high affinity at D2-like receptors with over 50-fold selectivity compared with D1-like receptors. Additionally, cabergoline binds with high affinity at 5-HT2A and 5-HT2B receptors. At the low dose used in the treatment of hyperprolactinemia , cabergoline does not appear to increase the risk of cardiac valve complications. Bromocriptine acts as an agonist at D2-like receptors and an antagonist at D1-like Receptors. Additionally, it exhibits high affinity at 5-HT2A and 5-HT2B receptors. Although bromocriptine acts as an agonist at 5-HT2A receptors, it shows partial agonism at 5-HT2B receptors.Compared with cabergoline , bromocriptine exhibits less dyskinesia , which may be related to its D1-antagonist activity

31. Bromocriptine Mesylate It is an ergot derivative. Bromocriptine mimics the action of dopamine. Addition of a bromine atom renders the alkaloid criptine a potent dopaminergic agonist at D2 receptor and an antagonist at D1 sites. Rapidly absorbed after oral administration Low systemic bioavailability because of its extensive first-pass metabolism. E nters the brain quickly with a half-life for uptake into the brain of approximately 0.3 hours; 8% of the drug crosses the BBB. The metabolites are excreted primarily in the bile and feces. The high first-pass hepatic metabolism implies an increased risk of drug interactions .

32. Concomitant administration with the DA antagonists, metoclopramide , or domperidone may aggravate parkinsonian symptoms and induce extrapyramidal side effects (EPS). Drug Interaction: highly plasma protein–bound drugs (e.g., warfarin , increased dyskinesia caused by bromocriptine ); macrolides antibacterials (enhanced dopaminergic effects); and caffeine (elevation in plasma bromocriptine concentrations). The combination of levodopa /AADC inhibitors with bromocriptine permits a reduction of the dose of levodopa . Thus , the side effects of levodopa are decreased, resulting in a more continuous stimulation of DA receptors. It is used as an adjunct to levodopa .

33. Cabergoline Oral administration, peak plasma conc. : 2 to 3 hours. Moderately bound to plasma proteins . The absolute bioavailability : unknown. Extensively metabolized by the liver, predominantly via hydrolysis of the acylurea bond of the urea moiety. Less than 4% is excreted unchanged in the urine. Fecal excretion: Main route of cabergoline elimination. There are no reports of interactions with other antiparkinsonian agents . Clarithromycin may elevate the plasma concentration of cabergoline by the inhibition of both CYP3A4 and P-glycoprotein. Cabergoline is a potent D2 receptor agonist. Use: I ndicated for the treatment of hyperprolactinemic disorders.

34. NONERGOT DERIVATIVES Pramipexole acts as an agonist at D2 and D3 receptors with greater affinity for D3 than D2 receptors. The compound has no appreciable affinity for D1, D5, 5-HT2A, and 5-HT2B receptors. The reduced dyskinesia associated with pramipexole compared with cabergoline may be related to its low affinity for the D1 receptor. Ropinirole has about 20-fold selectivity for cloned human D3 receptors compared with D2 receptors. Additionally, ropinirole has low affinity for 5-HT2A, 5-HT2B, and D1-like receptors . A recent study suggests that D3-agonists may be able to restore DA neurons and exert a neuroprotective effect . These developments could offer exciting new therapeutic options for parkinsonian patients.

35. Apomorphine An aporphine alkaloid of the benzoquinoline class . Poorly absorbed when given Orally and has a bioavailability of less than 4%. Upon SC administration , apomorphine is completely absorbed. Within 10 to 20 minutes: reach to CSF . Other potential routes of administration:continuous SC infusion , IV infusion, intranasal spray application, sublingual , and rectal administration. The agent is highly lipophilic in nature. Rapid diffusion across the BBB after injection. Short plasma half life : 6 to 90 minutes.

36. Displays a significant degree of interpatient variability in its pharmacokinetic profile. Apomorphine is extensively metabolized. Hypothesized routes include sulfation , N- demethylation , glucuronidation , and oxidation. SC injections : renally (major) and hepatically cleared, Dosage adjustments are needed in both liver and renal impairment. The activity is due to stimulation of postsynaptic D1- and D2-type receptors. Use: Indicated for the acute, intermittent treatment of hypomobility , “off” episodes associated with advanced PD

37. Pramipexole R eadily absorbed after oral administration. Undergoes minimal hepatic biotransformation Excreted virtually unchanged in the urine by the renal tubular secretion . Interacts with drugs excreted by renal tubular secretion (H2-antagonists, diuretics, verapamil,quinidine , quinine), which leads to a decreased clearance of pramipexole . Use: Indicated for treatment of the signs and symptoms of idiopathic PD, alone or in combination with levodopa . Indicated for symptomatic treatment of moderate to severe idiopathic restless legs syndrome (RLS).

38. Ropinirole Rapidly absorbed after oral administration Peak Plasma c onc.: about 1.5 hours Elimination half-life appears : approx. 3 hours. Rapidly and extensively distributed. Shows low plasma protein binding C leared by metabolism in the liver, with only 10% being excreted unchanged . The main metabolite : N- despropyl metabolite. The glucuronide of this metabolite and the carboxylic acid metabolite, 4-carboxymethylindolin-2-one , account only for 10% of the administered dose. None of the metabolites is pharmacologically active, and the excretion of ropinirole -derived products is mainly via the urine. Act as an agonist at postsynaptic D2 receptors. Use: Indicated for the treatment of the signs and symptoms of idiopathic PD and moderate to severe primary RLS.

39. Rotigotine Available as a silicone-based, self adhesive matrix , transdermal system for continuous delivery over a 24-hour period. Approx. 45 % of the drug is released within 24 hours. Terminal half-life :5 to 7 hours after removal of the patch. Plasma protein Binding: 90 % Extensive metabolism Major metabolites : glucuronide and sulfate conjugates Excreted in the urine (71%) and feces (11 %). Rotigotine was approved in May 2007 for the treatment of early-stage PD .

40. COMT Inhibitors AADC inhibitor + Levodopa : mainly metabolized by COMT. Peripheral metabolism with COMT inhibitor. Tolcapone is a selective and reversible inhibitor of COMT in the CNS and periphery . CNS delivery of levodopa : Administration of combination of levodopa , carbidopa , tolcapone Therefore , more continuous levels of levodopa and DA are maintained. Entacapone does not penetrate the BBB to any extent. Thus, inhibits only peripheral COMT. When combined with levodopa and carbidopa , entacapone provides less motor fluctuations in parkinsonian patients. Another advantage of entacapone over tolcapone is its lack of hepatotoxicity

41. Tolcapone rapidly absorbed after oral administration . Highly bound to plasma albumin (98 %), Its distribution is therefore restricted. H as low first-pass metabolism. It is almost completely metabolized in the liver before excretion, and 60% is excreted by the kidney. The major metabolite : glucuronide conjugate (Inactive). Use: Indicated as an adjunct to levodopa / carbidopa for the management of signs and symptoms of PD.

42. Entacapone A nitrocatechol ( pKa : 4.50). Rapidly absorbed after oral administration Does not cross the BBB. H igh plasma protein binding Completely metabolized before excretion. The main metabolic pathway is by isomerization to the cisisomer followed by direct glucuronidation of the parent and the cis -isomer. Eliminated in the feces (90%) and urine (10%). Use: Indicated as an adjunct to levodopa / carbidopa to treat patients with idiopathic PD who experience the signs and symptoms of end-of-dose wearing off.

43. Dopamine releasers Amantadine Mode of action: Amantadine appears to act by promoting presynaptic synthesis and release of dopamine in the brain . It acts on glutamate receptors through which dopaminergic system exerts the possible influence on regulating the D1 and D2 receptors. Amantadine an organic cage amine, is an antiviral agent useful in preventing and treating influenza A2. Use: possesses both antiparkinsonism and antiviral activity.

44. II. Anticholinergic agents Anticholinergic agents have been used in the early stages of PD , frequently with amantadine and selegiline . The most commonly employed anticholinergics are Biperiden , trihexyphenidyl , orphenadrine , and procyclidine . These compounds are most useful for treating the tremor aspect of PD . Because most individuals with PD are elderly, anticholinergics may impair cognitive function. Additionally, anticholinergics may produce various side effects through blockade of peripheral muscarinic receptors

45. a. Trihexyphenidyl introduced in 1949 , an antispasmodic : approx. half as active as atropine Have milder side effects, such as mydriasis , drying of secretions, and cardioacceleration . Good margin of safety, although it is about as toxic as atropine. It has found a place in the treatment of parkinsonism and is claimed to provide some measure of relief from the mental depression often associated with this condition. It is more effective than levodopa against Parkinson’s tremor.

46. Biperiden introduced in 1959, has a relatively weak visceral anticholinergic , but a strong nicotinolytic , action in terms of its ability to block nicotine induced convulsions . Its weak anticholinergic effects add to its usefulness in Parkinson syndrome by minimizing side effects. The drug is used in all types of Parkinson disease. H elps to eliminate akinesia , rigidity, and tremor . It is also used in drug-induced extrapyramidal disorders to eliminate symptoms and permit continued use of tranquilizers .

47. Procyclidine W as introduced in 1956. An effective peripheral anticholinergic Its clinical usefulness lies in its ability to relieve voluntary muscle spasticity by its central action . Therefore , it has been used with success in the treatment of Parkinson syndrome. It is said to be as effective as trihexyphenidyl and is used to reduce muscle rigidity in postencephalitic , arteriosclerotic, and idiopathic types of the disease. At therapeutic dosage levels, dry mouth is the most common side effect . Care must be taken, when it is administered to patients with glaucoma, tachycardia, or prostatic hypertrophy .

48. Central Antihistaminics Ethopropazine introduced to therapy in 1954 , Mode of action: h as antimuscarinic activity These drugs act by reducing the unbalanced cholinergic activity in the striatum of parkinsonian patients. Use: Especially useful in the symptomatic treatment of parkinsonism. In this capacity, it has value in controlling rigidity, and it also has a favorable effect on tremor. Useful adjunct to antiparkinson’s agents Side effect: Drowsiness and dizziness at ordinary dosage levels, and as the dose increases, mydriasis become evident. It is contraindicated in conditions such as glaucoma because of its mydriatic effect.

49. Diphenhydramine Exhibits antihistaminic,antidyskinetic , antiemetic, antitussive and antimuscarinic,and sedative properties. Not a highly active H1-antihistamine . Conversion to a quaternary ammonium salt does not alter the antihistaminic action greatly but does increase the anticholinergic action . Use: Various allergic conditions and, as an antitussive Parkinsonism drug . used in OTC sleep-aid products. Common side effect: Drowsiness , The concurrent use of alcohol and other CNS depressants should be avoided.