Anti Parkinsonian agents for bpharm sem 4

Anti Parkinsonian agents

1. ANTI PARKINSONIAN DRUGS By kaish pathan

2. INTRODUCTION Parkinsonism is a clinical syndrome Bradykinesia (slowness and poverty of movement) Muscular rigidity Resting tremor (which usually abates during voluntary movement) An impairment of postural balance leading to disturbances of gait and to falling

3. The most common form of parkinsonism is idiopathic PD, first described by James Parkinson in 1817 as paralysis agitans , or the “shaking palsy.” The pathological hallmark of PD is the loss of the pigmented dopaminergic neurons of the substantia nigra pars compacta , with the appearance of intracellular inclusions known as Lewy bodies . A loss of 70-80% of these dopamine-containing neurons accompanies symptomatic PD.

4. ETIOLOGIC FACTORS Ageing : The possible role of ageing in the pathogenesis of PD is suggested by its usual occurrence in late middle age, and by marked increases in its prevalence at older ages. Environmental Factors : with the discovery in 1983 that exposure to MPTP is capable of inducing Parkinsonism in humans.

5. Genetic: The most important advances in PD research in recent years - the identification of specific disease-causing mutations, making it possible for the first time to begin to explore pathogenesis at the molecular level. best documented and most widely investigated genetic causes being - synuclein and Parkinson’s .

6. CLINICAL SYMPTOMS Five Stages Flexion of the affected arm – tremor / leaning toward the unaffected side Slow shuffling ga it Increased difficulty walking – looks for support to prevent falls Further progression of weakness – assistance with ambulation Profound disability – may be confined to a wheelchair

7. Tremor First sign Affects handwriting – trailing off at ends of words More prominent at rest Aggravated by emotional stress or increased concentration “Pill rolling” – rotary motion of thumb and forefinger

8. Rigidity Increased resistance to passive motion when limbs are moved through their range of motion “Cogwheel rigidity” -- Jerky quality – intermittent catches of movement Caused by sustained muscle contraction Muscle soreness; feeling tired & achy Slowness of movement due to inhibition of alternating muscle group contraction & relaxation in opposing muscle groups

9. Bradykinesia Loss of automatic movements : Blinking of eyes, swinging of arms while walking, swallowing of saliva, self-expression with facial and hand movements, lack of spontaneous activity, lack of postural adjustment Results in: stooped posture, masked face, drooling of saliva, shuffling gait; difficulty initiating movement

10. TREATMENT Objectives of antiparkinsonian pharmacotherapy The dopaminergic/cholinergic balance may be restored by two mechanisms-

11. 1. Enhancement of DA-ergic activity by drugs which may: replenish neuronal DA by supplying levodopa , which is its natural precursor ; administration of DA itself is ineffective as it does not cross the BBB; act as DA agonists (bromocriptine, pergolide, cabergoline, etc.); prolong the action of DA through selective inhibition of its metabolism (selegiline); release DA from stores and inhibit reuptake (amantadine).

12. 2. Reduction of cholinergic activity by antimuscarinic drugs this approach is most effective against tremor and rigidity , and less effective in the treatment of bradykinesia.

13. Presynaptic Terminal : Dietary phenylalanine  is converted to  hepatic tyrosine , which further becomes  tyrosine . Tyrosine  is transported into the presynaptic terminal and converted to  DOPA  by the enzyme  TH . DOPA  is then converted to  DA (dopamine)  by the enzyme  AADC . Dopamine can be stored in vesicles by  VMAT2  or metabolized by  MAO/ALDH  to  HVA . Upon depolarization (Na+ and Ca2+ entry), dopamine is  released  into the synaptic cleft. Synaptic Cleft : Dopamine can bind to  D2 autoreceptor , inhibiting further release, or it can bind to  postsynaptic receptors , inducing an effector response. Dopamine can also be taken back up into the presynaptic terminal by  DAT/NET  or undergo neuronal reuptake for storage or metabolism. Postsynaptic Cell : Dopamine binds to  D1/D2 family of receptors , leading to an effector response. Dopamine can also be taken up post- synaptically by  OCT1, OCT2, OCT3 (ENT1)  transporters and metabolized into  HVA , further converted into  3MT .

14. LEVODOPA Mechanism: Because dopamine does not cross the blood-brain barrier levodopa, the precursor of dopamine , is given instead. Levodopa is formed L-tyrosine and is an intermediate in the synthesis of catecholamines . Levodopa itself has minimal pharmacologic activity, in contrast to its decarboxylated product dopamine. Levodopa is rapidly decarboxylated in the gastrointestinal tract . Prior to the advent of decarboxylase inhibitors (carbidopa), large oral doses of levodopa were required; thus, toxicity from dopamine was a limiting factor.

15. Pharmacokinetics: Levodopa is well absorbed from the small bowel ; however, 95% is rapidly decarboxylated in periphery . Peripheral dopamine is metabolized in the liver to dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) , which are then excreted in urine. LEVODOPA

16. Pharmacologic effects: The effects on bradykinesia and rigidity are more rapid and complete than the effects on tremor . Other motor defects in PD improve . The psychological well- being of patient is also improved . Tolerance to both beneficial and adverse effects occurs with time. Levodopa is most effective in the first 2-5 years of treatment. After 5 years of therapy, patients have dose-related dyskinesia, inadequate response or toxicity. LEVODOPA

17. LEVODOPA Adverse effect: Principal adverse effects include: Anorexia, nausea, and vomiting upon initial administration, which often limit the initial dosage. Cardiovascular effects, including tachycardia, arrhythmias, and orthostatic hypotension. Mental disturbances, including vivid dreams, delusions, and hallucinations . Hyperkinesia On-off phenomena Sudden discontinuation can result in fever, rigidity, and confusion. The drug should be withdrawn gradually over 4 days.

18. LEVODOPA Drug interactions: Vit B6 reduce s the beneficial effects of Levodopa by enhancing its extracerebral metabolism. Therapy with MAO inhibitors must be stopped 14 days prior to the initiation of levodopa therapy. Phenothiazines, reserpine, and butyrophenones antagonize the effects of levodopa because they lead to a junctional blockade of dopamine action.

19. CARBIDOPA Carbidopa is an inhibitor of dopa decarboxylase. Because it is unable to penetrate the blood-brain barrier, it acts to reduce the peripheral conversion of levodopa to dopamine. As a result, when carbidopa and levodopa are given concomitantly: It can decrease the dosage of levodopa. It can reduce toxic side effects of levodopa.

20. Levodopa Dose : The starting point represents the administered dose of Levodopa. Gut : 70% of the dose goes to the gut. Blood : 30% of the dose reaches the blood. Brain : Only 1–3% of the dose crosses the blood-brain barrier and reaches the brain. Peripheral Tissues (Toxicity) : About 27–29% of Levodopa ends up in peripheral tissues, which can lead to toxicity. Chemical transformation may occur in the brain.

21. Dose of l dopa ↓ to ¼ , plasma t ½ ↑ Less side effects: nausea, vomiting, tachycardia Effect of this combination not antagonised by pyridoxine On & off effect is minimized since cerebral dopamine levels more sustained Enhanced efficacy e.g of potentiation Advantages of L-dopa + carbidopa

22. BROMOCRIPTINE a derivative of ergot . It is a D 2 -receptor agonist , but also a weak alpha-blocker . Bromocriptine is commonly used with levodopa. It should be started at very low doses , increasing at weekly intervals and according to clinical response. It is also used for the treatment of prolactin-secreting adenomas, amenorrhea/galactorrhea to hyperprolactinemia, to stop lactation, and acromegaly. ADRs: Nausea and vomiting, which may be prevented with domperidone; postural hypotension (may cause dizziness or syncope)

23. Pergolide , another ergot derivative , directly stimulates dopamine receptors . It too has been widely used for parkinsonism. but has been associated with the development of valvular heart disease. CABERGOLINE, also an ergot derivative , has a t 1/2 >80h . This allows it to be used in a single daily (or even twice weekly) dose. Cabergoline alleviates night-time problems in parkinsonian patients.

24. PRAMIPEXOLE Pramipexole is not an ergot derivative , but it has preferential affinity for the D family of receptors. It is effective as monotherapy for mild parkinsonism and is also helpful in patients with advanced disease , permitting the dose of levodopa to be reduced and smoothing out response fluctuations . ROPINIROLE is a relatively pure D receptor agonist that is effective as monotherapy in patients with mild disease and as a means of smoothing the response to levodopa in patients with advanced disease and response fluctuations .

25. Side effects of dopamine agonists – GI – nausea, vomitting, constipation, dyspepsia. CVS – postural hypotension Dyskinesias Mental disturbences

26. MAO INHIBITORS Selegiline – a selective irreversible inhibitor of monoamine oxidase B at normal doses (at higher doses it inhibits monoamine oxidase A as well), retard the breakdown of dopamine, in consequence it enhances and prolongs the antiparkinsonism effect of levodop (thereby allowing the dose of levodopa to be reduced) It is therefore used as adjunctive therapy for patients with a declining or fluctuating response to levodopa.

27. Selegiline does not cause the cheese reaction, because MAO-A is still present in the liver to metabolize tyramine. MAO-A also metabolizes tyramine in the sympathetic nerve endings in periphery. Selegiline inhibits selectively only MAO-B in the CNS and protects DA from intraneuronal degradation. It is used as an adjunct drug in PD if levodopa/carbidopa or levodopa/benserazide therapy is deteriorating.

28. CATECHOL-O-METHYLTRANSFERASE INHIBITORS Inhibition of dopa decarboxylase is associated with compensatory activation of other pathways of levodopa metabolism, especially catechol- O –methyltransferase (COMT), and this increases plasma levels of 3- O- methyldopa (3-OMD) . Elevated levels of 3-OMD have been associated with poor therapeutic response to levodop a, Selective COMT inhibitors such as tolcapone and entacapone also prolong the action of levodopa by diminishing its peripheral metabolism.

29. AMANTADINE is an antiviral drug which, given for influenza to a Parkinsonian patient, was noted to be beneficial. Antiviral and antiparkinsonian effects of amantadine are unrelated . Antiparkinsonian effect is due to increased synthesis and release of DA, and diminished neuronal reuptake too. Amantadine also has a slight antimuscarinic effect. Amantadine ARs, include ankle oedema (probably a local effect on blood vessels), orthostatic hypotension, insomnia, hallucinations, and rarely – fits.

30. ARs of antimuscarinic drugs include dry mouth (xerostomia), blurred vision, constipation, urine retention, glaucoma, hallucinations, memory defects, toxic confusional states and psychoses (which should be distinguish from presenile dementia).

31. PHARMACOTHERAPY OF PD The main features that require alleviation are tremor, rigidity and bradykinesia. Drug therapy has the most important role in symptom relief , but it does not alter the progressive course of PD . Treatment should begin on ly when it is judged n ecessary in each individual case . Two objectives have to be balanced: the desire for satisfactory relief of current symptoms and the avoidance of ARs as a result of long-continued treatment.

32. Levodopa provides the biggest improvement in motor activity but its use is associated with the development of dyskinesia ( involuntary movement of the face and limbs ) after 5–10 years , and sometimes sooner. DA agonists have a much less powerful motor effect but are less likely to produce dyskinesias. The treatment usually begins with levodopa in low doses to get a good motor response and adds a DA agoni st when the initial benefit begins to wane.