Unit-2(C)Anti Parkinson Drugs complete .pptx

Unit-2(C)Anti Parkinson Drugs complete .pptx

1. Unit-II C: Anti-Parkinson’s Drugs By: Muhammad Aurangzeb Lecturer-INS/KMU

2. Objectives By the completion of this section the learners will be able to: Describe the action of anticholinergic drugs and dopaminergic drugs in treatment of Parkinsonism. Differentiate between the types of commonly used anti-Parkinson’s drugs. Describe the side effects of anti-Parkinson drugs. Discuss the nursing interventions including clients teaching of drugs used in the treatment of Parkinson’s disease Calculate the drug dosage accurately for oral and parental anti Parkinson’s drugs

3. Parkinsonism Parkinsonism is a progressive neurological disorder of muscle movement, characterized by tremors , muscular rigidity, bradykinesia (slowness in initiating and carrying out voluntary movements), and postural and gait abnormalities.

4. Parkinson Disease It is a Extrapyramidal motor disorder occurs due to degeneration of dopaminergic neurons in the substantia nigra pars compacta (SN-PC) result in dopamine deficiency It occur in 2% elderly population Classically disease of 7th decade of life An imbalance between dopaminergic(inhibitory neuron) and excitatory cholinergic neuron Cholinergic over activity

5. Pathogenesis Degeneration of dopamine-producing neurons in the substantia nigra of the midbrain Disrupts the balance of: Dopamine (DA) – neurotransmitter for normal functioning of the extrapyramidal motor system (control of posture, support, and voluntary motion) Acetylcholine (Ach) in the basal ganglia Symptoms do not occur until 80% of the neurons in the substantia nigra are lost.

6. Normal Parkinsonism Treatment In the basal ganglia, the dopaminergic activity is balanced by the cholinergic syst e m Parkinsonism results due to depletion of dopamine in relation to cholinergic activity Also antidopaminergic drugs e.g. Phenothiazines, Haloperidol, methyldopa etc. cause Parkinsonism Pathophysiology & Treatment Pharma c olog i cal strategy:- Restore normal dopamine Ach activity at muscarinic receptor in the striatum .

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

8. 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; DA agonists (bromocriptine, pergolide, etc.); prolong the action of DA through selective inhibition of its metabolism (selegiline); release DA from stores and inhibit reuptake (amantadine).

9. 2. Reduction of cholinergic activity by anti-muscarinic or anti-cholinergic drugs this approach is most effective against tremor and rigidity, and less effective in the treatment of bradykinesia.

10. CLASSIFICATION

11. Antiparkinsonian Drugs Dopaminergic Drugs Anticholinergic Drugs Dopamine P r ecursor Levodopa Dopamine Agonists Ergot Bromocriptine Pergoli de Lesuride (D 1 &D 2 agonist) Non-ergot Piribedil Ropinirole Premipexole Peripheral Decarboxylase Inhibitors Carbidopa Benserazide MAO-B Inhibitor Selegiline (Deprenyl) COMT Inhibitor E n tac apo n e Tolcapone Dopamine Facilitator Amantadine Anticholine r g i cs T rihexyphenid y l (Benzhexol) Procyclidine Biperiden

12. Levodopa(l-dopa) Metabolic precursor of dopamine Inactive by itself 95% of an oral dose is decarboxylated in the peripheral tissues (mainly gut and liver) and converted into DA Only about 1-2% of administered levodopa crosses to the brain Always used in combination with carbidopa/benserazide (Peripheral decarboxylase inhibitor )

13. l e vodopa Dopamine LD L D DA DA L D DA Carbidopa Carbidopa inhibit the peripheral decarboxylation of Levodopa hence more Levodopa reaches brain So advantages of the combination are: Less dose of Levodopa required and more effect of Levodopa Increased half-life of Levodopa Less side effects of Levodopa, peripherally VitB 6 interaction does not occur Levodopa is usually combined with Carbidopa

14. Pharmacokinetics Absorption:- Absorbed orally by active transport by the presence of food (especially amino acids) Administered on empty stomach Bioavailability affected by: Amino acids present in food compete for the same carrier for absorption (# should be given 30-60 min before meal) Distribution: L-dopa crosses BBB (CNS disturbance) The plasma t 1/2 of levodopa is 1 - 2 hours

15. Metabolism Peripheral dopamine is metabolized in the liver to dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), which are then excreted in urine . Levodopa undergoes high first pass metabolism in G.I. mucosa and liver Excretion:- Urine

16. Pharmacodynam i cs On CNS: - Marked symptomatic improvement occurs in Parkinson patients Effect on behavior: ‘General alerting response’ On CVS:- (+inotropic action )-The peripherally formed DA can cause tachycardia acting on β adrenergic receptors DA formed in brain central sympathetic flow- Postural hypotension

17. On CTZ:- Dopaminergic receptors are present in this area and DA acts as an excitatory transmitter Peripherally formed DA gains access to the CTZ elicits nausea and vomiting Endocrine action:- DA acts on pituitary mammotropes to inhibit prolactin release  In Parkinson's Disease:- Levodopa can reduce all sign and symptoms of PD. It doesn’t stop the progression of disease USES

18. Adverse effects At the initiation of therapy : a) CNS manifestations: Euphoria, anxiety, agitation, insomnia, psychological disturbances as confusion, delusions, hallucinations, Dyskinesia (abnormal involuntary movements which is corrected by dose reduction) b) GIT manifestations:- Anorexia, nausea, and vomiting due to stimulation of D2-receptors in CTZ Tolerance may develop to this adverse effect, but if nausea and vomiting persist, antiemetics are given; e.g. domperidone (D2 antagonist)

19. Adverse effects cont.. c) CVS manifestations: Postural hypotension- central sympathetic flow Tachycardia (direct β1 stimulation) Hypertension occurs with large doses or with non-selective MAO inhibitors ( α1 stimulation). Others:- Alteration of smell, taste sensation Abnormal movements-facial tics

20. After prolong therapy:- On- off phenomenon:- After prolong therapy(3-5 year) Duration of beneficial effect shortens as therapy progress Disease control become poor Fluctuation in symptoms occur frequently - This may be due to the interaction of DOPAC with H2O2 leading to formation of toxic oxygen free radicals which destroy dopamine storage vesicles (this can be prevented by adding selective MAO-B inhibitors as seligeline)

21. On-off phenomenon:- May be due to variable levels of dopamine in CNS In on state :- Patient enjoys normal mobility In off state :- loss of beneficial effect of drugs E.g.-patient unable to raise from chair on which he had sat few min ago. Fluctuation in plasma level because of short half life Treatment:- Sustained released formulation of (L-dopa+carbidopa) COMT-inhibitors Frequent administration of levodopa

22. Non selective MAO-inhibitor-(hypertensive Vit-B6 -(  metabolism, therapeutic failure) Reserpine, phenothiazine-( block dopamine Tricyclic antidepressant- ( absorption of L e v o d o pa crisis) Levodopa L e v o d o pa effect ) Levodopa levodopa ) Contraindication:- Psychoses Narrow angle glaucoma Melanoma Interaction

23. 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.

24. Dopamine Agonist An alternative to Levodopa These will act on striatal dopamine receptors even in advanced patients . Do not require enzymatic conversion Bromocriptine Ergot derivative Don’t require enzymatic conversion to active metabolites Longer duration of action than l-dopa Prevent motor complication Mechanism:- partial D1-Agonist Strong D2-Agonist

25. USES:- Parkinsonism- can be used alone, use as- adjuent to levodopa Serves improve control- ’ wearing of dose’ & ‘on off fluctuation ’ 2. Use in suppression of lactation (safer than estrogen) 3.Acromegaly and ACTH-dependent tumors Adverse effect:- hallucination,confusion,vomiting Contraindication:- Peptic ulcer,MI,mental illness

26. Ergot derivative Mechanism:- agonist at D1,D2 receptor Pharmacokinetics:- Absorption -rapidly orally Metabolism :- liver by CYP-450 system 50% BA(undergo-first pass metabolism) Excretion:- urine USES:- Idiopathic PD treatment AE:- Dyspepsia,constipation,hallucination

27. Ropinirole It Non-ergot derivative dopamine agonist . Mechanism of action: Selectivity at D2 receptor and less or no activity at D1 class site. Pharmacokinetics: Rapidly absorbed ,max plasma concentration is generally reached in 1-2 hours after oral absorption Bioavailability is 50% because of first pass metabolism. Metabolized by the liver by cytochrome P450 to inactive metabolites. Less than 10%excreted unchanged in urine.

28. Therapeutic uses: For treatment of idiopathic PD for early and advanced PD alone Adverse effects: dyspepsia, constipation and hallucinations.

29. It Non-ergot derivative dopamine agonist. It binds to presynaptic& postsynaptic dopamine D2 &D3receptors, but has the highest affinity for the D3 receptor subtype. Mechanism of action :- It stimulates presynaptic and post synaptic dopamine D2 receptors. Therapeutic uses:- Used as monotherapy in early PD. As an adjunct to levodopa in patients with advanced PD. Pramipexole

30. Adverse effects:- In early PD patients it causes nausea, dizziness,constipation, and hallucinations. In patients with advanced disease, the most common adverse effect is orthostatic hypotension. Drug interaction:- cimetidine, ranitidine, diltiazem, verapamil, quinidine,triamterene decrease the oral clearance of pramipexole by 20%.

31. MAO-B inhibitors Two different types of isoenzymes of MAO are found (MAO –A and MAO-B). MAO-B is responsible for most of the oxidative metabolism of dopamine in the brain. Selegiline Selective irreversible inhibitors of MAO-B Advantage:- Prolonging T1/2 of Endogenously produce dopamine Anti-parkinsonism effect of dopamine ‘ On-off’,’wearing off’ phenomena

32. Mechanism of action:- Selegiline retard the breakdown of dopamine in the CNS. Inhibition of dopamine reuptake from the synapse. Pharmacokinetics:- Extensively metabolized in the liver. metabolites Desmethyl-selegiline Methamphetamine Adverse effects:- postural hypotension, confusion, psychosis amphetamine

33. Interaction:- Seligiline Seligiline Seli g ili n e Tricyclic antidepressant Pethidine(excitement,rigidity) SSRI  Contraindication:- Contraindicated in patients with convulsive disorder. Newer selective MAO-B inhibitor. Advantage:- 5 time more potent than seligiline Longer acting Not metabolized to amphetamine Doesn’t produce excitatory side effects Rasagiline

34. Reversible COMT-inhibitors Only periphery action Mechanism of action:- Entacapone is a selective and reversible inhibitor of COMT . Adverse effects :- Dyskinesia, nausea, diarrhoea, abdominal pain, and urinary discoloration. It increases the side effects of levodopa. Entacapone

35. selective and reversible inhibitor of COMT Both action- Peripheral + Central action SE:- occasionally associated with hepatotoxicity

36. Amantadine:- Introduced as an antiviral agent Effective against influenza A2 virus. Mechanism of action: It acts presynaptically and postsynaptically. Presynaptically:- release of stored catecholamine from intact dopaminergic terminals Inhibits catecholamine reuptake process at the presynaptic terminal . Dopamine facilitator

37. Postsynaptically:- Activation of DA receptors directly. Anticholinergic action. NMDA receptor blocking effect. USES:- Only in milder cases as monotherapy. Supplement to levodopa for advanced cases. It serves to suppress motor fluctuations and abnormal movements. Side effect:- Insomnia, dizziness, confusion, nightmares

38. Central anti-cholinergic drugs Biperiden, Trihexyphenidyl, Triperiden They are synthetic compounds (central parasympatholytics). They benefit parkinsonism by blocking ACh receptors in the CNS, thereby partially redressing the imbalance created by decreased DA-ergic activity. They also produce modest improvement in tremor, rigidity, sialorrhoea (hypersalivation), muscular stiffness and leg cramp, but little in bradykinesia, which is the most disabling symptom of Parkinson’s disease.

39. Adverse effects of anti-cholinergic drugs Dry mouth (xerostomia), Constipation, Drowsiness urine retention, glaucoma,

40. Nursing care in Anti-Parkinson Drugs Administer drug with caution for patients exposed in hot weather or environments because patients are at increased risk for heat prostration due to decreased ability to sweat. Give drug with meals to alleviate GI irritation if present. Monitor bowel function and institute bowel program if constipation is severe. Have patient void before taking the drugs to decrease risk of urinary retention.

41. Cont… Provide safety measures (e.g. adequate lighting, raised side rails, etc.) to prevent injuries. Educate client on drug therapy to promote understanding and compliance. Monitor patient response to therapy (improvement in signs and symptoms of Parkinson’s disease). Monitor for adverse effects (e.g.CNS changes, urinary retention, GI depression, decreased sweating, etc).

42. References Karch, A. M., & Karch. (2011).  Focus on nursing pharmacology . Wolters Kluwer Health/Lippincott Williams & Wilkins . Katzung, B. G. (2017).  Basic and clinical pharmacology . McGraw-Hill Education. Lehne, R. A., Moore, L. A., Crosby, L. J., & Hamilton, D. B. (2004). Pharmacology for nursing care. Smeltzer, S. C., & Bare, B. G. (1992).  Brunner & Suddarth’s textbook of medical-surgical nursing . Philadelphia: JB Lippincott.