Antiparkinsonian Drugs.pdf
- 2. Parkinson’s Disease ◼ It is an extrapyramidal motor disorder characterized by rigidity, tremor and hypokinesia with secondary manifestations like defective posture and gait, mask- like face and sialorrhoea; dementia may accompany ◼ If untreated the symptoms progress over several years to end-stage disease in which the patient is rigid, unable to move, unable to breathe properly; succumbs mostly to chest infections/embolism.
- 3. Parkinson’s Disease ◼ A progressive, neurodegenerative disorder ◼ Associated with neurological consequences of decreased dopamine levels produced by the basal ganglia (substantia nigra the nigrostriatal (dopaminergic) tract) ◼ Neurones from the SN supply dopamine to the corpus 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.
- 4. ◼ Balance, posture, muscle tone and involuntary movement depends on the roles of: ◼ dopamine (inhibitory) and ◼ acetylcholine (excitatory) ◼ Loss of dopaminergic (DA) cells located in basal ganglia → decreased dopamine → Ach produces more of an effect ◼ Most symptoms do not appear until striatal DA levels decline by at least 70-80% ◼ Though the cholinergic system is not primarily affected, its suppression (by anticholinergics) tends to restore balance ◼ Basis to exploit by drugs: ◼ Restore dopamine function ◼ Inhibit Ach within corpus striatum
- 5. In Terms of Etiology and Clinical Picture, Major Symptoms Involve: ◼ Bradykinesia- Slowness in initiation and execution of voluntary movements ◼ Rigidity - Increase muscle tone and increase resistance to movement (arms and legs stiff) ◼ Tremor - Usually tremor at rest, when person sits, arm shakes, tremor stops when person attempts to grab something ◼ Postural Instability - Abnormal fixation of posture (stoop when standing), equilibrium, and righting reflex ◼ Gait Disturbance - Shuffling feet
- 6. Clinical Presentation ◼ Altered body image (depression) ◼ Poor balance ◼ Bradykinesia (slow movement) ◼ Bradyphrenia (slowness of thought) ◼ Constipation ◼ Dribbling/drooling ◼ Dyskinesias (involuntary movements) ◼ Dysphagia (difficulty in swallowing ◼ Dystonia (pain spasms) ◼ Excessive sweating (impaired thermoregulation) ◼ Festinating gait ◼ Postural hypotension ◼ Restless leg syndrome (leg aches, tingle, or burn) ◼ Rigidity ◼ Sleep disturbance ◼ Slurring/slowing of speech ◼ Tremor
- 7. Pathophysiology: Role Of Free Radicals ◼ The cause of selective degeneration of nigrostriatal neurones may be due to: ◼ Oxidation of DA by MAO-B and aldehyde dehydrogenase generates hydroxyl free radicals (•OH) in the presence of ferrous iron (basal ganglia are rich in iron) ◼ Normally these free radicals are quenched by glutathione and other protective mechanisms ◼ Age-related and/or otherwise acquired defect in protective mechanism allows the free radicals to damage lipid membranes and DNA resulting in neuronal degeneration
- 8. ◼ Ageing induces defects in mitochondrial electron transport chain ◼ Environmental toxins and/or genetic factors may accentuate these defects in specific areas. ◼ A synthetic toxin N-methyl-4-phenyl tetrahydropyridine (MPTP), which occurrs as a contaminant of some illicit drugs, produces nigrostriatal degeneration and manifestations similar to PD by imparing energy metabolism in dopaminergic neurones ◼ MPTP-like chemicals may be present in the environment, small quantities of which accelerate age related or otherwise predisposed neuronal degeneration of parkinsonism Pathophysiology: Role Of Environmental Toxins
- 9. Drug Therapy ◼ Drug therapy against Parkinson disease is aimed at bringing the basal ganglia back to balance ◼ Decrease cholinergic activity within basal ganglia and this can be done two ways: ◼ Activating dopamine receptors in substantia nigra feeding back to cholinergic cells in the striatum ◼ Antagonize acetylcholine receptors (Turn off the cholinergic cells, then things are brought back to balance)
- 10. The Drugs ◼ I. Drugs affecting brain dopaminergic system ◼ (a) Dopamine precursor : Levodopa (l-dopa) ◼ (b) Peripheral decarboxylase inhibitors : Carbidopa, Benserazide. ◼ (c) Dopaminergic agonists: Bromocriptine, Ropinirole, Pramipexole ◼ (d) MAO-B inhibitor: Selegiline ◼ (e) COMT inhibitors: Entacapone, Tolcapone ◼ (f) Dopamine facilitator: Amantadine. ◼ II. Drugs affecting brain cholinergic system ◼ (a) Central anticholinergics: Trihexyphenidyl , Procyclidine, Biperiden ◼ (b) Antihistaminics : Orphenadrine, Promethazine
- 11. LevoDopa (L-dopa) ◼ Can not administer dopamine directly, as it does not cross the blood brain barrier ◼ It is a natural amino acid that the brain converts into dopamine (replacement therapy) ◼ Dopamine decarboxylase converts L dopa to DA ◼ DA gets stored into secretory vesicles and gets released from basal ganglia
- 12. Levodopa ◼ Efficacy of Levodopa exceeds that of any other drug used alone. ◼ It is inactive by itself, but is the immediate precursor of the transmitter DA. ◼ More than 95% of an oral dose is decarboxylated in the peripheral tissues (mainly gut and liver). ◼ DA thus formed acts on heart, blood vessels, other peripheral organs and on CTZ (though located in the brain, i.e. floor of IV ventricle, it is not bound by blood- brain barrier)
- 13. Pharmacokinetics (GIT) ◼ Levodopa is rapidly absorbed from the small intestines by utilizing the active transport process meant for aromatic amino acids. ◼ Bioavailability of levodopa is affected by: ◼ (i) Gastric emptying: if slow, levodopa is exposed to degrading enzymes present in gut wall and liver for a longer time—less is available to penetrate blood-brain barrier (~ 1% of an oral dose actually crosses Blood Brain Barrier enters CNS) ◼ (ii) Amino acids present in food compete for the same carrier for absorption: blood levels are lower when taken with meals.
- 14. Pharmacokinetics ◼ Levodopa undergoes high first pass metabolism in g.i. mucosa and liver ◼ The peripheral and central pathway of metabolism of levodopa ◼ About 1% of administered levodopa that enters brain, aided by amino acid carrier mediated active transport across brain capillaries, also undergoes the same transformation ◼ The plasma t½ of levodopa is 1–2 hours ◼ Pyridoxal is a cofactor for the enzyme dopa-decarboxylase. ◼ The metabolites are excreted in urine mostly after conjugation.
- 15. Effects of L-Dopa on the Symptoms of Parkinson Disease ◼ Levodopa is fairly effective in eliminating most of the symptoms of parkinson disease ◼ Quick respose: decrease in bradykinesia and rigidity ◼ Continued therapy : reduction in tremor effect ◼ Levodopa less effective in eliminating postural instability and shuffling gait
- 16. Effects of L-Dopa on Behavior ◼ In terms of behavior, levodopa partially changes mood by elevating mood, and levodopa increases patient sense of well being ◼ The effect of levodopa on behaviour has been described as a ‘general alerting response’ ◼ In some patients this progresses to excitement— frank psychosis may occur ◼ Embarrassingly disproportionate increase in sexual activity has also been noted ◼ Dementia, if present, does not improve; rather it predisposes to emergence of psychiatric symptoms.
- 17. Effects of L-Dopa on Cardiovascular System ◼ The cardiovascular effects are cardiac stimulation due to adrenergic effect on heart ◼ Must be careful in treatment of elderly, most will have underlying cardiovascular problems, can transient tachycardia, cardiac arrhythmias and hypertension ◼ Treat with propranolol to block cardiac stimulation effects ◼ In some individuals, levodopa produces orthostatic hypotension (DA and NE formed in the brain decrease sympathetic outflow) ◼ Tolerance will develop within few weeks
- 18. Effects of L Dopa on Gastrointestinal System ◼ Very common gastrointestinal effects of levodopa include nausea, vomiting, and anorexia ◼ Probably due to stimulation of chemoreceptor trigger zone (CTZ) in medulla ◼ Tolerance develops in a few weeks to this effect ◼ Other GI disturbances are abdominal pain
- 19. GI cont. ◼ Some patients have diarrhoea and some patients have constipation ◼ May cause activation of peptic ulcer ◼ Control abdominal effect by giving drug in low doses and gradually increase dose ◼ Give drug with some food so as to have something in stomach
- 20. Effects of L-Dopa on Endocrine System ◼ DA acts on the anterior pitutary ◼ Inhibits prolactin secretion ◼ Increases GH release ◼ Levodopa causes decrease in prolactin from stimulation of dopamine receptors in tubularinfundibular system ◼ GH release is not affected by levodopa
- 21. Adverse Effects ◼ Side effects of levodopa therapy are frequent and often troublesome ◼ Most are dose-related and limit the dose that can be administered, but are usually reversible. ◼ Some are prominent in the beginning of therapy while others appear late.
- 22. Adverse Effects: At the initiation of therapy ◼ These can be minimized by starting with a low dose 1) Nausea and vomiting It occurs in almost every patient. Tolerance gradually develops and then the dose can be progressively increased. 2) Postural hypotension It occurs in about 1/3 of patients, but is mostly asymptomatic; some patients experience dizziness, few have fainting attacks; more common in patients receiving antihypertensives. Tolerance develops with continued treatment and BP normalizes. 3) Cardiac arrhythmias & Exacerbation of angina: Due to β adrenergic action of peripherally formed DA; more in patients with preexisting heart disease. 4) Alteration in taste sensation
- 23. Adverse Effects: After Prolonged Therapy ◼ 1. Abnormal movements (Tardive Dyskinesia): Facial tics, grimacing, tongue thrusting, choreoathetoid movements of limbs start appearing after a few months of use of levodopa at optimum therapeutic dose and progress with time to include practically all patients. No tolerance develops to this adverse effect, but dose reduction decreases severity. ◼ Abnormal movements may become as disabling as the original disease itself—are the most important dose- limiting side effects.
- 24. Adverse Effects: After Prolonged Therapy ◼ 2. Behavioral effects : Range from mild anxiety, nightmares, etc. to severe depression, mania, hallucinations, mental confusion or frank psychosis. ◼ Excessive DA action in the limbic system is probably responsible (antidopaminergic drugs are antipsychotic).
- 25. Adverse Effects: After Prolonged Therapy: On and Off effect ◼ 3. Fluctuation in motor performance : After 2–5 years of therapy, the level of control of parkinsonian symptomatology starts showing fluctuation. ◼ ‘End of dose’ deterioration (wearing off) which is initially gradual, develops into rapid ‘switches’ or ‘on-off’ effect ◼ With time ‘all or none’ response develops, i.e. the patient is alternately well and disabled ◼ Abnormal movements may jeopardise even the ‘on’ phase.
- 26. Adverse Effects: After Prolonged Therapy: On and Off effect ◼ This is probably a reflection of progression of the disorder: with progressive degeneration of DA neurones the ability to regulate storage and release of DA may be largely lost: DA is then synthesized in the striatum on a moment to moment basis resulting in rapid and unpredictable fluctuations in motor control ◼ Dose fractionation and more frequent administration tends to diminish these for a time ◼ Cautious use is needed in elderly; patients with ischaemic heart disease; cerebrovascular, sychiatric, hepatic and renal disease; peptic ulcer; glaucoma, gout ◼ Add COMT inhibitors
- 27. Treatment ◼ Treatment is to reduce dose and put person on drug holiday where all medication stopped for 3- 21 days and then slowly reinitiate therapy to gradually increasing doses
- 28. Drug Interactions with L Dopa ◼ Vitamin B6 (Pyridoxine) ◼ Vitamin B6 is a cofactor for decarboxylation of levodopa ◼ Vitamin B6 enhances conversion of levodopa to dopamine in periphery making it less readily for use in the CNS ◼ Levodopa is co-administered with carbidopa ◼ Antipsychotic & Antiemetic drugs (D2 receptors) ◼ Antipsychotic drugs block dopamine receptor – reverse the therapeutic effect of levodopa ◼ Domperidone doesn't interfere with levodopa as it doesn't cross the BBB
- 29. Drug Interactions cont ◼ Reserpine ◼ Reserpine depletes dopamine storage by preventing DA entry into synaptic vesicles ◼ Anticholinergics ◼ Used synergistically with levodopa as an antiparkinson agent, but anticholinergics act to decrease levodopa absorption since anticholinergics have an effect on gastric emptying time which delays crossing of GI membrane by levodopa
- 30. Drug Interactions cont ◼ Nonselective MAO inhibitors ◼ Prevent degradation of peripherally synthesized DA and NA – hypertensive crisis ◼ Antihypertensives ◼ Postural hypotension accentuated
- 31. Peripheral Decarboxylase Inhibitors ◼ Carbidopa and benserazide are extracerebral dopa decarboxylase inhibitors; they do not penetrate blood- brain barrier and do not inhibit conversion of levodopa to DA in the brain. ◼ Administered along with levodopa, they increase its t½ in the periphery and make more of it available to cross blood-brain barrier to reach its site of action.
- 32. Benefits of the combination 1. The plasma t½ of levodopa is prolonged and its dose is reduced to approximately 1/4th. 2. Systemic concentration of DA is reduced, nausea and vomiting are not prominent— therapeutic doses of levodopa can be attained quickly. 3. Cardiac complications are minimized. 4. Pyridoxine reversal of levodopa effect does not occur. 5. ‘On-off’ effect is minimized since cerebral DA levels are more sustained. 6. Degree of improvement may be higher; some patients, not responding adequately to levodopa alone, also improve.
- 33. Problems not resolved or accentuated ◼ 1. Involuntary movements ◼ 2. Behavioral abnormalities ◼ 3. Postural hypotension. ◼ Combination of levodopa with carbidopa has been given the name ‘Co-careldopa’.
- 34. Other Drugs for Treating PD ◼ Before using other drugs, first use L dopa until dosage of levodopa starts becoming too high for the patient; levodopa therapeutic and toxicity index figures become too close
- 35. Dopaminergic agonist: Bromocriptine ◼ An ergotamine derivative → potent dopamine D2 receptor agonist ◼ The drug produces little response in patients that do not react to levodopa ◼ If used alone , high doses are required ◼ Orally: onset within ½–1 hr, lasting for for 6–10 hours ◼ Side effects are vomiting, hallucinations, hypotension (in patients on antihypertensives), nasal stuffiness ◼ Expensive ◼ Used in combination with levodopa/later stages ◼ Improves control ◼ Smoothens ‘end of dose’ and ‘on-off’ effect ◼ Lesser dyskinesias
- 36. Ropinirole and Pramipexole ◼ Both are nonergot dopamine agonist with ◼ Selective activity at the D2/ D3 receptors ◼ Pramipexole :binds with higher affinity to D3 than to D2 or D4 receptor subtypes ◼ Used as monotherapy in early PD ◼ MOA ◼ Precise mechanism of action is unknown, although it is believed to be related to its ability to stimulate dopamine receptors in the striatum ◼ Slows down rate of neuronal degenration
- 37. Ropinirole and Pramipexole ◼ Better tolerated than Bromocriptine, dose titration is faster (1-2 weeks) ◼ P’kinetics ◼ Rapidly absorbed ◼ Extensively metabolised by CYP1A2 to inactive metabolites ◼ Elimination t1/2 is 6 hrs (hence added to L-dopa therapy required in advances cases of motor fluctuations) ◼ Side effects ◼ Nausea, dizziness, hallucination (higher incidence in elderly), drowsiness, postural hypotension
- 38. Amantadine ◼ Originally an antiviral drug, now used as conjunctive therapy for dyskinesis effects produced by Levodopa ◼ Suppresses motor fluctuations and abnormal movements MoA: ◼ Stimulates/ promotes presynaptic synthesis and release of DA stored in the synaptic terminals in brain ◼ Reduces reuptake of released dopamine by pre-synaptic neuron ◼ Acts on NMDA type of glutamate receptors, through which the striatal dopaminergic system exerts its influence
- 39. Amantadine ◼ Pharmacokinetics: ◼ Well absorbed, long half-life, excreted unchanged by the kidney ◼ Adverse effects: (potentiated in presence of anticholinergics) ◼ Not many ◼ Postural hypotension, nervousness, insomnia, hallucinations (high dose) ◼ Increases local release of CAs resulting in vasoconstriction- livedo reticularis and edema of ankles
- 40. Metabolism of DA
- 41. Selective monoamine oxidase B inhibitors: Selegiline ▪ Selegiline is selective irreversible inhibitor of monoamine oxidase B which metabolizes dopamine ▪ Mild parkinsonian effect ▪ Co-administration with l-dopa prolongs action of l-dopa, attenuates motor fluctuations, decreases ‘wearing off’ effect ▪ Reduces dose of L-dopa by 20-30% ▪ Not effective in advanced cases showing ‘on-off’ effect ▪ MoA: ▪ At low doses - prolongs the effects of levodopa as cerebral degradation of dopamine by MAO-B (predominant in brain) is prevented (that in periphery unaffected)
- 42. The Protective Effects of Selegiline • Oxidative reactions may contribute to the pathogenesis of Parkinson's disease • Although the factors responsible for the loss of nigrostriatal dopaminergic neurons in Parkinson's disease are not understood, the findings from neurochemical studies have suggested that the surviving striatal dopamine neurons accelerate the synthesis of dopamine, thus enhancing the formation of H202 or free radicals ◼ Oxidation of DA by aldehyde dehyrogenase produces hydroxyl free radicals in presence of iron (basal ganglia are rich in iron)
- 43. The Protective Effects of Selegiline MAO- B Dopamine + 02 + H20----------> H202 + NH3 + 3,4-dihydroxyphenylacetaldehyde Glutathione peroxidase H202 + 2 G S H ----------> G S-S G + 2 H20 ◼ The free radicals damage the lipid membranes and DNA resulting in neuronal degeneration
- 44. The Protective Effects of Selegiline ◼ In patients with Parkinson's disease: ◼ the ferritin level is decreased in the brain ◼ the iron content is increased in the substantia nigra ◼ the glutathione concentration is decreased in the substantia nigra ◼ 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP) is a synthetic toxin. ◼ It is not itself toxic but when oxidized by MAO-B to the methylphenylpyridium ion, it becomes a selective nigral toxin that interferes with mitochondrial respiratory mechanisms ◼ The toxicity of MPTP like environmental toxins may be prevented by pretreatment with a monoamine oxidase B inhibitor such as selegiline.
- 45. Catechol-O-methyltransferase (COMT) inhibitors Tolcapone and Entacapone - COMT inhibitors ◼ Increases the duration of effect of levodopa dose ◼ Can increase peak levels of levodopa ◼ Should be taken with carbidopa/levodopa → when peripheral decarboxylation of levodopa is blocked by carbidopa/benserazide, it is mainly metabolized by COMT to 3-O-methyldopa → prolongs the t½ of levodopa and allows a larger fraction of administered dose to cross to brain →can reduce carbidopa/levodopa dose by 20-30% ◼ Can be most beneficial in treating "wearing off" responses
- 46. COMT inhibitors: Entacapone (Comtess) ◼ MoA ◼ Inhibits the breakdown of levodopa ◼ Pharmacokinetics ◼ Variability of absorption, extensive first-pass metabolism, short half-life ◼ Adverse effects: ◼ Dyskinesias, hallucinations; N, V, Dia and abdominal pain ◼ Tolcapone: Acute hepatitis, rhabdomyolysis ◼ New combination – Levodopa/carbidopa/entacapone (Stalevo) as 1 tablet (50, 100, 150mg)
- 47. Central Anticholinergic Agents for Treating Parkinson Disease ◼ The antimuscarinic agents are much less efficacious than levodopa, and these drugs play only an adjuvant role in antiparkinson therapy ◼ The actions of atropine, scopolamine, benztropine, trihexyphenidyl, and biperiden are similar ◼ All of the above mentioned drugs have a higher central: peripheral anticholinergic action ratio ◼ Antimuscarinic/Anticholinergic Drugs: ◼ Trihexyphenidyl , Benztropine, Orphanadrine , Procycline
- 48. ◼ Reduce unbalanced cholinergic activity in the striatum of PD patients ◼ Produce 10-25% improvement in clinical picture ◼ Tremors are decreased ◼ Sialorrhoea is controlled by peripheral action ◼ Useful in drug (phenothiazine) induced PD ◼ Used alone when levodopa is contraindicated Central Anticholinergic Agents
- 49. Central Anticholinergic Agents ◼ MoA ◼ Blocking cholingeric (Ach) receptors to restore balance ◼ Pharmacokinetics ◼ Fairly well absorbed, extensive hepatic metabolism, intermediate to long half-lifes ◼ Adverse effects ◼ Dry mouth and confusion
- 50. PD Modifying Drugs: Overview