Anti-Parkinsonian 2022-2023 PDF

University of Baghdad College of Medicine 2022-2023 Title: Anti-Prkinsonian Grade:4th grade Module: CP Speaker:Ass. Prof. Dr. Mohammed Qasim Al Atrakji Date:22/2/2023 Learning Objectives University of Baghdad/ College of Medicine 2022-2023 Upon completion of this lecture, you will be able to: 1. Des...

University of Baghdad College of Medicine 2022-2023 Title: Anti-Prkinsonian Grade:4th grade Module: CP Speaker:Ass. Prof. Dr. Mohammed Qasim Al Atrakji Date:22/2/2023 Learning Objectives University of Baghdad/ College of Medicine 2022-2023 Upon completion of this lecture, you will be able to: 1. Describe the current theory of the cause of Parkinson’s disease and correlate this with the clinical presentation of the disease. 2. Describe the therapeutic actions, indications, pharmacokinetics, contraindications, most common adverse reactions, and important drug–drug interactions associated with antiparkinsonism agents. 3. Discuss the use of antiparkinsonism agents across the lifespan. 4. Compare and contrast the prototype drugs for each class of antiparkinsonism agents with the other drugs in that class and with drugs from the other classes used to treat the disease. Key words anticholinergic: drug that opposes the effects of acetylcholine at acetylcholine receptor sites. dopaminergic: drug that increases the effects of dopamine at receptor sites. bradykinesia: difficulty in performing intentional movements and extreme slowness and sluggishness; characteristic of Parkinson’s disease. corpus striatum: part of the brain that reacts with the substantia nigra to maintain a balance of suppression and stimulation. substantia nigra: a part of the brain rich in dopamine and dopamine receptors; site of degenerating neurons in Parkinson’s disease University of Baghdad/ College of Medicine 2022-2023 University of Baghdad/ College of Medicine 2022-2023 Parkinson’s disease: debilitating disease, characterized by progressive loss of coordination and function, which results from the degeneration of dopamineproducing cells in the substantia nigra zopanerni.sn scinvivitevs parkinsonism: Parkinson’s disease–like extrapyramidal symptoms that are adverse effects associated with particular drugs or brain injuries. z University of Baghdad/ College of Medicine 2022-2023 Anti-parkinsonians Parkinson’s disease: It is a chronic, progressive, motor(neurodegenerative) disorder characterized by: Tremor( resting) Rigidity( cogwheel) Akinesia ( bradykinesia) Postural Instability gait abnormalities(shuffling) University of Baghdad/ College of Medicine 2022-2023 University of Baghdad/ College of Medicine 2022-2023 Etiology University of Baghdad/ College of Medicine 2022-2023 Parkinson’s disease may develop in people of any age, but it usually affects those who are past middle age and entering their 60s or even later years. Free Radical Genetic Excitotoxicity Environmental triggers: ▫ Infectious agents – Encephalitis lethargica (epidemic) ▫ Environmental toxins - MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) ▫ Acquired Brain Injury Energy metabolism and aging Drug induced (metoclopromide , reserpine ) Genetic predisposition  Imbalance between Dopamine( inhibitory) and acetylcholine(excitatory) Increase Ach concentration and decrease Dopamine concentration University of Baghdad/ College of Medicine 2022-2023 Pathophysiology University of Baghdad/ College of Medicine 2022-2023 Although the cause of Parkinson’s disease is not known, it is known that the signs and symptoms of the disease relate to damaged neurons in the basal ganglia of the brain. Even though the actual cause is not known, then mechanism that causes the signs and symptoms of Parkinson’s disease is understood. In a part of the brain called the substantia nigra,( a dopamine-rich area), nerve cell bodies begin to degenerate. This process results in a reduction of the number of impulses sent to the corpus striatum in the basal ganglia. This area of the brain, in conjunction with the substantia nigra, helps to maintain muscle tone not related to any particular movement. The corpus striatum is connected to the substantia nigra by a series of neurons that use gammaaminobutyric acid,( an inhibitory neurotransmitter).GABA The substantia nigra sends nerve impulses back into the corpus stratum using the inhibitory neurotransmitter dopamine. The two areas then mutually inhibit activity in a balanced manner. University of Baghdad/ College of Medicine 2022-2023 Higher neurons originating in the cerebral cortex secrete acetylcholine (an excitatory neurotransmitter) in the area of the corpus striatum to coordinate intentional movements of the body. When dopamine decreases in the area, a chemical imbalance occurs that allows the cholinergic or excitatory cells to dominate. This affects the functioning of the basal ganglia and of the cortical and cerebellar components of the extrapyramidal motor system. The extrapyramidal system is one that provides coordination for unconscious muscle movements, including those that control position, posture, and movement. The result of this imbalance in the motor system is apparent as the manifestations of Parkinson’s disease University of Baghdad/ College of Medicine 2022-2023 Drugs Induce Parkinsonism University of Baghdad/ College of Medicine 2022-2023 Bradykinesia, rigidity, mild tremor, rabbit syndrome Caused by exposure to a dopamine-receptor blocking agent within 6 months of the onset of symptoms Offending drugs include: antipsychotics, anti-emetics, metoclopramide iguana 1.Mild cases can frequently remit after cessation of the offending drug 2.Usually unresponsive to dopaminergic therapy 3.Elderly patients are most susceptible 4.Treatment may include: tetrabenazine, reserpine, vitamin E, benzodiazepines Treatment University of Baghdad/ College of Medicine 2022-2023 At this time, there is no treatment that arrests the neuron degeneration of Parkinson’s disease and the eventual decline in patient function. Surgical procedures involving the basal ganglia have been tried with varying success at prolonging the degeneration caused by this disease. Drug therapy remains the primary treatment. Therapy is aimed at restoring the balance between the declining levels of dopamine, which has an inhibitory effect on the neurons in the basal ganglia, and the now-dominant cholinergic neurons, which are excitatory. This may help to reduce the signs and symptoms of parkinsonism and restore normal function for a time University of Baghdad/ College of Medicine 2022-2023 Patients should perform exercises to prevent the development of skeletal deformities, and to attend to their care as long as they can. Both the patient and family need instruction about following drug protocols and monitoring adverse effects, as well as encouragement and support for coping with the progressive nature of the disease. Because of the degenerative effects of this disease, patients may experience episodes of depression or be emotionally upset. Psychological support, as well as physical support, is a crucial aspect of care. University of Baghdad/ College of Medicine 2022-2023 Jurairive Classifications University of Baghdad/ College of Medicine 2022-2023 DRUGS THAT INCREASE DOPAMINE LEVELS DA PRECURSOR-LEVODOPA WITH Peripheral decarboxylase inhibitors – carbidopa and benserazide Levodopa DRUGS THAT RELEASE DOPAMINE-AMANTIDINE DOPAMINERGIC AGONISTS-BROMOCRIPTINE ,PERGOLIDE, LISURIDE, ROPINIROLE ,APOMORPHINE,PRAMIPEXOLE INHIBIT DOPAMINE METABOLISMMAO INHIBITORS (Selective MAO-B inhibitors )SELEGILINE, RASGILINE COMT INHIBITORS-TOLCAPONE, ENTACAPONE DRUGS INFLUENCING CHOLINERGIC SYSTEM CENTRAL ANTICHLINERGICS-BENZTROPINE, BENZHEXOL, BIPERIDINE ANTIHISTAMINES-DIPHENHYDRAMINE, ORPHENADRINE, PROMETHAZINE carbit Pa Dopaminergic Agents Dopaminergics—drugs that increase the effects of dopamine at receptor sites—have been proven to be even more effective than anticholinergics in the treatment of parkinsonism. Dopaminergic agents include: amantadine (Symmetrel), apomorphine (Apokyn), bromocriptine (Parlodel), levodopa (Dopar), carbidopa– levodopa (Sinemet), pramipexole (Mirapex), rasagiline (Azilect), and ropinirole (Requip). University of Baghdad/ College of Medicine 2022-2023 Therapeutic Actions and Indications University of Baghdad/ College of Medicine 2022-2023 Dopamine does not cross the blood–brain barrier. Therefore, other drugs that act like dopamine or increase dopamine concentrations indirectly must be used to increase dopamine levels in the substantia nigra or to directly stimulate the dopamine receptors in that area. This action helps to restore the balance between the inhibitory and stimulating neurons. Dopaminergic agents are effective as long as enough intact neurons remain in the substantia nigra to respond to increased levels of dopamine. After the neural degeneration has progressed beyond a certain point, these agents are no longer effective. The dopaminergics are indicated for the relief of the signs and symptoms of idiopathic Parkinson’s disease Levodopa-Carbidopa Levodopa is the mainstay of treatment for Parkinson’s disease. This precursor of dopamine crosses the blood–brain barrier and is converted into dopamine. In this way, it acts like a replacement therapy. Although levodopa is almost always given in combination form with carbidopa as a fixed-combination drug (Sinemet), other drugs besides carbidopa may be used (Adjunctive Therapy). University of Baghdad/ College of Medicine 2022-2023 University of Baghdad/ College of Medicine 2022-2023 When used with carbidopa(does not cross the blood– brain barrier), the enzyme dopa decarboxylase is inhibited in the periphery, diminishing the metabolism of levodopa in the gastrointestinal (GI) tract and in peripheral tissues, thereby leading to higher levels crossing the blood–brain barrier. Because the carbidopa decreases the amount of levodopa needed to reach a therapeutic level in the brain, the dose of levodopa can be decreased, which reduces the incidence of adverse side effects( nausea, vomiting, cardiac arrhythmias, and hypotension) Helps bradykinesia and rigidity (not really tremor) MY JPaminarai sun Levodopa University of Baghdad/ College of Medicine 2022-2023 Levodopa University of Baghdad/ College of Medicine 2022-2023 Therapeutic uses: University of Baghdad/ College of Medicine 2022-2023 Levodopa in combination with carbidopa is an efficacious drug regimen for the treatment of Parkinson’s disease. It decreases rigidity,hypokinesia ,lesser extent tremors, and other symptoms of parkinsonism. In approximately two-thirds of patients with Parkinson’s disease, levodopa–carbidopa substantially reduces the severity of symptoms for the first few years of treatment. Patients typically experience a decline in response during the 3rd to 5th year of therapy. Withdrawal from the drug must be gradual. Levodopa (Pharmacological actions) University of Baghdad/ College of Medicine 2022-2023 CNS: – Effective in Eliminating Most of the Symptoms of Parkinson Disease – Bradykinesia and Rigidity Respond Quickly – Reduction in Tremor Effect with Continued therapy – Handwriting , speech, facial expression and interest in life improves gradually – General alerting response – excitement, psychosis Disproportionate increase in sexual activity – L- Dopa less Effective in Eliminating Postural Instability and Shuffling Gait meaning Other Neurotransmitters are Involved in Parkinson Disease Levodopa University of Baghdad/ College of Medicine 2022-2023 CVS: ▫ Cardiac Stimulation due to Beta adrenergic effect on Heart - Propranolol reduce. ▫ Though stimulates peripheral adrenergic receptor – no rise in BP ▫ Orthostatic Hypotension - some individuals – central DA and NA action ▫ In elderly cardiovascular problems - transient tachycardia, cardiac arrhythmias and hypertension ▫ Tolerance to CVS action develops within few weeks CTZ: DA receptors cause stimulation – nausea and vomiting – Endocrine: Decrease in Prolactin level and decrease in GH level Levodopa (adverse effects) initial Nausea and vomiting - 80% of patients (CTZ outside BBB) Postural hypotension – 30 % of patients tolerance develops (Central alpha-2 action) Cardiac arrhythmias - due to beta adrenergic action Exacerbation of angina University of Baghdad/ College of Medicine 2022-2023 - Levodopa (adverse effects) Prolonged Therapy Abnormal movements: Facial tics, grimacing, tongue thrusting, choreoathetoid movements Behavioural effects: – – – – 20 to 25% of Population Trouble in Thinking (Cognitive Effects) L Dopa can induce: Anxiety, psychosis, confusion, hallucination, delusion Inappropriate Sexual Behavior; "Dirty Old Man“ – Drug Holiday University of Baghdad/ College of Medicine 2022-2023 Absorption and metabolism University of Baghdad/ College of Medicine 2022-2023 The drug is absorbed rapidly from the small intestine (when empty of food). Levodopa has an extremely short half-life (1 to 2 hours), which causes fluctuations in plasma concentration. This may produce fluctuations in motor response, which generally correlate with the plasma concentration of levodopa, or perhaps give rise to the more troublesome “on–off” phenomenon, in which the motor fluctuations are not related to plasma levels in a simple way Motor fluctuations may cause the patient to suddenly lose normal mobility and experience tremors, cramps, and immobility. Ingestion of meals, particularly if high in protein, interferes with the transport of levodopa into the CNS. Thus, levodopa should be taken on an empty stomach, typically 30 minutes before a meal Wear-Off University of Baghdad/ College of Medicine 2022-2023 In early disease, the number of residual dopaminergic neurons in the substantia nigra (typically about 20% of normal) is adequate for conversion of levodopa to dopamine. Thus, in new patients, the therapeutic response to levodopa is consistent, and the patient rarely complains that the drug effects “wear off.” Unfortunately, with time, the number of neurons decreases, and fewer cells are capable of converting exogenously administered levodopa to dopamine. Consequently, motor control fluctuation develops University of Baghdad/ College of Medicine 2022-2023 Wearing-off is a complication that can occur after a few years of using levodopa to treat Parkinson’s. During wearing-off, symptoms of Parkinson’s start to return or worsen before the next dose of levodopa is due, and improve when the next dose is taken. Your doctor can manage wearing-off by adding to or changing your medication, dose or schedule University of Baghdad/ College of Medicine 2022-2023 What can be done? Your doctor can help you manage wearing-off by adding to or changing your medication, dose or schedule. There are several ways to increase the time you spend ‘on’ and decrease your ‘off’ periods. These include: Changing your dose, dose frequency or timing of medication Changing your medication to include drug(s) that prevent breakdown of levodopa within your body (these can extend the duration of benefit of levodopa, and may be combined with levodopa in a single tablet or taken separately). Changing the formulation of your levodopa to provide controlled Release Adding another class of drug, such as a dopamine agonist, to your medication. Levodopa – Drug Interactions University of Baghdad/ College of Medicine 2022-2023 Pyridoxine – abolishes therapeutic effect of levodopa Antipsychotic Drugs – Phenothiazines, butyrophenones block the action of levodopa by blocking DA receptors (Also Metoclopramide) Antidopeminergic – domperidone abolishes nausea and vomiting – no influence on primary antiparkinsonian effect Anticholinergics – synergistic action but delayed gastric emptying – reduced effect of levodopa α University of Baghdad/ College of Medicine 2022-2023 Amantadine: is an antiviral drug that also seems to increase the release of dopamine, being effective as long as there is a possibility of more dopamine release. Apomorphine : is a newer adjunctive therapy for Parkinson’s disease that directly binds with postsynaptic dopamine receptors. Similar to apomorphine, bromocriptine and pramipexole act as direct dopamine agonists on dopamine receptor sites in the substantia nigra. Trecento iirecunt (Because bromocriptine does not depend on cells in the area to biotransform it or to increase the release of already produced dopamine, it may be effective longer than levodopa or amantadine). r.tk University of Baghdad/ College of Medicine 2022-2023 Ropinirole : is a newer drug that directly stimulates dopamine receptors. It is also used to treat restless leg syndrome. MCE were mao inhibitor Rasagiline : is another newer dopamine agonist that increases dopamine in the nerve synapse, particularly in areas of the brain responsible for controlling movement and coordination. It inhibits monoamine oxidase (MAO) type B, which is found primarily in the central nervous system (CNS). Because this drug works on an enzyme found mostly inside the CNS, it has fewer peripheral adverse effects. It can be used as initial monotherapy or as an adjunct therapy with levodopa. selective abopamine 6251151 selectivite in Is University of Baghdad/ College of Medicine 2022-2023 Selegiline also called deprenyl selectively inhibits monoamine oxidase (MAO) type B (metabolizes dopamine) at low to moderate doses. It does not inhibit MAO type A (metabolizes norepinephrine and serotonin) unless given above recommended doses, where it loses its selectivity. By decreasing the metabolism of dopamine, selegiline increases dopamine levels in the brain. When selegiline is administered with levodopa, it enhances the actions of levodopa and substantially reduces the required dose. Unlike nonselective MAOIs, selegiline at recommended doses has little potential for causing hypertensive crises. Selegiline is metabolized to methamphetamine and amphetamine, whose stimulating properties may produce insomnia if the drug is administered later than mid-afternoon. guess that is Selectve on Bant their lass selective in high 2088 is gele University of Baghdad/ College of Medicine 2022-2023 Catechol-O-methyltransferase (COMT) inhibitors Normally, the methylation of levodopa by (COMT) to 3-O-methyldopa is a minor pathway for levodopa metabolism. However, when peripheral dopamine decarboxylase activity is inhibited by carbidopa, a significant concentration of 3-O-methyldopa is formed that competes with levodopa for active transport into the CNS. net hepatic Entacapone and tolcapone selectively and reversibly inhibit COMT. Inhibition of COMT by these agents leads to decreased plasma concentrations of 3-O-methyldopa, increased central uptake of levodopa, and greater concentrations of brain dopamine. Both of these agents reduce the symptoms of “wearing-off” phenomena seen in patients on levodopa−carbidopa. The two drugs differ primarily in their pharmacokinetic and adverse effect profiles. University of Baghdad/ College of Medicine 2022-2023 Entacapone is used with carbidopa–levodopa to increase the plasma concentration and duration of action of levodopa. It is available in fixed-combination tablet containing levodopa, carbidopa, and entacapone called Stalevo. Tents inhibitor Adverse effects: University of Baghdad/ College of Medicine 2022-2023 Both drugs exhibit adverse effects that are observed in patients taking levodopa–carbidopa, including : diarrhea, postural hypotension, nausea, anorexia, dyskinesias, hallucinations, and sleep disorders. Most seriously, fulminating hepatic necrosis is associated with tolcapone use. Therefore, it should be used, along with appropriate hepatic function monitoring, only in patients in whom other modalities have failed. Entacapone does not exhibit this toxicity and has largely replaced tolcapone. University of Baghdad/ College of Medicine 2022-2023 Seligiline, Rasagiline ,tolcapone and entacapone all called Adjunctive Agents x̅ 8 Y Dopamine receptor agonists: (Bromocriptine, pramipexole, rotigotine and ropinirole) are effective in patients with Parkinson’s disease complicated by motor fluctuations and dyskinesias. However, these drugs are ineffective in patients who have not responded to levodopa. Central Anticholinergics we benztropine (Cogentin), diphenhydramine (Benadryl), trihexyphenidyl (Artane). procyclidine and biperiden These are the Drugs with higher central : peripheral anticholinergic action than Atropine Reduce unbalanced cholinergic activity in striatum Duration of action is 4-8 Hrs Tremor is benefited more than rigidity – least to hypokinesia Overall activity is lower than levodopa Used alone in mild cases and when levodopa is contraindicated Combination with levodopa to reduce its dose Also used in Drug Induced Parkinsonism Antihistaminic like Orphenadrine, Promethazine are used in PD for their anticholinergic action University of Baghdad/ College of Medicine 2022-2023