Anti-Parkinson's Drugs PDF

Notes Team Lec: Dopamine Agonist ‫لوان الثانية من نوت الدفعة السابقة‬3‫ا‬ Female side notes : Important: male side notes: important: CNSS- pharma Done by Reem alhumaidan Notes team female section Ashwag Alotaibi- Razan Alshehri Reem Alhumaidan- Khawlah Alrashed Sara Yati- Nouf Alkhalifah- Ilal alhut...

Notes Team Lec: Dopamine Agonist ‫لوان الثانية من نوت الدفعة السابقة‬3‫ا‬ Female side notes : Important: male side notes: important: CNSS- pharma Done by Reem alhumaidan Notes team female section Ashwag Alotaibi- Razan Alshehri Reem Alhumaidan- Khawlah Alrashed Sara Yati- Nouf Alkhalifah- Ilal alhuthailRenad alhomidi- Sara almawash- Ruba subh- Saja alghareeb- shoug alqarawiRand Alanazi- Lama Aljathalin- ghaida Almasari Male section abdulaziz Alaati -Fares AlQahtani- Yazeed Elshidi - Abdulrahman alotaibi - Saud aljaber - Abdulaziz aljanoubi-Ammar Algezlan Tremor Rigidity Akinesia Postural Problem Dopamine agonist DR.TALHA JAWAID PH.D LEARNING OBJECTIVE 1. Define dopamine ,biosynthesis , release and dopamine receptors. q Define Parkinson’s disease? Explain the hypothesis of Cholinergic & dopaminergic pathways. q Understand the drugs used in the treatment of Parkinson’s disease & explain in detail about Levodopa& Carbidopa. q Explain the adverse effect, clinical uses, doses & drug interaction of Levodopa. q Explain in detail about MAOIs in the treatment of Parkinsons disease. q Explain the mechanism of action , side effects , uses, doses and drug interaction of MAOIs. q Explain the pharmacodynamics of Anti cholinergic drugs & Amantadine used in the treatment of Parkinsons disease. q Explain the adverse effect , clinical uses and detail Pharmacokinetics of Anti cholinergic drugs & Amantadine in the treatment of Parkinson’s disease Parkinson's disease I Who was Known for First description of Parkinson's disease will Ach in NS if dopa releasesdopa I 3 Parkinson Disease Causes: decreased Dopamine Because of the degeneration of substantia Nigra in the Basal Ganglia and the nigrostriatal pathway. C Ischemia there are certain cells in the Substantia Nigra that has a main Jop → which is secreting Dopamine. in case of parkinson Disease, these cells are dying ↳ and this will cause a decreased Dopamine =Dopamine will naturally act through stimulating GABA (inhibitors) ↳If dopamine is not present , these cells will secreats Acetylcholine instaed (Acetylcholine level will rise) o o >So parkinsons is an imbalance between Dopamine and Acetylcholine< Decrease increase Eide There is One ☝ problem though : 5 CanenterBBB Levodopa gets broken down and metabolised first in the blood ! ! And thats becouse of the enzyme prephral decarboxilase , only little will reach the brain. present also CoarseResting tumors (Levodopa has no action alone) cogwheelRigidity Brodykinesiansiewmedent +(short) shuffling gait +Masked face +hypokinatic speach +micrographia they usually Die from: - Chest infection - Embolism Management We tried giving Dopamine as a replacement but it didn’t work, why? 1-Dopamine can’t cross BBB! 2-it gets metabolised in the blood! What we could do is: -Stimulate the Dopamine Receptors through other drugs that can mimic the dopamine action or -we could give a Dopamine precursor (which is better) = levodopa Levodopa will get absorbed and cross the BBB and then it gets metabolised to get Dopamine. inbrain All the extra free dopamine in the blood will act on the heart Beta Receptors > causing tachycardia Hypotension Nor firstLinetreatment So we must give Prephral decarboxilase inhibitors (carbidopa) along with levodopa. ofbenserisi.de dopa is tremors are : -coarse (where you can see the tremor) And - fine (which is barely Noticeable) Clinical features: T so goal of treatment 1 to dopamine 2 tobAch 2 Age group :effects elderly✅ decarboxilase types Central in theCNS to Prephrol intheblood theenzymethatmetabolises levodopatoDopamine No drug cure onlygives afewextrayears Over 3 to 5 years , substantia nigra is Progressively getting damaged irreversibly. and levodopa can’t stop this degeneration its only for symptomatic Relief. This damage may contribute to : on-off effect On-off effect is where we see that levodopa is no longer acting very well. So when the patient gets the medication $ he get hyperkinesia (on), and at the blood level when levodopa decrease patient will move to bradykinasia (off) , drastically not gradually. So in that case (not enough effect) we NEED to add another Drug! levodopa The cause of this on-off effect is another enzyme that breaks levodopa → called COMT (catechol-o-methyl transferase) Which will break down levodopa to levodopa metabolite (o-methyl transferase). Recap: so there is 2 enzymes breaking levodopa : 1-Decarboxilase 2-COMT (catechol-o-methyl transferase) This metabolite of levodopa and COMT enzyme can enter the BBB, And will compete with levodopa and will not allow levodopa to enter the brain which can effect the action of levodopa , here comes the: COMT inhibitors (entacapone,tolcapone) =levodopa will enter the brain without any competition Levodopa metabolite e E r E o U E n Levodopa Blood with levodopa hence they use the same channel to enter BBB Other drugs are also used ex: mono amino oxidase inhibitors (will be discussed in this lecture) Prolactin Brain Table1: Levodopa metabolite (3-o-methyldopa) will compete to delay this on-off effect , some doctors add from the beginning Dopamine Agonists which will act on dopamine receptors. (they will NOT going to increase dopamine NOR act on enzymes) they will only stimulate the dopamine receptors to delay the on-off effect. dopamine inhibits the release BBB of which hormone INTRODUCTION same family as epinephrine and Nor-epinephrine ¢ Dopamine belongs to the family of catecholamines ¢ Hormones, Epinephrine and Norepinephrine (other catecholamines) are derived from Dopamine Prolactin is a hormone that get effected by Dopamine level (prolactin decreases when dopamine increases) ¢ Significant role in learning, goal-directed behavior, regulation of hormones, motor control DA SYNTHESIS AND METABOLISM L phenylalanine (amino acid from diet) phenyalanine hydroxylase L- Tyrosine Tyrosine hydroxylase RLS L Dopa (also Called Levodopa) Dopa decarboxylase Dopamine (DA) Dopamine is synthesized from phenylalanine typesA Monoamine oxidase (MAO) B Catechol-O-methyl transferase (COMT) DOPAC + HVA DrMaria I will Notgothrough thisdetails After synthesis, dopamine is packaged into synaptic vesicles via the vesicular monoamine transporter (VMAT2) and stored there until its release into the synapse during neurotransmission. belongs to one family DOPAMINE RECEPTORS belongs to one family is Etypes D1 D2133,134,135 Newly discovered Metabotropic G-protein coupled receptors D1 – like family: (stimulatory Receptors) – – Includes subtypes D1 and D5 Activation is coupled to Gs ; activates adenylyl cylcase which leads to increase in concentration of cAMP D2 – like family: – 1 – – (Inhibitory Receptors) Includes D2, D3 and D4 Activation is coupled to Gi ; inhibits adenylyl cyclase leading to decrease in concentration of Camp o_0 Also open K channels & closes Ca influx These receptors are present in various location but concentrated in the limbic system and hypothalamus and substantia nigra and corpus striatum DOPAMINE RECEPTORS ñ Subtypes Ub Location Function D1 Putamen, nucleus accumbens i.e nigrostrial pathway Inhibition causes extrapyrimidal disorders D2 Striatum, substantia nigra, pituitary Control behaviour, voluntary, prolactin release D3 Midbrain, mucleus accumbens & hypothalamus D4 Frontal cortex, medulla and midbrain i.e mesocortical pathway D5 Hypothalamus, hippocampus DOPAMINERGIC PATHWAYS multible pathways Uses Dopamine : Mesolimbic Pathway Mesocortical Pathway Nigrostriatal Pathway Tuberoinfundibular Pathway Incertohypothalamic Pathway Medullary Periventricular Retinal 10 SIGNIFICANCE OF DOPAMINERGIC PATHWAYS Mesolimbic Pathway – through this Associated with pleasure, reward and goal directed behaviour Mesocortical Pathway – Associated with motivational and emotional responses f Nigrostriatal Pathway – Notgoing onlyknowthat Parkinson’s Disease Deals with this pathway Involved in coordination of movement (part of basal ganglia motor loop/EPS) Tuberoinfundibular Pathway – Regulates secretion of prolactin by pituitary gland and involved in maternal behavior DRUGS MODIFYING DOPAMINERGIC TRANSMISSION 21605 Mechanism Drug Effect Use Synthesis L-DOPA ↑ Synth Parkinsons disease 2 methyl-ptyrosine Inhibits tyrosine hydroxylase expts Carbidopa , Benserazide Inhibit dopa decarboxylase Parkinsonism Reserpine, Tetrabenzine Disrupt storage Tranquilizer MAO inhibitors Enhance storage Amphetamine, Tyramine, Mazindole Release dopamine on receptors Storage Release Anorectic, CNS stimulant DRUGS MODIFYING DOPAMINERGIC TRANSMISSION Mechanism Drug Inactivation of uptake Amphetamine, Cocaine, Effect CNS stimulant Anorectic Parkinson's disease Benztropine Benzhexol Inactivation of metabolism Use Iproniazid, Tranylcypromine, Nonselective MAO inhibitors Selegiline MAO inhibitors Parkinson's disease to my dopamine SCHIZOPHRENIA I will explain this in theNext class TORRANNUR ¢ Defective dopamine neurotransmission – relative excess of central dopaminergic activity ¢ An increase in DA function in the mesolimbic system and a decreased function in the mesocortical DA systems(D1 predominates) ¢ Behavior similar to the behavioral effects of psychostimulants DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA PARKINSON’S DISEASE ¢ ¢ degeneration❌ &. Parkinson’s sufferers have low levels of dopamine ¢ Parkinson’s: Its a neuro degenerative disease. all drugs will NOT be able to stop this at the level of substantia Nigra L-dopa raises DA activity People with Parkinson's develop schizophrenic symptoms if they take too much L-dopa o It is a neurodegneretive disease charasterised by rigidity,bradykinesia,dyskinesia and tremor. in the Nigrostriatal Pathway there are 2 important Neurotransmitters: In basal gangalia, the output neuron are controlled byydopamine and Inacetylcholine. o Due to their opposite action , a balance is required between these two neurotransmitter for proper functioning of basal gangalia. o Major Pathophysiology of Parkinsons is decrease in nigrostatial dopaminergic neuron , consequently cholinergic activity become dominant. o Thus Two major Startegies for the treatment of Parkinsons are to increase brain dopaminergic activity or to decrease central cholinerg activity. o In Parkinson’s disease there is an imbalance between them ,so we give centrally acting anticholinergic drugs additional to dopamine to correct the imbalance. Note: Parkinson´s disease (PD) was first described by an English physician, James Parkinson, in 1817 in “An Essay on the Shaking Palsy”. The famous French Neurologist, Charcot, further described the syndrome in the late 1800s. Parkinson, J. An Essay on the Shaking Palsy. Sherwood, Neely & Jones, London, 1817 In the basal ganglia, the 2 neurotransmitters "dopamine" & "acetylcholine" co-exist in a normal balance, where dopaminergic neurons exert an inhibitory effect on excitatory cholinergic neurons. DA ACh In Parkinson’s disease, the "nigrostriatal dopaminergic neurons" are degenerated (damaged) while cholinergic neurons are intact, resulting in a marked decrease in dopamine content (dopamine deficiency syndrome) and a relative predominance of cholinergic activity. Therefore, the strategy for treatment of Parkinsonism is to restore the normal balance between dopaminergic & cholinergic tones in the basal ganglia. Normal And Abnormal nson's = Parki Disease Role of substantia nigra in Parkinson's disease. when Dopamin secreted ach will not be secreted. And when dopamine decreases,ach will increase. T 21 Epidemiology of PD Most common movement disorder over the age of 65 years Affecting 1-2 % The second most common neurodegenerative disorder after Alzheimer´s disease (AD). CAUSES: 1) Drugs: D2 blockers Anti pychotics. 2) Neurotoxins-MPTP-oxidative stress Rotenone, Domoic acid 3) Stroke 4) Viral infection 5) Trauma Note: PD is the most common movement disorder affecting 1-2 % of the general population over the age of 65 years, and it is the second most common neurodegenerative disorder after Alzheimer´s disease (AD). Tanner, CM et al. Epidemiology and genetics of Parkinson´s disease. In: Watts RL, Koller WC, ed. Movement Disorders, Neurologic principles and practice. New York: McGrawhill, pp. 137-152, 1997. 1 I causes: ① Idiopathic ② vascular (ex: maybe atherosclerotic changes or viral infections or Neurotoxins) ③ Drugs induced parkinsonism or EPS (Extra pyramidal syndrome.) Any drug that blocks the dopamine receptors will causes acute muscle dystonia. (ex:metoclopramide and antipsychotics) When someone is vomiting and you gave him metoclopramide for the vomiting ' SE: it will give the patient Extra pyramidal syndrome and the patient now present with hyperkinetic movements and muscles dystonia! how can we treat this? Either by > decreasing the Ach level or by giving centrally acting anticholinergics (ex: benztropine,trihexyphenidyl and anti histamine specially the first generation like : promethazine because they have anticholinergic properties ). or >by increasing the dopamine level. Consequences of dopamine reductions 23 Drugs used to treat Parkinsonism do not stop the progression of the disease but they can only ameliorate the symptoms. Parkinsonism could be managed by: A. Enhancing dopaminergic activity using: 1. dopamine precurser drugs that replace dopamine (levodopa) antiviral drug that is used in influenza A2 2. drugs that release dopamine from its stores (amantadine) 3. drugs that prolong the action of dopamine by preventing its metabolism (seligiline) Like MAO inhibitors (specially the MAO B inhibitors) 4. drugs that mimic the action of dopamine (dopaminergic agonists) B. Reducing cholinergic activity by the use of anticholinergic drugs (benzatropine) C. Neurotransplantation (which is still in experimental phase). D. Physical therapy & regular exercise. Wf III Parkinsonism Sites of action of drugs used to treat Parkinson's disease. f f COMT Can both breakdown Levodopa And Dopamine 3-o-methyldopa y important CONT alwaysgivinw Carbidopa decarboxylase enzyme Levodopa + car bid op a Or rasagiline alwaysgive Selectives Dopamine agonists: P9TÉmapse release They’ll inhibit MAO B = Increase in dopamine for influenza virus And also for Parkinson’s (increase dopamine release from the stores) Or tolcapone They’ll inhibit COMT to decrease the amount of 3-o-methyldopa = Increase in dopamine uptake Therapeutic effect f 25 Drugs affecting brain dopaminergic system 1- Dopamine precursor – Levodopa 2- Peripheral Decarboxylase Inhibitors ◦ Carbidopa, Benserazide 3- Dopaminergic Agonists§ Bromocriptine, Pergolide § Ropinirole,Pramipexole Also Apomorphine 4- MAO-B inhibitors- Selegiline,Rasagiline 5- COMT inhibitors – Entacapone , Tolcapone 6- Dopamine Facilitator – Amantadine 7- Anti cholinergic drugs: Benzotropine, Trihexyphenidyl (Artane®) Increase the Release of Dopamine Specially used for drug induced Parkinsonism (no other drug will work EXCEPT these) Also Promethazine (first-generation antihistamine) given on emptystomach Always Drugs used in the treatment of parkinsonism MUST ADD 1- Levodopa (1) Carbidopa potgire.name will metaps St Levodopa is (the most effective drug used in the treatment of parkinsonism) eDoP0minecMoAy9 Metabolized d Chemistry: It is the metabolic precursor of dopamine( Pro drug) Mechanism of action: In the brain, levodopa is converted to dopamine by dopa decarboxylase primarily within the presynaptic terminals of dopaminergic neurons in the stratium (by action of L-aromatic amino acid decarboxylase). The dopamine produced is responsible for the therapeutic effectiveness of the drug in PD; after release, it is either transported back into dopaminergic terminals by the presynaptic uptake mechanism or metabolized by the actions of MAO and catechol-O- methyltransferase (COMT). dopodearbo.gl If you didn’t give carbidopa= Decarboxilase enzyme is present in various locations and will metabolize levodopa to dopamine in the prephri > and this excess dopamine will act on prephri : 1-act on the heart causing tachycardia ( 2-act on CTZ chemoreceptors trigger zone PrephrolDecarboxylase causing nausea and vomiting) ' 3-decrease central sympathetic out flow So carbidopa will decrease these side effects. Drugs used in the treatment of parkinsonism didn't through 1- Levodopa go If levodopa is administered alone, the drug is largely decarboxylated by enzymes in the peripheral sites so that little unchanged drug reaches the cerebral circulation. In addition, dopamine release into the circulation by peripheral conversion of levodopa produces undesirable effects. Dopamine itself does not cross the blood-brain barrier and therefore has no CNS effects. However, levodopa, as an amino acid is transported into the brain by amino acid transport systems, where it is converted to dopamine by the enzyme L-aromatic amino acid decarboxylase. LEVODOPA Dopamine (levodopa) must be administered on an empty stomach (At least half an hour before meals) Because the amino acids in the food will compete with levodopa and will not allow levodopa to enter the brain. In practice, levodopa is administered in combination with a peripherally acting inhibitor of aromatic L-amino acid decarboxylase, such as carbidopa, that do not penetrate into the CNS. will be given in the Ratio: 10:1 4:1 in markets* =100mg levodopa + 10mg carbidopa Or =100mg levodopa + 25mg carbidopa Inhibition of peripheral decarboxylase markedly increases the fraction of administered levodopa thatcrosses the blood-brain barrier and reduces the incidence of peripheral side effects. The most commonly prescribed form of carbidopa/levodopa is the 25/100 form, containing 25 mg carbidopa and 100 mg levodopa. I L ratio Adverse effect o Peripheral formed dopamine can lead to postural hypotension, Nausea and vomiting( CTZ stimulation hence domperidone can be used for vomiting). o ON –OFF Phenomenon: On means no symptom, Off full blown of symptom of PD. o Abnormal Choreiform movements: Dyskinesia of limbs, trunks and tongue can occur with prolonged high dose treatment. Carbidopa does not prevent or decrease this adverse effect; it responds to Amantadine. or + tachycardia to block Dopamine Receptors on the CTZ why we didn’t use metoclopramide ? Because it can cross BBB and will block the dopamine receptors in the brain + ❌ and domperidone will not cross BBB But Not always work , Selegiline Adverse effect Nevergive with Levodopa also known as vitamin B₆ T o Vitamin complex containing Pyridoxine decrease the effectiveness of levodopa. (Pyrodoxine is a co factor of dopa decarboxylase, that increases the For example : peripheral dopamine). Multivitamin (Which already contains all vitamin) Will decrease the efficacy of levodopa, because vitamin B6 will help decarboxylas enzyme breaking down the levodopa. o L-DOPA especially in elderly can result in hallucination, sleep disturbance and even Psychosis. Because of High dopamine level in the Brain Levodopa qUniversal antiparkinsonian drug q Metabolic precursor of Dopamine qTherapeutic effect ----decarboxylation in brain q95% of oral dose is decarboxylated in periphery only 1 -2 % crosses BBB q Always given along with peripheral decarboxylase inhibitor qHalf life – 1-3 hrs unless if you give Carbidopa along with it. Interactions BG 1 – Pyridoxine It will decrease the efficacy of levodopa will breakdown 2 – Phenothiazines , Butorphenones X Metoclopramide of Levodopa Dopamine antagonist will block the dopamine receptors Metoclopramide cross the BBB and Domperidone can’t ü Domperidone 3 – MAO inhibitorstypes If you give MAO inhibitors along with levodopa it’ll make excess amount of dopamine in the prephri MAO-A (acts on epinephrine, norepinephrine and dopamine) MAO-B (only acts on dopamine) - if you gave a non selective MAO inhibitor , it’ll inhibit both types A and B > will cause a significant increase in catecholamines = hypertensive crisis ⚠ of So you should never give non selective MAO inhibitor along with levodopa, And we only give Selective MAO inhibitor such as selegiline or rasagiline. Peripheral decarboxylase inhibitors Carbidopa , Benserazide Do not cross BBB Half life of L-Dopa increased Systemic side effects less Pyridoxine reversal does not occur Once you give peripheral decarboxylase inhibitors even pyridoxine will not have an effect on levodopa✅ ON/OFF phenomenon is minimized Degree of improvement higher Smooth control of symptoms Less diurnal fluctuations Because the half life increased LEVODOPA + CARBIDPOA Drugs inhibiting the metabolism of DOPAMINE 1) COMT( Cetechol –o-methyl transferase) Inhibitors 2) Mono amino Oxidase enzyme Inhibitors (MAOA,MAOB) so NO MAO AX only2 COMT INHIBITORS 1) Entacapone More common to use (can’t cross the BBB = less efficacy than tolcapone) 2) Tolcapone Acts better because it cross BBB but Can cause liver damage failure CanactcentrallyinCNS Catechol O methyl transferase inhibitors youcanRead throughit Tolcapone Mechanism of action: Inhibit catechol O methyl transferase (COMT) which is responsible for the conversion of dopa into methyl dopa. Elevated levels of methyldopa decreases the response to levodopa, because methyldopa competes with levodopa for an active carrier mechanism that governs its transport across the blood-brain barrier. Prolong the action of levodopa by diminishing its peripheral metabolism. These agents may be helpful in patients receiving levodopa to reduce dose and decrease fluctuations in response Side effects are similar to levodopa Dopa decarboxylase itsbroken down to Amphitamines1 thatswhyitsgiven earlyintheday COMT INHIBITORS Add on only Tolcapone ,Entacapone Inhibit levodopa metabolism ↑BA of levodopa Extends the t ½ of levodopa if you give it alone No effect will occure you must give it as a combination : No role as monotherapy (levodopa +Corbidopa + entacapone) together Indicated for patients with PD who have end-of-dose wearing off Talcapone inhibit COMT in periphery as well as brain whereas entacapone act only in Periphery. I Monoamine Oxidase Inhibitors (MAOIs) H R H NH2 Monoamine Oxidase (MAO) O2 H NH H2O O R R Hydrolytically unstable imine H Alcohol Dehydrogenase (ADH) HO O R + NH3 As shown above, monoamine oxidase is an enzyme that catalyzes the destruction of primary amines (such as dopamine, norepinephrine, serotonin) and secondary amines. The type B isoform of MAO (MAO-B) is primarily responsible for metabolism of dopamine. Mono amino oxidase inhibitors Two types of monoamine oxidase (MAO) have been distinguished. Monoamine oxidase (A) metabolizes norepinephrine and serotonin; monoamine oxidase (B) metabolizes dopamine. But in high Doses it can also inhibit MAO-A Selegiline: You should be careful and NOT give it along with Selective Serotonin Reuptake Inhibitors (SSRIs) Mechanism of action: Because it can lead to serotonin syndrome (hypertensive crisis)⚠ Selective inhibitor of monoamineT oxidase B (retards the breakdown of dopamine). MAO-B breaks down dopamine within the CNS Inhibition of MAO-B increases dopamine levels and function Because of increase in dopamine activity within CNS. Selegiline and SSRIs are contraindicated / Selegiline and cheese 0 are contraindicated / Side effects: (Because it contain tyramine *which is a source of serotonin) May cause insomnia when taken later during the day. Drug interactions: IN It should not be taken with tyramine ( CHEESE) because MAO enzyme causes the breakdown of Tyramine, by blocking these enzyme its leads to hypetensive crisis. The adverse effects of levodopa may be increased by selegiline. petecholamines Drug affecting the Cholinergic system Drugs affecting brain cholinergic system Drugs that act by blocking D2 receptors in the brain can causes Parkinsonism. In this condition increasing dopamine level is not effective because the receptors on which it act(D2) are already occupied, therefore anticholinergic drug is prefereed. This type of drug is also preferred if drug induced parkinsonism, particularly by using antipsychotic drugs. 1 – Central anticholinergic DOCfordruginduced µ Trihexiphenidyl,Benztropine,Biperiden Procyclidine 2 – Antihistamines; Promethazine,orphenadrine KINETICS Absorbed from small bowel – amino acid transporter Meal delays absorption 1 hr before and 1hr after food High first pass metabolism in liver, git it can also decrease the symptoms of Parkinson’s Disease like: - Sialorrhea (drooling or excessive salivation) -tremors and rigidity (they may work better then levodopa in controlling them) Central antiAch property Crosses BBB Dopamine Agonists Ergot Derivatives NON Ergot Derivatives Pramipexole (Mirapex®) bromocriptine Ropinirole (Requip®) Rotigitine (Neupro™) 7 Apomorphine (Apokyn®) given IV ForSevere ParkEmergency (cabergoline, lisuride) Can be given as transdermal patches ✓ Dopamine Agonists Stimulates dopamine receptors May be used as initial therapy for patients with mild disease or as “add on” therapy for patients with more severe disease May delay need for levodopa therapy in early patients Later stage patients may be able to decrease levodopa dosing if DA added Neuroprotective effect Dopamine receptor agonists: ERGOT fromfungus Retroperitonealfibrosis ◦ Bromocriptine ◦ Pergolide NON ERGOT ◦ Ropinirole ◦ Pramipexole : Dopamine receptor agonists Advantages : No enzymatic conversion needed You dint need an enzyme inhibitor to act with it Don’t require functional integrity of neurons Longer duration of action Less dyskinesia Less ON/OFF More selective BROMOCRIPTINE Not used any more Synthetic ergot derivative D2 agonist Levodopa like action, ↓GH and ↓Prolactin, Nausea & Vomiting Short acting and causes digital Vasospasm leading to gangerane. -----------t ½ -3-6 hours USES: Parkinsonism Hyperprolactinemia Because Dopamine decreases prolactin level Gynecomastia, impotence & sterility in men Acromegaly Dopamine also decreases GH level Suppress lactation Hepatic coma Many Side effects Of BROMOCRIPTINE Dr NotimportantBut still yara soyoushouldgo through Early ◦ Nausea, Postural hypotension, Vomiting, Constipation, nasal block Late ◦ Hallucination, psychosis, pulmonary infiltrates, retroperitoneal fibrosis, digital vasospasm, erythromelalgia it Iguessin PERGOLIDE Non Ergots and has a fewer side effects §D1 and D2 agonist §Increase ON time Increase the levodopa duration of action §Less dose of L- dopa You can use it on patient who can’t use §Withdrawn--- Valvular heart disease BROMOCRIPTINE (because of cardiovascular disease) §Non Ergot Dopamine agonist: Pramipexole and ropinirole do not have these limitation , these are long acting and do not causes gangerane, these are the first choice drugs for PD preferred over levodopa. AMANTADINE Dopamine facilitator Amantadine, an antiviral agent. Clinical Use Amantadine is less potent than levodopa and its effects disappear after only a few weeks of treatment Mechanism of action: It increases synaptic dopamine level by increasing presynaptic release and decrease its reuptake. Adverse Effects Ankle edema with pain Peripheral edema Heart failure postural hypotension urinary retention gastrointestinal disturbances (eg, anorexia, nausea, constipation, and dry mouth). Contraindications Amantadine should be used with caution in patients with a history of seizures or heart failure. Summary Amantadine for your intrest Summary of the Treatment of Parkinson’s Disease REFERENCES t Tripathi, K. D. (2018). Essentials of medical pharmacology (8th ed.). Jaypee Brothers Medical Goodman & Gillman’s: The Pharmacological Basis of Therapeutics, 13th edition. New York: McGraw-Hill, 2018 Lippincott Illustrated Reviews: Pharmacology(6th ed.). Philadelphia, PA: Wolters Kluwer Thank you and goodbye 1 Sponsored by: Notes group Special thanks : Dr.Maria Made by : yay2 Alshoyer Just remember: Levodopa Carbidopa Entacapone and tolcapone Selegiline Amantadine Dopamine agonists Remember their mechanism of action and their important SE