Parkinson's Disease Pharmacology Lecture Notes PDF

1 PM 719 Pharmacology II Lecture Notes (LN) Chapter 28 Parkinsonism Background (Terms to learn) (a) Tremor = rhythmic oscillatory movement around a joint (b) Tremor at rest = characteristic of Parkinson’s Syndrome (c) Intention tremor = tremo...

1 PM 719 Pharmacology II Lecture Notes (LN) Chapter 28 Parkinsonism Background (Terms to learn) (a) Tremor = rhythmic oscillatory movement around a joint (b) Tremor at rest = characteristic of Parkinson’s Syndrome (c) Intention tremor = tremor during movement, patients with lesions of the brain stem or cerebellum, or toxicity from alcohol or other drugs (d) Chorea = irregular, unpredictable, involuntary muscle jerks that occur in different parts of the body and impair voluntary activity. (e) Athetosis = abnormal movements slow and writhing (f) Dystonia = abnormal posture (g) Tics = sudden coordinated abnormal movements that tend to occur repetitively, particularly about the face and head Parkinsonism (a) characterized by rigidity, bradykinesia, tremor, postural instability (b) cognitive decline as the disease advances (c) DA (dopamine) in the basal ganglia is reduced in Parkinsonism (d) loss of DA neurons in the substantia nigra is typical Levodopa (a) Dopamine (DA) dose not cross the BBB (b) levodopa is the immediate precursor of DA (c) dopa decarboxylase (DDC) in the brain converts l-dopa to DA (d) DA blocker drugs can induce Parkinsonism (check that out). (e) the loss of DA and DA neurons is the hall mark of Parkinsonism (f) only about 1-3% of a po dose of l-dopa enters the brain due to decarboxylation in the peripheral system (g) a peripheral decarboxylase enzyme inhibitor, carbidopa, protects l- dopa and reduces the dose required by as much as 75% (h) effects of l-dopa diminish after 3-4 years of treatment (i) Sinemet = l-dopa plus carbidopa (100 mg + 25 mg) (j) drug reduces the bradykinesia from the disease process Levodopa ADRS (a) anorexia, nausea and vomiting in 80% of patients (b) when given with a decarboxylase inhibitor the incidence is reduced to 20% (c) l-dopa is converted in the peripheral system after po dosing to DA  2 which leads to increased catecholamine levels and tachycardia and ventricular extrasystoles, incidence is reduced when decarboxylase is given (d) up to 80% of patients develop dyskinesias (e) mood changes include anxiety, agitation, insomnia, somnolence, confusion, delusions, hallucinations, nightmares, euphoria (f) on-off phenomenon, improved mobility, fluctuations in clinical response unrelated to timing of dose (g) drug holidays of up to 3-21 days with no drug may improve response to l-dopa but are not recommended Dopamine Receptor Agonists Used to Raise DA Levels (a) Bromocriptine (1) a dopamine D2 receptor agonist (2) ergot derivative (b) Pergolide (1) a dopamine D1 and D2 receptor agonist (2) ergot derivative (3) drug no longer used due to ADR (4) both ergot drugs have been replaced with safer drugs (c) Pramipexole (1) a dopamine D3 receptor agonist (2) not from ergot (3) may be used as monotherapy for mild Parkinsonism (d) Ropinirole (1) pure D2 receptor agonist Dopamine Receptor Agonists: ADRs (a) GI effects include anorexia, nausea and vomiting (b) postural hypotension (c) dyskinesias like with l-dopa, reduce dose (d) confusion, hallucinations, delusions etc Monoamine Oxidase (MAO) Inhbitors (a) MAO A biotransforms NE, 5HT, and DA (b) MAO B biotransforms “mostly” DA (c) Selegiline (deprenyl) is a selective inhibitor of MAO B at normal doses (d) Selegiline at higher doses inhibits both MAO A and B  3 (e) MAO inhibitors retard the breakdown of DA and permit lower doses of l-dopa (f) Rasagiline, a MAO B inhibitor (g) both selegiline and rasagiline at regular doses are MAO B selective Catechol-O-Methyltransferase (COMT) Inhbitors (a) COMT enzyme in the peripheral system produces 3-o-methyldopa which competes with l-dopa for entry into the brain (b) tolcapone and entacapone inhibit COMT (c) both drugs prolong the actions of l-dopa by inhibiting the actions of COMT (d) tolcapone has actions in both the CNS and periphery, entacapone only in the periphery (e) tolcapone may produce liver disease, patient consent form required and liver enzymes every two weeks for the first year of treatment required. (f) Stalevo (trade name) = levodopa + carbidopa + entacapone Apomorphine (a) DA agonist given sc (b) drug used for “rescue” during off periods of akinesia in patients on optimized therapy with regular drugs (c) rapidly enters the brain (d) many ADRs Amantadine (a) an antiviral drug (go figure) (b) mechanism unknown (c) may potentiate DA function by influencing synthesis, release or reuptake (d) effect may last only a few weeks (e) ADRs include restlessness, depression, irritability, insomnia etc (f) overdose can produce acute psychotic episode Acetylcholine (Ach)-Blocking Drugs (a) centrally acting antimuscarinic drugs (b) drugs improve tremor and rigidity but no effect on bradykinesia (c) drugs include benztropine biperiden  4 orphenadrine procyclidine trihexyphenidyl (d) ADRs include all the effects of anti-muscarinics (dry mouth etc.) Surgical Procedures (a) implanted electrode and stimulator by implanted electrodes (b) transplant of fetal substantia nigra tissue, results are not clear Drug-Induced Parkinsonism (a) reserpine and tetrabenazine deplete biogenic amines from their stores in neurons (b) haloperidol, metoclopramide, and penothiazines block DA receptors (c) MPTP & Parkinsonism (Important and discussed in detail in the slides and the Katzung book). Treatment of General Movement Disorders Diffetrent Types of Tremor (a) rhythmic oscillatory movements (b) Essential Tremor, often drug induced, find out which drug and discontinue (c) Intention Tremor, present during movement but not at rest, a toxic manifestation of alcohol or drugs or a neurological disorder (d) Rest tremor, is due to Parkinsonism  5 Chapter 28 Required Drugs in Bold below and all those listed in the text above. (1) Levodopa and Combinations levodopa converted to DA in the CNS levodopa + carbidopa carbidopa inhibits conversion of levodopa to DA in PNS levodopa + carbidopa + entacapone (2) Dopamine Agonists pramipexol non-ergot direct DA receptors agonist bromocriptine ergot DA receptor agonist apomorphine non-ergot DA receptor agonist, sc only (3) MAO Inhibitors rasagline inhibits MAO-B, and MAO-A at higher doses selegline same as rasagline (4) COMT Inhibitors entacapone inhibits COMT in PNS, does not enter CNS tolcapone inhibits COMT in PNS and enters CNS (5) Antimuscarinics  6 benztropine muscarinic receptor antagonist PM 719 Chap 28 Parkinson’s Disease BRIEF SUMMARY The role of enzymes and enzyme inhibitor drugs. L-DOPA: (1) The goal of drug therapy is to raise/replace dopamine (DA) levels in the CNS because Parkinson Disease is due to the loss of DA neurons in the substantia nigra of the brain. (2) DA will not cross the BBB. (3) L-Dopa will cross the BBB and inside the CNS it is converted to DA by the enzyme dopa decarboxylase (4) Dopa decarboxylase in the PNS converts L-dopa to DA which cannot cross the BBB. The drug L-dopa is rendered useless by the enzyme dopa decarboxylase. (5) SOLUTION: Inhibit dopa decarboxylase in the PNS (not CNS) and block this enzyme from destroying the drug L-dopa. (6) Carbidopa inhibits dopa decarboxylase in the PNS and not the CNS. L-dopa is always given in combination with carbidopa (combination called Sinemet and others). Monoamine Oxidase B (MAO-B): (1) MAO-B in the CNS removes (digests) DA. (2) Inhibit MAO-B in the CNS and DA levels are not degraded by this enzyme. (3) Lower doses of L-dopa (which becomes DA in the CNS) become possible, that’s good. (4) Inhibit MAO-B in the CNS with selegiline or rasagiline Catechol-O-methyltransferase (COMT): (1) COMT uses various substrates in the PNS to generate 3-O-methyldopa (2) 3-O-methyldopa blocks the entry of L-dopa into the CNS (3) Inhibit COMT with tolcapone or entacapone. (4) When COMT is inhibited in the PNS it can not generate 3-O-methyldopa which would block entry of L-dopa into the CNS. 7