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Antiparkinson Drugs Parkinson Disease Definition • • Disturbance in motor function Characterized by o Rigidity o Masked face o Stooped posture o Gait disturbances o Slowing of voluntary movement o Pill-rolling tremor Parkinsonism is not a disease, it is per se a collections of signs and symptoms of underlying diseases. BUT in a case of absence in underlying causes (which is the most common), Parkinsonism is cosidered to be a disease of its own Antiparkinson Drugs These line of drugs are use in the intention of relieving the symptoms of Parkinson Disease It is either acting by through • Increasing the level of Dopamine • Reducing the activity of Acetylcholine Classification of Drugs 1. Drugs that increase the level and activity of Dopamine a. L-Dopa/Levodopa b. Mono Amine Oxidase B (MAOB) Inhibitors i. Selegiline ii. Rasagiline c. Catechol – O – Methyl Transferase (COMT) Inhibitor i. Tolcapone ii. Entacapone d. Dopamine Receptor Agonist i. Bromocriptine 2. Drugs that decrease the activity of Acetylcholine a. Anticholinergic Agent i. Benzatropine Drugs That Affect the Level and Activity of Dopamine Drugs Levodopa/ L-Dopa • It is biologically produced by the human body as the precursor of Catholamines such as o Norepinephrine o Epinephrine o Dopamine Pharmacokinetic Mechanism of Action • L-Dopa is the precursor of Dopamine; therefore Absorption by administering L-Dopa with hope it will increase • Readily absorp orally the level of Dopamine in the brain • Bioavailibility is quite low – 25-30% • L-Dopa will be converted into Dopamine in the Distribution brain by an enzyme called the Aromatic – L – • Upon absorption, L-Dopa will be Amino Acid Decarboxylase/ DOPA Decarboxylase either o This reaction needs Pyridoxine (Vitamin B6) as o Converted by the Aromatic – its cofactor L- Amino Acid o Hence L-Dopa is often be given together with Decarboxylase/ DOPA supplementary Vitamin B6 Decarboxylase into Dopamine o But if the Vitamin B6 is given solely without DOPA Carboxylase inhibitors (discussed below) at the peripheral nervous with L-Dopa, it will accelerate the peripheral system metabolism of L-Dopa Dopamine CANNOT pass • But, L-Dopa is also being converted into the Blood Brain Barrier Dopamine at the peripheral nervous system o Directly pass the BBB and o Physiologically Dopamine CANNOT pass the BBB. In order to pass this peripheral converted into the Dopamine metabolism, L-Dopa is given together with by the same enzyme DOPA Decarboxylase Inhibitors (DDCI) such as Metabolism Carbidopa • Metabolize by Aromatic – L – Benserazide Amino Acid Decarboxylase o DDCI will inhibit the enzyme in the peripheral nervous system from converting the L-Dopa • Half life is short; therefore duration into Dopamine of action is also short o This will therefore lead to Excretion Increase the level of L-Dopa that can pass • Via urine the BBB Increase the half life of L-Dopa from 50 minutes to 11/2 hours Indirectly increase the level of Dopamine in the brain with respect to increase in the half life Reduce the effects of hyperdominergic side effects secondary to increase in peripheral dopamine level Adverse Effects Common side effects • Hypotension • Arrythmias • Nausea o Reduced by taking with food o BUT protein ay interfere with its absorption • Allopecia • Confusion • Disorientation • Anxiety • Excessive libido • Somnolence • Narcolepsy • Insomnia Side effects due to chronic admin • On-off oscillation • Resistance • Dyskinesia • Dopamine Dysregulation Syndrome • Depletion of serotonin Drugs Mono Amine Oxidase B (MAOB) Inhibitors • Selegiline • Rasagiline It is not useful as a single therapy. Therefore should always be given as adjuvant therapy Pharmacokinetic Absorption • Poorly absorp orally • But it happens that it increases when taken with high fat content foods due to its liposolubility Distribution • Readily distributed across the body compartments • 90% bounded to plasma proteins Metabolism • Metabolized in the liver through DEMETHYLATION • This process may be inhibited if Selegiline is given with Oral Contraceptive (OCP) as OCP may inhibit demethylation process o This will increase the plasma level of Selegiline up to 10-20 folds o Increase the level of Selegiline in the plasma will shift its selectivity from only MAOB to both MAOA and MAOB Therefore it will Reduce the efficacy of Selegiline Leads to Cheese Effect o Cheese effect is an Hypertensive crisis due to increase in the level of tyramine (Tyramine in high in cheese) o Cheese effect happens due to the nonselectivity of selegiline towards MAO MAOA is enzyme that metabolizes epinephrine, norepinephrine and serotonin • Selegiline primary metabolites are o L-Amphitamine o L-Methamphitamine Excretion • Half life o After a single dose 1 ½ hours o After long admin 9 hours • Excreted via urine Mechanism of Action • MAOB will deaminate Dopamine into Homovanillic acid • Selegiline will covalently bind to MAOB and leads to irreversible inhibition of the activity of the enzyme • This will therefore reduce the metabolism of Dopamine which leads to o Increase of level of Dopamine o Increase the efficacy of LDopa • • • • • • Adverse Effects Dizziness Dry mouth Insomnia Muscle pain Nausea Constipation Severe side effects • Severe headache • Tachycardia • Arrhythmias • Hallucinations • Chorea • Difficulty in breathing Drugs Catechol-OMethyl Transferase (COMT) Inhibitors • Tolcapone (already withdrawn off the market) • Entacapone It is not useful as a single therapy. Therefore should always be given as adjuvant therapy Dopamine Receptor Agonist Bromocriptine Pharmacokinetic Absorption • Readily absorb orally • Low bioavailibility – 30% Distribution • Readily distributed across body comparments • Readily passes the BBB • 99% bound to plasma albumin Metabolism • Hepatic CYP450 Excretion • 90% feaces • 10% urine Absorption Readily absorp orally Low bioavailibility – 28% Distribution Readily distributed in all body compartments Passes the BBB Metabolism Remains unknown Excretion 85% feaces Mechanism of Action • COMT will metabolize L-Dopa into 3Methoxy-4-Hydroxy-L-Phenylalanine (3-OMD)in the periphery • COMT also metabolizes Dopamine into Homovanillic acid in the brain • COMT inhibitors are somehow similar to that of Carbidopa, in a sense that COMT inhibitors inhibit the activity of COMT in the periphery as well as in the brain o This will therefore Reducing peripheral metabolism of L-Dopa into 3-OMD Hence, increasing the level of L-Dopa reaching the CNS Reducing the cerebral metabolism of Dopamine into Homovanillic acid Therefore increasing the level and activity of Dopamine Bromocriptine is a potent agonist at dopamine D2 receptors and various serotonin receptors It also inhibits the release of glutamate, by reversing the glutamate GLT1 transporter Other Indications of Bromocriptine Hyperprolactineamia Galactorrhea Amenorrhea Type 2 Diabetes Mellitus o Bromocriptine is fund t reduce HbA1c up to 0.5% (FDA) Adverse Effects Side effects primarily due to increase level of L-Dopa Dyskinesia Hepatotoxicity – primarily in Tolcapone That’s why it has been withdrawn from the market Nausea Orthostatic hypotension Headache Vomiting Worsening of liver problems Drugs That Decrease the Activity of Acetylcholine Drugs Anticholinergic Agents Benzatropine Benzatropine is a drug that is manufactured through combining tropine portion of Atropine with Benzohydryl portion of Diphenhydramine Pharmacokinetic Absorption Readily absorp orally o Onset at about 1-2 hours But the onset increases drastically to only minutes if given through I/V or I/M Other pharmcokinetic of Benzatropine are remained largely unknown Mechanism of Action Benzatropine is a centrally acting anticholinergic/antihistamine agent resulting from the combination of the tropine portion of the atropine molecule and the benzohydryl portion of diphenhydramine Benzatropine antagonises the effect of acetylcholine, decreasing the imbalance between the neurotransmitters acetylcholine and dopamine, which may improve the symptoms of early Parkinson's disease Adverse Effects Dry mouth Blurred vision Cognitive changes Constipation Urinary retention Tachycardia Anorexia