Anti-parkinsonism Drugs Course Coordinator Jamaluddin Shaikh, Ph.D. School of Pharmacy, University of Nizwa Lecture-21 & 22 November 21, 2011

Clinical Features of Parkinson’s Disease Parkinsonism is a progressive neurologic disorder characterized by Tremor Rigidity Bradykinesia Postural instability Poor balance, falls Bradykinesia is a Greek term that means "slow movement”

Parkinson Disease (PD): Causes The cause of PD is unknown for most patients Correlated with destruction of DAergic neurons in the substantia nigra with a consequent reduction of DA actions in the corpus striatum Genetic factors do not play a dominant role in the etiology of PD, although they may exert some influence on an individual's susceptibility to the disease Etiology: The study of causes or origins

Dopamine Neurotransmission

Strategies for treatment of PD ↑Dopamine activity: Administration of Dopamine (precursor) Activating Dopamine receptors (agonists) Release of endogenous Dopamine ↓Metabolism of Dopamine ↓Ach activity

Strategies for treatment of PD ↑Dopamine activity: Administration of Dopamine (precursor) Activating Dopamine receptors (agonists) Release of endogenous Dopamine ↓Metabolism of Dopamine ↓Ach activity

Levodopa and Carbidopa Levodopa is a metabolic precursor of DA It restores DAergic neurotransmission in the corpus striatum by enhancing synthesis of DA Patients with early disease, number of residual DAergic neurons is adequate for conversion of levodopa to DA Relief provided by levodopa is only symptomatic, and it lasts only while the drug is present in the body Restore: to bring back to a former or normal condition

Levodopa and Carbidopa: Mechanism of Action DA itself does not cross the blood-brain barrier, but its immediate precursor, levodopa, is actively transported into the CNS and is converted to DA in the brain Large doses of levodopa are required, because much of the drug is decarboxylated to DA in the periphery Effects of levodopa on the CNS can be greatly enhanced by coadministering carbidopa. Carbidopa diminishes the metabolism of levodopa in the gastrointestinal tract and peripheral tissues; thus, it increases the availability of levodopa to the CNS

Levodopa and Carbidopa: Pharmacokinetics The drug is absorbed rapidly from the small intestine Levodopa has an short half-life (1 to 2 hours) Ingestion of meals, particularly if high in protein, interfere with the transport of levodopa into the CNS Large, neutral amino acids (i.e., leucine and isoleucine) compete with levodopa for absorption from the gut. Thus, levodopa should be taken on an empty stomach, typically 45 minutes before a meal

Levodopa and Carbidopa: Adverse Effects Anorexia, nausea, and vomiting occur Tachycardia results from DAergic action on the heart Hypotension may also develop Saliva and urine are a brownish color because of the melanin produced from catecholamine oxidation Visual and auditory hallucinations may occur Cause mood changes, depression, psychosis, and anxiety Anorexia: the symptom of poor appetite whatever the cause Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate

Levodopa and Carbidopa: Drug Interaction MAO inhibitors can produce hypertensive reactions if given concurrently with levodopa The hypotensive actions of other drugs are potentiated by levodopa Pyridoxine increases the peripheral breakdown of levodopa and diminishes its effectiveness Pyridoxine is one of the compounds that can be called vitamin B6

Strategies for treatment of PD ↑Dopamine activity: Administration of Dopamine (precursor) Activating Dopamine receptors (agonists) Release of endogenous Dopamine ↓metabolism of Dopamine ↓Ach activity

Dopamine-receptor Agonists This group of compounds includes ergot derivative (bromocriptine) nonergot drugs (ropinirole, rotigotine) Durations of action longer than that of levodopa and, thus, have been effective in patients exhibiting fluctuations in their response to levodopa Effective in patients with advanced Parkinson's disease complicated by motor fluctuations and dyskinesias Dyskinesia is a movement disorder which consists of effects including diminished voluntary movements

Strategies for treatment of PD ↑Dopamine activity: Administration of Dopamine (precursor) Activating Dopamine receptors (agonists) Release of endogenous Dopamine ↓metabolism of Dopamine ↓Ach activity

Amantadine It has several effects on a number of neurotransmitters implicated in causing PD, including increasing the release of DA, blockading cholinergic receptors, and inhibiting the NMDA receptors The drug may cause restlessness, agitation, confusion, and hallucinations Orthostatic hypotension, urinary retention, peripheral edema, and dry mouth also may occur Amantadine is less efficacious than levodopa Peripheral edema is the swelling of tissues, usually in the lower limbs, due to the accumulation of fluids NMDA receptor: Glutamate receptor

Strategies for treatment of PD ↑Dopamine activity: Administration of Dopamine (precursor) Activating Dopamine receptors (agonists) Release of endogenous Dopamine ↓Metabolism of Dopamine ↓Ach activity

Monoamine Oxidase Type-B Inhibitor Selegiline selectively inhibits MAO-B (which metabolizes DA) at low to moderate doses By decreasing the metabolism of DA, selegiline has been found to increase DA levels in the brain Selegiline substantially reduces the required dose of levodopa Rasagiline, a MAO-B inhibitor, has five times the potency of selegiline

Selegiline and rasagiline: Adverse Effects If selegiline is administered at high doses, the patient is at risk for severe hypertension Selegiline is metabolized to methamphetamine and amphetamine, whose stimulating properties may produce insomnia if the drug is administered later than mid-afternoon Unlike selegiline, rasagiline is not metabolized to an amphetamine-like substance

Catechol-O-methyltransferase Inhibitors Methylation of levodopa by catechol-O-methyl-transferase (COMT) to 3-O-methyldopa is a pathway for levodopa metabolism When peripheral DA decarboxylase activity is inhibited by carbidopa, significant concentration of 3-O-methyldopa is formed that competes with levodopa for active transport into the CNS Inhibition of COMT by entacapone or tolcapone leads to decreased plasma concentrations of 3-O-methyldopa, increased central uptake of levodopa, and greater concentrations of DA

Catechol-O-methyltransferase Inhibitors: Pharmacokinetics Oral absorption occurs readily and is not influenced by food They are extensively bound to plasma albumin, with limited volumes of distribution Tolcapone has a relatively long duration of action compared to entacapone Both drugs are extensively metabolized and eliminated in the feces and urine Adverse Effects Adverse effects include diarrhea, postural hypotension, nausea, dyskinesias, hallucinations, and sleep disorders

Strategies for treatment of PD ↑Dopamine activity: Administration of Dopamine (precursor) Activating Dopamine receptors (agonists) Release of endogenous Dopamine ↓metabolism of Dopamine ↓Ach activity

Antimuscarinic Agents These agents are much less efficacious than levodopa and play only an adjuvant role in PD therapy Few drugs of this group: Benztropine Procyclidine Biperiden They can induce mood changes and produce dryness of the mouth and visual problems Blockage of cholinergic transmission produces effects similar to augmentation of DAergic transmission Adjuvant-agents that modifie others effects