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

2. 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”

3. 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

5. Dopamine Neurotransmission

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

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

8. 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

9. 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

11. 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

12. 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

13. 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

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

15. 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

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

17. 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

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

19. 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

20. 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

21. 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

22. 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

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

24. 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