Lecture 10 - Pharmacology of Parkinson Disease and Antiepileptic Agents Flashcards
List examples of neurodegenerative diseases
- Alzheimer’s disease
- Parkinson’s disease
- Prion disease
- Huntington”s disease
- spinal muscular atrophy
Define
Parkinson’s disease
A disorder of the basal ganglia caused by a deficiency of dopamine, which produces movement disorder. Most common neurodegenerative cause of parkinsonism.
Define
Parkinsonism
A collective clinical syndrome charachterized by tremor, dradykinesia, rigidity, and postural instability. Can be caused by neurotoxins, reserpine, some antipsychotic drugs, corticobasal degeneration, stoke, and PD
PD symptoms - preliminary phase
- Fatigue
- depressive tendencies
PD symptoms - Disease phase
Motor symptoms: bradykinesia (slowed movement), postural instability (impaired balance and coordination), rigidity (stiffness of limbs), resting temor (in arms, hands, leg and face)
Cognitive symptoms: habit learning deficit and other deficits but does not affect working memory
Where is the majority of dopamine synthesized in the brain?
Substantia nigra
What is the name of the reward center of the brain?
Ventral tegmental area
How can you visualize PD in the brain?
Cut a section of the midbrain where a portion of the substantia nigra is visible and look for lack of melanin
Catecholamine (Dopamine) Metabolism
Dopamine –> 3-methoxytyramine via Catechol-O-methyltransferase (COMT) OR –> Dihydroxyphenylacetic acid via Monoamine oxidase (MAO) –> via opposite enzyme to homovanilic acid (HVA) which is secreted in urine
What parts of the brain does dopamine affect?
Prefrontal cortex, nucleus accumbens, caudate nucleus, putamen, substantia nigra, ventral tegmental area
What parts of the brain does acetylcholine affect?
Cingulate bundle, fornix, septal nuclei, nucleus basalis, pontomesencephalotegmental complex
Relationship of DA to ACH in parkinson’s disease
Lowered dopamine
Normal acetylcholine relative to the base level
Relationship of DA and ACH in Huntington’s chorea and tourette’s syndrome
Lowered acetylcholine
Normal dopamine relative to base level
What enzyme converts L-DOPA to dopamine?
DOPA decarboxylase (DDC)
D1 receptor family
D1 –> straitum, neocortex
D5 –> hippocampus, hypothalamus
Second messenger systems: increased cAMP via Gs, PIP2 hydrolysis which leads to Ca2+ mobilization and PKC activation
D2 receptor family
D2 –> Straitum, substantia nigra, pituitary gland
D3 –> Olfactory tubercle, nucleus accumbens, hypothalamus
D4 –> frontal cortex, medulla, midbrain
Second messenger systems: decreased cAMP via Gi, increased K+ currents, decreased voltage gated Ca2+ current
What is Levodopa?
Drug that can cross the blood-brain barrier and converts to dopamine to decrease parkinsonian symptoms
Pharmacokinetics of levodopa
- Administered orally
- Well absorbed in the GI tract
- co-administered with carbidopa (inhibits DDC)
What drugs inhibit metabolism od Levodopa and DA?
- Carbidopa - inhibits only peripheral DDC
- MAO-B inhibitors - irreversible, slegiline and rasagiline
- COMT inhibitors - tolcapone and enacapone
where do dopamine receptor agonists bind?
Bind to and stimulate dopamine receptors in basal ganglia
List some dopamine receptor agonists
- Bromocriptine (first used, stimulates DA, alpha-adrenergic, and serotonin recpetors)
- Pramipexole and rapinirole (preferred)
- Apomorphine (suncutaneously administered)
Miscellaneous drugs
Benzotropine (centrally-acting anticholinergic drugs)
Blocks ACH actions in oder to decrease cholinergic activity
Benzotropine is a selective M1 muscarinic acetylcholine receptor antagonist. Partially blocks cholinergic activity in the basal ganglia and increases the availability of dopamine by blocking its reuptake and storage
Miscellaneous drug
Amantadine
- M2 proton channel blocker, treats flu
- Increases DA release, blocks reuptake
- Effective only in early stages of PD
- Also a weak NMDA-type glutamate receptor antagonist
Antiparkinson drug actions
- drugs that form dopamine
- drugs that inhibits metabolism of levodopa or DA
- dopamine receptor agonist
- miscellaneous drugs
