Parkinson's Disease -what is it? -age of onset? -characteristics?
A progressive disorder of movement that occurs most commonly in the elderly. Age of onset = 55 years old. - Resting tremor -muscle rigidity -Bradykinesai (slowness of movement) -Impairment of postural balance leading to disturbance of gait and falling.
What are the neurons affected by parkinson's disease
loss of dopaminergic (DA) neurons in substantial nigra pars compact (SNpc) in the basal ganglia. -up to 70-80% of DA loss occurs before disease is clinically recognizable. -decrease in dopaminergic terminals in the striatum
parkinson's disease is diagnosed at an advanced stage of cell loss
What happens with the loss of DA in the corpus striatum
DA loss = effect of acetylcholine is relatively increased.
Loss of neurons in substancia nigra = decrease signaling to striatum.
Net effect results in decreased stimulation of the motor cortex by the basal ganglia
Proposed cause of PD
3. Oxidative stress
4. Energy metaoblism and aging
Mostly genes invovled in protein degradation, mitochondrial function, and response to oxidative stress.
* alpha- synuclein --> Lewy bodies
* Parkin, DJ-1, PINK 1, LRRK2
* contribution of genetic factors is rather low
MOST PD IS IDIOPATHIC
MPTP (contaminator of synthetic heronin) is metabolized to free radical MPP+ which produces oxidative stress and cell death.
MPP+ is actively transported to neurone via a dopamine transpoert.
Things that increase risk factor for Parkinson's disease
2. hemolytic exposure
Things that decrease chance of PD
1. coffee drinking
2. use of anti-inflammatory
Where does Oxidative Stress come from?
Metabolism of dopamine.
-Dopamine -- MAO--> DOPAC + H2O2 ---Glutathione--> 2 H2O
If system is not working properly, then it can lead to the formation of radicals.
Energy metabolism and aging
Aging decreases the capacity of neurons to undergo oxidative metabolism
- function of complex 1 in mitochondria is reduced in patients with PD
What are the mechanisms of treating PD
1. exogenous dopamine precursor
2. increase relase of endogenous dopamine
3. Direct dopamine agonist
4. Inhibitors of dopamine metabolism
Synthesized from tyrosine -- exogenous deopmain precursor
Decarboxylation (L-amino acid decarboxylase) converts to Dopamine.
Less than 1% penetrates CNS is administered alone.
Absorption rate of Levadopa
Depends on gastric emptying, pH of gastric juice and time of exposure to degradative enzymes.
Absorbed rapidly from small intestine by active transport system.
-competes with aromatic amino acids
- high protein meal will delay absorption and reduce peak plasma concentration
Levadoopa transport to brain?
Levadopa--> dopamine via decarboxylase
---COMT--> 3-O Methyldopa
COMT (Catechol-O- methyltransferse) makes compoudn that is actively transported to Brain
-substrate competes with dietray protein
L-aromatic amino acid inhibitor
-does not penetrate BBB
-increase fraction of unmetabolized levodopa
-increases half-life of Levodopa
-Increases plasma concentration of Levodopa
-Allows a reduction in levodopa dosage -- decrease peripheral side effects
Sinemet and Sinement CR
Levodopa + carbidopa - fixed concentration
1:4 and 1:10 where 1 = 25mg
Sustained release formulation (Sinemet CR)
* increase among of drug going into brain
What are the types of adverse effects associated with Levodopa Therapy?
1. GI effects
2. Cardiovascular effects
3. CNS effects
4. Long term effects
What are the GI effects associated with Levodopa treatment?
when given alone 80% of patients suffer the following:
-Anorexia, Nausea, Vomitting
-stimulation of emetic center located in brain stem outside of blood-brain barrier
-combination with carbidopa reduces GI effects of only 20% of patients.
What are the GI effects associated with Levodopa treatment?
-Postural hypotension (activation of vascular dopamine receptors)
What is the danger of prescribing Levodopa with nonspecific MAO inhibitor?
Accentuates levodopa actions and may precipitate a lifethreatening hypertensive crisis
What are the CNS adverse effects of Levodopa?
-decrease tremor, rigidity, and bradykinesia
-hallucinations, confusion, anxiety
What is the conventional anti-psychotic agent that are effect for psychological disease but actually make parkinson's worse?
What is another anti-psychotic medication that can be used and does not worsen parkinson's?
What are the long term effects of Levodopa therapy?
1. Response fluctuations
-Endo of dose
2. increase side effects
3. May require adjuctive therapy.
What is End-of Dose Deterioration?
Early PD: nigrostriatal dopamine system retains some capaciy to store and relase dopamine (" buffering effect").
After long-term use of Levodopa: "buffering effect" is lost. Patients motor state may fluctuate drmatically with each dose of levodopa --> "wearing-off- phenomena"
-dose of levodopa may improve symptoms for 1 or 2 hours before wearing off.
On-Off phenomena with Levodopa therapy
Patients fluctuate rapidly between having no apparent effects of medication (off) and having effects of medication (on).
Off periods are marked with akinesia (state of being without movement) --> improved mobililty but often marked dyskinesia.
this is probably due to the brain adapting to variations in levodopa levels (alterations in function of dopamine receptors)
what is drug that can be used if Levodopa has caused sever off-periods and person is not responding to other measures?
Drug interactions with Levodopa Therapy
MAO -A- inhibitors : life-threatening hypertensive crisis
Pyridoxine (vit B enhances extracerebral metabolism of levodopa)
Contraindications with Levodopa Therapy
Active peptic ulcer
Use with caution if history of melanoma (Levodopa is a precursor for melanin)
What are the two types of dopamine agonists?
Exictatory (D1 receptor family)
Inhibitory (D2 receptor family)
-do not require to be enzymatically metabolized-- elimits production of toxic metabolites ( levodopa was made outside of the CNS and had toxic effects)
-well absorbed orally
-half life of 2-3 hours
-used in combination with levodopa/carbidopa for advanced disease to smooth on/off response fluctuations.
Adverse Effects of Bromocriptine?
-Same as Levodopa
Ergot adverse effects: (vasoconstriction)
-erythromelalgia (blockage and inflammation of blood vessels)
-Digital vasospasm (constriction of small arteries of the finger)
Metabolized by CYP1A2 -- drugs metabolized by liver will significantly reduce clearance of drug.
Excreted largely unchanged in urine.
Ropinirole and Pramipexole benefits/usage
-Effective as monotherapy in patients with mild disease
-Effective as measn of smoothing response fluctuations in patients on levodopa therapy with more advanced disease.
Adverse effects of ropinirole and pramipexole
Similar to Levodopa:
-Orthostatic Hypotension, arrhythmias
-hallucinations and confusion
Ergot side effects:
-uncontrollabe tendency to fall asleep at inappropriate times; requires discontinuation of medication.
Subcutaneous injection to treat "off" episodes in patients with advanced PD.
Apomorphine Adverse Effects
-Emesis (vomitting/nausea) and requires pretreatment with ANTIEMETIC TRIMETHOBENZAMIDE 3 days before itital treatment and continued for at least two months.
Apomorphine is contradicted with what drug?
Antimetics of the 5HT3 receptor class --> causes severe hypotension and loss of conciousness
metabolize dopamine selectively
metabolizes norepinephrine, serotonin, and dopamine; also found in liver and GI tract
Irriversible MAO-B inhibitor
-retards breakdown of dopamine in the striatum without inhibiting peripheral metabolism of catecholamines
-modest beneficial effect when used alone.
-also used in combination with levodopa/carbidopa to decrease response fluctuations in late PD patients.
Adverse effects of Selegiline?
-accentuate motor and cognitive effects of levodopa therapy
Selegiline should not be taken with which drugs?
1. analgesic meperidine -- stupor, rigidity, agitation, and hyperthermia, tramadol, methadone, cyclobenzaprine, St. John's wort.
2. tricyclic antidepressants OR Serotonin-reuptake inhibitors -- risk of acute serotonin syndrome!
more selective MAO-B inhibitor
-does not produce amphetamine metabolites
-may prevent progression of PD in early PD.
-use in combination with levodopa/carbidopa to decrese respone fluctuations in late PD patients.
-Monotherapy in mild disease.
Adverse effects of Rasagiline
-Accentuate adverse motor and cognitive effects of levodopa therapy
What are drugs that should not be taken with Rasagiline?
1. Analgesic meperidine -- stupor, rigidity, agitation
2. tricyclic antidepressants or serotonin reuptake inhibitors
Rasagiline Treatment of early PD -- Neuroprotective effect
1. decrese synthesis of toxic metabolites
2. neuroprotection by reducing oxidation of dopamine
What are the 3 drugs in the Catechol-O-methyl Transferase Inhibitors
1. Tolcapone (central and peripheral effects)
2. entacapone (peripheral effects)
5. Stalevo -- levodopa/carbidopa/entacapone
Benefits of Tolcapone and entacapone
-Inhibition of COMT prolongs plasma half-life of levodopa and increases availability of levodopa in brain.
-adjunct to levodopa/carbidopa = reduction of levodopa dose
-approved for patients with late PD who have developed response fluctuations.
Adverse effects of tolcapone and entacapone
Levodopa related dopaminergic effects
-Diarrhea, abdominal pain, sleep disturbances
What drugs should you be aware of when using tolcapone and entacapone?
-Drug interactiosn with drugs notmally metabolzied by COMT
-concurrent with non-specific MAO inhibitor could severely limit metabolism of levodopa.
Half-life 2-3 hrs
- can increase aminotransferase and transaminase activity -- indicator of liver damage.
Less potent that Tolcapone
Half life= 1-2 hrs
NO incidence of hepatotoxicity and is therefore, generally prefered.
Anti-cholinergics drugs (5):
2. benzotropine mesylate
-May improve tremor and rigidity
-Little effect on bradykinesia
-If fail to respond to one drug, try others.
Adverse effects of Anti-cholinergics
CNS effects: drowsiness, restlessness, inattention, confusion, delusions, hallucinations, mood changers..etc.
other adverse effects:
-Dry mouth, constipation, nausea vomiting, tachycardia, increased IOP, palpitation, blurring of vision, mydriasis...etc.
-mechanism is unclear: increase dopamine release, blocks dopamine uptake, stimulates dopamine receptors.
-short lived but favorably influences bradykinesia, rigidity and tremor; it also ha antidyskinetic properties.
-used as initial therapy of mild PD and as adjunct therapy in patients on levodopa with dose-dependent fulctuations and dyskinesias.
Adverse effects of amatadine
-restlessness, hallucinations, confusion, sleep disturbance, nausea
-overdose may cause acute toxic psychosis
- Livedo reticularis (swelling of small veins)
When should you be hesitant of prescribing amatadine?
-patients with history of seizure or heart failure