Anti-Parkinson Drugs Flashcards
Cardinal features of Parkinson
- Resting tremor
- Muscle rigidity (Cogwheel rigidity)
- Bradykinesia
- Gait impairment
Etiology of Parkinson
Loss of neurons in the Dopaminergic Nigrostriatal pathway
Dopamine Synthesis
- Tyrosine (transported across BBB by System-L in a Na-independent manner)
- Tyrosine (Tyrosine hydroxylase - RLS) –> DOPA (DOPA Carboxylase) –> Dopamine
Inc Dopamine formation by Inc substrates
Dopamine receptors related to Parkinson
- D1 Receptors
- Inc adenylyl cyclase - D2 Receptors
- Dec adenylyl cyclase
- Inc K conductance
- Dec Ca conductance
Treatment of Parkinson is mostly focused on D2 but needs D1 for maximal effect
Dopamine pathways in Brain
- Nigrostriatal
- Make focus for PD - Destruction of neurons - Mesolimbic
- Mesocortical
- Tuberoinfundibular
Pathophysiology of Parkinson Disease
NORMAL
GABAergic output from Striatum
- Inhibited by Dopaminergic neuron in Substantia nigra
- Stimulated by Cholinergic neurons
PARKINSON
- Destruction of Dopaminergic neurons in Nigrostriatal pathway –> Loss of muscle control/ movement
- 70% neuron loss for symptoms to appears
Aim of Anti-Parkinson Drugs
- Restoring dopamine in basal ganglia
2. Antagonizing the excitatory effect of cholinergic neurons
Classes of Drugs used to treat Parkinson
1 Drugs that restore Dopamine actions
- Dopamine precursors
- Dopamine receptor agonists
- Inhibitors of Dopamine metabolism
- Amantadine
- Acetylcholine Antagonists
- Antimuscarinics
Dopamine Precursors (Names)
Levodopa
Mechanism of Levodopa
Levodopa is a precursor for Dopamine
Levodopa is transported into CNS and converted to Dopamine by Dopa-carboxylase (mostly in the periphery)
- Restores dopamine in the Extrapyramidal centers
Why does the effects of Levodopa decrease as the disease progress.
As the disease progresses there are less neurons so less Levodopa can be taken up and converted to Dopamine.
Function of Carbidopa
Dec the metabolism of Levodopa in the GI tract & periphery tissues –> Inc Levodopa availability to CNS
Levodopa–> GI= 70%, Periphery = 28% & Brain - 2%
Sinemet –> GI = 40%, Periphery = 50% & Brain = 10%
Sinemet
Dopa preparation of both Carbidopa & Levodopa in fixed proportions
- 1:10 OR 1:4
Pharmacokinetics of Levodopa
- Rapid absorption in SI
- Food delays appearance in plasma
- Some A.a compete w/ drug for absorption from gut
Clinical uses & Response to Levodopa
Levodopa/Carbidopa –> DOC for PD treatment
- Response decrease w/ 3-5 years of therapy
- Response completely lost overtime due to lost of neurons
- Does NOT stop PD progression; just helps with symptom management
Adverse effects of Levodopa
GI
- Anorexia, Nausea & vomiting
CVS
- Tachycardia, Ventricular extrasystoles & Hypotension
CNS
- Hallucinations (visual & auditory), Dyskinesias, Mood changes, Depression, Anxiety, Agitation & Insomnia
Fluctuations in Response to Levodopa
- Wearing-Off Reactions
- On-Off Phenomenon
- switch between mobility and immobility in levodopa-treated patients, which occurs as an end-of-dose
Interactions & Contraindications of Levodopa
Do NOT give:
- Psychotic pts/ Concomitant antipsychotic use - worsen symptoms
- Angle-closure glaucoma - activate D1 receptors in eyes which Inc aqueous humour production & ICP
- Nonspecific MAOI concomitant use - Hypertensive crisis
MONITOR/
- Cardiac pts- Arrhythmias
- Anti-HTN drug use - Orthostatic Hypotension
- Active peptic ulcer - GI bleeding
Dopamine Receptor Agonist (class & names)
- Ergot Dopamine Agonists
- Bromocriptine - Non-ergot Dopamine Agonists
- Pramipexole
- Ropinirole
- Rotigotine
Does NOT require enzymatic conversion - Do NOT depend on the functional capabilities of Nigrostriatal neurons
Bromocriptine
- D2 agonist
- Rarely used now
Pramipexole & Ropinirole
- Initial treatment of PD for younger pts.
- Well tolerated
- Less effective than Levodopa in treating motor symptoms; but less likely to cause motor fluctuation & dyskinesia
- Older pts. are more vulnerable to cognitive AE
Rotigotine
- Transdermal formulation - Once-daily use
GI Adverse effects of Dopamine Agonists
- Anorexia
- Nausea & vomiting
- Constipation
- Peptic ulcer bleeds
CVS Adverse effects of Dopamine Agonists
- Postural hypotension
- Cardiac arrhythmias
- Peripheral edema
- Painless digital vasospasm (Ergot agonists)
Motor & Mental Adverse effects of Dopamine Agonists
- Abnormal movements
- Confusion
- Hallucinations & Delusions
- Compulsive behaviors
Other Adverse effects of Ergot Dopamine Agonists
- Headache
- Nasal congestion
- Inc arousal
- Pulmonary infiltrates
- Pleural & retroperitoneal fibrosis
- Erythromelalgia
Other Adverse effects of Non-ergot Dopamine Agonists
Uncontrollable Somnolence
- Discontinue use
Drug Interactions of Dopamine Agonists
- Antipsychotic drugs antagonize Dopamine - Dec efficacy
- CNS depressants -Inc somnolence & confusion
Contraindication of Dopamine agonists
- Hx of psychotic illness
- Recent MI
- Active Pectic Ulcer
Rescue therapy
APOMORPHINE (Non-ergot agonists)
- Treatment of “off episodes” of akinesis in pts on dopaminergic therapy
- Pretreatment w/ antiemetic agent TRIMETHOBENZAMIDE
Why is Trimethobenzamide used before Apomorphine
Apomorphine is an Emetogenic agent so pretreatment with an antiemetic agent is recommended
Adverse effects of Apomorphine
- QT prolongation
- Dyskinesia
- Drowsiness
- Sweating
- Hypotension
Inhibitors of Dopamine Metabolism (class & name)
- MAO Inhibitors
- Selegiline
- Rasagiline - COMT Inhibitors
- Tolcapone
- Entacapone
Selegiline MOA
Inhibits MAO-B –> Stops Dopamine breakdown in brain
- Selective to MAO-B
- Irreversible
Clinical uses of Selegiline
Adjunct to Levodopa
- Allows Levodopa dose to be reduced & therefore enhances its effects
Metabolism of Selegiline
Metabolized to
- Methamphetamine
- Amphetamine
Adverse effects of Selegiline
Insomnia (due to presence of metabolites)
Should NOT be used late evenings
Rasagiline
MAO-B Inhibitor
- Irreversible
MAO-I Drug Interactions
- MAOI + Serotonergics –> Hypertensive crisis & Serotonin syndrome
- MAOI + Sympathomimetic amines –> Severe HTN
MOA of COMT Inhibitors
NORMAL
- COMT breaks down Levodopa to 3-o-methyl dopa which competes with Levodopa for transport across the intestinal mucosa & BBB
COMT-I prevent the formation of 3-0 methyl dopa
Amantadine
Antimuscarinics (names)
- Benztropine
- Trihexyphenidyl
Contraindications of Amantadine
CAUTION w/:
- Hx of seizures
- Hx of Heart failure
Adverse effects of Amantadine
- Restlessness, agitation, confusion & hallucinations
- Acute toxic psychosis (High- dose)
- Headache, Heart failure, Orthostatic hypotension, Dry mouth, Urinary retention & GI disturbances
- Peripheral edema
- Livedo reticularis - rash that usually clears within a month of drug discontinuation
Adverse effects of COMT Inhibitors
- Fulminating Hepatic Necrosis (Tolcapone)
Clinical uses of Antimuscarinics
ADJUVANT therapy
- may improve tremor & rigidity
- little effect on bradykinesia
Adverse effects of Antimuscarinics
- Mood changes
- Xerostomia
- Pupillary dilation
- Confusion
- Hallucinations
- Urinary retention
Contraindications of Antimuscarinics
- Glaucoma
- Prostatic hypertrophy
- Pyloric stenosis
How to control the Peripheral edema caused by Amantadine?
Diuretics
Carbidopa
Dopa Decarboxylase Inhibitor
- Does NOT cross the BBB
- Given in combination w/ Levodopa
